Kidney Transplantation, Bioengineering and Regeneration. Kidney Transplantation in the Regenerative Medicine Era [1st Edition] 9780128018361, 9780128017340

Table of contents :
Content:
Front-matter,Copyright,List of Contributors,Biographies,Kidney Transplantation, Bioengineering, and RegenerationEntitled to full textPart I: Kidney TransplantationSection I: Epidemiology of Kidney Disease and TransplantationChapter 1 - Epidemiology of End-Stage Renal Failure: The Burden of Kidney Diseases to Global Health, Pages 5-11, Matias Trillini, Norberto Perico, Giuseppe Remuzzi
Chapter 2 - Transplant Programs Worldwide and the Spanish Miracle, Pages 13-27, Rafael Matesanz, Beatriz Domínguez-Gil, Elisabeth Coll, Beatriz Mahíllo, Gloria de la Rosa, María O. Valentín
Chapter 3 - The Deceased Kidney Donor, Pages 31-39, Hany El Hennawy, Jeffrey Rogers
Chapter 4 - The Living Donor, Pages 41-50, Andrea Pietrabissa, Luigi Pugliese, Massimo Abelli, Elena Ticozzelli, Teresa Rampino
Chapter 5 - Criteria for Kidney Allocation in the United States, Pages 51-58, Linda Ohler
Chapter 6 - Strategies to Increase the Donor Pool, Pages 59-83, Michael A. Rees, David E. Fumo
Chapter 7 - Kidney Preservation, Pages 87-100, Ina Jochmans, John M. O’Callaghan, Rutger J. Ploeg, Jacques Pirenne
Chapter 8 - Ex-vivo Normothermic Perfusion in Renal Transplantation, Pages 101-109, Sarah A. Hosgood, Michael L. Nicholson
Chapter 9 - Kidney Transplant Recipient Surgery, Pages 111-125, Fabio Vistoli, Vittorio Perrone, Gabriella Amorese, Ugo Boggi, Giuseppe Orlando
Chapter 10 - Robotic-Assisted Kidney Transplantation, Pages 127-133, Ivo Tzvetanov, Pier C. Giulianotti, Giuseppe D’Amico, Raquel G. Roca, Enrico Benedetti
Chapter 11 - Orthotopic Kidney Transplantation, Pages 135-140, Bulang He
Chapter 12 - Kidney Transplantation Combined With Other Organs, Pages 141-157, Junichiro Sageshima, Linda Chen, Gaetano Ciancio, Alberto Pugliese, George W. Burke III
Chapter 13 - Pediatric Renal Transplantation, Pages 159-184, Ashton Chen, Jen-Jar Lin, Andrew M. South
Chapter 14 - Indications for Renal Transplantation: Evaluation of Transplant Candidates, Pages 187-197, Opas Traitanon, Lorenzo Gallon
Chapter 15 - Early Postoperative ICU Care of the Kidney Transplant Recipient, Pages 199-210, Xavier Wittebole, Diego Castanares-Zapatero, Michel Mourad, Virginie Montiel, Christine Collienne, Pierre-François Laterre
Chapter 16 - Approaches to Minimize Delayed Graft Function in Renal Transplantation, Pages 211-219, Maria Francesca Egidi, Domenico Giannese
Chapter 17 - Histocompatibility Testing in the Transplant Setting, Pages 223-234, Michael D. Gautreaux
Chapter 18 - The Immune Response to the Allograft, Pages 235-246, Fiona Carty, Karen English
Chapter 19 - Induction Immunosuppression in Kidney Transplantation, Pages 247-258, Josep M. Grinyó, Oriol Bestard
Chapter 20 - Maintenance Immunosuppression in Kidney Transplantation, Pages 259-276, Monica Cortinovis, Giuseppe Remuzzi, Norberto Perico
Chapter 21 - Novel Drugs in Kidney Transplantation, Pages 277-290, Sindhu Chandran, Flavio Vincenti
Chapter 22 - Hematopoietic Stem Cell Transplantation for Induction of Allograft Tolerance, Pages 291-301, Kiyohiko Hotta, Tetsu Oura, A. Benedict Cosimi, Tatsuo Kawai
Chapter 23 - Regulatory T Cell Therapy in Transplantation, Pages 303-318, Scott McEwen, Qizhi Tang
Chapter 24 - Mesenchymal Stromal Cells to Improve Solid Organ Transplant Outcome: Lessons From the Initial Clinical Trials, Pages 319-331, Marlies E.J. Reinders, Johannes W. De Fijter, Maarten L. Zandvliet, Ton J. Rabelink
Chapter 25 - Renal Transplantation Across HLA and ABO Barriers, Pages 333-354, Shaifali Sandal, Robert A. Montgomery
Chapter 26 - Pathology of the Renal Allograft, Pages 357-372, Loredana Melchiorri, Christian C. Morrill, Gino Coletti, Paul Persad
Chapter 27 - Imaging-Based Monitoring of the Renal Graft, Pages 373-402, Corinne Deurdulian, Hisham Tchelepi
Chapter 28 - Immune Monitoring in Kidney Transplantation, Pages 403-417, Mark Nguyen, Anna Geraedts, Minnie Sarwal
Chapter 29 - Renal Function Measurements, Pages 419-427, Esteban Porrini
Chapter 30 - Pharmacokinetics and Genomics of Immunosuppressive Drugs, Pages 429-443, Marek Drozdzik
Chapter 31 - Gene Expression Technology Applied to Kidney Transplantation, Pages 445-457, Richard Danger, Sophie Brouard
Chapter 32 - Acute Cellular Rejection, Pages 461-474, Madhav C. Menon, Paolo Cravedi, Fadi El Salem
Chapter 33 - Acute Antibody-Mediated Rejection, Pages 475-487, Ivy A. Rosales, Robert B. Colvin
Chapter 34 - Vascular Complications in Renal Transplantation, Pages 491-502, Hany El-Hennawy, Christian C. Morrill, Giuseppe Orlando, Alan C. Farney
Chapter 35 - Infections in Kidney Transplant Recipients, Pages 503-512, Aynaa Alsharidi, Deepali Kumar, Atul Humar
Chapter 36 - Metabolic Disorders Following Kidney Transplantation, Pages 513-523, Quirino Lai, Francesco Pisani
Chapter 37 - Cancer After Kidney Transplantation, Pages 525-542, Renaud Snanoudj, Jacques Dantal, Céleste Lebbé, Christophe Legendre
Chapter 38 - Cardiovascular Disease and Renal Transplantation, Pages 543-554, Robert J. Applegate, P. Matthew Belford, Sanjay K. Gandhi, Michael A. Kutcher, Renato M. Santos, David X. Zhao
Chapter 39 - Graft and Patient Survival, Pages 557-571, Aneesha A. Shetty, Ekamol Tantissattamo, Bing Ho, Anton Skaro, Lihui Zhao, Samantha Montag, Michael Abecassis
Chapter 40 - Urological Complications of the Renal Graft, Pages 573-587, Tristan Keys, Majid Mirzazadeh
Chapter 41 - Impact of De Novo Donor-specific Alloantibody in Primary Renal Allografts, Pages 589-596, Matthew J. Everly
Chapter 42 - De Novo and Recurrence of Renal Disease, Pages 597-608, Quirino Lai, Fabio Melandro, Francesco Pisani
Chapter 43 - Kidney Transplantation in the Elderly, Pages 611-631, Robert J. Stratta
Chapter 44 - Dual Kidney Transplantation, Pages 633-642, Paolo Cravedi, Andrea Angeletti, Piero Ruggenenti
Chapter 45 - Kidney Transplantation in the Diabetic Patient, Pages 643-651, Angelika C. Gruessner, Rainer W.G. Gruessner
Chapter 46 - Kidney Transplantation in the Hepatitis C Infected Recipient, Pages 653-663, Roberta Angelico, Giuseppe Iaria, Mario Angelico
Chapter 47 - Pregnancy After Kidney Transplantation, Pages 665-676, Marialuisa Framarino-dei-Malatesta
Chapter 48 - Nutrition of the Kidney Transplant Recipients, Pages 677-683, Paolo Dionigi, Mario Alessiani
Chapter 49 - Kidney Transplantation in Developing Countries, Pages 687-698, Goce Spasovski, Mirela Busic, Mirjana S. Matovinovic, Francis L. Delmonico
Chapter 50 - Health-Related Quality of Life Outcomes After Kidney Transplantation, Pages 699-708, Aneesha A. Shetty, Jason A. Wertheim, Zeeshan Butt
Chapter 51 - Costs of Kidney Transplantation, Pages 709-718, Charles Strom, Yanik Bababekov, David Axelrod
Chapter 52 - Kidney Transplantation: Have the Promises Been Kept and Needs Met, Pages 721-736, Charles Strom, Eliot Heher, A. Benedict Cosimi
Chapter 53 - Innovations in Kidney Transplant Research, Pages 737-751, Sarwat Ahmad, Eric Siskind, Jonathan S. Bromberg
Chapter 54 - Converging Organ Transplantation Towards Regenerative Medicine, Pages 757-767, Ravi Katari, Riccardo Tamburrini, Lauren Edgar, Giuseppe Orlando
Chapter 55 - A Systems Engineering Approach to Restoring Kidney Structure and Function, Pages 769-784, David F. Williams
Chapter 56 - Kidney Development in the Mammal, Pages 787-799, Melissa H. Little
Chapter 57 - Renal Branching Morphogenesis, Pages 801-814, Joshua Blake, Norman D. Rosenblum
Chapter 58 - Principles of Stem Cell Biology Applied to the Kidney, Pages 817-827, Brooke E. Chambers, Rebecca A. Wingert
Chapter 59 - Extracellular Matrix Biology Applied to the Kidney, Pages 829-841, Rachel Lennon
Chapter 60 - Interplay Between Growth Factor Receptors, Small GTPases, and Mechanical Stress in the Maintenance of Kidney Glomerular Homeostasis, Pages 843-859, Manuel Chiusa, Xiwu Chen, Roy Zent, Ambra Pozzi
Chapter 61 - Bioengineering Approach to Immunomodulation, Pages 861-872, Lauren Brasile, Bart Stubenitsky
Chapter 62 - Principles of Organ Bioengineering, Pages 873-876, Abritee Dhal, Matthew Brovold, Anthony Atala, Shay Soker
Chapter 63 - Recellularization of Kidney Scaffold With Stem Cells, Pages 877-886, Marina Figliuzzi, Giuseppe Remuzzi, Andrea Remuzzi
Chapter 64 - Bioreactors for Cell Culture Systems and Organ Bioengineering, Pages 889-899, Chiara Attanasio, Paolo A. Netti
Chapter 65 - Synthetic Biomaterial for Regenerative Medicine Applications, Pages 901-921, Tiziana Nardo, Irene Carmagnola, Francesca Ruini, Silvia Caddeo, Stefano Calzone, Valeria Chiono, Gianluca Ciardelli
Chapter 66 - Immune Responses to Biomaterials Used in Renal Engineering, Pages 923-933, David F. Williams
Chapter 67 - Regeneration of Kidney From Human Reprogrammed Stem Cells, Pages 937-955, Melissa H. Little, Kenji Osafune
Chapter 68 - Bioprinting Complex 3D Tissue and Organs, Pages 957-971, Carlos Kengla, Amritha Kidiyoor, Sean V. Murphy
Chapter 69 - Principles of Kidney Regeneration, Pages 973-988, Maria L. Angelotti, Francesca Becherucci, Benedetta Mazzinghi, Anna Peired, Paola Romagnani
Chapter 70 - Markers of Repair and Regeneration in the Marginal Kidney, Pages 989-996, Stephen J. Walker, Susan Y. Zhao
Chapter 71 - Nephron Repair in Mammals and Fish, Pages 997-1003, Zhenzhen Peng, Veronika Sander, Alan J. Davidson
Chapter 72 - Imaging of Glomerular Regeneration, Pages 1005-1011, János Peti-Peterdi, Kengo Kidokoro, Anne Riquier-Brison
Chapter 73 - Reversibility of Renal Fibrosis, Pages 1013-1023, Christos E. Chadjichristos, Panagiotis Kavvadas, Jean-Claude Dussaule, Ahmed Abed, Christos Chatziantoniou
Chapter 74 - Pharmacological Induction of Kidney Regeneration, Pages 1025-1037, Elena Gagliardini, Ariela Benigni, Norberto Perico
Chapter 75 - Developmental Approaches to Kidney Regeneration, Pages 1039-1050, Valentina Benedetti, Barbara Imberti, Christodoulos Xinaris, Giuseppe Remuzzi
Chapter 76 - Nephron Progenitors, Pages 1053-1065, Ilaria Santeramo, Bettina Wilm, Patricia Murray
Chapter 77 - Urine Progenitor Cells for Potential Application in Renal Tissue Repair, Pages 1067-1073, Peng Li, Xiongbing Lu, Junhong Deng, Andrea Peloso, Yuanyuan Zhang
Chapter 78 - Endothelial Progenitor Cells in Kidney Disease, Pages 1075-1082, Michael S. Goligorsky
Chapter 79 - Mesenchymal Stromal Cells for Acute Renal Injury, Pages 1085-1095, Cinzia Rota, Serge Cedrick Mbiandjeu Toya, Marina Morigi
Chapter 80 - Amniotic Fluid Cells: Kidney Injury and Regeneration, Pages 1097-1107, Stefano Da Sacco, Astgik Petrosyan, Laura Perin
Chapter 81 - Renal Cells From Spermatogonial Germline Stem Cells for Protection Against Kidney Injury, Pages 1109-1115, Sharmila Fagoonee, Letizia De Chiara, Elvira Smeralda Famulari, Lorenzo Silengo, Fiorella Altruda
Chapter 82 - Kidney-on-a-Chip: Technologies for Studying Pharmacological and Therapeutic Approaches to Kidney Repair, Pages 1119-1133, Rosalinde Masereeuw, Jelle Vriend, Martijn J. Wilmer
Chapter 83 - Renal Replacement Devices, Pages 1135-1149, Christopher J. Pino, H. David Humes
Chapter 84 - Xenotransplantation and Kidney Regenerative Technology, Pages 1151-1161, Kazuhiko Yamada, Masayuki Tasaki, Adam Griesemar, Jigesh Shah
Chapter 85 - Embryonic Organoid Transplantation, Pages 1163-1166, Shinya Yokote, Takashi Yokoo
Chapter 86 - Lineage Reprogramming Toward Kidney Regeneration, Pages 1167-1175, Yun Xia, Nuria Montserrat, Josep M. Campistol, Juan Carlos Izpisua Belmonte
Chapter 87 - Regenerating Kidney Structure and Function: An Industry Perspective, Pages 1177-1187, Joydeep Basu, Timothy A. Bertram, John W. Ludlow
Index, Pages 1189-1225

Citation preview

KIDNEY TRANSPLANTATION, BIOENGINEERING, AND REGENERATION

KIDNEY TRANSPLANTATION, BIOENGINEERING, AND REGENERATION Kidney Transplantation in the Regenerative Medicine Era Edited by

GIUSEPPE ORLANDO Wake Forest University Health Sciences, Winston-Salem, NC, United States

GIUSEPPE REMUZZI IRCCS—Mario Negri Institute for Pharmacological Research, Bergamo, Italy Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy University of Milan, Milan, Italy

DAVID F. WILLIAMS Wake Forest Institute of Regenerative Medicine, Winston-Salem, NC, United States

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1800, San Diego, CA 92101-4495, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright r 2017 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-801734-0 For Information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Mica Haley Acquisition Editor: Mica Haley Editorial Project Manager: Fenton Coulthurst Production Project Manager: Sue Jakeman Designer: Miles Hitchen Typeset by MPS Limited, Chennai, India

List of Contributors

Michael Abecassis Northwestern University Feinberg School of Medicine, Chicago, IL, United States; Oakland University William Beaumont School of Medicine, Royal Oak, MI, United States

Valentina Benedetti IRCCS—Istituto di Farmacologiche “Mario Negri,” Bergamo, Italy

Ahmed Abed Tenon Hospital, Paris, France; Sorbonne University, Paris, France

Timothy A. Bertram NC, United States

University of Pavia, Pavia, Italy

Massimo Abelli

Mario Alessiani University of Pavia Medical School, IRCCS San Matteo Hospital Foundation, Pavia, Italy Aynaa Alsharidi Canada

University Health Network, Toronto, ON,

Fiorella Altruda

University of Turin, Torino, Italy University of Pisa, Pisa, Italy

Tor Vergata University Hospital, Rome, Tor Vergata University Hospital, Rome,

Maria L. Angelotti University of Florence, Florence, Italy Robert J. Applegate Wake Forest School of Medicine, Winston-Salem, NC, United States Anthony Atala Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States Chiara Attanasio Napoli, Italy

IIT@CRIB Istituto Italiano di Tecnologia,

David Axelrod Lahey Hospital Burlington, MA, United States

and

Medical

Center,

Yanik Bababekov Massachusetts General Hospital, Boston, MA, United States Joydeep Basu States

University of Barcelona, Barcelona, Spain

Joshua Blake Division of Nephrology and Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, and Departments of Paediatrics and Physiology, University of Toronto, Toronto, Ontario, Canada Lauren Brasile

Andrea Angeletti Recanati Miller Transplant Institute and Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Roberta Angelico Italy

RegenMedTX LLC, Winston-Salem,

Ugo Boggi University of Pisa, Pisa, Italy

Gabriella Amorese

Mario Angelico Italy

Ariela Benigni IRCCS—Istituto di Ricerche Farmacologiche “Mario Negri,” Bergamo, Italy

Oriol Bestard

Sarwat Ahmad University of Maryland School of Medicine, Baltimore, MD, United States

Ricerche

Tengion, Inc., Winston-Salem, NC, United

Francesca Becherucci Meyer Hospital, Florence, Italy

Children’s

University

P. Matthew Belford Wake Forest School of Medicine, Winston-Salem, NC, United States Enrico Benedetti University of Illinois Hospital & Health Sciences System, Chicago, IL, United States

BREONICS, Inc., Albany, NY, United States

Jonathan S. Bromberg University of Maryland School of Medicine, Baltimore, MD, United States Sophie Brouard Universite´ de Nantes, Nantes, France; Institut de Transplantation Urologie Ne´phrologie (ITUN), Nantes, France; CIC Biotherapy, Nantes, France Matthew Brovold Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States George W. Burke III University of Miami Miller School of Medicine, Department of Surgery, Miami Transplant Institute, Miami, FL, United States; University of Miami Miller School of Medicine, Diabetes Research Institute, Miami, FL, United States Mirela Busic

Ministry of Health, Zagreb, Croatia

Zeeshan Butt Northwestern University Feinberg School of Medicine, Chicago, IL, United States Silvia Caddeo Politecnico di Torino, Polytechnic University of Turin, Turin, Italy Stefano Calzone Politecnico di University of Turin, Turin, Italy Josep M. Campistol Barcelona, Spain

Hospital

Irene Carmagnola Politecnico di University of Turin, Turin, Italy Fiona Carty Ireland

Torino, Clinic

of

Torino,

Polytechnic Barcelona, Polytechnic

National University of Ireland, Maynooth,

Diego Castanares-Zapatero St Luc University Hospital, Universite´ Catholique de Louvain (UCL), Brussels, Belgium

xvii

xviii

LIST OF CONTRIBUTORS

Weill Cornell Medical College, New

Christos E. Chadjichristos Tenon Hospital, Paris, France; Sorbonne University, Paris, France

Letizia De Chiara York, USA

Brooke E. Chambers University of Notre Dame, Notre Dame, IN, United States

Johannes W. De Fijter Leiden University Medical Center, Leiden, The Netherlands

Sindhu Chandran University of California, San Francisco, CA, United States

Gloria de la Rosa Madrid, Spain

Christos Chatziantoniou Tenon Hospital, Paris, France; Sorbonne University, Paris, France

Francis L. Delmonico MA, United States

Ashton Chen Wake Forest Baptist Health, Winston-Salem, NC, United States

Junhong Deng Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States; Guangzhou University, Guangdong, China

Linda Chen University of Miami Miller School of Medicine, Department of Surgery, Miami Transplant Institute, Miami, FL, United States Xiwu Chen States

Vanderbilt University, Nashville, TN, United

Valeria Chiono Politecnico di University of Turin, Turin, Italy

Torino,

Polytechnic

Vanderbilt University, Nashville, TN,

Manuel Chiusa United States

Gaetano Ciancio University of Miami Miller School of Medicine, Department of Surgery, Miami Transplant Institute, Miami, FL, United States

Corinne Deurdulian Keck School of Medicine of USC, Los Angeles, CA, United States Abritee Dhal Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States Paolo Dionigi University of Pavia Medical School, IRCCS San Matteo Hospital Foundation, Pavia, Italy Beatriz Domı´nguez-Gil Madrid, Spain Marek Drozdzik Poland

National Transplant Organization,

Pomeranian Medical University, Szczecin,

Jean-Claude Dussaule Tenon Hospital, Paris, France; Sorbonne University, Paris, France; Saint-Antoine Hospital, Paris, France

San Salvatore Hospital of L’Aquila, L’Aquila,

Lauren Edgar Wake Forest School of Medicine, WinstonSalem, NC, United States

Elisabeth Coll Spain

Torino,

National Transplant Organization, Madrid,

Christine Collienne St Luc University Hospital, Universite´ Catholique de Louvain (UCL), Brussels, Belgium Robert B. Colvin Massachusetts General Hospital, Boston, MA, United States Monica Cortinovis IRCCS Mario Negri Pharmacological Research, Bergamo, Italy A.

Harvard Medical School, Boston,

Polytechnic

Gianluca Ciardelli Politecnico di University of Turin, Turin, Italy Gino Coletti Italy

National Transplant Organization,

Benedict Cosimi Massachusetts Boston, MA, United States

Institute

General

for

Hospital,

Paolo Cravedi Icahn School of Medicine at Mount Sinai, New York, NY, United States; Recanati Miller Transplant Institute and Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States Giuseppe D’Amico University of Illinois Hospital & Health Sciences System, Chicago, IL, United States Stefano Da Sacco GOFARR laboratory for Organ Regenerative Research and Cell Therapeutics, Children‘s Hospital Los Angeles, Los Angeles, CA, United States; University of Southern California, Los Angeles, CA, United States Richard Danger Universite´ de Nantes, Nantes, France; Institut de Transplantation Urologie Ne´phrologie (ITUN), Nantes, France Jacques Dantal

Nantes University Hospital, Nantes, France

Alan J. Davidson New Zealand

The University of Auckland, Auckland,

Maria Francesca Egidi

University of Pisa, Pisa, Italy

Hany El Hennawy Wake Forest Baptist Medical Center, Winston-Salem, NC, United States Karen English Ireland

National University of Ireland, Maynooth,

Matthew J. Everly Terasaki Angeles, CA, United States

Research

Institute,

Los

Sharmila Fagoonee University of Turin, Torino, Italy; Institute of Biostructure and Bioimaging (IBB)-CNR, Torino, Italy Elvira Smeralda Famulari

University of Turin, Torino, Italy

Alan C. Farney Wake Forest Baptist Health, WinstonSalem, NC, United States Marina Figliuzzi IRCCS—Istituto di Farmacologiche Mario Negri, Bergamo, Italy Marialuisa Framarino-dei-Malatesta of Rome, Rome, Italy

Ricerche

University Sapienza

David E. Fumo University of Toledo Medical Center, Toledo, OH, United States; Alliance for Paired Donation, Perrysburg, OH, United States Elena Gagliardini IRCCS—Istituto di Farmacologiche “Mario Negri,” Bergamo, Italy

Ricerche

Lorenzo Gallon Northwestern University, Chicago, IL, United States Sanjay K. Gandhi Wake Forest School of Medicine, Winston-Salem, NC, United States

xix

LIST OF CONTRIBUTORS

Michael D. Gautreaux Wake Forest School of Medicine, Winston-Salem, NC, United States Anna Geraedts Netherlands

Maastricht University, Maastricht, The

Domenico Giannese

Deepali Kumar Canada

University of Pisa, Pisa, Italy

Pier C. Giulianotti University of Illinois Hospital & Health Sciences System, Chicago, IL, United States Michael S. Goligorsky New Valhalla, NY, United States

York

Medical

Kengo Kidokoro University of Southern California, Los Angeles, CA, United States; Kawasaki Medical School, Kurashiki, Japan

College,

Adam Griesemar Columbia University College of Physicians and Surgeons, New York, NY, United States Josep M. Grinyo´ University of Barcelona, Barcelona, Spain Angelika C. Gruessner SUNY Upstate Medical University, Syracuse, NY, United States; University of Arizona, Tucson, AZ, United States Rainer W.G. Gruessner SUNY Upstate Medical University, Syracuse, NY, United States; University of Arizona, Tucson, AZ, United States Bulang He Sir Charles Gairdner Hospital, Perth, Western Australia; The University of Western Australia, Perth, Australia

University Health Network, Toronto, ON,

Michael A. Kutcher Wake Forest School of Medicine, Winston-Salem, NC, United States Quirino Lai

University of L’Aquila, L’Aquila, Italy

Pierre-Franc¸ois Laterre St Luc University Hospital, Universite´ Catholique de Louvain (UCL), Brussels, Belgium Ce´leste Lebbe´ Public Assistance - Paris Hospitals, Paris, France; Paris Diderot University, Paris, France; SaintLouis Hospital, Paris, France Christophe Legendre Public Assistance - Paris Hospitals, Paris, France; Paris Descartes University, Paris, France; Necker Hospital, Paris, France Rachel Lennon University of Manchester, Manchester, United Kingdom; Manchester Academic Health Science Centre (MAHSC), Manchester, United Kingdom

Eliot Heher Massachusetts General Hospital, Boston, MA, United States

Peng Li Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States; Nantong University, Nantong, China; The Neural Regeneration Co-innovation Center of Jiangsu Province, Nantong, China

Bing Ho Northwestern University Feinberg School of Medicine, Chicago, IL, United States

Jen-Jar Lin Wake Forest Baptist Health, Winston-Salem, NC, United States

Sarah A. Hosgood University of Cambridge, Cambridge, United Kingdom

Melissa H. Little Murdoch Children’s Research Institute, Melbourne, VIC, Australia; University of Melbourne, Melbourne, VIC, Australia

Kiyohiko Hotta Massachusetts General Hospital, Boston, MA, United States Atul Humar Canada

University Health Network, Toronto, ON,

H. David Humes Innovative BioTherapies, Inc, Ann Arbor, MI, United States; University of Michigan Medical School, Ann Arbor, MI, United States Giuseppe Iaria Italy

Tor Vergata University Hospital, Rome,

Barbara Imberti IRCCS—Istituto di Farmacologiche “Mario Negri,” Bergamo, Italy

Ricerche

Juan Carlos Izpisua Belmonte Salk Institute for Biological Studies, La Jolla, CA, United States Ina Jochmans Belgium

University

Hospitals

Leuven,

Leuven,

Ravi Katari Wake Forest School of Medicine, WinstonSalem, NC, United States Panagiotis Kavvadas Tenon Hospital, Paris, France Tatsuo Kawai Massachusetts General Hospital, Boston, MA, United States Carlos Kengla Wake Forest Baptist Winston-Salem, NC, United States

Medical

Center,

Xiongbing Lu Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States; Nanchang University, Nanchang, China John W. Ludlow Tengion, Inc., Winston-Salem, NC, United States Beatriz Mahı´llo Spain

National Transplant Organization, Madrid,

Rosalinde Masereeuw Utrecht University, Utrecht, The Netherlands Rafael Matesanz National Madrid, Spain Mirjana S. Matovinovic Zagreb, Croatia

Transplant

Merkur

Benedetta Mazzinghi Meyer Hospital, Florence, Italy

Organization,

University

Children’s

Hospital, University

Serge Cedrick Mbiandjeu Toya IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy Scott McEwen Case Western Reserve University School of Medicine, Cleveland, OH, United States Fabio Melandro Sapienza University of Rome, Rome, Italy

Tristan Keys Wake Forest University School of Medicine, Winston-Salem, NC, United States

Loredana Melchiorri San Salvatore Hospital of L’Aquila, L’Aquila, Italy

Amritha Kidiyoor Wake Forest Baptist Medical Center, Winston-Salem, NC, United States

Madhav C. Menon Icahn School of Medicine at Mount Sinai, New York, NY, United States

xx

LIST OF CONTRIBUTORS

Majid Mirzazadeh Wake Forest University School of Medicine, Winston-Salem, NC, United States Samantha Montag Oakland University William Beaumont School of Medicine, Royal Oak, MI, United States Robert A. Montgomery NYU Langone Transplant Institute, New York, NY, United States Virginie Montiel St Luc University Hospital, Universite´ Catholique de Louvain (UCL), Brussels, Belgium Nuria Montserrat Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain Marina Morigi IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy

Laura Perin GOFARR laboratory for Organ Regenerative Research and Cell Therapeutics, Children‘s Hospital Los Angeles, Los Angeles, CA, United States; University of Southern California, Los Angeles, CA, United States University of Pisa, Pisa, Italy

Vittorio Perrone

Paul Persad Wake Forest School of Medicine, WinstonSalem, NC, United States Ja´nos Peti-Peterdi University of Southern California, Los Angeles, CA, United States Astgik Petrosyan GOFARR laboratory for Organ Regenerative Research and Cell Therapeutics, Children‘s Hospital Los Angeles, Los Angeles, CA, United States; University of Southern California, Los Angeles, CA, United States Andrea Pietrabissa

University of Pavia, Pavia, Italy

Christian C. Morrill Utah State University, Logan, UT, United States; Wake Forest Baptist Health, WinstonSalem, NC, United States

Christopher J. Pino Innovative BioTherapies, Inc, Ann Arbor, MI, United States

Michel Mourad St Luc University Hospital, Universite´ Catholique de Louvain (UCL), Brussels, Belgium

Jacques Pirenne University Hospitals Leuven, Leuven, Belgium

Sean V. Murphy Wake Forest Baptist Medical Center, Winston-Salem, NC, United States

Francesco Pisani

Patricia Murray Kingdom

University of Liverpool, Liverpool, United

University of L’Aquila, L’Aquila, Italy

Rutger J. Ploeg University of Oxford, Oxford, United Kingdom University of La Laguna, Tenerife, Spain

Esteban Porrini

Tiziana Nardo Politecnico di University of Turin, Turin, Italy

Torino,

Polytechnic

Ambra Pozzi Vanderbilt University, Nashville, TN, United States

Paolo A. Netti IIT@CRIB Istituto Italiano di Tecnologia, Napoli, Italy; CRIB, Universita´ degli studi di Napoli Federico II, Napoli, Italy

Alberto Pugliese Diabetes Research Institute, Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Department of Microbiology and Immunology, Miami, FL, United States

Mark Nguyen University of California, San Francisco, CA, United States Michael L. Nicholson University Cambridge, United Kingdom John M. O’Callaghan Kingdom

of

Cambridge,

University of Oxford, Oxford, United

Linda Ohler George Washington University Transplant Institute, Washington, DC, United States Giuseppe Orlando Wake Forest University Health Sciences, Winston-Salem, NC, United States; Wake Forest Baptist Health, Winston-Salem, NC, United States; Wake Forest School of Medicine, Winston-Salem, NC, United States Kenji Osafune Center for iPS Application (CiRA), Kyoto, Japan

Cell

Research

and

Tetsu Oura Massachusetts General Hospital, Boston, MA, United States Anna Peired

University of Florence, Florence, Italy

Andrea Peloso Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States; University of Pavia, Pavia, Italy Zhenzhen Peng New Zealand

The University of Auckland, Auckland,

Norberto Perico IRCCS Mario Negri Pharmacological Research, Bergamo, Italy

Institute

for

Luigi Pugliese

University of Pavia, Pavia, Italy

Ton J. Rabelink Leiden University Medical Center, Leiden, The Netherlands Teresa Rampino

University of Pavia, Pavia, Italy

Michael A. Rees University of Toledo Medical Center, Toledo, OH, United States; Alliance for Paired Donation, Perrysburg, OH, United States Marlies E.J. Reinders Leiden University Medical Center, Leiden, The Netherlands Andrea Remuzzi IRCCS—Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy; University of Bergamo, Bergamo, Italy Giuseppe Remuzzi IRCCS Mario Negri Institute for Pharmacological Research, Bergamo, Italy; Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy; University of Milan, Milan, Italy Anne Riquier-Brison University of Southern California, Los Angeles, CA, United States Raquel G. Roca University of Illinois Hospital & Health Sciences System, Chicago, IL, United States Jeffrey Rogers Wake Forest Baptist Winston-Salem, NC, United States Paola Romagnani

Medical

Center,

University of Florence, Florence, Italy

xxi

LIST OF CONTRIBUTORS

Ivy A. Rosales Massachusetts General Hospital, Boston, MA, United States

Bart Stubenitsky St. Antonius Ziekenhuis, Nieuwegein, The Netherlands

Norman D. Rosenblum Division of Nephrology and Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, and Departments of Paediatrics and Physiology, University of Toronto, Toronto, Ontario, Canada

Riccardo Tamburrini Wake Forest School of Medicine, Winston-Salem, NC, United States

Cinzia Rota IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy

Qizhi Tang University of California, San Francisco, San Francisco, CA, United States Ekamol Tantissattamo Oakland University William Beaumont School of Medicine, Royal Oak, MI, United States

Piero Ruggenenti Mario Negri Institute for Pharmacological Research, Bergamo, Italy; Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy

Masayuki Tasaki Massachusetts General Hospital, Boston, MA, United States

Francesca Ruini Politecnico di University of Turin, Turin, Italy

Elena Ticozzelli

Torino,

Polytechnic

Junichiro Sageshima University of California, Davis, Department of Surgery, Division of Transplantation, Sacramento, CA, United States; Wake Forest Baptist Health, Winston-Salem, NC, United States Fadi El Salem Icahn School of Medicine at Mount Sinai, New York, NY, United States Shaifali Sandal QC, Canada

McGill University Health Centre, Montreal,

Veronika Sander New Zealand

The University of Auckland, Auckland,

Ilaria Santeramo University United Kingdom

of

Liverpool,

Liverpool,

Renato M. Santos Wake Forest School of Medicine, Winston-Salem, NC, United States Minnie Sarwal University of California, San Francisco, CA, United States Jigesh Shah Massachusetts General Hospital, Boston, MA, United States Aneesha A. Shetty Northwestern University Feinberg School of Medicine, Chicago, IL, United States Lorenzo Silengo University of Turin, Torino, Italy Eric Siskind University of Maryland School of Medicine, Baltimore, MD, United States Anton Skaro Northwestern University Feinberg School of Medicine, Chicago, IL, United States; Oakland University William Beaumont School of Medicine, Royal Oak, MI, United States Renaud Snanoudj Paris, France

Public Assistance - Paris Hospitals,

Shay Soker Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States Andrew M. South Wake Forest Baptist Health, WinstonSalem, NC, United States Goce Spasovski University Ss Cyril and Methodius, Skopje, Macedonia Robert J. Stratta Wake Forest Baptist Medical Center, Winston-Salem, NC, United States Charles Strom Tufts University School of Medicine, Boston, MA, United States

Hisham Tchelepi Keck School of Medicine of USC, Los Angeles, CA, United States University of Pavia, Pavia, Italy

Opas Traitanon Northwestern University, Chicago, IL, United States; Thammasart University Hospital, Pathumthani, Thailand Matias Trillini IRCCS—Mario Negri Pharmacological Research, Bergamo, Italy

Institute

for

Ivo Tzvetanov University of Illinois Hospital & Health Sciences System, Chicago, IL, United States Marı´a O. Valentı´n National Transplant Organization, Madrid, Spain Flavio Vincenti University of California, San Francisco, CA, United States Fabio Vistoli University of Pisa, Pisa, Italy Jelle Vriend Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands Stephen J. Walker Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States; Wake Forest University Health Sciences, Winston-Salem, NC, United States Jason A. Wertheim Northwestern University Feinberg School of Medicine, Chicago, IL, United States; Jesse Brown VA Medical Center, Chicago, IL, United States David F. Williams Wake Forest Institute of Regenerative Medicine, Winston-Salem, NC, United States Bettina Wilm University of Liverpool, Liverpool, United Kingdom Martijn J. Wilmer Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands Rebecca A. Wingert University of Notre Dame, Notre Dame, IN, United States Xavier Wittebole St Luc University Hospital, Universite´ Catholique de Louvain (UCL), Brussels, Belgium Yun Xia Salk Institute for Biological Studies, La Jolla, CA, United States; Nanyang Technological University, Singapore Christodoulos Xinaris IRCCS—Istituto di Farmacologiche “Mario Negri,” Bergamo, Italy

Ricerche

xxii

LIST OF CONTRIBUTORS

Kazuhiko Yamada Columbia University College of Physicians and Surgeons, New York, NY, United States

Yuanyuan Zhang Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States

Takashi Yokoo The Jikei University School of Medicine, Tokyo, Japan

David X. Zhao Wake Forest School of Medicine, WinstonSalem, NC, United States

Shinya Yokote The Jikei University School of Medicine, Tokyo, Japan Maarten L. Zandvliet Leiden University Medical Center, Leiden, The Netherlands

Lihui Zhao Northwestern University Feinberg School of Medicine, Chicago, IL, United States; Oakland University William Beaumont School of Medicine, Royal Oak, MI, United States

Roy Zent Vanderbilt University, Nashville, TN, United States

Susan Y. Zhao Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States

Biographies

Giuseppe Orlando Dr. Orlando is an abdominal organ transplant surgeon scientist. His main achievements have been in the field of steroid-free immunosuppression, immunosuppression minimization, and clinical tolerance after liver transplantation. More recently, his research interest has switched towards the bioengineering, regeneration, and repair of transplantable organs. He has been successful in developing clinically relevant models for organ bioengineering consisting of scaffolds produced through the decellularization of porcine or human organs. He has been instrumental in popularizing the concept of recycling discarded human organs for tissue engineering purposes and is currently proposing the use of discarded human kidneys and pancreas as platforms for kidney and endocrine pancreas bioengineering and regeneration. The ultimate goal of these investigations is to provide “organson-demand” through the development of technologies that will eventually address the two most urgent needs in organ transplantation, namely, the identification of a new and potentially inexhaustible source of organs and immunosuppression-free transplantation. His literature output aims at merging the field of organ transplantation to regenerative medicine, and supports the idea that organ transplantation should transition towards a regenerative medicine-focused type of research with organ bioengineering and regeneration becoming the new Holy Grail for modern transplantation. This idea generates from the firm belief that no other field of health science has as keen an interest in investing in regenerative medicine as does organ transplantation; for our future, more than the future of any other field of health sciences, is being shaped by regenerative medicine. He has authored more than 200 research papers, review articles, book chapters, and books. He regularly serves as reviewer and board member or editor for numerous journals, as well as lecturer and moderator at national and international transplant and regenerative medicine conferences and symposia. This book follows his first book, Regenerative Medicine Technologies Applied to Organ Transplantation. He is the recipient of the 2017 Rising Star in Transplantation Award bestowed by the American Society of Transplant Surgeons. Giuseppe Remuzzi Professor of Nephrology, Director of the Department of Medicine of the Ospedali Riuniti di Bergamo (Papa Giovanni XXIII Hospital), Italy and Director of the Division of Nephrology and Dialysis of the same hospital. He also directs the Negri Bergamo Laboratories of the “Mario Negri” Institute for Pharmacological Research, a group of basic scientists and clinicians devoted to the study of human renal diseases and their corresponding animal models from the perspective of pathophysiology and therapeutic intervention. He touched major advances in many areas of nephrology. For example, his studies have led to new insights into many disorders, including the interactions between platelets and endothelium, pathophysiology of glomerular diseases, and the factors that influence the progressive loss of kidney function. Work focused on improving the outlook for patients with end stage renal disease. Giuseppe Remuzzi pays tribute to the work of pioneers such as Barry Brenner, who delved deep into the processes behind glomerular function and their possible reversibility. Early work on the use of angiotensin-converting enzyme inhibitors to slow the decline of glomerular filtration rates proved dialysis was avoidable, not inevitable. Studies on immunologic mechanisms that influence the survival of transplanted organs, understanding of immunologic tolerance in the disorders that are linked to autoimmunity, and finally, genetic diseases of the kidney have also been areas of investigation. Concerned by kidney donation shortages and deploring the current practice of discarding suboptimal donor kidneys, his team has shown that transplanting

xxiii

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BIOGRAPHIES

such kidneys in pairs is feasible and has set up an international effort to validate this approach. Giuseppe Remuzzi is investigating the kidney’s ability to regenerate itself. He has authored and coauthored more than 1201 scientific articles, reviews, and monographs and serves on editorial boards of numerous journals. He is member of the International Advisory Board of The Lancet and was an Editorial Board member of the New England Journal of Medicine from 1995 to 2013. During his professional career he received the International Society of Nephrology (ISN) Jean Hamburger Award (World Congress of Nephrology (WCN) 2005, Singapore), the John P. Peters Award (American Society of Nephrology (ASN) 2007, San Francisco), and the ISN AMGEN Award (WCN 2011, Vancouver). In November 2011, he won the Third Edition of the International Award “Luis Hernando” assigned by the In˜igo Alvarez de Toledo Renal Foundation (FRIAT) in Madrid, Spain. Since June 2013 he has been President of the ISN for the period 2013 15. David F. Williams Professor Williams has had 48 years experience in biomaterials, medical device and tissue engineering, working mostly at the University of Liverpool, United Kingdom, where he was ultimately Professor of Biomaterials and Biomedical Engineering, Director of the UK Centre for Tissue Engineering, and Senior Pro-Vice Chancellor of the University. During his career he has published over 30 books and 400 papers; his latest book, Essential Biomaterials Science, was published by Cambridge University Press in June 2014. He was Editor-in-Chief of Biomaterials, the world’s leading journal in this field between 2000 and 2014. He has received the major awards from the United States, European, and Indian societies of biomaterials including the Founders Award of the US Society for Biomaterials in 2007, and received the prestigious Acta Biomaterialia Gold Medal in 2012. In 1999 he was elected as a Fellow of the Royal Academy of Engineering and is a Foreign Fellow of the Indian National Academy of Engineering and a Fellow of the American Institute of Medical and Biological Engineering, all in recognition of his contributions to engineering in medicine. He was global President of the Tissue Engineering & Regenerative Medicine International Society from 2013 to 2015. He was a scientific advisor to several divisions of the European Commission during the 1990s and wrote several opinions on which European actions were taken. He has, over the last 20 years, given evidence in several major product liability and patent legal cases in the United States, Europe, and Australia. Professor Williams left the University of Liverpool in 2007. While retaining the title of Emeritus Professor at Liverpool, he is currently Professor and Director of International Affairs, Wake Forest Institute of Regenerative Medicine, North Carolina, USA. In addition, he is a Visiting Professor in the Christiaan Barnard Department of Cardiothoracic Surgery, Cape Town, South Africa; and a Guest Professor at Tsinghua University, Beijing, an Advisory Professor at Shanghai Jiao Tong University and Honorary Professor at Sichuan University, Chengdu, in China. He is Visiting Chair Professor of Biomedical Materials, Taipei Medical University, Taiwan. In Cape Town, along with Professor Peter Zilla, the current Christiaan Barnard Professor of Surgery, he has formed a company that will produce low-cost but high-technology medical devices that can be used with minimally invasive procedures to treat young adults in Subsaharan Africa who are suffering from rheumatic heart disease but currently have no therapies available to them.

Kidney Transplantation, Bioengineering, and Regeneration INTRODUCTION End stage organ disease has long provided significant challenges for the medical profession. Treatment options vary from organ to organ, largely depending on the principal functions of the organs themselves, and in many situations major developments and successes have been achieved over recent decades. Nevertheless, the challenges persist and we are far from a position in which we can be comfortable in our provision of clinically effective and socially acceptable procedures for the majority of patients presenting with these diseases. Irrespective of the organ, the potential treatment options include transplantation, mechanical or physical assist devices, and organ regeneration. Thus, with end stage heart failure, there is the technically very feasible heart transplantation; the expensive, demanding, but quite successful ventricular assist or total artificial heart; or the experimental stem cell therapy for myocardial regeneration. With end stage renal disease, there again is the transplantation option, with various forms of dialysis, the potential for bioartificial kidneys, and scaffold-based tissue engineering of the kidney. This book attempts to place these transplantation, bioengineering, and regenerative approaches for the kidney into perspective. The fundamental driving forces behind the search for improved options are the worldwide mismatch between the number of patients requiring a transplant and the number of donor kidneys available; the lack of improvement over several decades in the outcomes of dialysis therapies; and the increasing number of elderly patients with end stage kidney disease, and possibly comorbidities, who are less receptive to either conventional transplantation or dialysis. The treatment of kidney disease involves a great deal more than removal of waste products from blood by some filtration method, but even more than that, the paradigms of renal replacement therapies have to subsume a wide variety of economic, ethical, and societal issues as well as biological, physiological, pharmacological, clinical, and bioengineering challenges. We have attempted to bring all of these relevant aspects together in this one volume. As Editors, we first of all have to thank the many contributors who accepted our invitations eagerly and produced an excellent collection of authoritative chapters. We also express our appreciation to the staff of Elsevier, initially Jeff Rossetti and then Fenton Coulthurst for overseeing the extensive task of coordinating the publication of the book. Giuseppe Orlando, Giuseppe Remuzzi and David F. Williams

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C H A P T E R

1 Epidemiology of End-Stage Renal Failure: The Burden of Kidney Diseases to Global Health Matias Trillini1, Norberto Perico1 and Giuseppe Remuzzi1,2,3 1

IRCCS—Mario Negri Institute for Pharmacological Research, Bergamo, Italy 2Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy 3University of Milan, Milan, Italy

1.1 THE GLOBAL BURDEN OF NONCOMMUNICABLE DISEASES Over the last century, communicable diseases have been the focus of global health strategies because they easily spread beyond national borders and have been extraordinarily unequal across the globe. These diseases threatened the lives of millions of people particularly in low- and middle-income countries with underdeveloped health care systems.1,2 Thus targeting these diseases was essential to resolve major global health issues. Lately, improvements in sanitation, prevention strategies, and medical science have helped to markedly reduce infectious disease burden and related causes of death.1 3 By 1990, noncommunicable diseases (NCDs) had already overtaken communicable diseases as the leading cause of mortality and disability worldwide.4 7 In 2008, NCDs accounted for nearly 36 million of the total global deaths (57 million).7,8 There is a consensus among public health professionals and policymakers that this epidemiological shift towards NCDs is globally established and it will continue to grow in the coming decades.1,4 12 Four main NCDs make the largest contribution to the current global burden of NCDs’ mortality.5,7 11 Major cardiovascular diseases take the largest proportion, with more than 17 million deaths/year worldwide, followed by cancers, respiratory diseases, and diabetes mellitus.5,8,10,13 The Global Burden of Disease study reported that in 2013 cardiovascular deaths accounted for one-third of total deaths globally, leading with ischemic heart disease, ischemic stroke, and hemorrhagic stroke.6 Even though declines in age-specific death rates from cardiovascular diseases represented the most common epidemiologic pattern worldwide, predictions for the future are based on aging and growth of populations that clearly outweigh improvements in treatment and prevention.14 Cancer is the second largest contributor to deaths worldwide with more than 8 million deaths in 2013.15 Morbidity and mortality due to cancer is predicted to increase in the next few decades due to the high prevalence of certain risk factors and because of improving survival of the elderly. Though some cancers have falling age-standardized trends, their decreasing rates do not significantly reduce the number of global absolute cases, which determine greater challenges in low resources settings, particularly in countries in transition.15,16 Chronic respiratory diseases affect hundreds of millions of people worldwide with major impact in morbidity and mortality. More than 4 million people die prematurely from chronic respiratory diseases each year.17 Asthma and chronic obstructive pulmonary disease (COPD) are associated with occupational exposures or air pollution and other conditions; however, cigarette active and passive smoking is by far the most important risk factor for COPD.18,19 Smoking impact has been generally decreasing and tobacco-attributable deaths

Kidney Transplantation, Bioengineering, and Regeneration. DOI: http://dx.doi.org/10.1016/B978-0-12-801734-0.00001-1

5

© 2017 Elsevier Inc. All rights reserved.

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1. THE BURDEN OF KIDNEY DISEASES AND END-STAGE RENAL FAILURE

are projected to decline by almost 10% between 2002 and 2030 in high-income countries, but to double to approximately 7 million in low- and middle-income countries, which have the highest incidence of smokers among young men.8,12 Diabetes mellitus represents a well-known established pandemic. Its prevalence has been increasing steadily in the last few decades both in developed and developing countries.20,21 From 1990 to 2013, worldwide mortality and years lived with disability due to diabetes significantly increased when both all ages and age-standardized rates were considered.6,22 Uniform epidemiological research has forecasted that diabetes mellitus prevalence is expected to at least double by the 2030s with a maximum increase in India that will reach almost 80 million diabetics followed by China and the United States.5,12,20,23,24 Overall, the rising trends in NCDs will have a significant economic impact with an outstanding projected burden that will surpass US$20 trillion by 2030.25 27 Therefore, NCDs are among the most severe threats to global economic development.5 Although recent attention has focused on the epidemiological weight of these aforementioned main NCDs, most of the global NCDs burden (55%) arises from other NCDs that have been largely neglected and, in many cases, cause more health burden through chronic disability rather than premature death. Among the most important are musculoskeletal disorders, depression, substance use disorders, liver cirrhosis, congenital diseases, hemoglobinopathies, road injuries, and chronic kidney disease (CKD).28 A large body of literature investigating CKD and particularly end-stage renal disease (ESRD) has been published in recent years. Although there is definitive evidence of the impact of kidney disease on the poor global health outcomes, it is still not recognized as a separate target.29 This chapter focuses on the epidemiology of CKD and ESRD, and their impact as key determinant contributors to the poor global health outcomes.

1.2 GLOBAL INCIDENCE AND PREVALENCE OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE CKD describes a permanent state of progressive loss of kidney function and/or kidney damage that develops over a period of months to years. ESRD, the last stage of CKD, is the irreversible deterioration of renal function to an extent that is incompatible with life without renal replacement therapy (RRT)30 in the form of dialysis or transplantation.31 Because of several conditions determined by the status of the disease itself and characteristics of the population studied, there is uncertainty on how to measure CKD incidence and prevalence in the general population.32 34 Epidemiological studies on CKD have three major limitations: lack of agreement on formulas to estimate incidence and prevalence in the early stages of the disease, consideration of CKD as solely defined by estimated glomerular filtration rate (eGFR) not including albuminuria, and uneven and scarce data on advanced CKD stages because data on ESRD is retrieved from registries that only consider population on RRT.5,31,35,36 Worldwide applicability of screening approaches undertaken in developed countries is unclear.37 A recent systematic literature review of the methodology used in reporting CKD prevalence in Europe found considerable drawbacks in epidemiological studies. Among the most important limitations were significant diversity in population sample selection methods, lack of description of methods used to assess the condition, and heterogeneity on reporting results.38

1.2.1 Population Rate and Time Trends Not all CKD is represented by the ESRD population. Patients on RRT depict only the tip of the iceberg whereas the greater proportion of individuals in the CKD stages 1 4 account for approximately 90% of the CKD population. Thus, a proper assumption of the global burden of pre-RRT CKD disease is difficult to obtain and only rough estimates exist.5,31,37,39,40 In the last few decades, large efforts have been made to improve detection of early, advanced, and terminal renal disease worldwide.41 There is current consensus among epidemiologists and nephrologists that both nondialysis and dialysis-dependent CKD are relatively common in the general population.42,43 CKD incidence and prevalence are not equally distributed worldwide and a large gap still stands regarding epidemiology among the poor, minority populations, and developing countries, where projected trends have the fastest raises because

I. KIDNEY TRANSPLANTATION

1.2 GLOBAL INCIDENCE AND PREVALENCE OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE

7

of the high population and/or rapid growth of the elderly.29,36,37,44 46 Prevalence seems to be increasing particularly in older individuals partly because of an increasing prevalence of diabetes and hypertension.32 On the other hand, unlike previous massive increasing trends in a frail population that were the standard for almost three decades, since 2012, a flattened pattern has been present on incidence rates of CKD in the United States and other developed countries.29,39 However, although incidence rates in the United States leveled off and showed a fewer total number of new incident cases for the years 2011 and 2012 when compared to 2010, the prevalence of ESRD still continues to rise.47 In 2012, in the United States, 402,514 ESRD patients were receiving hemodialysis therapy, 40,605 were being treated with peritoneal dialysis, and 175,978 had a functioning graft.47 CKD prevalence in the rest of the world has also achieved epidemic proportions, reaching 10% 13% of the populations in Norway, Taiwan, Iran, Japan, South Korea, China, Canada, and India.39,48 As for ESRD, worldwide prevalence ranges from 2447 cases pmp (patients per million population) in Taiwan to 10 cases pmp in Nigeria. In Latin America the ESRD prevalence ranges from 1019 pmp in Uruguay to 34 pmp in Honduras, a difference that may also reflect the relationship with the gross national product.5 Much less is known in Africa, with the highest prevalence of ESRD in Tunisia (713 pmp) and Egypt (669 pmp). A recent study showed that the prevalence and incidence of global maintenance dialysis due to ESRD have increased 1.7 and 2.1 times from 1990 to 2010, respectively.49 Thus, CKD population varies enormously around the globe and has been expanding at a rate of 7% per year with a current worldwide population of B2 million in ESRD who are alive only because they have access to one form or another of RRT.5,29,49 However, this population represents less than 10% of those who need it.

1.2.2 Age and Gender Declines in fertility, but mainly health system improvements, have increased average life expectancy and boosted the global phenomenon of population aging.50 Progressive nephrosclerosis due to the aging process might partially contribute to CKD development; however, the GFR decline associated with normal aging is not only explained by histological changes, so the manner in which age interacts with other risk factors for CKD has yet to be fully elucidated.51 54 Nevertheless, so far the prevalence of CKD has been considered strongly age-related, even within the same study population. A systematic review of studies performed in the United States, Europe, and Asia that considered middle- and old-aged subjects ($30 years old) showed that CKD prevalence could vary from 1.5% to 43.3%.42 CKD prevalence stages 1 4 assessed with eGFR and albuminuria in US population ranges from 6.44% among 20- to 39-year-old young adults to almost 50% in subjects aged 70 years and older.55 Other population-based studies and national cohort surveys performed in developed countries found that CKD prevalence invariably increased when the eldest subgroups were considered, even if the overall number could vary among them.56 59 Data concerning age-related CKD epidemiology in developing countries are scarce and narrowed by the scant health systems.60 A population-based study in Thailand found age-specific CKD prevalence near 50% for those aged 70 or older, results that are similar to industrialized countries and other Asian population-based studies.61 In sub-Saharan Africa, CKD is more prevalent among young adults.62 Results from a cross-sectional pilot study in Democratic Republic of Congo also showed higher CKD prevalence in young adults when compared with developed countries.63 Little is known about the clinical course and outcome of older individuals with CKD. Available data is inconclusive and current knowledge does not allow clinicians to reliably distinguish between those whose CKD will and will not progress.64 A prospective cohort study in the United States, which included more than 1000 adults aged 65 and older and with a median follow-up of more than 9 years, found that patients with CKD (GFR ,60 mL/minute/1.73 m2) were 13-fold and 6-fold more likely to die from any cause and from CV disease related causes than from ESRD, respectively.65 Since the competing risk for death at older ages is high, the majority of older adults with CKD will not develop ESRD. Some authors suggest that because of existing considerable heterogeneity in outcomes among patients of different ages and similar levels of eGFR, a uniform CKD stage-based approach promoted by the majority of practice guidelines could not be adequate.66,67 In contrast, other investigators found that, regardless of age, the presence of CKD increased mortality risk and consequently supported the use of current guidelines.68 Thus, further studies are needed in order to understand age-related changes in kidney function and clinical outcomes, which in turn will allow proper strategies to screen CKD and target therapies objectively. Although few specific studies analyzed the role of gender on CKD, differences between men and women have been published by several authors.69 71 In the United States, the National Health and Nutrition Evaluation

I. KIDNEY TRANSPLANTATION

8

1. THE BURDEN OF KIDNEY DISEASES AND END-STAGE RENAL FAILURE

Survey (NHANES, 1999 2012) has shown that overall age-adjusted CKD (stages 1 4) prevalence in adults changes from 14.8% to 13.5% and 15.9%, for males and females respectively, when gender was considered.55 A Norwegian 10-year population-based study found that CKD stage 3 was more prevalent in women than in men; still, male gender had a negative effect on both decline on GFR and hazard of renal failure.72 Two community-based studies, one in Taiwan in an area with a high prevalence of dialysis and the other in China including rural and urban populations, found that independent of age the prevalence of CKD was higher in women than in men.46,51 When ESRD is considered, Japanese men have higher dialysis incidence and prevalence than women and are also younger when started on RRT programs.69 Also in the United States, the adjusted incidence rate of ESRD is higher in men than in women (57.8% vs 42.2%, respectively).47 A metaanalysis of more than 10,000 patients with nondiabetic renal disease matched for blood and lipid levels showed that men had faster renal disease progression when compared to women.73 Although the “protective” effect favoring women has been a matter of debate, most of the evidence in animal and human studies confirmed the negative trend in renal disease progression in the male gender.72,74 Gender-based genetic variability has been linked to differences in blood pressure in both black and white individuals.75 Other authors suggested that as well as systolic blood pressure, hormonal status, lifestyle, and/or the prevalence of metabolic syndrome may also contribute to the gender difference in the age-related decline in GFR.70,74

1.2.3 Race/Ethnicity and Minorities Though they are distinct, race and ethnicity are rarely detached concepts in epidemiology and clinical practice. Because this overlap extends to medical literature, we consider race and ethnicity as a unique term for their assessment as risk factors that foster CKD progression and affect the burden of ESRD. Although ESRD incidence and prevalence have increasing trends in almost all races, they have the highest rates in racial/ethnic minorities in most epidemiological studies.76 Despite having similar rates for CKD in early stages, ESRD rates for racial/ethnic minorities are 1.5 4.0 times those of age-adjusted for whites.77 In the United States, African Americans have the highest incidence adjusted rate of ESRD, almost triple that of other races; among them, those living in the Southeast have a higher-than-average risk for developing ESRD. The higher prevalence of diabetes in African Americans may explain these differences. Hispanics, Asians, and Native Americans also have increased incidence rate trends of ESRD when compared to whites. Nevertheless, in recent years, incidence trends of ESRD across races in the United States have shown a reduction pattern or at least plateaued, except for Asian ethnicity, which has continued to increase.78,79 Other well-known minorities, such as Pacific Islanders, have a higher incidence of treated ESRD compared to Caucasians.80 A multiethnic population-based study in Singapore including three major Asian ethnic groups— Chinese, Malaysians, and Indians—found that the overall prevalence of CKD was higher in Malaysians compared to Indians and Chinese. Also, overall prevalence of CKD was higher than other Asians and Western populations but not for CKD stages 3 5.81 Less is known about ESRD epidemiology in diverse ethnicities across Africa and the Middle East because of paucity of studies, but differences could be regarded as a consequence of disparities in socioeconomic conditions more than race/ethnicity diversity. The factors underlying the epidemiological differences in CKD and ESRD in different races/ethnicities and minorities are not completely understood. Potential confounders could be the different prevalence of risk factors for CKD progression like hypertension or diabetes, other chronic or infectious diseases, genetic susceptibility, environmental factors, and inequalities in access to health resources, among others.76,77 Of note, among dialysis-treated ESRD patients, ethnic minorities are less likely to be listed for transplantation, wait longer for a transplant, and are less likely to receive allografts.76

1.2.4 Developing Countries and Socioeconomic Status The current literature has emphasized how disadvantaged populations and low socioeconomic status communities of developing countries suffer a disproportionate burden of nondialysis-dependent CKD and ESRD. Most of these differences are the consequence of direct stress factors associated with societal and health system level inequities, but also in part related to epigenetic alterations that through metabolic, inflammatory, and hormonal pathways can influence the expression of CKD and CKD risk factor genes and signaling.82 Complicated urinary tract infections, renal tuberculosis, parasitic diseases like schistosomiasis and leishmaniasis, HIV-associated nephropathy (HIVAN), hepatitis C, and other infectious diseases with glomerular involvement are

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REFERENCES

9

major epidemiological problems in developing countries and may contribute to the burden of chronic nephropathies. In these settings, also acute kidney injury often leads to ESRD due to the uncontrolled use of nonsteroidal antiinflammatory medications, as well as of traditional medicines in the primary-care environment.5,83,84 Diabetes prevalence is more strongly associated with poverty, and diabetes and diabetic nephropathy are increasing at alarming rates in developing countries.85 By 2030, more than 70% of patients with ESRD will live in low-income countries of Asia and Africa.86 Eight of the 10 largest countries in the world (China, India, Indonesia, Brazil, Pakistan, Bangladesh, Nigeria, and Russia) until recently have been classified as “developing countries.” Most of them have the highest population growth rates worldwide and a great part of their population living in extreme poverty. With important variations depending on the regions, China and India have high rates of annual ESRD prevalence growths, but only 10% 15% of all their ESRD patients are on maintenance RRT.36 However, epidemiological data on ESRD from developing countries are underrepresented, since renal registries only include patients on chronic RRT for whom maintenance dialysis or transplantation are available and/or affordable. Thus, ESRD incidence and prevalence in these settings may depend more on the level of wealth and health care system/conditions than true epidemiology variations.5 Not all CKD/ESRD epidemiology differences associated with socioeconomic status are confined by national boundaries. Two different studies in the United States showed that neighborhood and individual poverty are associated with increased risk of CKD and progression towards ESRD.87 Other studies in the United Kingdom, Germany, Sweden, Denmark, and Australia found association between economically disadvantaged populations and higher incidence of ESRD.88 Even in developing countries, low access to health care and scant resources increase the gap within their population and may create a bidirectional relationship between poverty and CKD/ESRD.86

CONCLUSIONS Evidence of the importance of CKD to public health and its contribution to the global burden of major NCDs has been accumulating, but there is little equity worldwide. A more concerted, strategic, and multisectorial approach, underpinned by solid research, is essential to help reverse the negative trend in the incidence of CKD and its risk factors, not just for a few beneficiaries but on a global health equity program. Thus, a pragmatic approach to reduce the global burden of renal diseases has to be adopted. For that, well-defined screenings of communities or high-risk populations followed by intervention programs have to be initiated, especially in lowand middle-income countries. Moreover, the International Society of Nephrology has urged WHO member states to recognize kidney diseases as a major NCD requiring the development of specific policies for effective awareness, early detection, and treatment, as part of the WHO action plan for the prevention and control of NCDs. There is an urgent need to establish surveillance networks for kidney disease in low- and middle-income countries, and incorporate simple, inexpensive strategies for preventing kidney disease and its complications in government health programs as part of their global strategy to improve public health. Some examples are the National Health Program in Uruguay, which has already incorporated CKD into its NCD prevention programs, and the Strategic Network of Health Services against CKD in Mexico. All these efforts will create major health gain, save lives, and minimize the present health inequity, which arises especially from the elevated costs of maintenance RRT if end-stage kidney disease is not prevented.

References Schlipko¨ter U, Flahault A. Communicable diseases: achievements and challenges for public health. Public Health Rev 2010;32:90 119. Cohen ML. Changing patterns of infectious disease. Nature 2000;406(6797):762 7. Murray CJL, Lopez AD. Measuring the global burden of disease. N Engl J Med 2013;369(5):448 57. Gwatkin DR, Guillot M, Heuveline P. The burden of disease among the global poor. Lancet 1999;354(9178):586 9. Perico N, Remuzzi G. Chronic kidney disease: a research and public health priority. Nephrol Dial Transplant 2012;27(Suppl. 3):iii19 26. Naghavi M, Wang H, Lozano R, et al. Global, regional, and national age sex specific all-cause and cause-specific mortality for 240 causes of death, 1990 2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015;385(9963):117 71. 7. Beaglehole R, Bonita R, Alleyne G, et al. UN High-level meeting on non-communicable diseases: addressing four questions. Lancet 2011;378 (9789):449 55. 8. Alwan A. Global status report on noncommunicable diseases. World Health Organization; 2010. Available from: http://www.who.int/nmh/ publications/ncd_report_full_en.pdf. 1. 2. 3. 4. 5. 6.

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9. Global health and aging 2011. World Health Organization. Available from: http://www.who.int/ageing/publications/global_health/en/. 10. Roura LC, Arulkumaran SS. Facing the noncommunicable disease (NCD) global epidemic The battle of prevention starts in utero The FIGO challenge. Best Pract Res Clin Obstet Gynaecol 2015;29(1):5 14. 11. Global action plan for the prevention and control of noncommunicable diseases 2013 2020. World Health Organization. Available from: http://apps.who.int/iris/bitstream/10665/94384/1/9789241506236_eng.pdf. 12. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006;3(11):e442. 13. Smith SC, Collins A, Ferrari R, et al. Our time: a call to save preventable death from cardiovascular disease (heart disease and stroke). Glob Heart 2012;7:297 305. 14. Roth GA, Forouzanfar MH, Moran AE, et al. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med 2015;372(14):1333 41. 15. Fitzmaurice C, Dicker D, Pain A, et al. The global burden of cancer 2013. JAMA Oncol 2015;1(4):505 27. 16. Popat K, McQueen K, Feeley TW. The global burden of cancer. Best Pract Res Clin Anaesthesiol 2013;27(4):399 408. 17. Ferkol T, Schraufnagel D. The global burden of respiratory disease. Ann Am Thorac Soc 2014;11(3):404 6. 18. Pauwels RA, Rabe KF. Burden and clinical features of chronic obstructive pulmonary disease (COPD). Lancet 2004;364(9434):613 20. 19. Burney P, Jarvis D, Perez-Padilla R. The global burden of chronic respiratory disease in adults. Int J Tuberc Lung Dis 2015;19(1):10 20. 20. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014;103(2):137 49. 21. Hu FB, Satija A, Manson JE. Curbing the diabetes pandemic: the need for global policy solutions. JAMA 2015;313(23):2319 20. 22. Vos T, Barber RM, Bell B, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990 2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015;386(9995):743 800. 23. Kaveeshwar SA, Cornwall J. The current state of diabetes mellitus in India. Australas Med J 2014;7(1):45 8. 24. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes estimates for the year 2000 and projections for 2030. Diab Care 2004;27(5):1047 53. 25. The growing danger of non-communicable diseases: acting now to reverse course. Conference Edition 2011. The World Bank. Available from: http://siteresources.worldbank.org/HEALTHNUTRITIONANDPOPULATION/Resources/Peer-Reviewed-Publications/ WBDeepeningCrisis.pdf. 26. Alleyne G, Binagwaho A, Haines A, et al. Embedding non-communicable diseases in the post-2015 development agenda. Lancet 2013;381 (9866):566 74. 27. Beaglehole R, Bonita R, Horton R, et al. Priority actions for the non-communicable disease crisis. Lancet 2011;377(9775):1438 47. 28. Lopez AD, Williams TN, Levin A, et al. Remembering the forgotten non-communicable diseases. BMC Med 2014;12(1):200. 29. Couser WG, Remuzzi G, Mendis S, Tonelli M. The contribution of chronic kidney disease to the global burden of major noncommunicable diseases. Kidney Int 2011;80(12):1258 70. 30. Roderick P. Epidemiology of end-stage renal disease. Clin Med 2002;2(3):200 4. 31. Anand S, Bitton A, Gaziano T. The gap between estimated incidence of end-stage renal disease and use of therapy. PloS One 2013;8(8): e72860. 32. Levey AS, Coresh J. Chronic kidney disease. Lancet 2012;379(9811):165 80. 33. Remuzzi G, Benigni A, Finkelstein FO, et al. Kidney failure: aims for the next 10 years and barriers to success. Lancet 2013;382 (9889):353 62. 34. Caskey FJ, Kramer A, Elliott RF, et al. Global variation in renal replacement therapy for end-stage renal disease. Nephrol Dial Transplant 2011;26(8):2604 10. 35. Levin A, Stevens PE. Early detection of CKD: the benefits, limitations and effects on prognosis. Nat Rev Nephrol 2011;7(8):446 57. 36. Jha V, Wang AY-M, Wang H. The impact of CKD identification in large countries: the burden of illness. Nephrol Dial Transplant 2012;27 (Suppl. 3):iii32 8. 37. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet 2013;382(9888):260 72. 38. Bru¨ck K, Jager KJ, Dounousi E, et al. Methodology used in studies reporting chronic kidney disease prevalence: a systematic literature review. Nephrol Dial Transplant 2015;30(Suppl. 4):iv6 16. 39. Perico N, Remuzzi G. Need for chronic kidney disease prevention programs in disadvantaged populations. Clin Nephrology 2015;83(7 Suppl. 1):42 8. 40. El Nahas AM, Bello AK. Chronic kidney disease: the global challenge. Lancet 2005;365(9456):331 40. 41. Levey AS, Atkins R, Coresh J, et al. Chronic kidney disease as a global public health problem: approaches and initiatives - a position statement from Kidney Disease Improving Global Outcomes. Kidney Int 2007;72(3):247 59. 42. Zhang Q-L, Rothenbacher D. Prevalence of chronic kidney disease in population-based studies: systematic review. BMC Public Health 2008;8(1):117. Available from: http://dx.doi.org/10.1186/1471-2458-8-117. 43. Levey AS, Andreoli SP, DuBose T, Provenzano R, Collins AJ. Chronic kidney disease: common, harmful and treatable World Kidney Day 2007. Am J Nephrol 2007;27(1):108 12. 44. Cravedi P, Sharma SK, Bravo RF, et al. Preventing renal and cardiovascular risk by renal function assessment: insights from a cross-sectional study in low-income countries and the USA. BMJ Open 2012;2(5):e001357. 45. Rhee CM, Kovesdy CP. Spotlight on CKD deaths—increasing mortality worldwide. Nat Rev Nephrol 2015;11(4):199 200. 46. Zhang L, Wang F, Wang L, et al. Prevalence of chronic kidney disease in China: a cross-sectional survey. Lancet 2012;379(9818):815 22. 47. United States Renal Data System. USRDS annual data report: epidemiology of kidney disease in the United States. National Institutes of Health; 2015. Available from: www.usrds.org. 48. Stenvinkel P. Chronic kidney disease: a public health priority and harbinger of premature cardiovascular disease. J Intern Med 2010;268 (5):456 67. 49. Thomas B, Wulf S, Bikbov B, et al. Maintenance dialysis throughout the World in Years 1990 and 2010. J Am Soc Nephrol 2015;26:2621 33. 50. Beard JR, Officer A, de Carvalho IA, et al. The World report on ageing and health: a policy framework for healthy ageing. Lancet 2016;387:2145 54.

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51. Lin M-Y, Chiu Y-W, Lee C-H, et al. Factors associated with CKD in the elderly and nonelderly population. Clin J Am Soc Nephrol 2013;8:33 40. 52. Glassock RJ, Rule AD. The implications of anatomical and functional changes of the aging kidney: with an emphasis on the glomeruli. Kidney Int 2012;82(3):270 7. 53. Zu¨rbig P, Decramer S, Dakna M, et al. The human urinary proteome reveals high similarity between kidney aging and chronic kidney disease. Proteomics 2009;9(8):2108 17. 54. Glassock RJ, Oreopoulos DG. Aging and chronic kidney disease. Nephron Clin Pract 2011;119(Suppl. 1):c1. Available from: http://dx.doi. org/10.1159/000328007. 55. NHANES. Age-Adjusted Prevalence of CKD Stages 1 4 by Gender 1999 2012. Available from: http://www.cdc.gov/diabetes/programs/initiatives/kidney.html. 56. Gambaro G, Yabarek T, Graziani MS, et al. Prevalence of CKD in northeastern Italy: results of the INCIPE study and comparison with NHANES. Clin J Am Soc Nephrol 2010;5:1946 53. 57. van Blijderveen JC, Straus SM, Zietse R, Stricker BH, Sturkenboom MC, Verhamme KM. A population-based study on the prevalence and incidence of chronic kidney disease in the Netherlands. Int Urol Nephrol 2014;46(3):583 92. 58. Juutilainen A, Kastarinen H, Antikainen R, et al. Comparison of the MDRD Study and the CKD-EPI Study equations in evaluating trends of estimated kidney function at population level: findings from the National FINRISK Study. Nephrol Dial Transplant 2012;27(8):3210 17. 59. Arora P, Vasa P, Brenner D, et al. Prevalence estimates of chronic kidney disease in Canada: results of a nationally representative survey. CMAJ 2013;185:E417 23. 60. Perico N, Bravo RF, De Leon FR, Remuzzi G. Screening for chronic kidney disease in emerging countries: feasibility and hurdles. Nephrol Dial Transplant 2009;24(5):1355 8. 61. Ingsathit A, Thakkinstian A, Chaiprasert A, et al. Prevalence and risk factors of chronic kidney disease in the Thai adult population: Thai SEEK study. Nephrol Dial Transplant 2010;25(5):1567 75. 62. Arogundade FA, Barsoum RS. CKD prevention in Sub-Saharan Africa: a call for governmental, nongovernmental, and community support. Am J Kidney Dis 2008;51(3):515 23. 63. Sumaili EK, Krzesinski J-M, Zinga CV, et al. Prevalence of chronic kidney disease in Kinshasa: results of a pilot study from the Democratic Republic of Congo. Nephrol Dial Transplant 2009;24(1):117 22. 64. Tonelli M, Riella M. Chronic kidney disease and the aging population. Nephrol Dial Transplant 2014;29(2):221 4. 65. Dalrymple LS, Katz R, Kestenbaum B, et al. Chronic kidney disease and the risk of end-stage renal disease versus death. J Gen Intern Med 2011;26(4):379 85. 66. Moynihan R, Glassock R, Doust J. Chronic kidney disease controversy: how expanding definitions are unnecessarily labelling many people as diseased. BMJ 2013;347:f4298. 67. O’Hare AM, Choi AI, Bertenthal D, et al. Age affects outcomes in chronic kidney disease, J Am Soc Nephrol 2007;18(10):2758 65. 68. Hallan SI, Matsushita K, Sang Y, et al. Age and association of kidney measures with mortality and end-stage renal disease. JAMA 2012;308(22):2349 60. 69. Iseki K. Gender differences in chronic kidney disease. Kidney Int 2008;74(4):415 17. 70. Halbesma N, Brantsma AH, Bakker SJ, et al. Gender differences in predictors of the decline of renal function in the general population. Kidney Int 2008;74(4):505 12. 71. Carrero JJ. Gender differences in chronic kidney disease: underpinnings and therapeutic implications. Kidney Blood Press Res 2010;33 (5):383 92. 72. Eriksen BO, Tomtum J, Ingebretsen OC. Predictors of declining glomerular filtration rate in a population-based chronic kidney disease cohort. Nephron Clin Pract 2010;115(1):c41 50. 73. Neugarten J, Acharya A, Silbiger SR. Effect of gender on the progression of nondiabetic renal disease a meta-analysis. J Am Soc Nephrol 2000;11(2):319 29. 74. Silbiger S, Neugarten J. Gender and human chronic renal disease. Gend Med 2008;5:S3 10. 75. Norris K, Nissenson AR. Race, gender, and socioeconomic disparities in CKD in the United States. J Am Soc Nephrol 2008;19(7):1261 70. 76. Feehally J. Ethnicity and renal disease. Kidney Int 2005;68(1):414 24. 77. Harawa NT, Norris KC. The role of ethnic variation and CKD. Clin J Am Soc Nephrol 2015;10:1708 10. 78. Saran R, Li Y, Robinson B, et al. US Renal Data System 2015 Annual Data Report: epidemiology of kidney disease in the United States. Am J Kidney Dis 2016;67(3 Suppl. 1):S1 434. 79. Palmer AT, Lewis J. Racial differences in chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the United States: a social and economic dilemma. Clin Nephrol 2010;74:S72 7. 80. Collins JF. Kidney disease in Maori and Pacific people in New Zealand. Clin Nephrol 2010;74(Suppl.1):s61 5. 81. Sabanayagam C, Lim SC, Wong TY, Lee J, Shankar A, Tai ES. Ethnic disparities in prevalence and impact of risk factors of chronic kidney disease. Nephrol Dial Transplant 2010;25(8):2564 70. 82. Nicholas SB, Kalantar-Zadeh K, Norris KC. Socioeconomic disparities in chronic kidney disease. Adv Chronic Kidney Dis 2015;22(1):6 15. 83. Swanepoel CR, Wearne N, Okpechi IG. Nephrology in Africa—not yet uhuru. Nat Rev Nephrol 2013;9(10):610 22. 84. Stanifer JW, Jing B, Tolan S, et al. The epidemiology of chronic kidney disease in sub-Saharan Africa: a systematic review and metaanalysis. Lancet Glob Health 2014;2(3):e174 81. 85. Hossain MP, Goyder EC, Rigby JE, El Nahas M. CKD and poverty: a growing global challenge. Am J Kidney Dis 2009;53(1):166 74. 86. Garcı´a-Garcı´a G, Jha V. World Kidney Day 2015: CKD in disadvantaged populations. Am J Kidney Dis 2015;65(3):349 53. 87. Young BA. The interaction of race, poverty, and CKD. Am J Kidney Dis 2010;55(6):977 80. 88. Patzer RE, McClellan WM. Influence of race, ethnicity and socioeconomic status on kidney disease. Nat Rev Nephrol 2012;8(9):533 41.

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C H A P T E R

2 Transplant Programs Worldwide and the Spanish Miracle Rafael Matesanz, Beatriz Domı´nguez-Gil, Elisabeth Coll, Beatriz Mahı´llo, Gloria de la Rosa and Marı´a O. Valentı´n National Transplant Organization, Madrid, Spain

2.1 INTRODUCTION In 2010, the World Health Assembly adopted Resolution WHA 63.22, urging Member States “to strengthen national and multinational authorities and/or capacities to provide oversight, organization and coordination of donation and transplantation activities, with special attention to maximizing donation from deceased donors and to protect the welfare of living donors with appropriate health-care services and long-term follow-up.”1 The Resolution was adopted 2 months after participants in the third World Health Organization (WHO) Global Consultation on Organ Donation and Transplantation (Madrid, Spain), called governments to take responsibility in the progress towards self-sufficiency in transplantation, and therefore in satisfying the transplantation needs of their patients, by using resources within their own patient population.2 Self-sufficiency should encompass strategies targeted both to decrease the burden of chronic diseases treatable with transplantation and to increase organ availability, with priority given to donation from the deceased. Initiatives for self-sufficiency should have a solid ethical basis respectful to the WHO Guiding Principles on Human Cell, Tissue and Organ Transplantation3 and the Declaration of Istanbul on Organ Trafficking and Transplant Tourism.4 These WHO straightforward messages were launched to address the universal shortage of organs; the more than 115,000 solid organ transplants performed globally every year barely cover 10% of the transplant needs and there are huge disparities in transplantation activities observed across countries.5 Differences in deceased donation greatly account for the extreme variability in access to transplantation therapies. Disparities in deceased donation are evident even when comparing countries with a high level of development, ranging between nonexistent to more than 30 deceased donors per million population (pmp) (Fig. 2.1).6 In this scenario, Spain occupies a worldwide privileged position, with the highest deceased donation rate ever recorded for a large country, and reaching a maximum 40 donors pmp in 2015. Transplantation activities in the country are well over 100 transplant procedures pmp, something hard to imagine for the majority of countries throughout the world. With around 14 donors pmp at the end of the eighties, the activity in Spain was at the mid-low position when compared to other European countries. The increase in deceased donation (Fig. 2.2), and consequently in the number of solid organ transplants (Fig. 2.3), resulted from the implementation of a set of measures, mainly of an organizational nature, altogether internationally named as the Spanish Model of Organ Donation and Transplantation.7,8 These measures were adopted after the Spanish National Transplant Organization (Organizacio´n Nacional de Trasplantes—ONT) was created in 1989. ONT was conceived as a technical agency embedded within the Ministry of Health, and in charge of overseeing and coordinating donation and transplantation activities in the country. The Spanish system is founded on two basic principles: a proper organization around the process of donation after death, along with innovation and continuous adaptation to the change.

Kidney Transplantation, Bioengineering, and Regeneration. DOI: http://dx.doi.org/10.1016/B978-0-12-801734-0.00002-3

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© 2017 Elsevier Inc. All rights reserved.

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2. ORGAN DONATION: THE SPANISH MIRACLE

FIGURE 2.1 Deceased donation activity (rates per million population) in the world. Donors after brain death and donors after circulatory death. The absolute number of deceased donors is shown in brackets. Year 2014. DBD, donation after brain death; DCD, donation after circulatory death; pmp, per million population. Source: WHO-ONT Global Observatory on Organ Donation and Transplantation. I. KIDNEY TRANSPLANTATION

2.2 THE SPANISH MODEL OF ORGAN DONATION AND TRANSPLANTATION

15

FIGURE 2.2 Deceased donation activity (absolute number and rate per million population) in Spain. Years 1989 2015. pmp, per million population. Source: Organizacio´n Nacional de Trasplantes.

FIGURE 2.3 Solid organ transplantation activity in Spain. Absolute numbers. Years 1989 2015. Source: Organizacio´n Nacional de Trasplantes.

2.2 THE SPANISH MODEL OF ORGAN DONATION AND TRANSPLANTATION Measures implemented in the country were developed on an appropriate healthcare, legal and technical background. The Spanish healthcare system is a public one with a universal coverage of the population, and universal access to transplantation. Technically, the country counts on extraordinarily prepared, enthusiastic, innovative, and motivated transplant teams. The Spanish Law on Transplantation was first enacted in 1979 and contained the

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2. ORGAN DONATION: THE SPANISH MIRACLE

TABLE 2.1 Main Elements of the Spanish Model of Organ Donation and Transplantation Donor coordination network at three levels: national, regional, hospital. Special profile of donor coordinators • • • •

Medical doctors, mainly critical care physicians, supported by nurses. Part-time dedication to the transplant coordination activities. Independence from the transplant teams. Appointed by and reporting to the hospital medical director. Main objective: deceased donation. Progressively more involved in: promotion, training and education, relation with the mass media, management of resources, research. Donor Coordinators inside the hospitals. Central Office (ONT) as a support agency. Quality Assurance Program in the deceased donation process: continuous clinical chart review of deaths at intensive care units of procurement hospitals. Two phases: internal and external audit. Great effort in medical training through different types of courses. Targets: donor coordinators, intensive care physicians and nurses, emergency and urgency physicians and nurses, other healthcare professionals. Close attention to the mass media with a special communication policy. Hospital reimbursement for donation and transplantation activities.

basic elements of any western transplant law.9 An opting-out system for consent to donation was devised and has been in place since then. However, the presumed consent policy is not strictly applied in practice; relatives are always approached and still have the final veto.10,11 Political competencies in the country are transferred to 17 Autonomous Regions, so any national initiative has to reach an interregional consensus, and this also applies to the field of donation and transplantation. This particular political situation has determined a mode of work in the field that aims at the cohesion of the system and the sharing of best practices. The core principle of the Spanish system is a very specific organizational approach to the process of donation after death, to ensure the systematic identification of opportunities for organ donation and their transition to actual organ donation. The main elements of the Spanish Model are summarized in Table 2.1 and described below.

2.3 DONOR COORDINATION NETWORK The coordination of donation activities has been structured at three different but related levels: national (ONT), regional (17 Regional Coordination offices), and hospital. The first two levels act as an interface between the technical and the political strata, and in support of the process of deceased donation. These two levels are appointed by and report to the national and regional health-care authorities, respectively. Any national decision on donation and transplantation activities is agreed upon by the National Transplant Committee of the Inter-territorial Health-Care Council, which comprises the ONT as chair and the 17 Regional Coordinators. The hospital level of coordination is composed of a network of hospitals specifically authorized for organ procurement activities by the relevant authorities, where the process of organ donation and procurement is developed. The network of donor hospitals grew from less than 20 in 1989 to 118 in 1992, a rapid evolution which reflects the significant efforts made by the system and the political support received in its initial years. The network has continued to increase, today comprising 186 hospitals throughout the country.

2.4 SPECIFIC PROFILE OF THE DONOR COORDINATOR As specified in the national legislation, each hospital authorized for organ procurement activities must count on a dedicated donor coordination team, variable in its composition, but always led by a figure with a very specific profile, a key element of the Spanish system.12 Donor coordinators are in-house professionals, members of staff at the procurement hospital concerned. They are nominated by and report to the medical direction of the hospital and the corresponding Regional Coordinator. Most of the donor coordinators are involved in donation activities on a part-time basis, which enables them to be appointed even at hospitals with a low deceased donor potential.

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2.6 QUALITY ASSURANCE PROGRAM IN DECEASED DONATION

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Most notably, the majority of donor coordinators are intensive care physicians who develop their daily work at those units where about 12% of deaths occur in persons with a clinical condition consistent with brain death.13 This feature has been the driving force for the Spanish intensive care community to consider organ donation as a routine component of end-of-life care. The following examples make evident the embracement of deceased donation by the intensive care community. The Spanish Society of Intensive, Critical Care Medicine and Coronary Units (Sociedad Espan˜ola de Medicina Intensiva, Crı´tica y Unidades Coronarias—SEMICYUC) specifically acknowledges organ donation as its responsibility at its Ethics Code of Practice.14 In consequence and in cooperation with ONT, this Society supports the continuous training of intensive care physicians in organ donation and procurement activities from the outset of their clinical practice. Moreover, SEMICYUC lists a set of indicators related to donor identification and conversion of potential into actual organ donors as key indicators of quality in intensive care.15

2.5 ONT AS A CENTRAL AGENCY IN SUPPORT OF THE SYSTEM Besides its key role as organ sharing office, ONT acts as an agency in support of the network of procurement hospitals and the successful development of the deceased donation process. In close cooperation with the Regional Coordination Offices, ONT issues the regulatory framework of practice, provides advice for the designation of appropriate professionals as in-hospital donor coordinators, ensures continuous professional training and public education, designs national protocols and programs to promote organ donation and improve practices, and monitors activities to identify opportunities for improvement. The support provided by ONT and some Regional Offices is particularly important for small hospitals, with more difficulties to develop the process of deceased donation on their own.

2.6 QUALITY ASSURANCE PROGRAM IN DECEASED DONATION The Quality Assurance Program in Deceased Donation has been in place since 1999, and has inspired national, regional, and local strategies for continuous improvements.13 So far focused on the process of donation after brain death (DBD), the program aims at monitoring the potential donor pool, evaluating performance in deceased donation and identifying areas where improvement is possible. The program is based on a continuous audit of clinical charts of patients dead in intensive care units (ICUs). It includes an internal audit performed by donor coordinators locally. Information compiled during the internal audit is reported to ONT, which provides national indicators of reference to the network (Table 2.2). With differences between hospitals with and without neurosurgical activities, as a mean 12% of patients dead in the Spanish ICUs die in conditions consistent with brain death. Main reasons why these potential DBD donors do not transition to actual DBD donors are medical unsuitability (25%) and consent declined to proceed with organ recovery (13%). Failure to identify and refer potential DBD donors barely accounts for 3% of donor losses. Hospitals that deviate from these national indicators are prompted to take measures for improvement. The program also includes external audits carried out following a specific methodology described in detail elsewhere.13 At a national level, this component of the program has offered undisputed evidence that improvement is possible. With 21,065 ICU deaths externally audited between 2001 and 2011, 2635 persons with a brain death condition were identified in the clinical chart review, of which 6% were never referred to the donor coordinator. Twenty-three percent of potential donors were considered medically unsuitable for donation, although in 11% of these cases, medical contraindications were deemed inappropriate by external observers. Hemodynamic instability leading to an early cardiac arrest and refusals to organ donation were the reasons behind 2% and 14% of losses, respectively, some considered avoidable. The program reveals that the number of actual donors in the country could be 21% higher if all potential donors were identified and preventable losses avoided.13 External audits also represent great opportunities for exchanging best practices and releasing recommendations for improvement to the donor coordination team and the hospital managers of the audited hospitals.

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2. ORGAN DONATION: THE SPANISH MIRACLE

TABLE 2.2 Data From the Spanish Quality Assurance Program in Deceased Donations. Years 1999 201316 ICU deaths audited

276,356

PD audited

33,310

Actual DBD donors

19,168

DBD POTENTIAL % PD/Hospital deaths

2.2

% PD/ICU deaths

12.3

LOSSES IN THE PROCESS % PD not referred to the donor coordination/PD

3.4

% Medical Contraindications/PD (including not referred cases)

24.8

% Maintenance problems/PD (including not referred cases)

2.9

% Family refusals/PD

12.9

% Judicial refusals/PD

0.3

% Brain death diagnosis not confirmed/PD

0.1

% Lack of suitable recipients/PD

0.6

% Logistic problems/PD

0.4

OVERALL PERFORMANCE % Actual DBD donors/PD

56.8

DBD, donation after brain death; ICU, intensive care unit; PD, potential DBD donor. Potential DBD donor, Person with a clinical condition consistent with brain death.

2.7 CONTINUOUS PROFESSIONAL TRAINING Training is an essential component of the Spanish system. The Spanish government and the regional authorities have promoted regular courses targeted to all professionals who directly or indirectly participate in the process of deceased donation—donor coordinators, intensive and emergency care professionals, neurologists, judges, coroners, and journalists. Since 1991, over 16,000 professionals have been trained through these courses in Spain.

2.8 CLOSE COOPERATION WITH THE MEDIA The objective of constructing a positive social climate towards donation and generating society’s trust in the system has not been achieved through any sort of promotional campaign, but through a close cooperation with the mass media.17,18 The communication policy of ONT and its network is based on four basic principles: (1) a 24-hour telephone for consultation; (2) easy and permanent access to the media; (3) connection with journalists built through dedicated meetings aimed at learning about mutual needs; (4) delivery of messages with no intermediaries. These measures have led the media to handle information about donation and transplantation appropriately, and allowed the system to efficiently neutralize any negative news.

2.9 REIMBURSEMENT OF DONATION AND PROCUREMENT ACTIVITIES Finally, as with any other medical activity performed within the public health-care system, hospitals are reimbursed for their procurement activities. The corresponding regional healthcare authorities allocate a specific budget to cover both the human and material resources needed for the effective development of these activities at every hospital.19

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2.10 CURRENT CHALLENGES IN ORGAN DONATION IN SPAIN

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2.10 CURRENT CHALLENGES IN ORGAN DONATION IN SPAIN Despite the important transplant activity performed annually in Spain (Fig. 2.3), the transplantation needs of the population are still far from being adequately met.20 The prevalence and incidence of end-stage renal disease in the country is of 500 and 150 cases pmp, respectively.21 With an estimated 20% of prevalent and 30% 40% of incident patients being candidates to kidney transplantation, the kidney transplant activity should be as high as 150 160 kidney transplants pmp to meet the demand, which greatly exceeds the 60 procedures pmp reached in the year 2015. Six to eight percent of patients waiting for nonkidney transplants die each year in the country.20 This is possibly an underestimation of the true mortality on the waiting list, since a similar percentage of patients are withdrawn from the list every year, in many instances due to a deterioration of their clinical condition. The chronic inability to adequately satisfy the transplant needs is challenged by substantial epidemiological changes in the country and by improvements in the care of critical patients in general terms and neurocritical patients in particular. Mortality related to cerebrovascular diseases and traffic accidents has fortunately decreased in Spain over the years, leading the country to hold one of the lowest mortalities relevant to organ donation in Europe.22 The decrease in the occurrence of events potentially leading to devastating brain injuries, as a result of transport and work safety measures, along with a best approach to the treatment of these events, explain such a decrease in mortality. The extended use of decompressive craniectomy and other neurosurgical interventions has also contributed to a progressive decline in the pool of potential DBD donors in the country. According to data from the Quality Assurance Program in Deceased Donation, the incidence of brain death has evolved from 65 cases pmp in 2001 to less than 50 pmp in the very last years (Fig. 2.4). Changes have also occurred in the type of care provided to critical patients at the end-of-life, in accordance with new guidance issued by the relevant professional societies.23 Far from what the Ethicus study described for Southern European countries at the beginning of the century, where deaths in the ICU following the withdrawal of life-sustaining therapy (WLST) were rare,24 at present more than 30% of deaths in the Spanish ICUs and close to 20% of deaths in patients with a devastating brain injury follow the decision to WLST because this is no longer in the best clinical interests of the patient.25,26 Until recently, controlled donation after circulatory death (cDCD) was not possible in the country, since the framework for its practice had not been developed yet and a moratorium existed since 1996 on this particular activity.27

FIGURE 2.4 Potential and actual donors after brain death per million population in Spain. Years 2001 13. Potential donor after brain death: Person with a clinical condition consistent with brain death (medical contraindications included). Source: Organizacio´n Nacional de Trasplantes.

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2.11 THE 40 DONORS PER MILLION POPULATION PLAN The situation described above prompted the system to consider new strategies to meet the demand of organs for transplantation and to ensure that the option of organ donation was posed in all circumstances of death. In 2008, ONT devised the 40 donors pmp Plan, establishing this objective in deceased organ donation to all Autonomous Regions in the country.28 The objective was not arbitrary. When comparing performance between regions and hospitals, profound differences could be observed, not easily explained by disparities in the pool of possible donors.29 These differences suggested that there was still large room for improvement within the Spanish system. Actions under development to yield a level of activity almost achieved for the country as a whole and already surpassed by several Spanish Regions (Fig. 2.5) are summarized below.

2.12 PROMOTING THE IDENTIFICATION OF POSSIBLE ORGAN DONORS OUTSIDE OF THE ICU AND CONSIDERING ELECTIVE NONTHERAPEUTIC INTENSIVE CARE Early identification and referral of persons with a devastating brain injury in whom further treatment has been deemed futile (possible donors) to consider elective nontherapeutic intensive care can substantially modify the pool of potential donors. In recent years, a group of hospitals had reached an outstanding performance of over 60 70 donors pmp, levels that challenged any previous assessment of the deceased donor potential in the country. However, former estimations of the DBD pool were focused exclusively on the ICU. Many factors determine the number of persons who finally die with a devastating brain lesion within an ICU and in conditions consistent with brain death.30 Some of these factors are not easily modifiable, such as the availability of ICU

FIGURE 2.5 Deceased donors per million population in Spanish regions. Year 2015. Source: Organizacio´n Nacional de Trasplantes.

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resources. However, admission criteria to the ICU and initiation/continuation of intensive care when this is deemed futile are acknowledged as variable but modifiable factors, very much dependent upon the level of professional knowledge and ownership of the deceased donation activity. In 2009, ONT promoted a benchmarking study targeted to identify best performing hospitals in the country in the different phases of the DBD process.31 The study identified 10 hospitals with outstanding results in the identification and referral of possible organ donors to the ICU to facilitate organ donation. Qualitative questionnaires pointed out critical factors for success at this stage—these hospitals had devised a pathway of care for the neurocritical patient inclusive of the consideration of organ donation when the responsible professional or team shifted from active treatment to palliative and end-of-life care. When prognosis was ominous and further treatment deemed futile by the responsible physician, organ donation was discussed with the relatives along with the need to initiate/continue intensive care with the aim of facilitating organ donation. The practice was a routine reflected at local protocols, well accepted and properly monitored. This finding was reflected in a Guide of Best Practices in Organ Donation released to the network with specific recommendations for the implementation of this principle in practice.32 Further work focused on the quantitative and qualitative description of possible organ donors who currently die outside of the ICU. The first national assessment was performed in the context of a study jointly undertaken by ONT and the Spanish Society of Emergency Care (Sociedad Espan˜ola de Medicina de Urgencias y Emergencias—SEMES). Possible organ donors accounted for 1 out of 2000 patients attended to at the emergency department of procurement hospitals—69% of these possible donors admitted to the hospital through the emergency department finally died outside of the ICU (in the emergency room itself or at the hospital ward) with no consideration of organ donation. More recently, the ACCORD-Spain study assessed end-of-life care practices relevant to organ donation at 68 hospitals in the country.26 Almost 40% of possible organ donors were never admitted to the ICU because further treatment was considered futile and because the option of organ donation had not been facilitated (Fig. 2.6). Notably, 43% of these patients were octogenarian and/or had significant comorbidities, and most were not ventilated at the moment when the decision was made not to continue intensive treatment. The study pointed out

FIGURE 2.6 Scenario that best describes the type or care provided at the end-of-life to patients dying as a result of a devastating brain injury in Spain. ICU, intensive care unit; WLST, withdrawal of life-sustaining therapy. Source: ACCORD Spain study. The study compiled information on 1970 possible donors aged 1 month-85 years identified in 68 of the 186 hospitals authorized for organ procurement activities in the country during the period 11/1/2014 4/30/2015.

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some of the many challenges of elective nontherapeutic intensive care—the frequent need of initiating elective ventilation, the uncertainties about contraindications to organ donation that might become evident once the decision has been made to continue intensive care, summed up to the difficulties of anticipating that brain death will occur within a reasonable period of time. The practice and the challenges of elective nontherapeutic intensive care have become components of the national curriculum for donor coordinators, intensive and emergency care professionals in the country.33,34 Jointly with SEMES, ONT has recently produced recommendations on the role of emergency care professionals in organ donation.35 A working group designated by ONT and SEMICYUC is now preparing guidelines for elective nontherapeutic intensive care targeted to harmonize and improve practices in this particular setting. Today the contribution of elective nontherapeutic intensive care to actual donation rates is evident. ACCORDSpain has revealed that 24% of organ donors in the country have been patients admitted to the ICU with the aim of incorporating organ donation into their end-of-life care pathway.26

2.13 FOSTERING THE USE OF ORGANS FROM EXPANDED CRITERIA AND NONSTANDARD RISK DONORS 2.13.1 Expanded Criteria Donors In the context of the fortunate progressive reduction in the number of deaths due to traffic accidents over the years, if criteria for organ donation had remained unaltered, the deceased donation activity in Spain would have dramatically decreased. However, the Spanish coordination and transplantation system has progressively adopted more flexible criteria for donor selection. As a result, the number of aged donors, mostly dead as a result of cerebrovascular accidents, has sustainably increased in Spain (Fig. 2.7). In 2015, more than 50% of deceased

FIGURE 2.7 Age group of deceased organ donors in Spain. Years 2000 15. Source: Organizacio´n Nacional de Trasplantes.

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organ donors were aged 60 years or older, falling under the age criterion that defines the expanded criteria donor kidney at the UNOS.36 Moreover, 30% of deceased donors were over 70 years, and 10% over 80 years. An “old for old” allocation strategy has been devised from the very beginning, whereby aged kidneys are preferentially allocated to aged recipients irrespective of HLA mismatch, as also performed in other European programs.37,38 More than 40% of the deceased kidney, 51% of the liver, 7% of the heart and 23% of the lung transplant procedures are performed with organs recovered from donors aged $ 60 years.20 Discard rates of organs recovered from expanded criteria donors, however, remain high. Further analysis and work should lead the system to conclude whether organ discard is based on objective factors determinant of posttransplant outcomes and to determine the role of, e.g., ex vivo perfusion techniques in better assessing organ viability.

2.13.2 Nonstandard Risk Donors The Quality Assurance Programme in Deceased Donation reveals that 25% of persons in a brain death condition are not considered medically suitable organ donors, though some of these medical contraindications are inappropriately established by the donor coordinator or the treating physician.13 While safety of the process is an unquestionable professional standard, a scientific analysis of the risks should deeply guide decisions about transplantation at a moment of shortage. The ageing of the donor population is also inherently linked to progressively more difficult assessments of donor suitability. ONT has a 24-hour medical team available for donor coordinators to ask for a second opinion regarding the evaluation of potential donors. National Consensus Documents on the evaluation of organ donors to prevent the transmission of neoplastic diseases and with regards to infections have also been important elements in meeting this need.39,40 These documents have been the bases for recommendations on donor suitability at the Council of Europe level.41 More recently, in order to clearly define safety limits in the use of organs for transplantation, a specific national registry on the follow-up of recipients transplanted from nonstandard risk donors (i.e., history of malignancy or active infection) has been developed by ONT. Information provided by this registry will indeed contribute to increasing the level of evidence to guide future risk-benefit assessments.

2.14 DEVELOPING THE FRAMEWORK FOR THE PRACTICE OF DONATION AFTER CIRCULATORY DEATH Contrary to what is described for other countries, donation after circulatory death (DCD) in Spain had been classically focused on what the First International Workshop on the so-called Non Heart Beating Donation, held in Maastricht in 1995, defined as category II or uncontrolled DCD (uDCD) donation from persons who have been declared dead following an unsuccessfully resuscitated cardiac arrest.42 This particular type of DCD implies a very important logistical effort, both inside and outside of the hospital, and a smooth cooperation between the different stakeholders involved.43 Legal, ethical, and the aforementioned difficulties have precluded many countries to embark on this type of donation despite efforts to emulate this program in other realities.44 Even within Spain, because of the degree of sophistication required, the activity was initially limited to three Spanish cities— A Corun˜a, Barcelona, and Madrid. Following national recommendations, and support by national and local authorities, other programs have been initiated,45 with a positive impact upon the number of uDCD donors, although the activity has stabilized thereafter (Fig. 2.8). At present, there are 11 uDCD programs in the country yielding an important number of kidneys with impressive results.46 48 Liver transplants from uDCD donors have been made possible with a normothermic regional perfusion approach which leads to reasonable results close to those obtained with livers from DBD donors.49,50 Results of lung transplantation from uDCD donors are comparable to those obtained with DBD donors.51,52 The contribution of ex vivo preservation strategies to the validation of these lungs is currently under study. cDCD had not been devised as an option in our country for many years. Until recently, a moratorium was in place on the use of organs from this type of donor and no regulatory framework had been established for its practice. The aforementioned changes to end-of-life care were the main reason to reconsider the position of the country towards cDCD. A National Consensus Conference on DCD set down the basis for this practice in Spain and was followed by the development of a new legislation that accommodated this possibility and established the minimum requisites for its development.12,53 Along with institutional support and efforts in professional training and public education the results have been impressive (Fig. 2.8). Today more than 50 hospitals in the

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FIGURE 2.8 Donation after circulatory death in Spain. Absolute numbers and rate per million population. Maastricht categories. Years 1995 2015. Source: Organizacio´n Nacional de Trasplantes.

country are embarked in cDCD which already contributes to 10% of the overall deceased donation rates and has had a substantial impact on the kidney, but also the liver and lung transplantation activity, with excellent posttransplant results.54,55

2.15 PROMOTING LIVING KIDNEY DONATION WHILE ENSURING COMPREHENSIVE DONOR PROTECTION AND CARE Living donation remained a rather anecdotal activity in Spain for many years, something to be understood in the global context of a country with an emerging and soon robust deceased donation program during the 1990s. Only a few highly experienced centers maintained a certain level of living kidney donation during those years. However, living kidney donation is now considered an essential element in dealing with the transplantation needs of patients. The evidence of excellent results of living kidney transplantation,56 the knowledge gained about the short-, mid-, and long-term safety of the donor as long as an appropriate framework of donor care is provided,57 60 and the incorporation of novel surgical approaches for donor nephrectomy have yielded a progressive change in the conception of living kidney donation in the country. This occurred alongside changes in international institutions such as the Council of Europe, which progressed from restrictive principles61 to the consideration of new strategies to increase the living donor pool, such as altruistic donation or kidney pair exchange.62,63 Variable experience in living transplantation between centers, living kidney donation not being offered as an alternative for ESRD patients, and ABO and HLA incompatibility were recognized obstacles in our system to living kidney donation.64,65 Training courses aimed at multidisciplinary teams of professionals (such as nephrologists, urologists, donor coordinators and nurses) from transplantation hospitals, dialysis centers and outpatient clinics have been developed over the last years. Donor coordinators are being incorporated as figures facilitating the process and covering the informative needs of patients and their relatives. The Spanish Society of Nephrology and ONT have issued comprehensive professional guidelines on living kidney donation and transplantation.66 A solid program of kidney pair exchange has been developed with more than 150 kidney transplant procedures performed since 2009.67 A program of altruistic donation is already in place, which, combined with the crossover

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FIGURE 2.9 Living kidney transplantation activity in Spain. Absolute number and rate per million population. Years 1991 2015. Source: Organizacio´n Nacional de Trasplantes.

donation program, has led to increased possibilities of living kidney transplantation.68 Living donation is finally developed under a framework of comprehensive donor protection and care. As a result of all these initiatives, living kidney transplantation has progressively increased, today representing 13% of all kidney transplant procedures performed in the country (Fig. 2.9).

2.16 FINAL REMARKS Organization around the process of deceased donation is the key to success for the Spanish system. This approach has been totally or partially replicated by other countries and regions resulting in a progression in the pursuit of self-sufficiency in transplantation through deceased organ donation. New challenges are being confronted effectively by the system: the transplantation needs of our population are expected to increase, while the potential of donation might continue decreasing in the upcoming years, particularly for DBD. Novel strategies to adapt to this changing scenario are being explored and successfully implemented in Spain. Finally, the pillars of the deceased and living donation program and the measures developed to increase organ availability are respectful with fundamental international ethical standards—which are solid elements of the Spanish Model per se.

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6. 2013 Report of the Global Observatory on Donation and Transplantation. Global Observatory on Donation and Transplantation website. ,https://view.publitas.com/ont/20151215_basic_slides_2013_con_datos_de_libya_de_2011/page/1. [accessed March 2016]. 7. Matesanz R, Domı´nguez-Gil B. Strategies to optimize deceased organ donation. Transplant Rev 2007;21:177 88. 8. Matesanz R, Domı´nguez-Gil B, Coll E, de la Rosa G, Marazuela R. Spanish experience as a leading country: what kind of measures were taken? Transpl Int 2011;24(4):333 43. 9. Ley 30/1979, de 27 de octubre, sobre extraccio´n y trasplante de o´rganos. ,https://www.boe.es/buscar/doc.php?id 5 BOE-A-197926445. [accessed March 2016] [in Spanish]. 10. Matesanz R, Domı´nguez-Gil B. Pros and cons of a regulated market in organs. Lancet 2009;374(9707):2049. 11. Fabre J, Murphy P, Matesanz R. Presumed consent: a distraction in the quest for increasing rates of organ donation. BMJ 2010;341:c4973. 12. Real Decreto 1723/2012, de 28 de diciembre, por el que se regulan las actividades de obtencio´n, utilizacio´n clı´nica y coordinacio´n territorial de los o´rganos humanos destinados al trasplante y se establecen requisitos de calidad y seguridad. ,https://www.boe.es/diario_boe/txt.php?id 5 BOE-A-2012-15715. [accessed March 2016] [in Spanish]. ´ lvarez J, Araiz J, et al. Continuously evaluating performance in deceased 13. de la Rosa G, Domı´nguez-Gil B, Matesanz R, Ramo´n S, Alonso-A donation: the Spanish quality assurance program. Am J Transplant 2012;12(9):2507 13. 14. Cabre´ Pericas LL, Abizanda Camposb R, Baigorri Gonza´lez F, Blanch Torra L, Campos Romero JM, Iribarren Diarasarri S, et al. Code of ethics of the Spanish Society of Intensive Care, Critical and Coronary Units (SEMICYUC)]. Med Intensiva 2006;30(2):68 73 [Article in Spanish]. 15. Quality Indicators in Critically Ill Patients. Update 2011. ,http://www.semicyuc.org/temas/calidad/indicadores-de-calidad. 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Health at a glance 2014. ,http://www.oecd-ilibrary.org/social-issues-migration-health/health-at-a-glance-2015_health_glance-2015-en. [accessed March 2016]. 23. Monzo´n Marı´n JL, Saralegui Reta I. Abizanda i Campos R, Cabre´ Pericas L, Iribarren Diarasarri S, et al. Treatment recommendations at the end of the life of the critical patient. Med Intensiva 2008;32(3):121 33 [Article in Spanish]. 24. Sprung CL, Cohen SL, Sjokvist P, Baras M, Bulow HH, Hovilehto S, et al. End-of-life practices in European intensive care units: the Ethicus Study. JAMA 2003;290(6):790 7. 25. Herna´ndez-Tejedor A, Martı´n-Delgado MC, Cabre´ L, Algora A, EPIPUSE study group. Limitation of life-sustaining treatment in patients with prolonged admission to the ICU. Current situation in Spain as seen from the EPIPUSE Study. Medicina Intensiva 2015;39(7):395 404 [Article in Spanish]. 26. Report on the ACCORD Spain Study. ,http://www.ont.es/infesp/Paginas/ProyectosenMarcha.aspx. [access March 2016] [in Spanish]. 27. Matesanz R. Documento de consenso espan˜ol sobre extraccio´n de o´rganos de donantes en asistolia. Nefrologı´a 1996;16(Suppl. 2):48 53 [Article in Spanish]. 28. Matesanz R, Marazuela R, Domı´nguez-Gil B, Coll E, Mahillo B, de la Rosa G. The 40 donors per million population plan: an action plan for improvement of organ donation and transplantation in Spain. Transplant Proc 2009;41(8):3453 6. 29. Coll E, Miranda B, Domı´nguez-Gil B, Martı´n E, Valentı´n M, Garrido G, et al. Organ donors in Spain: evolution of donation rates per regions and determinant factors. Med Clin (Barc) 2008;131(2):52 9 [Article in Spanish]. 30. Cuende N, Cuende JI, Fajardo J, Huet J, Alonso M. Effect population aging on the international organ donation rates and the effectiveness of the donation process. Am J Transplant 2007;7(6):1526 35. 31. Matesanz R, Coll E, Domı´nguez-Gil B, de la Rosa G, Marazuela R, Arra´ez V, et al. Benchmarking in the process of donation after brain death: a methodology to identify best performer hospitals. Am J Transplant 2012;12(9):2498 506. 32. Good practice guidelines in the process of organ donation. ,http://www.ont.es/publicaciones/Paginas/Publicaciones.aspx. [accessed March 2016]. 33. Matesanz R. Papel de los Servicios de Urgencias y Emergencias en la donacio´n de o´rganos. Emergencias 2010;22:68 71 [Article in Spanish]. 34. Escudero D, Otero J. Intensive care medicine and organ donation: exploring the last frontiers? Med Intensiva 2015;39(6):373 81. 35. El profesional de urgencias y el proceso de donacio´n. Recomendaciones ONT-SEMES. ,http://www.ont.es/infesp/Paginas/ DocumentosdeConsenso.aspx. [accessed March 2016] [in Spanish]. 36. Port FK, Bragg-Gresham JL, Metzger RA, Dykstra DM, Gillespie BW, Young EW, et al. Donor characteristics associated with reduced graft survival: an approach to expanding the pool of kidney donors. Transplantation 2002;74(9):1281 6. 37. Frei U, Noeldeke J, Machold-Fabrizii V, Arbogast H, Margreiter R, Fricke L, et al. Prospective age-matching in elderly kidney transplant recipients--a 5-year analysis of the Eurotransplant Senior Program. Am J Transplant 2008;8(1):50 7. 38. Arns W, Citterio F, Campistol JM. ‘Old-for-old’--new strategies for renal transplantation. Nephrol Dial Transplant 2007;22(2):336 41. 39. Criterios de seleccio´n del donante de o´rganos respecto a la Transmisio´n de infecciones. 2a edicio´n. 2004. ,http://www.ont.es/infesp/ % Paginas/DocumentosdeConsenso.aspx. [accessed March 2016] [in Spanish]. ´ 40. Criterios para prevenir la transmisio´n de enfermedades neopla´sicas en la donacio´n de Organos. ,http://www.ont.es/infesp/Paginas/ DocumentosdeConsenso.aspx.; 2006 [accessed March 2016] [in Spanish].

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41. Guide to the quality and safety of organs for transplantation. 5th Edition. ,https://www.edqm.eu/en/organ-tissues-cells-transplantation-guides-1607.html. [accessed March 2016]. 42. Kootstra G, Daemen JH, Oomen A. Categories of non-heart-beating donors. Transplant Proc 1995;27:2983 4. 43. Domı´nguez-Gil B, Duranteau J, Mateos A, Nu´n˜ez JR, Cheisson G, Corral E, et al. Uncontrolled Donation after Circulatory Death: European practices and recommendations for the development and optimization of an effective programme. Transplant Int 2015. Available from: http://dx.doi.org/10.1111/tri.12734. 44. Domı´nguez-Gil B, Haase-Kromwijk B, Van Leiden H, Neuberger J, Coene L, Morel P, et al. Current situation of donation after circulatory death in European countries. Transpl Int 2011;24(7):676 86. 45. Pe´rez-Villares JM, Lara-Rosales R, Pino-Sa´nchez F, Fuentes-Garcı´a P, Gil-Pin˜ero E, Osuna Ortega A, et al. Alpha code. The start of a new non-heart beating donor program. Med Intensiva 2013;37(4):224 31. 46. Sa´nchez-Fructuoso AI, Marques M, Prats D, Conesa J, Calvo N, Pe´rez-Contı´n MJ, et al. Victims of cardiac arrest occurring outside the hospital: a source of transplantable kidneys. Ann Intern Med 2006;145(3):157 64. 47. de Gracia MC, Osorio JM, Pe´rez-Villares JM, Galindo P, Ruiz MC, Pe´rez-Marfil A, et al. A new program of kidney transplantation from donors after cardiac death in Spain. Transplant Proc 2012;44(9):2518 20. 48. Miranda-Utrera N, Medina-Polo J, Pamplona M, de la Rosa F, Rodrı´guez A, Duarte JM, et al. Donation after cardiac death: results of the SUMMA 112 - Hospital 12 de Octubre Program. Clin Transplant 2013;27(2):283 8. 49. Fondevila C, Hessheimer AJ, Ruiz A, Calatayud D, Ferrer J, Charco R, et al. Liver transplant using donors after unexpected cardiac death: novel preservation protocol and acceptance criteria. Am J Transplant 2007;7(7):1849 55. 50. Jime´nez-Galanes S, Meneu-Diaz MJ, Elola-Olaso AM, Pe´rez-Saborido B, Yiliam FS, Calvo AG, et al. Liver transplantation using uncontrolled non-heart-beating donors under normothermic extracorporeal membrane oxygenation. Liver Transpl 2009;15(9):1110 18. 51. De Antonio DG, Marcos R, Laporta R, Mora G, Garcı´a-Gallo C, Ga´mez P, et al. Results of clinical lung transplant from uncontrolled nonheart-beating donors. J Heart Lung Transpl 2007;26(5):529 34. 52. Rodrı´guez A, del Rı´o F, Fuentes ME, Naranjo S, Moradiellos J, Go´mez D, et al. Lung transplantation with uncontrolled non-heart-beating donors; donor prognostic factor and immediate evolution post transplant. Arch Bronconeumol 2011;47(8):403 9. 53. Documento de Consenso Nacional sobre Donacio´n en Asistolia. ,http://www.ont.es/infesp/Paginas/DocumentosdeConsenso.aspx.; An˜o 2012 [accessed March 2016] [in Spanish]. 54. Hessheimer AJ, Domı´nguez-Gil B, Fondevila C, Matesanz R. Controlled donation after circulatory determination of death in Spain. Am J Transplant 2016. Available from: http://dx.doi.org/10.1111/ajt.13762. 55. Memoria de donacio´n en asistolia 2014. ,http://www.ont.es/infesp/Paginas/Memorias.aspx. [access March 2016] [in Spanish]. 56. Terasaki PI, Cecka JM, Gjertson DW. Takemoto S. High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med 1995;333(6):333 6. 57. Delmonico FL. A report of the Amsterdam Forum on the Live Kidney Donor: data and medical guidelines. Transplantation 2005;79(Suppl. 6): S53 66. 58. Segev DL, Muzaale AD, Caffo BS, Mehta SH, Singer AL, Taranto SE, et al. Perioperative mortality and long-term survival following live kidney donation. JAMA 2010;303(10):959 66. 59. Ibrahim HN, Foley R, Tan L, Rogers T, Bailey RF, Guo H, et al. Long-term consequences of kidney donation. N Engl J Med 2009;360 (5):459 69. 60. Cozzi E, Biancone L, Lo´pez-Fraga M, Nanni-Costa A. Long-term outcome of living kidney donation: Position paper of the European Committee on Organ Transplantation, Council of Europe. Transplantation 2016;100(2):270 1. 61. Conclusions of the 3rd Conference of European Health Ministers (Paris, 16-17 November 1987). Council of Europe website. ,http:// www.coe.int. [access March 2016]. 62. Resolution CM/Res (2008) 6, on transplantation of kidneys from living donors who are not genetically related to the recipient. Council of Europe website. ,http://www.coe.int. [access March 2016]. 63. Resolution CM/Res(2013)56 on the development and optimisation of live kidney donation programmes and its Explanatory memorandum. ,https://www.edqm.eu/en/organ-transplantation-recommendations-resolutions-74.html#Council of Europe and CD P TO framework. [access March 2016]. 64. Domı´nguez-Gil B, Pascual J. Living donor renal transplantation in Spain: a great opportunity. Nefrologia 2008;28(2):143 7. 65. Valentı´n MO, Domı´nguez-Gil B, Martı´n Escobar E, Matesanz Acedos R. Not indicating live transplants is a poor practice. Nefrologia 2009;29(5):379 81. 66. Guı´a SEN-ONT sobre trasplante renal de donante vivo. ,http://www.ont.es/infesp/Paginas/DocumentosdeConsenso.aspx. [access March 2016]. 67. Progama de donacio´n renal cruzada. ,http://www.ont.es/infesp/Paginas/DocumentosdeConsenso.aspx. [access March 2016] [in Spanish]. 68. Protocolo de donacio´n renal altruista. ,http://www.ont.es/infesp/Paginas/DocumentosdeConsenso.aspx. [access March 2016] [in Spanish].

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C H A P T E R

3 The Deceased Kidney Donor Hany El Hennawy and Jeffrey Rogers Wake Forest Baptist Medical Center, Winston-Salem, NC, United States

3.1 BRAIN DEATH Death is an irreversible, biological event that consists of permanent cessation of the critical functions of the organism as a whole.1 Brain death is defined as the permanent absence of cerebral and brainstem functions. Trauma and subarachnoid hemorrhage are the most common events leading to brain death. Others causes include intracerebral hemorrhage, hypoxic ischemic encephalopathy, and ischemic stroke.2 4 The diagnosis of brain death is made by neurologic examination, provided that the underlying etiology is capable of causing neuronal death, and confounding processes such as drug intoxication, poisoning, metabolic derangements, and hypothermia have been excluded.5,6 The neurologic examination must demonstrate coma, no brain-generated response to external stimuli, and absent brainstem reflexes, including response to painful stimuli above the neck, or other brainoriginating movements, such as seizures, decerebrate or decorticate posturing. Other physical findings include absent pupillary light reflex, pupils that are midposition or dilated (4 9 mm), absent corneal reflexes, absent oculovestibular reflexes (caloric responses), absent jaw jerk, absent gag, sucking, or rooting reflexes, absent cough with tracheal suctioning, and apnea as demonstrated by an apnea test.5,7 The number and the expertise of the examiners required to make a brain death varies by state and country.5,6 The examiner making the diagnosis of brain death should be familiar with the clinical criteria and comfortable in performing all aspects of the examination.8 Moreover, the examiner should be someone other than the treating physician and someone other than the physician involved in the recovery of organs for transplantation.9 11 The duration of observation required to determine brain death varies extensively among countries.11 A follow-up evaluation after 24 hours was initially required for brain death diagnosis in the United States, but subsequent requirements were made age dependent. A 48-hour evaluation interval is required for infants aged 7 days to 2 months, 24 hours for those older than 2 months to 1 year, and 12 hours for those between 1 and 18 years.5 However, rates of organ donation have been noted to decrease with longer intervals between examinations.12 Ancillary tests are required to diagnose brain death when clinical criteria cannot be applied and to supplement the clinical examination in young children. Tests of brain blood flow, especially those of brain perfusion, are the most reliable “stand alone” laboratory examinations when a clinical diagnosis is not possible.13 For patients with primary supratentorial or hypoxic brain injury aged 2 years or more, repeat clinical examinations or one complete examination combined with an ancillary test are equally accurate. Ancillary tests are rarely used by physicians based at the treating hospital (31.1%) but are frequently utilized by external care providers (93.4%). The risk of death due to permanent cardiac arrest before completion of the brain death examination has been shown to increase approximately sevenfold when a neurological or neurosurgical consultation with ancillary studies was not performed.6,11,13 Cerebral blood flow tests include four vessel cerebral angiography, transcranial Doppler, magnetic resonance angiography, computed tomographic angiography, and nuclear medicine radionuclide scanning.14 Electrophysiologic tests used in the diagnosis of brain death include electroencephalogram (EEG) and evoked potentials. Electrocerebral inactivity may be confirmed when a 30-minute good quality EEG recording shows complete electrocerebral silence, defined as no cerebral activity greater than 2 uV, having first ruled out the possible influence of sedative drugs, metabolic disorders, or hypothermia.15 It is essential to support the family of a patient with a progressively worsening severe acute brain injury,

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and to do this with the utmost understanding of the patient’s ultimate hopelessness for meaningful recovery. Any conversation should start with a clarification of the catastrophic nature of the illness and with establishing the “point of no return.” When brainstem reflexes are lost and the patient has become apneic, family members should be appropriately informed. Communicating with family members also necessarily involves a discussion regarding the potential suitability for organ donation,16 although the highest success rates for obtaining consent for organ donation are achieved by trained requestors whom are not involved with the medical care of the potential donor.17

3.2 DECEASED DONATION In 2012, 17,305 kidney transplants were performed in the United States, 11,535 of which were from deceased donors. 340 fewer kidney transplants were performed in 2012 than in 2011. The number of kidney transplants has remained relatively stable since 2005, paralleling a leveling off of the end stage renal disease (ESRD) incidence rate. The waiting list continues to grow, with a seven percent increase from 2011 to 2012, reaching 81,981 patients at the end of 2012.18 Rates of deceased donation increased slightly in 2011, to 22.4 donors per million population. Deceased donor transplant rates remained steady in 2011, at 2.5 per 100 patient years on dialysis19 and at 5.65 per 1000 deaths.18 Since 2005, deceased donation rates by race have been highest among Blacks, reaching 27% in 2011, compared to 9.3% and 8.4% among Native Americans and Asians. Perhaps more concerning than relatively unvarying donation rates is that an increasing number of kidneys recovered for transplant are discarded. The discard rate has increased steadily from 12.7% in 2002 to 17.9% in 2011. The percentage of expanded criteria donor (ECD) and intended dual kidneys recovered but not transplanted in the United States remains significantly high (42% and 20%, respectively).20 This is particularly striking when compared to the 8% overall kidney discard rate reported by the Eurotransplant Consortium.21 The most common donor-specific reasons for kidney discard after procurement were biopsy findings (37.3%), poor organ function (9.2%), and anatomic abnormalities (7.1%).22 The odds of kidney discard are 12 times higher when biopsy shows .20% glomerulosclerosis (GS) than if GS is ,5%.23 In a death-censored adjusted Cox model, Tanriover et al. demonstrated that GS 15% 50% was not associated with higher risk of allograft failure compared to a reference group with GS , 15%. Overall, GS does not appear to be an accurate histologic indicator of subsequent renal function.20 In the future, more uniform and inclusive biopsy report system (vessels, glomeruli, tubules, and interstitium) and a better understanding of the significance of various histopathologic findings will be necessary to reduce discard rates and increase transplant rates of recovered organs.20 Furthermore, in 2011, kidneys were not recovered from 9% of donors in whom at least one other organ was recovered for transplant, primarily due to poor organ function and donor medical history. The increasing rates of kidney discard and nonrecovery undoubtedly reflect a deceased donor pool that is clearly aging and has more associated risks for graft failure. Improvements in organ donation, utilization, and allocation are needed to maximize the benefits of transplant from an aging and relatively static donor pool.19

3.3 EXPANDING THE DONOR POOL The ongoing organ shortage crisis challenges the transplant community to maximize and optimize the use of kidneys from all consented deceased donors. The fact that the waiting list continues to grow in the face of a relatively unchanged donor pool requires an ongoing reappraisal of the limits of acceptability when considering whether or not a recovered kidney can or should be transplanted. The annual mortality of a patient on the waiting list is approximately 6% and as high 10% in diabetic candidates. When the risk of waitlist mortality is weighed against the mortality related to a potential transplant recipient’s age and other comorbidities, it is clear that the amount of time different patients can tolerate waiting for a kidney transplant is highly variable. More aggressive utilization of “marginal” kidneys takes into account that, in appropriately selected recipients, more timely transplantation and improved patient survival in exchange for decreased long-term graft survival may represent a worthwhile trade-off. The next several sections focus on various strategies which are being utilized in ongoing efforts to maximize the rates of recovery and transplantation of deceased donor kidneys.

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3.3.1 Expanded Criteria Donors Over the past two decades, there has been a shift toward increasing numbers of older donors and older recipients in kidney transplantation, with cerebrovascular events now the leading cause of brain death in deceased donation.24 The aging recipient and donor population have inevitably resulted in increased transplantation of kidneys from older donors. The value of transplanting such kidneys was previously questioned because of concerns over decreased graft survival and poorer predicted outcomes.25 27 In October 2007, The United Network of Organ Sharing (UNOS) defined the term “expanded criteria donor” (ECD) as a donor age 60 years and older or 50 59 years old with at least two of the following criteria: history of hypertension, terminal serum creatinine $ 1.5 mg/ dL, and cerebrovascular cause of death. This definition was derived from a Scientific Registry of Transplant Recipients (SRTR) retrospective analysis of primary deceased donor adult kidney transplant recipients which demonstrated that ECD kidneys had a 70% higher risk of graft failure compared to a reference group of kidneys from donors aged 10 to 39, without hypertension, cerebrovascular cause of death, or terminal serum creatinine 1.5 mg/ dL.25 27 Optimal use of ECD kidneys continues to be debated, although there is general agreement that these kidneys should be used to improve patient access to transplantation when life expectancy on dialysis is shorter than the expected waiting time for a kidney, particularly in older patients and diabetics.28 Although there are reports of inferior graft survival and poorer intermediate-term results, Stratta et al. have contended that ECD kidneys are defined by suboptimal nephron mass and that appropriate donor and recipient selection may optimize outcomes with ECD kidney transplantation.24 Transplantation of ECD kidneys into selected “low risk” and “low functional need” recipients, specifically older patients with low body mass index (BMI), and low immunologic risk, has achieved acceptable intermediate-term outcomes, with graft survival comparable to a group of concurrently transplanted standard criteria donor (SCD) kidneys. ECD kidney graft survival has improved with era, possibly due to introduction of mycophenolate and subsequent decreases in calcineurin inhibitor doses and target levels. Unfortunately, kidney quality and graft survival is highly variable within the ECD category, with some ECD kidneys having better functional outcomes and superior graft survival compared to SCD kidneys. Consequently, a continuous kidney donor risk index (KDRI) was proposed in 2009, combining donor and transplant variables to quantify graft failure risk.29 There was a considerable overlap in KDRI distribution according to ECD and SCD classification. The graded impact of KDRI on graft outcome is thought to provide a more useful decision-making tool compared to simply categorizing donors as ECD or SCD. KDRI forms the basis of the kidney donor profile index (KDPI), which is utilized to stratify deceased donor kidneys according to expected graft survival in the newly implemented kidney allocation system in the United States, discussed in more detail later in this chapter. KDPI includes 10 donor factors (age, height, weight, ethnicity, history of hypertension and diabetes, cause of death, serum creatinine level, hepatitis C status, and DCD), with lower scores associated with increased graft longevity. It is anticipated that use of KDPI rather than ECD criteria will facilitate matching expected graft survival with recipient survival, thereby optimizing allocation of graft life years.

3.3.2 Donation After Circulatory Death The increasing use of kidneys from controlled donation after circulatory death (DCD) donors has the potential to positively impact organ recovery and transplant rates. The United Kingdom, the Netherlands, and Belgium now have very successful DCD donor programs with 7.0 9.5 DCD donors per million population in 2013. The United States, Australia, Spain, and Croatia also have well-developed DCD programs with 2.1 3.8 DCD donors per million population. However, many countries have no or limited experience with DCD donors and would benefit from this important source of deceased donor kidneys.30 Although overall donation rates have not changed significantly in recent years, the percentage of transplants performed from donation after cardiac death (DCD) donors in the United States has increased steadily from 1.4% in 1998 to 15.8% in 2011.22 Compared with kidneys recovered from donation after brain death donors (DBD), DCD kidneys have a higher incidence of delayed graft function (DGF) and are more vulnerable to the detrimental effect of prolonged preservation time.30 DCD kidneys are subjected to variable periods of warm ischemia after withdrawal of life support, followed by declaration of death by cardiocirculatory arrest with subsequent organ procurement.31 Warm ischemia is known to be associated with acute tubular necrosis, irreversible cell damage, and reduced graft survival after kidney transplantation. Despite the warm ischemia associated with DCD donation, numerous studies have demonstrated comparable short- and intermediate-term graft survival rates between brain dead non-ECD kidneys and DCD non-ECD kidneys. DGF is more common in kidneys from DCD donors, with an incidence of 25% 90%.32 Older donor age, and more specifically ECD status, appears to adversely affect kidney graft survival. In a study by Farney et al., DCD-ECD kidney graft survival at 3 years was 48%

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compared to 79% for non-ECD-DCD kidney.32 It has been suggested that utilizing DCD-ECD kidneys as dual kidney transplants could potentially improve outcomes. Interestingly, several studies have shown that DGF does not have the same detrimental effect on graft survival after transplantation of DCD kidneys as it does after transplantation of DBD kidneys.33 35 Two different studies of machine preservation reported opposite conclusions regarding the efficacy of machine preservation in reducing the incidence of DGF after DCD kidney transplantation, with an incidence of DGF 50% in both studies.36,37 Early experience with extracorporeal support to reduce ischemic injury and DGF is promising, although application of this technology is limited to date.

3.3.3 Kidneys From Donors With Acute Kidney Injury Until relatively recently, kidneys from donors with acute kidney injury (AKI) were almost universally declined for transplantation because outcomes were expected to be poor. A landmark series by Anil Kumar et al. in 2006 compared the outcome of 55 kidneys transplanted from donors with AKI with 55 concurrent and matched recipients of SCD kidneys and 55 concurrent and matched recipients of ECD kidneys.38 AKI kidneys were accepted for transplantation from donors aged ,50 years with no history of kidney disease and a pretransplant kidney biopsy without evidence of significant chronic changes. Three-year patient and graft survival was 90% and 90% in the AKI group, 100% and 89% in the SCD group, and 83% and 66% in the ECD group. Rates of biopsy proven acute rejection were comparable among groups; however, chronic allograft nephropathy was more prevalent in the ECD group. Mean serum creatinine levels were 1.9, 1.9, and 2.2 mg/dL in the AKI, SCD, and ECD groups, respectively (SCD and AKI vs ECD, P5.04). This study demonstrated that transplantation of kidneys from selected donors with AKI provides comparable graft survival and function to non-AKI donors, despite a higher DGF rate, and that transplantation of kidneys from appropriately selected AKI donors may help expand the donor pool. In 2009, Kayler et al. reviewed SRTR data from 1995 to 2007 to study the outcome and utilization of kidneys from deceased donors with AKI.39 The relative risk for graft failure in ECD recipients significantly increased with increasing serum creatinine. Among potential SCD donors, elevated serum creatinine was identified as a strong independent risk factor for kidney discard. However, when kidney transplantation was performed, elevated donor terminal creatinine was not a risk factor for graft failure. This study clearly underscored the fact that potentially transplantable kidneys are being discarded on the basis of elevated serum creatinine, and that a more aggressive approach to transplanting kidneys from donors with terminal AKI may increase the number of deceased donor kidneys available for transplantation. Others studies have similarly reported good results with transplantation of kidneys from donors with AKI, with long-term graft survival rates and functional outcomes comparable to non-AKI kidneys despite a significantly higher incidence of DGF with AKIs kidneys.40 42

3.3.4 Dual Kidney Transplants The use of kidneys “marginal” or ECD donors is an appealing strategy to expand the pool of organs available for transplantation. Concerns over the limited life span of “marginal” kidneys have led some to perform dual kidney transplantation (DKT) based on the concept that poor long-term outcomes associated with ECD kidneys may be the consequence of a discrepancy between the functional nephron mass provided by the graft and the metabolic requirements of the recipient.43,44 Simultaneous transplantation of two kidneys into one recipient, with appropriate donor and recipient selection, could increase the transplanted nephron mass and could improve long-term function and graft survival compared to single kidney transplantation (SKT) from a “marginal” donor. In some cases, DKT might even produce acceptable outcomes with donor kidneys thought to be unsuitable for SKT, which would otherwise be discarded. Selection of optimal candidates for DKT is important because it is a more extensive procedure and is typically performed in elderly recipients who tend to have less physiologic reserve than younger recipients. Appropriate recipient selection is critical to achieving good outcomes with DKT. While it is possible to perform DKT in elderly recipients, it is important to select patients with adequate cardiac reserve and without extensive iliac artery atherosclerosis. Selecting patients with BMI less than 30 kg/m2 may be preferable from a technical standpoint and may also help improve functional outcomes by maximizing nephron mass in recipients with lower muscle mass and lower metabolic demand.43 Remuzzi et al. used a scoring system to determine criteria for DKT versus SKT. The authors reported excellent short- and long-term results after allocation of kidneys from donors .60 years of age based on a preimplant biopsy 12-point histologic scoring system proposed by the Dual Kidney Transplant Group that assesses vessels, glomeruli, tubules and interstitium. Their results suggest that the histologic evaluation of donor kidneys serves to reduce variability in predicting outcomes.45 Unfortunately, the absence of UNOS data

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on features other than GS limits the ability to validate the usefulness of histopathology in predicting outcomes. Several reports have described improved graft function or survival with the use of DKT rather than SKT. Criteria for choosing to perform DKT have generally included older donor age and one or more other parameters, such as preimplant kidney biopsy, donor estimated creatinine clearance, kidney weight, machine perfusion characteristics and length of preservation time.44,46,47 Klair et al., used SRTR data of de novo kidney transplant recipients of adult deceased donor kidneys from 1995 to 2010 to examine outcomes of SKT and DKT stratified by KDRI group # 1.4 (n 5 49,294), 1.41 1.8 (n 5 15,674), 1.81 2.2 (n 5 6523) and .2.2 (n 5 2791). They noticed that DKT of kidneys with KDRI .2.2 was associated with significantly better overall graft survival compared to SKT with KDRI .2.2. Moreover, DKT was associated with significantly decreased odds of DGF (top 2 KDRI categories) and significantly decreased odds of 1-year serum creatinine level .2 mg/dL (top 3 KDRI categories). Furthermore, among SKT and DKT from KDRI .2.2 there were 16.1 and 13.9 graft losses per 100 patient follow-up years, respectively. Additionally, there were no differences in overall patient survival with the use of DKT with kidneys from any KDRI category. However, there was a trend toward a survival benefit with each increasing category of KDRI. They concluded that KDRI . 2.2 is a useful discriminatory cut-off for the determination of graft survival benefit with the use of DKT. It is noteworthy that the benefit of increased graft years was less than half that of SKT from donors in the same KDRI range.43 Over the past decade, the surgical technique DKT has evolved from a bilateral iliac fossa approach (either intraperitoneal or extraperitoneal) to an extraperitoneal unilateral approach. This shortens operating time by limiting iliac artery and vein dissection to one side and preserves the contralateral iliac vessels should retransplantation become necessary in the future. Despite the increased duration and technical complexity of DKT, surgical complication rates have been shown to be comparable to those of SKT.48

3.3.5 Kidneys From Small Pediatric Donors There has been controversy regarding the optimal use of kidneys from young pediatric donors ever since the first pediatric en bloc kidney transplant into an adult was performed in 1972.49 Concerns regarding long-term graft survival and function, particularly with kidneys from donors younger than 12 months of age, as well as a general reluctance to separate pediatric kidneys for transplantation into two recipients, have historically limited use of these kidneys. Reports of an increased incidence of vascular and urinary complications and higher rates of acute cellular rejection and DGF are often cited as the primary deterrents to transplantation of small, pediatric, deceased donor kidneys into adults.50 However, several studies have suggested that, when initial complications are avoided, pediatric kidneys may be considered excellent rather than marginal quality grafts for transplantation into adults.51 53 Pediatric en bloc kidneys have double the number of nephrons, and several studies have shown better long-term function than living donor kidney transplants, presumably due to the increased functional glomerular reserve these kidneys possess.54 Sharma et al. reported excellent long-term outcomes after pediatric en bloc kidney transplantation from donors weighing less than or equal to 15 kg, which were comparable to results following living donor kidney transplant.55 Separation of en bloc pairs has been suggested when the renal allograft measures greater than 6 cm in length and the donor weight is greater than 14 kg. Other series have shown that kidneys from donors 1 to 3 years old and/or weighing 9 15 kg can be successfully transplanted en bloc, and that those from donors more than 3 years old and/or weighing more than 15 kg were best transplanted as single grafts.56 A study by Bresnahan et al. showed better results using en bloc kidneys from donors younger than 5 years old compared with single grafts from donors weighing more than 15 kg. However, recipients of previous transplants, prolonged ischemia time, black recipients, and those with a BMI greater than 24 kg/m2 were considered risk factors for poor results.57 A recent analysis of UNOS data demonstrated that long-term outcomes of pediatric en bloc kidney transplants (donor younger than 5 years of age) were superior to matched recipients of solitary pediatric kidney transplants (donor younger than 5 years of age) and SCD adult kidney recipients.58 The ongoing disparity between static supply and increasing demand for organs has prompted some surgeons to explore the limits of acceptability of SKT from small pediatric donors into two recipients. Despite a higher incidence of posttransplantation vascular and urological complications, long-term graft survival after single KT (in weight-matched pediatric donors and selected adult recipients) was comparable with that after SCD kidney transplantation.59 Laurence et al. constructed a decision analysis model to predict outcome in life years for patients with ESRD on the waiting list, depending on whether they received en bloc or solitary pediatric transplants.60 At all recipient ages, the projected life years of both recipients of a solitary transplant exceeded the projected life years of an en bloc kidney transplant. Only recipients of solitary kidney transplants from donors weighing less than 10 kg had an estimated net loss of life years. In a review of OPTN data, Sureshkumar et al. also found that the graft failure risk of solitary pediatric kidneys was

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consistently lower when the donor weight exceeded 10 kg.61 Some studies have shown that kidneys from small donors may be at increased risk for late graft failure if they are transplanted into large recipients, and therefore, the relative size of the donor and recipient should be taken into account.62 In conclusion, these studies indicate that more liberal transplantation of kidneys from pediatric donors may expand the donor pool. Solitary rather than en bloc transplantation of kidneys from donors weighing more than 10 kg offers more cumulative graft years and maximizes organ utilization without compromising outcomes.

3.3.6 Centers for Disease Control and Prevention High-Risk Kidneys The use of kidneys from donors designated by the Centers for Disease Control and Prevention (CDC) as being at higher risk for transmission of viral infections is being increasingly recognized as another alternative for expanding the donor pool. The risk of transplanting organs from such donors is the possibility of transmitting potentially life threatening viral infections, such as human immunodeficiency virus, hepatitis C, and hepatitis B, rather than the potential for decreased graft survival associated with “marginal” donors. Unfortunately, transplantation of kidneys from CDC high-risk donors remains controversial because of limited data on risks and outcomes. The reported incidence of viral transmission with CDC high-risk donors is actually quite low63,64 and may even be less than the risk of viral infection associated with long-term hemodialysis.65 Despite these facts, CDC high-risk donors remain underutilized because of physician and patient perception that the risk of viral transmission is greater than the data would indicate. Introduction of nucleic acid testing has significantly narrowed the window between the time of infection and detection, and recent broader implementation of this testing should further minimize the risks of viral transmission with transplantation. A recent, single center, retrospective study of 50 recipients of kidneys from CDC high-risk donors revealed no instances of seroconversion with nearly 1 year of follow-up.66 Donors in this study were younger and less like to be ECD. Willingness to accept a kidney from a CDC high-risk donor was associated with significantly shorter time on the wait list prior to transplantation. Education of transplant physicians, surgeons, and prospective transplant recipients regarding the actual risks and benefits associated with using kidneys from CDC high-risk donors is necessary so that informed decisions can be made and so that these potentially lifesaving organs are appropriately utilized.

3.3.7 New Kidney Allocation System in the United States After more than a decade of ongoing development and revision via a consensus driven process, a new kidney allocation system was implemented in the United States in December 2014. The major areas of concern with the previous allocation system that are addressed in the new system are as follows: (1) Some potentially transplantable kidneys were being discarded because of how donors were classified and how organs were offered. Although an increase in donation rates was obviously desirable, it was felt that more transplants could still be performed by making better use of existing organs. (2) There was no maximum life year benefit in the previous system, in which there were often significant mismatches between the projected longevity of kidneys and the expected survival of recipients. As a result, some patients with long expected survival who received less than ideal kidneys required retransplantation, thereby lowering the chances for others to receive a first transplant. (3) Access to transplantation was found to be highly variable among candidates. In many cases, highly sensitized patients were waiting much longer than average for a transplant. Several new policy changes in the new allocation system have been implemented to address these concerns, with the intent of enhancing recipient survival, making better use of available kidneys, and increasing transplant opportunities for highly sensitized patients.67 69 The key components of the system are: (1) KDPI and EPTS: The Kidney Donor profile Index is a formula that has been established to estimate the expected graft survival of a donor kidney. Estimated Posttransplant Survival (EPTS) is a second formula which is used to estimate the likely benefit a specific patient would derive from transplantation. The system provides consideration for the 20% of kidneys with the best KDPI (longest estimated graft survival) to the 20% of candidates estimated by EPTS to have the longest time to benefit from a kidney transplant. For the remaining 80% of candidates, organ allocation remains similar to the previous system unless the patient falls into one of the “hard-to-match” categories. KDPI provides more detailed information than previous classifications of SCD and ECD, and it is believed that a graded rather than binary assessment of expected graft survival will improve kidney utilization and increase transplant rates. (2) Blood type subgroup matching: Blood type B is relatively uncommon and is present in only about 16% of kidney transplant candidates, many of whom are ethnic minorities. Although patients with blood type B could receive kidneys from blood type

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O donors, this practice would reduce access to deceased donor kidneys for blood type O recipients who can only receive blood type O kidneys. It has been shown that donors with the A2 subtype of blood type A are compatible with blood type B recipients and provide good outcomes after kidney transplantation. In the new system, kidneys from donors with blood type A2 can be offered to blood type B candidates on a national basis in order to improve access and reduce waiting time for blood type B candidates. (3) Immune sensitivity matching: For many years, the kidney allocation system has offered some additional priority in the form of extra allocation points for candidates with a panel-reactive antibodies (PRA) of 80% or higher, since these patients tend to wait longer for transplant because of increased difficulty obtaining an organ from an HLA compatible donor. However, in the previous system, no extra points were awarded as PRA increased, nor were points given to sensitized patients with PRA ,80%. Based on the results of a time-to-kidney offer analysis according to PRA, the new system gives priority points to sensitized patients using a sliding scale, starting at a PRA of 20%. The most highly sensitized patients (PRA 98%, 99%, and 100%) receive significantly more priority than they did previously. It is expected that this will provide more equitable access to transplant for a group of patients with the longest waiting times as a result of compatibility obstacles. (4) Dialysis waiting time: In the previous system, the duration of time on the waiting list was the predominant factor in prioritization of organ offers. Whereas some patients have regular access to medical care and are promptly placed on the waiting list when they begin dialysis or have a glomerular filtration rate of ,20 mL/minute, other patients reach ESRD and may be on dialysis for many years prior to being placed on the waiting list. Since waiting time is a priority factor, patients who are listed late for a transplant will likely be on dialysis longer than patients listed at an earlier stage of renal failure. Many patients who are not listed promptly have socioeconomic disadvantages. Consequently, in the new allocation system, waiting time points begin when a candidate is placed on the waiting list and has a glomerular filtration rate or creatinine clearance # 20 mL/minute or has started dialysis. For candidates listed after starting dialysis, waiting time is backdated to the date of dialysis initiation.

3.4 CONCLUSION Ongoing efforts continue to expand the deceased donor kidney pool by maximizing organ donation and utilization as well as improving organ allocation. Ideally, these strategies should increase transplant rates, optimize life years gained from transplantation, and minimize the need for retransplantation. Despite the progress that has been made, the demand for kidney transplantation rapidly continues to outpace organ availability. Ongoing advances in our understanding of immunologic and nonimmunologic mechanisms of allograft failure and less reliance on nephrotoxic immunosuppression regimens are paramount to optimizing long-term graft survival in deceased donor transplantation. Increasing the number of living donor transplants performed via desensitization protocols, ABO incompatible transplantation, kidney paired exchange (discussed elsewhere in this book), and other novel strategies, will be critical in order to make more deceased donor kidneys available for candidates who do not have the opportunity to receive a living donor kidney. Tolerance induction, cell transplantation, bioartificial organ technology, and other advances in regenerative medicine continue to represent the frontiers of transplantation science, and may ultimately be the best hope for clinical solutions that will one day mitigate the widening disparity between organ supply and demand.

References 1. Wijdicks EF. The diagnosis of brain death. N Engl J Med 2001;344:1215 21. 2. Goudreau JL, Wijdicks EF, Emery SF. Complications during apnea testing in the determination of brain death: predisposing factors. Neurology 2000;55:1045 8. 3. Saposnik G, Bueri JA, Maurino J, Saizar R, Garretto NS. Spontaneous and reflex movements in brain death. Neurology 2000;54:221 3. 4. Wijdicks EF, Rabinstein AA, Manno EM, Atkinson JD. Pronouncing brain death: contemporary practice and safety of the apnea test. Neurology 2008;71:1240 4. 5. Practice parameters for determining brain death in adults (summary statement). The Quality Standards Subcommittee of the American Academy of Neurology. Neurology 1995;45:1012 4. 6. Wijdicks EF, Varelas PN, Gronseth GS, Greer DM. Evidence-based guideline update: determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2010;74:1911 18. 7. Citerio G, Murphy PG. Brain death: the European perspective. Semin Neurol 2015;35:139 44. 8. Booth CM, Boone RH, Tomlinson G, Detsky AS. Is this patient dead, vegetative, or severely neurologically impaired? Assessing outcome for comatose survivors of cardiac arrest. JAMA 2004;291:870 9. 9. Baumgartner H, Gerstenbrand F. Diagnosing brain death without a neurologist. BMJ 2002;324:1471 2.

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10. Shemie SD, Doig C, Dickens B, et al. Severe brain injury to neurological determination of death: Canadian forum recommendations. CMAJ 2006;174:S1 13. 11. Wijdicks EF. Brain death worldwide: accepted fact but no global consensus in diagnostic criteria. Neurology 2002;58:20 5. 12. Lustbader D, O’Hara D, Wijdicks EF, et al. Second brain death examination may negatively affect organ donation. Neurology 2011;76:119 24. 13. Hoffmann O, Masuhr F. Access to brain death diagnostics. Nervenarzt 2014;85:1573 81. 14. Ala TA, Kuhn MJ, Johnson AJ. A case meeting clinical brain death criteria with residual cerebral perfusion. Am J Neuroradiol 2006;27:1805 6. 15. Szurhaj W, Lamblin MD, Kaminska A, Sediri H. EEG guidelines in the diagnosis of brain death. Neurophysiol Clin 2015;45:97 104. 16. Kompanje EJ. Families and brain death. Semin Neurol 2015;35:169 73. 17. Rodrigue JR, Cornell DL, Howard RJ. Organ donation decision: comparison of donor and nondonor families. Am J Transplant 2006;6:190 8. 18. Saran R, Li Y, Robinson B, Ayanian J, et al. US Renal Data System 2014 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J Kidney Dis 2015;65:A7. 19. Collins AJ, Foley RN, Chavers B, et al. US Renal Data System 2013 Annual Data Report. Am J Kidney Dis 2014;63:A7. 20. Tanriover B, Mohan S, Cohen DJ, et al. Kidneys at higher risk of discard: expanding the role of dual kidney transplantation. Am J Transplant 2014;14:404 15. 21. Vinkers MT, Smits JM, Tieken IC, de Boer J, Ysebaert D, Rahmel AO. Kidney donation and transplantation in Eurotransplant 2006-2007: minimizing discard rates by using a rescue allocation policy. Prog Transplant 2009;19:365 70. 22. Matas AJ, Smith JM, Skeans MA, et al. OPTN/SRTR 2011 Annual Data Report: kidney. Am J Transplant 2013;13(Suppl. 1):11 46. 23. Sung RS, Christensen LL, Leichtman AB, et al. Determinants of discard of expanded criteria donor kidneys: impact of biopsy and machine perfusion. Am J Transplant 2008;8:783 92. 24. Stratta RJ, Rohr MS, Sundberg AK, et al. Intermediate-term outcomes with expanded criteria deceased donors in kidney transplantation: a spectrum or specter of quality? Ann Surg 2006;243:594 601. 25. Metzger RA, Delmonico FL, Feng S, Port FK, Wynn JJ, Merion RM. Expanded criteria donors for kidney transplantation. Am J Transplant 2003;3(Suppl. 4):114 25. 26. Ojo AO, Hanson JA, Meier-Kriesche H, et al. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant candidates. J Am Soc Nephrol 2001;12:589 97. 27. Port FK, Bragg-Gresham JL, Metzger RA, et al. Donor characteristics associated with reduced graft survival: an approach to expanding the pool of kidney donors. Transplantation 2002;74:1281 6. 28. Pascual J, Zamora J, Pirsch JD. A systematic review of kidney transplantation from expanded criteria donors. Am J Kidney Dis 2008;52:553 86. 29. Rao PS, Schaubel DE, Guidinger MK, et al. A comprehensive risk quantification score for deceased donor kidneys: the kidney donor risk index. Transplantation 2009;88:231 6. 30. Summers DM, Watson CJ, Pettigrew GJ, et al. Kidney donation after circulatory death (DCD): state of the art. Kidney Int 2015;88:241 9. 31. Abt PL, Fisher CA, Singhal AK. Donation after cardiac death in the US: history and use. J Am Coll Surg 2006;203:208 25. 32. Farney AC, Hines MH, al-Geizawi S, Rogers J, Stratta RJ. Lessons learned from a single center’s experience with 134 donation after cardiac death donor kidney transplants. J Am Coll Surg 2011;212:440 51. 33. Ojo AO, Wolfe RA, Held PJ, Port FK, Schmouder RL. Delayed graft function: risk factors and implications for renal allograft survival. Transplantation 1997;63:968 74. 34. Singh RP, Farney AC, Rogers J, et al. Kidney transplantation from donation after cardiac death donors: lack of impact of delayed graft function on post-transplant outcomes. Clin Transplant 2011;25:255 64. 35. Yarlagadda SG, Coca SG, Formica Jr. RN, Poggio ED, Parikh CR. Association between delayed graft function and allograft and patient survival: a systematic review and meta-analysis. Nephrol Dial Transplant 2009;24:1039 47. 36. Jochmans I, Moers C, Smits JM, et al. Machine perfusion versus cold storage for the preservation of kidneys donated after cardiac death: a multicenter, randomized, controlled trial. Ann Surg 2010;252:756 64. 37. Watson CJ, Wells AC, Roberts RJ, et al. Cold machine perfusion versus static cold storage of kidneys donated after cardiac death: a UK multicenter randomized controlled trial. Am J Transplant 2010;10:1991 9. 38. Anil Kumar MS, Khan SM, Jaglan S, et al. Successful transplantation of kidneys from deceased donors with acute renal failure: three-year results. Transplantation 2006;82:1640 5. 39. Kayler LK, Garzon P, Magliocca J, et al. Outcomes and utilization of kidneys from deceased donors with acute kidney injury. Am J Transplant 2009;9:367 73. 40. Greenstein SM, Moore N, McDonough P, Schechner R, Tellis V. Excellent outcome using “impaired” standard criteria donors with elevated serum creatinine. Clin Transplant 2008;22:630 3. 41. Lin NC, Yang AH, King KL, Wu TH, Yang WC, Loong CC. Results of kidney transplantation from high-terminal creatinine donors and the role of time-zero biopsy. Transplant Proc 2010;42:3382 6. 42. Molina M, Apaza J, Gonzalez Monte E, et al. Results of kidney transplantation from deceased donors with acute kidney injury. Transplant Proc 2015;47:42 4. 43. Klair T, Gregg A, Phair J, Kayler LK. Outcomes of adult dual kidney transplants by KDRI in the United States. Am J Transplant 2013;13:2433 40. 44. Nardo B, Bertelli R, Cavallari G, et al. Analysis of 80 dual-kidney transplantations: a multicenter experience. Transplant Proc 2011;43:1559 65. 45. Remuzzi G, Cravedi P, Perna A, et al. Long-term outcome of renal transplantation from older donors. N Engl J Med 2006;354:343 52. 46. Kayler LK, Mohanka R, Basu A, Shapiro R, Randhawa PS. Single versus dual renal transplantation from donors with significant arteriosclerosis on pre-implant biopsy. Clin Transplant 2009;23:525 31.

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47. Ruggenenti P, Perico N, Remuzzi G. Ways to boost kidney transplant viability: a real need for the best use of older donors. Am J Transplant 2006;6:2543 7. 48. Ekser B, Furian L, Broggiato A, et al. Technical aspects of unilateral dual kidney transplantation from expanded criteria donors: experience of 100 patients. Am J Transplant 2010;10:2000 7. 49. Meakins JL, Smith EJ, Alexander JW. En bloc transplantation of both kidneys from pediatric donors into adult patients. Surgery 1972;71:72 5. 50. Modlin C, Novick AC, Goormastic M, Hodge E, Mastrioanni B, Myles J. Long-term results with single pediatric donor kidney transplants in adult recipients. J Urol 1996;156:890 5. 51. Dharnidharka VR, Stevens G, Howard RJ. En-bloc kidney transplantation in the United states: an analysis of united network of organ sharing (UNOS) data from 1987 to 2003. Am J Transplant 2005;5:1513 17. 52. Merkel FK, Matalon TA, Brunner MC, et al. Is en bloc transplantation of small pediatric kidneys into adult recipients justified? Transplant Proc 1994;26:32 3. 53. Nghiem DD, Hsia S, Schlosser JD. Growth and function of en bloc infant kidney transplants: a preliminary study. J Urol 1995;153:326 9. 54. Sureshkumar KK, Reddy CS, Nghiem DD, Sandroni SE, Carpenter BJ. Superiority of pediatric en bloc renal allografts over living donor kidneys: a long-term functional study. Transplantation 2006;82:348 53. 55. Sharma A, Fisher RA, Cotterell AH, King AL, Maluf DG, Posner MP. En bloc kidney transplantation from pediatric donors: comparable outcomes with living donor kidney transplantation. Transplantation 2011;92:564 9. 56. Borboroglu PG, Foster 3rd CE, Philosophe B, et al. Solitary renal allografts from pediatric cadaver donors less than 2 years of age transplanted into adult recipients. Transplantation 2004;77:698 702. 57. Bresnahan BA, McBride MA, Cherikh WS, Hariharan S. Risk factors for renal allograft survival from pediatric cadaver donors: an analysis of united network for organ sharing data. Transplantation 2001;72:256 61. 58. Bhayana S, Kuo YF, Madan P, et al. Pediatric en bloc kidney transplantation to adult recipients: more than suboptimal? Transplantation 2010;90:248 54. 59. Sharma A, Ramanathan R, Behnke M, Fisher R, Posner M. Single pediatric kidney transplantation in adult recipients: comparable outcomes with standard-criteria deceased-donor kidney transplantation. Transplantation 2013;95:1354 9. 60. Laurence JM, Sandroussi C, Lam VW, Pleass HC, Eslick GD, Allen RD. Utilization of small pediatric donor kidneys: a decision analysis. Transplantation 2011;91:1110 13. 61. Sureshkumar KK, Patel AA, Arora S, Marcus RJ. When is it reasonable to split pediatric en bloc kidneys for transplantation into two adults? Transplant Proc 2010;42:3521 3. 62. Nakatani T, Uchida J, Yamazaki T, et al. Cadaveric renal transplantation from a non-heart-beating pediatric donor into adult recipients. Urol Int 2003;70:216 18. 63. Kucirka LM, Namuyinga R, Hanrahan C, Montgomery RA, Segev DL. Provider utilization of high-risk donor organs and nucleic acid testing: results of two national surveys. Am J Transplant 2009;9:1197 204. 64. Kucirka LM, Singer AL, Segev DL. High infectious risk donors: what are the risks and when are they too high? Curr Opin Organ Transplant 2011;16:256 61. 65. Freeman RB, Cohen JT. Transplantation risks and the real world: what does ‘high risk’ really mean? Am J Transplant 2009;9:23 30. 66. Lonze BE, Dagher NN, Liu M, et al. Outcomes of renal transplants from Centers for Disease Control and Prevention high-risk donors with prospective recipient viral testing: a single-center experience. Arch Surg 2011;146:1261 6. 67. Bray RA, Gebel HM. The new kidney allocation system (KAS) and the highly sensitized patient: expect the unexpected. Am J Transplant 2014;14:2917. 68. Friedewald JJ, Samana CJ, Kasiske BL, et al. The kidney allocation system. Surg Clin North Am 2013;93:1395 406. 69. Pondrom S. What you need to know about the new Kidney Allocation System. Am J Transplant 2014;14:1470.

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C H A P T E R

4 The Living Donor Andrea Pietrabissa, Luigi Pugliese, Massimo Abelli, Elena Ticozzelli and Teresa Rampino University of Pavia, Pavia, Italy

4.1 BACKGROUND The modern history of organ transplantation began on December 23, 1954, with the first identical-twin kidney transplantation. Previous attempts at transplanting a kidney in humans had invariably failed due to the immunological barrier, with little understanding of the rejection mechanism and no immunosuppressive drugs available. The medical and ethical issues behind the first live donation were raised and partially addressed by the pioneer kidney transplant team at Peter Bent Brigham Hospital in Boston, which comprised Drs. John P. Merrill (Head of Nephrology), J. Hartwell Harrison (Chief of Urology), Gustave Dammin (Pathologist-in-Chief), and Joseph E. Murray, the chief surgeon who was awarded the Nobel prize in 1990. In his autobiography, Dr. Murray recalls their awareness of being about to compromise the physician’s injunction to “do no harm,” and the difficulty of dealing with such an unprecedented situation, including the need to inform the patients and their family about the potential risks of an unknown procedure.1 At the same time, without the alternative of dialysis, not yet as effective as it is today, they were committed to attempting the transplant, as the patient was otherwise doomed to die. Apart from the commitment of the transplant team, it was also the determination of the donor twin to save his brother’s life that forced everybody towards the dawn of the new era. “On the eve of the operation,” Murray tells us, “the recipient twin wrote an urgent note to his brother: get out of here and go home.” The donor twin, in a return note, replied: “I am here and I am going to stay.” The success of the procedure demonstrated that organ transplantation could be lifesaving, despite the fact that at the time it was a solution only for those whose immune systems were identical (Fig. 4.1). Although many things have changed since 1954, and over one million patients have since been successfully transplanted, the unique circumstances of the live donor operation remains a challenge for the patients involved, their families, and transplant surgeons. Some of the original ethical issues of living donation are still under debate, while new ones have arisen along the way.2 The use of a kidney from a living donor represents the best possible option of treatment for most patients with end-stage chronic renal disease. Extensive evidence has now proven that live donor kidney transplantation is superior to dialysis and to deceased donor kidney transplantation, yielding longer graft and patient survival, better quality of life and higher cost-effectiveness.3,4 Relative to dialysis, the life expectancy of a transplanted patient, whether from a living or deceased donor, has been shown to be significantly longer, with the procedure also granting patients more control over their lifestyle. Apart from the freedom from the time spent on dialysis, a functioning transplant results in a better perception of health on the part of the patient and entails no dietary restrictions. With regard to transplants, the use of a live donor has many advantages over a deceased donor. The transplant procedure can be planned, which eliminates the need to be on a waiting list, and makes it possible to transplant patients before they start dialysis treatment—the so-called “pre-emptive transplantation.” Avoidance of dialysis is not only beneficial for the patient’s quality of life, but also prevents physical deterioration that can affect the results of a subsequent kidney transplant as well as the long-term survival of the graft. The possibility

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FIGURE 4.1 Dr. John P. Merrill (left) explains the workings of a then-new machine called an artificial kidney to the Herrick twins, after their successful kidney transplant. From http://www.kjonline.com/news/transplant-just-one-chapter-of-first-organ-donors-life_2011-01-01.html (Free use).

to schedule the transplant operations, both for the donor and the recipient, usually also means that the best surgical teams are employed, during daytime hours, thus minimizing the risk of technical failures due to lack of experience or fatigue. And in fact, the immediate results of a live donor kidney transplant are superior to that of a cadaveric graft. The delayed graft function, which occurs in 50% of cadaveric grafts, is seen in only 5% of live donor kidneys. The rejection rate in the immediate posttransplant period is also reduced after live donor transplantation. But what truly makes live donor kidney transplantation superior to transplantation from cadaveric kidneys is the resulting long-term graft survival. Ten years after the transplant, a cadaveric kidney has a 50% chance to still be functioning, whereas the same proportion of live donor kidneys will still be functioning 20 years after the transplant. And that number rises to 35 years in the case of an excellent genetic match between the donor and a sibling recipient. Obviously, these advantages have to be weighed against the risk run by the donor.5,6 Every surgery entails immediate risks, and the long-term risks related to the function of the remaining kidney, including the possibility of developing mono-kidney related diseases, must also be carefully considered.7 This applies even when selecting apparently healthy donor candidates. The recent appearance of altruistic donors,8 or Good Samaritan donors—complete strangers who donate an organ to an unknown recipient—poses new ethical questions as well on the practice of living organ donation. The rate of living kidney donation has increased worldwide since 1995, following the introduction of the laparoscopic technique by Ratner and Kavoussy.9 The new procedure, which replaced the previous lumbotomy incision, significantly reduced the surgical trauma to the donor, without compromising the quality of the graft. As such, it was effective in overcoming the medical barriers to living kidney donation, and elicited new interest on the part of surgeons and nephrologists. Several modifications of the original technique have subsequently been proposed,10,11 including the hand-assisted approach,12 the retroperitoneoscopic procedure,13 the roboticassisted technique,14 and the single-incision technique.15 In addition, in the attempt to further reduce the invasiveness of kidney procurement, a transvaginal delivery of the graft has been suggested in selected cases.16 Although in the last 5 years the figures have shown a decline in the rate of living kidney donation, for a number of reasons, more than one-third of kidney transplants performed in the United States still come from live donors. And new recommendations have recently been released to improve access to, and optimize the education and care of potential donors in order to push their numbers back up.17

4.2 DONOR SELECTION Nephrologists and transplant surgeons are challenged with the often-conflicting responsibility to preserve the health of individual donors while respecting their autonomy in deciding to donate. In April 2004, over 100 transplant surgeons and nephrologists met in Amsterdam to develop an international standard of care for the live donor.18 The Amsterdam Forum Guidelines state that prior to donation, the live kidney donor must receive a complete medical

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and psychosocial evaluation, and appropriate informed consent must be obtained. All donors must have standard tests performed to ensure that donating a kidney will not significantly affect their health, screening for the following conditions: hypertension, obesity, dyslipidemia, urine analysis for protein and blood, diabetes, stone disease malignancy, urinary tract infection, pulmonary and cardiovascular risk, alcohol and tobacco abuse. Living kidney donation guidelines have similarly been formulated by national transplantation associations worldwide, though significant variability is common with respect to donor age, body mass index (BMI), and hypertension.19 The overall donor outcome has proven to be excellent, leading to an extension of donor acceptance criteria in many transplant centers. In the United States, the vast majority of centers now accept donors with older age, vascular anomalies, or a BMI above 30 kg/m2 (in other words class I obesity). Donors with mild hypertension on a single-drug treatment, and women of childbearing age and an ASA of class 2 or higher are also increasingly being accepted as potential donors in Europe too.20 In 2014, the European Best Practice Guidelines group (EBPG) issued new guidelines on the evaluation and selection of kidney donors.21 Among the core recommendations, the group advised that the donor be evaluated by a physician who is not part of the transplant team and is not involved in the daily care of the recipient, as well as by a psychologist. It was also recommended that the simultaneous presence of more than one risk factor (hypertension, obesity, proteinuria, impaired glucose tolerance, hematuria) preclude donation. Under their guidelines, a BMI above 35 kg/m2 is considered a contraindication to donation, as is a diagnosis of diabetes mellitus. Old age in itself is not a contraindication to donating a kidney. As a consequence of such changes in the eligibility criteria for living kidney donation, it is possible that the long-term consequences of nephrectomy could pose new problems regarding donor safety. While it seems reasonable to accept in selected instances one of these extended criteria, a combination of two or more is likely to be high-risk for the donor and should be avoided. In general, any extended criteria donors should be referred to high-volume centers.22

4.3 SURGICAL TECHNIQUES Historically, donor nephrectomy began as an open technique, through a lumbotomy approach, defined as a 15 20 cm loin incision. Its associated prolonged convalescence and risk of long-term morbidity were likely disincentives to donate. In fact, several randomized trials have now shown there to be a shorter convalescence, less pain, and better quality of life after a laparoscopic donor nephrectomy when compared with the open technique.23 25 Nonetheless, a survey published in 2012, involving 12 European countries and 97 transplant centers, showed that 37 centers (39%) still use the open approach, with 31 employing the technique exclusively.20 Some of this conservatism may have to do with the newness of the laparoscopic approach; indeed, its adoption by transplant surgeons may initially lead to an increase in donor risk, potentially compromising the safety of an established procedure.7

4.3.1 Laparoscopic Technique The technique of the laparoscopic donor nephrectomy was first described in 1995 at the Johns Hopkins Medical Center.9 The basic steps have not changed since the original report, where the kidney was approached transperitoneally, and removed through a Pfannenstiel incision, thus providing a superior cosmetic result. The left kidney is usually preferred, in the absence of functional or anatomical barriers, due to the longer vein. It is recommended to over-hydrate the patient during the operation to overcome the depressive effect of CO2 pneumoperitoneum on renal perfusion. With the patient in the flank position and using 3 4 trocars, the left colon is reflected medially to expose the anterior aspect of the kidney. The hilum is dissected first, leaving the Gerota’s fascia and the retroperitoneal attachment intact to facilitate suspension of the kidney and ideal exposure of its vessels. The ureter is mobilized, paying attention to its delicate vascular supply, and is followed until it crosses the common iliac artery. Any “stripping” of the distal ureter should be avoided, as this will result in posttransplant urologic complications. Leaving the gonadal vein in situ does not seem to lead to increased ureteric complications, and can prevent postoperative testicular pain in the donor.26 The gonadal vein is followed to trace the left renal vein, which is then isolated from adventitial attachments. At that point, the left adrenal vein, the lumbar veins and the gonadal vein are divided. The use of clips to secure these vessels should be weighed carefully against the possibility that a clip on the renal vein might later interfere with the Endo GIA during the final steps of the nephrectomy. For this reason we prefer to ligate the venous collaterals on the renal vein side or use radio

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FIGURE 4.2 Operative setting of a live donor laparoscopic nephrectomy. Position of the three trocars and the Pfannenstiel incision.

frequency activated devices to control these relatively small vessels.27 The renal artery is exposed with a cautery hook dissection by dividing the lymphatic and sympathetic tissue that surrounds the vessel. Care must be taken to avoid injury to early branching of the artery, which is the most common cause of massive intraoperative bleeding and conversion.28 If the artery shows signs of vasospasm, topical papaverine will usually reverse it.29 Once the main renal vessels have been fully exposed, including polar arteries if present, the kidney is mobilized from its fatty attachments. The upper pole is the most demanding area to free, and one must be careful to preserve the left adrenal gland and not damage the renal artery, which can run very close to this structure. Visualization of the upper pole can be difficult, but this area can be reached with a dissecting instrument by directly pushing on the kidney capsule. Occasional superficial tears on the kidney might result from this maneuver. Once the full mobilization of the kidney is accomplished, a 7 10 cm Pfannenstiel incision is made for extraction, leaving the peritoneum intact (Fig. 4.2). A 15-cm specimen retrieval bag is inserted through a small opening in the peritoneum of the delivery incision and the kidney is preloaded, after division of the ureter and gonadal vessels, to improve the exposure of the renal vessels and reduce the warm ischemia time. Then an endovascular GIA is fired across the artery, followed by the vein. The use of a noncutting stapler (Endo-TA) can be considered in order to increase the length of the vessel, particularly that of the right renal vein. The bag is then closed and the peritoneum layer at the Pfannenstiel incision enlarged with finger traction to extract the kidney. The arterial and venous stumps are cut below the rows of staplers’ clips and the kidney is flushed on a back table with cold perfusion. Before division of the renal vessels, systemic heparin is generally administered, although its real value has recently come under question.30 The use of locking polymer clips for management of the renal hilum has been associated with major postoperative hemorrhage, which has occasionally resulted in donor death.31 33 The rationale for adopting clips to secure the main renal vessels lies in the desire to preserve as much artery length as possible, particularly when this vessel shows early branching; in such a case, indeed, the use of the endoGIA often results in two or more arteries being reimplanted, and is also more expensive.34 However, since 2005, there have been multiple reports of severe hemorrhage due to the slippage of polymer clips, to the point that a Class II recall was issued by the FDA in 2006 on the use of Hem-o-lok (Teleflex, Limerick, Pennsylvania, USA) polymer clips on the renal artery in laparoscopic donor nephrectomy. Nonetheless, clips continue to be used, posing an unjustified risk to the donor.35,36 Sufficient evidence has now been provided to support the exclusive use of transfixing methods to secure the renal artery during donor nephrectomy, through the use of either endovascular staplers or intracorporeal suturing. Stapler misfiring has also been reported, but this might partially be related to the use of metallic clips around the main renal vessels, a practice that should be avoided by using intracorporeal knot-tying, bipolar coagulation or radio frequency devices to secure the tributaries of the renal vein.

4.3.2 Hand-Assisted Technique Hand-assisted laparoscopic donor nephrectomy was introduced in 200137 to enhance the safety of the pure laparoscopic procedure. The hand-assisted technique (HALS) approach, in fact, has the theoretical advantage of

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offering direct finger control in case of intraoperative hemorrhage, helping to dissect the renal pedicle by providing optimal exposure and reducing the warm ischemia time, thanks to the quick extraction of the kidney, grasped by the intracorporeal hand. The hand-access device can be inserted through a Pfannenstiel incision. Some surgeons will consequently prefer to remove the right kidney, as the left (nondominant) hand can be ergonomically inserted through this incision. Alternatively, the assistant’s hand will be used when the left kidney is preferred. Other technical options entail the insertion of the hand-access device in the midline in the subxiphoid region or in the right subcostal area. These technical variations can result in poorer cosmetic outcomes. Comparisons of donor outcomes following HALS and pure laparoscopy have failed to show significant differences in intraoperative or early postoperative morbidity, leaving the choice between the two techniques to patient and surgeon preference. At this stage, approximately half of the transplant centers in the United States and two-thirds in Europe11 prefer HALS as opposed to pure laparoscopy. The use of HALS may indeed aid those unfamiliar with the advanced laparoscopic technique, providing a shorter learning curve.38

4.3.3 Retroperitoneoscopic Technique A posterior approach to the kidney via both pure laparoscopy and HALS has recently been reported.39,40 Avoiding entry into the peritoneal cavity can prevent potential postoperative complications, such as intestinal occlusion secondary to adhesions or internal hernia, and limits the occurrence of injury to the colon and spleen. However, the small working space reduces visibility, particularly when suction is used to clean the field of vision. In addition, extraction of the kidney is achieved through a high-flank incision, which reduces the cosmetic advantage of the laparoscopic approach. This technique is less commonly performed, also because transplant surgeons are more familiar with the transperitoneal approach to control the renal vascular pedicle. The retroperitoneoscopic technique proves particularly useful when the donor has previously undergone major abdominal surgery and is therefore likely to have multiple adhesions that might limit the exposure of the kidney.

4.3.4 Mini-Open Nephrectomy Some centers, fearing the potential morbidity of laparoscopy, have modified the open donor nephrectomy technique in the attempt to achieve some of the benefits associated with the minimally-invasive approach, while mitigating the risks.41 The mini-open nephrectomy is performed extraperitoneally through a 6 10 cm high-flank incision, external to the rectus muscle. Specialized sets of long, curved surgical instruments and retractors are occasionally used to facilitate dissection in the limited working space. The technical steps do not differ from those of a standard open nephrectomy.42 45 It has obvious limitations when performed in obese donors.

4.3.5 Single-Site Technique Recent technical advances have focused on further reducing the morbidity of laparoscopic surgery and improving cosmesis. Single-access surgery has been extensively adopted for cholecystectomy, but also for advanced procedures including colorectal surgery and solid organ removal. The “scarless” philosophy of this technical variation calls for performing surgery through a single opening, typically located at the umbilicus, where a natural scar is already present. A single-site donor nephrectomy was first reported by Gill in 2009.46 Procuring a viable renal allograft with current single-access technology poses a clear technical challenge, which limits its application to selected donors who meet specific anatomical criteria. Additionally, the potential benefit of a no-scar approach should carefully be weighed against the ensuing risk of incisional hernia. In other procedures, no advantage in postoperative pain could be seen when comparing this technique to full laparoscopy, and even the cosmetic advantage was questioned.47 New technical improvements will have to be developed, likely with the incorporation of robotics, before single-access or possibly transvaginal donor procurement may be considered as safe alternatives to standard laparoscopy (Fig. 4.3).

4.3.6 Transvaginal Extraction and NOTES Despite significant interest in NOTES (Natural Orifices Transluminal Endoscopic Surgery), its application to kidney donor procedures is currently limited to the extraction of the graft as the final step of a laparoscopic procedure (Hybrid NOTES).48 The technique was first reported by Montgomery,49 who proved its feasibility in a

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FIGURE 4.3 Operative set-up for single-access robotic surgery. Reproduced with permission from A. Pietrabissa.

hysterectomized donor. Later, the procedure was shown to be reproducible in the presence of a normal uterus.50 Alcaraz and his team from Barcelona have performed the largest series of transvaginal kidney extractions in living donors.16 When comparing the outcomes of their first 20 patients to what is expected with the conventional laparoscopic technique, no difference was noted in operative time, blood loss, or length of hospital stay, neither was any sexual dysfunction observed after donation. The presence of a distensible and elastic vagina is now a prerequisite to be eligible for the procedure, as well as the absence of varicosity of the uterine vessels, which was the cause of severe bleeding in one patient. A transvaginal trocar can be employed at the beginning of the operation to assist in retracting the colon and exposing the kidney; it should be placed in the midline to avoid damage to the uterine vessels, followed by digital tearing of the vaginal wall shortly after/just before graft extraction. The principal advantage of transvaginal extraction is the avoidance of the 5 10 cm Pfannenstiel incision to deliver the kidney. While the cosmetic benefit seems evident, a clear reduction in postoperative pain perception remains uncertain, since most donors require little or no analgesic even with the conventional laparoscopic approach. At this stage, perhaps it is an illusion to hope for further containment of postoperative pain as a consequence of technical refinement. The possibility of a true NOTES donor nephrectomy, performed completely through a transvaginal route, without the assistance of instruments inserted through abdominal trocars, is only theoretical. New technology has to be developed to overcome the challenge of controlling the instruments and optics that must travel in a parallel path from the deep pelvis to the upper pole of the kidney. Perhaps this will become possible only with the employment of flexible robotic systems, capable of separating the physical challenge from the resulting ergonomic problems. Early prototypes of robotic single-site platforms have proven effective for basic transumbilical procedures, such as cholecystectomy and simple hysterectomy; however, their use for NOTES operations has not yet been reported.

4.3.7 Use of Robotic Technology The robotic da Vinci Surgical System has been used in almost every area of abdominal surgery, including living kidney donation. The rationale of adding the cost of the robot to an already expensive procedure is to further minimize the associated risk for the donor. The possibility of more efficient suturing, the three-dimensional high-definition view, and the dexterity provided by wristed instruments with seven degrees of freedom51 can all potentially enhance the safety of the nephrectomy. In fact, the majority of conversions during laparoscopic live donor nephrectomies have been associated with intraoperative bleeding, resulting from arterial and venous tearing during dissection. With the endo-wristed robotic instruments, which allow for a more gentle approach to the renal vascular pedicle, there is the possibility to reach and dissect posterior branches of the main vessels with little trauma to the surrounding tissue. This may in turn reduce the risk of intraoperative bleeding, and should it occur, the easy placement of vascular sutures can limit its consequences. Suturing the tributaries of the renal vein with transfixion stitches, instead of clipping, prevents possible misfiring of the endoGIA during the final division of the renal vessels. Both a pure laparoscopic as well as a HALS technique have been proposed with the aid of robotic technology.52 During the final steps of the procedure, which entail endoGIA division of the renal pedicle and extraction

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of the kidney through the suprapubic incision, the robot is usually undocked and the procedure is resumed as in conventional laparoscopy. No evidence has been provided to date that the use of the da Vinci Surgical System is capable of reducing donor morbidity. A very large series of patients will have to be entered in a prospective study for that to be shown.

4.4 OUTCOME AND COMPLICATIONS OF THE SURGERY FOR THE DONOR There are good reasons for the donor surgeon to have a poor night’s sleep before a scheduled donor nephrectomy. The first live donor procurement was in fact nearly a misadventure. Retired transplant surgeon Nicholas L. Tilney, in his memoirs,53 recalls how the vascular clamp on the short arterial stump of Ronald Herrick—the first identical-twin donor—slipped off, and the surgeon, Dr. J.H. Harrison, managed to control the heavy bleeding. The patient’s recovery was uneventful, and the rest is history. Living donor nephrectomy raises the question of how to weigh the surgeon’s imperative to do no harm against patients’ individual choice to put themselves at risk in order to benefit others. Donor mortality can never be completely eliminated, and surgeons caring for donors must always do their best to mitigate this risk.54 In general, the 90-day risk of death following live donor nephrectomy is considered to be 3.1 per 10,000 donors (about one death every 3000 donors).55 This figure is more or less equivalent to the risk of dying in a car accident within any given 12-month period and, as such, seems to be acceptable for the public. Notably, at least eight donor deaths have occurred in the era of laparoscopic procurement, all related to the use of clips to secure the renal artery or vein.56 Most of these fatal hemorrhages occurred following closure of the surgical incisions, in the recovery room or in the surgical ward, meaning that the surgeon was apparently satisfied with the final hemostasis achieved in the operative field. The hemorrhage was therefore caused by a late slippage of the clips, minutes or hours after their placement.28 An additional unspecified number of serious, though nonfatal, hemorrhagic complications have also occurred following the use of nontransfixing methods to secure the renal vascular pedicle. The safest way to secure the renal artery and vein appears to be the use of staplers, either endoGIA or endoTA, should the surgeon need to preserve a longer segment of these vessels. This recommendation has been stressed by several journal articles, and was recently circulated by the American Society of Organ Transplantation to its members and US transplant centers.35 In general, major postoperative complications, i.e., Clavien grade 3 or higher, have been reported to occur in between 2.9%7 and 5.8%57 of donors. These complications include nonfatal hemorrhage, injury to the spleen or pancreas, perforation of the colon or small bowel, and postoperative intestinal occlusion. The most common complication of donor nephrectomy is infection of the extraction wound, which can lead to the late development of an incisional hernia. Although some physiologic changes inevitably occur in donors after nephrectomy, overall these do not result in significant long-term morbidity or a shorter life expectancy, when compared with nondonors. Gestational hypertension and preeclampsia are however more likely to be diagnosed in kidney donors than in matched nondonor controls.58 Information on this potential risk should be included in clinical practice guidelines, and donors of childbearing age should be informed accordingly. The most significant potential risk for donors may be the progressive deterioration of renal function. In the general non-Black population, the lifetime probability of end-stage renal disease (ESRD) is about 3%.59 The risk for a live donor to develop ESRD, and therefore require a kidney transplant, is surprisingly not any higher; however, following donation, ESRD tends to appear about 10 years earlier. To date, there have been about 325 living kidney donors who have been put on the US deceased donor kidney waiting list.60 Diabetes causes more postdonation ESRD than all other renal diseases combined. For the donor, maintaining normal body weight postdonation will therefore reduce this risk and help preserve renal function. Yearly checks of donor renal function, blood glucose levels and blood pressure are recommended to allow for early detection and possible early treatment of common conditions (such as hypertension or diabetes) capable of deteriorating the function of the residual kidney.

4.5 LIFE EXPECTANCY OF THE DONOR Two long-term studies analyzing outcomes of kidney donors were published between 2009 and today.6,61 One of them, following 80,000 live kidney donors dating back to 1994, found donor survival to be similar to that of

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the general control population, matched for age, sex, and race. However, it would be reasonable to anticipate some potential risk of reduced survival for the donor when more accurate prospective analyses are performed on the current donor population. Indeed, the typical living kidney donor of the 1990s was significantly different from the donors that are accepted today.62,63 In light of the increasing incidence of diabetes in the general population, it is possible that more donors will eventually develop progressive loss of renal function in the decades to come, even if the absolute increase in the 15-year incidence of ESRD from donation was recently reported to be below 0.5%.64 In addition, today’s donors are likely to be older, heavier, and have higher blood pressure than 20 years ago. Most donor programs around the world no longer have an upper age limit, and controlled hypertension and moderate obesity (BMI between 30 and 35) are not seen as absolute contraindications to donation. These factors will possibly have some bearing on the future life expectancy of current donors. Several studies have shown that donors are willing to accept higher risks for those close to them.2 Clearly, this raises the ethical issue of autonomy, and whether donors, once properly informed, should be allowed to accept added risk or not. The threshold for acceptable risk may also vary between transplant centers and between clinicians. In the end, donor consent and autonomy are necessary, but not sufficient on their own to proceed with kidney donation.18,65 Donor autonomy, in other words, cannot overrule medical judgment and decision-making. Accordingly, the British Transplantation Society guidelines2 state that when a fully informed donor wishes to proceed with a nephrectomy that involves risks of mortality or morbidity greater than what the transplant team finds acceptable, they are under no obligation to proceed. Referral for a second opinion would be appropriate in this case.

References 1. Murray JE. Surgery of the soul: reflections on a curious career. USA: Boston Medical Library. Science History Publications; 2012. 2. Maple NH, Hadjianastassiou V, Jones R, et al. Understanding risk in living donor nephrectomy. J Med Ethics 2010;36:142 7. 3. Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Eng J Med 1999;341:1725 30. 4. Hariharan S, Johnson CP, Bresnahan BA, et al. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Eng J Med 2000;342:605 12. 5. Glannon W. Underestimating the risk in living kidney donation. J Med Ethics 2008;34:127 8. 6. Ibrahim HN, Foley R, Tan L, et al. Long-term consequences of kidney donation. N Eng J Med 2009;29:459 69. 7. Mjoen G, Oyen O, Holdaas H, et al. Morbidity and mortality in 1022 consecutive living donor nephrectomies: benefits of a living donor registry. Transplantation 2009;88:1273 9. 8. Ferrari P, Weimar W, Johnson RJ, et al. Kidney paired donation: principles, protocols and programs. Nephrol Dial Transplant 2014;7:309. 9. Ratner LE, Ciseck LJ, Moore RG, et al. Laparoscopic live donor nephrectomy. Transplantation 1995;15:1047 9. 10. Piros L, Langer RM. Laparoscopic donor nephrectomy technique. Curr Opin Organ Transplant 2012;17:401 5. 11. Banga N, Nicol D. Techniques in laparoscopic donor nephrectomy. BJUI 2012;110:1368 73. 12. Rajab A, Pelletier RP. The safety of hand-assisted laparoscopic living donor nephrectomy: the Ohio State University experience with 1500 cases. Clin Transplant 2015;29:204 10. 13. Tokodai K, Takayama T, Amada N, et al. Retroperitoneoscopic living donor nephrectomy: short learning curve and our original hybrid technique. Urology 2013;82:1054 8. 14. Tzvetanov I, Bejarano-Pineda L, Giulianotti PC, et al. State of the art of robotic surgery in organ transplantation. World J Surg 2013;37:2791 9. 15. Desai MM, Berger AK, Brandina R, et al. Laparoendoscopic single-site surgery: initial hundred patients. Urology 2009;74:805 12. 16. Alcaraz A, Musquera M, Peri L, et al. Feasibility of transvaginal natural orifice translumenal endoscopic surgery-assisted living donor nephrectomy: is kidney vaginal delivery the approach of the future?. Eur Urol 2011;59:1019 25. 17. La Pointe Rudow D, Hays R, Baliga P, et al. Consensus conference on best practices in live kidney donation: recommendations to optimize education, access, and care. Am J Transplant 2015;15:914 22. 18. Delmonico F. Council of the transplantation society. A report of the Amsterdam forum on the care of the live kidney donor: data and medical guidelines. Transplantation 2005;79:S53 66. 19. Arunachalam C, Garrues M, Biggins F, et al. Assessment of living kidney donors and adherence to national live donor guidelines in the UK. Nephrol Dial Transplant 2013;28:1952 60. 20. Klop WJK, Dols LFC, Kok NFM, et al. Attitudes among surgeons towards live-donor nephrectomy: a European update. Transplantation 2012;94:263 8. 21. Abramowicz D, Chocat P, Claas FHJ, et al. European renal best practice guideline on kidney donor and recipient evaluation and perioperative care. Nephrol Dial Transplant 2014;0:1 8. 22. Ahmadi AR, Lafranca JA, Claessens LA, et al. Shifting paradigms in eligibility criteria for live kidney donation: a systematic review. Kidney Int 2015;87:31 45. 23. Kok NF, Lind MY, Hansson BM, et al. Comparison of laparoscopic and mini incision open donor nephrectomy: single blind, randomised controlled clinical trial. MBJ 2006;333:221. 24. Andersen MH, Mathisen L, Oyen O, et al. Postoperative pain and convalescence in living kidney donors-laparoscopic versus open donor nephrectomy: a randomized study. Am J Transplant 2006;333:221.

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25. Oyen O, Andersen M, Mathisen L, et al. Laparoscopic versus open living-donor nephrectomy: experiences from a prospective, randomized, singe-center study focusing on donor safety. Transplantation 2005;79:1236. 26. Shirodkar SP, Gorin MA, Sageshima J, et al. Technical modification for laparoscopic donor nephrectomy to minimize testicular pain: a complication with significant morbidity. Am J Transplant 2011;11:1031 4. 27. Pietrabissa A, Boggi U, Moretto C, et al. Laparoscopic and hand-assisted laparoscopic live donor nephrectomy. Semin Laparosc Surg 2001;8:161 7. 28. Janki S, Verver D, Klop KWJ, et al. Vascular management during live donor nephrectomy: an online survey among transplant surgeons. Am J Transplant 2015;15(6):1701 7. 29. Zacherl J, Bock S, Feussner H, et al. Periarterial application of papaverine during laparoscopic donor nephrectomy improves early graft function after kidney transplantation in pigs. Surg Endosc 2004;18:417 20. 30. Friedersdorff F, Wolff I, Deger S, et al. No need for systemic heparinization during laparoscopic donor nephrectomy with short warm ischemia time. World J Urol 2011;29:561 6. 31. Friedman AL, Peters TG, Jones KW, et al. Fatal and nonfatal hemorrhagic complications of living kidney donation. Ann Surg 2006;243:126 30. 32. Baumert H, Ballaro A, Arroyo C, et al. The use of polymer (Hem-o-lok) clips for management of the renal hilum during laparoscopic nephrectomy. Eur Urol 2006;49:816 19. 33. Goh YS, Cheong PS, Lata R, et al. A necessary step toward kidney donor safety: the transition from locking polymer clips to transfixion techniques in laparoscopic donor nephrectomy. Transplant Proc 2014;46:310 13. 34. Jellison FC, Shah SK, Mashni Jr JW, et al. Vessel length following laparoscopic donor nephrectomy: impact of vascular ligation technique on allograft vessel length. J Endourol 2008;22:973 7. 35. Friedman AL, Peters TG, Ratner LE. Regulatory failure contributing to deaths of live kidney donors. Am J Transplant 2012;12:829 34. 36. Simforoosh N, Sarhangnejad R, Basiri A, et al. Vascular clips are safe and a great cost-effective technique for arterial and venous control in laparoscopic nephrectomy: single-center experience with 1834 laparoscopic nephrectomies. J Endourol 2012;26:1009 12. 37. Tokuda N, Nakamura M, Tanaka M, et al. Hand-assisted laparoscopic live donor nephrectomy using newly produced LAP DISC: initial three cases. J Endourol 2001;15:571 4. 38. Gaston KE, Moore DT, Pruthi RS. Hand-assisted laparoscopic nephrectomy: prospective evaluation of the learning curve. J Urol 2004;171:63 7. 39. Kohei N, Kazuya O, Hirai T, et al. Retroperitoneoscopic living donor nephrectomy: experience of 425 cases at a single center. J Endourol 2010;24:1783 7. 40. Gjertsen H, Sandberg AK, Wadstro¨m J, et al. Introduction of hand-assisted retroperitoneoscopic living donor nephrectomy at Karolinska University Hospital Huddinge. Transplant Proc 2006;38:2644 5. 41. Antcliffe D, Nanidis TG, Darzi AW, et al. A meta-analysis of mini-open versus standard open and laparoscopic living donor nephrectomy. Transplant Int 2009;22:463 74. 42. Kim SI, Rha KH, Lee JH, et al. Favorable outcomes among recipients of living-donor nephrectomy using video-assisted minilaparotomy. Transplantation 2004;77:1725 8. 43. Shenoy S, Lowell JA, Ramachandran V, et al. The ideal living donor nephrectomy “mini-nephrectomy” through a posterior transcostal approach. J Am Coll Surg 2002;194:240 6. 44. Mital D, Coogan CL, Jensik SC. Microinvasive donor nephrectomy. Transplant Proc 2003;35:835 7. 45. Redman JF. An anterior extraperitoneal incision for donor nephrectomy that spares the rectus abdominis muscle and anterior abdominal wall nerves. J Urol 2000;164:1898 900. 46. Desai MM, Berger AK, Brandina R, et al. Laparoendoscopic single-site surgery: initial hundred patients. Urology 2009;74:805 12. 47. Marks JM, Phillips MS, Tacchino R, et al. Single-incision laparoscopic cholecystectomy is associated with improved cosmesis scoring at the cost of significantly higher hernia rates: 1-year results of a prospective randomized, multicenter, single-blinded trial of traditional multiport laparoscopic cholecystectomy vs single-incision laparoscopic cholecystectomy. J Am Coll Surg 2013;216:1037 47. 48. Kaouk JH, Khalifeh A, Laydner H, et al. Transvaginal hybrid natural orifice transluminal surgery robotic donor nephrectomy: first clinical application. Urology 2012;80:1171 5. 49. Allaf ME, Singer A, Shen W, et al. Laparoscopic live donor nephrectomy with vaginal extraction: initial report. Am J Transplant 2010;10:1473 7. 50. Pietrabissa A, Abelli M, Spinillo A, et al. Robotic-assisted laparoscopic donor nephrectomy with transvaginal extraction of the kidney. Am J Transplant 2010;10:2708 11. 51. Petros FG, Angell JE, Abaza R. Outcomes of robotic nephrectomy including highest complexity cases: largest series to date and literature review. Urology 2015;86:1352 8. 52. Giacomoni A, Di Sandro S, Lauterio A, et al. Evolution of robotic nephrectomy for living donation: from hand-assisted to totally robotic technique. Int J Med Robot 2014;10:286 93. 53. Tilney NL. Transplant: from myth to reality. New Heaven: Yale University Press; 2003. 54. Morrissey PE, Monaco AP. Living kidney donation: evolution and technical aspects of donor nephrectomy. Surg Clin North Am 2006;86:1219 35. 55. Segev DL, Muzaale AD, Caffo BS, et al. Perioperative mortality and long-term survival following live kidney donation. JAMA 2010;10:959 66. 56. Dekel Y, Mor E. Hem-o-lok clip dislodgment causing death of the donor after laparoscopic living donor nephrectomy. Transplantation 2008;86:887. 57. Richstone L, Seideman C, Baldinger L, et al. Conversion during laparoscopic surgery: frequency, indications and risk factors. J Urol 2008;180:855 9. 58. Garg AX, McArthur E, Lentine KL. Gestational hypertension and preeclampsia in living kidney donors. Donor Nephrectomy Outcomes Research (DONOR) Network. N Engl J Med 2015;372:1469 70.

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59. Steiner RW, Ix JH, Rifkin DE, et al. Estimating risks of de novo kidney diseases after living kidney donation. Am J Transplant 2014;14:538 44. 60. Ross LF. Living kidney donors and ESRD. Am J Kidney Dis 2015;30:S0272-6386(15)00539-9. 61. Muzaale AD, Massie AB, Wang MC, et al. Risk of end-stage renal disease following live kidney donation. JAMA 2014;311:579 86. 62. Reese PP, Bloom RD, Feldman HI, et al. Mortality and cardiovascular disease among older live kidney donors. Am J Transplant 2014;14:1853 61. 63. Tong A, Chapman JR, Wong G, et al. Living kidney donor assessment: challenges, uncertainties and controversies among transplant nephrologists and surgeons. Am J Transplant 2013;13:2912 23. 64. Lam NN, Lentine KL, Garg AX. End-stage renal disease risk in live kidney donors: what have we learned from two recent studies? Curr Opin Nephrol Hypertens 2014;23:592 6. 65. Ethics Committee of the Transplantation Society. The consensus statement of the Amsterdam Forum on the Care of the Live Kidney Donor. Transplantation 2004;78:491 2.

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C H A P T E R

5 Criteria for Kidney Allocation in the United States Linda Ohler George Washington University Transplant Institute, Washington, DC, United States

5.1 INTRODUCTION: HISTORY OF KIDNEY ALLOCATION As solid organ transplantation developed in the United States, there initially was no oversight or organizational structure for identifying suitable donors for recipients with end organ diseases. Early in the 20th century there were reports of organs being transplanted from corpses and animals in Russia, France, and the United States, but without success beyond a few weeks.1 Between 1951 and 1953, Dr. David Hume and his colleagues reported transplantation of kidneys from deceased donors who had succumbed to cardiac death. There were no brain death laws at that time. Aside from cortisone, there were no immunosuppressive medications and the longterm outcomes of these kidney transplants were poor. Dr. Hume reported that, “ACTH and Cortisone did not appear to exert any pronounced beneficial effect on the survival of human renal transplants.”2 Dr. Joseph Murray performed the first successful kidney transplant in the United States in 1954. The transplant was performed between identical twins and immunosuppression was not an issue in this case. The recipient survived for 8 years and his twin brother survived 56 years.1 Based on the early reported outcomes of this case several other successful transplants occurred between identical twins. In 1962, the first successful deceased donor kidney transplant was also performed by Dr. Murray and his colleagues in Boston.3 Because there was no structured organ allocation system in the early days of transplantation, deceased donors were arranged by surgeons and nurses who would call hospitals and ask if there were any potential donors whose kidneys could be used for patients with end stage renal disease. In 1969, Drs. Hume and Amos founded the South Eastern Organ Procurement Foundation (SEOPF) in Richmond, Virginia, which was one of seven organ procurement organizations funded by the Federal Government.4 Originally known as the South Eastern Regional Organ Procurement Program (SEROPP), the name was changed in 1975 to SEOPF. The goal of this organization was to improve transplant outcomes through matching and sharing of kidneys for transplantation. In 1976 SEOPF developed a computer system they called the United Network for Organ Sharing. This new system for communication was made available for any transplant center in the United States who wished to register their patients and match them with potential kidney donors.4 In 1984 Congress passed the National Organ Transplant Act (NOTA). This new law (PL 98-507) prohibited the sale of organs, established grants for organ procurement organizations, and called for a national system of organ sharing.5 In preparation for passage of NOTA, a committee was formed between staff at SEOPF and members of the American Society of Transplant Surgeons (ASTS) to write the articles of incorporation of UNOS and establish it as a 501c3.4 This was in preparation for the newly formed 501c3 to apply for the contract with the United States Department of Health and Human Services (HHS) that would implement NOTA. HHS granted the contract to UNOS, which it has held for the past 30 years. With this contract the OPTN has provided the United States with policies for allocation of each organ transplanted, a system for organ placement, a process for data collection, and public and professional education regarding organ transplantation. The OPTN, under the direction and

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administration of UNOS, has coordinated close to 500,000 deceased donor transplants. Since 1986 UNOS has grown considerably from the original staff of five to a current staff of more than 300. In 1985, the information technology (IT) department for UNOS consisted of one person and a 32-bit microprocessor. By 2014 the IT department at UNOS had grown to more than 130 personnel.6 Currently UNOS has 22 Committees, which are composed of transplant professionals in the community. These committees develop policies to provide equitable organ allocation and to ensure patient safety.6 The UNOS Board of Directors is the governing body that oversees policy development. Each organ system has a committee such as the Kidney Committee, Thoracic Committee, Liver Committee, etc. Also part of NOTA, the OPTN required a process and program for data analysis which is performed by the Scientific Registry for Transplant Recipients (SRTR). This contract is currently held by the Minneapolis Medical Research Foundation in Minnesota. OPTN contracts are renewed every 3 years. NOTA was also charged with creating a multidisciplinary task force that would examine organ donation and transplantation in the United States. This resulted in the Uniform Anatomical Gift Act, which established organ and tissue donation as the right of any individual 18 years old and over.5

5.2 METHODS OF EARLY ORGAN SHARING The Omnibus Budget Reconciliation Act of 1986 required that all transplant centers and organ procurement organizations become part of the OPTN. This was the beginning of establishing a national system for organ allocation and sharing. Prior to implementation of the Omnibus Budget Reconciliation Act, the sharing of kidneys for transplantation was accomplished on a personal phone call basis, or with twins. Once liver and heart transplantation began demonstrating signs of success, the need for deceased organs became more prevalent and the necessity for a defined, protocol driven national system became even more evident. In the early 1970s procurement groups were beginning to form around transplant centers that were performing organ transplants such as kidney, liver, and heart. For example, there was SEOPF in Richmond, Virginia; the Regional Organ Procurement Agency (ROPA) in Los Angeles, California and in Pennsylvania there was the Delaware Valley Transplant Program in Philadelphia and the Pittsburgh Transplant Foundation.4,7,8 Public education was a mission of each of the procurement programs developing across the United States as the need for deceased organs increased. Public awareness and education became a critical part of increasing organ donation. In 1982, Don Denny of Pittsburgh collaborated with NATCO, the organization of transplant professionals, to help organize the allocation system through a phone communication system at 412-24-ALERT. This system provided the names and locations of patients in need of an organ transplant. The recording was updated daily. Other attempts were being made to systemize organ allocation. Howard Nathan and his colleagues in Philadelphia were developing a national system to rank the severity of illness of patients in need of a transplanted organ. The higher the number, the more critical the need was for a transplant. A rank of 4 was the highest and indicated the most urgent need. A status 3 patient was hospitalized but not in critical condition.7 Status 2 and 1 patients were not hospitalized. This was the first attempt at developing a status system for allocation of organs in the United States. As patient outcomes were improving for each organ transplanted, the demand for organs increased steadily. Patients began requesting transplantation as an option for their end organ disease processes. Successes were now being reported in lung transplantation and the need for a national system increased even more.9

5.3 EVOLUTION OF NATIONAL ORGAN ALLOCATION SYSTEMS With the transplant community call for increases in deceased organs for transplantation and for equitable distribution of the organs, UNOS, the OPTN contractor, set out to develop consensus-based policies through the committee structures within UNOS. Committees were focused not only on ways to increase organ donation but also to organize systems for ranking potential transplant recipients on the basis of critical need and outcomes that evaluated graft and patient survival. The initial Kidney Allocation System (KAS) was based on observations that long-term graft survival was best in a national sharing of 6 antigen matched or zero antigen mismatched kidneys.5 When this matching system did not result in a candidate for a deceased donor kidney, the kidney could then be allocated locally based on ABO compatibility and a point system that included length of waiting time on the UNOS list, presensitization, and quality of HLA matching.5 In this allocation scheme, children were given preference and received extra points based on their age at the time of UNOS listing.5

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A positive final crossmatch for any potential recipient would create the need for the organ to be allocated to the next potential candidate. Allocation was applied to transplant hospitals within OPO in which the donor was identified. If no potential recipients matched with the specific donor, then allocation was expanded to the region. With still no suitable candidates, the kidney was then offered nationally. While this system was originally planned to be a national allocation system for all deceased donor kidneys, local jurisdictions developed exceptions or variances that were also known as Alternative Local Units (ALUs) with special sharing agreements. These variances may have constituted subsections of an OPO, an entire state, or UNOS regions. They were considered alternative point systems within an OPO, state, or region and gave greater weight to factors within the allocation system such as time on the waiting list, presensitization, or any other strategy deemed important for that region or state. Some OPOs gave special consideration for diabetic candidates who required a kidney pancreas transplant, allowing a donor kidney to be allocated with a recovered pancreas from the same deceased donor. Any variance or exception to the allocation policy required ratification by the UNOS Board of Directors and required periodic review to ensure the variance continued to be patient driven rather than transplant center driven.5 During this time UNOS committees overseeing allocation of hearts, livers, and lungs began developing allocation systems prioritizing patients based on the medical condition of the candidate; however, no priority system was allocated to kidney candidates since all had access to dialysis.

5.3.1 Allocation Criteria: Concerns for Equitable Distribution In 1991, a report from the HHS Inspector General’s office described what many in the transplant community had expressed concerns about. This report quantified the issue with data stating that Blacks on the UNOS kidney list were waiting 13.9 months compared with 7.6 months for Caucasians.10 The report also noted that highly sensitized patients waited almost 4 times as long for a kidney transplant as other patients. In addition to these disparities, it was noted that geography also entered into the waiting times with some patients waiting over 18 months at centers while others waited less than 6 months.10 As we learned more about HLA tissue typing, trends began to demonstrate the disparity in using 6 antigen matching and zero antigen mismatching. It was reported that Blacks received only 22% of deceased donor kidneys in 1990 while 31% of those waiting for a suitable donor kidney were Black.10 Kasiske et al.11 noted the frequencies of ABO blood groups and HLA antigens are two factors that can impact on the rate of transplanting Blacks on the kidney transplant list. For instance, twice as many Blacks have ABO Blood type B as compared to Caucasians. Because ABO compatibility is a requirement for organ allocation, those with blood type B must wait for a kidney from a blood type B donor. Racial differences among HLA antigens also influence matching donors and potential recipients. The majority of 6 antigen HLA matching has been reported to be among those from within the same race. These facts have influenced the long waiting periods for Blacks on the transplant list. Gaston et al. advised in 1993 that, “if racial equity in renal transplantation was to be achieved, alternative allocation strategies must be formulated that address the interests of all potential recipients.”12 The point system had been added in an attempt to correct inequities for patients who were difficult to match due to race and high levels of preformed antibody. Starzl et al.13 had demonstrated the use of the point system in 1986 with a cohort of 270 deceased kidney donors at the University of Pittsburgh. A stratification system was set up in a computer using wait time, antigen matching, preformed antibodies, and medical urgency which was defined as exhausted access sites for dialysis patients. Logistic practicality was also included in the stratification system and was defined as the ease and rapidity with which a transplant could be performed. This factor considered ischemic time of the donor and availability of the candidate in terms of close proximity to the transplant center.12 Of the 253 kidney transplant recipients who met the study’s selection criteria, 247 kidneys were transplanted into recipients with the highest point score. The conclusion was that the use of a point system provided a more objective system for kidney allocation.12 In 1993 The California Transplant Donor Network (CTDN) received a variance that allowed local kidney allocation based solely on waiting time. There were no considerations for HLA typing during this 6-year study that included 1301 locally allocated kidneys. This cohort was compared to 37,858 concurrent kidney transplants performed nationally with allocation based on HLA matching. Interestingly there was no difference in the outcomes between the groups at 1, 3, 5, and 10 years posttransplant. The local kidney recipients within this OPO area had less HLA matching but shorter ischemic times.14 The authors concluded that a kidney allocation scheme that does not include points for HLA matching makes distribution more equitable among minorities.14

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Studies continued to demonstrate the pros and cons of current allocation systems and to call for more equitable distribution of kidneys. Issues of geography were often thought to be a result of the variances within OPOs and transplant centers. Many of the OPOs and transplant centers with variances studied those variances to determine if the variance impacted on overall outcomes that addressed factors such as race, ABO, HLA matching and highly sensitized patients.

5.3.2 Strategies to Increase Equity Over the past several years the OPTN/UNOS Kidney Transplantation Committee has worked diligently to develop what are thought to be more equitable changes to the KAS. Several strategies were considered in an attempt to provide eligible candidates with the most equitable distribution of kidneys for transplantation. Factors reviewed as part of this transition to a new system included geography, ABO, and degree of sensitization. Considerations for this new process for kidney allocation was being planned and restructured for 6 years before it was formalized and released to the transplant community for comment on February 16, 2011.15 The comment period was opened until April 1, 2011. During this period more than 260 comments were received including those from professional groups such as the National Kidney Foundation, American Society of Transplantation, the ASTS, and the American Society of Nephrology. Each group provided feedback and recommendations for additional changes. The major concerns at that time were about the potential for age discrimination and lack of changes to geographical boundaries for kidney distribution. Changes have been made in the kidney allocation policy over the years and include such changes summarized in Table 5.1. In 2003 the OPTN Board of Directors charged the Kidney Transplantation Committee with reviewing the current allocation system for limitations and developing improvements. In the process two public forums took place in Dallas, Texas (2007) and St. Louis (2009) whereby recommendations for improvement were received with some incorporated into the new KAS. A concept document was released for public comment in 2011 and in 2013 the OPTN Board of Directors approved the revised KAS. This new system went into effect on December 4, 2014. TABLE 5.1 Major Changes in Kidney Allocation Criteria 1989 2014 Year

Policy/Criteria Changes

1989

Points added for sensitized candidates

1995

Points added for waiting time

1996

Points assigned for living donors who develop end stage renal disease

1998

Points added for pediatric candidates

2003

HLA-B matching points eliminated Kidney candidates begin to accrue waiting time in inactive status

2004

Prioritized donors aged ,35 years to pediatric candidates after 0 mismatch, high CPRA, prior living donors and before paybacks

2009

Eliminated 0 mismatch for nonsensitized adults

2009

Change from PRA to Calculated PRA (CPRA)

2014

Use of Kidney Donor Profile Index (KDPI) to estimate deceased donor kidney’s expected survival (eliminates classifications of standard or expanded criteria donors)

2014

Accrual of waiting time for kidney transplantation determined by dialysis start date rather than date of listing for transplant or for those not on dialysis, accrual time begins on the date when GFR is documented to be less than or equal to 20 mL

2014

Eliminates payback system

2014

Prioritizes pediatric kidney transplant candidates to deceased donor kidneys with KDPI ,35%

2014

Eliminates regional variances in organ allocation

2014

Increases priority for sensitized patients

2014

Allows allocation of A2/A2B to B blood types to increase access to deceased donor kidneys

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The previous KAS was highly reliant on a candidate’s time on the waiting list. The new KAS addresses three major concerns about the current allocation system for kidneys: waste of usable kidneys, longevity matching, and inequities to access.15,16 Each of these concerns is discussed below. In developing a new allocation system, two ethical issues were considered: Equity and Utility. Utility is addressed in the new allocation system with the focus on improving outcomes. Equity is addressed with the focus on changes that improve access to kidney transplantation.17 The goals of the new allocation system have been planned to provide a more accurate estimate of graft and recipient outcomes by promoting posttransplant kidney function for kidney candidates with the longest potential survival. It is believed this improvement in matching will reduce differences based on racial/ethnic minority groups, pediatric candidates, and sensitized patients awaiting a suitable kidney donor.17

5.3.3 Waste or Discarding Usable Kidneys Waste or discarding usable kidneys has been a concern of the current allocation system because discard rates of kidneys have been higher than acceptable. Some discards have been related to high risk or extended criteria donors (ECD) but some standard criteria donor (SCD) kidneys have also been reported to have been discarded. In an attempt to decrease the discard of potentially usable kidneys, the new KAS offers kidneys with a Kidney Donor Profile Index (KDPI) of .85% to a wider geographic area. The use of KDPI in this situation has the potential to increase allocation of kidneys. The terms SCD, ECD, and Donation after Cardiac Death (DCD) will be replaced with the KDPI system that assesses donor risk index more accurately. In this new KAS program, kidneys at risk for discard could be offered as a Dual Kidney Transplant (DKT). Dual kidney transplantation allows the transplantation of both donor kidneys into a single recipient under certain circumstances such as older recipients. According to UNOS policy organ procurement organizations must allocate one kidney to one candidate unless the donor has at least two of the following criteria18: • • • • •

Donor age .60 Donor creatinine clearance ,65 mL/minute on admission Rising serum creatinine .2.5 mg/dL Donor comorbidities such as hypertension and diabetes Adverse renal histopathology

It has been reported that the use of two marginal or compromised kidneys result in more functioning nephrons as would be found in a single ideal kidney. Thus, use of the DKT may actually enhance transplant options and decrease the discard rate in the United States. Notably, the discard rate of organs in Europe was reported in one study as only 7.5% due to use of a rescue allocation policy that included more liberal donor criteria.19 In the United States it has been reported that over half of the expanded criteria donor kidneys have been discarded.20 The most recent data describes a 13% discard rate for organs recovered in the United States.21 With the new KAS use of the KDPI it is hoped this discard rate will decrease.

5.3.4 Inefficiencies in the Previous Allocation Systems Another concern that the new KAS policy addresses is the inefficiencies in the previous systems in terms of long-term patient and graft survival. Longevity matching can be achieved in the new KAS through the use of two scoring systems: The KDPI and the Estimated Posttransplant Survival (EPTS) Score. With the new KDPI, an estimate can be calculated for a deceased donor kidney’s quality and expected length of survival.18 Risk factors included in the calculations present clinicians with a Kidney Donor Risk Index (KDRI). Once the KDRI is calculated, the score is mapped from a relative risk scale to a cumulative percentage scale known as the KDPI.22 Factors for the calculation include the following clinical parameters and demographic considerations: • • • • • • •

Donor age Height and weight of the donor Ethnicity History of hypertension History of diabetes Cause of death Serum creatinine

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5. CRITERIA FOR KIDNEY ALLOCATION IN THE UNITED STATES

• Anti-HCV • Donor meets DCD criteria A higher KDPI percentage is associated with lower donor kidney quality whereas a lower KDPI percentage is associated with a high donor kidney quality.22 This scoring system helps to ensure the best quality donor kidneys are allocated to recipients who are likely to have a corresponding longevity rate. Longevity can be calculated for kidney transplant candidates using EPTS, which is a score developed to predict long-term outcomes in transplant recipients. The EPTS score is calculated for all adult candidates on the waiting list and can range from 0% to 100%. Calculations are based on 4 candidate factors23: • • • •

Time on dialysis Diabetes status Prior solid organ transplant Age of the candidate

A listed kidney transplant candidate with an EPTS score of 20% or less will be prioritized for kidneys from donors with KDPI scores of 20% or less before other candidates at local, regional, or national levels.23 An EPTS score of 20% estimates that a candidate is likely to survive longer than 80% of other recipients nationally. The EPTS score is not stagnant. It changes as the age of the candidate increases and the length of time on dialysis increases. Exceptions to the EPTS/KDPI system include candidates who are listed for multiorgan transplants, highly sensitized candidates and pediatric transplant candidates. Transplant programs must obtain informed consent from candidates who decided to accept donors with high KDPI scores of greater than 85%.

5.3.5 Overcoming Inequities of Access to Transplantation Much of the concern over allocation throughout the 50 plus years of kidney transplantation in the United States has surrounded the issue of access to transplantation. The new KAS system addresses this concern through the ABO system by allowing the A2/A2B donors to be allocated to blood type B candidates. Blood type B is most commonly seen in the Black race. In many parts of the United States candidates with blood group B wait longer than other ABO groups. Thus, finding a solution to this inequity required some investigation into the ABO subtypes. Because blood group A has many subtypes, it was determined that A1 and A2 can be less reactive than other subtypes, thus allowing non-A recipients to have successful kidney transplants from A2 donors. This strategy has been used successfully with both B and O recipients and has led to a reduction in waiting time for kidney patients.17,24,25 Candidates must be screened to determine that they have a low anti-A antibody titer that is acceptable for transplantation. Candidates must also sign a consent stating they have received education on the A2/A2B to B transplants and agree to participate in this process.

5.3.6 Accrual of Wait Time The new KAS allows candidates to accrue wait time based on the start date of dialysis.17,24 This requires source documentation of the start date with the use of form CMS 2728 to ensure accuracy of the dialysis start date entered into UNet. Thus, at the time a dialysis patient is registered on the UNOS list for transplantation, the candidate receives credit for time on dialysis. A patient who started dialysis 4 months prior to being listed will already have 120 days of accrued time at the time of UNOS registration. A patient who started dialysis 2 years prior to being registered with UNOS will receive approximately 730 days of wait time. Patients who are not on dialysis may be listed preemptively with the use of their documented glomerular filtration rate (GFR) of 20 mL or less. Any time a patient is listed for transplantation with UNOS, source documentation of the selection criteria used by the transplant team to list the candidate must be documented in the patient’s chart. In addition, source documentation must also be available demonstrating the start date of dialysis or the patient’s GFR at the time of listing. Preemptive listing for kidney transplantation is considered a best practice. Preemptively registered patients accrue time based on the date of listing in UNet. Accrual time for preemptive listing begins on the day of listing as opposed to the date of GFR testing. Pediatric candidates for kidney transplantation will also receive credit for their time on dialysis prior to being registered with UNOS. Thus the child’s dialysis start date is factored into accrual time on the wait list when registered for a kidney transplant with UNOS.26

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5.3.7 Sensitized Candidates The Calculated Panel of Reactive Antibodies or cPRA is being used in the new KAS to prioritize patients.26,27 When unacceptable antigens are identified by the HLA laboratory for a specific transplant candidate, the antigens are entered into the UNOS computer calculator. An established formula is used to calculate the cPRA using the unacceptable values that were entered. The cPRA is used to assess the number of incompatible donors for the candidate. If, at any time, additional unacceptable antigens are entered, the system automatically recalculates the cPRA value. Sensitized candidates with a cPRA value of 80% or higher receive points in the new KAS system.17 A cPRA score of 98% 100% must be reviewed and signed by the HLA laboratory director and the candidate’s transplant physician or surgeon to ensure the unacceptable antigens have been carefully assessed and documented in the patient’s medical record.26 The intent of this prioritization for sensitized patients in the new allocation system was to improve overall posttransplant survival and to improve access for highly sensitized patients. However, concerns have been expressed that this prioritization of highly sensitized patients does not decrease the risk for rejections and potential poor outcomes in this population.24,28 One problem identified is the fact that HLA DPB and HLA DQA antigens were not included in the simulation performed by the SRTR;28 Bray et al. found that the majority of candidates with cPRA .98% possessed antibodies against these two antigens. Prior to the new allocation system assigning priority to sensitized candidates, most individuals with cPRA .98% had prolonged wait times and a higher incidence of death while waiting for a suitable donor organ.29 With the new system these candidates have the highest priority for local, regional, and national sharing.26,28 Kucheryavaya et al. have reported that only 51% of HLA laboratories are reporting deceased donor DPB.30 It is unknown how many HLA laboratories are testing for DQA in deceased donors. With the majority of highly sensitized candidates exhibiting HLA, DPB, and DQA antibodies and more than half of deceased donors not being tested for these antigens, there is a high probability that there will be a high rate of positive crossmatches between these candidates and their respective donors.28 A recommendation is being made for mandatory testing of DPB and DQA for all deceased donors to help alleviate this identified impediment to equalizing the allocation of kidneys to highly sensitized transplant candidates.28

5.3.8 Additional Changes to the KAS System The payback system has been eliminated in the new KAS system. The payback system was implemented in the early 1990s with OPTN/UNOS Policy 3.5.5 for OPOs that receive a kidney from another OPO based on a zero antigen mismatch to payback a kidney of the same blood type to the national pool. It was found that payback kidneys had more cold ischemic times and a higher risk for delayed graft function. Therefore, the policy and practice have been eliminated.31 Variances have been eliminated as well. However, two variances were incorporated into the new KAS. The first variance is a committee-sponsored variance that allows for back-dating of dialysis time prior to listing patients for transplantation, and the other variance allows for A2 and A2B kidneys to be offered to patients with blood type B.32 Both variances were part of the plan to equalize distribution and allocation of kidneys.

5.4 CONCLUSIONS The new Kidney Allocation went into effect on December 4, 2014. Outcomes of the changes are being evaluated. The UNOS Kidney Allocation Committee spent considerable time and applied much thought and consideration to their plans to equalize the allocation of kidneys to disadvantaged candidates such as those with reported disparities in geography, race, and those who are highly sensitized from previous transplants, pregnancies, or blood transfusions. One unintended consequence has been identified within the highly sensitized population. Attempts are being made to address the problem by requiring HLA, DPB, and DQA on deceased donors. We will not know the full impact on the new system for a few years as data is collected in each of the areas where changes have been made. Initially, the system has certainly made significant strides in making changes to meet the needs of many candidates awaiting kidney transplantation.

References 1. Tilney Nicholas L. Transplant: from myth to reality. New Haven, CT: Yale University Press; 2003. 2. Hume DM, Merrill JP, Miller BF, Thorn G. Experiences with renal homotransplantations in the human: a report of 9 cases. J Clin Invest 1955;34(2):327 82.

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3. Merrill JP, Murray JE, Takacs FJ, Hager EB, Wilson RE, Dammin GJ. Successful transplantation of a kidney from a human cadaver. JAMA 1963;185:347 53. 4. Transplantation contributions: organ procurement and transplantation. ,http://johncmcdonald.org/transplantation-procurement.html. (accessed 24.05.15). 5. Neylan JF, Sayegh MH, Coffman TM, et al. The allocation of cadaver kidneys for transplantation in the United States: consensus and controversy. J Am Soc Nephrol 1999;10:2237 43. 6. UNOS Membership Network: committees. ,http://www.unos.org/donation/index.php?topic=network. (accessed 24.05.15). 7. Ohler L. Courage and character leaders and legends: an interview with Howard Nathan. Prog Transplant 2012;22(1):4 6. 8. Ohler L. Pacesetters and pathfinders: an interview with Barbara Schulman. Prog Transplant 2015;25(1):4 5. 9. Trulock EP, Egan TM, Kouchoukos NT, et al. Single lung transplantation for severe chronic obstructive pulmonary disease, Washington University Lung Transplant Group. Chest 1989;96(4):738 42. 10. Kusserow RP. The distribution of organs for transplantation: expectations and practices. ,https://oig.hhs.gov/oei/reports/oei-01-8900550.pdf. (accessed 30.05.15). 11. Kasiske BL, Neylan JF, Riggio RR, et al. The effect of race on access and outcome in transplantation. New Engl J Med 1991;324:302 7. 12. Gaston RS, Ayers I, Dooley LG, Diethelm AG. Racial equity in renal transplantation: the disparate impact of HLA based allocation. JAMA 1993;270(11):1352 6. 13. Starzl TE, Hakala TR, Tzakis A. A multifactorial system for equitable selection of cadaver kidney recipients. JAMA 1987;257:3073 5. 14. Hirose K, Cherikh WS, Tomlanovich S, et al. Allocating kidneys without points for HLA matching distributes organs more equitably without adversely affecting outcomes. Am J Transplant 2006;6(Suppl. s2):140 World Transplant Congress Abstract 221. 15. Ladin K, Hanto D. Rational rationing or discrimination: balancing equity and efficiency considerations in kidney allocation. Am J Transplant 2011;11:2317 21. 16. OPTN/UNOS Kidney Transplantation Committee Report to the Board of Directors. ,http://optn.transplant.hrsa.gov/converge/ CommitteeReports/board_main_KidneyTransplantationCommittee_7_1_2011_10_38.pdf. (accessed 31.05.15). 17. Friedewald JJ, Samana CJ, Kasiske BL, Israni AK, Stewart D, Cherikh W, et al. The kidney allocation system. Surg Clin North Am 2013;93:1395 406. 18. UNOS Policy 8.6 Double Kidney Allocation. ,http://optn.transplant.hrsa.gov/ContentDocuments/OPTN_Policies.pdf. (accessed 5.07.15). 19. Vinkers MT, Smits JM, Tieken IC, et al. Kidney donation and transplantation in Eurotransplant 2006-2007: minimizing discard rates by using a rescue allocation policy. Prog Transplant 2009;19(4):365 70. 20. Tanriover B, Mohan S, Cohen DJ, Radhakrishnan J, et al. Kidneys at higher risk for discard: expanding the role of dual kidney transplantation. Am J Transplant 2014;14:404 15. 21. Israni AK, Zaun DA, Rosendale JD, Snyder JJ, Kasiske BL. OPTN/SRTR 2013 annual data report: deceased organ donation. Am J Transplant 2015;15(Suppl. 2):1 13 ,http://dx.doi.org/10.1111ajt.13202. 22. A guide to calculating and interpreting Kidney Donor Profile Index. ,http://optn.transplant.hrsa.gov/ContentDocuments/ Guide_to_Calculating_Interpreting_KDPI.pdf. (accessed 31.05.15). 23. Organ Procurement and Transplantation Network. Estimated Post Transplant Survival Calculator (EPTS). ,http://optn.transplant.hrsa. gov/converge/resources/allocationcalculators.asp?index=82. (accessed 5.07.15). 24. Israni AK, Salkowski N, Gustafson S, Snyder JJ, Friedewald JJ, Formica RN, et al. New National allocation policy for deceased donor kidneys in the United States and possible effects on patient outcomes. J Am Soc Nephrol 2013;25:1842 8. 25. Hurst FP, Sajjad I, Elster EA, et al. Transplantation of A2 kidneys into B and O recipients leads to reduction in waiting time: USRDS experience. Transplantation 2010;89(110):1396 402. 26. UNOS Policy 8. Kidney Allocation. ,http://optn.transplant.hrsa.gov/ContentDocuments/OPTN_Policies.pdf. (accessed 5.07.15). 27. CPRA and Its Importance in organ Transplantation. ,https://www.unos.org/docs/CPRA_Patients.pdf. (accessed 31.05.15). 28. Bray RA, Brannon P, Breitenbach C, Bryan C, et al. The new OPTN kidney allocation policy: potential for inequitable access among highly sensitized patients. Am J Transplant 2015;15(1):284 5. 29. Bray R, Gebel HM. The new Kidney Allocation System (KAS) and the highly sensitized patient: expect the unexpected (Letter to the Editor). Am J Transplant 2014;14:2917. 30. Kucheryavaya A, Tyan D, Boyle G, Kiger D, et al. A substantial increase in reporting of HLA DPB typing of deceased donors in the U.S. Am J Transplant 2014;14:590. 31. American Society of Nephrology. Improvements to the kidney allocation system. What does it mean to eliminate the payback system? ,https://www.asn-online.org/policy/webdocs/deceased_donor.pdf. (accessed 5.05.15). 32. Organ Procurement and Transplantation Network. Information for OPOs preparing for new kidney allocation system. ,http://optn. transplant.hrsa.gov/news/information-for-opos-preparing-for-new-kidney-allocation-system/. (accessed 5.07.15).

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C H A P T E R

6 Strategies to Increase the Donor Pool Michael A. Rees1,2 and David E. Fumo1,2 1

University of Toledo Medical Center, Toledo, OH, United States 2Alliance for Paired Donation, Perrysburg, OH, United States

6.1 BACKGROUND For those with end-stage renal disease (ESRD), renal transplantation is not only more cost-effective, but it also provides an average of 10 extra years of life compared to dialysis.1 Unfortunately, the number of patients requiring a kidney transplant far exceeds the current supply (Fig. 6.1). The number of people on the deceased donor waitlist has increased by 82% over the last 10 years, and 7271 patients either died or became too sick to transplant while on the waiting list in 2012.2 Living donor kidneys have not only increased the supply, but have also been shown to have improved 5 and 10 year graft survival rates.2 However, as many as 35% of willing donor-recipient pairs will be ABO incompatible, and an additional 30% will be unable to donate for immunological reasons.3 Kidney paired donation (KPD) has overcome this immunological barrier by allowing recipients with willing but incompatible living donors to exchange kidneys with other incompatible pairs, such that each patient is able to receive a transplant from a

FIGURE 6.1 Number of people on the kidney transplant waitlist compared to the number of people transplanted.2

Kidney Transplantation, Bioengineering, and Regeneration. DOI: http://dx.doi.org/10.1016/B978-0-12-801734-0.00006-0

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6. STRATEGIES TO INCREASE THE DONOR POOL

compatible donor.4 Unfortunately, the number of living donor transplants has decreased from 6647 in 2004 to 5622 in 2012.2 Many attempts have been made to circumvent the organ shortage problem. The use of animal cells and organs has the longest history, with the first attempts to perform animal to human blood transfusions as early as the 17th century.5 Porcine Xenotransplantation currently holds the most promise, due to similarities in organ size, physiology, and the potential for genetic modification to correct molecular incompatibilities. Indeed, preclinical trials have shown that pig kidneys are capable of supporting life for weeks to months in primates.6 8 However, the inability to overcome strong humoral and cellular immune responses to porcine antigens, combined with concerns about the contraction of unknown infections in immunocompromised patients, places xenotransplantation several years into the future.9 Dialysis poses significant limitations for ESRD patients waiting or unqualified for transplantation. Hemodialysis is limited by noncontinuous treatment and dependence on dialysis centers, while peritoneal dialysis (PD) requires patients to be connected to a machine overnight. Advancements in technology have allowed the creation of wearable PD and HD devices, which are currently undergoing both preclinical and clinical trials.10 13 The ultimate advancement in dialysis technology would be an implantable artificial kidney, though issues of component miniaturization, blood flow and coagulation, waste elimination, and device lifespan have yet to be solved. Such a device may also prove to be cost-prohibitive.14 Dialysis is inherently limited in its capacity as a renal replacement, both due to the inadequacy of dialysis membranes and the inability to perform hemostatic, metabolic, and endocrine regulation. The development of bioartificial kidneys is a solution to this problem.15,16 Investigations range from constructing renal tubule assist devices using synthetic scaffolds and renal tubule epithelial cells, to recellularizing whole organ extracellular matrix scaffolds. Though promising, bioartificial renal replacement strategies come with their own complications, and their clinical use is years away. Unfortunately, not all attempts to overcome the kidney shortage problem have been positive. Transplant tourism, or the buying and selling of organs, has been a scourge on the field of organ transplantation. It has been estimated that as many as 10% of the 106,879 organs transplanted in 2010 were procured and transplanted through black markets, 68.5% of which were kidneys.17 Black markets thrive in developing countries such as the Philippines, China, India, and Pakistan, where wealthy patients are charged between $100,000 and $200,000 for a transplant. The majority of this money goes to the brokers, while donors are paid as little as $1000, exposed to dangerous conditions, and left with little to no follow-up care.18 Regulatory agencies such as the World Health Organization (WHO) developed policies to curtail organ trafficking.18 20 However, enforcement continues to be a problem, as the countries which transplant tourists originate from and travel to are largely responsible for policing organ trafficking.21 Thus, the development and enforcement of ethical and legal policies on transplantation remains a prominent concern in global health. The solution lies not just in the development and enforcement of policies, but in increasing the supply of deceased and living donor organs available.

6.2 CURRENT PRACTICES In order to discuss methods of increasing the supply of donor kidneys, it is necessary to begin with the development of legal and ethical standards that govern kidney transplantation. As early as the 1930s, deceased donor kidneys were being used to treat acute renal failure, but the lack of immunosuppression precluded graft survival. In 1954, the first successful living donor transplant was performed by Joseph Murray at Peter Bent Brigham Hospital on a pair of identical twins.22 The discovery and experimentation of 6-Mercaptopurine as an immunosuppressant began in the late 1950s, led by Sir Roy Calne (Fig. 6.2). In 1962 a deceased donor kidney graft survived for over a year, thus beginning the modern clinical era of kidney transplantation.23,24 In 1968, the Uniform Anatomical Gift act in the United States established legislation recognizing the power of individuals to make the decision while alive to donate their organs in the event of their untimely death. This act required donors to document the desire to donate one’s organs, or the ability of a power of attorney to make this decision in the event that no documentation exists. The ESRD Program of 1972 amended Medicare to include financial responsibility for dialysis and transplantation. In 1984, Congress passed the National Organ Transplant Act, which established regulations on organ procurement, mandated

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FIGURE 6.2 Sir Roy Calne with his dog, Loli, who was successfully immunosuppressed with 6-MP.

the development of a scientific registry to evaluate clinical outcomes, and prohibited the purchase of organs. Policies for the allocation of donor organs, discussed in depth in previous chapters, were established based on two guiding principles: Utility and Justice. To maximize these principles, organs would be allocated to patients with the best chance of benefiting, and those with the most urgent need or longest wait time. By 1990, yearly kidney transplant rates rose above 9000 in the United States, of which 2094 came from living donors.25 Despite advancements in immunosuppression, living kidney donation was still limited. Approximately onethird of willing donors are ABO incompatible with their intended recipients, while 30% of patients are highly sensitized and potentially HLA incompatible with their donors.26 28 In 1986 Felix Rapaport suggested that ABOand HLA-incompatible pairs could exchange kidneys in a practice known today as KPD4 (Fig. 6.3). The first KPD exchange was performed in South Korea in 1991, followed by an exchange in Switzerland in 1999.29,30 Though the first KPD exchange in the United States took place in 2000, it was not until the passage of the Charlie W. Norwood Act in 2007, which stated that paired donation is not considered valuable exchange, that KPD became legal. Today, paired donation accounts for approximately 10% of kidney donations in the United States.2 In reviewing the history of transplantation, the categories of donor kidneys have been defined. Deceased donors are currently the most numerous, accounting for approximately 7000 transplants annually. Living kidney donors account for approximately 5500 transplants per year, and come in several forms. Compatible donors are those that can give directly to their intended recipient. Incompatible donors cannot give to their intended recipient but, when entered into paired exchange programs, can swap kidneys with other incompatible pairs. The final source for kidneys is from nondirected donors (NDD), or people without an intended recipient who wish to give a kidney to anyone in need. In order to increase the pool of kidney donors, it will be critical to not only increase the number, but also the utility of all four sources of donor kidneys.

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FIGURE 6.3 Example of a two-way paired exchange.

6.3 DECEASED DONORS In 2001, a conference was held to discuss the growing organ shortage problem. At this time, it was noted that the deceased donor kidney discard rate was 15%, and as high as 50% for donors over the age of 60.31 The members of the kidney work group noticed that, while the size of the OPTN transplant waitlist in the United States had grown by 230% over the previous 10 years, the kidney waitlist in Spain had decreased by 28%.32 It was concluded that this effect was primarily due to the increased utilization of donors over the age of 60, and that adoption of this model in the United States could increase the number of donors by 38%.32,33 In collaboration with the OPTN, the final proposal developed by this conference defined a new class, “expanded criteria donors,” based on age $ 60 or age 50 59 with any two of the following conditions: Cerebrovascular accident as the cause of death, serum creatinine .1.5 mg/dL, or history of hypertension. These expanded criteria donors have a relative risk of graft failure of .1.7 compared with the reference group of “standard criteria donors (SCD),” who do not meet the criteria of ECDs.31 When this policy went into effect in late 2002, transplant candidates could choose whether or not they were willing to receive an ECD kidney if one were to become available. The effectiveness of this policy has been analyzed from several different perspectives. Because ECD kidneys have, by definition, a graft failure 1.7 times that of SCD kidneys, one would expect the graft and patient survival to be lower. Most studies found this to be the case, with ECD donor 1 and 5-year graft survival ranging from 81% to 83% and 48.6% to 64.1%, respectively, compared to 89.3% 91% and 65.2% 74% for non-ECD donors.33 37 However, and more importantly, recipients of ECD kidneys experienced a 5-year increase in survival compared to matched waitlist recipients who did not receive a kidney (Fig. 6.4).36 The obvious ethical question that arises is how to appropriately allocate these kidneys to both increase the donor pool and increase patient survival. In other words, which patients should be listed for ECD kidneys? In 2002 a work group entitled “Expanded Criteria Donor Kidneys: Who Should Get Them?” convened to answer this question. Utilizing data from the Scientific Registry of Transplant Recipients (SRTR), this group determined that ECD kidneys would provide the greatest benefit in patients older than 60 years old, older than 40 years old with diabetes mellitus, patients with failed vascular access, and patients whose expected wait time far exceeds their life expectancy.37 39 Sung et al. and Schold et al. both analyzed the effect of implementing these policies, and found that after 36 months there was a 16% increase in the number of ECD kidneys transplanted.37,40 Older recipients and patients with diabetes were significantly more likely to both be listed for and receive an ECD kidney after the policy took effect. Both groups found a minimal overall effect on wait times, but noted that wait

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FIGURE 6.4 Mortality risks in two groups of cadaveric renal transplant recipients relative to wait-listed dialysis patients.37

TABLE 6.1

Estimated Kidney Graft Survival Rates by Donor KDRI41 Estimated SINGLE kidney graft survival rates

KDPI (%)

KDPI

1 Year (%)

2 Years (%)

3 Years (%)

5 Years (%)

8 Years (%)

1

0.57

95.3

92.7

89.9

83.3

72.2

5

0.63

94.8

92.0

88.9

81.8

69.9

10

0.67

94.4

91.4

88.1

80.6

68.1

20

0.75

93.8

90.5

86.8

78.6

65.1

30

0.82

93.2

89.5

85.6

76.7

62.3

40

0.91

92.5

88.5

84.2

74.5

59.2

50

1.00

91.7

87.3

82.6

72.2

55.9

60

1.11

90.8

86.0

80.8

69.6

52.4

70

1.23

89.8

84.5

78.9

66.7

48.6

80

1.39

88.6

82.6

76.5

63.3

44.2

90

1.62

86.7

79.9

72.9

58.3

38.2

95

1.84

85.0

77.5

69.8

54.2

33.5

99

2.25

81.8

72.9

64.2

46.9

25.9

times were reduced for centers that showed discretion in the number of patients listed for ECD kidneys. They concluded that appropriate listing criteria will improve the effective utilization of these kidneys. In the most recent OPTN allocation policy the ECD criteria has been replaced with a Kidney Donor Profile Index (KDPI), which is a continuous metric based on 10 donor characteristics (Table 6.1).41 The KDPI ranges from 1% to 100%, such that a kidney with a KDPI of 1% would be predicted to have a graft survival better than 98% of all kidneys, while a kidney with a KDPI of 100% is among the bottom 1% of all kidneys in terms of graft survival.

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Survival distribution function

Survival distribution function

1.00

0.75

0.50

0.25

0.00

0.75

0.50

0.25

0.00 0

20

40

60

80

100

120

0

20

Time 1 STRATA:

40

60

80

100

120

Time 1 group-DCD

group-ECD

group-ECD/DCD

group-SCD

FIGURE 6.5 (Top) Graft survival by donor type, P 5 .0116. (Bottom) Patient survival by donor type, P 5 .2215.49

A second group of donors have also been utilized to increase the deceased donor pool. As opposed to donation after brain death (DBD), donation after cardiac death (DCD) refers to donors in whom cessation of cardiopulmonary function occurred before the organs were procured and do not meet the criteria for DBD. Controlled DCD donors are those whose hemodynamic stability and respiratory function were maintained until organ procurement, while uncontrolled DCD donors experienced cardiac arrest before consent for donation can be obtained. European countries have been using DCD kidneys since the early 1990s with excellent results.42 45 In 2005, a national conference on Donation after Cardiac Death was convened to determine DCD criteria, develop criteria to predict DCD candidacy, and create protocols to maximize the successful recovery and utilization of DCD organs in the United States. It was subsequently shown that, although DCD donor kidneys have significantly higher rates of delayed graft function (DGF), DCD recipients had no difference in graft survival, patient survival, or acute rejection episodes.46 50 However, and not unexpectedly, results for combined DCD-ECD kidneys were poor (Fig. 6.5).49 Though the use of DCD and high KDPI kidneys has increased from 17% to 30% since 1999, the total number of deceased donor kidneys has actually decreased.2 This shift away from SCD and DBD donors may be due to the increase in the number of donors with cerebrovascular disease compared to trauma donors, an improvement in life-saving interventions such as craniostomy, craniotomy, cooling, etc.51,52 It is possible that the benefits of current deceased donor practices have reached a peak, and explorations of additional measures are necessary to increase the donor pool. In the United States, one must choose to be an organ donor through an active consent process. If no choice is made, the status quo is that consent has not been given, and organs will not be removed unless a family member consents. It has been proposed that instead of the current “opt-in” policy, those that have not explicitly refused to be an organ donor would have given presumed consent. This “opt-out” policy has the potential to increase deceased donation rates. Abadie et al. compared opt-in and opt-out policies in 22 countries, and found that opt-out legislation increases the rate of donation, independent of confounding factors (Fig. 6.6).53 Their results suggest that presumed consent legislation could potentially increase the number of deceased donor kidneys by 25% 30%. Objections to opt-out legislation include concerns about violating liberty and autonomy, religious objections, and a fear of a negative public perception of the transplant community under such policies.54 56 It has also been argued that presumed consent may have no impact on donation, and could even decrease the number of living donors.57,58 Despite these arguments, many organs are lost in patients for whom no consent can be obtained, and it is reasonable to argue that at least some of the patients would have consented if given the opportunity. Presumed consent legislation has the potential to increase deceased donation, though it will necessitate a collaborative effort to inform the public, deter negative impressions, and minimize effects on living donation rates.54,59,60 Efforts have been made in recent years to increase the rates of deceased donor registrations. Studies have shown that some groups, in particular minorities, are less likely to donate.61 64 Programs run through the department of motor vehicles, universities, and workplaces have demonstrated success in targeting these groups, particularly if the interventions contained an interpersonal component.65,66 Indeed, the number of registered donors has increased from 60 million in 2006 to 124.6 million today.55,67 However, the same time period has not yielded

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6.3 DECEASED DONORS

Cadaveric donors per million population, 2002

40.00 35.00

Presumed consent countries Informed consent countries

30.00 25.00 20.00 15.00 10.00 6.00

Spain Austria Latvia Portugal Belgium USA Estonia Ireland France Italy Slovenia Finland Hungary Czech Republic Norway Denmark Canada UK Poland Netherlands Germany Sweden Australia Switzerland Israel New zealand Croatia Cyprus Lithuania Slovak republic Luxemburg Greece Turkey Bulgaria Romania Japan

0.00

Country

FIGURE 6.6 Cadaveric donation rates in 2002 by country.53

an equivalent increase in the number of deceased donors. The simple explanation for this is that not enough time has passed for the benefits of these efforts to come to fruition, and future years will see an increase in deceased donation. It is also possible that these new registrants, who would not previously have registered, are individuals whose family would likely have given consent anyway, such that a large group of hard to reach donors is still being missed.55 Future work should be directed toward evaluation of these campaigns, as well as efforts to target these hard to reach donors. Financial incentives for deceased donors have been suggested, but have not been attempted in the United States. However, serious ethical objections to such policies have been raised, including coercion, exploitation of the poor, violations to freedom and autonomy, and a concern about public opinion toward the transplant community.68 70 Possible mechanisms for donor reimbursements include tax incentives, healthcare premiums, and payments to family to defray funeral costs.71,72 Current discussion centers around what methods of compensation would be permissible within the current laws, as well as exploring new policies that would uphold ethical and legal standards.73 Center level factors may also have an effect on deceased donor utilization. Developing policies for financial support, quality assurance, improvement processes, and governing the use of donor organs can benefit transplant centers.74 Conversely, government oversight aimed at quality improvement metrics such as graft and patient survival are used to credential transplant centers, which may act as a disincentive to transplant highrisk donors.55,75 Recently, insurance companies have mandated specific periods of medical care coverage postoperatively, which can also deter transplant centers from utilizing high-risk donors. Because patients who receive a high-risk kidney still do better than patients on dialysis, it would likely be beneficial and costeffective to remove these disincentives.36,76 78 Creating a sliding scale of reimbursements and quality improvement/center certification metrics based on donor and recipient risk factors could increase the willingness of centers to utilize higher risk kidneys.77 The utilization of kidneys from patients with both documented infections and high infection risk is also an important topic. The ability to accurately test high-risk kidneys while balancing delays in transplanting these kidneys and unnecessary discards due to false-positive test results requires further investigation.55,79,80 Transplants from donors with known hepatitis C infection into serology-matched recipients has been shown to be both effective and safe.81,82 While positive long-term outcomes in HIV-positive transplant recipients have been demonstrated, these patients also drew from the pool of uninfected donors.83 85 Through an investigation of the National Inpatient Sample (NIS) and UNOS databases, Boyarasky et al. estimated that a potential pool of

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6. STRATEGIES TO INCREASE THE DONOR POOL

TABLE 6.2 Characteristics of Potential HIV Infected Organ Donors Identified in HIVRN 2000 0886* National estimate n 5 494 Range: 441 533 Mean age death (year), SD

48.3, 9.7

, 30 years old

2%

30 49 years old

56%

50 59 years old

30%

60 69 years old

12%

Gender Male

81%

Female

19%

Race/ethnicity Caucasian

42%

African American

37%

Hispanic

14%

Other/unknown

7%

HIV primary risk factor** MSM

42%

IDU

26%

MSI

5%

HET

21%

HEI

5%

Other/unknown

2%

Median CD4 (IQR)

396 (314 566)

Median VL (IQR)

50 (50 54)

Median creatinine (IQR)

1.0 (0.9 1.3)

HCV Positive

16%

Negative

28%

Unknown

56%

HBV Positive

18%

Negative

33%

Unknown

49%

*Clinical and HIV characteristics of potential HIVDD identified from HIVRN relevant to organ donation are presented. **MSM: men who have sex with men; IDU: injection drug users; MSI: MSM and IDU; HET: heterosexuals; HEI: HET and IDU.

500 600 HIV-infected donors per year could be created, from which HIV-positive patients could draw (Table 6.2).86 In 2013, the HIV Organ Policy Equity (HOPE) Act lifted the ban on the ability to transplant HIV infected organs into HIV-positive recipients. The benefits of this policy, as well as the need for further policies to increase the utilization of these kidneys, are areas of active research.87 89 I. KIDNEY TRANSPLANTATION

6.4 LIVING DONATION

67

6.4 LIVING DONATION According to the most recent SRTR annual report of 2012 data, the deceased donor waitlist increased from 88,910 to 92,885 between 2011 and 2012.2 Over 30,000 patients were added to the list, while only 16,000 patients were transplanted. Despite current and future efforts to increase deceased organ donation, deceased donation will inevitably hit a ceiling well short of the number needed to satisfy the waitlist. As this chapter is being written in 2015, 101,209 ESRD patients are waiting for a deceased donor’s kidney in the United States (Fig. 6.1).2 Thus, rather than relying on deceased donors to satisfy the growing need for suitable organs for transplantation, alternative solutions to the organ shortage are needed. In recent years, the largest growth area has been found in living donors, but this growth has been limited to nonbiologically-related kidney donors. Overall, living kidney donation peaked in 2004 at just under 7000, and has declined almost every year to a nadir of 5817 in 2014 (Fig. 6.7).25 In 2014 Testa et al. proposed a shift in the focus on deceased donor promotion from the government and transplant community to promote living donation as the preferred source of donor kidneys, based on three premises: (1) the growing gap between kidney supply and demand; (2) the vast potential of living donors compared to deceased donors; and (3) the superior outcomes for recipients of living donor kidneys.90 Objectors to such a policy express concern over the ethics of performing surgery on healthy individuals to benefit others, the ability of transplant professionals to properly present the risks of donation, and the role of government in promoting living donation.90 92 Thus, it is necessary to explore potential mechanisms to increase living donation and the ethical issues that arise.

FIGURE 6.7 Counts of Deceased Donor and Living Donor Transplants by Year, 1993 2012.25

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6. STRATEGIES TO INCREASE THE DONOR POOL

TABLE 6.3 Educational and Clinical Recommendations From the Consensus Conference on Best Practices in Live Kidney Donation99 Education Levels100 Highest priority • LDKT education of patients with advanced stages of CKD should occur repeatedly throughout disease progression and transplantation processes (e.g., at evaluation, waiting list, reevaluation) • Educate general nephrologists and primary care physicians about LDKT so patients have access to transplant education earlier in the disease process • Integrate essential components of LDKT content and processes across centers, to include comprehensive risk and benefit information about LKD, known fears or concerns about LKD, and opportunities for interaction between transplant candidates and LDKT recipients as well as with former living donors • Create a LKD Financial Toolkit, which includes a summary of LKD financial risks, estimation of costs, available financial resources for the donor, state tax laws pertaining to donation, and how the Medicare Cost Report can best be optimized by programs HIGH PRIORITY • Develop a philosophical approach that LDKT is the best option for most transplant candidates and reflect this philosophy in educational processes • Provide more culturally-tailored LDKT education to racial/ethnic minority patients, with historically lower LDKT rates, and their support systems • Provide patients and their caregivers with training about how to identify and approach potential living donors • Increase awareness of the National Living Donor Assistance Center among providers, patients, and potential living donors • Develop a process to ensure that transplant and dialysis team members attain competency in living donation risks, methods for communicating risks and benefits, and ways to provide guidance to transplant candidates on effective and ethical approaches to engaging potential donors • Improve and expand the use of technology to better educate patients • Implement an independent, national clearinghouse (e.g., website) for the general public and potential donors

6.5 DONOR AND RECIPIENT EDUCATION In order to improve living kidney donation rates, it is critical to increase the awareness and willingness of both donors and recipients to participate in living donor transplantation. Over the last 10 years, significant efforts have been directed toward identifying barriers experienced by both of these groups. Waterman et al. identified recipient barriers to living donor transplantation, including comfort with dialysis, lack of education about the benefits of living donation, concern for potential donors, and difficulty broaching the subject with potential donors.93 Recipients are particularly concerned with financial, emotional, and physical burdens that may be placed on donors, the prospect of future kidney disease in donors, and the potential of regret experienced by donors.93,94 Patients also expressed that asking someone to donate a kidney was difficult and overwhelming. Rodrigue et al. found that 56% of transplant candidates had a low willingness to ask for a kidney, which was particularly prevalent in nonwhite patients and patients with lower. However, the biggest worry for potential donors appears to be a concern for their recipient’s health, with anxiety about testing, surgery, pain, finances, recovery, and long-term health risks being secondary.95 Pradel et al. found that laparoscopic nephrectomy, a less invasive surgery with shorter recovery time and less postoperative pain, was more likely to influence recipients rather than donors regarding their willingness to participate in living kidney donation.96,97 Waterman et al. found that 23.1% of potential donors expressed a lack of understanding about testing and surgical procedures.95 They further showed that 79% of potential donors who utilized educational resources were “very comfortable” with donation, versus 58% who did not use educational resources (χ2 5 3.91, P 5 .05). In another study, Pradel et al. identified that satisfaction with information that dialysis patients received on living donation was strongly correlated with willingness to discuss living donor kidney transplantation (LDKT) with potential donors.98 In June 2014, a consensus conference was held to discuss best practices in live kidney donation.99 The work group on educational and clinical recommendations determined that patient education early and often in the disease process was of highest priority (Table 6.3).99 In a retrospective review of 304 transplant recipients, only 54% 66% of patients received transplant information from dialysis or primary care providers.101 Preemptive transplantation has numerous quality of life benefits, including decreased psychological stress, fewer dietary restrictions, and higher employment rates.102 104 Additionally, these patients may be more motivated to seek transplantation as an option to maintain their current quality of life. Therefore, it is critical

I. KIDNEY TRANSPLANTATION

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6.5 DONOR AND RECIPIENT EDUCATION

for chronic kidney disease (CKD) patients to be educated about transplant options before starting dialysis. Boulware et al. showed that implementation of an educational program, Talking about Live Kidney Donation, which included both educational materials and a social worker, increased the number of CKD patients who pursued transplantation conversations with family and physicians.105 Numerous educational interventions for ESRD patients, including nephrologist training, home-based education, and intensive educational programs that incorporate previous transplant recipients and specific living donor educators have demonstrated success in moving potential recipients through the transplant process.106 108 Transplant centers should implement such procedures, and employ living donor-specific coordinators to facilitate patient education.99 Improving donor education is equally important as increasing LDKT. A work group on potential living donor educational processes has made recommendations to transplant centers on how to ensure potential donors are fully informed of the process of LDKT, including implementing a living donor advocate, developing culturally competent home visits and web-based tools, and methods of discussing psychosocial and health risks of donation.99,109 112 Waterman et al showed that donors who contacted a transplant center for assessment had often resolved many of their concerns with donation, most commonly by speaking with family members, potential recipients, and though educational resources.95 Potential donors are increasingly utilizing internet resources for educational purposes. In a review of 86 websites, Moody et al. found that while the accuracy of presented information was high, 98% were written above the recommended reading level, an average of only 38% of recommended information was included (range 8% 76%), and information related to benefits and medical/psychological risks were consistently lacking (Table 6.4).113 The development of an independent, neutral, and standardized internet resource for donors and recipients should be created to strengthen the understanding and trust between the public and the transplant community.99 As discussed previously, transplant candidates have often found it difficult to ask potential donors for a kidney. While educated patients may have an easier time conversing with potential donors, Garonzik-Wang et al. have suggested that a “living donor champion” would feel more comfortable advocating on behalf of the patient.114 Fifteen transplant candidates were asked to identify a living donor champion, who was educated on the process of LDKT over a 6-month period that included five information sessions. As a result of these sessions, living donor champions demonstrated an increased comfort in approaching potential donors, and increased the number of donor inquiries, workups, and living donor transplants on behalf of their recipients compared to matched controls. Future studies should seek to validate the efficacy of living donor champions, and work to incorporate this procedure into the recipient education process.

TABLE 6.4

Website Coverage and Accuracy of Recommended Information on Living Donation Topics113 Of websites that covered the topic Amount of coverage (%)a

Accuracy (%)b

No. of sites which Topics in living kidney donation covered topic (n, (%))

Minimal (,20%)

Moderate (20% 50%)

Mostly Full .50% 50% 90% .90% (51% 80%) ( . 80%) incorrect correct correct

General information about kidney 86 (100%) failure and treatments

1

29

70

0

0

0

100

Short-term medical risks to donor 75 (87%)

16

39

36

9

0

2

98

Long-term medical risks to donor 41 (48%)

27

56

17

0

0

12

88

Psychological risks and long-term 39 (45%) course

41

43

8

8

0

2

98

Benefits to donor

35 (41%)

68

26

6

0

0

0

100

Risks and benefits to recipient

79 (92%)

16

60

24

0

0

0

100

Financial considerations

52 (60%)

33

40

23

4

0

0

100

Voluntarism

36 (42%)

39

36

19

6

0

0

100

Donor evaluation process

79 (92%)

10

56

33

1

0

0

100

a

The amount of coverage was defined by the mean percentage of checklist items covered by the website. Accuracy was defined by the mean percentage of items which were described correctly.

b

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6. STRATEGIES TO INCREASE THE DONOR POOL

6.6 UNRELATED DONORS AND SOLICITATION Positive results using unrelated kidney donors has obviated the restrictions on human leukocyte antigen matching and donor/recipient relationship.115,116 The number of unrelated donors increased from 27% of living donors in 2000 to 51% in 2012.2 While paired donation has accounted for a significant portion of this change, many donors are reaching out to social networks or making public solicitations for organs via social media, kidney matching websites, and public advertising. Likewise, altruistic NDD may make the decision to donate, and then seek out potential candidates using any of these sources. Outreach through religious communities is increasingly common. Renewal, a Brooklyn-based nonprofit group, facilitates as many as 30 kidney transplants a year by connecting recipients with potential donors within the Jewish community.117 Religious and spiritual motivations have prompted potential donors to direct kidneys to recipients within their community or found on the internet.118 120 Potential recipients using websites for organ solicitation in the form of recipient advertising venues, networks of potential donors, and social media pages have found success and comfort in this less intrusive method of asking for an organ.121,122 Matchingdonors.com, a registry that links potential donors with recipients, has facilitated numerous transplants, and utilizes an approach where NDD register their desire to donate for free and are provided with a list of recipient biographical summaries. These summaries are provided by potential recipients, who pay for the ability to post their summary for nondirected donor consideration. Some authors have raised ethical concerns about such an approach.123 Numerous other examples exist, and the use of community and public outreach has likely contributed to the increase in unrelated living donation rates. Ethical concerns have been raised regarding unrelated living donation. Unlike the donation of blood or bone marrow, kidney donation entails the potential for serious harm to the donor. While it is not difficult to fathom undertaking the risk of donation for a loved one, such an altruistic act for a stranger or mere acquaintance raises concerns among the transplant community. These arrangements may be influenced by coercion between employers and supervisors, emotional exploitation, the presence of donor psychosocial issues, and subverted payments for donation.124 127 Public solicitation poses risks to a fair allocation system, as organs would be distributed to those with the means and ability to present the most compelling story, not those in greatest need.127 This is particularly the case for deceased donor solicitation and directed deceased donation, which would allow candidates to receive a transplant ahead of those higher on the list. The OPTN has been tasked with developing strict policies regarding the allocation of deceased donor organs.20,115 Finally, the ability to direct donation allows potential donors to stipulate racial, religious, or ethnic requirements. Such discriminatory practices would be particularly difficult to prevent without prohibiting directed donation entirely.124,127 Contrary arguments appeal to donor autonomy to direct an organ to a recipient of choice, the ability of religious and community ties to be strong altruistic motivators, and the potential for solicitation to increase public awareness of the organ shortage problem.120,124,127,128 Transplant centers are increasingly willing to utilize unrelated donors in LDKT, though transplantation between strangers and of publicly solicited organs remains controversial (Table 6.5).126,129 With the current dearth of organs available for transplantation, the approach in the United States has been to avoid imposing carte blanche restrictions on donor/recipient relationships, as has occurred in other countries.130 In a 2006 policy, the OPTN stated that it “cannot regulate or restrict the ways relationships are developed in our society with respect to live organ donation, nor does it seek to do so. The obligation of the OPTN and its members is to uphold the provisions of the National Organ Transplantation Act (NOTA) that make it a felony ‘for any person to knowingly acquire, receive or otherwise transfer any human organ for valuable consideration for use in human transplantation.’”115 Rather, the OPTN has developed policies for the psychosocial evaluation of living donors to ensure that donation is undertaken voluntarily, without coercion, and that the donor is aware of the risks and benefits of their gift.131

6.7 DONOR INCENTIVES In Greek mythology, the Strait of Messina was flanked by two hazards: Scylla, a rock shoal, and Charybdis, a whirlpool (Fig. 6.8). One could not successfully navigate a safe distance from one without passing too close to the other. This choice between two evils is reminiscent of the conundrum of removing disincentives for living kidney donors. In attempting to provide reasonable compensation to increase the rates of living donation, thereby

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6.7 DONOR INCENTIVES

TABLE 6.5

Psychosocial Issues and Whether They Are Considered a Contraindication (Absolute, Relative) to Living Donation or Not126 N

Absolute

Relative

None

Knowledge of financial gain or reward

131

118 (89)

10 (8)

3 (2)

Active substance abuse/dependence

125

108 (86)

15 (12)

2 (2)

Active mental health problems or instability

127

96 (76)

31 (24)

0 (0)

Desire for secondary gain

126

49 (39)

66 (52)

11 (9)

Lack of disclosure to spouse/partner, or next-of-kin who may be affected most by donation

128

45 (35)

75 (59)

8 (6)

Motivated primarily by desire for medical care

125

38 (30)

66 (53)

21 (17)

Unrealistic expectations about donor experience

129

38 (29)

85 (66)

6 (5)

History of poor adherence to healthcare recommendations

127

28 (22)

91 (72)

8 (6)

Strained donor-recipient relationship

126

28 (22)

87 (69)

11 (9)

Lack of family or social support

129

26 (20)

90 (70)

13 (10)

Lack of healthcare coverage

125

19 (15)

53 (42)

53 (42)

Donation strongly advised by faith community leaders

127

17 (13)

69 (54)

41 (32)

Financial instability

131

7 (5)

94 (72)

30 (23)

No history of past altruistic behaviors

125

0 (0)

21 (17)

104 (83)

FIGURE 6.8 James Gillray, Britannia between Scylla and Charybdis (1793).

decreasing the burden of ESRD, the transplant community runs the risk of commodifying the human body. Discussions aimed at navigating these waters must include ethical, legal, and financial consideration, and the transplant community stands divided on many of these issues. Policies are currently in place in the United States to remove disincentives for living kidney donors, which include donor reimbursement for travel, housing, and lost wages.73,99 However, the line between and legality of financial incentives versus the removal of disincentives for living kidney donors is less clear. Proponents of incentivizing donors believe that such a system would increase donation, increase the pool of living donors, decrease the number of deaths due to renal failure, and cripple the economic support for the black market and

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6. STRATEGIES TO INCREASE THE DONOR POOL

FIGURE 6.9 Break-even point to society if all vendors and current donors were paid. Cost-effective point includes impact of gain in Quality of Life Years.133

transplant tourism.132 Furthermore, due to the difference in cost of transplantation compared to dialysis, increasing the pool of living donors would work to relieve the financial burden of ESRD. A financial analysis by Matas et al. revealed that transplantation has the potential to save between $90,000 and $269,000 per ESRD patient (Fig. 6.9).133 The authors posited that a kidney vendor program could break even while providing up to $90,000 to living kidney donors. Financial programs for kidney donors are currently being used abroad. In 2008 Israel adopted the Organ Transplantation Law, which includes specific clauses to remove disincentives by providing donor compensation for lost wages, transportation costs, medical and life insurance, and psychological consultations.134 Iran has adopted a program through which donors are both financially compensated and provided with healthcare.135 The introduction of these programs has resulted in an increase in kidney donation and a reduction in the transplant waitlist. Opponents of financial compensation believe that such a system would not only fail to increase the supply of available organs, but would also cause harm to donors and result in an immoral commodification of the human body.136 Those who adhere to this view feel that paying potential donors would exploit vulnerable populations (e.g., those with low socioeconomic status) and create income-based disparities in access to transplantation.68,137 Furthermore, donor incentives would put recipients at risk because organ vendors would have significant motivation not to disclose information that may put them at risk of being disqualified as a donor.136 The Iranian model demonstrates that paid donors were in poorer health and had lower social functioning scores than unpaid donors.135 Finally, there is concern that payments for donors would be viewed negatively by the public as commodification of the human body, which would lead to mistrust of the transplant community and decreased donation rates.68,137,138 In June 2014, the ASTS and AST held a workshop on increasing organ donation in the United States.73 It was agreed that the continued removal of donor disincentives should be the first priority. Members of this incentive work group went on to explore the possibility of providing incentives for living donors and suggest that a pilot project would work to test assumptions about the impact of incentives on living donation. Fisher et al. provide ethical justification of such a project, and challenge arguments claiming that incentives would exploit vulnerable populations, cause undue influence for donors, damage the doctor patient relationship, and negatively impact public opinion.138 They also discuss the need to strike a balance between providing adequate compensation and avoiding “toxic” incentive amounts that would risk causing undue influence. Opponents argue that pilot programs would reshape the attitudes of the population regarding their expectations of financial rewards, which would be solidified even if the project were abandoned.136 Furthermore, if the project failed to increase donation rates, proponents would be unlikely to abandon the attempt, but rather increase compensation rates without regard for the detrimental effects on donor autonomy. Finally, there is concern that financial programs in the United States would foster a return to unregulated organ markets abroad. In navigating through these challenges, the transplant community must pass between two perils. Doing so will require the conjoined effort of members of the transplant community, public policy experts, and members of congress, and must do so with the support of the general public.73

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6.8 IMMUNOLOGICAL BARRIERS

73

6.8 IMMUNOLOGICAL BARRIERS Despite the growing number of HLA sensitized candidates, recent national data shows that as few as 4.9% of living donor transplants have been performed on highly sensitized candidates (cPRA .80%) annually.2 Additionally, ABO incompatibility is present in 35% of potential donors.3 Desensitization has allowed for transplants to be performed across both blood group and HLA incompatibilities. Transplant centers utilize varying regimens of plasmapheresis and intravenous immunoglobin for antibody removal, and antibody synthesis blocking agents for antibody attenuation.139 141 Long-term follow up data demonstrates that ABOincompatible graft and patient survival is similar to compatible living donor outcomes, with the potential caveat of an increased risk of graft loss in the first 14 postoperative days.142 146 Patients who underwent desensitization across HLA-incompatibilities have had higher rejection rates, as well as graft and patient survival rates below the national average.147,148 However, Montgomery et al. demonstrated that HLA desensitization provides improved long-term patient survival compared to remaining on dialysis or waiting for a compatible kidney, providing compelling evidence that desensitization may be the best option for highly sensitized patients (Fig. 6.10).149 Several barriers to desensitization still need to be resolved. Morbidity and mortality rates, most prominently cardiac events and infections, are higher among recipients who undergo desensitization.147,149 151 Variations in HLA laboratory procedures, desensitization protocols, and center-specific assessment of the need for desensitization based on antibody strength have made comparing outcome data difficult.139,152 In a survey of 125 transplant centers representing 84% of the living kidney donor volume, 74% reported using desensitization (Table 6.6).152 However, only 24% of these centers performed ABO-incompatible transplants, and the number of incompatible transplants performed at each center was not quantified. Because desensitization carries the risk of reduced patient and graft survival, regulatory pressures may discourage centers from performing desensitization, particularly at smaller centers.152 Statistical derivation of expected outcomes must allow for incorporation of the reduced patient and graft survival inherent in desensitization in order for this approach to reach its full potential. Future work should be directed toward homogenizing laboratory and desensitization protocols, developing new pharmaceutical agents, and creating policies to increase utilization using survival on dialysis as a comparator rather than compatible transplantation, yet striving to maintain positive outcomes overall.

FIGURE 6.10

Survival benefit of desensitization in HLA-incompatible kidney recipients.149

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74 TABLE 6.6

6. STRATEGIES TO INCREASE THE DONOR POOL

Results of desensitization

Type

Performed?a

Desensitize?b

PP/IVIgc

IVIgc

Otherc

CD20d

PLNF

86/123

50/86

37/50

23/50

14/50

27/49

70%

58%

74%

46%

28%

55%

63/123

48/63

34/48

21/48

14/48

25/47

51%

76%

71%

44%

29%

53%

22/123

22/22

18/22

8/22

5/22

13/22

18%

100%

82%

36%

23%

59%

30/124

24/30

20/24

7/24

7/24

16/26

83%

29%

29%

62%

PFNC

PCC

ABOi

24%

e

80%

a

Numbers represent the percent on the basis of those from the overall cohort who answered the given question. For example, there were 86 centers that performed PLNF transplants, representing 70% of the 123 centers that responded to the set of questions about PLNF transplants. b Numbers represent the percent on the basis of those who reported performing the given modality. For example, of those 86 centers that performed PLNF transplants, 50 of 86 (58%) used preoperative desensitization in that situation. c Numbers represent the percent on the basis of those who reported using desensitization. For example, of those 50 centers that desensitized PLNF recipients, 37 (74%) used PP/ IVIg. d Numbers represent the percent on the basis of those who answered the question about anti-CD20 antibody. For example, of 49 centers reporting use of anti-CD20, 27 stated that they never used it in PLNF situations. e For ABOi transplants, the number represents those who precondition with A2, B, or A1 donors. Of 30 centers that performed ABOi transplants, 24 (80%) precondition one of those blood type donors and 15 (50%, not shown in table) reported always preconditioning for ABOi transplants.152 PP/IVIg, plasmapheresis and low-dose intravenous Ig; IVIg, high-dose intravenous Ig; PLNF, positive Luminex, negative flow crossmatch; PFNC, positive flow, negative cytotoxic crossmatch; PCC, positive cytotoxic crossmatch; ABOi, ABO incompatible.

6.9 KIDNEY PAIRED DONATION KPD represents the fastest growing source of transplantable kidneys by overcoming the immunological barriers that render approximately 1/3 of potential kidney donors incompatible with their intended recipient.3,153 159 First suggested by Felix Rappaport in 1986, KPD was first reduced to practice in South Korea in 1991.29,160 It wasn’t until nearly a decade later that the first kidney exchange was performed in the United States in 2000.161 For a variety of reasons, including concerns about the NOTA prohibition against donating an organ for valuable consideration, it was not until the passage of the Charlie Norwood Amendment of NOTA in 2007 that KPD began to gain traction in the United States.153,162 164 Of the more than 3500 KPD transplants performed to date, 70% have been performed in the last 5 years.165 In its simplest form, KPD involves 2 incompatible pairs exchanging kidneys, such that each patient receives a transplant from a compatible living donor (Fig. 6.11A).3,26,153,166 In 2001, UNOS region 1 began performing list exchange, in which an incompatible donor donated a living donor kidney to a recipient on the deceased donor kidney transplant waiting list, and in exchange, their intended incompatible recipient was given priority for a future deceased donor kidney (Fig. 6.11C).153,167 Concerns about disadvantaging blood type O candidates on the deceased donor waiting list limited the application of list exchange so that early kidney exchanges in the United States were primarily limited to simple two-way exchanges between pairs with willing but incompatible living donors. With the advent of computer-aided matching algorithms, it became apparent that exchanges between three or more willing but incompatible pairs would increase the number transplants possible.167,168 The incorporation of NDDs into KPD allowed for the creation of a transplant chain in which each donor pays their kidney forward to the next incompatible pair until no further matches exist in the current pool. In domino paired donation (DPD), this leftover donor is directed to the deceased donor waitlist (Fig. 6.11D),153 while nonsimultaneous extended altruistic donor (NEAD) chains allow for the leftover donor to become a “bridge donor” and be reentered into the pool to continue the chain at a later date (Fig. 6.11E).153,167,169,170 As with list exchange, initial concerns were raised that using NDDs in KPD would disadvantage blood type O waitlist candidates. However, the ability of all types of chains to provide additional transplant opportunities for patients with willing incompatible donors, previously relegated to the waitlist, has generally been accepted as beneficial.171 177 The United States has at least seven single and multicenter KPD registries that utilize matching algorithms to create potential kidney exchanges. Algorithms in general operate using optimization or rule-based hierarchical systems, each with distinct advantages and disadvantages, and there is no consensus on the “best” matching strategy.178

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6.9 KIDNEY PAIRED DONATION

75 FIGURE 6.11 A history of KPD from its original proposal by Felix Rapaport to the present day. (A) Two incompatible pairs swap kidneys in a two-way exchange. (B) A three-way exchange with no reciprocal exchanges so hard-to-match pairs are better matched. (C) In a list exchange, an incompatible donor donates to a wait-list candidate in exchange for wait-list priority for the recipient. (D) DPD pairs an altruistic donor with an incompatible recipient. The donor then continues the chain or donates to a wait-list candidate. (E) A compatible pair can join an exchange helping hard-to-match pairs. (F) NEAD chains are like domino chains except the last donor becomes a bridge donor and awaits more pairs to perpetuate the chain at a later time.153

Multiregional registries require complex levels of coordination between transplant centers, and various strategies have been adopted.179 181 The ability to overcome geographic barriers has been greatly aided by the ability to safely and efficiently ship kidneys nationally.182 185 Despite these advancements, KPD appears to have hit a plateau, and 2014 saw the first decrease in the number of KPD transplants performed compared to the previous year. Overcoming the multitude of challenges currently inhibiting KPD stands to have the biggest impact on both the quality of life and healthcare burden in patients with ESRD. The rapid dissemination of KPD among transplant centers that took place between 2006 and 2008 has slowed since that time.186 While the top 10% of KPD centers perform an average of 5.52 KPD transplants per 100 LDKTeligible patients, most centers perform less than one.186 In a survey of transplant center attitudes toward KPD, Clark et al. found that the most prominent barriers to KPD were (1) unequal quality of kidneys, (2) logistics of donor travel, (3) logistics of working with other centers and KPD registries, and (4) the dedication, training, and payment of staff to handle KPD programs.185 They further noted that the biggest barriers to implementing KPD were not the most frequently cited concerns (Fig. 6.12). Utilizing the knowledge obtained from high-performing KPD centers can help overcome many of the cited barriers of donor travel, dedicating and training KPD staff, and working with other transplant centers. Furthermore, KPD actually has the potential to increase the quality of kidneys by matching donor/recipient ages and decreasing HLA mismatches.186 If all transplant centers utilized KPD at the level of the highest performing KPD centers, an additional 1099 2000 transplants could be performed per year.186,187 Public support of KPD is generally high, with 85% of respondents to a national survey extremely or very willing to participate188. KPD pools have a distinctly lower proportion of blood type O donors and type AB recipients, since these two groups are always ABO compatible. It has been estimated that the incorporation of compatible pairs in KPD could double the proportion of matched pairs.166,189,190 This practice has been pejoratively called altruistically unbalanced paired kidney exchange (AUPKE), as compatible donors are asked to be doubly altruistic by not only

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FIGURE 6.12 Most frequently cited major and minor barriers to implementing kidney paired donation.185

donating a kidney, but to also forego donating to their compatible recipient for the benefit of an incompatible pair.174 Ross et al. further suggested that asking compatible pairs to participate in KPD represents a conflict of interest for the physician, who has a moral obligation to act in the best interests of the patient. Nonetheless, some of these same authors have subsequently conceded that there is equipoise regarding the incorporation of compatible pairs in kidney exchange.191 Modeling and execution of such exchanges have shown that compatible pairs have the potential to receive a higher quality kidney (younger or fewer HLA mismatches), and surveys suggest that approximately one-third of compatible pairs would be willing to participate.187,189,192 195 In 2006 Gentry et al. produced a consensus KPD matching statement, which includes participation of compatible pairs as a parameter to be considered in designing a national KPD matching program196,197. In 2012, a consensus conference was held to discuss the dynamic challenges inhibiting optimal adoption of KPD.178 Though competition among the KPD registries has inspired innovation, it has inadvertently led to fragmented implementation methods throughout the country. The consensus conference called for standardization and collaboration in implementing and executing KPD in the United States. One observation was the pattern in which transplant centers enroll incompatible pairs. Centers may withhold easy to match pairs, preferring to perform internal exchanges. While this may be logistically and financially beneficial for a particular transplant center, it is detrimental to the pool overall.154 Secondly, pairs can be enrolled in multiple registries to increase the probability of finding a match. While this is of benefit to the individual patient, it has the potential to create waste when a registry attempts to create an exchange using a pair that has already been matched or transplanted elsewhere.178,179,198 Perhaps one of the biggest challenges in KPD is the complexity of paying for donor evaluations, histocompatibility testing, administrative costs, nephrectomy and complication costs, and transportation costs.180,199 The Alliance for Paired Donation has received AHRQ grant funding to develop a standard acquisition charge model to alleviate these challenges.179 Many of the barriers to maximizing KPD could be overcome by the creation of a national registry. Several countries have implemented national KPD registries, including the Netherlands, South Korea, the United Kingdom, Canada, and Australia, with great success.156,159,200 202 The United States presents a unique challenge based on the shear number and geographic distribution of transplant centers and payers. Simulations by Segev et al. have suggested that a national optimized KPD program could result in more transplants, better HLA concordance, increased matching of highly sensitized patients, and shorter travel distances for donors.3 HLA standardization could be achieved by a single national tissue-typing laboratory. National KPD programs in Australia and the Netherlands have successfully employed a single-laboratory approach.158,203 However, these programs differ significantly from the United States in the number of centers, geographic area, presence of a single payer and the number of potential incompatible pairs that would need to be crossmatched. The national KPD programs in Canada and the United Kingdom have developed standardized crossmatch criteria, which may be a reasonable alternative for combating the overwhelming volume a single laboratory would have to deal with in the United States.159,200 Variations in HLA testing and reporting, unacceptable antigen levels, and crossmatching were discussed at the national consensus conference, and recommendations were made to streamline this process

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TABLE 6.7

77

Recommended Guidelines for KPD Histocompatibility Testing178

• HLA typing: Should be DNA based for HLA-A, -B, -C, -DRB1, -DRB3 5, -DQA1, -DQB1, -DPB1 loci and inclusive of certain specific alleles and common null alleles, as needed. Extended donor typing may be required depending upon antibody specificities • Antibody testing: Two methods should be used, at least one being a solid phase immunoassay. Antibody specificity should be confirmed by a single antigen assay. Assay limitations should be recognized and considered in interpretation. Antibody testing should be performed at least quarterly and after any proinflammatory/sensitizing event • Unacceptable antigens: Unacceptable antigens should be assigned based on the transplant center’s crossmatch acceptance criteria and should be updated whenever antibody tests indicate a change. There should be two levels of unacceptable antigens, high and low risk; possible listing of antigen combinations to address multiple, weak antibodies. Definition of sensitization should be based on the calculated panel reactive antibody • Virtual crossmatching: Correlation of antibody assays with transplant center risk criteria is essential. Labs should achieve 95% accuracy in crossmatch prediction. Labs should try to identify combinations of multiple, weak antibodies that could yield a positive crossmatch when a donor has all of the corresponding antigens • Crossmatching: Flow cytometric crossmatches are recommended for sensitized patients. Unexpected positive results should be resolved, and unacceptable antigens updated. Patients should be inactive until reasons for failed crossmatches have been resolved and unacceptable antigens are updated. Cryopreserved donor cells should be available for preaccepted, “exploratory” crossmatches • Exchange of specimens and data: There should be standardized practices for test requisitions, labeling, and shipment of shared samples. Data entry should be verified by two person audit, at least one of whom should have histocompatibility expertise • Communication: Histocompatibility Laboratory Directors should participate in the evaluation of proposed paired donation matches and be available to provide consultation. KPD programs should have a Histocompatibility Advisory Committee comprised of physicians, surgeons, coordinators, and histocompatibility experts to provide quality assurance review and facilitate logistical planning for testing

(Table 6.7).178 Finally, a national KPD program would require an analysis of the myriad of strategies employed by current KPD programs to generate potential exchanges to develop a single algorithm with an allocation rubric that maximizes both the quality and quantity of exchanges.166,175,190,195,196,204 207

6.10 SUMMARY Over the last 75 years, advancements in the field of renal replacement therapy have reversed the death sentence that was previously placed on ESRD patients. The question is no longer how do we treat this disease, but which modality should we utilize? Immunosuppressive therapies have broken down the immunological barriers to renal transplantation, while dialysis has provided a bridge for those waiting for a transplant. Changes in healthcare policy, public opinion, and allocation protocols have increased the number of both living and deceased kidney donors. Innovative thinking has led to the development and utilization of KPD and desensitization to further overcome donor-recipient incompatibility. More recently, the idea of incentivizing both living donors and deceased donor’s families has become an intriguing matter of discussion. However, despite these efforts, thousands die every year while waiting for a kidney. While bioengineering and genetic manipulation to allow for xenotransplantation and stem cell therapy has promise for the future, the immediate solution is to increase the supply of kidney donors. Doing so will require the collaborative effort of the transplant community, government, and policy makers, and the support of the general public. By continuing to explore new strategies to increase both living and deceased organ donation, observing what has proved beneficial abroad, and remaining vigilant over the ethical responsibilities to both donors and recipients, we can continue to work toward the goal of giving the gift of life to every person in need of a kidney.

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81. Veroux M, Corona D, Sinagra N, Giaquinta A, Zerbo D, Ekser B, et al. Kidney transplantation from donors with hepatitis C infection. World J Gastroenterol 2014;20(11):2801 9. 82. Abbott KC, Lentine KL, Bucci JR, Agodoa LY, Peters TG, Schnitzler MA. The impact of transplantation with deceased donor hepatitis cpositive kidneys on survival in wait-listed long-term dialysis patients. Am J Transplant 2004;4(12):2032 7. 83. Locke JE, Montgomery RA, Warren DS, Subramanian A, Segev DL. Renal transplant in HIV-positive patients: long-term outcomes and risk factors for graft loss. Arch Surg 2009;144(1):83 6. 84. Locke JE, Segev DL. Renal transplantation in HIV-positive recipients. Curr Infect Dis Rep 2010;12(1):71 5. 85. Stock PG, Roland ME. Evolving clinical strategies for transplantation in the HIV-positive recipient. Transplantation 2007;84(5):563 71. 86. Boyarsky BJ, Hall EC, Singer AL, Montgomery RA, Gebo KA, Segev DL. Estimating the potential pool of HIV-infected deceased organ donors in the United States. Am J Transplant 2011;11(6):1209 17. 87. Health R, Services Administration DoH, Human S. Organ procurement and transplantation: implementation of the HIV Organ Policy Equity Act. Final rule. Fed Regist 2015;80(89):26464 7. 88. Richterman A, Blumberg E. The challenges and promise of HIV-infected donors for solid organ transplantation. Curr Infect Dis Rep 2015;17(4):471. 89. Richterman A, Sawinski D, Reese PP, Lee DH, Clauss H, Hasz RD, et al. An assessment of HIV-infected patients dying in care for deceased organ donation in a United States urban center. Am J Transplant 2015;15(8):2105 16. 90. Testa G, Siegler M. Increasing the supply of kidneys for transplantation by making living donors the preferred source of donor kidneys. Medicine (Baltimore) 2014;93(29):e318. 91. Mandelbrot DA, Pavlakis M, Danovitch GM, Johnson SR, Karp SJ, Khwaja K, et al. The medical evaluation of living kidney donors: a survey of US transplant centers. Am J Transplant 2007;7(10):2333 43. 92. Starzl TE. Will live organ donations no longer be justified? Hastings Cent Rep 1985;15(2):5. 93. Waterman AD, Stanley SL, Covelli T, Hazel E, Hong BA, Brennan DC. Living donation decision making: recipients’ concerns and educational needs. Prog Transplant 2006;16(1):17 23. 94. Pradel FG, Mullins CD, Bartlett ST. Exploring donors’ and recipients’ attitudes about living donor kidney transplantation. Prog Transplant 2003;13(3):203 10. 95. Waterman AD, Covelli T, Caisley L, Zerega W, Schnitzler M, Adams D, et al. Potential living kidney donors’ health education use and comfort with donation. Prog Transplant 2004;14(3):233 40. 96. Flowers JL, Jacobs S, Cho E, Morton A, Rosenberger WF, Evans D, et al. Comparison of open and laparoscopic live donor nephrectomy. Ann Surg 1997;226(4):483 9. discussion 9 90. 97. Pradel FG, Limcangco MR, Mullins CD, Bartlett ST. Patients’ attitudes about living donor transplantation and living donor nephrectomy. Am J Kidney Dis 2003;41(4):849 58. 98. Pradel FG, Suwannaprom P, Mullins CD, Sadler J, Bartlett ST. Haemodialysis patients’ readiness to pursue live donor kidney transplantation. Nephrol Dial Transplant 2009;24(4):1298 305. 99. LaPointe Rudow D, Hays R, Baliga P, Cohen DJ, Cooper M, Danovitch GM, et al. Consensus conference on best practices in live kidney donation: recommendations to optimize education, access, and care. Am J Transplant 2015;15(4):914 22. 100. Rodrigue JR, Cornell DL, Kaplan B, Howard RJ. Patients’ willingness to talk to others about living kidney donation. Prog Transplant 2008;18(1):25 31. 101. Waterman AD, Barrett AC, Stanley SL. Optimal transplant education for recipients to increase pursuit of living donation. Prog Transplant 2008;18(1):55 62. 102. Dahabreh Z, Dimitriou R, Giannoudis PV. Health economics: a cost analysis of treatment of persistent fracture non-unions using bone morphogenetic protein-7. Injury 2007;38(3):371 7. 103. Hays R, Waterman AD. Improving preemptive transplant education to increase living donation rates: reaching patients earlier in their disease adjustment process. Prog Transplant 2008;18(4):251 6. 104. Tomasz W, Piotr S. A trial of objective comparison of quality of life between chronic renal failure patients treated with hemodialysis and renal transplantation. Ann Transplant 2003;8(2):47 53. 105. Boulware LE, Hill-Briggs F, Kraus ES, Melancon JK, Falcone B, Ephraim PL, et al. Effectiveness of educational and social worker interventions to activate patients’ discussion and pursuit of preemptive living donor kidney transplantation: a randomized controlled trial. Am J Kidney Dis 2013;61(3):476 86. 106. Rodrigue JR, Cornell DL, Lin JK, Kaplan B, Howard RJ. Increasing live donor kidney transplantation: a randomized controlled trial of a home-based educational intervention. Am J Transplant 2007;7(2):394 401. 107. Sullivan C, Leon JB, Sayre SS, Marbury M, Ivers M, Pencak JA, et al. Impact of navigators on completion of steps in the kidney transplant process: a randomized, controlled trial. Clin J Am Soc Nephrol 2012;7(10):1639 45. 108. Weng FL, Brown DR, Peipert JD, Holland B, Waterman AD. Protocol of a cluster randomized trial of an educational intervention to increase knowledge of living donor kidney transplant among potential transplant candidates. BMC Nephrol 2013;14:256. 109. Gill JS, Tonelli M. Understanding rare adverse outcomes following living kidney donation. JAMA 2014;311(6):577 9. 110. Hays RE, LaPointe Rudow D, Dew MA, Taler SJ, Spicer H, Mandelbrot DA. The independent living donor advocate: a guidance document from the American Society of Transplantation’s Living Donor Community of Practice (AST LDCOP). Am J Transplant 2015;15 (2):518 25. 111. Kaplan B, Ilahe A. Quantifying risk of kidney donation: the truth is not out there (yet). Am J Transplant 2014;14(8):1715 16. 112. Thiessen C, Kim YA, Formica R, Bia M, Kulkarni S. Written informed consent for living kidney donors: practices and compliance with CMS and OPTN requirements. Am J Transplant 2013;13(10):2713 21. 113. Moody EM, Clemens KK, Storsley L, Waterman A, Parikh CR, Garg AX, et al. Improving on-line information for potential living kidney donors. Kidney Int 2007;71(10):1062 70. 114. Garonzik-Wang JM, Berger JC, Ros RL, Kucirka LM, Deshpande NA, Boyarsky BJ, et al. Live donor champion: finding live kidney donors by separating the advocate from the patient. Transplantation 2012;93(11):1147 50.

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115. Delmonico FL. Commentary: the WHO resolution on human organ and tissue transplantation. Transplantation 2005;79(6):639 40. 116. Terasaki PI, Cecka JM, Gjertson DW, Takemoto S. High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med 1995;333(6):333 6. 117. Wolf B. Do Chareidim Contribute Their ‘Fair Share’ of Organs. The Algemeiner. 2013 7/31/2013;Sect. Spirituality/Tradition. 118. Dixon DJ, Abbey SE. Religious altruism and the living organ donor. Prog Transplant 2003;13(3):169 75. 119. Henderson AJ, Landolt MA, McDonald MF, Barrable WM, Soos JG, Gourlay W, et al. The living anonymous kidney donor: lunatic or saint? Am J Transplant 2003;3(2):203 13. 120. Mueller PS, Case EJ, Hook CC. Responding to offers of altruistic living unrelated kidney donation by group associations: an ethical analysis. Transplant Rev (Orlando) 2008;22(3):200 5. 121. Costello KL, Murillo AP. “I want your kidney!” Information seeking, sharing, and disclosure when soliciting a kidney donor online. Patient Educ Couns 2014;94(3):423 6. 122. Williams ME. Internet organ solicitation, explained. Adv Chronic Kidney Dis 2006;13(1):70 5. 123. Neidich EM, Neidich AB, Cooper JT, Bramstedt KA. The ethical complexities of online organ solicitation via donor-patient websites: avoiding the “beauty contest”. Am J Transplant 2012;12(1):43 7. 124. Hanto DW. Ethical challenges posed by the solicitation of deceased and living organ donors. N Engl J Med 2007;356(10):1062 6. 125. Jowsey SG, Schneekloth TD. Psychosocial factors in living organ donation: clinical and ethical challenges. Transplant Rev (Orlando) 2008;22(3):192 5. 126. Rodrigue JR, Pavlakis M, Danovitch GM, Johnson SR, Karp SJ, Khwaja K, et al. Evaluating living kidney donors: relationship types, psychosocial criteria, and consent processes at US transplant programs. Am J Transplant 2007;7(10):2326 32. 127. Truog RD. The ethics of organ donation by living donors. N Engl J Med 2005;353(5):444 6. 128. Glazier AK, Sasjack S. Should it be illicit to solicit? A legal analysis of policy options to regulate solicitation of organs for transplant. Health Matrix Clevel 2007;17(1):63 99. 129. Spital A. Evolution of attitudes at U.S. transplant centers toward kidney donation by friends and altruistic strangers. Transplantation 2000;69(8):1728 31. 130. Biller-Andorno N, Agich GJ, Doepkens K, Schauenburg H. Who shall be allowed to give? Living organ donors and the concept of autonomy. Theor Med Bioeth 2001;22(4):351 68. 131. Dew MA, Jacobs CL, Jowsey SG, Hanto R, Miller C, Delmonico FL, et al. Guidelines for the psychosocial evaluation of living unrelated kidney donors in the United States. Am J Transplant 2007;7(5):1047 54. 132. Matas AJ, Hippen B, Satel S. In defense of a regulated system of compensation for living donation. Curr Opin Organ Transplant 2008;13 (4):379 85. 133. Matas AJ, Schnitzler M. Payment for living donor (vendor) kidneys: a cost-effectiveness analysis. Am J Transplant 2004;4(2):216 21. 134. Lavee J, Ashkenazi T, Stoler A, Cohen J, Beyar R. Preliminary marked increase in the national organ donation rate in Israel following implementation of a new organ transplantation law. Am J Transplant 2013;13(3):780 5. 135. Fallahzadeh MK, Jafari L, Roozbeh J, Singh N, Shokouh-Amiri H, Behzadi S, et al. Comparison of health status and quality of life of related versus paid unrelated living kidney donors. Am J Transplant 2013;13(12):3210 14. 136. Delmonico FL, Martin D, Dominguez-Gil B, Muller E, Jha V, Levin A, et al. Living and deceased organ donation should be financially neutral acts. Am J Transplant 2015;15(5):1187 91. 137. Jha V, Chugh KS. The case against a regulated system of living kidney sales. Nat Clin Pract Nephrol 2006;2(9):466 7. 138. Fisher JS, Butt Z, Friedewald J, Fry-Revere S, Hanneman J, Henderson ML, et al. Between Scylla and Charybdis: charting an ethical course for research into financial incentives for living kidney donation. Am J Transplant 2015;15(5):1180 6. 139. Sharif A, Alachkar N, Kraus E. Incompatible kidney transplantation: a brief overview of the past, present and future. QJM 2012;105(12):1141 50. 140. Gloor JM, Winters JL, Cornell LD, Fix LA, DeGoey SR, Knauer RM, et al. Baseline donor-specific antibody levels and outcomes in positive crossmatch kidney transplantation. Am J Transplant 2010;10(3):582 9. 141. Montgomery RA. Renal transplantation across HLA and ABO antibody barriers: integrating paired donation into desensitization protocols. Am J Transplant 2010;10(3):449 57. 142. Flint SM, Walker RG, Hogan C, Haeusler MN, Robertson A, Francis DM, et al. Successful ABO-incompatible kidney transplantation with antibody removal and standard immunosuppression. Am J Transplant 2011;11(5):1016 24. 143. Fuchinoue S, Ishii Y, Sawada T, Murakami T, Iwadoh K, Sannomiya A, et al. The 5-year outcome of ABO-incompatible kidney transplantation with rituximab induction. Transplantation 2011;91(8):853 7. 144. Genberg H, Kumlien G, Wennberg L, Berg U, Tyden G. ABO-incompatible kidney transplantation using antigen-specific immunoadsorption and rituximab: a 3-year follow-up. Transplantation 2008;85(12):1745 54. 145. Montgomery JR, Berger JC, Warren DS, James NT, Montgomery RA, Segev DL. Outcomes of ABO-incompatible kidney transplantation in the United States. Transplantation 2012;93(6):603 9. 146. Okumi M, Toki D, Nozaki T, Shimizu T, Shirakawa H, Omoto K, et al. ABO-incompatible living kidney transplants: evolution of outcomes and immunosuppressive management. Am J Transplant 2015;9(3):567 77. 147. Haririan A, Nogueira J, Kukuruga D, Schweitzer E, Hess J, Gurk-Turner C, et al. Positive cross-match living donor kidney transplantation: longer-term outcomes. Am J Transplant 2009;9(3):536 42. 148. Vo AA, Peng A, Toyoda M, Kahwaji J, Cao K, Lai CH, et al. Use of intravenous immune globulin and rituximab for desensitization of highly HLA-sensitized patients awaiting kidney transplantation. Transplantation 2010;89(9):1095 102. 149. Montgomery RA, Lonze BE, King KE, Kraus ES, Kucirka LM, Locke JE, et al. Desensitization in HLA-incompatible kidney recipients and survival. N Engl J Med 2011;365(4):318 26. 150. Baek CH, Yang WS, Park KS, Han DJ, Park JB, Park SK. Infectious risks and optimal strength of maintenance immunosuppressants in rituximab-treated kidney transplantation. Nephron Extra 2012;2(1):66 75. 151. Kahwaji J, Sinha A, Toyoda M, Ge S, Reinsmoen N, Cao K, et al. Infectious complications in kidney-transplant recipients desensitized with rituximab and intravenous immunoglobulin. Clin J Am Soc Nephrol 2011;6(12):2894 900.

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152. Garonzik Wang JM, Montgomery RA, Kucirka LM, Berger JC, Warren DS, Segev DL. Incompatible live-donor kidney transplantation in the United States: results of a national survey. Clin J Am Soc Nephrol 2011;6(8):2041 6. 153. Wallis CB, Samy KP, Roth AE, Rees MA. Kidney paired donation. Nephrol Dial Transplant 2011;26(7):2091 9. 154. Ashlagi I, Roth AE. Free riding and participation in large scale, multi-hospital kidney exchange. Theoretical Economics 2014;9(3):7. 155. Cole E, Malik S. Foundations and principles of the Canadian living donor paired exchange program. Can J Kidney Health Disease 2014;1(6):7. 156. de Klerk M, Keizer KM, Claas FH, Witvliet M, Haase-Kromwijk BJ, Weimar W. The Dutch national living donor kidney exchange program. Am J Transplant 2005;5(9):2302 5. 157. Delmonico FL, Morrissey PE, Lipkowitz GS, Stoff JS, Himmelfarb J, Harmon W, et al. Donor kidney exchanges. Am J Transplant 2004;4 (10):1628 34. 158. Ferrari P, Fidler S, Wright J, Woodroffe C, Slater P, Van Althuis-Jones A, et al. Virtual crossmatch approach to maximize matching in paired kidney donation. Am J Transplant 2011;11(2):272 8. 159. Johnson RJ, Allen JE, Fuggle SV, Bradley JA, Rudge C, Kidney Advisory Group UKTN. Early experience of paired living kidney donation in the United kingdom. Transplantation 2008;86(12):1672 7. 160. Park K, Lee JH, Huh KH, Kim SI, Kim YS. Exchange living-donor kidney transplantation: diminution of donor organ shortage. Transplant Proc 2004;36(10):2949 51. 161. Zarsadias P, Monaco A, Morrissey P. A pioneering paired kidney exchange. Student BMJ 2010;18:c1562. 162. An Act to amend the National Organ Transplant Act, S. 301, The Senate of the United States, 110th Congress, 1st Session Sess (2007). 163. Rees MA, Bargnesi D, Samy K, Reece L. Altruistic donation through the Alliance for Paired Donation. Clin Transpl 2009:235 46. 164. United S. National Organ Transplant Act: Public Law 98-507. US Statut Large 1984;98:2339 48. 165. Transplant: Transplant Year by Donor Relation (1988 2015) [Internet]. U.S. Department of Health and Human Resources. 2015 [cited 11/12/2015]. Available from: http://optn.transplant.hrsa.gov/converge/latestData/rptData.asp. 166. Roth AE, Sonmez T, Unver MU. Kidney Exchange. Quart J Econ 2004;119(2):32. 167. Roth AE, Sonmez T, Unver MU, Delmonico FL, Saidman SL. Utilizing list exchange and nondirected donation through ‘chain’ paired kidney donations. Am J Transplant 2006;6(11):2694 705. 168. Saidman SL, Roth AE, Sonmez T, Unver MU, Delmonico FL. Increasing the opportunity of live kidney donation by matching for twoand three-way exchanges. Transplantation 2006;81(5):773 82. 169. Rees MA, Kopke JE, Pelletier RP, Segev DL, Rutter ME, Fabrega AJ, et al. A nonsimultaneous, extended, altruistic-donor chain. N Engl J Med 2009;360(11):1096 101. 170. Montgomery RA, Gentry SE, Marks WH, Warren DS, Hiller J, Houp J, et al. Domino paired kidney donation: a strategy to make best use of live non-directed donation. Lancet 2006;368(9533):419 21. 171. Ashlagi I, Gilchrist DS, Roth AE, Rees M. NEAD Chains in Transplantation. Am J Transpl 2011;11(12):2. 172. Gentry SE, Segev DL, Montgomery RA. A comparison of populations served by kidney paired donation and list paired donation. Am J Transplant 2005;5(8):1914 21. 173. Melcher ML, Veale JL, Javaid B, Leeser DB, Davis CL, Hil G, et al. Kidney transplant chains amplify benefit of nondirected donors. JAMA Surg 2013;148(2):165 9. 174. Ross LF. The ethical limits in expanding living donor transplantation. Kennedy Inst Ethics J 2006;16(2):151 72. 175. Woodle ES, Daller JA, Aeder M, Shapiro R, Sandholm T, Casingal V, et al. Ethical considerations for participation of nondirected living donors in kidney exchange programs. Am J Transplant 2010;10(6):1460 7. 176. Ross LF, Rubin DT, Siegler M, Josephson MA, Thistlethwaite Jr. JR, Woodle ES. Ethics of a paired-kidney-exchange program. N Engl J Med 1997;336(24):1752 5. 177. Ross LF, Zenios S. Practical and ethical challenges to paired exchange programs. Am J Transplant 2004;4(10):1553 4. 178. Melcher ML, Blosser CD, Baxter-Lowe LA, Delmonico FL, Gentry SE, Leishman R, et al. Dynamic challenges inhibiting optimal adoption of kidney paired donation: findings of a consensus conference. Am J Transplant 2013;13(4):851 60. 179. Fumo DE, Kapoor V, Reece LJ, Stepkowski SM, Kopke JE, Rees SE, et al. Historical matching strategies in kidney paired donation: the 7year evolution of a web-based virtual matching system. Am J Transplant 2015;15(10):2533 786. 180. Mast DA, Vaughan W, Busque S, Veale JL, Roberts JP, Straube BM, et al. Managing finances of shipping living donor kidneys for donor exchanges. Am J Transplant 2011;11(9):1810 14. 181. Veale J, Hil G. National Kidney Registry: 213 transplants in three years. Clin Transpl 2010;333 44. 182. Montgomery RA, Katznelson S, Bry WI, Zachary AA, Houp J, Hiller JM, et al. Successful three-way kidney paired donation with crosscountry live donor allograft transport. Am J Transplant 2008;8(10):2163 8. 183. Segev DL, Veale JL, Berger JC, Hiller JM, Hanto RL, Leeser DB, et al. Transporting live donor kidneys for kidney paired donation: initial national results. Am J Transplant 2011;11(2):356 60. 184. Simpkins CE, Montgomery RA, Hawxby AM, Locke JE, Gentry SE, Warren DS, et al. Cold ischemia time and allograft outcomes in live donor renal transplantation: is live donor organ transport feasible? Am J Transplant 2007;7(1):99 107. 185. Clark E, Hanto R, Rodrigue JR. Barriers to implementing protocols for kidney paired donation and desensitization: survey of U.S. transplant programs. Prog Transplant 2010;20(4):357 65. 186. Massie AB, Gentry SE, Montgomery RA, Bingaman AA, Segev DL. Center-level utilization of kidney paired donation. Am J Transplant 2013;13(5):1317 22. 187. Bingaman AW, Wright FH, Murphey CL. Kidney paired donation in live-donor kidney transplantation. N Engl J Med 2010;363 (11):1091 2. 188. Segev DL, Powe NR, Troll MU, Wang NY, Montgomery RA, Boulware LE. Willingness of the United States general public to participate in kidney paired donation. Clin Transplant 2012;26(5):714 21. 189. Gentry SE, Segev DL, Simmerling M, Montgomery RA. Expanding kidney paired donation through participation by compatible pairs. Am J Transplant 2007;7(10):2361 70. 190. Roth AE, Unver MU, Sonmez T. A Kidney Exchange Clearinghouse in New England. Am Econ Rev Papers Prec 2005;95(2):5.

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191. Cuffy MC, Ratner LE, Siegler M, Woodle ES. Equipoise: ethical, scientific, and clinical trial design considerations for compatible pair participation in kidney exchange programs. Am J Transplant 2015;15(6):1484 9. 192. Bingaman AW, Wright Jr. FH, Kapturczak M, Shen L, Vick S, Murphey CL. Single-center kidney paired donation: the Methodist San Antonio experience. Am J Transplant 2012;12(8):2125 32. 193. Kranenburg LW, Zuidema W, Weimar W, Passchier J, Hilhorst M, de Klerk M, et al. One donor, two transplants: willingness to participate in altruistically unbalanced exchange donation. Transpl Int 2006;19(12):995 9. 194. Ratner LE, Rana A, Ratner ER, Ernst V, Kelly J, Kornfeld D, et al. The altruistic unbalanced paired kidney exchange: proof of concept and survey of potential donor and recipient attitudes. Transplantation 2010;89(1):15 22. 195. Hanto RL, Reitsma W, Delmonico FL. The development of a successful multiregional kidney paired donation program. Transplantation 2008;86(12):1744 8. 196. Roth AE, Sonmez T, Unver MU. Kidney paired donation with compatible pairs. Am J Transplant 2008;8(2):463. 197. gentry SE, Rees MA, Roth AE. Consensus kidney paired donation matching statement. Proposal for a National Kidney Paired Donation Program. Kidney Transplantation Committee, 2006 12/18/2006. Report No. 198. Liu W, Treat E, Veale JL, Milner J, Melcher ML. Identifying opportunities to increase the throughput of kidney paired donation. Transplantation 2015;99(7):1410 15. 199. Rees MA, Schnitzler MA, Zavala EY, Cutler JA, Roth AE, Irwin FD, et al. Call to develop a standard acquisition charge model for kidney paired donation. Am J Transplant 2012;12(6):1392 7. 200. Cole EH, Nickerson P, Campbell P, Yetzer K, Lahaie N, Zaltzman J, et al. The Canadian Kidney Paired Donation Program: a national program to increase living donor transplantation. Transplantation 2014;22(1):45 6. 201. Kute VB, Vanikar AV, Shah PR, Gumber MR, Patel HV, Modi PR, et al. Facilitators to national kidney paired donation program. Transpl Int 2013;26(5):e38 9. 202. Ferrari P, de Klerk M. Paired kidney donations to expand the living donor pool. J Nephrol 2009;22(6):699 707. 203. de Klerk M, Witvliet MD, Haase-Kromwijk BJ, Claas FH, Weimar W. A highly efficient living donor kidney exchange program for both blood type and crossmatch incompatible donor-recipient combinations. Transplantation 2006;82(12):1616 20. 204. Ashlagi I, Gilchrist DS, Roth AE, Rees MA. Nonsimultaneous chains and dominos in kidney- paired donation-revisited. Am J Transplant 2011;11(5):984 94. 205. Gentry SE, Montgomery RA, Swihart BJ, Segev DL. The roles of dominos and nonsimultaneous chains in kidney paired donation. Am J Transplant 2009;9(6):1330 6. 206. Montgomery RA. Living donor exchange programs: theory and practice. Br Med Bull 2011;98:21 30. 207. Veale J, Hil G. The National Kidney Registry: 175 transplants in one year. Clin Transpl 2011;255 78.

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C H A P T E R

7 Kidney Preservation Ina Jochmans1, John M. O’Callaghan2, Rutger J. Ploeg2 and Jacques Pirenne1 1

University Hospitals Leuven, Leuven, Belgium 2University of Oxford, Oxford, United Kingdom

7.1 PRINCIPLES OF KIDNEY PRESERVATION 7.1.1 Oxygen Deprivation As soon as circulation to the donor kidney diminishes and stops, cells become oxygen and nutrient deprived. A detrimental cascade of processes is started that ends in cellular injury and death. 1. Anaerobic metabolism is activated to maintain adenosine triphosphate (ATP) dependent membrane pumps that ensure intracellular ion composition (mainly of Na1, K1 and Ca21). ATP stores rapidly deplete since substrates for ATP production are not being delivered. 2. As membrane pumps fail, Na1 is no longer excreted and the intracellular environment becomes hyperosmolar. H2O enters the cell and causes cell swelling. 3. ATP-dependent Ca21 transport stops and Ca21 accumulates, both in the cytoplasm and the mitochondria. This cytosolic calcium will activate a large number of enzymes such as phospholipases, proteases, ATPases and endonucleases, leading to destruction of cellular integrity. The calcium overload also plays a role in the opening of the mitochondrial permeability transition pore after circulation is restored, which is a critical event in the progression of cell death.1,2 4. Lactate produced during anaerobic metabolism leads to an acidotic intracellular environment. Severe acidosis activates phospholipases and proteases, causing lysosomal damage and cell death.3 5. Reactive oxygen species (ROS) are formed when cells are deprived of oxygen and the stage is set for increased oxidative damage at the time or reperfusion.4,5 Reoxygenation will increase ROS production and the ROScoping mechanisms of the cell are flooded. ROS damage all components of the cell, including proteins, lipids, and DNA, leading to cell injury and death. From this, it is evident that kidneys need to be protected during the prolonged ischemic phase between retrieval and transplantation. One method of kidney preservation would be to sustain oxygen and nutrient supply in a near-physiological environment. In 1813, Julien-Jean-Cesar Le Gallois said, “if one could replace for the heart some kind of injection of artificial blood, either natural or artificially made . . . one could succeed easily in maintaining alive indefinitely any part of the body.”6 Although normothermic organ preservation is no longer science fiction (see Chapter 8: Ex-vivo Normothermic Perfusion in Renal Transplantation), intentional cooling of the kidney to 0 4 C is still the key factor for successful preservation.

7.1.2 Hypothermia Cooling the kidney by 10 C halves the metabolic rate, and cooling to 4 C reduces metabolism to about 5% 8% of the rate at normothermic temperatures. Cooling effectively increases organ viability. This is often referred to as the “temperature effect.” Simple cooling of dog kidneys with ice water sustained kidney viability and allowed successful transplantation after 12 hours.7 However, there are deleterious effects of rapid cooling itself Kidney Transplantation, Bioengineering, and Regeneration. DOI: http://dx.doi.org/10.1016/B978-0-12-801734-0.00007-2

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TABLE 7.1 Composition of the Most Commonly Used Preservation Solutions for Static Cold Storage SCS solutions EC UW

HOC

HTK

Celsior

IGL-1

HMP solution Belzer MPS

Electrolytes (mM) Na

10

30

84

15

100

120

100

K

115

120

84

9

15

25

25

Lactobionate Raffinose Hydroxyethyl starch

Citrate Mannitol Mannitol

Lactobionate Mannitol

Lactobionate Raffinose Polyethylene glycol

Glucose Gluconate Mannitol Ribose Hydroxyethyl starch

Citrate

Histidine

Histidine

Phosphate

Phosphate

Glutathione Adenosine

Adenine

Impermeant Glucose

Buffer

Phosphate Phosphate

ROS scavenger

Glutathione Allopurinol

Tryptophan

Nutrients

Adenosine

Ketoglutarate Glutamate

Belzer MPS, Belzer machine perfusion solution; EC, Euro-Collins; HMP, hypothermic machine perfusion; HOC, hyperosmolar citrate (also called Marshall’s solution); HTK, histidine-tryptophan-ketoglutarate; IGL-1, Institut Georges Lopez-1; SCS, static cold storage; UW, University of Wisconsin solution.

that superimpose on those of ischemia. Membranes lose their selective permeability as the phospholipid layer undergoes changes.8 Furthermore, membrane pumps are also inhibited by the cold, resulting in increased Na1 and Ca21 concentrations and several detrimental enzymes are released into the cytoplasm, causing cell injury and death.8

7.1.3 Preservation Solution As cooling can only slow down the detrimental effects of oxygen deprivation, and indeed some are even enhanced by the cold state, additional protection is needed during preservation. Preservation solutions were designed for this purpose. To effectively preserve, a cold preservation solution needs to contain: 1. A balanced electrolyte composition (Na1 and K1). There are in general two types of solutions, those with an intracellular electrolyte composition (i.e., high K1, low Na1) and those with an extracellular composition (i.e., low K1, high Na1). K1-rich solutions may result in a K1-overload upon organ reperfusion in the recipient. Furthermore, K1 can cause vasoconstriction making K1-rich solutions less desirable for use with machine perfusion preservation. 2. Impermeants to counteract cell swelling. These are saccharides (glucose, mannitol, sucrose, raffinose), anions (citrate, gluconate, lactobionate), and colloids (hydroxyethyl starch, polyethylene glycol). These large molecules remain in the interstitial space after equilibration with the perfusion solution, increasing osmotic pressure and as such counteracting cell swelling by diminishing the number of water molecules that enter the cell. 3. An adequate pH-buffer to prevent acidosis. Anaerobic metabolism continues in the cold and will result in acidosis. Mild acidosis (pH 6.9 7.0) inhibits lactate formation and as such offers a little cellular protection. But profound acidosis destabilizes the lysosomes causing cell death.3 The most commonly used buffers in preservation solutions are phosphate and histidine. 4. Antioxidants These may neutralize ROS such as allopurinol, glutathione, tryptophan. Table 7.1 summarizes the composition of the most commonly used preservation solutions.

7.2 STATIC COLD STORAGE Static cold storage (SCS) consists of a washout of the kidney with a cold preservation solution, first in situ and then a second rinse ex situ, after which the kidney is submerged in the solution and packed on ice. SCS is a simple, affordable preservation technique that allows unsupervised shipment of kidneys by any form of transport. It is the most prevalent preservation method in use today. Successful SCS hinges on the preservation solution used. Collins’ solution, introduced in 1969, was the first to be used.9 It was Euro-Collins’ (EC)—a modified Collins’ solution with omission of magnesium—that was implemented by the international organ sharing organization Eurotransplant in I. KIDNEY TRANSPLANTATION

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the 1970s.10 Shortly thereafter, hyperosmolar citrate solution (HOC), currently mainly used in Australia and the United Kingdom, was introduced by Ross and Marshall.11 In the late 1980s, Belzer and Southard developed the University of Wisconsin (UW) solution, containing hydroxyethyl starch and antioxidants.12 In Germany, Bretschneider presented histidine-tryptophan-ketoglutarate (HTK) for cardioplegia during cardiac surgery.13 Experimental work showed that HTK, with its powerful buffering capacity, could also be used for organ preservation.14 Institut George Lopez-1 (IGL-1) solution is a recent preservation solution that has built on UW, the major difference being an extracellular electrolyte composition and the use of polyethylene glycol as impermeant.15,16

7.2.1 Are All Static Cold Storage Preservation Solutions Equal? A number of randomized controlled trials (RCTs) have been performed over the years comparing the different SCS solutions for kidney preservation and these have been discussed in a recent systematic review.17 The use of both UW and HTK results in significantly lower delayed graft function (DGF) rates when compared to EC.18 There does not seem to be a difference in the incidence of DGF between the use of UW and HTK, as long as large volumes (10 15 L) of HTK are used and cold ischemic times are not prolonged.19 21 There are limited data with respect to graft survival and acute rejection rates, however both are likely influenced by the incidence of DGF.22 HOC has not been compared with either UW or HTK in a randomized controlled way. When choosing a SCS solution it is important to keep in mind that most of the time other (abdominal) organs will be retrieved from the same donor. In this light, analyses performed by the European Liver Transplant Registry show that preservation of the liver with HTK is an independent factor of graft loss.23

7.2.2 Is Static Cold Storage Too Simple? SCS has been the most prevalent form of kidney preservation ever since SCS preservation solutions became available. Around that time a turning point in the donor profile was also reached. The concept of brain death was penetrating the transplantation community and radically changed the process of organ donation. Donor death was no longer diagnosed on circulatory criteria (donation after circulatory death: DCD) but on neurological criteria (donation after brain death: DBD).24,25 The typical donor was young and suffered major trauma that led to brain death. The pristine kidneys from these donors could tolerate the detrimental effects of brain death and the following cold ischemic time in SCS quite well. However, since then our deceased donor profile has significantly changed again and continues to change. Median donor age has increased considerably. In the Eurotransplant region median donor age for kidneys has increased from 36 years in 1990 to 53 years in 2013 (Fig. 7.1).26 As increasing age correlates with comorbidities such as arterial hypertension, cardiovascular accidents, etc. we see that expanded criteria donor (ECD) kidneys are increasingly used.27 Furthermore, DCDs— both controlled and uncontrolled DCDs—have returned to clinical practice and are now an important contributor to the deceased donor pool in a number of countries, such as the United States, United Kingdom, the Netherlands, Belgium, France, and Spain.28 32 Not only has the use of DCDs increased exponentially, these donors are also becoming older, combining risk factors for decreased graft function. In Belgium, the Netherlands, and the United Kingdom, 60% of DCD donors are now older than 50 years, and 40% are older than 60 years.26,33 These higher-risk kidneys—ECD and DCD—are particularly susceptible to preservation-induced injury, DGF, and primary nonfunction (PNF) and can experience reduced long-term graft survival. SCS of higher-risk kidneys seems to have reached its limits and improved preservation is needed.

7.3 MACHINE PERFUSION PRESERVATION Hypothermic machine perfusion (HMP) was the first kidney preservation technique to be used clinically, before the availability of cold storage solutions. The pioneering work of Belzer in the 1960s, showing that cryoprecipitated plasma could be used to perfuse canine kidneys, led to the first successful human HMP-kidney transplant in 1968.34 37 HMP was commonly used, predominantly in the United States during the 1970s, but was quickly replaced by SCS after preservation solutions were shown to adequately preserve kidney grafts. It appeared that the use of large and nontransportable HMP units was no longer necessary. Nevertheless, Belzer continued his work on HMP and developed a synthetic HMP solution replacing his previous human albumin-containing solution. Belzer MPS could preserve canine kidneys for up to 5 days and is still the standard HMP solution today (Table 7.1).12,38 I. KIDNEY TRANSPLANTATION

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FIGURE 7.1 Median donor age of deceased donor kidneys in Eurotransplant between 1995 and 2013. Graph constructed using Eurotransplant data.26

FIGURE 7.2 Currently available hypothermic machine perfusion devices for clinical kidney preservation. Panel A: RM3 (Waters Medical systems, Birmingham, Alabama, USA), www.wtrs.com; panel B: LifePort Kidney Transporter (Organ Recovery Systems, Itasca, Illinois, USA), www.organ-recovery.com; panel C: Kidney Assist (Organ Assist, Groningen, the Netherlands); www.organ-assist.nl.

Thanks to technological advances, user-friendly, portable HMP devices are now commercially available (Fig. 7.2). In parallel with the changing donor profile, the use of HMP is increasing (Fig. 7.3).

7.3.1 Does Hypothermic Machine Perfusion Provide Better Preservation Than Static Cold Storage? Relatively few well-conducted RCTs have compared HMP to SCS. A meta-analysis of all 16 studies39 57 prospectively comparing HMP with SCS between 1971 and 2001 showed that HMP is associated with a relative risk of DGF of 0.80 (0.67 0.96) compared to SCS.58,59 No effect of HMP on 1-year graft survival was detected, however all studies were severely underpowered with respect to the likely impact on graft survival.58 Furthermore,

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FIGURE 7.3 Percentage of deceased donor kidneys preserved by hypothermic machine perfusion in the United States of America each year. Graph constructed using OPTN data.145

the evidence spreads out over decades during which SCS solutions, donor profile, outcome measures etc. have changed considerably. 7.3.1.1 Hypothermic Machine Perfusion in Deceased Donor Kidneys In 2009, the report of an international RCT in Eurotransplant comparing HMP to SCS of kidneys from all deceased donor types (standard criteria donors (SCD), ECD, controlled DCD) was published.60 DGF occurred in 21% of HMP-kidneys versus 27% in SCS-kidneys. Logistic regression showed that HMP reduced the risk of DGF (adjusted odds ratio (AOR) 0.57 (0.36 0.88)). If DGF developed, its duration was 3 days shorter after HMP (10 days vs 13 days, P 5 .04). PNF occurred in 2% of HMP-kidneys and in 5% of SCS-kidneys (P 5 .08). Graft survival was also improved by HMP (94% vs 90%, P 5 .04). Cox regression analysis showed that HMP reduced the risk of graft failure in the first year after transplantation (adjusted hazard ratio (AHR) 0.52 (0.29 0.93)). The 3-year follow-up data of this trial confirmed the improved graft survival of HMP-kidneys (91% vs 87%; AHR 0.60 (0.37 0.97)) (Fig. 7.4).61 7.3.1.2 Hypothermic Machine Perfusion of Expanded Criteria Donor Kidneys The beneficial effect of HMP might be more pronounced in ECD kidneys.27,62 Multivariate regression of the 91 randomised ECD kidney pairs in the Eurotransplant HMP trial showed that HMP reduced the risk of DGF compared with SCS (AOR 0.46; (0.21 0.99)). PNF was also lower in HMP compared to SCS-kidneys (3% vs 12%, P 5 .04).63 One-year graft survival was higher after HMP (92% vs 80%, P 5 .02) with an AHR of 0.35 (0.15 0.86). The 3-year graft survival advantage after HMP was maintained for ECD kidneys (86% vs 76%, AHR 0.38; (0.18 0.80) (Fig. 7.4).61 The presence or absence of DGF seems to have an impressive effect on graft survival, especially in SCS-ECD-kidneys. If DGF occurred in ECD kidneys that had undergone HMP, the 1-year graft survival was 10% lower than HMP-ECD-kidneys with immediate function, although this difference was not significant (94% vs 85%, P 5 .16). However, in SCS-kidneys that developed DGF, graft survival was significantly worse compared to when the graft functioned immediately (41% vs 97%, P , .0001). If only recipients of grafts that developed DGF were analyzed, there was a significant difference in 1-year graft survival between HMP and SCSkidneys (85% vs 41%, P 5 .003) (Fig. 7.4). 7.3.1.3 Hypothermic Machine Perfusion of Kidneys Donated After Circulatory Death Previous studies have suggested that HMP of DCD kidneys results in better early graft function and improved graft survival compared to SCS. However, other studies do not support this conclusion.39,64 67 A comprehensive meta-analysis failed to show a significant risk reduction of DGF in HMP-DCD-kidneys.58,59 Although the Eurotransplant HMP trial included DCD donors, 88% of inclusions were DBD kidneys. In a separate randomised extension of the Eurotransplant HMP trial, data from 82 Maastricht III DCD kidney pairs were analyzed.68 HMP

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FIGURE 7.4 Three-year graft survival of deceased donor kidneys included in the Eurotransplant HMP trial. Panel A shows graft survival in 672 kidney recipients, with a hazard ratio for graft failure in the machine-perfusion group of 0.60 (95% confidence interval, 0.37 0.97; P 5 .04). Panel B shows the post hoc analysis of a subgroup of 588 recipients of kidneys donated after brain death, with data split according to whether delayed graft function developed in the recipient. Delayed graft function was defined as the need for dialysis in the first week after transplantation. From Moers, C., Pirenne, J., Paul, A., & Ploeg, R.J. (2012). Machine perfusion or cold storage in deceased-donor kidney transplantation. New England Journal of Medicine, 366(8), 770 771 Copyright r (2012) Massachusetts Medical Society. Reprinted with permission.

reduced the risk of DGF (AOR 0.43 (0.20 0.89)). Of HMP-DCD-kidneys, 54% developed DGF compared to 70% of SCS-DCD-kidneys (P 5 .007). PNF occurred in two cases in each study arm. HMP did not result in an increased 1-year or 3-year graft survival (94% for HMP-kidneys vs 95% for SCS-kidneys). Although equal outcome might seem contradictory, this finding is in line with an increasing number of reports showing similar medium-term graft survival for DCD and DBD kidneys despite higher rates of DGF in DCD kidneys.31,69 72 An RCT analyzing outcome of 45 Maastricht III DCD kidney pairs in the UK showed no difference in DGF between HMP and SCS (58% vs 56%; P 5 .99; AOR 1.14 (0.38 3.49)).73 One kidney in the HMP group suffered from PNF. One-year graft survival was similar in both groups (93% in the HMP group and 98% in the SCS group, P 5 .3). The contradicting results between the two trials, currently the largest RCTs performed and the best available evidence, might be related to the setting in which HMP is used. In the Eurotransplant HMP trial, kidneys were placed on the HMP device at the donor center, immediately after retrieval, whereas in the UK HMP trial, those kidneys removed away from the transplant center were cold stored during transfer, after which HMP was started. As such, it could be that HMP needs to be used in a continuous setting to achieve a benefit. An ongoing RCT in the United Kingdom is duplicating the set-up of the Eurotransplant HMP trial with continuous HMP being compared to SCS (ISRCTN 50082383). 7.3.1.4 Meta-Analyses A number of meta-analyses have recently been published reviewing the evidence of HMP and SCS in kidney transplantation. Two studies analyzed data from all donor types and reported a decreased risk for DGF with HMP (AORs of 0.83 (0.72 0.96)74 and 0.81 (0.71 0.98)18). Two meta-analyses analyzed data from DCD kidneys and found a protective effect of HMP on DGF (AORs of 0.56 (0.36 0.86)75 and 0.64 (0.43 0.95)76). There is one meta-analysis that combined the data of HMP in ECD kidneys which also showed a protective effect of HMP on DGF (AOR 0.59 (0.54 0.66)77). Overall, even with the meta-analysis of prospective data, numbers have not been large enough to identify a benefit of HMP on outcomes that are relatively rare, such as PNF and 1-year graft loss. In studies that have individually identified a difference, this has largely been in ECDs.

7.3.2 Is Machine Perfusion Cost-Effective? Meta-analyses assessing the cost-effectiveness of HMP have not drawn any conclusions because of a lack of properly powered studies. Published economic evidence at the time was of poor quality and not based on randomized studies.58,78 An economic evaluation of the Eurotransplant HMP trial data combined the 1-year results based on the empirical data from the study with a Markov model with a 10-year time horizon.79 Short-term

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evaluation showed that HMP results in lower average costs in the first year posttransplant when compared to SCS and across all deceased donor types but mostly apparent in the ECD group, related to the increased 1-year graft survival of pumped ECD kidneys. The costs of dialysis and readmission were mainly responsible. The longterm analyses showed a similar benefit; the Markov model revealed cost savings of $86,750 per life-year gained in favor of HMP. The corresponding incremental cost-utility ratio was minus $496,223 per quality-adjusted lifeyear gained.

7.3.3 Does Timing or Duration of Hypothermic Machine Perfusion Matter? It is well known that renal vascular resistance (RR) falls during HMP, whilst perfusate flow increases.80,81 This has prompted the question of whether or not there is a required minimum duration of perfusion for any potential benefit of HMP to be evident. Recently published experimental studies have found that between 1 and 4 hours of HMP before reperfusion with blood could reduce RR and improve creatinine clearance compared to kidneys preserved by SCS alone.82,83 Then again, other studies have shown that despite reaching mean perfusate flows after 2 hours of perfusion, RR values continue to improve at 6 hours.80 As it is frequently necessary to transport organs many miles between donor and recipient, a beneficial effect of a short period of end-ischemic HMP sounds attractive and avoids the logistics of transporting machines. Nevertheless, there is some suggestion that when following long periods of SCS, relatively short periods of HMP (less than 4 hours) have either reduced or no benefit compared to continuous HMP throughout.84 Clinical trials that have shown significant benefits with HMP have used continuous HMP with the kidney being pumped for many hours, on average the majority of the total cold ischemic time (median 11 15 hours).60,63,68,85 Recent large registry analyses (over 90,000 kidneys) have shown that in the case of SCD kidneys, HMP reduces the risk of DGF compared to SCS regardless of a very short or very long cold ischemic time.86 In the same study, the risk of DGF was reduced for ECD kidneys only if the total cold ischemic time was greater than 6 hours, and in the case of DCD only if 6 24 hours.86 These discrepancies may be a function of the numbers available for power but if not, have important consequences. Furthermore, there is currently no good evidence to suggest that HMP allows for lengthening of cold ischemic times. As total cold ischemic time is a well-established predictor of DGF, a balance between minimizing cold ischemic time and any potential benefit of HMP is required.87 It seems that just a few hours of HMP, following SCS, can have a positive impact on early graft function compared to SCS alone as long as the total cold ischemic time is not extended. Currently an RCT comparing end-ischemic HMP with SCS in DBD kidneys is ongoing (ISRCTN 35082773). However, to the best of our knowledge, there are no clinical trials comparing continuous with end-ischemic HMP.

7.3.4 Does Machine Perfusion Predict Graft Viability and Quality? HMP allows the study of perfusion characteristics such as RR and perfusate biomarkers that might provide an assessment of kidney graft viability and quality before transplantation. 7.3.4.1 The Value of Renal Vascular Resistance Retrospective evidence suggests that RR and flow rate during HMP correlate with kidney graft function.58 However, in most of these studies, a selection bias was introduced because kidneys were systematically discarded based on arbitrarily defined parameter thresholds. Today, “poor” perfusion dynamics are still frequently used to discard kidneys even though their true prognostic value on graft outcome had never been studied until recently. Indeed, more than 15% of HMP-kidneys are discarded annually in the United States, partly based on elevated RR.88 In the Eurotransplant HMP trial, the preservation method was not revealed at the time of organ offer and HMP clinicians had no knowledge of the RR value. The decision to accept a given kidney was based solely on traditional donor data, making it possible to elucidate the true prognostic value of RR on PNF, DGF, and 1-year graft survival.89 Analysis showed that RR at the end of HMP was an independent risk factor for the development of DGF, independent of donor type (AOR 38.1 (1.56 934)). However, the predictive power of RR was low (AUC of the ROC curve 0.58). This means that, despite the association of RR and DGF, RR has a limited value in the prediction of DGF for a specific donor-recipient pair. RR was also a risk factor for 1-year graft failure but again with low predictive power (AHR 12.3 (1.11 136.9)). A retrospective study on RR in DCD kidneys showed that RR at the start of HMP is a risk factor for both DGF (AOR 2.34 (1.11 4.96)) and PNF (AOR 2.04 (1.36 3.06)) but again the predictive power was only moderate at best (0.61).90 Available evidence indicates that kidneys should not be discarded based on RR criteria alone.

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7.3.4.2 The Value of Perfusate Injury Biomarkers Retrospective data, systematically reviewed recently,91 also suggest that biomarker concentrations in the perfusate of HMP-kidneys correlate with graft outcome. The groups of Newcastle and Maastricht have previously determined the perfusate concentration of total glutathione-S-transferase (GST), heart-type fatty acid binding protein (H-FABP), and alanine-aminopeptidase and found higher concentrations in perfusate of discarded kidneys.92 94 Furthermore, lactate dehydrogenase (LDH) and GST concentrations correlated with warm ischemia time, and GST and H-FABP were higher in Maastricht II compared to Maastricht III DCD kidneys. However, these data are confronted with the same methodological design and selection bias as the RR data, and none of the previous studies investigated whether perfusate biomarkers were independently associated with graft outcome. In prospectively collected perfusate of the Eurotransplant HMP trial, GST, N-acetyl-β-D-glucosaminidase, and H-FABP were found to be independent predictors of DGF, but not of PNF or graft survival.95 The predictive power of these three biomarkers was also moderate at best (0.67, 0.64, and 0.64, respectively). A retrospective study in DCD kidneys showed that LDH and IL-18 perfusate concentrations were associated with PNF (AOR 1.001 (1.000 1.002) for both markers) but that the predictive power was poor (0.62 and 0.59).96 Thus, similar to RR, perfusate biomarkers alone should not lead to kidney discard. As there are multiple donor, preservation, and recipient factors influencing graft outcome, it is not surprising that RR and individual perfusate biomarkers are not sufficient on their own to be used as sole predictors of outcome. However, given the fact that they do independently correlate with DGF (RR, biomarkers) and with graft survival (RR), they are valuable in assisting clinicians in decision-making. Perhaps that implementation of these markers in existing quality scores for DGF and graft survival will increase their predictive power.97 99 Emerging technologies such as proteomics and metabolomics open new doors to investigating viability and quality assessment during HMP.

7.3.5 Can Hypothermic Machine Perfusion Be Used for Active Repair of the Injured Kidney? The capabilities of HMP to repair damaged organs and its use as a method to deliver a variety of therapies have been tested in several ways. The particular strength of this method is the ability to provide local effects without systemic exposure or uptake of drugs, cells, etc. 7.3.5.1 Reconditioning One potential use of HMP is in the reconditioning of organs prior to transplantation. Any mechanistic effect that HMP has on the kidney graft is not well understood, other than the drop in RR that is clearly evident.81 As a downstream effect there is some evidence from experimental kidney transplant studies that biomarkers of injury and of ischemia reperfusion injury are reduced by HMP.100 102 Kidneys preserved by HMP in these studies had improved tubular and renal cell function, and less protein excretion after reperfusion.100 There is some evidence that HMP improves ATP recovery, reduces perforin expression and proapoptotic signals.103 Potentially the upregulation of HIF-1α and altered expression of caspase proteins may play a protective role.104 The preserved expression of flow dependent genes might also be important.105 7.3.5.2 An Improved Preservation Solution Currently, Belzer’s HMP solution is used to perfuse kidneys. It is a gluconate-based perfusate that contains hydroxyethyl starch and, contrary to the SCS preservation solution, has a low K1 concentration to avoid vasoconstriction (Table 7.1). The constitution of the perfusion solution is likely to play an important role in the outcome of the graft after transplantation. Keeping in mind the mechanisms of ischemia reperfusion injury, it is possible that improved solutions or the addition of specific reagents targeting these mechanisms to the preservation solution could be developed. New solutions that resemble cell culture media (AQIX RS-I, Lifor) show potential.106,107 They contain amino acids, metabolic substrates, vitamins, salts, and organic buffers that make them ideal potential new solutions for HMP. 7.3.5.3 Drug Delivery HMP has proven to be a useful way to deliver potentially protective therapies to the kidney during preservation without systemic administration. Administration in this way permits adequate penetration of vascular compartments without altering perfusion dynamics and allows assessment of the degree of uptake during perfusion.108 So far experience with this method of delivery has included heparin conjugates that adhere to

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vascular endothelium.108 A water-soluble preparation of the drug Propofol has also been added to HMP with improved early graft function.109 These studies demonstrate the potential to administer therapies in this way; however, clinical results are yet to be reported. An ongoing clinical study aims to administer the inhibitor of complement, Mirococept, during HMP, which would act locally and not affect systemic complement activation (ISRCTN49958194). There are several chemical compounds including hydrogen sulfide, carbon monoxide, and nitrous oxide, which have antiapoptotic and vasodilatory effects when applied in experimental conditions.110 These could be applied during HMP. In experimental models of ischemia reperfusion injury, hydrogen sulfide administration during ischemia results in reduced TNF-alpha and IL-2 levels and neutrophil invasion with improved microvascular circulation and subsequently improved renal function.111 113 7.3.5.4 Gene-Therapy The transfection of genes targeted at inhibiting harmful pathways or stimulating protective ones is also a potential adjunct to HMP. Delivering gene-therapy during perfusion would mean that the vector (usually a virus) does not have to be administered systemically to the patient. Several gene-therapy targets have been identified which may improve ischemia reperfusion injury in transplanted kidneys.114 Potential targets to reduce acute rejection include genes that up-regulate IL-4, IL-10, IL-13, Fas-ligand or blockades of costimulatory molecules.114 Tolerogenic strategies and stimulation of regeneration are also potential avenues for gene-therapy that are now being explored.114 This technique is in the very early stages of investigation and so far there is limited evidence that renal cells can be transfected in the cold and during normothermic perfusion.115,116 7.3.5.5 Stem Cells HMP may allow the direct administration of mesenchymal stem cells (MSC) to the kidney during preservation.117 In a murine model of acute kidney failure the administration of MSC improved recovery from ischemia reperfusion injury and subsequent early kidney function.118 In a ground-breaking clinical study of living-related kidney transplants, the administration of MSC, at reperfusion and 2 weeks later, resulted in lower rates of acute rejection, less infection, and improved graft function at 1 year compared to IL-2 receptor antagonists.119 Subsequent studies have assessed the potential role of donor-derived MSC in a regimen to reduce immune suppression, administered to the recipient.120 Pretransplant administration of autologous MSC has also been tested in very small series, with some advantages over posttransplant administration.121 Further research is required to assess HMP as a potential method to deliver MSC directly to the organ, bypassing the difficulty of trafficking cells to the desired site. So far these studies have administered MSC under normothermic conditions only.

7.3.6 How Can Hypothermic Machine Perfusion Be Improved? 7.3.6.1 Effect of Temperature Traditionally both static storage and machine perfusion of kidney grafts has been done at ice-cold temperatures in order to slow down metabolism as much as possible. Machine preservation at temperatures below normothermia, but above ice-cold temperatures, has been investigated (subnormothermia) but the mechanism of action is not fully understood and the results so far in kidney transplantation are experimental only. A recent animal study in a DCD model found that kidneys stored by machine perfusion at 20 C had improved creatinine clearance compared to both SCS and oxygenated HMP.122 Given the higher metabolic demands at higher temperatures, it seems that provision for oxygenation and higher perfusate flow need to be made.122 Another experimental model of kidney preservation used “room temperature” perfusion with Lifor as perfusion solution. This type of preservation was associated with improved perfusate flow and reduced renal resistance during perfusion.123 Preservation at temperatures just below normal (30 C) with AQIX RS-I has been tested for short periods (2 hours).124 The same fluid was also tested as a potential subnormothermic flush before SCS in experimental studies.125 More work has been done with liver models of subnormothermic preservation at temperatures as diverse as 7 21 C, however the information available is still limited in its scope and applicability to clinical practice.126 Maintaining a kidney graft at temperatures closer to normothermia comes with ongoing metabolism at a faster pace that must be supported with oxygen, nutrients, and clearance of metabolites, making it a much more complex technique compared to HMP.127 The use of normothermic machine perfusion has also been extensively investigated over the past decade and has recently been introduced in the clinics.127 133 An in-depth review on normothermic machine perfusion of kidneys is given in Chapter 8, Ex-vivo Normothermic Perfusion in Renal Transplantation.

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7.3.6.2 The Addition of Oxygen Although the rational of using oxygen to sustain metabolic cell processes makes perfect sense, it is quite paradoxical that the majority of clinically applied preservation methods nowadays do not use oxygen. However, with the availability of high-tech perfusion platforms, the deteriorating quality of donor kidneys and the need to “repair” these higher-risk kidneys prior to transplantation, oxygenation is finding its way into transplant research. Increasing evidence suggests that kidneys preserved by HMP will consume oxygen, and that the level of oxygen consumption is correlated with postpreservation glomerular filtration rate.134 In that sense, adding oxygen to the preservation solution would be beneficial, especially when it comes to restoring cellular levels of ATP after the kidney has been exposed to ischemia.135 On the other hand, the presence of oxygen could potentially increase the production of radical oxygen species, thereby causing increased injury.136 The delicate balance between active oxygenation and antioxidant properties of the preservation solution will no doubt need to be taken into account. Oxygen can be delivered in a number of ways: by simple retrograde persufflation of oxygen directly through the renal vein (without necessarily using machine perfusion); during machine perfusion where oxygen can be dissolved into the perfusate; or by adding artificial oxygen carriers (e.g., acellular solution based of perfluorocarbons by Brasile et al.137 139, Hemo2Life140). The most recent studies have used technology in which a membrane oxygenator complements a more typical HMP device. There are animal auto-transplant studies published which have found indications for some benefit of oxygen provision, particularly if following a prolonged warm ischemic time.141 The major benefit seen so far is in the early kidney graft function; the study was unfortunately too small to comment on graft survival. A similar study however did not find such a stark difference in renal function when following a DBD model, with no first warm ischemic time.142 Other recent studies have compared oxygenated HMP against SCS, rather than HMP, again showing some improvement in early graft function.143,144 The use of oxygen during kidney preservation has recently been reviewed by Hosgood et al.135 As there is no clear clinical evidence to support widespread use of HMP with supplemental oxygenation, clinical trials with new technology are required. Ongoing trials of oxygenated HMP are investigating the benefit of end-ischemic oxygenated HMP versus SCS in ECD kidneys (ISRCTN63852508) and continuous oxygenated HMP versus HMP in DCD kidneys (ISRCTN32967929).

7.4 CONCLUSION SCS of the kidney in appropriate cold storage preservation solutions is still the most prevalent form of kidney preservation today. SCS is easy and affordable and can be used worldwide with acceptable results. However, with the increasing use of higher-risk kidneys we are pushing the boundaries of SCS. Technological advances, increased insight into ischemia reperfusion injury, the need to evaluate kidney quality and viability before transplantation, and the wish to repair injured organs has opened the field of machine perfusion preservation once more. For now, machine perfusion is mostly used in its hypothermic form. There is good evidence showing a reduction in DGF and survival benefit in ECD when kidneys are preserved by HMP compared to SCS. Numbers have not been large enough to identify a clear benefit of HMP on outcomes that are relatively rare, such as PNF and 1-year graft loss, despite meta-analysis of available data. Furthermore, more consistent good data are needed that focus on the benefit of HMP on graft function, including 6 and 12 months glomerular filtration rate. It appears that there is a minimum time the kidney needs to be pumped to benefit from HMP but we do not know the exact number of hours required. Other remaining questions are whether pumping should be continuous or whether a short period of (oxygenated) HMP before transplantation (end-ischemic HMP) is enough, and evidence has to be gained that HMP can be used to prolong cold ischemia. Increasing evidence suggests a benefit of oxygenated HMP, however this remains to be confirmed in clinical trials. It is also still unclear whether (sub)normothermic temperatures could improve outcomes. HMP provides additional insight on viability and quality of the kidney, however none of these data should be used as stand-alone tools to decide whether to accept or discard kidneys. Contrary to SCS, HMP offers the opportunity to repair the kidney by reconditioning, adding several drugs acting against ischemia reperfusion injury, or stem cells and this is an important challenge to be explored in preclinical and clinical trials. To date, we see a number of emerging techniques allowing in vivo and ex-vivo normothermic perfusion of organs showing good initial outcome after transplantation. In the coming years we will have to unravel which type of donor kidney will benefit most from what kind of combination of SCS, hypothermic and/or normothermic reperfusion technique—with or without active repair—to result in both optimal kidney function and longer graft survival.

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Watson PF, Morris GJ. Cold shock injury in animal cells. Symp Soc Exp Biol 1987;41:311 40. 9. Collins GM, Bravo-Shugarman M, Terasaki PI. Kidney preservation for transportation. Initial perfusion and 30 hours’ ice storage. Lancet 1969;2(7632):1219 22. 10. Eurotransplant International Foundation. Annual Report 1976. Leiden: Eurotransplant; 1976. 11. Ross H, Marshall VC, Escott ML. 72-hr canine kidney preservation without continuous perfusion. Transplantation 1976;21(6):498 501. 12. Hoffmann RM, Southard JH, Lutz M, Mackety A, Belzer FO. Synthetic perfusate for kidney preservation. Its use in 72-hour preservation of dog kidneys. Arch Surg 1983;118(8):919 21. 13. Bretschneider HJ. Myocardial protection. Thorac Cardiovasc Surg 1980;28(5):295 302. 14. Holscher M, Groenewoud AF. Current status of the HTK solution of Bretschneider in organ preservation. Transplant Proc 1991;23 (5):2334 7. 15. Codas R, Petruzzo P, Morelon E, et al. IGL-1 solution in kidney transplantation: first multi-center study. Clin Transplant 2009;23 (3):337 42. 16. Dondero F, Paugam-Burtz C, Danjou F, Stocco J, Durand F, Belghiti J. A randomized study comparing IGL-1 to the University of Wisconsin preservation solution in liver transplantation. Ann Transplant 2010;15(4):7 14. 17. O’Callaghan JM, Knight SR, Morgan RD, Morris PJ. Preservation solutions for static cold storage of kidney allografts: a systematic review and meta-analysis. Am J Transplant 2012;12(4):896 906. 18. O’Callaghan JM, Morgan RD, Knight SR, Morris PJ. Systematic review and meta-analysis of hypothermic machine perfusion versus static cold storage of kidney allografts on transplant outcomes. Br J Surg 2013;100(8):991 1001. 19. de Boer J, De Meester J, Smits JM, et al. Eurotransplant randomized multicenter kidney graft preservation study comparing HTK with UW and Euro-Collins. Transplant Int 1999;12(6):447 53. 20. Roels L, Coosemans W, Donck J, et al. Inferior outcome of cadaveric kidneys preserved for more than 24 hr in histidine-tryptophanketoglutarate solution. Leuven Collaborative Group for Transplantation. Transplantation 1998;66(12):1660 4. 21. Klaus F, Castro DB, Bittar CM, et al. Kidney transplantation with Belzer or Custodiol solution: a randomized prospective study. Transplant Proc 2007;39(2):353 4. 22. Pascual M, Theruvath T, Kawai T, Tolkoff-Rubin N, Cosimi AB. Strategies to improve long-term outcomes after renal transplantation. N Engl J Med 2002;346(8):580 90. 23. Adam R, Delvart V, Karam V, et al. Compared efficacy of preservation solutions in liver transplantation: a long-term graft outcome study from the European Liver Transplant Registry. Am J Transplant 2015;15(2):395 406. 24. Beecher H. A definition of irreversible coma. Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. JAMA 1968;205(6):337 40. 25. Selby R, Selby MT. Status of the legal definition of death. Neurosurgery 1979;5(4):535 40. 26. Eurotransplant. www.eurotransplant.org. 2015. 27. Metzger RA, Delmonico FL, Feng S, Port FK, Wynn JJ, Merion RM. Expanded criteria donors for kidney transplantation. Am J Transplant 2003;3(Suppl. 4):114 25. 28. Kootstra G, Daemen JH, Oomen AP. Categories of non-heart-beating donors. Transplant Proc 1995;27(5):2893 4. 29. Morrissey PE, Monaco AP. Donation after circulatory death: current practices, ongoing challenges, and potential improvements. Transplantation 2014;97(3):258 64. 30. Jochmans I, Darius T, Kuypers DR, et al. Kidney donation after circulatory death in a country with a high number of brain dead donors: 10-year experience in Belgium. Transplant Int 2012;25(8):857 66. 31. Summers DM, Watson CJ, Pettigrew GJ, et al. Kidney donation after circulatory death (DCD): state of the art. Kidney Int 2015;2:241 9. 32. Dominguez-Gil B, Haase-Kromwijk B, Van Leiden H, et al. Current situation of donation after circulatory death in European countries. Transplant Int 2011;24(7):676 86. 33. NHS Blood and Transplant: Transplant activity in the UK. 2013. http://www.uktransplant.org.uk/ukt/statistics 34. Belzer FO, Park HY, Vetto RM. Factors influencing renal blood flow during isolated perfusion. Surg Forum 1964;15:222 4. 35. Belzer FO, Ashby BS, Dunphy JE. 24-hour and 72-hour preservation of canine kidneys. Lancet 1967;2(7515):536 8. 36. Belzer FO, Ashby BS, Huang JS, Dunphy JE. Etiology of rising perfusion pressure in isolated organ perfusion. Ann Surg 1968;168(3):382 91. 37. Belzer FO, Ashby BS, Gulyassy PF, Powell M. Successful seventeen-hour preservation and transplantation of human-cadaver kidney. N Engl J Med 1968;278(11):608 10. 38. McAnulty JF, Ploeg RJ, Southard JH, Belzer FO. Successful five-day perfusion preservation of the canine kidney. Transplantation 1989; 47(1):37 41. 39. van der Vliet JA, Kievit JK, Hene RJ, Hilbrands LB, Kootstra G. Preservation of non-heart-beating donor kidneys: a clinical prospective randomised case-control study of machine perfusion versus cold storage. Transplant Proc 2001;33(1 2):847. 40. Kosieradzki M, Danielewicz R, Kwiatkowski A, et al. Rejection rate and incidence of acute tubular necrosis after pulsatile perfusion preservation. Transplant Proc 1999;31(1 2):278 9.

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41. Gage F, Ali M, Alijani MR, et al. Comparison of static versus pulsatile preservation of matched-paired kidneys. Transplant Proc 1997;29(8): 3644 5. 42. Veller MG, Botha JR, Britz RS, et al. Renal allograft preservation: a comparison of University of Wisconsin solution and of hypothermic continuous pulsatile perfusion. Clin Transplant 1994;8(2 Pt 1):97 100. 43. Matsuno N, Sakurai E, Tamaki I, Uchiyama M, Kozaki K, Kozaki M. The effect of machine perfusion preservation versus cold storage on the function of kidneys from non-heart-beating donors. Transplantation 1994;57(2):293 4. 44. Matsuno N, Kozaki M, Sakurai E, et al. Effect of combination in situ cooling and machine perfusion preservation on non-heart-beating donor kidney procurement. Transplant Proc 1993;25(1 Pt 2):1516 17. 45. Matsuno N, Sakurai E, Uchiyama M, Kozaki K, Tamaki I, Kozaki M. Use of in situ cooling and machine perfusion preservation for nonheart-beating donors. Transplant Proc 1993;25(6):3095 6. 46. Merion RM, Oh HK, Port FK, Toledo-Pereyra LH, Turcotte JG. A prospective controlled trial of cold-storage versus machine-perfusion preservation in cadaveric renal transplantation. Transplantation 1990;50(2):230 3. 47. Jaffers GJ, Banowsky LH. The absence of a deleterious effect of mechanical kidney preservation in the era of cyclosporine. Transplantation 1989;47(4):734 6. 48. Mendez R, Mendez RG, Koussa N, Cats S, Bogaard TP, Khetan U. Preservation effect on oligo-anuria in the cyclosporine era: a prospective trial with 26 paired cadaveric renal allografts. Transplant Proc 1987;19(1 Pt 3):2047 50. 49. Halloran P, Aprile M. A randomized prospective trial of cold storage versus pulsatile perfusion for cadaver kidney preservation. Transplantation 1987;43(6):827 32. 50. Heil JE, Canafax DM, Sutherland DE, Simmons RL, Dunning M, Najarian JS. A controlled comparison of kidney preservation by two methods: machine perfusion and cold storage. Transplant Proc 1987;19(1 Pt 3):2046. 51. Alijani MR, Cutler JA, DelValle CJ, et al. Single-donor cold storage versus machine perfusion in cadaver kidney preservation. Transplantation 1985;40(6):659 61. 52. Marshall VC. Renal preservation prior to transplantation. Transplantation 1980;30(3):165 6. 53. Toledo-Pereyra LH. Renal hypothermic storage with a new hyperosmolar colloid solution. Boletin de la Asociacion Medica de Puerto Rico 1983;75(8):347 50. 54. Beck TA. Machine versus cold storage preservation and TAN versus the energy charge as a predictor of graft function posttransplantation. Transplant Proc 1979;11(1):459 64. 55. Marshall VC, Ross H, Scott DF, McInnes S, Thomson N, Atkins RC. Preservation of cadaveric renal allografts-comparison of flushing and pumping techniques. Proc Eur Dial Transplant Assoc 1977;14:302 9. 56. Marshall VC. Problems in clinical organ preservation. Med J Aust 1977;2(11):361 4. 57. Sterling WA, Pierce JC, Hutcher NE, Lee HM, Hume DM. A comparison of hypothermic preservation with hypothermic pulsatile perfusion in paired human kidneys. Surg Forum 1971;22:229 30. 58. Wight J, Chilcott J, Holmes M, Brewer N. The clinical and cost-effectiveness of pulsatile machine perfusion versus cold storage of kidneys for transplantation retrieved from heart-beating and non-heart-beating donors. Health Technol Assess 2003;7(25):1 94. 59. Wight JP, Chilcott JB, Holmes MW, Brewer N. Pulsatile machine perfusion vs. cold storage of kidneys for transplantation: a rapid and systematic review. Clin Transplant 2003;17(4):293 307. 60. Moers C, Smits JM, Maathuis MH, et al. Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med 2009;360(1):7 19. 61. Moers C, Pirenne J, Paul A, Ploeg RJ. Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med 2012; 366(8):770 1. 62. Polyak MM, Arrington BO, Stubenbord WT, et al. The influence of pulsatile preservation on renal transplantation in the 1990s. Transplantation 2000;69(2):249 58. 63. Treckmann J, Moers C, Smits JM, et al. Machine perfusion versus cold storage for preservation of kidneys from expanded criteria donors after brain death. Transplant Int 2011;24(6):548 54. 64. Plata-Munoz JJ, Muthusamy A, Quiroga I, et al. Impact of pulsatile perfusion on postoperative outcome of kidneys from controlled donors after cardiac death. Transplant Int 2008;21(9):899 907. 65. Moustafellos P, Hadjianastassiou V, Roy D, et al. The influence of pulsatile preservation in kidney transplantation from non-heart-beating donors. Transplant Proc 2007;39(5):1323 5. 66. St Peter SD, Imber CJ, Friend PJ. Liver and kidney preservation by perfusion. Lancet 2002;359(9306):604 13. 67. Opelz G, Terasaki PI. Advantage of cold storage over machine perfusion for preservation of cadaver kidneys. Transplantation 1982;33(1):64 8. 68. Jochmans I, Moers C, Smits JM, et al. Machine perfusion versus cold storage for the preservation of kidneys donated after cardiac death: a multicenter randomized controlled trial. Ann Surg 2010;252(5):756 64. 69. Kokkinos C, Antcliffe D, Nanidis T, Darzi AW, Tekkis P, Papalois V. Outcome of kidney transplantation from nonheart-beating versus heart-beating cadaveric donors. Transplantation 2007;83(9):1193 9. 70. Brook NR, Waller JR, Nicholson ML. Nonheart-beating kidney donation: current practice and future developments. Kidney Int 2003;63(4): 1516 29. 71. Kootstra G, van Heurn E. Non-heartbeating donation of kidneys for transplantation. Nat Clin Pract Nephrol 2007;3(3):154 63. 72. Summers DM, Johnson RJ, Hudson A, Collett D, Watson CJ, Bradley JA. Effect of donor age and cold storage time on outcome in recipients of kidneys donated after circulatory death in the UK: a cohort study. Lancet 2012. 73. Watson CJE, Wells AC, Roberts RJ, et al. Cold machine perfusion versus static cold storage of kidneys donated after cardiac death: a UK multicenter randomized controlled trial. Am J Transplant 2010;10:1991 9. 74. Lam VW, Laurence JM, Richardson AJ, Pleass HC, Allen RD. Hypothermic machine perfusion in deceased donor kidney transplantation: a systematic review. J Surg Res 2013;180(1):176 82. 75. Deng R, Gu G, Wang D, et al. Machine perfusion versus cold storage of kidneys derived from donation after cardiac death: a metaanalysis. PLoS One 2013;8(3):e56368. 76. Bathini V, McGregor T, McAlister VC, Luke PP, Sener A. Renal perfusion pump vs cold storage for donation after cardiac death kidneys: a systematic review. J Urol 2013;189(6):2214 20.

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77. Jiao B, Liu S, Liu H, Cheng D, Cheng Y, Liu Y. Hypothermic machine perfusion reduces delayed graft function and improves one-year graft survival of kidneys from expanded criteria donors: a meta-analysis. PLoS One 2013;8(12):e81826. 78. Bond M, Pitt M, Akoh J, Moxham T, Hoyle M, Anderson R. The effectiveness and cost-effectiveness of methods of storing donated kidneys from deceased donors: a systematic review and economic model. Health Technol Assess 2009;13(38):1 156 iii iv, xi xiv 79. Groen H, Moers C, Smits JM, et al. Cost-effectiveness of hypothermic machine preservation versus static cold storage in renal transplantation. Am J Transplant 2012;12(7):1824 30. 80. Patel SK, Pankewycz OG, Nader ND, Zachariah M, Kohli R, Laftavi MR. Prognostic utility of hypothermic machine perfusion in deceased donor renal transplantation. Transplant Proc 2012;44(7):2207 12. 81. Jochmans I, Moers C, Smits JM, et al. The prognostic value of renal resistance during hypothermic machine perfusion of deceased donor kidneys. Am J Transplant 2011;11(10):2214 20. 82. Gallinat A, Paul A, Efferz P, et al. Hypothermic reconditioning of porcine kidney grafts by short-term preimplantation machine perfusion. Transplantation 2012;93(8):787 93. 83. Gallinat A, Efferz P, Paul A, Minor T. One or 4 h of “in-house” reconditioning by machine perfusion after cold storage improve reperfusion parameters in porcine kidneys. Transplant Int 2014;27(11):1214 19. 84. Hosgood SA, Mohamed IH, Bagul A, Nicholson ML. Hypothermic machine perfusion after static cold storage does not improve the preservation condition in an experimental porcine kidney model. Br J Surg 2011;98(7):943 50. 85. Gallinat A, Moers C, Treckmann J, et al. Machine perfusion versus cold storage for the preservation of kidneys from donors ./ 5 65 years allocated in the Eurotransplant Senior Programme. Nephrol Dial Transplant 2012;27(12):4458 63. 86. Gill J, Dong J, Eng M, Landsberg D, Gill JS. Pulsatile perfusion reduces the risk of delayed graft function in deceased donor kidney transplants, irrespective of donor type and cold ischemic time. Transplantation 2014;97(6):668 74. 87. Opelz G, Dohler B. Multicenter analysis of kidney preservation. Transplantation 2007;83(3):247 53. 88. Sung RS, Christensen LL, Leichtman AB, et al. Determinants of discard of expanded criteria donor kidneys: impact of biopsy and machine perfusion. Am J Transplant 2008;8(4):783 92. 89. Jochmans I, Moers C, Smits JM, et al. The prognostic value of renal resistance during hypothermic machine perfusion of deceased donor kidneys. Am J Transplant 2011;11:2214 20. 90. de Vries EE, Hoogland ER, Winkens B, Snoeijs MG, van Heurn LW. Renovascular resistance of machine-perfused DCD kidneys is associated with primary nonfunction. Am J Transplant 2011;11(12):2685 91. 91. Bhangoo RS, Hall IE, Reese PP, Parikh CR. Deceased-donor kidney perfusate and urine biomarkers for kidney allograft outcomes: a systematic review. Nephrol Dial Transplant 2012;27(8):3305 14. 92. Gok MA, Pelsers M, Glatz JF, et al. Use of two biomarkers of renal ischemia to assess machine-perfused non-heart-beating donor kidneys. Clin Chem 2003;49(1):172 5. 93. Gok MA, Pelzers M, Glatz JF, et al. Do tissue damage biomarkers used to assess machine-perfused NHBD kidneys predict long-term renal function post-transplant?. Clin Chim Acta 2003;338(1 2):33 43. 94. Daemen JW, Oomen AP, Janssen MA, et al. Glutathione-S-transferase as predictor of functional outcome in transplantation of machinepreserved non-heart-beating donor kidneys. Transplantation 1997;63(1):89 93. 95. Moers C, Varnav OC, van Heurn E, et al. The value of machine perfusion perfusate biomarkers for predicting kidney transplant outcome. Transplantation 2010;90(9):966 73. 96. Hoogland ER, de Vries EE, Christiaans MH, Winkens B, Snoeijs MG, van Heurn LW. The value of machine perfusion biomarker concentration in DCD kidney transplantations. Transplantation 2013;95(4):603 10. 97. Irish WD, Ilsley JN, Schnitzler MA, Feng S, Brennan DC. A risk prediction model for delayed graft function in the current era of deceased donor renal transplantation. Am J Transplant 2010;10:2279 86. 98. Irish WD, McCollum DA, Tesi RJ, et al. Nomogram for predicting the likelihood of delayed graft function in adult cadaveric renal transplant recipients. J Am Soc Nephrol 2003;14(11):2967 74. 99. Rao PS, Schaubel DE, Guidinger MK, et al. A comprehensive risk quantification score for deceased donor kidneys: the kidney donor risk index. Transplantation 2009;88(2):231 6. 100. Hosgood SA, Yang B, Bagul A, Mohamed IH, Nicholson ML. A comparison of hypothermic machine perfusion versus static cold storage in an experimental model of renal ischemia reperfusion injury. Transplantation 2010;89:830 7. 101. Vaziri N, Thuillier R, Favreau FD, et al. Analysis of machine perfusion benefits in kidney grafts: a preclinical study. J Transl Med 2011;9:15. 102. Codas R, Thuillier R, Hauet T, Badet L. Renoprotective effect of pulsatile perfusion machine RM3: pathophysiological and kidney injury biomarker characterization in a preclinical model of autotransplanted pig. BJU Int 2012;109(1):141 7. 103. La Manna G, Conte D, Cappuccilli ML, et al. An in vivo autotransplant model of renal preservation: cold storage versus machine perfusion in the prevention of ischemia/reperfusion injury. Artif Organs 2009;33(7):565 70. 104. Jani A, Zimmerman M, Martin J, et al. Perfusion storage reduces apoptosis in a porcine kidney model of donation after cardiac death. Transplantation 2011;91(2):169 75. 105. Gracia-Sancho J, Villarreal Jr. G, Zhang Y, et al. Flow cessation triggers endothelial dysfunction during organ cold storage conditions: strategies for pharmacologic intervention. Transplantation 2010;90(2):142 9. 106. Kay MD, Hosgood SA, Harper SJ, Bagul A, Waller HL, Nicholson ML. Normothermic versus hypothermic ex vivo flush using a novel phosphate-free preservation solution (AQIX) in porcine kidneys. J Surg Res 2011;171:275 82. 107. Gage F, Leeser DB, Porterfield NK, et al. Room temperature pulsatile perfusion of renal allografts with Lifor compared with hypothermic machine pump solution. Transplant Proc 2009;41(9):3571 4. 108. Sedigh A, Larsson R, Brannstrom J, et al. Modifying the vessel walls in porcine kidneys during machine perfusion. J Surg Res 2014; 191(2):455 62. 109. Snoeijs MG, Vaahtera L, de Vries EE, et al. Addition of a water-soluble propofol formulation to preservation solution in experimental kidney transplantation. Transplantation 2011;92(3):296 302. 110. Snijder PM, de Boer RA, Bos EM, et al. Gaseous hydrogen sulfide protects against myocardial ischemia-reperfusion injury in mice partially independent from hypometabolism. PLoS One 2013;8(5):e63291.

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111. Hunter JP, Hosgood SA, Patel M, Rose R, Read K, Nicholson ML. Effects of hydrogen sulphide in an experimental model of renal ischaemia-reperfusion injury. Br J Surg 2012;99(12):1665 71. 112. Zhu JX, Kalbfleisch M, Yang YX, et al. Detrimental effects of prolonged warm renal ischaemia-reperfusion injury are abrogated by supplemental hydrogen sulphide: an analysis using real-time intravital microscopy and polymerase chain reaction. BJU Int 2012;110 (11 Pt C):E1218 27. 113. Hosgood SA, Nicholson ML. Hydrogen sulphide ameliorates ischaemia-reperfusion injury in an experimental model of non-heartbeating donor kidney transplantation. Br J Surg 2010;97(2):202 9. 114. Sandovici M, Deelman LE, de Zeeuw D, van Goor H, Henning RH. Immune modulation and graft protection by gene therapy in kidney transplantation. Eur J Pharmacol 2008;585(2-3):261 9. 115. Yang B, Elias JE, Bloxham M, Nicholson ML. Synthetic small interfering RNA down-regulates caspase-3 and affects apoptosis, IL-1 beta, and viability of porcine proximal tubular cells. J Cell Biochem 2011;112(5):1337 47. 116. Brasile L, Stubenitsky BM, Booster MH, Arenada D, Haisch C, Kootstra G. Transfection and transgene expression in a human kidney during ex vivo warm perfusion. Transplant Proc 2002;34(7):2624. 117. Van Raemdonck D, Neyrinck A, Rega F, Devos T, Pirenne J. Machine perfusion in organ transplantation: a tool for ex-vivo graft conditioning with mesenchymal stem cells?. Curr Opin Organ Transplant 2013;18(1):24 33. 118. Lange C, Togel F, Ittrich H, et al. Administered mesenchymal stem cells enhance recovery from ischemia/reperfusion-induced acute renal failure in rats. Kidney Int 2005;68(4):1613 17. 119. Tan J, Wu W, Xu X, et al. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA 2012;307(11):1169 77. 120. Peng Y, Ke M, Xu L, et al. Donor-derived mesenchymal stem cells combined with low-dose tacrolimus prevent acute rejection after renal transplantation: a clinical pilot study. Transplantation 2013;95(1):161 8. Available from: http://dx.doi.org/10.1097/TP.0b013e3182754c53 121. Perico N, Casiraghi F, Gotti E, et al. Mesenchymal stromal cells and kidney transplantation: pretransplant infusion protects from graft dysfunction while fostering immunoregulation. Transplant Int 2013;26(9):867 78. 122. Hoyer DP, Gallinat A, Swoboda S, et al. Subnormothermic machine perfusion for preservation of porcine kidneys in a donation after circulatory death model. Transplant Int 2014;27(10):1097 106. 123. Gage F, Leeser DB, Porterfield NK, et al. Room temperature pulsatile perfusion of renal allografts with Lifor compared with hypothermic machine pump solution. Transplant Proc 2009;41(9):3571 4. 124. Kay MD, Hosgood SA, Harper SJF, et al. Static normothermic preservation of renal allografts using a novel nonphosphate buffered preservation solution. Transplant Int 2007;20(1):88 92. 125. Kay MD, Hosgood SA, Harper SJ, Bagul A, Waller HL, Nicholson ML. Normothermic versus hypothermic ex vivo flush using a novel phosphate-free preservation solution (AQIX) in porcine kidneys. J Surg Res 2011;171(1):275 82. 126. Graham JA, Guarrera JV. “Resuscitation” of marginal liver allografts for transplantation with machine perfusion technology. J Hepatol 2014;61(2):418 31. 127. Hosgood SA, van Heurn E, Nicholson ML. Normothermic machine perfusion of the kidney: better conditioning and repair? Transplant Int 2014. 128. Patel M, Hosgood S, Nicholson ML. The effects of arterial pressure during normothermic kidney perfusion. J Surg Res 2014;191(2):463 8. 129. Hosgood SA, Nicholson ML. Ex vivo normothermic perfusion of declined human kidneys after inadequate in situ perfusion. Am J Transplant 2014;14(2):490 1. 130. Nicholson ML, Hosgood SA. Renal transplantation after ex vivo normothermic perfusion: the first clinical study. Am J Transplant 2013; 13(5):1246 52. 131. Hosgood SA, Nicholson ML. Normothermic kidney preservation. Curr Opin Organ Transplant 2011;16(2):169 73. 132. Hosgood SA, Nicholson ML. First in man renal transplantation after ex vivo normothermic perfusion. Transplantation 2011;92(7):735 8. 133. Hosgood SA, Barlow AD, Yates PJ, Snoeijs MG, van Heurn EL, Nicholson ML. A pilot study assessing the feasibility of a short period of normothermic preservation in an experimental model of non-heart beating donor kidneys. J Surg Res 2011;171(1):283 90. 134. Bunegin L, Tolstykh GP, Gelineau JF, Cosimi AB, Anderson LM. Oxygen consumption during oxygenated hypothermic perfusion as a measure of donor organ viability. ASAIO J 2013;59(4):427 32. 135. Hosgood SA, Nicholson HF, Nicholson ML. Oxygenated kidney preservation techniques. Transplantation 2012;93(5):455 9. 136. Fuller BJ, Lee CY. Hypothermic perfusion preservation: the future of organ preservation revisited? Cryobiology 2007;54(2):129 45. 137. Brasile L, Stubenitsky BM, Booster MH, Arenada D, Haisch C, Kootstra G. Hypothermia--a limiting factor in using warm ischemically damaged kidneys. Am J Transplant 2001;1(4):316 20. 138. Brasile L, Stubenitsky BM, Booster MH, et al. Overcoming severe renal ischemia: the role of ex vivo warm perfusion. Transplantation 2002;73(6):897 901. 139. Brasile L, Stubenitsky BM, Haisch CE, Kon M, Kootstra G. Repair of damaged organs in vitro. Am J Transplant 2005;5(2):300 6. 140. Thuillier R, Dutheil D, Trieu MT, et al. Supplementation with a new therapeutic oxygen carrier reduces chronic fibrosis and organ dysfunction in kidney static preservation. Am J Transplant 2011;11(9):1845 60. 141. Thuillier R, Allain G, Celhay O, et al. Benefits of active oxygenation during hypothermic machine perfusion of kidneys in a preclinical model of deceased after cardiac death donors. J Surg Res 2013;184(2):1174 81. 142. Gallinat A, Paul A, Efferz P, et al. Role of oxygenation in hypothermic machine perfusion of kidneys from heart beating donors. Transplantation 2012;94(8):809 13. 143. Maathuis M-HJ, Manekeller S, van der Plaats A, et al. Improved kidney graft function after preservation using a novel hypothermic machine perfusion device. Ann Surgery 2007;246(6):982 8. 144. Doorschodt BM, Schreinemachers MC, Florquin S, et al. Evaluation of a novel system for hypothermic oxygenated pulsatile perfusion preservation. Int J Artif Organs 2009;32(10):728 38. 145. OPTN. 2009 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1999 2008. U.S. Department of Health and Human Services, Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation, Rockville, MD. 2009. http://optn.transplant.hrsa.gov

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C H A P T E R

8 Ex-vivo Normothermic Perfusion in Renal Transplantation Sarah A. Hosgood and Michael L. Nicholson University of Cambridge, Cambridge, United Kingdom

8.1 INTRODUCTION Since the 1970s, organ preservation has relied on the principle of cooling to reduce cellular metabolism and slow the injury processes.1 This allows the organ to be allocated nationally to the most suitable and best immunologically matched recipient. However, the boundaries of kidney transplantation are increasingly being extended and there is more reliance on the use of so-called marginal donors to accommodate the increasing demand.2,3 These kidneys present with higher incidences of early graft dysfunction4 and reduced survival compared to the traditional donor sources.5 The inferior outcome of these kidneys is directly influenced by the hypothermic temperatures during preservation.2,6 The widespread adoption of hypothermic preservation in organ transplantation was based on the early experimental studies by Lapchinsky in the Soviet Union in the 1950s,7 and the work of Carrel and Lindbergh in the 1930s.8
12 They showed that ischemic injury could be minimized by reducing the temperature. In 1963, Calne et al. used the concept of hypothermic temperatures to extend the preservation time and successfully transplanted canine kidneys after 12 hours of storage.13 This led to the universal application of hypothermic preservation in clinical organ transplantation. Hypothermic temperatures act to inhibit the enzymatic processes and prevent injury. There is a two- to threefold decrease in metabolism for every 10 C reduction in temperature.14,15 This slows the degrading processes, but at the same time the anaerobic environment leads to progressive damage. The intracellular pH is lowered, which causes lysosomal instability. The depletion of adenosine triphosphate (ATP) allows the build-up toxic metabolites, adenosine, inosine, and hypoxanthine. Inactivation of the NA1/K1 ATPase pumps allows the accumulation of calcium, sodium, and water within the cell. The damage caused by hypothermic conditions is evident upon reperfusion when normal circulation is restored to the organ.16,17 The downstream effects of ischemia reperfusion (I/R) injury results in the impairment of blood flow to the kidney and reduced urine output after transplantation.18 I/R injury is a major determinant of acute kidney injury (AKI) and delayed graft function (DGF).19,20 This also has important consequences on long-term graft survival. Large data series have shown that the cold ischemic time is an independent risk factor for graft failure.2,21 An alternative technique of preservation is to use normothermic temperatures, to support circulation and metabolism and prevent cellular deterioration.

8.2 THE ORIGIN OF NORMOTHERMIC PERFUSION The concept of organ preservation was first proposed by the French physician, scientist, and philosopher, Julien Jean Cesar le Gallois, in 1813.22 He stated that, “If one could replace for the heart some kind of injection of Kidney Transplantation, Bioengineering, and Regeneration. DOI: http://dx.doi.org/10.1016/B978-0-12-801734-0.00008-4

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artificial blood, either natural or artificially made . . . one could succeed easily in maintaining alive indefinitely any part of the body.” Alexis Carrel, a French surgeon and scientist in the early 1900s, was one of the first to study the effects of tissue preservation at both hypothermic and normothermic temperatures.8
12 In 1912, he won the Nobel Prize for his work on vascular sutures and the experimental transplantation of blood vessels and organs. He discovered that cooling allowed tissues to retain viability for longer periods compared to normal temperatures, and demonstrated the ability to transplant blood vessels after several days when stored in a specially designed solution (Locke’s solution). Nonetheless, he pursued the idea of keeping organs alive and functioning at warmer temperatures. With the help of Charles Lindbergh, an engineer and pilot, he developed the first organ perfusion device, in 1935. The system was capable of maintaining a sterile, pulsating circulation of fluid through a living organ. It was made up of three glass chambers, an organ chamber at the top, a pressure equalizing chamber in the middle, and fluid chamber on the bottom. A mixture of oxygen, carbon dioxide, and nitrogen was pulsated by compressed air into the perfusate through the equalizing chamber and into the organ. They perfused a variety of organs such as the thyroid, suprarenal gland, ovary, spleen, heart, and kidney from adult fowls and cats. The organs were perfused with a nutrient fluid designed to culture the organs which often contained blood, serum, or solutions containing proteinsplit products such as hemin, cysteine, insulin, thyroxine, glutathione, vitamin A, and ascorbic acid. This perfusion system allowed the organs to be studied in an ex vivo environment to acquire knowledge on the metabolic processes and nutrient requirements of individual organs.8
12 Towards the end of his career, his political and radical views were questioned, and his research at this time was disregarded by many. Nonetheless, his research pioneered the development of the extracorporeal perfusion systems that are widely used today in cardiac surgery and indeed for the last decade, to perfuse isolated organs at normothermic temperatures ex vivo.

8.3 TECHNOLOGY In the 1990s, driven by the shortage of donors and increasing use of what was then termed nonheart beating donor kidneys, an interest in normothermic perfusion techniques was renewed. Several groups identified a need for alternative techniques of preservation to allow more marginal organs to be used and to improve their outcome. Brasile et al. published a series of manuscripts detailing an acellular normothermic perfusion system.23
26 The exsanguinous metabolic support (EMS) system was a pressure-controlled device which included an oxygenator and pulsatile pump with controllers to maintain PaO2, PaCO2, pH, and temperature. Kidneys were perfused at a subnormal temperature of 32 C and mean arterial pressure of approximately 35 mmHg with an acellular culture-like medium solution. In 2006, our group (Hosgood & Nicholson) reported the use of an adapted pediatric cardiopulmonary bypass system incorporating a centrifugal pump, a membrane oxygenator, venous reservoir, and heat exchanger. Kidneys were perfused at a near physiological pressure (75 mmHg) and temperature (36 C) with a packed red cell based solution.27
29 A priming solution containing a crystalloid solution with mannitol, an infusion of a vasodilator (prostacyclin), and nutrient solution, provided a stable environment for the kidney. There are other isolated reports of systems that have adapted or modified hypothermic perfusion technology,30 or used custom-made devices with roller pumps and dialysis circuits31,32 to obtain optimal renal function. There is one commercially available system; “The Kidney Assist” made by a Dutch company “Organ Assist.” It is a transportable, oxygenated kidney perfusion system that can be used at hypothermic or normothermic temperatures. It is a pressure-controlled device which includes a rotary pump to deliver a pulsatile flow. A hollow fiber oxygenator is also included in the system to oxygenate the blood based solution. Despite the availability of this system there are no current reports of its application in kidney transplantation.

8.4 PERFUSION CONDITIONS 8.4.1 Artificial Solutions One of the crucial requirements of a normothermic perfusion medium is the inclusion of an oxygen carrier to ensure adequate aerobic metabolism. The first reports by Brasile et al. describing the use of an acellular normothermic solution included a perflourocarbon (PFC) emulsion (Perflubron) as the oxygen carrier.23 It was mixed with an enriched tissue culture-like medium containing essential and nonessential amino acids, lipids, and

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carbohydrates to provide nutritional support. PFCs are inert solutions that have a high capacity for dissolving oxygen.33 However, the first generation PFCs used at this time were relatively unstable solutions with variable half-lives and an inability to be sterilized. When administered intravenously they caused side effects such as anaphylaxis, hypotension, reduced platelet count, and complement activation.33 As a result they were not applied clinically. Historically, other artificial hemoglobin based oxygen carriers have also been used as preservation mediums.34 A stroma-free hemoglobin based solution was an effective oxygen carrier however it was found to cause toxic effects on the kidney. A more stable pyridoxalated hemoglobin-polyoxyethylene solution has proved to be more successful and Brasile et al. went on to replace the PFC in their perfusion medium with this solution.35 New more stable 2nd and 3rd generation PFCs are being developed, mainly as blood substitutes, and there is interest in their use as a kidney preservation medium. In a unique study, Humphreys et al. used a commercially made PFC (Oxygent) to provide oxygenation and reduce ischemic injury.36 Rabbit kidneys were perfused using a retrograde infusion through the urinary collecting system. These new generation PFCs could potentially be developed as normothermic preservation solutions. However, due to the complexity of manufacturing, the cost is considerable, which may limit their adaptation. Other novel solutions such as Lifor, an artificial preservation medium containing a nonprotein oxygen carrier, nutrients, and a growth factor have also been used for preservation at more normothermic temperatures.37 Gage et al. showed that porcine kidneys perfused with Lifor at room temperature had higher flow rates and lower levels of resistance compared to kidneys perfused with UW at room temperature or at 4 C.37 There was no information on the outcome of the kidney, however the higher perfusion flows suggested better preservation of the cellular structure. AQIX-RS-I is a nonphosphate buffered solution designed to support cellular activity at a normothermic temperature.38 The composition of AQIX-RS-1 reflects physiological ionic concentrations, osmolarity, and ion conductivity, to maintain the cell membrane and enzymatic processes. AQIX-RS-1 is capable of carrying oxygen in solution or when mixed with red blood cells. Studies in the heart have shown an advantage compared to a standard cardioplegia solution.39 In the kidney, our group showed that kidneys could be flushed and statically stored for 2 hours at 32 C using AQIX-RS-1 solution and therefore it has potential as a normothermic perfusion medium.38 Hemarina-M101 is a new extracellular hemoglobin derived from a marine invertebrate.40 It has been formulated into an oxygen carrier called Hemoxycarrier. It has a high affinity for oxygen accompanied with an antioxidant activity and has been added to cold storage (CS) solutions with favorable results. It functions over a wide range of temperatures (4
37 C), which makes it attractive as a future normothermic perfusion solution.

8.4.2 Blood Based Solutions Blood based solutions were previously considered to have their limitations with prolonged periods of perfusion causing gross hemolysis, platelet activation, and deterioration in the oxygen carrying capacity of the red blood cells.41 High intrarenal resistance and tissue edema was a significant problem. However, with the development of improved atraumatic centrifugal pumps and equipment used in cardiac bypass surgery, hemolysis is less of a problem. Modern pumps reduce the risk of stress and hemolysis and the membrane oxygenators enable filtration and highly efficient oxygenation.42 They provide a more natural environment and at present are more cost effective as a perfusate compared to the artificial solutions. The use of banked packed red cells has the added advantage of the absence of leukocytes, platelets, and complement, limiting neutrophil infiltration and the inflammatory response in the kidney during perfusion.8

8.4.3 Temperature A variety of temperatures have been used in kidney normothermic systems, ranging from 32 C to normal body temperature. They all appear to have successful outcomes but there have been no direct comparisons between the conditions. Schopp et al. proposed that the abrupt change in temperature from CS to reperfusion could lead to mitochondrial dysfunction and proapoptotic signal transduction.43 In a series of experiments with porcine kidneys they showed that a gradual controlled rewarming preserved renal function and reduced

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postischaemic injury to the mitochondria. This is a technique that could be simply applied during ex vivo normothermic perfusion (EVNP) and warrants further investigation.

8.5 END EX-VIVO NORMOTHERMIC PERFUSION Normothermic perfusion can be carried out for prolonged periods to avoid hypothermic injury. However, logistically this is difficult when kidneys are transported from donor to recipient centers. At present there is little evidence for the necessity to normothermically perfuse kidneys for a prolonged period. Much of the recent work has focused on using normothermic perfusion in conjunction with hypothermic techniques. This simplifies the logistical problems and also appears to be beneficial. A brief period of normothermic perfusion can upregulate protective mechanisms such as heat shock protein 70.44 This aids the repair process and primes the kidney in preparation for reperfusion. A central component of protection is the replenishment of ATP, which prevents the further breakdown of metabolites and restores normal cellular function. Brasile et al. found that although kidneys could be maintained for a significant period of time, up to 48 hours,45 a short period of ex vivo warm perfusion at the end of the preservation period can adequately resuscitate the kidney.46 Our group adopted this principle and demonstrated in porcine kidneys that 2 hours of end EVNP with leukocyte depleted blood could enhance the renal blood flow during reperfusion and reverse some of the detrimental effects of warm and cold ischemic injury.29 The technique was assessed in a porcine autotransplantation model and we found that animals that received a kidney that had been resuscitated using EVNP recovered function sooner than those undergoing hypothermic machine perfusion alone.47 The technique was concluded to be a safe and feasible method of kidney preservation and provided the evidence needed to translate the technique into clinical practice.

8.5.1 Clinical end Ex-Vivo Normothermic Perfusion Brasile et al. was the first to report the perfusion of human kidneys using the EMS system, however these were only used in an experimental setting and not transplanted.48 Based on the evidence from our experimental work, in 2011 our group reported the first case of EVNP followed by the transplantation of an extended criteria donor (ECD) kidney.49 The technology was identical to our experimental model except that a unit of oxygenated compatible packed red cells from the blood bank was used instead of leukocyte depleted autologous blood. The donor had an out-of-hospital cardiac arrest (1 hour) and based on the history, the kidney was declined by six transplant centers in the United Kingdom. On arrival at the recipient center the kidney had a short period of EVNP (35 minutes) after nearly 11 hours of cold ischemia. The recipient, a 55-year-old dialysis dependent lady, had slow graft function after the transplant but remained dialysis free. She had good graft function at 3 months posttransplant and at 4 years posttransplant her kidney function remains excellent. In the second report we demonstrated the feasibility and safety of the technique in a series of ECD kidneys.50 Using the same technique and technology, 17 kidneys underwent EVNP for just over 60 minutes prior to transplantation. The outcome was compared to a matched control group of 47 ECD kidneys which had CS alone. Only 1/17 (5.6%) patients in the EVNP group had DGF compared to 17/47 (36.2%) in the control group. A randomized controlled trial is planned to assess EVNP and will recruit 400 patients undergoing a DCD kidney transplantation (Maastricht Categories III & IV). Recruits will be allocated at random in a 1:1 ratio to either static CS plus 1 hour of EVNP or CS only. The primary outcome measure will be DGF defined as the need for dialysis in the first 7 days posttransplantation. Secondary outcome measures will include measures of early and longer-term graft function (12 months), length of hospital stay, graft and patient survival, and episodes of rejection.

8.6 INTERMEDIATE EX VIVO NORMOTHERMIC PERFUSION Reestablishing cellular function using EVNP can also be carried out at an earlier time point, e.g., in between periods of hypothermic preservation. Clinically this would be practical when access to theater may be delayed. In the 1980s, van Der Wijk et al. used this technique of intermediate normothermic perfusion to extend the preservation period.51 Canine kidneys were preserved for 144 hours using a combination of hypothermic and normothermic preservation techniques. Halfway through the preservation period kidneys were perfused with blood

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before returning to hypothermic preservation. Three and four hours of perfusion were deemed necessary to reverse the ischemic damage. In another report Rijkmans et al. was able to extend the preservation period to 6 days with a 3-hour period of normothermic perfusion in the middle.52 Although rather extreme durations of preservation, these studies support the use of normothermic perfusion in this way.

8.6.1 Clinical Intermediate Ex Vivo Normothermic Perfusion We reported a single case of intermediate EVNP in clinical kidney transplantation.53 The ECD kidney had 10 hours 30 minutes of cold ischemia before undergoing 60 minutes of EVNP using the same cardiopulmonary bypass technology. The kidney demonstrated a good level of renal function during perfusion. After EVNP, the kidney was flushed with cold preservation solution and repacked in ice. Due to ill health of the first intended recipient the kidney had a second period of cold ischemia (5 hours and 21 minutes). The kidney was transplanted without any complications and the recipient had immediate graft function. There were no untoward effects of the additional cold ischemic insult after EVNP, implying that this technique was feasible and safe. Although further evidence is needed, EVNP applied in this way may be an effective way to reduce the effects of cold ischemic injury or perhaps extend the length of preservation as shown in the early experimental models.

8.7 KIDNEY MANIPULATION/CONDITIONING Normothermic preservation provides a unique opportunity to manipulate or treat the kidney prior to transplantation. This ensures the direct administration of a therapy to the targeted organ and avoids unwanted side effects in the recipients that are associated with many therapies. Brasile et al. found that the protective gene hemeoxygenase-1 (HO-1) could be up-regulated within the kidney with the administration of cobalt protoporphyrin (CoPP) during normothermic perfusion even after significant periods of warm ischemia.54 In contrast, CoPP administered during hypothermic machine perfusion had no effect on the expression of HO-1. HO-1 is one of the three isoforms that catalyze the conversion of heme to biliverdin, free iron and carbon monoxide. These compounds reduce free radical injury and have antiinflammatory actions. Brasile et al. also demonstrated that kidneys could be repaired after 2 hours of warm ischemia with the addition of fibroblast growth factors during normothermic perfusion.55 They showed that cellular processes should be supported, and protein synthesis was evident during 24 hours of ex vivo perfusion of nontransplanted human kidneys. More recently they have explored the application a of nanobarrier membrane (NB-LVF4) during 3 hours of normothermic perfusion to delay the onset of rejection in canine kidneys.56 Delivering genes to block or stimulate protective pathways targeting acute and chronic rejection or ischemia reperfusion injury is an attractive therapy in transplantation.57 Brasile et al. demonstrated that the kidney could be effectively transfected during 24 hours of EVNP.45 They administered the recombinant adenovirus, Ad5, CMV5 GFP encoded with green fluorescence protein and found that effective transfection and synthesis occurred. The reporter gene GFP localized in the intima of the blood vessels, demonstrating the ability to deliver and target the vascular endothelium. RNA interference using a 21-nucleotide small interfering RNA (siRNA) is another approach to modulating and protecting the kidney.58,59 The introduction of a double-stranded RNA elicits the selective degradation of homologous mRNA transcripts. siRNA are capable of blocking gene expression in mammalian cells and have proved to be a potent and specific method of gene silencing.58,59 We have demonstrated siRNA’s ability to reduce caspase 3 expression and reduce some of the effects of reperfusion injury in the isolated kidney when added to the cold preservation solution.60 The effect maybe greater when administered under normothermic conditions, but it is likely that prolonged periods of EVNP are needed to ensure that the kidney is modified before reperfusion. Nonetheless, shorter periods of perfusion may be used to deliver the genes and target the later events in the reperfusion and immune cascade. Experimentally, we have also explored the use of gaseous molecules administered during EVNP to further ameliorate the effects of ischemic injury.61 Gaseous molecules such as nitric oxide donors or carbon monoxide in the form of soluble carbon monoxide-releasing molecules (CORMs) can enhance renal blood flow via the activation of soluble hem-containing guanylate cyclase to produce guanosine 30 , 50 -cyclic monophosphate (cGMP) in vascular smooth muscle, causing relaxation. In an ex vivo model, kidneys were treated with a carbon monoxidereleasing molecule (CORM-3). These kidneys had improved renal and tubular cell function and lower intra renal resistance after reperfusion compared to kidneys treated with a nitric oxide donor.61

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In the clinical setting there has been no reported use of the treatment of kidneys during normothermic perfusion. Nonetheless, with further development of the technology and more prolonged perfusion times, normothermic perfusion could be used to manipulate the kidney, targeting specific genes associated with ischemia reperfusion injury, rejection, or fibrosis.

8.8 RESUSCITATION EVNP may also be used to recover kidneys that have been declined for transplantation. Inadequate in situ perfusion at the time of retrieval is particularly common in kidneys from DCD donors. Inadequately perfused kidneys are likely to have additional warm ischemic injury due to incomplete cooling during retrieval.62,63 The microcirculation is also likely to be compromised and the cumulative damage caused by a period of hypothermic preservation can result in irreversible injury. Therefore, many of these kidneys are regarded as unsuitable for transplantation. We reported a single case of a pair of human kidneys declined for transplantation due to inadequate in situ perfusion.64 Both kidneys were retrieved from a 42-year-old DCD donor. The donor had no previous medical history and the kidneys were retrieved using a standard technique of in situ cooling via an aortic cannula and flush-out with cold University of Wisconsin (UW) solution. After the in situ flush both kidneys appeared inadequately perfused. An attempt was made to flush the kidneys on the back table but both failed to flush properly and they were deemed unsuitable for transplantation. The kidneys were offered for research and after approximately 9 hours, an attempt was made to flush the kidneys again. Some blood was cleared from each kidney but they remained patchy in appearance (Fig. 8.1A). The kidneys were then perfused using EVNP for 60 minutes. Both kidneys appeared pink and evenly perfused and the blood flow improved throughout perfusion (Fig. 8.1B). Each kidney also produced a significant amount of urine. A biopsy was taken after EVNP which showed significant donor-related changes and some evidence of acute tubular injury, but the nuclei appeared normal and there was no evidence of cortical necrosis in either kidney. Although the kidneys were not transplanted, this case shows the ability of EVNP to recover organs and assess the functional capacity of a kidney prior to transplantation.

8.9 VIABILITY/QUALITY ASSESSMENT Reestablishing renal function ex vivo is likely to be an informative measure of organ quality and acceptability for transplantation. Brasile et al. were able to measure renal function and metabolism during perfusion to assess the level of damage.65 They used a viability score based on the sum of three indices. Oxidative index: changes in oxygen consumption, Perfusion index: thresholds of pressure and flow, and Vascular index: changes in the platelet count during perfusion. Thresholds of oxygen consumption, perfusion pressure and flow, and levels of platelets measured in the perfusate were defined. A higher score indicated less damage. This score correlated with the degree of acute tubular necrosis (ATN) in canine kidneys after transplantation. Dogs with the least severe ATN had the highest viability score. Our group proposed an assessment of quality by measuring the level of function and macroscopic appearance.66 The assessment was made using a series of 74 human kidneys that were declined for transplantation. Each kidney underwent EVNP for 60 minutes as previously described. The red cell-based solution used to perfuse the kidneys allows any abnormalities or areas of inadequate perfusion to be visualized easily. We formulated a scoring system to assess the quality of the kidney based on a combination of the macroscopic appearance FIGURE 8.1 (A) A picture of a human kidney declined for transplantation due to inadequate in situ perfusion. (B) A picture of the same kidney after 60 min of ex vivo normothermic perfusion.

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TABLE 8.1

Potential Parameters to Assess Viability During Ex Vivo Normothermic Kidney Perfusion

Viability assessment Perfusion parameters

Renal function

Tubular function

Renal blood flow

Urine output

Filtration fraction

Intracellular enzymes/molecular markers AST, GGT, GST, LDH 1

Intrarenal resistance

Creatinine levels

Fractional excretion Na

Free iron

Oxygen consumption

Creatinine clearance

Total protein

NGAL

Acid base balance

Oxidative damage

AST, Aspartate aminotransferase; GGT, gamma-glutamyltransferase; GST, glutathione S-transferase; LDH, lactate dehydrogenase; NGAL, neutrophil gelatinaseassociated lipocalin.

and thresholds of renal blood flow and urine output. Renal blood flow was used as an index of vascular integrity and urine production as a simple index of glomerular filtration and tubular function. The combination of the perfusion parameters renal blood flow, urine output, and macroscopic assessment provided an overall measure of kidney quality. The scores ranged from 1, indicating the least injured and therefore the highest quality, to 5, the most injured and lowest quality kidneys. This scoring system was applied to a series of 36 marginal kidneys that underwent EVNP followed by transplantation at the same center. Kidneys with an EVNP assessment score of 3 had a significantly higher incidence of DGF (3 of 8) than those with a score of 1 (1 of 17) or 2 (0 of 11). Posttransplant renal function was also significantly worse in these kidneys, with higher serum creatinine levels and a lower eGFR at 12 months. This study suggests that EVNP could be a useful aid in the pretransplant assessment of marginal kidneys. There is also scope for EVNP to provide a more detailed assessment. The addition of other measures of renal and tubular function, histological evaluation or the use of biomarkers to determine the severity of renal injury may be advantageous in kidneys with higher EVNP assessment scores to aid the decision process67
70 (Table 8.1). Approximately 12% of kidneys in the United Kingdom and up to 18% of kidneys in the United States are donated and retrieved for transplantation but are subsequently declined due to concerns about their quality.71
73 This technology could be used to increase the number of kidney transplants and provide the transplanting surgeon with a more detailed appraisal of the kidney.

8.10 SUMMARY & CONCLUSION During the last decade the transplant community has endorsed alternatives to hypothermic techniques for organ preservation. Although the clinical use of normothermic perfusion in kidney transplantation pales in comparison to the expansion of heart, lung, and liver clinical programs, the results are extremely encouraging. The technique has generated a great deal of interest in the kidney transplant community and it is likely that other centers will adopt this technology in the near future. EVNP has many advantages over hypothermic techniques. Early indications suggest that a short resuscitation period can improve early kidney graft function. In the future it could be used to repair damaged organs by administering therapeutic agents, altering gene expression, and adding growth factors or stem cells directly to the kidney. The assessment of quality is also an important factor with many kidneys being retrieved but subsequently deemed unsuitable for transplantation. Ex vivo normthermic perfusion provides a comprehensive assessment of function and perfusion that can aid the surgeon in the decision process. This technology may help to increase the transplant numbers and prevent the unnecessary discard of organs. The advantages of EVNP techniques in kidney transplantation have been explored by a small number of surgeons and researchers. Without doubt this technology will advance over the next decade and have a wider impact in clinical kidney transplantation.

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4. 53. Hosgood SA, Nicholson ML. The first clinical case of intermediate ex vivo normothermic perfusion in renal transplantation. Am J Transplant 2014;14(7):1690
2. 54. Brasile L, Buelow R, Stubenitsky BM, Kootstra G. Induction of heme oxygenase-1 in kidneys during ex vivo warm perfusion. Transplantation 2003;76(8):1145
9. 55. Brasile L, Stubenitsky B, Haisch CE, Kon M, Kootstra G. Potential of repairing ischemically damaged kidneys ex vivo. Transplant Proc 2005;37(1):375
6. 56. Brasile L, Glowacki P, Castracane J, Stubenitsky BM. Pretransplant kidney-specific treatment to eliminate the need for systemic immunosuppression. Transplantation 2010;90(12):1294
8. 57. Sandovici M, Deelman LE, de Zeeuw D, van Goor H, Henning RH. Immune modulation and graft protection by gene therapy in kidney transplantation. Eur J Pharmacol 2008;585(2-3):261
9. 58. Zheng X, Zhang X, Feng B, et al. Gene silencing of complement C5a receptor using siRNA for preventing ischemia/reperfusion injury. Am J Pathol 2008;173(4):973
80. 59. Yang B, Elias JE, Bloxham M, Nicholson ML. Synthetic small interfering RNA down-regulates caspase-3 and affects apoptosis, IL-1 beta, and viability of porcine proximal tubular cells. J Cell Biochem 2011;112(5):1337
47. 60. Yang B, Hosgood SA, Nicholson ML. Naked small interfering RNA of caspase-3 in preservation solution and autologous blood perfusate protects isolated ischemic porcine kidneys. Transplantation 2011;91(5):501
7. 61. Hosgood SA, Bagul A, Kaushik M, Rimoldi J, Gadepalli RS, Nicholson ML. Application of nitric oxide and carbon monoxide in a model of renal preservation. Br J Surg 2008;95(8):1060
7. 62. Gok MA, Bhatti AA, Asher J, et al. The effect of inadequate in situ perfusion in the non heart-beating donor. Transpl Int 2005;18 (10):1142
6. 63. Snoeijs MG, Dekkers AJ, Buurman WA, et al. In situ preservation of kidneys from donors after cardiac death: results and complications. Ann Surg 2007;246(5):844
52. 64. Hosgood SA, Nicholson ML. Ex vivo normothermic perfusion of declined human kidneys after inadequate in situ perfusion. Am J Transplant 2014;14(2):490
1. 65. Stubenitsky BM, Booster MH, Brasile L, Araneda D, Haisch CE, Kootstra G. Pretransplantation prognostic testing on damaged kidneys during ex vivo warm perfusion. Transplantation 2001;71(6):716
20. 66. Hosgood SA, Barlow AD, Hunter JP, Nicholson ML. Ex-vivo normothermic perfusion - An innovative technology for quality assessment of marginal donor kidney transplants. Br J Surg 2015;102(11):1433. 67. Waller HL, Harper SJ, Hosgood SA, et al. Biomarkers of oxidative damage to predict ischaemia-reperfusion injury in an isolated organ perfusion model of the transplanted kidney. Free Radic Res 2006;40(11):1218
25. 68. Ruggenenti P, Perico N, Remuzzi G. Ways to boost kidney transplant viability: a real need for the best use of older donors. Am J Transplant 2006;6(11):2543
7. 69. Malyszko J, Lukaszyk E, Glowinska I, Durlik M. Biomarkers of delayed graft function as a form of acute kidney injury in kidney transplantation. Sci Rep 2015;5:11684. 70. Bhangoo RS, Hall IE, Reese PP, Parikh CR. Deceased-donor kidney perfusate and urine biomarkers for kidney allograft outcomes: a systematic review. Nephrol Dial Transplant 2012;27(8):3305
14. 71. Callaghan CJ, Harper SJ, Saeb-Parsy K, Hudson A, Gibbs P, Watson CJ, et al. The discard of deceased donor kidneys in the UK. Clin Transplant 2014;28(3):345
53. 72. Dare AJ, Pettigrew GJ, Saeb-Parsy K. Preoperative assessment of the deceased-donor kidney: from macroscopic appearance to molecular biomarkers. Transplantation 2014;97(8):797
807. 73. Matas AJ, Smith JM, Skeans MA, et al. OPTN/SRTR 2012 Annual Data Report: kidney. Am J Transplant 2014;14(Suppl. 1):11
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9 Kidney Transplant Recipient Surgery Fabio Vistoli1, Vittorio Perrone1, Gabriella Amorese1, Ugo Boggi1 and Giuseppe Orlando2 1

University of Pisa, Pisa, Italy 2Wake Forest University Health Sciences, Winston-Salem, NC, United States

9.1 INTRODUCTION In the past 30 years, the results of kidney transplantation have improved, especially because of prevention and treatment of acute rejection episodes, management of posttransplant complications, and a better knowledge of immunosuppressive medications. As a result, transplantation has become the mainstay and preferred treatment for patients of all ages with end-stage renal disease (ESRD). In the first part of the 20th century, the work of Alexis Carrel produced a tremendous progression in vascular surgical techniques and generated great interest in the possibility to replace diseased organs with new ones from a different individual. However, it was only in the second part of the same century that the era of human organ transplantation could begin, following progress in human and transplant immunology. The first successful transplant of a kidney between identical twin brothers was performed on December 23, 1954 in Boston.1 Today, kidney transplantation has become a common procedure performed all over the world. The basic principles of kidney transplant recipient surgery have remained fairly constant during the last 60 years, and the wide variety in individual specialist practices address the many different ways in which a solid technical result can be obtained. Also, the surgical procedure for renal transplantation has changed little from the original pelvic operation portrayed in 1951 by Kuss et al.2 It appears that the operation has become a standard and there is little requirement for further talks over the theme. Actually, the argumentation on this surgical technique has never stopped since its introduction, and in order to improve the surgical results, numerous parts of operative techniques have been changed and novel strategies have been designed. Additionally, in the contemporary immunosuppressive era, the number of surgical complications has increased and has presented some new elements. The indication for renal transplantation is irreversible renal failure that requires, or will soon require, dialysis, in any modality it is performed. Generally accepted contraindications are noncompliance, active malignancy, active infection, high probability of operative mortality, and unsuitable anatomy for technical success. The surgical act is always the key to obtaining a successful transplantation, and surgical strategies are continually measured with the morbidity and mortality of the patients. Today, kidney transplantation is the treatment of choice for patients with ESRD, with a low incidence of technical complications. Compared with dialysis, it is associated with increased patient survival and better quality of life, and it is cost effective.3 Herein we describe the standard operations performed today and present redesigned surgical approaches, together with the major surgical complications and the development of their detection tools and treatment strategies.

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9.2 PREPARATION OF THE RENAL GRAFT (SYNONYMOUS TO BENCH PROCEDURE OR BENCHING) The renal graft is prepared (5benched) before implantation at the back table (5bench). The kidney is placed in a plastic bag containing the preservation solution of choice, which sits in a bowl containing clean saline and ice (Fig. 9.1). During benching, the temperature of the fluid should range between 1 C and 4 C. Kidneys from living donors require short and little back-table preparation because most of the dissection has already been done during the nephrectomy. On the other hand, in case of en bloc kidney procurement, the degree of graft preparation could be longer and significant. We start the preparation by putting a mosquito clamp on the end of the ureter, maintaining it off to the side to prevent incidental damages. The renal vein(s) and the artery(ies) are then cleaned, and any side branches that do not enter the kidney are ligated. The last part of the preparation is dedicated to accurate lymphostasis of the fatty tissue around the renal hilum that is accurately ligated to reduce the risk of lymphorrea after graft reperfusion.

9.2.1 Preparation of the Renal Vein The length of the left renal vein is usually sufficient once the adrenal, lumbar, and gonadal branches are ligated (Fig. 9.1). It is not mandatory to dissect away the entire gonadal vein: Despite the presence of small tributary branches from the kidney and the ureter that could bleed, the simple ligation of both ends is sufficient to obtain a good hemostasis after reperfusion. When multiple renal veins are of similar size, they should be preserved, either by conjoining or by using a jump graft. In contrast, because the venous drainage communicates within the kidney, small accessory renal veins may be tied off. The right renal vein is shorter than the left renal vein and is often thinner, especially in its posterior aspect. In a living donor, a small cuff of donor cava can give thicker tissue and wider lumen to anastomose. In a cadaveric donor, when the kidneys are split, the entire remaining cava should be sent with the right kidney. This allows the use of cava to extend the right renal vein, often to a length equal to or exceeding the right renal artery. When inspecting the donor cava, first ensure that the suprarenal portion is intact, as it may be damaged during removal of the liver.

FIGURE 9.1 The upper left panel shows a right kidney sitting in the basin containing preservation solution. The upper right panel shows a living donor graft right after procurement. The lower panels show a right deceased donor graft before and after benching; the vena cava conduit has been reconstructed and will serve as new renal vein.

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The most common reconstruction technique is to cut the cava in line with the right renal vein and to then sew the superior and inferior parts of the cava with 5 0 or 6 0 Prolene suture. The left renal vein orifice is often used for anastomosis to the recipient. If the length is not sufficient, then the vena cava can be rotated in line with the right renal vein and only the superior opening sewn with a running suture. The lower opening of the vena cava can be anastomosed end to side directly to the recipient. Use of the full stump of the vena cava requires careful ligation of all lumbar venous branches coming from the cava and may result in a very wide anastomosis. After any reconstruction, testing of the vessels by irrigating with heparinized perfusion or saline solution should show any missed branches or large holes in the vessel, sutures or ligations that have to be sewn.

9.2.2 Preparation of the Renal Artery The renal artery orifice should be examined for injury: Especially flaps of intimal plaque or aneurysms, which may not be visible when the artery is not completely distended. The artery should be cleaned and followed up to the hilum, preserving any renal branches. In fact, all renal arteries are end arteries, so any branches that are ligated will result in a region of nonperfused renal parenchyma. This is important, in particular, for inferior pole branches, which often provide the only blood supply for the donor ureter. On the other hand, a superior pole branch may appear to be just an adrenal artery, yet in tracing its path could be possible to find out that it takes a turn into the renal parenchyma. When the renal artery does not have donor aorta attached (living donor or diseased cadaveric aorta) we prefer to put a stitch on the superior aspect of the vessel for orientation. When donor aorta is attached and healthy, a small rim of aorta can be preserved (the so called “Carrel patch”), which reduces trauma to the renal artery intima during anastomosis suture. Multiple renal arteries can be managed by a variety of techniques, according to number, size, relative length, presence and health of donor aorta, and distance along the aortic patch.4,5 In a cadaveric donor, the recommended approach is to use a patch of donor aorta that includes all the renal artery orifices. This needs a longer recipient arteriotomy, however not longer than 3 4 cm, alternatively, it can be reconstructed on the back table to still allow a shorter single recipient anastomosis. In the case the donor aorta is not available or is too diseased, arteries can be anastomosed individually, also the smaller the size, the more difficult the anastomosis. If two arteries are of similar length and size, they can be sewn together to form one single orifice. Each artery is spatulated facing each other and then the apices stitched together with 6 0 or 7 0 Prolene. The suture line can then be run up each side of the arteries to form a unique larger orifice. In the case of two renal arteries in which one is smaller and/or shorter than the other, an end-toside anastomosis of the smaller to the larger can be done with running or interrupted suture. A small, plastic cannula placed in the larger artery, faced in the side hole, can help to prevent suturing of the posterior wall.

9.2.3 Preparation of the Ureter The entire vascularization of the donor ureter comes from the donor renal arteries. For this reason, preservation of the ureteral blood supply is essential (Fig. 9.2). The best way to maintain donor ureter arterial supply is by accurately preserving the fat and adventitial tissue found in the triangle formed by the ureter, lower renal graft pole, and renal artery (or arteries). In fact in this space there are the small branches (coming from the renal artery) responsible for the arterial supply to the ureter. In the case of two ureters, they can be anastomosed individually on the vescica or conjoined together on the back table spatulating the end of both of them, suturing together at the apex, and then sewing the two different sides of the ureteral edge.

9.2.4 Completion of the Bench Preparation Once the vessels and ureter are prepared, the perirenal fat is removed and care is taken not to tear the renal capsule. Then, lymphostasis of the hilum is achieved with multiple silk ties, aimed at reducing the risk of lymphorrea after reperfusion. Importantly, all solid lesions that are accidentally identified while benching should be biopsied and sent for frozen section; as well, any large cyst should be deroofed (Fig. 9.3) and its margin secured with 4/0 PDS running suture, to ensure that no internal solid component is present, taking care of possible communication with the excretory renal system. All vessels should be flushed manually with cold heparinized perfusion solution to ensure that there are no leaks requiring ligation or suture.

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FIGURE 9.2 The upper left panel shows a normal ureter in a renal graft from a living donor. The periureteral tissue is adequate and well viable. The other panels show the case of a stripped ureter which was completely lacking any periureteral tissue. The organ was eventually discarded.

FIGURE 9.3 Post reperfusion appearance of a renal graft which had been refused by several centers due to the presence of a very large cyst in the lower pole. However, as the donor was otherwise excellent and the overall renal mass satisfactory, we accepted the kidney which was implanted after deroofing and placement of a 4/0 PDS running suture on the edge of the cyst in order to prevent bleeding. The graft reperfused extremely well and the recipient experienced initial graft function.

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9.3 STANDARD SURGICAL TECHNIQUE OF KIDNEY TRANSPLANTATION The standard kidney transplant procedure is the pelvic operation originally used by French surgeons Ku¨ss, Dubost, and Servelle and their associates in 1951 and refined subsequently by Murray and Harrison for the first successful kidney transplantation in 1954. The heterotopic pelvic approach has been accepted worldwide for its multiple advantages and is considered, up to today, the standard access.

9.3.1 Site The most common site for placing a standard kidney transplant is in the retroperitoneal iliac or pelvic fossa; either side can be used for either kidney but there is no universal agreement on the criteria for selecting the appropriate one to place the transplant. It has been proposed placing the donor kidney in the recipient’s contralateral side (e.g., left kidney to right side; right kidney to left side) so that the renal pelvis and ureter are anterior in case of future surgeries for ureteral reconstruction in the face of donor ureteral necrosis or stenosis are required. Others stated that the more important issue is to stay away from sites of previous transplants, other operations, or peritoneal dialysis catheters, although dissection on the right side is a little simpler. When both sides are equally available, most surgeons favor the right side because the right external iliac vessels are longer and more horizontal and the vein is usually more superficial compared to the left side, which facilitates the vascular anastomoses. Moreover, on the right side, in case the iliac vessels prove unsuitable, it is easier to move up to the aorta and inferior vena cava, while still remaining retroperitoneal. Rarely, if the pelvis is not feasible, an orthotopic transplant can be done by removing the left native kidney and anastomosing the donor vein to the recipient renal vein, the donor artery to the renal or splenic artery, and the donor ureter to the recipient ureter. With advances of surgical strategy and increase of clinical experience the idea of selecting the right iliac fossa as the favored site for the first transplantation has been widely acknowledged. Despite this, the ipsilateral serious atherosclerotic vascular disease or venous disorders (e.g., previous deep venous thromboses; femoral dialysis catheters) should be routinely excluded. The left iliac fossa is the preferred side when a simultaneous pancreas and kidney transplant is being performed or when the patient is a candidate for a future pancreas after kidney transplant. Vascular anastomoses sites are performed on the external or internal iliac artery and on the external iliac vein and ureteral anastomosis directly on the bladder. There are several practical advantages for these heterotopic choices. Staying out of the peritoneal cavity allows more rapid return of bowel function and any hemorrhage or urine leak is confined to a smaller nonabsorptive space, making diagnosis easier and more rapid. The kidney lies just under the skin without any interposed bowel, which simplifies ultrasound monitoring and percutaneous biopsy. Finally, the distance to the bladder is short, allowing for use of the better vascularized proximal part of the donor ureter for implantation. The peritoneal dialysis catheters and previous minor abdominal operation such as appendectomy, conventional herniorrhaphy are not absolute contraindications. It additionally evokes one issue for nephrologists in that the initial peritoneal dialysis catheter is on the left side for the potential renal recipients. The same argument is valid for femoral dialysis catheter (better on the left than on the right side), also if the best choice is to put the catheter on the jugular or axillary vein, to preserve both inguinal sides for transplantation. The standard Gibson or the “hockey stick” incision can stay away from most stoma of peritoneal dialysis catheters. Then again, the minor transperitoneal surgeries or little operations on abdominal wall for the most part yield limited adhesion at the place to perform the transplantation. On the other hand, the transplantation is not suggested at the side where there is a background of herniorrhaphy with propylene mesh or ipsilateral open operation of ureter and bladder. The propylene mesh results in an inflammatory reaction and connective tissue proliferation leading to fibrosis formation and a thick scar plate on the internal surface of lower abdominal wall, which could make the dissection of bladder difficult. Past ipsilateral pelvic surgeries for the most part preclude transplantation on that side because of remodeled anatomical characteristics and serious perivesical tissue proliferation. Great polycystic kidneys are difficult for surgeons, so it is better choose the side of the smaller kidney. However, bilateral greatly enlarged polycystic kidneys would make the transplant surgery extremely troublesome or impossible. In that event, right or bilateral nephrectomy may be considered. For the second transplantation recipients the kidney is implanted on the contralateral side, usually left side. The patient is positioned supine. In our practice we prefer the patient have both arms out, for easy access to anesthesia if additional venous or arterial access is required. We place a Foley catheter with a Y-shaped connector attached to a urinary bag and to a 1 L bag of saline containing iodine solution. A small volume of fluid is used to irrigate the bladder, especially if the patient is anuric. This clears debris of the bladder, which will later be opened into the retroperitoneum.

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9.3.2 Incision and Exposure The kidney transplant can be performed by means of a wide range of different routes, however two important issues must be considered when choosing the incision for a renal transplant: A good access to the iliac fossa and bladder and a low rate of wound related morbidity. Traditionally, three classic incisions have been suggested for kidney transplant surgery: pelvic Gibson incision, the hockey stick incision, and oblique incision. The pelvic Gibson incision is a curvilinear incision made in lower quadrant of the abdomen which provides atraumatic access to the iliac fossa and bladder for renal transplantation. Oblique incision and inverted J-shaped incision (hockey stick incision) are the other two more frequently used incisions. In terms of incidence of long-term complications, the oblique surgical incision is better than the hockey stick incision for lower incidence of hernia and abdominal wall relaxation and more favorable cosmetic results.6 Paramedian, midline incision, and even transverse incision were introduced in living kidney transplantation surgery for better cosmesis, although these cuts present the drawback of difficult exposure of the operative field and reserved for selected candidates only. When a Gibson incision is made, incision extends from the midline one finger’s breadth above the symphysis pubis to a point two finger’s breadth medial to the anterior superior iliac spine through skin and muscle layers. The external oblique muscle and fascia are divided in the line of the incision and split to the side of the wound. The internal oblique and transverse muscles are opened with the cautery in the line of the cut, or in a more helpful manner to separate the two layers of muscles on the intersection of the oblique muscles and the rectus sheath, which avoids the section of the internal oblique and transversus muscles. The latter method has two major advantages: First, it reduces the blood loss resulting from muscle wound surface during the transplantation; second, the muscle fibers could disrupt during closure because of high tension of the wound covering the graft. The pararectus division of muscles and aponeurosis facilitates wound closure and reduces the incidence of wound complications. The inferior epigastric vessels can be preserved or ligated and divided, but if there are multiple renal arteries, the inferior epigastric artery can be used for anastomosis to a lower polar renal artery. In women, the round ligament is usually transected, but in men an effort is made to preserve the cord. The spermatic cord has freed laterally and retracted medially. The cord may be transected to aid in exposure, but testicular atrophy and hydrocele may be more likely in that case. The exposure of iliac vessels is an easy process, however extension and stretching of the extraperitoneal space may tear off the peritoneum and eventually cause enterocele, an uncommon complication called “renal paratransplant hernia.” If a peritoneal defect is produced, it should therefore be closed immediately to prevent this complication. A self-retaining retractor is inserted to obtain optimal exposure, which allows the assistant to free both hands to assist the anastomoses. However, the position of the retractor should be checked carefully before fixing it because the inadvertent retractor injury is responsible of femoral nerve injury causing reversible muscle weakness or paralysis of hip flexion. The lymphatic structures along and over the vessels must be ligated with a nonabsorbable suture and divided, rather than cauterized, to prevent the later occurrence of lymphorrea causing lymphocele. Attention should be paid to identify the genitofemoral nerve often mistaken for a lymph vessel. The nerve lies on the medial edge of the psoas muscle, and a branch may cross the distal external iliac artery.

9.3.3 Vascular Reconstruction In general, the end-to-side venous anastomosis is performed first, and then the end-to-side arterial one (Fig. 9.4). Some may prefer to perform the arterial anastomosis first if the renal artery is anastomosed to the internal iliac artery. The internal iliac artery is not the preferred site for the arterial anastomosis compared with external iliac artery today, although it was once the classical pattern, especially in living kidney transplantation. Dissection of the internal iliac artery is not as simple as that of the external iliac artery. To obtain a good control of the internal iliac artery, a mobilization of a tract of the external and common iliac arteries is also needed, with the increase of the operative time and risk of surgical complications. The risk of end-to-end anastomosis site stenosis and erectile dysfunction is higher than that of end-to-side external iliac artery following the transplantation. Lastly, the short internal iliac artery and variation are common. In summary, today, end-to-end anastomosis to the internal iliac artery is not recommended. Transplant surgeons have developed different techniques for arterial and venous anastomoses since the first 3-point technique for an end-to-end allograft arterial anastomosis described in 1902 by Carrel. Most efforts have been made to reduce ischemic time and increase the quality of anastomosis. The traditional and universally used technique is the 2-point anastomosis, with initial sutures placed at either end of the venotomy or arteriotomy. Some place an anchor suture at the midpoint of the lateral wall to avoid posterior or anterior wall being caught up in the suture line. Another running anastomoses

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FIGURE 9.4 The upper left panel shows a benched left living donor kidney graft ready for implantation. The upper right panel shows the external iliac vessels after thorough dissection and preparation; notably, the vessels are mounted on two different vessel loops. The lower left panel shows the renal graft wrapped in a stockinette containing slush, that allows gentle handling and cooling of the kidney during the anastomosis. The right lower panel shows the renal vein clamped with a double curve vascular clamp.

technique (“1-suture, 1-knot technique”), which does not need to turn the kidney medial and lateral, has shown some advantages especially in obese patients and recipients with deep iliac fossa. Semisutureless anastomosis was performed both on artery and vein, using 4-stay sutures and several vascular clips for each anastomosis, without a continuous vascular suture.7 Other sutureless vascular anastomosis techniques using vascular clips or titanium ring pin staplers have been described and suggested as safe and time-saving in small series,8,9 but not one of them has become popular. Vascular occlusion during the anastomosis can be achieved with side-biting clamps (e.g., Satinsky, C-Clamp), bulldog clamps, Rommel tourniquets, or angled padded clamps (e.g., Fogarty). At the start of the vascular anastomosis it is worth pausing to ensure with the nurses that all suture material is ready and with anesthesia that preoperative medications (e.g., antibiotics, steroids, immunosuppressive induction drugs) have been given. We usually will give a “kidney cocktail” containing albumin, mannitol, and furosemide that runs in during the anastomosis and ask for a target mean arterial pressure of about 80 100 mmHg. 9.3.3.1 Venous Anastomosis As the vein is usually deeper, we prefer beginning with the venous anastomosis (Fig. 9.5). The renal graft vein is anastomosed end-to-side, usually to the external iliac vein using a continuous 6 0 or 5 0 monofilament nonadsorbable vascular suture following an appropriate external iliac venotomy. If the iliac vein is very deep, ligation and transection of the internal iliac vein can improve mobilization. We place a Satinsky side-biting vascular clamp and create a venotomy with a #11 scalpel blade. The interior of the vessel is flushed with heparinized saline and the opening cut to exact size with angled scissors. We routinely use 6 0 Prolene suture for the end to side anastomosis between renal vein and iliac vein, sewing and tying a single double-armed suture at the cranial end of the anastomosis and then sewing towards the caudal apex (Fig. 9.6). At this point, we routinely place a bulldog clamp across the renal vein and remove the iliac vein clamp. This allows early detection of venous anastomotic leakage and reduces the amount of hardware in what is sometimes a tight space. In rare conditions (e.g., thrombosis, hypoplasia of both iliac veins), the renal graft vein has to be anastomosed to other site. The inferior vena cava (infrarenal or infrahepatic) is the most common alternative, associated or not with a native nephrectomy. Portal venous drainage system, inferior mesenteric vein, superior mesenteric vein, even venous collaterals with large caliber due to thrombosis of the inferior vena cava and iliac veins (e.g., presacral collateral vein, left ovarian vein) have been used for renal graft vein drainage with satisfactory results.10 Short right renal vein, particularly from living donors, represent a technical challenge to the transplant surgeon. A satisfactory anastomosis can be achieved by complete mobilization of the recipient external iliac vein. Right renal vein extension using the inferior vena cava is an excellent option to elongate donor vein, when required, especially in obese recipients. These techniques are used in deceased kidney transplantation, but are not suitable for living donors. Extensive

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FIGURE 9.5 The upper and lower left panels show the venotomy before and after placement of the 5/0 prolene sutures that will be used to perform the anastomosis, as well as of the 6/0 prolene stay stitches that are placed at 6 and 12 o’clock in order to maintain the lumen open during the anastomosis. The upper right panel shows the placement of the sutures in the renal vein, while the lower right panel illustrates the suture while it is ran on the back wall of the veins.

FIGURE 9.6 The upper left panel shows completion of the posterior wall of the venous anastomosis. The upper right and lower left panels show an almost complete and complete anastomosis, respectively. Once the anastomosis is complete, it is tested by opening the vascular clamp after placement of a plastic bulldog clamp.

elongation of renal vein should be avoided either in live or deceased transplantation for prophylaxis of occurrence of renal vein thrombosis. However a number of techniques have been developed to elongate the short live donor vein: extension techniques using saphenous, gonadal vein, or superficial femoral vein grafts or a polytetrafluoroethylene graft have demonstrated good results. 9.3.3.2 Arterial Anastomosis The end-to-side arterial anastomosis is generally placed more proximally than the vein, usually performed using an appropriately trimmed cuff of aorta attached to the renal artery with a continuous 5 0 or 6 0

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FIGURE 9.7 The yellow arrow shows the renal artery. After completion of the venous anastomosis, a vascular clamp is placed on the external iliac artery (white arrow). In the upper left panel, the surgeon is about to do an arteriotomy. Afterward, an arterial punch (upper right panel) is used to create an adequately large breach (lower left panel) in the wall of the external iliac artery. At this point, the anastomosis is started by running the 6/0 prolene on the posterior wall.

monofilament vascular suture after an external iliac arteriotomy (Fig. 9.7). Great care should be taken in application of the arterial clamps to avoid detachment of vascular plaques. Endarterectomy is rarely needed. Some prefer to produce an opening with artery puncher in order to facilitate the anastomosis of renal arteries from living kidney donors or in cadaveric ones in absence of “Carrel patch.” To obtain a normal blood flow to the renal graft a careful suture performance is important: full-thickness suture of arterial wall in each stitch, in particular in arteriosclerotic recipients, plays a crucial role. The arterial clamp is placed on the external iliac artery, usually superior to the venous anastomosis. After incising the anterior surface of the artery with a #11 scalpel blade, we prefer to complete the opening with the same #11 scalpel or with scissors which cut all vessel wall layers equally, even if there is plaque. For the end-to-side anastomosis, we prefer 7 0 Prolene. If a Carrel patch is available, we will place 5 0 Prolene suture at cranial end of the anastomosis and sew along each side to the caudal apex. If it is a small artery with no patch, we usually prefer to sew a single suture circumferentially. In that case, care should be taken to not cinch the suture too tightly when tying the knot (“growth factor”) so that as the arteries fill with blood the anastomosis is not narrowed. There are various anastomosis patterns for kidneys with multiple arteries: Anastomosis of two arteries close together on an aortic patch of a left-sided deceased donor kidney is the simpler situation. If arteries are more than 2 cm apart, two separate anastomoses are recommended in order to minimize excessive stretching of the vessels and ultimately the risk for kinking and thrombosis. Double arteries to a right-sided kidney frequently make situating of the kidney troublesome without kinking one or the other artery, so the branches have to be shortened and two separate anastomoses performed. The most complicated cases are encountered in the living donor setting where the aortic cuff is absent, and multiple, short arteries are common. For double arteries, two separate parallel anastomoses to the external iliac artery are required. Sometimes the lower hilar artery or lower polar artery can be anastomosed to internal iliac artery or inferior epigastric artery in an end-to-end fashion. Very small accessory renal arteries at the upper pole can be ligated without problems. Arteries reconstruction during the back-table preparation before revascularization is an effective method. The advantages of this approach are that they preserve the small accessory renal arteries by an end-to-side or conjoined anastomosis to renal artery and reduce the operative time by simplifying the anastomosis on the recipient. 9.3.3.3 Reperfusion of the Kidney Graft Upon completion of the anastomosis, the vascular clamps are removed and the kidney reperfuses and pinks up almost immediately. It is vital for the patient to be adequately perfused and not have a low blood pressure (Fig. 9.8). The venous clamp is removed first followed by the arterial. If bulldogs were used on the artery, the distal clamp is removed first to test the anastomosis. The kidney is warmed with saline poured on the surface.

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FIGURE 9.8 After completion of the arterial anastomosis (upper left panel), the stockinette is cut off (upper right panel) and the bulldog first, and the vascular clamp thereafter, are removed.

Anastomotic bleeding can be carefully sutured if a large gap is present, but bleeding from needle holes will typically stop with time and mild pressure. Bleeding on the renal surface can be controlled with the electrocautery or the Argon beam coagulator. Attention should be paid to bleeding from small hilar arterial vessels which might be in spasm when the kidney is cold but will start bleeding as the kidney warms and perfuses. The kidney may pink up slowly in the face of ischemia-reperfusion injury, but if there is an anatomic line of demarcation between perfused and nonperfused kidney, immediately search for a possibly missed or transected arterial branch. To improve renal perfusion, especially in kidneys from cadaveric donors, somebody injects 5 mg of verapamil into the renal artery unless the patient is heavily beta blocked, in which case the combination of a calcium channel blocker may lead to heart block.

9.3.4 Urinary Tract Reconstruction Reconstruction of the urinary tract starts after a successful graft revascularization. There is a range of urinary tract reconstruction techniques. The standard procedure is the ureteroneocystostomy (Fig. 9.9). Pyeloureterostomy and ureteroureterostomy ordinarily are considered rescue techniques when the transplant ureter’s blood supply is not sufficient or the urinary bladder is hard to distinguish. No difference was found comparing the overall incidence of urological complications between ureteroureterostomy and ureteroneocystostomy in kidney transplantation. Ureteroureterostomy decreases the incidence of urine leakage and is considered a good first option for urinary tract reconstruction with a greater possibility of resolving a ureteral stenosis with endourology and no risk of reflux.11 In other comparison series the outcomes from routine pyeloureterostomy group were even better and also had the similar advantages as the ureteroureterostomy group.12 In any case, ureteroneocystostomy is still the favored choice of urinary tract remaking for most specialists in view of its advantages: it is a common method applied in general urological surgeries; profound dissection of native ureter and native nephrectomy are superfluous; it can be performed irrespective of the quality or presence of the native ureter, and it holds the possibility of change to a ureteroureterostomy or pyeloureterostomy if the implant fails. The location of ureteroneocystostomy is typically a few centimeters away from the vascular anastomoses, which facilitates the examination and remedy of a urinary complication during the reinterventions. 9.3.4.1 Ureteroneocystostomy There is a range of methods for ureteroneocystostomy, categorizable into transvesical or extravesical and antireflux or nonantireflux. The Leadbetter-Politano (LP) technique is the transvesical ureteroneocystostomy depicted

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FIGURE 9.9 The cystoureteral anastomosis is performed using two 5/0 PDS running sutures, on a protective 6 French double J stent. At the end, an antireflux valve is created using 3/0 PDS (in the form of either a running suture or multiple stitches).

by Murray et al. in 1954 for the first successful renal transplant. This strategy uses one cystostomy to get to the inside of the bladder and another cystostomy to reproduce another ureteric hole in a normal anatomic position. The ureter is tunneled in the submucosal space to avoid reflux. The extravesical ureteroneocystostomy was initially described by Witzel in 1896, then again by Gregoir in April 1961, and soon after by Lich et al., who published the method in November 1961.13 The Lich-Gregoir (LG) technique was intended to avoid a second cystostomy, yet hold an antireflux component. It makes a 2 3 cm submucosal tunnel with muscle backing of the ureter to give a valve effect. Other advantages were less bladder dissection, a shorter ureteral length, and no interference with native ureteral function. The LG technique was noted to be fast and actually less demanding to perform than the LP strategy. A few varieties of the LG implantation have been described, e.g., the utilization of running rather than interrupted sutures to make the ureteral-mucosal anastomosis; execution of a tunnel by submucosal blunt dissection rather than muscular imbrications; placement of a single horizontal Halsted stitch at the proximal apex of the bladder incision to the ureter to avoid tension at the acute angle of the anastomosis; position of an anchor stitch on the distal ureteral tip to the full thickness of the bladder, collapsing back the tip of the ureter to make a terminal cuff; incorporation of the muscular layer with the mucosal layer of the bladder in the anastomosis and the parallel-incision method with a submucosal tunnel made between the two parallel cuts in the lateral bladder. All of these “modified” Lich ureteroneocystostomies include extravesicular access, the formation of an antireflux tunnel, and an urothelial anastomosis. Another extravesical way to deal with ureteroneocystostomy that also incorporates an antireflux tunnel but does not have an urothelial anastomosis, is known as the U-stitch technique. This technique was demonstrated to abbreviate operative times even more than the LG method thanks to the elimination of the urothelial anastomosis. But it is associated with an augmented risk of urinary complications and abandoned in numerous institutions worldwide. The procedures without an antireflux mechanism are rarely described. Early comparisons have failed to demonstrate significant differences amongst reflux and antireflux methods, but most nonantireflux systems have been abandoned. The management of double ureters is similar to that of dual arteries. If there is a common part, a simpler ureteroneocystostomy can be performed as a single ureter. Two separate ureteroneocystostomy using LG technique is preferred when two ureters are not in one common sheath. The dual ureters can also be reconstructed on back table conjoining them into one common conduit to anastomose with bladder or native ureter. The bladder dissection is facilitated by filling the bladder via the Foley catheter and clamping the outflow. Minimal length of donor ureter that allows a tension free anastomosis should be used to minimize distal ischemia. We prefer the Lich-Gregoir or extravesical technique. The donor ureter is anastomosed to the recipient bladder mucosa using 6 0 PDS running anastomosis suture (ureteroneocystostomy) and to prevent reflux, the seromuscular layers is closed over it with interrupted 3 0 Vicryl sutures.

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9.3.4.2 Other Alternatives There are some uncommon types of urinary tract reconstruction strategy utilizing as a part of particular conditions (e.g., pyelopyelostomy in orthotopic renal transplantation; ureteroenterostomy into an intestinal conduit or an intestinal pouch; pyelovesicostomy). Regardless of what technique is utilized, a tension free and watertight anastomosis is essential.

9.3.5 Conclusion of the Surgery Hemostasis, reexamination and placement of drains are the steps taken before closing the wound. Accurate hemostasis is essential for each surgery particularly in a uremic patient. Attention should be paid to the vascular anastomosis site and renal pedicle region to search active bleeding from an unrecognized leak or an unligated vessel, which could be a reason for reoperation during the early postoperative period. The role of reexamination is to discover if there are some grave technical errors and correct them before the closure. Vessels have to be accurately checked: The quality of renal artery pulsation and the vascular tension of renal vein should be explored gently using fingers, modifying the position of the renal graft if there is a kinking or compression of long vessels. The ureter should be tension and burden free from structures after the graft is appropriately put. No urine leakage is allowed. Drain placement is another very important step before closure. The value of a baseline biopsy obtained before closure remains controversial, but it is, without any doubt, a risk factor for vascular complications. A capsulotomy of the transplanted kidney before closure has been abandoned in adult transplantation because it is of no use on the whole. Closure is less easy than incision making (Fig. 9.10). Muscular tension often is higher either from the additional renal graft or descending effect of muscle relaxant. Some centers routinely close muscles and aponeurosis with single-layer #1 polydioxanone (PDS) running suture, which reduces the closing time but is also a risk factor of wound complications. Our experience is to close the wound with twolayer #2 polypropylene nonabsorbable suture: interrupted stitches in muscle layer and interrupted stitches in the external oblique muscle fascia layer, which has been proved an appropriate method. A subcutaneous absorbable suture layer completes the wound closure. Attention should also be paid to avoid injuring the peritoneum or the transplanted ureter when closing the incision. Furthermore, excessive tension on the suture may lead to compression of the kidney or lead to defects resulting in wound complications.

FIGURE 9.10

Appearance of the surgical site at the end of the procedure.

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9.3.6 Stent, Catheter and Drains Double J stent capacity in renal transplants to significantly diminish ureteric complications is broadly accepted. One metaanalysis has shown that the prophylactic routine stenting in renal transplants is cost effective.14 Increased risk of urinary tract infection, additional cystoscopy and patient discomfort from bladder spasm is relatively unimportant and controllable and cannot balance the reduced incidence of ureteric complications, which can be a cause of graft loss. The optimal duration of prophylactic stenting has not been determined. Based on center preference, it is usually 2 6 weeks. In our practice we also use a Bracci catheter to selectively drain the urine produced by the grafted kidney. The catheter is placed during transplantation percutaneously and transvescically to stent the graft ureter anastomosis. In this way the urinary output from the grafted kidney can be selectively collected, measured, and analyzed during the posttransplant period. The catheter is pulled back and removed after 12 days. Acute vascular rejection usually occurs 1 2 weeks after transplantation, a selective graft catheterization is helpful for the patients to detect the early sharp reduction of graft urine output, a usual signal of acute rejection. A dwelling catheter is necessary for every kidney transplantation patient. It is important to maintain the catheter in an unobstructed condition during the early postoperative period. The reported duration time usually is 5 7 days; our practice is 5 days in case of double J ureter stenting and 14 days in case of Bracci catheter ureter stenting. There is controversy over the need and term of perigraft drains. Some authors recommended nondrains closure if hemostasis is satisfactory because drain tubes increase the infection risk in immunosuppressive patients. But most others support placing a closed suction retroperitoneal drain at the time of transplant and a considerable majority of them suggest removal of drains in 48 hours in case of infection. Based on our practice, we suggest a “three-drain policy” routinely for every transplant patient. The incidence of postoperative hematomas and lymphoceles in renal transplantation is higher than general surgeries’ for multiple reasons. In the early posttransplant period, bleeding is from the operative field. Even a week later, the spontaneous bleeding of graft can also develop a problematic hematoma. Moreover, most lymphoceles formations and urine leaks occur approximately 1 week after transplantation: Too early removal of drains increases the risk. The reason for three drains is based on the fact that there are basically three isolated dead spaces created by the allograft: over the upper pole and under the lower pole of the transplant kidney, and in the perivesical space. One lower drain often cannot drain the bleeding from the upper pole. We place one drain onto the upper pole of graft, another down the lower pole near to the vessels and a third one in the prevesical space, centimeters away from the ureter. The upper and lower poles drains usually are removed 4 5 days posttransplant or until drainage is less than 20 mL daily, the perivesical drain is routinely removed 1 day after the catheter removal if there is no evidence of urine leak or lymphorrhea.

9.4 SURGICAL CONSIDERATIONS IN PEDIATRIC RECIPIENTS AND DONORS 9.4.1 Pediatric Recipients In pediatric recipients, the standard surgical technique applied in adults conveys two primary disadvantages. In the first place, there is a size mismatch between the usable extraperitoneal space and adult sized grafted kidney. Second, the recipient artery might be small compared to the artery of the graft. This can make the vascular anastomosis more troublesome and may put at risk the blood pressure and flow required for the donor kidney to survive; the classic approach is to consider the same transplant technique as for adults if the child body weight is more than 20 kg. If weight is less than 20 kg, the right Gibson incision can be carried up to the costal margin to increase exposure of the right extraperitoneal space or can be used a transperitoneal incision. Some centers usually perform transperitoneal kidney transplantation in pediatric recipients under 5 years of age. Others centers perform extraperitoneal renal transplantation in children under 15 kg of body weight, which limits potential gastrointestinal complications and allows the confinement of potential surgical complications, such as bleeding and urinary leakage. When a transperitoneal approach is used, a midline incision from the xiphoid to the pubis is done and the posterior peritoneum is incised lateral to the ascending colon. Ligating and dividing two to three lumbar veins posteriorly is often necessary to facilitate the application of vascular occluding clamp. The terminal aorta is dissected free at its junction with the right or left common iliac artery. The donor artery is either anastomosed to the distal aorta to obtain the best arterial inflow, or with one of the common iliac arteries in an end-toside fashion using 5 0 or 6 0 monofilament vascular suture. The use of common iliac artery prevents a complete occlusion of the aorta, which is associated with temporary acidosis of both lower extremities. The donor vessels

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are often without the aortic cuff and may be spatulated to ensure a wider anastomosis and to avoid kinking. The ureter of an adult size kidney is usually long and wide enough to obtain a tension-free ureteroneocystostomy, however if it is too long it may kink or twist easily, and may even cause internal hernia; therefore, sometimes the long ureter should be shortened to obtain best results. Ureteral stenting is beneficial in avoiding urological complications, but special attention should be paid to the removing strategy because standard cystoscopy in adults is not suitable for younger children. It is a smart approach to attach the stent with the indwelling bladder or reservoir catheter and removing it as the catheter is pulled back. An antireflux strategy is needed for pediatric patients. Because a large number of recipients are a result of obstructive urological diseases due to outflow obstruction, small capacity or poor function of the bladder, which all predisposes to vesicoureteral reflux of the transplanted kidney.

9.4.2 Pediatric En-Bloc Transplant In small pediatric donors (kidney smaller than 8 cm), better results are obtained by transplanting both kidneys together, still attached to the aorta and inferior vena cava. During the preparation of the kidneys on the backtable, all lumber branches along the aorta and inferior vena cava are carefully ligated. The suprarenal segments of aorta and inferior vena cava are oversewn with Prolene. These kidneys often have very little hilar fat, and great care has to be taken to preserve the blood supply to both ureters.

9.5 ORTHOTOPIC KIDNEY TRANSPLANTATION Orthotopic kidney transplantation is only occasionally performed because of its difficult procedure with highly related morbidity. However, an expanding rate of patients with ESRD at present are not candidates for a heterotopic kidney transplant for reasons of associated severe vascular pathology, obesity, or retained iliac fossae from a previous kidney graft. The surgical technique comprises a retroperitoneal approach to the splenic hilum with a lumbotomy. To protect its whole length, the vein is ligated near the renal parenchyma including its bifurcation. The native renal artery is often restricted and cannot be utilized. The recipient’s urinary tract is dissected and protected. In most of the reported cases, renal graft revascularization was performed utilizing the recipient’s splenic artery and left renal vein. Artery revascularization is obtained with end-to-end anastomoses between graft renal artery and native splenic artery, renal artery or inferior mesenteric artery, or end-to-side anastomoses between graft renal artery and aorta. Vein revascularization is obtained with end-to-end anastomoses between graft renal vein and native renal vein or splenic vein or end-to-side anastomoses between graft renal vein and inferior vena cava. The excretory system is reconstructed using pyelo-pyelic anastomoses in most cases, and uretero-ureteral anastomoses, uretero-pyelic anastomoses, ureterocalicostomy in the others. Overall vascular complication rate is about 5.4%, and total urological complication rate is about 8.1%. No significant differences are observed between orthotopic and heterotopic transplant series when comparing overall patients and graft survival.15 Chapter 11, Orthotopic Kidney Transplantation, will discuss orthotopic kidney transplantation more in depth.

9.6 CONCLUSIONS Renal transplantation is the preferred therapy for patients with ESRD. Patient and graft survival rates are excellent but long-term outcomes have not shown much change. Surgical intervention is the first, critical step of a successful kidney transplant. Few grafts are lost due to severe surgical complications, which are frequently associated with technique errors. Meticulous surgical technique during transplantation may help to avoid the majority of preventable surgical complications and related morbidity and mortality. The long-term renal graft loss rate remains a concern as it has not improved much in the past three decades.16 Shortage of organs remains the major challenge, with about 100,000 patients waiting for a kidney transplant (https://www.unos.org/data/transplanttrends/#waitlists_by_organ, accessed on June 18, 2016). Continued efforts to improve surgical transplantation technique and above all to increase the donor pool are needed to alleviate the donor shortage.

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References 1. Guild WR, Harrison JH, Merrill JP, Murray J. Successful homotransplantation of the kidney in an identical twin. Trans Am Clin Climatol Assoc 1955;67:167 73. 2. Kuss R, Teinturier J, Milliez P. Some attempts at kidney transplantation in man. Mem Acad Chir (Paris) 1951;77(22 24):755 64. 3. Winkelmayer WC, Weinstein MC, Mittleman MA, Glynn RJ, Pliskin JS. Health economic evaluations: the special case of end-stage renal disease treatment. Med Decis Making 2002;22(5):417 30. 4. Orlando G, Gravante G, D’Angelo M, et al. A renal graft with six arteries and double pelvis. Transpl Int 2008;21(6):609 11. 5. Benedetti E, Troppmann C, Gillingham K, et al. Short- and long-term outcomes of kidney transplants with multiple renal arteries. Annals Surg 1995;221(4):406 14. 6. Nanni G, Tondolo V, Citterio F, et al. Comparison of oblique versus hockey-stick surgical incision for kidney transplantation. Transplant Proc 2005;37(6):2479 81. 7. Mital D, Foster PF, Jensik SC, et al. Renal transplantation without sutures using the vascular clipping system for renal artery and vein anastomosis--a new technique. Transplantation 1996;62(8):1171 3. 8. Jones JW. A new anastomotic technique in renal transplants reduces warm ischemia time. Clin Transplant 1998;12(1):70 2. 9. Ye G, Mo HG, Wang ZH, Yi SH, Wang XW, Zhang YF. Arterial anastomosis without sutures using ring pin stapler for clinical renal transplantation: comparison with suture anastomosis. J Urol 2006;175(2):636 40 discussion 40. 10. Wong VK, Baker R, Patel J, Menon K, Ahmad N. Renal transplantation to the ovarian vein: a case report. Am J Transplant 2008;8(5): 1064 6. 11. Nie Z, Zhang K, Huo W, Li Q, Zhu F, Jin F. Comparison of urological complications with primary ureteroureterostomy versus conventional ureteroneocystostomy. Clin Transplant 2010;24(5):615 19. 12. Timsit MO, Lalloue F, Bayramov A, et al. Should routine pyeloureterostomy be advocated in adult kidney transplantation? A prospective study of 283 recipients. J Urol 2010;184(5):2043 8. 13. Linn R, Ginesin Y, Bolkier M, Levin DR. Lich-Gregoir anti-reflux operation: a surgical experience and 5-20 years of follow-up in 149 ureters. Eur Urol 1989;16(3):200 3. 14. Mangus RS, Haag BW. Stented versus nonstented extravesical ureteroneocystostomy in renal transplantation: a metaanalysis. Am J Transplant 2004;4(11):1889 96. 15. Musquera M, Peri LL, Alvarez-Vijande R, Oppenheimer F, Gil-Vernet JM, Alcaraz A. Orthotopic kidney transplantation: an alternative surgical technique in selected patients. Eur Urol 2010;58(6):927 33. 16. Orlando G, Soker S, Stratta RJ. Organ bioengineering and regeneration as the new Holy Grail for organ transplantation. Ann Surg 2013;258(2):221 32.

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C H A P T E R

10 Robotic-Assisted Kidney Transplantation Ivo Tzvetanov, Pier C. Giulianotti, Giuseppe D’Amico, Raquel G. Roca and Enrico Benedetti University of Illinois Hospital & Health Sciences System, Chicago, IL, United States

10.1 INTRODUCTION Contemporary kidney transplantation is a process where the ultimate goal is to provide excellent graft function with no or minimal complications. The surgical procedure is a crucial part of this process. The traditional open approach was developed in the 1950s and has been performed with minimal changes for more than 60 years. The significant changes in the morbidity of the general population, and especially the epidemic prevalence of obesity for the last two decades, have posed new dilemmas for surgeons to resolve. At the same time, constantly increasing expectations in society regarding the healthcare outcomes have led to the development of quality improvement projects, which has made a high incidence of surgical complications unacceptable. The applications of minimally invasive approaches in many surgical specialties, by minimizing surgical trauma, have led to improved outcomes and higher patient satisfaction.1,2 Because of its higher complexity and necessary precision, kidney transplantation was not considered feasible with the conventional laparoscopic techniques. After the introduction of more advanced robotic technology, with its three-dimensional, higher resolution visual system and wrist-like, multidimensional instrument motions, the idea of minimally invasive kidney transplantation became real.3 After the first reports of the late 2000s,4 robotic-assisted kidney transplantation (RAKT) has slowly but steadily gained popularity throughout the world. Within the past 5 years this has become obvious in the increasing number of publications from the US, Europe, India, and Taiwan. The newest surgical manuals constantly include chapters on robotics in transplantation and the largest transplant forums have specialized sessions on the topic. Epidemiological data indicate that 20% 50% of patients on dialysis are obese. Obese patients have longer wait times until kidney transplantation (KT) and inferior patient outcome, to a great extent due to much higher incidence of wound complications and infections.5 8 If these complications could be avoided, obese patients could have the same outcomes as nonobese recipients. Our group at the University of Illinois in Chicago recognized this significant disparity and found the solution to some of the main problems posed by the obese recipients in the application of the robotic minimally invasive technique for KT. By minimizing the size of the incision and changing its anatomical location on the abdomen we were able to minimize wound complications and almost completely avoid wound infections. Other centers see advantages for nonobese patients also, including reduced level of pain and better cosmetics.

10.2 UNIVERSITY OF ILLINOIS’ EXPERIENCE The initiation of the robotic kidney transplant program at the University of Illinois in Chicago occurred in 2009, when we performed our first robotic-assisted transabdominal renal transplant (RAKT) from a diseased donor.9 After this first successful case we performed a series of RAKTs from living donors. Our only selection criterion was obesity (BMI . 30). Once the recipient has been accepted for transplantation if a living donor (LD) is Kidney Transplantation, Bioengineering, and Regeneration. DOI: http://dx.doi.org/10.1016/B978-0-12-801734-0.00010-2

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available, the surgical approach depends on the patient’s BMI. If the patient has a BMI , 30 kg/m2, an open surgical approach is chosen. Otherwise, if the patient is obese, with a BMI $ 30 kg/m2, the patient is approached by a minimally invasive robotic-assisted technique. Patients without LD are placed on the waiting list and if BMI $ 30 kg/m2, a weight-loss program is started. Once a deceased donor becomes available, obese patients undergo robotic-assisted surgery and nonobese patients undergo open surgery. Previous surgeries are not considered a contraindication to performing a roboticassisted procedure. The only exclusion criteria are severe atherosclerosis of the iliac vessels of the recipient or the graft (for a deceased donor). We do not consider age or immunologic risk status as a contraindication for RAKT.

10.2.1 Surgical Technique 10.2.1.1 Patient Positioning and Port Placement After induction of general anesthesia, a three-way Foley catheter is placed. This allows filling of the bladder with 100 150 mL of diluted Methylene blue solution after completion of the vascular anastomosis, which facilitates identification of the bladder and prevents spatial interference during the vascular suturing. The patient is positioned supine, with parted and flexed legs; shoulder block and tape are used to avoid patient sliding during the operation. After the patient is prepared in the sterile fashion, a 7 cm mid-line incision approximately 5 cm below the xiphoid process is made, and a hand access device is placed. Depending on the body habitus of the recipient, the location of this mid-line incision could be closer to the umbilicus in order to allow easier access to the surgical field for the bedside hand-assisting surgeon. After pneumoperitoneum is obtained at 15 mmHg, the laparoscopic ports are positioned in the following manner for right sided implantation: (1) 12 mm port for the 30 degrees robotic scope on the right side of the umbilicus; (2) 8 mm robotic port high in the right flank; (3) 8 mm robotic port in the left lower quadrant; (4) 12 mm port is then placed for assistance on the left side of the umbilicus between the camera and the left lower quadrant robotic port. Once the ports are placed, the patient is placed in a 30 degrees Trendelenburg position, with the right side elevated (for implantation to the right external iliac vessels). The robotic tower is docked into position from the patient’s right leg site, parallel and slightly diagonal to the body. 10.2.1.2 Graft Implantation and Reperfusion The right colon is mobilized, and right external iliac artery and vein exposed. The iliac vessels are dissected free, using a bipolar forceps and a hook electrocautery. In order to facilitate the exposure and the dissection around the external iliac vein, a vessel loop is used to retract the artery upwards. Another vessel loop is placed around the iliac vein to allow dissection of the posterior surface of the vein. If small venous branches are identified, they are suture ligated. Once the external iliac vessels are completely dissected free, two robotic bulldog clamps are used to occlude the external iliac vein proximal and distal. Robotic Potts scissors are used to create a venotomy to about 15 mm. A 12 cm, double-needle, 5 0 Gore-Tex suture with a knot in the middle is placed at the corner of the venotomy. Kidney graft is inserted in the abdominal cavity by the assisting surgeon and positioned parallel to the dissected iliac vessels. Previous marking of the renal vessels of the graft facilitates the extremely important step of initial orientation. Veno-venous anastomosis is completed in an end-to-side fashion with running suture (Fig. 10.1).

FIGURE 10.1 Venous anastomosis.

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If needed, interrupted stitches of 5 0 Prolene are used to reinforce the corners of the anastomosis. Subsequently, the external iliac artery is clamped between robotic bulldogs, and an oval window (proportional to the size of the renal artery of the graft) is made in the anterior wall of the artery with robotic scissors. To facilitate this precise step, a 5 0 Prolene stitch is placed trough the anterior wall of the external iliac artery and gentle pulling is applied. The arterial anastomosis is completed in an end-to-side fashion with a 12 cm double-needle 6 0 GoreTex suture with a knot in the middle (Fig. 10.2). Once vascular suturing is completed, venous clamps are removed first, followed by immediate removal of the arterial clamps. The reperfusion of the organ and hemostasis are verified and bleeding points secured with 6 0 Prolene suture. With meticulous back bench preparation of the graft, bleeding after reperfusion may be completely avoided. We routinely use a robotic fluorescence camera and intravenous injection of 3 mL Indocyanine green (ICG). This confirms the complete and homogeneous reperfusion of the graft. At this point, the pressure of the pneumoperitoneum is decreased to 10 mmHg to minimize the possible negative effect of high intraabdominal pressure on the graft perfusion. 10.2.1.3 Ureterocystoneostomy The urinary bladder is filled with diluted methylene blue solution in order to facilitate its identification. Distending the bladder at the beginning of the operation could cause spatial interference, especially in patients with preserved diuresis from the native kidneys. Once the dome of the bladder is localized, the muscular layers are incised and the bladder mucosa is prepared. The ureter is anastomosed to the bladder with 5-0 Monocryl running suture using typical antireflux technique, suturing full thickness of the ureteral wall with the mucosal layer of the bladder (Fig. 10.3). Utilization of a ureteral stent is optional. Upon completion of the anastomosis, the seromuscular layer is closed over the ureterocystostomy with 3-0 Vicryl suture to create an antireflux mechanism. At the end of the procedure, the minilaparotomy is closed with running 0 Polydioxanone suture. The 12 mm port sites are closed with an endosuture needle and 0 Vicryl. Skin incisions are closed cosmetically. Placement of drains is not necessary.

10.2.2 Kidney Biopsy When needed, we prefer to perform kidney biopsies under laparoscopic guidance, considering the intraperitoneal location of the graft. Ultrasound guided biopsy potentially can cause significant bleeding. The procedure is completed under general anesthesia and antibiotic prophylaxis is routinely given. Our preference for port positioning is one infra umbilical and one in the upper quadrant on the site of the graft. A Tru-cut biopsy needle, usually 18 G, is introduced through the abdominal wall and directed towards the upper pole of the graft. Bleeding from biopsy sites is controlled effectively with cauterization. The patient is observed for 6 hours and discharged home unless immediate initiation of treatment is needed. Using this technique we did not observed any complications.

FIGURE 10.3 FIGURE 10.2

Arterial anastomosis.

Uretero-vesical anastomosis with the utilization of a ureteral

stent.

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10.2.3 Our Data In 2009, our group reported the first fully RAKT.9 The recipient was a 29-year-old woman with a body mass index (BMI) of 41 kg/m2 who had been on hemodialysis for 5 years. The operative time was 223 minutes, and the blood loss was less than 50 cc. The kidney had immediate graft function. No perioperative complications were observed, and the patient was discharged on postoperative day 5 with normal kidney function. The RAKT was performed with the technique described above. The indication for a robotic approach was morbid obesity since higher body mass index (BMI) in kidney transplant recipients is associated with increased risk of surgical site infections which negatively impact graft survival.6 In 2013 we conducted a case-control study.10 From June 2009 to December 2011, a prospective cohort of 39 obese patients with ESRD underwent RAKT at University of Illinois Hospital & Health Sciences System. 28 of these patients completed a follow-up period of at least 6 months after transplant. We compared the early posttransplant outcome from these 28 patients with those of a retrospective cohort control group of 28 obese patients, who underwent standard open kidney transplantation prior to June 2009 at our institution. The mean BMI of the robotic group was 42.6 6 7.8 kg/m2 compared to 38.1 6 5.4 kg/m2 in the control group (P 5 .02). The mean cold ischemia time was 2.8 6 3.6 hours in the robotic group and 2 6 4.5 in the control group (P 5 .48), and the mean warm ischemia time was 47.7 6 7.8 minutes in the robotic group and 49.2 6 25.2 minutes in the control group. There were no surgical site infections (SSI) in the robotic group, while 28.6% (8/28) in the control group developed SSI (P 5 .004). This initial experience showed that RAKT may enable obese patients with ESRD to access KT and may thereby reduce health disparities in groups with a high prevalence of obesity and ESRD. Within the last 6 years we have applied this standardized technique for over 150 robotic-assisted kidney transplants in obese recipients. We were able to almost completely avoid wound infections, which reach more than 30% in open surgery for this patient population. The 1- and 3-year graft survival were 95% and 89%, respectively. The 1- and 3-year patient survival were 97% and 96%, respectively. Forty-one patients were at high immunological risk (data not published). Moreover, in 2015 we reported for the first time a combined robotic sleeve gastrectomy and RAKT.11 The patient was a 35-year-old woman with a BMI of 42 kg/m2 (96.8 kg) and ESRD. After 24 months follow-up the patient was well, with good kidney function and almost complete loss of the excess body weight.

10.2.4 Training and Learning Curve Robotic kidney transplantation is a highly complex operation. A surgeon planning to perform this procedure needs to have extensive experience with the robotic system and at the same time to be proficient in open transplantation. Frequent performances of more routine procedures, such as robotic cholecystectomy, hernia repair, bowel resections, etc. is very important in order to develop necessary ease with the surgical robot. In our institution we routinely perform robotic donor nephrectomies. Regular practice of vascular suturing in a “dry” robotic lab followed by animal models transplantation would be the optimal step. Multiple assistances and close observations cannot be overemphasized. The performance of the actual transplant has to start stepwise under the guidance of an experienced surgeon. The stages of the operation which are not time sensitive, such as vascular dissection and ureterocystoneostomy, have to be mastered first. The vascular implantation on well selected cases has to be done as the last step of the training. We consider that proficiency will be achieved after at least 20 fully completed cases.

10.3 RAKT IN THE WORLD The first partial RAKT was performed in France and reported in 2001.4 The recipient was undergoing a second transplant using a kidney procured from a deceased donor. The first graft had been transplanted through an open surgery. For RAKT in the left iliac fossa, the patient was placed in supine position with legs spread and flexed to allow rolling in the surgical cart. The assistant standing on the left side of the patient made an incision in the left lower quadrant and placed the self-retaining retractor after retraction of peritoneum. During the remaining part of the procedure the assistant surgeon’s role was to perform hemostasis, placing the vascular clamps and maintaining traction on the running sutures placed by the robot trough the incision. Besides a camera arm, two other instrument arms were used for arteriotomy, venotomy, vascular anastomosis, and ureteroneocystostomy. Cold ischemia time was 26 hours and 45 minutes. Operative time was 178 minutes. Vascular anastomosis was performed in 57 minutes and immediate graft function was achieved.

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The first transabdominal RAKT in Europe was performed by Boggi et al.12 in 2011. The recipient was a 37year-old woman with lupus nephritis, on dialysis for 32 months. She weighted 59 kg. The patient was positioned supine, with the right flank slightly elevated. The table was then tilted 25 degrees to the left, further elevating the right flank, and 15 degrees in Trendelenburg’s position. A 7 cm suprapubic incision was made along the previous Pfannenstiel incision and hand access device was inserted. The robot was placed on the patient’s right side, and a 0 degree telescope was used. The renal vein was anastomosed end-to-side to the common iliac vein using two half running sutures of 6-0 expanded Polytetrafluoroethylene. The same technique was used to create an end-toside arterial anastomosis between the renal artery and the common iliac artery. The uretero-vesical anastomosis was fashioned through the suprapubic incision using open surgical technique (Gregoir-Lich extravesical anastomosis). Before closure of the Pfannenstiel incision, the graft was covered by cecum and pelvic peritoneum with an attempt to keep it in the retroperitoneal location. The warm ischemia time was 51 minutes and immediate graft function was noted on release of vascular clamps. One day after transplant, the patient was ambulating and started oral intake. Pain was minimal, and no analgesia was required after 48 hours. Later, Menon et al.13 15 from Detroit collaborated with Ahlawat in Gurgaon, and Modi in Ahmedabad in establishing two kidney transplant programs in India. In 2014, they published a prospective study of 50 consecutive patients who underwent RAKT. The mean BMI was 24.1 kg/m2. The robot was docked between the splitlegs of the patient in a lithotomy position. A Gel-point port was used to seal the mid-line incision in the periumbilical region. The pelvic bed was cooled to 18 20 C with the introduction of 180 240 mL ice slush via modified Toomey syringes. A temperature probe was used to continuously monitor renal cooling. The graft was inserted into the abdomen through the Gel-point port incision. The vascular anastomosis and the ureteroneocystostomy were performed robotically. The vascular anastomosis time was 25.4 minutes and the ureterovescical anastomosis time was 17.4 minutes. Mean intraoperative renal surface temperature was 20.3 C. The average incision length was 6.1 cm. The kidney graft was retroperitonealized for the final position. The 6-month outcome of 67 patients who underwent RAKT was recently reported.16 There were no instances of graft vascular thrombosis, stenosis, and leak. There was no delayed graft function. The mean 6-month serum creatinine was 1.2 mg/dL. The patient survival at latest follow-up was 96.3% and the graft survival (death-censored) at latest follow-up was 100%. There was no surgical site infection. During the same year, Tsai et al. from Taiwan17 reported their experience with 10 patients. The kidney was placed in the retro-peritoneum through the Gibson incision (7.7 6 1.04 cm) in the iliac fossa. The robot was docked from behind the patient’s back and the assistant surgeon stood between the two legs of the patient. The robotic arms were attached to the robotic ports and set to lift the abdominal wall about 3 cm higher. A 30-degree endoscope was placed over the Gibson incision. The kidney was placed into the abdomen through the Gibson incision. Vascular anastomosis was carried out by the robot using two half continuous sutures of 6.0 polytetrafluoroethylene. The ureteral implantation was done through the Gibson incision using the Gregoir-Lich extravesical technique. Their mean BMI was 22.8 6 3.5 kg/m2 (range: 18.9 28.2). All of the patients with robotic surgery resumed oral intake and ambulation within 24 hours after operations. Overall, the average posttransplant hospital stay was 13.6 6 3.5 days.

10.4 DISCUSSION Minimally invasive surgical approaches, including open with mini incision, laparoscopic and robotic kidney transplantation, are feasible and safe. The da Vinci robotic surgical system has the clear advantages of threedimensional vision and control of the camera by the surgeon. Articulated instruments with a wide range of movements allow for ease of suturing. Tracks of the surgeon’s movements 1300 times/s eliminates the tremor and increases the precision, essential for performing a reliable vascular anastomosis. However, vascular anastomosis through robotic arms can be technically demanding due to a lack of tactile feedback.18 This issue can be overcome using expanded polytetrafluoroethylene suture which is more resistant to grasp and less likely to break. Our experience demonstrates the benefit of RAKT in obese recipients,10 also in terms of graft survival compared to open technique. It is known that obese patients who are able to avoid SSI have the same kidney transplant success rate as patients with a normal BMI.6 We strongly believe that RAKT offers a real alternative to dialysis for obese renal failure patients, and may help to reduce health disparities due to end-stage renal disease in populations with a higher prevalence of obesity. Furthermore, considering the low success rate of medical weight loss before transplantation,19 as an evolution of our idea for the treatment of the obese patients with

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ESRD, we proposed to well selected patients a combined approach with robotic sleeve gastrectomy and RAKT. We hypothesized that the weight loss and comorbidity management may further improve the outcomes after transplantation. In the literature, different techniques have been proposed. Both transperitoneal and extraperitoneal approaches to kidney transplantation are feasible. Also the incisions made for the graft placement are at different anatomical locations. Every technique has its advantages, described by the authors. Hand assistance, easier through an upper mid-line incision, could facilitate some operative steps, such as handling the graft during performance of the vascular anastomoses, and improving exposure especially in obese recipients. In case of sudden hemorrhage, the hand-assisting surgeon could save unnecessary blood loss. Incision in the upper abdomen also avoids the highly colonized pubic and groin areas. However, this type of incision puts the patient at a slightly higher risk of developing incisional hernia. In the rare case of conversion this incision should be extended to gain full access to iliac vessels. Moreover, in our view, working transperitoneally avoids the traditional disadvantages of retroperitoneoscopy, such as limited working space, easy collapse during suctioning, and blurred vision, while still maintaining the option of the graft placement in a retroperitoneal pocket. In our series, the graft remained in an intraperitoneal location and we have been satisfied with this approach, although some complications such as a para-transplant hernia20 and renal pedicle torsion21 are possible. Furthermore, the intraperitoneal location of the graft increases the risk for complications related to standard ultrasonography-guided percutaneous kidney graft biopsy. For this reason, we have chosen to perform kidney graft biopsies under laparoscopic guidance. Intraoperative regional hypothermia proposed by Menon et al. is a reasonable technique. We believe that this approach can be useful for surgeons with limited experience in robotic suturing as a protection if a longer time to perform the anastomosis is needed. If the anastomosis time is kept to the 30 40 minutes range, intraoperative cooling of the graft may not be necessary. For achievement of immediate function of the graft we consider it important to decrease the level of the pneumoperitoneum to below 10 mmHg. This maneuver seems to decrease the potential negative effect to the microcirculation of the graft from the higher intraperitoneal pressure.

10.5 CONCLUSION Robotic-assisted kidney transplantation is an emerging modality of minimally invasive surgery and an increasing number of surgeons worldwide are trying to apply different techniques. Despite the enthusiasm for RAKT, the current high cost is the most prohibitive factor for its widespread use. By achieving adequate kidney graft function and minimizing surgical complications, robotic-assisted renal transplantation gives an opportunity for the disadvantaged group of obese patients with ESRD to have more realistic access to transplantation with good outcomes. We believe that in the long term this will compensate for the initial cost and will prove effective even from a financial viewpoint. However, robotic surgery in organ transplantation is a very advanced application of this technology and a high level of expertise is needed for any surgeon who considers this approach.

References 1. Trinh QD, Sammon J, Sun M, et al. Perioperative outcomes of robot-assisted radical prostatectomy compared with open radical prostatectomy: results from the nationwide inpatient sample. Eur Urol 2012;61(4):679 85. 2. Sood A, Jeong W, Peabody JO, Hemal AK, Menon M. Robot-assisted radical prostatectomy: inching toward gold standard. Urol Clin North Am 2014;41(4):473 84. 3. Hockstein NG, Gourin CG, Faust RA, Terris DJ. A history of robots: from science fiction to surgical robotics. J Robot Surg 2007;1(2):113 18. 4. Hoznek A, Zaki SK, Samadi DB, et al. Robotic assisted kidney transplantation: an initial experience. J Urol 2002;167(4):1604 6. 5. Segev DL, Simpkins CE, Thompson RE, Locke JE, Warren DS, Montgomery RA. Obesity impacts access to kidney transplantation. J Am Soc Nephrol 2008;19(2):349 55. 6. Lynch RJ, Ranney DN, Shijie C, Lee DS, Samala N, Englesbe MJ. Obesity, surgical site infection, and outcome following renal transplantation. Ann Surg 2009;250(6):1014 20. 7. Meier-Kriesche HU, Vaghela M, Thambuganipalle R, Friedman G, Jacobs M, Kaplan B. The effect of body mass index on long-term renal allograft survival. Transplantation 1999;68(9):1294 7. 8. Meier-Kriesche HU, Arndorfer JA, Kaplan B. The impact of body mass index on renal transplant outcomes: a significant independent risk factor for graft failure and patient death. Transplantation 2002;73(1):70 4. 9. Giulianotti P, Gorodner V, Sbrana F, et al. Robotic transabdominal kidney transplantation in a morbidly obese patient. Am J Transplant 2010;10(6):1478 82.

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10. Oberholzer J, Giulianotti P, Danielson KK, et al. Minimally invasive robotic kidney transplantation for obese patients previously denied access to transplantation. Am J Transplant 2013;13(3):721 8. 11. Ayloo SM, D’Amico G, West-Thielke P, et al. Combined robot-assisted kidney transplantation and sleeve gastrectomy in a morbidly obese recipient. Transplantation 2015;99(7):1495 8. 12. Boggi U, Vistoli F, Signori S, et al. Robotic renal transplantation: first European case. Transpl Int 2011;24(2):213 18. 13. Abaza R, Ghani KR, Sood A, et al. Robotic kidney transplantation with intraoperative regional hypothermia. BJU Int 2014;113(4):679 81. 14. Menon M, Sood A, Bhandari M, et al. Robotic kidney transplantation with regional hypothermia: a step-by-step description of the Vattikuti Urology Institute-Medanta technique (IDEAL phase 2a). Eur Urol 2014;65(5):991 1000. 15. Menon M, Abaza R, Sood A, et al. Robotic kidney transplantation with regional hypothermia: evolution of a novel procedure utilizing the IDEAL guidelines (IDEAL phase 0 and 1). Eur Urol 2014;65(5):1001 9. 16. Sood A, Ghosh P, Jeong W, et al. Minimally invasive kidney transplantation: perioperative considerations and key 6-month outcomes. Transplantation 2015;99(2):316 23. 17. Tsai MK, Lee CY, Yang CY, Yeh CC, Hu RH, Lai HS. Robot-assisted renal transplantation in the retroperitoneum. Transpl Int 2014;27(5): 452 7. 18. Patel M, Porter J. Robotic retroperitoneal surgery: a contemporary review. Curr Opin Urol 2013;23(1):51 6. 19. Wu T, Gao X, Chen M, van Dam RM. Long-term effectiveness of diet-plus-exercise interventions vs. diet-only interventions for weight loss: a meta-analysis. Obes Rev 2009;10(3):313 23. 20. Gao Z, Zhao J, Sun D, Yang D, Wang L, Shi L. Renal paratransplant hernia: a surgical complication of kidney transplantation. Langenbecks Arch Surg 2011;396(3):403 6. 21. Roza AM, Johnson CP, Adams M. Acute torsion of the renal transplant after combined kidney-pancreas transplant. Transplantation 1999;67(3):486 8.

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C H A P T E R

11 Orthotopic Kidney Transplantation Bulang He1,2 1

Sir Charles Gairdner Hospital, Perth, Western Australia 2The University of Western Australia, Perth, Australia

11.1 INTRODUCTION Kidney transplantation is a definitive treatment for patients with end stage kidney disease. The standard surgical technique for kidney transplantation has been well established since the 1950s1; in it, the kidney graft is placed in the extraperitoneal space of the lower abdomen with renal vein anastomosed to the external iliac vein and renal artery anastomosed to the internal or external iliac artery. However, in certain circumstances, such as occlusion of the iliac vessels or severe adhesions due to repeated previous pelvic surgery, it may not be possible to place the kidney graft at the lower abdomen. In such situations, the kidney graft can be transplanted at the original location or immediately next to the native kidney. This is called an orthotopic kidney transplant (OKT). OKT was first described by Gil-Vernet et al. in 1978.2 A large series study of OKT has demonstrated equivalent patient and graft long-term survival in comparison with heterotopic kidney transplant at the iliac fossa.3

11.2 INDICATIONS OKT is not commonly practiced in most transplant centers as it is technically more challenging. However it should be considered in the following conditions: (1) poor quality or occlusive iliac vessel disease; (2) multiple previous pelvic surgeries and expected severe extensive adhesions; (3) bilateral retained kidney grafts from previous transplants; (4) pediatric kidney transplant in small children; (5) demand in contact sports such as football players.

11.3 SURGICAL TECHNIQUES 11.3.1 Orthotopic Kidney Transplant by Open Surgery In open surgery, OKT can be performed either at the left or right side through a flank or midline incision. However, the left side is the preferred approach in the literature.3,4 Nephrectomy is performed first with preservation of longer renal vein and renal artery. The dissection is usually extended to the renal hilum at the level of segmental arteries. The ureter is divided at a level superior to the pelvis ureter junction. Following nephrectomy, the splenic artery is dissected and prepared for renal artery anastomosis if the renal artery is deemed not suitable for reanastomosis. The kidney graft is placed at the orthotopic region with the renal vein anastomosed to the recipient renal vein in an end-to-end fashion. To avoid renal vein anastomotic stricture, interrupted stitches are preferred. Alternatively, a growth factor is left in situ allowing the anastomosis extension if running sutures are used. The renal artery is often anastomosed to the splenic artery in end-to-end fashion as the renal artery is often of small caliber or poor quality. The renal artery can be anastomosed directly onto the aorta if the aorta is of good quality. In cases of severe aortoiliac occlusive disease, a bifurcated Dacron vascular graft may be used with one end anastomosed to the aorta and one branch end for renal artery anastomosis while another branch Kidney Transplantation, Bioengineering, and Regeneration. DOI: http://dx.doi.org/10.1016/B978-0-12-801734-0.00011-4

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end is sutured closed.5 The employment of a vascular graft will allow caliber-matched anastomosis to avoid technical failure and graft loss. After completion of vessel anastomosis, the kidney graft is reperfused and hemostasis is checked. The urinary tract is reconstructed by renal pelvis to pelvis (pyelo pyelic) anastomosis or ureter-toureter anastomosis with a ureteric stent placed in situ. 5/0 or 6/0 reabsorbable stitches are used in running suture or interrupted suture fashion. In the case of pediatric kidney transplant in a small child, the kidney graft is placed at the flank area of the orthotopic region.6 The renal vein is anastomosed to the inferior vena cava and the renal artery is anastomosed to the aorta in an end-to-side fashion. The kidney is reperfused following completion of vessel anastomosis. The ureter is usually anastomosed to the bladder using the Lich Gregoir technique with a stent placed in situ. 11.3.1.1 Outcomes of Orthotopic Kidney Transplant by Open Surgery From a large series study by Musquera,3 the long-term patient and graft survival are comparable between OKT and heterotopic kidney transplant (62.5% vs 65.9% and 34.5% vs 29.2% respectively at 20 years). Complications included renal artery stenosis in 3.6%, renal artery thrombosis in 4.8%, and renal vein thrombosis , 1%. Urinary fistula occurred in 9.5% and urinary tract obstruction is seen in 2.3%.

11.3.2 Orthotopic Kidney Transplant by Laparoscopic Surgery Kidney transplant by laparoscopic surgery has been explored over the last decade; there are increasing reports of kidney transplant by laparoscopic surgery7,8 or robotic surgery.9 11 The benefits would be similar to other minimally invasive surgeries including a smaller incision, less analgesia use, quicker recovery, and better cosmesis. To date, there has been no clinical case report of OKT by laparoscopic surgery. In a large live animal model, He et al.12 have reported successful OKT by laparoscopic surgery. This technique may be employed in the human OKT in the future. In the animal pig model, the technique is described as follows: 11.3.2.1 Laparoscopic Donor Nephrectomy on Left Side The pig is placed on right lateral recumbency after intubation for general anesthesia. The camera port is first inserted via a small incision (1.5 cm) at left of midline and cranial to the umbilicus (Fig. 11.1). Pneumoperitoneum is established with pressure set at 12 mmHg. The other ports are placed under vision forming a “V” shape (Fig. 11.1). The left kidney is identified and the bowel dissected medially to expose the renal hilum. The renal artery, vein, and ureter are subsequently dissected. The renal artery is dissected to the origin of aorta and the renal vein to the origin of vena cava to maximize vessel length and facilitate transplantation (Fig. 11.2). The kidney is mobilized free from its attachments. The ureter is divided first at the level of the lower pole of the kidney (Fig. 11.3). A small lower midline abdominal incision (6 cm) (Fig. 11.1) is made. The muscular layer is incised through the left paramidline. The peritoneal layer remained intact at this stage prior to dividing of renal artery and vein. The renal artery and vein are clamped by endoscopic Bulldog (B Brown, Germany) and then divided (Fig. 11.4). The kidney is delivered by opening the peritoneum layer through the precreated midline incision. FIGURE 11.1 (1) Camera port, (2) For fan retractor, (3) For left hand, (4) For right hand, (5) For irrigation and suction, (6) A small midline incision.

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FIGURE 11.2 Laparoscopic donor nephrectomy. The renal artery and vein are dissected to the aorta and vena cava respectively.

FIGURE 11.3 The ureter is divided.

FIGURE 11.4

Endoscopic Bulldog placed over the renal artery (RA) and renal vein (RV) respectively just beyond aorta and vena cava.

11.3.2.2 Laparoscopic Kidney Transplant in an Orthotopic Region The kidney graft is prepared on a back table. The mark suture is placed at upper and lower corner of the renal vein (Fig. 11.5). The kidney graft is wrapped in a tailored surgical pack for easy handling during the transplantation and is delivered to the orthotopic region through the same midline incision. The renal artery is anastomosed in end-to-end fashion to the renal artery stump (Fig. 11.6) and the renal vein is anastomosed in end-to-end fashion to the renal vein stump (Fig. 11.7) by 5/0 Prolene sutures using laparoscopic technique. For venous anastomosis, the posterior side can be anastomosed with a continuous suture pattern and the anterior side by interrupted sutures. Alternatively, two separate running sutures can be used for posterior side and anterior side anastomosis then two sutures are tied with a growth factor to prevent anastomotic stricture (Fig. 11.7B). For

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FIGURE 11.5 The kidney graft is wrapped in tailored surgical pack. A mark suture is placed at superior and inferior corner. RA, renal artery; RV, renal vein.

FIGURE 11.6

Renal artery anastomosis in end-to-end fashion by 5/0 Prolene interrupted suture.

FIGURE 11.7 (A B), Renal vein anastomosis in end-to-end fashion by using running 5/0 Prolene suture, one for posterior side and one for anterior side. The two sutures are tied with a “growth factor.”

arterial anastomosis, an interrupted suture pattern is preferred (Fig. 11.6). Alternatively, two separate continuous sutures are used for posterior side and anterior side anastomosis. The two sutures are tied after removing the proximal vascular clamp, allowing the blood flow through the anastomosis and distension of the anastomosis. The kidney is reperfused following completion of vessel anastomosis (Fig. 11.8). The ureter is anastomosed in an end-to-end fashion by interrupted 5/0 polydioxanone sutures (Fig. 11.9). Lastly, the kidney graft is fixed by three separate 4/0 polydioxanone sutures at the site of upper pole, lateral side, and lower pole (Fig. 11.10). Hemostasis is checked again and the wound and port incision are closed in layers. 11.3.2.3 Outcomes of Orthotopic Kidney Transplant by Laparoscopic Surgery In large live animal pig model, laparoscopic kidney transplant at the orthotopic region has been demonstrated feasible and safe.12 The estimated blood loss from surgery was minimal. The hemoglobin was stable on blood test at pre- and postsurgery. The kidney graft functioned immediately after reperfusion as long as the vessel anastomosis

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FIGURE 11.8 The kidney is reperfused following completion of the renal vein (RV) and renal artery (RA) anastomosis.

FIGURE 11.9

FIGURE 11.10

The ureter anastomosis is in an end-to-end fashion by interrupted 5/0 PDS sutures.

The kidney graft is fixed at the orthotopic region by a suture (4/0 PDS) at upper pole, interpolar, and lower pole.

is satisfactory. Doppler ultrasound showed normal perfusion waveforms of kidney parenchyma. The animal survived on the transplant kidney graft with creatinine level peaked at about 200 µmol/L on day 3 and recovered and normalized at the level of 120 µmol/L from day 7 posttransplant without need of renal replacement therapy over the 4-week study period. There was no urine leakage. However, there was mild narrowing of ureter anastomosis as a result of mucosa edema. Histopathology of kidney graft revealed normal kidney cortex or mild changes secondary to mild hydronephrosis. Understandably, at this early phase, the vessel anastomotic time is longer than OKT. The anastomotic time may improve in the future with increased proficiency in laparoscopic suture skill.

11.4 CONCLUSION OKT is an alternative procedure where heterotopic kidney transplant is not feasible due to the medical conditions of the patient or the demands of sport. The retroperitoneal approach with flank incision is a preferred technique. The splenic artery is often used for renal artery end-to-end anastomosis. The renal vein is most always

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used for renal vein end-to-end anastomosis. The pyelo pyeli anastomosis is usually performed with a ureteric stent placed in situ. The patient and graft survival is comparable to the conventional heterotopic kidney transplant. The vascular and urological complications are within the acceptable range. Recently, minimally invasive laparoscopic surgery has been employed successfully in OKT in the large animal pig model. This technique may be translated to the clinical OKT in the near future.

References 1. Murray JE, Merrill JP, Harrison JH. Kidney transplantation between seven pairs of identical twins. Ann Surg 1958;148(3):343 59. 2. Gil-Vernet JM, Caralps A, Ruano D. New approach to the splenic vessels. J Urol 1978;119(3):313 15. 3. Musquera M, Peri LL, Alvarez-Vijande R, Oppenheimer F, Gil-Vernet JM, Alcaraz A. Orthotopic kidney transplantation: an alternative surgical technique in selected patients. Europ Urol 2010;58(6):927 33. 4. Gil-Vernet JM, Gil-Vernet A, Caralps A, Carretero P, Talbot-Wright R, Andreu J, et al. Orthotopic renal transplant and results in 139 consecutive cases. J Urol 1989;142(2 Pt 1):248 52. 5. Rodrigues P, D’Imperio M, Campagnari M, Azevedo LA, Campagnari JC, van Bellen B. Alternative grafting technique for patients unsuited to heterotopic transplantation due to diseased pelvic conditions. Urol Int 2004;73(4):316 19. 6. Mackie FE, Kennedy SE, Rosenberg AR, Kainer G, Frawley JE, Haghighi KS. Safety and adequacy of percutaneous biopsies in pediatric orthotopic kidney transplantation. Int J Organ Transplant Med 2012;3(1):26 31. 7. Modi P, Pal B, Modi J, Singla S, Patel C, Patel R, et al. Retroperitoneoscopic living-donor nephrectomy and laparoscopic kidney transplantation: experience of initial 72 cases. Transplantation 2013;95(1):100 5. 8. He B, Mou L, Sharpe K, Swaminathan R, Hamdorf J, Delriviere L. Laparoscopic kidney transplant by extra peritoneal approach: the safe transition from laboratory to the clinic. Am J Transplant 2014;14(8):1931 6. 9. Menon M, Sood A, Bhandari M, Kher V, Ghosh P, Abaza R, et al. Robotic kidney transplantation with regional hypothermia: a step-bystep description of the Vattikuti Urology Institute-Medanta technique (IDEAL phase 2a). Europ Urol 2014;65(5):991 1000. 10. Abaza R, Ghani KR, Sood A, Ahlawat R, Kumar RK, Jeong W, et al. Robotic kidney transplantation with intraoperative regional hypothermia. BJU Int 2014;113(4):679 81. 11. Tzvetanov I, D’Amico G, Benedetti E. Robotic-assisted kidney transplantation: our experience and literature review. Curr Transplant Rep 2015;2(2):122 6. 12. He B, Musk GC, Mou L, De Boer B, Delriviere L, Hamdorf J. Laparoscopic surgery for orthotopic kidney transplant in the pig model. J Surg Res 2013;184(2):1096 101.

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12 Kidney Transplantation Combined With Other Organs Junichiro Sageshima1, Linda Chen2, Gaetano Ciancio2, Alberto Pugliese3 and George W. Burke III2,4 1

University of California, Davis, Department of Surgery, Division of Transplantation, Sacramento CA, United States 2 University of Miami Miller School of Medicine, Department of Surgery, Miami Transplant Institute, Miami, FL, United States 3Diabetes Research Institute, Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Department of Microbiology and Immunology, Miami, FL, United States 4University of Miami Miller School of Medicine, Diabetes Research Institute, Miami, FL, United States

12.1 PREAMBLE It was posited that a chapter on the role of kidney transplantation following a previous transplant of a different organ would be less than relevant for a book on kidney transplantation, bioengineering, and regeneration—perhaps an afterthought. Taking the liberty of pursuing a metaphysical conceit (with apologies to John Donne) and as a prism through which to analyze this further, it may be inferred, as a metric of organ importance, that the shorter the distance (length of the arterial tree) from the heart to the organ, the greater the importance of that organ. For those intraabdominal organs, including liver, spleen, and tail of the pancreas, the arterial supply is from the celiac axis, making them a higher priority than the head of the pancreas and small bowel (arterial supply derived from the superior mesenteric artery (SMA)). The renal arteries come off laterally just inferior to the SMA, putting the kidneys next in line. However, the nearness (or distance) of the kidneys to the heart needs to be tempered with the need for the kidneys to be connected to the bladder, some 20 cm distant. This anatomical directive, which required the development of ureters to bridge the transabdominal distance between the kidneys and bladder, forces one to rethink the original premise of organ importance, and distance from the heart. In fact, for the kidneys this represents a critical balance between cardiac proximity (for perfusion of the kidneys) and bladder proximity (for transit of urine through the ureters). This critical balance actually emphasizes the importance of the role of the kidneys, which would likely be located much closer to the heart were it not for the need to transport urine into the bladder. Thus the kidneys could be judged as the jewels of the abdomen and while their importance does not carry the immediacy of a transplant of the heart or liver, it does have a considerable impact on the longevity of the recipient.1,2 The kidneys play a central role relative to their location. Perhaps arterial distance from the kidneys, rather than arterial distance from the heart, should be the new metric for organ priority, following the compass analogy of John Donne.3 This compass was initially centered on the heart (in our conceit); perhaps it should be repositioned to trace circles (orbs and distance) from the kidneys, to recreate a new, revitalized order of organ importance. The following is a description detailing the benefit that many other organ transplants—including pancreas, liver, and heart—experience from the addition of a kidney transplant.

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12.2 KIDNEY COMBINED WITH PANCREAS TRANSPLANTATION This section describes simultaneous pancreas kidney (SPK), pancreas after kidney (PAK), kidney after pancreas (KAP) transplantation, and the kidney transplant alone (KTA). Pancreas transplantation is performed to restore euglycemia and long-term insulin independence. It has the potential to improve patient survival when combined with a kidney transplant. This has become the optimal therapy for patients with type I diabetes (T1D) and end-stage renal disease (ESRD).4,5 The importance of glycemic control was established in a series of papers published by the Diabetes Control and Complications Trial (DCCT), the landmark paper of which was published in the New England Journal of Medicine in 1993.6 Since that time glycemic control has been shown to be important in limiting the progression of diabetic complications, particularly retinopathy, nephropathy, and neuropathy.6,7 More recently the importance of glycemic control has been demonstrated to have long-term beneficial effects on the risk of cardiovascular disease.8 11 Together this series of reports emphasizes the importance of long-term glycemic control in the health of patients with T1D, although this effect may take decades to become evident. Patients with T1D and ESRD who underwent SPK transplantation were (somewhat surprisingly) identified, in a large proportion of instances, to have evidence of hypercoagulability. This was reported in a publication looking at thromboelastograms that were performed intraoperatively at the time of transplantation and that demonstrated a hypercoagulable pattern in a remarkably high percentage of patients.12 In addition, many patients have a clinical history of clotting (dialysis access, deep venous thrombosis, etc.), or laboratory data suggesting a tendency towards hypercoagulability that includes low PT/INR, elevated fibrinogen, and/or platelet count.12 Furthermore, the pancreas transplant venous system is positioned to develop venous stasis since the portal vein, splenic vein, and superior mesenteric vein are high-capacitance vessels (returning venous blood from the spleen and small bowel), which are only receiving venous return from the pancreas itself when transplanted. The reduced venous flow through these large veins within the pancreas contributes to venous stasis. When combined with endothelial cell damage that occurs in every solid organ transplant, this establishes the three criteria for Virchow’s triad of venous thrombosis (hypercoagulability, venous stasis, and endothelial cell damage), and explains why the incidence of thrombosis of pancreas transplants is the highest of any solid organ. In addition, the pancreas transplant recipient often presents technical challenges since patients with T1D and renal failure often have comorbidities that include atherosclerosis, which may involve the heart as well as peripheral arteries. The pancreas transplant exocrine component is drained either into the small bowel or into the bladder. At the Miami Transplant Institute, bladder drainage has been performed for over 25 years. This allows the drainage of the duodenum and pancreas exocrine secretions into the bladder and is a very safe way to handle the exocrine enzymes. The pH of the urine generally is between 7 and 9, which is protective, keeping the pancreatic exocrine enzymes from becoming activated. The alternative is enteric drainage, which is more physiologic, avoiding the metabolic acidosis that can be a consequence of bladder exocrine drainage. Enteric drainage is performed by most US pancreas transplant programs. Ultimately, since the goal of pancreas transplantation is long-term restoration of euglycemia, the specific technique of exocrine drainage, bladder or enteric, is center-dependent, where the team can determine if their technique associates favorably with long-term pancreas transplant survival. The venous drainage of the pancreas transplant is generally through the systemic system either through the external iliac vein or the inferior vena cava. Other approaches include venous drainage through the mesenteric tree or the portal vein, which ultimately allows the more physiologic first pass of insulin through the liver. However, in studies over time, results have not been shown to be different between venous drainage through mesenteric or systemic tributaries.13 The result of venous drainage through the systemic venous tree, bypassing the liver, is hyper C-peptidemia, generally in the context of euglycemia. It is theoretically possible that the high levels of c-peptide may contribute to maintaining normal HbA1c, in the context of immunosuppressive agents that are associated with insulin resistance (e.g., calcineurin inhibitors (CNI) (tacrolimus and cyclosporine A), steroids, and rapamycin). The arterial in-flow approaches for the pancreas transplant include the creation of a Y-graft that utilizes the donor external iliac artery, which is generally anastomosed to the SMA of the pancreas transplant and the internal iliac artery, which is anastomosed to the splenic artery of the pancreas transplant. The common iliac artery of the donor Y-graft is then anastomosed to the arterial tree of the recipient, generally to the external iliac or common iliac artery. Many variations of this arterial anastomosis have been applied depending on the degree of

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143

atherosclerotic changes within the recipient arterial tree.14 16 In some centers, both kidney and pancreas transplants are placed on the ipsilateral side.17 Immunosuppression in patients who receive an SPK transplant has evolved over the recent decades. A number of antibodies have been used at the time of transplantation for induction therapy.18 These have included anti-CD 25 monoclonal antibodies19,20 (currently the only anti-CD 25 formulation available is basiliximab). At the University at the Miami Transplant Institute, anti-CD 25 monoclonal antibody has been used in combination with the polyclonal, rabbit-derived antibody mixture thymoglobulin for induction therapy.21,22 Other centers have used alemtuzumab for induction.23,24 Maintenance immunosuppression generally includes tacrolimus and mycophenolate mofetil with or without steroids.19,25 In our experience at the Miami Transplant Institute, in a prospective, randomized 10-year study comparing mycophenolate mofetil to rapamycin, the results with rapamycin were significantly better from the standpoint of reduced rate of acute rejection over time.21 Furthermore rapamycin was better tolerated specifically from the standpoint of gastrointestinal function, whereas mycophenolate mofetil generally exacerbated the underlying gastroparesis that occurs in many patients with T1D. The death-censored kidney graft survival was not different between the two groups (Fig. 12.1A), 74% in the rapamycin group versus 70% in the mycophenolate mofetil group. Death-censored pancreas 10-year graft survival (Fig. 12.1B) was 98% in the rapamycin group, whereas for mycophenolate mofetil the 10-year death-censored pancreas transplant survival rate was 84% (P 5 12). This was not statistically significant, however, the rate of acute rejection was statistically significantly better in the rapamycin than the mycophenolate mofetil group.21 With longer followup, the reduced rate of rejection for pancreas transplant recipients treated with rapamycin may result in greater graft survival, and hence longer periods of euglycemia, which may translate to prolonged patient survival.9 From a metabolic standpoint there was also evidence of rapamycin-related insulin resistance. Thus, HbA1c was higher throughout the 10 years of followup in the rapamycin versus mycophenolate mofetil group, with equivalent c-peptide secretion. Nonetheless, the HbA1c in the rapamycin group was normal at all time points over the 10 years.21 Over the course of time there are suggestions that pancreas transplantation may have a positive impact on the complications of T1D. For example, similar to results of the DCCT studies over time, reversal of diabetes changes requires clearly more than 5 years of normoglycemia and oftentimes 10 20 years.26,27 There is evidence for improvement in renal function after pancreas transplantation documented by reduction of proteinuria and stable creatinine clearance.28,29 For those patients without ESRD, a higher percentage of patients experienced improved or stabilized retinopathy after pancreas transplantation alone than intensive insulin therapy.30 There has been some question regarding the optimal form of transplantation involving the kidney and pancreas transplant.31 Much data, in particular recently, suggest that the combination of SPK transplant offers the best outcome for both kidney and pancreas.32,33 However, a living donor kidney offers excellent kidney transplant survival, and, if this is then followed by a pancreas transplant, this can also result in very good kidney and pancreas transplant survival.34,35 The loss of either pancreas or kidney graft has a significant impact on patient survival with kidney loss being more important. The loss of kidney transplant function is predicted to have over five- or sixfold greater importance than the loss of a pancreas transplant.1,2 However, long-term normoglycemia and kidney function is certainly possible with either approach to transplantation.32,36 In most analyses that compare SPK to kidney transplant alone, the incremental improvement in patient survival related to pancreas transplantation survival is modest. Overall survival outcomes are superior for SPK recipients compared with recipients of deceased donor kidneys, but not for recipients of living donor kidney transplants. It should also be mentioned that pancreas transplantation with enteric drainage, pancreas after kidney (PAK) transplantation, is a risk factor for duodenal leak. This may be related to the long-term immunosuppression necessary to preserve renal function in the kidney transplant recipient.37 If the pancreas transplant is performed within 1 year of the kidney transplant, there is a smaller risk of immunosuppression-related complications.

12.2.1 Recurrence of Autoimmunity in the Pancreas Transplant Challenges for pancreas transplantation in the future include recognizing and addressing the recurrence of autoimmunity in the pancreas transplant after transplantation.38 In our experience generally this occurs somewhere between five and up to 20 years after SPK transplantation.39 This has been identified in patients who return with significant hyperglycemia (oftentimes frank diabetic ketoacidosis) in the context of unchanged creatinine and stable measurements of urine amylase, i.e., exocrine pancreas transplant function. This is then

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(A) 100

% Kidney graft survival

90

80 74% 70 70% 60 Rapa (N=84, 10 events)

50

P = .16 MMF (N=86, 18 events)

0 0

12

24

36

48 60 72 84 Months since transplant

96

108

120

(B) 98%

100

90 % Pancreas graft survival

84% 80

70

60

Rapa (N=84, 2 events)

50

P = .12

MMF (N=86, 7 events) 0 0

12

24

36

48 60 72 84 Months since transplant

96

108

120

FIGURE 12.1 Simultaneous pancreas kidney transplant recipient treated with rapamycin versus mycophenolate mofetil. (A) Percent death-censored kidney transplant survival. (B) Percent death-censored pancreas transplant survival.

confirmed by biopsy of the pancreas as well as the kidney transplant, in order to show the autoimmune process in the pancreas (as well as the lack of rejection in the kidney and pancreas) as the explanation for the hyperglycemia. In fact, these biopsies generally demonstrate the presence of insulitis with T-cell infiltrates and variable insulin staining. The T-cell infiltrates generally include CD4 and CD8 T cells. In the most severe case, where beta cell insulin staining is absent, we have demonstrated the presence of insulin staining in the exocrine ductal cells, along with markers of cell proliferation (KI-67).40 We also have demonstrated the importance of measuring autoantibodies, specifically GAD65, IA-2, and ZnT8, which tend to rise between 3 months and several years prior to the development of clinical hyperglycemia (Fig. 12.2). Autoreactive T cells have also been identified in the peripheral blood as well as the pancreas transplant and the peripancreas transplant tissues in those patients who develop recurrence of autoimmunity.41,42 This approach, specifically the potential to identify T-cell subsets and/or biomarkers in the pancreas transplant biopsy, may allow insight into the pathogenesis of T1D.

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145

FIGURE 12.2 Kaplan Meier analysis of T1DR-free survival according to autoantibodies on followup among 193 SPK recipients followed at the University of Miami who either developed T1DR or remained normoglycemic. (A) Autoantibody positivity: positive versus negative, hazard ration (HR)=14.53, P=.0005. (B) Number of autoantibodies: overall, P=.0001; 1 versus 0, HR=3.53, P=.2672; 2 versus 0, HR=14.60, P=.0005*; 3 versus 0, HR=53.88, P , .0001*; 2 versus 1, HR=5.65, P=.0131**; 3 versus 1, HR=17.04, P , .0001*; 3 versus 2, HR=3.00, P=.0261**; P value *was or **was not significant after correction for multiple comparisons. (C) Autoantibody conversion: overall, P , .0001; persistence versus negative, HR=1.88, P=.6486; conversion versus negative, HR=27.11, P , .0001*; conversion versus persistence, HR=15.57, P=.0003*; *significant P values after correction for multiple comparisons. Modified from Vendrame F, Hopfner Y-Y, Diamantopoulos S, et al. Risk factors for type 1 diabetes recurrence in immunosuppressed recipients of simultaneous pancreas-kidney transplants. Am J Transplant 2015. doi:10.1111/ajt.13426, American Journal of Transplantation, John Wiley and Sons Publisher, 1 Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

The particular importance of this finding relates to the principle of this book (as applied to the pancreas, not the kidney), which is the potential for bioengineering concepts to lead to replacement of chronically failed organs, and providing a cure for specific, organ-related diseases. From our work, it has become clear that in order to effectively treat T1D, attention must also be directed to treatment of the autoimmune process. It will not be enough to replace the pancreas physically. The issue of recurrence of autoimmunity after pancreas transplantation may help to lead to interventions that might benefit T1D primarily, or contribute to effective pancreas regeneration approaches that incorporate avoidance of recurrent autoimmunity.

12.2.2 Conclusion The challenges for SPK transplantation in the future will be finding the balance between immunosuppression that protects from rejection with resultant long-term graft function and the potential side effects of this

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immunosuppression, which include cancer and infections. Immunosuppression has evolved over the past 20 years so low rates of acute rejection with excellent graft survival and low rates of viral sequelae and lymphoproliferative disorders have been demonstrated. Improved monitoring for both rejection (alloimmunity) and the development of autoimmunity are goals for the future. Ideally, the Holy Grail of transplantation is the development of tolerogenic protocols that may allow lifelong organ function with freedom from chronic immunosuppression.

12.3 KIDNEY COMBINED WITH LIVER TRANSPLANTATION Since its first report in 1984,43 simultaneous liver and kidney transplantation (SLK) has been performed for numerous medical conditions.44 46 First, chronic kidney disease (CKD) may develop during the course of various end-stage liver diseases47; e.g., membranous nephropathy in hepatitis B virus cirrhosis48 and membranoproliferative, fibrillary, and other type of glomerulonephritis in hepatitis C virus cirrhosis49 51 (Table 12.1). Second, liver disease may develop and progress to end-stage liver disease in patients with end-stage kidney disease52; e.g., hepatitis C.53 55 Third, both liver and kidney may be affected by structural diseases; e.g., polycystic liver and kidney disease.56,57 Fourth, metabolic disorders may affect the kidney function as they progress over time58; e.g., primary hyperoxaluria,59 61 methylmalonic academia,62,63 and atypical hemolytic uremic syndrome.64 66 Lastly, advanced liver disease may be accompanied by acute kidney injury (AKI), including hepatorenal syndrome.67,68 This secondary kidney dysfunction is more prevalent than primary kidney disease in adult patients with advanced cirrhosis. Extrarenal vasodilatation in such patients may lead to systemic circulatory dysfunction, intrarenal vasoconstriction, and eventual kidney failure that is refractory to plasma volume expansion. While hepatorenal syndrome accounts for only one-third of AKI in hospitalized patients with cirrhosis,69 the overall incidence of AKI in this population is 20% and the mortality rate reaches 58% at 1 month—a sevenfold increase as compared with patients without kidney injury.70 For these patients with poor prognosis, SLK potentially provides complete recovery of combined organ failure and likely offers survival benefit over liver transplantation alone.71 75 However, not all AKIs in liver transplant candidates become permanent,76 78 nor do all parenchymal kidney diseases progress to CKD requiring renal replacement therapy.79,80 Indeed, the recovery of native kidney function after SLK has been reported.81,82 Furthermore, some of the patients with liver and kidney failure may be too sick to undergo SLK with unacceptably high mortality and morbidity rates.83,84 Of note, the patient and graft survival of SLK recipients is inferior to that of kidney alone or kidney pancreas recipients of contralateral kidney allografts owing to a higher mortality rate during the first year posttransplant.85 Thus the fair and just allocation scheme is desired for kidney, liver, and kidney liver transplant candidates. The model for end-stage liver disease (MELD) scoring system, currently used for adult liver allocation, was validated in the different patient populations with advanced liver disease. It has been accepted as an objective TABLE 12.1

Common Kidney Diseases Associated With Liver Disease

Kidney disease

Liver disease

Membranoproliferative GN

HCV, HBV, PSC, A1AT deficiency

Membranous glomerulopathy

HBV, HCV, PBC, PSC

Diabetic nephropathy

HCV

IgA nephropathy

Alcoholic cirrhosis

Fibrillary GN

HCV

ANCA-associated vasculitis

PBC, PSC

Anti-GBM disease

A1AT deficiency

Autoimmune complex GN

Autoimmune hepatitis

Tubulointerstitial nephritis

PBC, PSC, HCV

A1AT, alpha-1 antitrypsin; ANCA, antineutrophil cytoplasmic autoantibody; GBM, glomerular basement membrane; GN, glomerulonephritis; HBV, hepatitis B; HCV, hepatitis C; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.

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scale of disease severity and predictor of liver waitlist mortality.86 Since its introduction to liver graft allocation in 2002, the number of adult SLK has increased substantially in the United States, mainly because of prioritization of liver transplant candidates with kidney dysfunction (Fig. 12.3). The percentage of SLK, however, varies significantly among the Organ Procurement and Transplantation Network (OPTN) regions from 3% to 12% of all liver transplantation and from 0% to 44% at a center level.87,88 This nonuniformity raised the concern about over- or underutilization of kidney grafts due to variable selection criteria and different philosophies among transplant centers, because the preferential use of kidneys in liver recipients will increase wait time for solitary kidney transplant candidates. To standardize the evaluation and selection of SLK candidates, the expert panels held several consensus conferences and published recommendations (Table 12.2).88 91 Although the details of these recommendations differ, there are a few key components in common.

12.3.1 The Reversibility of AKI Estimated by the Duration of AKI The initial SLK guideline excluded patients with AKI who are not on dialysis89; most AKI that required dialysis was also considered possibly reversible.76,77,93 SLK was not recommended if the duration of dialysis is short (i.e., for # 6 weeks)89 because a single-center study demonstrated no benefit of SLK over liver transplantation in patients requiring pretransplant dialysis for short time.94 Subsequent SLK guidelines, however, included AKI patients even without requiring dialysis using various definitions of AKI.88,90,91 The difference among the guidelines may be in part attributed to recent increase in waiting time for liver transplant candidates with prolonged kidney insult while waiting. The duration of kidney dysfunction—even without dialysis—was shown to predict posttransplant kidney function,95,96 and a certain proportion of patients with pretransplant kidney dysfunction will progress to consideration for kidney transplantation.96,97 There is no universal consensus as to the duration of AKI beyond which no kidney recovery is possible. It is difficult to set single thresholds for recoverability prediction because the AKI reversibility may also be affected by etiology of AKI and other coexisting conditions.96 99 For example, hepatitis C virus infection and diabetes mellitus are associated with post liver transplant kidney failure.79,100 Thus it is probably reasonable to use a longer AKI threshold (e.g., 8 12 weeks) to allocate a kidney graft for patients without other comorbid conditions and a shorter AKI threshold (e.g., 4 6 weeks) for patients with comorbidities that can chronically affect kidney function.

600

10

8 7

400

6 300

5 4

200

3 2

100

% Liver–kidney transplant

Number of liver–kidney transplant

9 500

1 0

20

00 20 01 20 02 20 03 20 04 20 05 20 06 20 07 20 08 20 09 20 10 20 11 20 12 20 13 20 14

0

Year of transplant

FIGURE 12.3 Total number and percentage of simultaneous liver kidney transplantation in the United States. Columns indicate the number of liver kidney transplants; a solid line indicates percentage of liver kidney transplants of total deceased-donor liver transplants; and a broken line indicates percentage of liver kidney transplants of total deceased-donor kidney transplants. Organ Procurement and Transplantation Network (OPTN, http://optn.transplant.hrsa.gov) accessed on July 7, 2015. Note the model for end-stage liver disease (MELD) prioritization for liver transplantation was implemented in February 2002.

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TABLE 12.2

Published Guidelines on Simultaneous Liver Kidney Transplantation

References

Recommendations for clinical practice

89

Davis et al.

Eason et al.88

a. b. c. d. a. b. c. d. e.

Charlton et al.90

f. a. b. c. d.

Nadim et al.91

e. f. a.

b.

Martin et al.92

a. b. c.

Patients with CKD with a measured CCr of # 30 mL/min Patients with AKI and/or HRS on dialysis for $ 6 weeks SLK not recommended in patients with AKI not requiring dialysis Patients with prolonged AKI with kidney biopsy showing fixed renal damage Patients with ESRD (with cirrhosis and symptomatic portal hypertension or hepatic vein wedge pressure gradient $ 10 mmHg) Patients with CKD with GFR # 30 mL/min Patients with AKI or HRS with creatinine $ 2 mg/dL and dialysis $ 8 weeks Patients with CKD and kidney biopsy demonstrating .30% glomerulosclerosis or 30% fibrosis Other criteria to be considered in granting exceptions are the presence of comorbidities such as diabetes, hypertension, or other preexisting renal disease, along with proteinuria, renal size, and duration of elevated creatinine $ 2 mg/dL Net benefit should be considered when evaluating patients .65 year old, given the unfavorable outcomes in the elderly Patients with ESRD on dialysis Patients with CKD not on dialysis but with GFR ,30 mL/min (by MDRD-6 equation or direct measurement) and proteinuria ( . 3 g/day with 24-h measurement or urine protein/creatinine ratio . 3) Patients with sustained AKI requiring dialysis for .6 weeks (at least 2 times per week) Patients with sustained AKI not requiring dialysis but with GFR ,25 mL/min (by MDRD-6 equation or direct measurement) for .6 weeks Patients with categories (c) or (d) above for total of .6 weeks Patients with metabolic or genetic diseases Patients with persistent AKI for $ 4 weeks with one of the following: i. Stage 3 AKI as defined by modified RIFLE, i.e., a threefold increase in creatinine from baseline, creatinine $ 4 mg/dL with an acute increase of $ 0.5 mg/dL or on dialysis ii. eGFR # 35 mL/min (MDRD-6 equation) or GFR # 25 mL/min (iothalamate clearance) Patients with CKD as defined by the National Kidney Foundation for 3 months with one of the following: i. eGFR # 40 mL/min (MDRD-6 equation) or GFR # 30 mL/min (iothalamate clearance) ii. Proteinuria $ 2 g/day iii. Kidney biopsy showing .30% global glomerulosclerosis or .30% interstitial fibrosis iv. Metabolic disease Patients with CKD with GFR ,30 mL/min Patients with AKI with dialysis .8 weeks Patients with extensive glomerulosclerosis

AKI, acute kidney injury; CCr, creatinine clearance; CKD, chronic kidney disease; ESLD, end-stage liver disease; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HRS, hepatorenal syndrome; MDRD, modification of diet in renal disease; RIFLE, risk, injury, failure, loss of kidney function, and end-stage kidney disease; Scr, serum creatinine; SLK, simultaneous liver kidney.

12.3.2 The Severity of Chronic Kidney Disease Defined by the Estimated Glomerular Filtration Rate While patients with CKD stage V (estimated glomerular filtration rate (eGFR) , 15 mL/minute/1.73 m2 for at least 3 months) require an assessment whether to start dialysis or to receive kidney transplantation,101 clinical guidelines do not recommend preemptive solitary kidney transplantation when eGFR is above 20 mL/minute.101,102 This recommendation is supported by registry data and multicenter data analyses.103,104 Nevertheless, the SLK guidelines include patients with higher pretransplant eGFR (i.e., 30 mL/minute or higher) in the SLK candidacy.88,90 92 One reason to include such patients is inaccuracy to estimate kidney function in patients with advanced liver disease using conventional methods. Even a small increase in serum creatinine levels may indicate significant deterioration of kidney function; the MDRD and Cockcroft Gault formulae were shown to overestimate the kidney function in this population.105 107 Another reason that justifies the use of higher eGFR cutoff is the impact of nephrotoxic medication, which will be used after transplantation; e.g., calcineurin inhibitors (CNI: cyclosporine, tacrolimus).90 Although it is uncommon,88,108 patients with marginal pretransplant kidney function may progress to CKD and end-stage kidney disease after liver transplantation,79,96,97,109 which translate into poor patient survival.99,100 A recent registry data analysis demonstrated significantly inferior survival during the first 4 months after liver transplantation in patients who were listed for SLK but received an isolated liver graft.74 While several risk scores were proposed to predict posttransplant kidney function,80,110 no single method is universally accepted thus far.

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12.3 KIDNEY COMBINED WITH LIVER TRANSPLANTATION

12.3.2.1 Histological Changes of Native Kidneys In addition to the standard kidney imaging studies such as Doppler ultrasonography and kidney nuclear scan, kidney biopsy may help assess the chronicity and reversibility of the kidney disease. Besides conventional percutaneous needle biopsy, transjugular biopsy has been shown to be safe and efficacious to evaluate injury to the kidney in liver transplant candidates.111,112 Open wedge or needle biopsy performed during liver transplantation may help decide if a patient also requires a kidney transplant. We have, in selected cases, intentionally delayed kidney transplantation after liver transplantation,113 while preserving the kidney graft on a perfusion machine.114 This will allow us to hemodynamically stabilize a patient and evaluate permanent kidney biopsy sections if the reversibility of kidney dysfunction is uncertain. This strategy did not adversely affect the patient survival (Fig. 12.4). Often pathological findings of kidney biopsy correlate with impaired kidney function; however, the amount of histological changes (e.g., interstitial fibrosis, glomerulosclerosis) required to cause irreversible kidney failure is controversial. Studies on age-related glomerulosclerosis have demonstrated significant glomerular changes in healthy subjects older than 50 years.115,116 Although the degree of interstitial fibrosis and glomerulosclerosis may be associated with the impaired kidney function,117,118 a single cutoff point (i.e., 30% for both interstitial fibrosis and glomerulosclerosis used in the guidelines88,91) may not adequately classify the severity and irreversibility of functional damage, implying the need for a composite histological scoring system similar to donor kidney biopsy grading.119,120 SLK likely benefits many of the patients who have end-stage liver and kidney disease on dialysis as compared with receiving isolated liver transplantation and remaining on dialysis.71 73 However, the overall outcome of SLK has declined since the introduction of MELD.121 The etiologies of kidney dysfunction and liver disease have a significant impact on the transplant outcome.122,123 For example, hepatitis C virus infection—the leading cause of liver disease requiring liver transplantation—has been identified as a poor prognostic factor of the SLK outcome.113,123 125 For a patient with hepatitis C and other comorbidities, the transplant risk may be exceptionally high and the benefit of SLK (or the additional kidney to the liver transplant) may be minimal. If kidney grafts that are lost early in SLK recipients (i.e., death with functioning graft) were allocated to patients waiting for a solitary kidney graft, the net societal benefit could be greater.126 Until the newer treatments for hepatitis C totally shift the paradigm,127,128 it is important to take these factors into consideration. Similarly, the donor factors affect the SLK outcomes, raising the debate as to whether marginal donors such as donors after circulatory death should be used for SLK.129,130

100

% Patient survival

90

80

70

60

Delta CIT > 12 h (N=28, 6 events)

50

Delta CIT ≤ 12 h (N=38, 12 events) 0 0

4

8

12 16 Months since transplant

20

24

FIGURE 12.4 The patient survival after combined liver and kidney transplantation at the University of Miami/Jackson Memorial Hospital, stratified by the delta cold ischemia time (delta CIT: kidney cold ischemia time minus liver cold ischemia time). When a patient is hemodynamically unstable after liver transplantation or the reversibility of kidney dysfunction is uncertain, kidney transplantation from the same donor was intentionally delayed, while preserving the kidney graft on a perfusion machine. Intraoperative kidney biopsy was performed in selected cases and permanent sections were reviewed to determine the need for kidney transplantation. Additional ischemia time to the kidney did not alter the patient outcome.

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12. KIDNEY WITH OTHER ORGAN TRANSPLANT

Modifiable factors, such as immunosuppressive treatment, need to be optimized to maximize the outcome. Because infection is the major cause of morbidity and mortality, it may be important to avoid overimmunosuppression caused by depleting antibody induction.131,132 The proper management of CNI and other immunosuppressive medication is also the key to maintaining kidney function after SLK or liver transplantation.90,133,134 While the introduction of CNIs significantly improved overall survival in virtually all types of transplantation, their well-known side effect—nephrotoxicity—is the dominant causative factor for kidney disorders in nonrenal transplant recipients.135 The early posttransplant exposure to CNI can render healing from AKI difficult. Kidney function declines to 60% of pretransplant after liver transplantation in patients with normal kidney function.76,79 While mechanisms of functional and structural nephrotoxicity by CNIs have been well studied,136 methods to predict or prevent nephrotoxicity have not been established. Theoretically, CNIs and other classes of immunosuppressive or antiinflammatory agents may stabilize primary kidney diseases of liver transplant patients; however, the effect of CNI in this setting is still unclear.47 Conversely, renal vasoconstriction causing ischemic kidney dysfunction associated with severe liver failure will be exacerbated by CNIs. Optimization of immunosuppression using a nonnephrotoxic combination may decrease the need for renal replacement therapy in combination with or after the liver transplantation. However, when pretransplant kidney failure persists or new onset kidney failure develops after liver transplantation, kidney transplantation provides a better survival rate than remaining on dialysis.109,137 In contrast to the increasing number of SLK in adult patients, SLK is still uncommon in children and adolescents.46,138 Metabolic liver diseases causing end-stage kidney disease, especially primary hyperoxaluria, are the most common indication. Primary hyperoxaluria type 1 is an autosomal recessive disorder by gene mutations encoding liver-specific peroxisomal enzyme. Overproduced oxalate is excreted in the urine, where it forms oxalate stone, nephrocalcinosis, and eventual kidney failure. Unless preemptive liver transplantation is performed before the development of kidney disease,139 SLK (or sequential) transplantation is often required.59 61,140,141 Autosomal recessive polycystic kidney disease—the second most common indication—is caused by fibrocystin gene mutations and leads to end-stage kidney and liver disease.56 Because the disease manifestations can vary in kidney and liver, an individualized assessment and management is required whether to transplant solitary kidney or SLK.142 The SLK outcome in children depends on the cause of liver and kidney disease; generally children with a metabolic disease have a good prognosis. However, transplantation of a reduced-size graft with an adult kidney into a small child can still present a technical challenge.138,143

12.4 KIDNEY COMBINED WITH HEART TRANSPLANTATION Patients with concomitant end-stage heart failure and irreversible renal insufficiency are candidates for simultaneous heart and kidney transplantation (SHK). While SHK is relatively uncommon—around 100 cases annually, accounting for only 1% of deceased donor kidney transplants in the United States—the actual number of SHK is increasing (Fig. 12.5) in response to the increasing number of waitlisted patients.144 Similar to other nonrenal transplant candidates, heart transplant candidates with renal insufficiency have higher waitlist mortality. In US registry data analyses, the hazard ratios (HR) of waitlist mortality or becoming too sick to transplant were 1.6 for CKD stage III and 3.2 for CKD stage IV/V or dialysis-dependent patients.145 The 3-month and 1-year waitlist mortality rates of SHK waitlisted patients were 7% and 19% for nondialysis-dependent patients and 21% and 31% for dialysis-dependent patients, respectively.144 In contrast to dismal waitlist mortality, multiple studies demonstrated that the posttransplant survival of SHK recipients was identical to isolated heart transplant recipients, reaching 87% at 1 year and 75% at 5 years; SHK seems to mitigate the negative effect of renal insufficiency without conferring significant procedural risks.144,146 148 In a time-varying Cox proportional hazard model, SHK was shown to have greater mortality reduction (HR: 0.25) than isolated heart transplantation (HR: 0.67) from time of SHK listing.144 Although the impact of SHK is striking in patients who are on dialysis, the long-term impact of SHK is modest in patients who are not on dialysis.147 For example, 1-year and 5-year survival rates were significantly higher in SHK recipients than propensity-matched heart-alone recipients with dialysis dependence (84% vs 69% and 73% vs 51%, respectively), whereas the differences were small between SHK and heartalone recipients without dialysis dependence (91% vs 81% and 80% vs 69%, respectively).144 Therefore, despite potential benefits of SHK, the routine use of kidney grafts in heart transplant candidates with moderate renal insufficiency is not recommended, ensuring the fair utilization of the limited resource of kidneys for kidneyalone transplant candidates. When SHK candidates (eGFR , 33 mL/minute) are stratified by recipients’ risk factors, only low-risk patients were shown to clearly benefit from SHK over heart transplant alone, underscoring the importance of patient selection.149 Additionally, some of the renal insufficiency is considered reversible after

I. KIDNEY TRANSPLANTATION

151

12.5 PROTECTION OF KIDNEY BY OTHER ORGANS

120

10

8 7

80

6 60

5 4

40

3 2

20

% Heart–kidney transplant

Number of heart–kidney transplant

9 100

1 0

20 00 20 01 20 02 20 03 20 04 20 05 20 06 20 07 20 08 20 09 20 10 20 11 20 12 20 13 20 14

0

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FIGURE 12.5 Total number and percentage of simultaneous heart kidney transplantation in the United States. Columns indicate the number of heart kidney transplants; a solid line indicates percentage of heart kidney transplants of total heart transplants; and a broken line indicates percentage of heart kidney transplants of total deceased-donor kidney transplants. Organ Procurement and Transplantation Network (OPTN, http://optn.transplant.hrsa.gov) accessed on July 7, 2015.

isolated heart transplantation (i.e., certain forms of cardiorenal syndrome).150 While no universal criteria for SHK indications have been established,151,152 a thorough assessment of chronicity using kidney imaging studies and biopsies may reduce unnecessary kidney transplantation. We implemented staged SHK from a single donor using machine preservation of the kidney in order to hemodynamically stabilize the patient after heart transplantation and to increase the time to assess the kidney status.153 The efficacy of other strategies, such as using a ventricular assist device, to maintain or enhance kidney function has yet to be evaluated.154 As is the case with kidney failure after liver transplantation, kidney failure after heart transplantation is a negative predictor of posttransplant survival, and a kidney transplant after heart transplantation offers significant survival benefit.137,155,156 Because dialysis time prior to kidney transplantation affects graft survival,157 it may be reasonable to prioritize kidney transplantation in a heart transplant recipient whose marginal pretransplant kidney function is unlikely to recover after heart transplantation. Interestingly, there seems to be no difference in kidney graft survival by the quality of the kidney donor in prior heart transplant recipients; living donor, standard criteria deceased donor, and even extended criteria deceased donor transplants seem to provide similar advantages.157 Thus in a prior heart transplant recipient, shorter waiting time by accepting extended criteria donors may be beneficial, when no living donor is available157,158.

12.5 PROTECTION OF KIDNEY BY OTHER ORGANS When a kidney is transplanted with another organ, a lower rejection rate and prolonged graft survival have been observed. Traditionally, this observation was seen when the kidney was transplanted with the liver, establishing its reputation as an immunoprotective organ.159 161 Even in patients with positive pretransplant crossmatch, hyperacute rejection may not occur and the crossmatch may become negative.162 164 The kidney grafts last longer in liver transplant recipients from the same donor,85,165 and kidney graft rejection rates are lower when a liver allograft is placed concurrently,161 offering immunological advantage in SLK patients. This phenomenon was also observed in pediatric patients.166,167 Olausson et al. transplanted a partial auxiliary liver merely to facilitate the kidney transplantation in highly sensitized patients together with a kidney from the same crossmatch-positive donor.168 In five of seven cases, crossmatch turned negative with excellent graft function and no rejection, whereas two remained crossmatch positive with one primary nonfunction and one early graft failure. In contrast, others reported that liver is not always protective against kidney rejection.169 172 While the liver may help improve kidney graft survival in sensitized patients,173,174 Dar et al. demonstrated persistence of preexisting HLA class II antibodies and antibody-mediated rejections in SLK patients.175 Preexisting or de novo class II

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donor specific antibodies were also shown to be an independent predictor of patient death and liver allograft loss.176 Interestingly, the protection is also observed with nonliver organs. Opelz et al. demonstrated prolongation of long-term kidney graft survival not only in SLK recipients but also in SHK recipients.177 Heart seems to protect kidney and vice versa.146,178,179 Using the US registry data, Rana et al. also demonstrated the protective effect of a liver, heart, and kidney graft for the other cotransplanted organ, but failed to demonstrate the protective effect of pancreas or intestine grafts.180 Several mechanisms have been proposed to explain how one organ protects the other, but the exact mechanism remains to be explored further.181 184

Acknowledgements The authors would like to express their appreciation to Ms. Zulimi Pastor Clark for her persistence and patience in the preparation of this manuscript.

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126. Kiberd B, Skedgel C, Alwayn I, Peltekian K. Simultaneous liver kidney transplantation: a medical decision analysis. Transplantation 2011;91(1):121 7. 127. Coilly A, Roche B, Duclos-Vallee JC, Samuel D. Management of post-transplant hepatitis C in the direct antiviral agents era. Hepatol Int 2015;9(2):192 201. 128. Price JC, Terrault NA. Treatment of hepatitis C in liver transplant patients: interferon out, direct antiviral combos in. Liver Transpl 2015;21(4):423 34. 129. Wadei HM, Bulatao IG, Gonwa TA, et al. Inferior long-term outcomes of liver-kidney transplantation using donation after cardiac death donors: single-center and organ procurement and transplantation network analyses. Liver Transpl 2014;20(6):728 35. 130. Alhamad T, Spatz C, Uemura T, Lehman E, Farooq U. The outcomes of simultaneous liver and kidney transplantation using donation after cardiac death organs. Transplantation 2014;98(11):1190 8. 131. Hibi T, Nishida S, Sageshima J, et al. Excessive immunosuppression as a potential cause of poor survival in simultaneous liver/kidney transplantation for hepatitis C. Transpl Int 2014;27(6):606 16. 132. Uemura T, Schaefer E, Hollenbeak CS, Khan A, Kadry Z. Outcome of induction immunosuppression for liver transplantation comparing anti-thymocyte globulin, daclizumab, and corticosteroid. Transpl Int 2011;24(7):640 50. 133. McKenna GJ, Trotter JF, Klintmalm E, et al. Limiting hepatitis C virus progression in liver transplant recipients using sirolimus-based immunosuppression. Am J Transplant 2011;11(11):2379 87. 134. Manzia TM, Angelico R, Toti L, et al. Long-term, maintenance MMF monotherapy improves the fibrosis progression in liver transplant recipients with recurrent hepatitis C. Transpl Int 2011;24(5):461 8. 135. Ojo AO. Renal disease in recipients of nonrenal solid organ transplantation. Semin Nephrol 2007;27(4):498 507. 136. Campistol JM, Sacks SH. Mechanisms of nephrotoxicity. Transplantation 2000;69(12 Suppl):SS5 10. 137. Cassuto JR, Reese PP, Sonnad S, et al. Wait list death and survival benefit of kidney transplantation among nonrenal transplant recipients. Am J Transplant 2010;10(11):2502 11. 138. Jalanko H, Pakarinen M. Combined liver and kidney transplantation in children. Pediatr Nephrol 2014;29(5):805 14 quiz 12. 139. Kemper MJ. The role of preemptive liver transplantation in primary hyperoxaluria type 1. Urol Res 2005;33(5):376 9. 140. Hoppe B. An update on primary hyperoxaluria. Nat Rev Nephrol 2012;8(8):467 75. 141. Malla I, Lysy PA, Godefroid N, et al. Two-step transplantation for primary hyperoxaluria: cadaveric liver followed by living donor related kidney transplantation. Pediatr Transplant 2009;13(6):782 4. 142. Telega G, Cronin D, Avner ED. New approaches to the autosomal recessive polycystic kidney disease patient with dual kidney-liver complications. Pediatr Transplant 2013;17(4):328 35. 143. Sakamoto S, Kasahara M, Fukuda A, et al. Pediatric liver-kidney transplantation for hepatorenal fibrocystic disease from a living donor. Pediatr Transplant 2012;16(1):99 102. 144. Schaffer JM, Chiu P, Singh SK, Oyer PE, Reitz BA, Mallidi HR. Heart and combined heart-kidney transplantation in patients with concomitant renal insufficiency and end-stage heart failure. Am J Transplant 2014;14(2):384 96. 145. Singh TP, Almond CS, Taylor DO, Graham DA. Decline in heart transplant wait list mortality in the United States following broader regional sharing of donor hearts. Circ Heart Fail 2012;5(2):249 58. 146. Narula J, Bennett LE, DiSalvo T, Hosenpud JD, Semigran MJ, Dec GW. Outcomes in recipients of combined heart-kidney transplantation: multiorgan, same-donor transplant study of the International Society of Heart and Lung Transplantation/United Network for Organ Sharing Scientific Registry. Transplantation 1997;63(6):861 7. 147. Gill J, Shah T, Hristea I, et al. Outcomes of simultaneous heart-kidney transplant in the US: a retrospective analysis using OPTN/UNOS data. Am J Transplant 2009;9(4):844 52. 148. Karamlou T, Welke KF, McMullan DM, et al. Combined heart-kidney transplant improves post-transplant survival compared with isolated heart transplant in recipients with reduced glomerular filtration rate: analysis of 593 combined heart-kidney transplants from the United Network Organ Sharing Database. J Thorac Cardiovasc Surg 2014;147(1):456 61 e1. 149. Russo MJ, Rana A, Chen JM, et al. Pretransplantation patient characteristics and survival following combined heart and kidney transplantation: an analysis of the United Network for Organ Sharing Database. Arch Surg 2009;144(3):241 6. 150. Cruz DN, Bagshaw SM. Heart-kidney interaction: epidemiology of cardiorenal syndromes. Int J Nephrol 2010;2011:351291. 151. Lewis RM, Verani RR, Vo C, et al. Evaluation of chronic renal disease in heart transplant recipients: importance of pretransplantation native kidney histologic evaluation. J Heart Lung Transplant 1994;13(3):376 80. 152. Labban B, Arora N, Restaino S, Markowitz G, Valeri A, Radhakrishnan J. The role of kidney biopsy in heart transplant candidates with kidney disease. Transplantation 2010;89(7):887 93. 153. El Hinnawi A, Sageshima J, Ciancio G, et al. Renal graft outcome after single-donor staged heart-kidney transplantation using pulsatile machine perfusion of the renal grafts. Am J Transplant 2013;13:48 [Abstract]. 154. Singh M, Shullo M, Kormos RL, et al. Impact of renal function before mechanical circulatory support on posttransplant renal outcomes. Ann Thorac Surg 2011;91(5):1348 54. 155. Bourge RC, Naftel DC, Costanzo-Nordin MR, et al. Pretransplantation risk factors for death after heart transplantation: a multiinstitutional study. The Transplant Cardiologists Research Database Group. J Heart Lung Transplant 1993;12(4):549 62. 156. Lonze BE, Warren DS, Stewart ZA, et al. Kidney transplantation in previous heart or lung recipients. Am J Transplant 2009;9(3):578 85. 157. Cassuto JR, Reese PP, Bloom RD, et al. Kidney transplantation in patients with a prior heart transplant. Transplantation 2010;89(4):427 33. 158. Srinivas TR, Stephany BR, Budev M, et al. An emerging population: kidney transplant candidates who are placed on the waiting list after liver, heart, and lung transplantation. Clin J Am Soc Nephrol 2010;5(10):1881 6. 159. Calne RY, Sells RA, Pena JR, et al. Induction of immunological tolerance by porcine liver allografts. Nature 1969;223(5205):472 6. 160. Fung J, Makowka L, Tzakis A, et al. Combined liver-kidney transplantation: analysis of patients with preformed lymphocytotoxic antibodies. Transplant Proc 1988;20(Suppl. 1):88 91. 161. Rasmussen A, Davies HF, Jamieson NV, Evans DB, Calne RY. Combined transplantation of liver and kidney from the same donor protects the kidney from rejection and improves kidney graft survival. Transplantation 1995;59(6):919 21.

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162. Morrissey PE, Gordon F, Shaffer D, et al. Combined liver-kidney transplantation in patients with cirrhosis and renal failure: effect of a positive cross-match and benefits of combined transplantation. Liver Transpl Surg 1998;4(5):363 9. 163. Neumann UP, Lang M, Moldenhauer A, et al. Significance of a T-lymphocytotoxic crossmatch in liver and combined liver-kidney transplantation. Transplantation 2001;71(8):1163 8. 164. Creput C, Durrbach A, Samuel D, et al. Incidence of renal and liver rejection and patient survival rate following combined liver and kidney transplantation. Am J Transplant 2003;3(3):348 56. 165. Simpson N, Cho YW, Cicciarelli JC, Selby RR, Fong TL. Comparison of renal allograft outcomes in combined liver-kidney transplantation versus subsequent kidney transplantation in liver transplant recipients: analysis of UNOS Database. Transplantation 2006; 82(10):1298 303. 166. de la Cerda F, Jimenez WA, Gjertson DW, Venick R, Tsai E, Ettenger R. Renal graft outcome after combined liver and kidney transplantation in children: UCLA and UNOS experience. Pediatr Transplant 2010;14(4):459 64. 167. Rogers J, Bueno J, Shapiro R, et al. Results of simultaneous and sequential pediatric liver and kidney transplantation. Transplantation 2001;72(10):1666 70. 168. Olausson M, Mjornstedt L, Norden G, et al. Successful combined partial auxiliary liver and kidney transplantation in highly sensitized cross-match positive recipients. Am J Transplant 2007;7(1):130 6. 169. Eid A, Moore SB, Wiesner RH, DeGoey SR, Nielson A, Krom RA. Evidence that the liver does not always protect the kidney from hyperacute rejection in combined liver-kidney transplantation across a positive lymphocyte crossmatch. Transplantation 1990;50(2):331 4. 170. Katznelson S, Cecka JM. The liver neither protects the kidney from rejection nor improves kidney graft survival after combined liver and kidney transplantation from the same donor. Transplantation 1996;61(9):1403 5. 171. Askar M, Schold JD, Eghtesad B, et al. Combined liver-kidney transplants: allosensitization and recipient outcomes. Transplantation 2011;91(11):1286 92. 172. Nilles KM, Krupp J, Lapin B, Sustento-Reodica N, Gallon L, Levitsky J. Incidence and impact of rejection following simultaneous liverkidney transplantation. J Hepatol 2015;62(2):340 5. 173. Hanish SI, Samaniego M, Mezrich JD, et al. Outcomes of simultaneous liver/kidney transplants are equivalent to kidney transplant alone: a preliminary report. Transplantation 2010;90(1):52 60. 174. Leca N, Warner P, Bakthavatsalam R, et al. Outcomes of simultaneous liver and kidney transplantation in relation to a high level of preformed donor-specific antibodies. Transplantation 2013;96(10):914 18. 175. Dar W, Agarwal A, Watkins C, et al. Donor-directed MHC class I antibody is preferentially cleared from sensitized recipients of combined liver/kidney transplants. Am J Transplant 2011;11(4):841 7. 176. O’Leary JG, Gebel HM, Ruiz R, et al. Class II alloantibody and mortality in simultaneous liver-kidney transplantation. Am J Transplant 2013;13(4):954 60. 177. Opelz G, Margreiter R, Dohler B. Prolongation of long-term kidney graft survival by a simultaneous liver transplant: the liver does it, and the heart does it too. Transplantation 2002;74(10):1390 4 discussion 70 71. 178. Luckraz H, Parameshwar J, Charman SC, Firth J, Wallwork J, Large S. Short- and long-term outcomes of combined cardiac and renal transplantation with allografts from a single donor. J Heart Lung Transplant 2003;22(12):1318 22. 179. Pinderski LJ, Kirklin JK, McGiffin D, et al. Multi-organ transplantation: is there a protective effect against acute and chronic rejection? J Heart Lung Transplant 2005;24(11):1828 33. 180. Rana A, Robles S, Russo MJ, et al. The combined organ effect: protection against rejection? Ann Surg 2008;248(5):871 9. 181. Sumimoto R, Kamada N. Specific suppression of allograft rejection by soluble class I antigen and complexes with monoclonal antibody. Transplantation 1990;50(4):678 82. 182. Murase N, Starzl TE, Tanabe M, et al. Variable chimerism, graft-versus-host disease, and tolerance after different kinds of cell and whole organ transplantation from Lewis to brown Norway rats. Transplantation 1995;60(2):158 71. 183. Cre´put C, Durrbach A, Menier C, et al. Human leukocyte antigen-G (HLA-G) expression in biliary epithelial cells is associated with allograft acceptance in liver-kidney transplantation. J Hepatol 2003;39(4):587 94. 184. Ingelsten M, Gustafsson K, Olausson M, Haraldsson B, Karlsson-Parra A, Nystrom J. Rapid increase of interleukin-10 plasma levels after combined auxiliary liver-kidney transplantation in presensitized patients. Transplantation 2014;98(2):208 15.

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C H A P T E R

13 Pediatric Renal Transplantation Ashton Chen, Jen-Jar Lin and Andrew M. South Wake Forest Baptist Health, Winston-Salem, NC, United States

ABBREVIATIONS AAMR ACR AMR AR ATN BKVN BP CAMR CAN CCR CMV CNI CVD CVP DD DM DSA EBV ELISA ESRD FSGS GI GSR HUS IL-2 IVIG LD MMF MPGN mTOR NAPRTCS OPTN PRA PSR PTLD

acute antibody-mediated rejection acute cellular rejection antibody-mediated rejection acute rejection acute tubular necrosis BK virus nephropathy blood pressure chronic antibody-mediated rejection chronic allograft nephropathy chronic cellular rejection cytomegalovirus calcineurin inhibitor cardiovascular disease central venous pressure deceased-donor diabetes mellitus donor-specific antibodies Epstein Barr virus enzyme-linked immunosorbent assay end-stage renal disease focal segmental glomerulosclerosis gastrointestinal graft survival rate hemolytic uremic syndrome interleukin-2 intravenous immunoglobulin living-donor mycophenolate mofetil membranoproliferative glomerulonephritis mammalian target of the rapamycin North American Pediatric Renal Trials and Collaborative Studies Organ Procurement and Transplantation Network panel-reactive antibodies patient survival rate posttransplant lymphoproliferative disorder

Kidney Transplantation, Bioengineering, and Regeneration. DOI: http://dx.doi.org/10.1016/B978-0-12-801734-0.00013-8

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© 2017 Elsevier Inc. All rights reserved.

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Scientific Registry of Transplant Recipients United Network for Organ Sharing United States Renal Data System urinary tract infection vesicoureteral reflux

13.1 INTRODUCTION There are many benefits to transplant compared to dialysis in children, including improved quality of life and survival and decreased risk of cardiovascular disease, metabolic bone disease, and growth delay associated with chronic renal failure and dialysis (see the following paragraphs). The precise selection criteria for pediatric kidney transplantation vary from center to center, but generally include up-to-date immunizations, particularly with live vaccine (varicella and MMR), stable home environment and social support network, absence of active infection or malignancy, and a urinary bladder with adequate capacity, high compliance, and efficient emptying by spontaneous voiding or intermittent catheterization. The incidence of end-stage renal disease (ESRD) in children is 16 per 1 million in Whites, 15 per 1 million in African Americans, and 18 per 1 million in other races.1 There is an increased incidence of ESRD with increasing age, with the highest rate in adolescents age 15 19 (21 per 1 million). Cystic, hereditary, and congenital kidney diseases are the most common causes of pediatric ESRD in the United States (34%) while primary glomerular disease accounts for 22% and secondary glomerulonephritis/vasculitis accounts for 11% of cases.1 The etiology of ESRD differs between White and African American children. The most common causes of ESRD in Whites are renal aplasia/hypoplasia/dysplasia (16%), obstructive uropathy (15%), and focal segmental glomerulosclerosis (FSGS) (12%). In African American recipients, FSGS is the most common cause (23%), followed by obstructive uropathy (15%) and renal aplasia/hypoplasia/dysplasia (13%). Causes of ESRD are similar between Hispanic and White children.2 The survival of pediatric renal grafts in earlier years was meager due to complications from allograft thrombosis and limited immunosuppression,3 but it has improved since the 1980s, as indicated in the 1987 2007 data from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS), which demonstrated an improvement in 10-year patient survival rate and graft survival rate (GSR) in both living-donor (LD) and deceased-donor (DD) transplantation.4 Similarly, the short- and long-term survival of pediatric renal grafts has improved in the past 25 years according to the 1987 2012 data from Scientific Registry of Transplant Recipients.5 Furthermore, high-risk pediatric recipients based on peak panel-reactive antibodies (PRA), previous transplant history, and human leukocyte antigen (HLA) mismatch have had a similar improvement in death-censored graft survival as low-risk groups, while highly sensitized pediatric recipients experienced a better improvement in PSR.5 The implementation of Share-35 policy in 2005 by American Organ Procurement and Transplantation Network has changed the donor characteristics of pediatric recipients. With this policy, the priority for kidneys from deceased donors less than 35 years old was assigned to recipients less than 18 years old, zero mismatch transplants, recipients with a PRA greater than 80%, or candidates receiving a kidney and a nonrenal organ.6 It has increased HLA-mismatching and DD grafts for pediatric recipients.7,8 According to a 2010 NAPRTCS report, the age distribution of recipients remained unchanged with 13 17 years being the most common age at transplantation (39.2%), followed by 6 12 years (32.8%), 2 5 years (14.7%), and less than 1 year (5.3%). Recipients were 59% male, 59% Whites, 17% Hispanics, 17% African Americans, and 7% other races. Adolescents were more likely to receive a DD graft. Children less than 5 years old were more likely to receive a LD graft. LD transplant increased from 43% in 1987 to 61% in 2001 but it decreased to its lowest point in 2007 at 37%, likely related to Share-35 policy. About 24% primary transplants were preemptive. Among them, Whites were 31%, African Americans 13%, and Hispanics 16%.4 Many studies have demonstrated racial and ethnic minority pediatric patients in the United States and other countries have a longer waiting time for transplantation and lower rates of preemptive and LD transplantation.9,10 Main causes of death in pediatric recipients are infection (28.5%), cardiopulmonary events (14.7%), malignancy (11.3%), and dialysis-related complications (3.1%).4 The primary causes of graft failure are chronic rejection (35%) and acute rejection (13%). Risk factors for a decreased GSR include DD kidney, African Americans, prior dialysis, and prior transplant.4 A lower GSR in adolescents,5,11 13 female recipients,5 pretransplant dialysis,5,14 and recipients with FSGS5,12,15 was also reported in other studies. Compared with Whites, African Americans have a lower 3- and 5-year GSR.16 Analysis of nearly 14,000 pediatric kidney transplant recipients from the United States Renal

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Data System demonstrated approximately a twofold higher rate of graft loss in African Americans compared with Whites.17 Reasons for racial disparities in transplant outcomes are unclear and require further study.

13.2 SURGICAL ASPECT OF PEDIATRIC RENAL TRANSPLANTATION 13.2.1 Native Nephrectomy Prior to Transplantation Data in pediatric pretransplant native nephrectomy are limited. Polyuria is not an indication for native nephrectomy since it may interfere with fluid management and blood pressure control during dialysis. However, there are circumstances in which native kidneys are removed because they may cause short- or long-term risks to the recipients or grafts, such as intractable hypertension, recurrent kidney infections, heavy proteinuria, large polycystic kidneys, and risk of malignancy.18 20 Heavy proteinuria and hypoalbuminemia increase the risk of thromboembolic events during surgery.19,21 Removal of nephrotic native kidneys reduces the risk of acute graft thrombosis, intravascular volume depletion, nutritional deficit, and delayed wound healing.22 An improved serum protein level during surgery improves posttransplant fluid management23 and is associated with a favorable posttransplant graft function in children.20

13.2.2 Transplant Surgery The kidney graft can be placed intra- or extraperitoneally, depending on the child’s body shape, height, and the sizes of blood vessels. The minimum weight and/or age limit for kidney transplantation varies among pediatric centers, ranging from 6 months old/5 6 kg weight to 12 months old/10 kg.24 The best option is a LD,25 followed by an adult-sized DD.26 The last choice is a pediatric donor, preferably .6 years of age.22,27 29 The exception is a recipient with a thrombosed inferior vena cava who will require a smaller kidney with a graft vein implanted in patent pelvic vein.30,31 Grafts of less than 24 hours of cold ischemia time are favored since those greater than 24 hours are 1.5 times more likely to fail regardless of donor age.27 In general, a midline abdominal incision is usually made for recipients less than 10 kg. The graft is placed within the right side of the abdomen by anastomosing the donor artery to the aorta below the inferior mesenteric artery and the donor vein to the inferior vena cava below the left renal vein using end-to-side technique.32 The donor’s ureter is implanted into the recipient’s bladder using either a Ledbetter Politano procedure or one of its modifications.33 For infants weighing 10 20 kg, the graft is placed extraperitoneally when possible34,35 with the renal artery and vein anastomosed to the common or external iliac artery and vein, respectively. For those recipients greater than 30 kg, the surgical technique is the same as those for adult recipients.36,37 The extraperitoneal approach allows earlier oral feeding, avoids postoperative intestinal adhesion, prevents twisting or kinking of the graft, and reduces motility of ureteral anastomosis.33,38 Recently, some centers have successfully performed extraperitoneal renal transplantation on infants less than 10 kg using a J-shaped external pararectal incision extending cranially to a point near the costal border.31,38,39 The graft is placed in a position similar to that of the native kidney. This incision avoids muscle splitting leading to less postoperative pain, permits good exposure of the great vessels, prevents handling the intestine with subsequent ileus, enables the whole length of the graft ureter to remain extraperitoneally, preserves peritoneal dialysis access, and keeps possible surgical complications within the retroperitoneum.39,40 As a result, surgical success in small children has improved, equivalent to those achieved in older children and adolescents.31,41,42 Immediate postoperative complications include lymphocele, renal artery or venous thrombosis, renal artery stenosis, urinary leakage from anastomosis, ureteral stenosis, and ureteral necrosis.39,43 Prophylactic placement of an indwelling double-J ureteral stent does not reduce the risk of urinary leakage or obstruction. Stent migration and the need of general anesthesia to remove the stents are common.44 In addition, an association between ureteral stent and BK nephropathy has been reported.45 In general, the ureteral stent is not recommended except for selected cases in small children.33

13.2.3 En Bloc Pediatric Kidney Transplant To expand the donor pool, en bloc kidney transplantation from young pediatric donors to adult recipients has been advocated but in an earlier report it suffered a high incidence of renal artery stenosis, venous thrombosis, and ureteral complication.46 With improved surgical technique, its complications have been reduced, similar to that in adult single allografts.47

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13.2.4 Perioperative Management Factors contributing to early graft loss in small children include inadequate surgical technique, postoperative vessel angulation, and the increased hemodynamic need of an adult graft in a small child.48 Recipients less than 2 years old are at risk of vascular thrombosis due to the smaller size of blood vessels and inadequate renal perfusion.41,49 Other risk factors for vascular thrombosis are cold ischemia time greater than 24 hours and acute tubular necrosis.50 An adult kidney sequesters 250 300 mL of blood so an infant’s cardiac output needs to be doubled to perfuse the adult graft.51 Therefore, intraoperative and immediate postoperative volume management is critical to maintain anastomosis patency and avoid hypoperfusion of grafts in small pediatric recipients.38,48 Usually central venous pressure is kept greater than 10 cm H2O and mean arterial pressure greater than 60 mmHg with crystalloid, colloid, and sometimes mannitol prior to the release of vascular clamping.52 Postoperatively, the intravenous fluid is usually given as insensible loss plus full replacement of urine output with Ringer’s lactate or saline plus bicarbonate solution to maintain CVP greater than 10 cm H2O during the first 24 48 hours. Inotropic agents such as dopamine can be added to maintain urine output or mean BP above 60 mmHg. When there is an unexplained decrease in urine output, sonogram of the graft should be performed to rule out vascular thrombosis. Arterial hypertension is usually managed with calcium channel blockers. Perioperative antibiotics such as cephalexin are used to prevent wound infection, followed by cotrimoxazole to prevent urinary tract infection (UTI) and Pneumocystis jiroveci pneumonia.53

13.2.5 Posttransplant Urologic Complications Bladder dysfunction including abnormal bladder capacity (26%), abnormal urinary flow (50%), and residual urine (32%) occurs in pediatric recipients but does not seem to affect graft function.54 Patients with augmented cystoplasty have a higher incidence of UTI after transplantation. This is related to vesicoureteral reflux (VUR) or noncompliance with clean intermittent catheterization.55 VUR into a graft is more frequent in children than in adult recipients even with the same surgical team using the same techniques.56 Its incidence was 36%57 to 58%58 before 1992 but has been reduced to 14.5% after 1998 due to improvement in surgical technique.59 The incidence of UTI was not different between pediatric recipients with and without,57,59 but those with VUR had a higher incidence of acute pyelonephritis57,58 which could be prevented by antibiotic prophylaxis.58 Correction of VUR in pediatric recipients reduced the incidence of UTI in a small series but it was associated with obstructive complications.60 Whether antireflux surgery can reduce the risk of febrile UTI in a large pediatric cohort is unclear. VUR was associated with worse graft function and survival in two pediatric studies61,62 but not in others.59,63 It has been linked to the pathologic findings of interstitial fibrosis and tubular atrophy in pediatric recipients.64 In this aspect, persistent inflammation in areas of interstitial fibrosis and tubular atrophy were negative prognostic indicators for long-term graft function.65,66 Therefore, it remains a controversy whether the presence or degree of VUR in pediatric recipients affects graft outcome. A similar controversy exists in the association of UTI with graft function in pediatric recipients. Despite acute graft dysfunction during febrile UTI, long-term renal function was not different between pediatric patients with and without infection in some reports59,67,68 but others reported lower graft function in those with recurrent UTI.58,69 In this regard, analysis of 1996 2000 USRDS data that included 28,942 Medicare adult and pediatric recipients showed that UTIs occurring after 6 months posttransplant were associated with an increased risk of death and graft loss.70

13.3 DESENSITIZATION 13.3.1 ABO Incompatibility Blood group antigens A and B are targets of natural antibodies of IgM and/or IgG types that can cause renal allograft rejection.71 In contrast, the presence of antibodies against non-A/B blood group antigens such as RH, Kell, Duffy, etc., does not seem to affect kidney allograft survival since they are not expressed on the endothelium.72 Plasmapheresis or immunoadsorption, depletion of B-cells prior to transplantation, and maintenance immunosuppression after transplantation are strategies to reduce the risk of acute rejection in ABO-incompatible recipients. Plasmapheresis indiscriminately removes all plasma proteins including anti-A or anti-B antibodies. Immunoadsorption using columns coated with protein A (binding most of IgG) or sheep antihuman

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immunoglobulin (binding most antibody isotypes) removes only antibodies but is not antigen-specific. Antigenspecific immunoadsorption73 is coated with Staphylococcus A protein on which either isoagglutinin A (anti-A column) or B (anti-B column) is implanted to adsorb anti-A or anti-B immunoglobulins, respectively. In general, a 1/4 or 1/32 reduction in anti-A or -B immunoglobulins prior to transplantation is accepted by many centers but a titer of 1/256 or less has been advocated.74 Due to a preparative regimen of several days, immunoadsorption and plasmapheresis are largely restricted to LD transplant. Splenectomy or cyclophosphamide to deplete B-cells is now replaced by rituximab, which is usually given within a month before transplantation to reduce the risk of antibody rebound.75 The typical posttransplant maintenance immunosuppression after ABO desensitization includes tacrolimus, mycophenolate mofetil (MMF), and corticosteroids. Plasmapheresis or immunoadsorption is used in cases with a significant rise of antibody titers.76 Grafts after ABO-incompatible kidney transplantation in pediatric patients have a good outcome. Tyden et al. showed 100% and 90% GSR at 1 year and 3 years, respectively, in ABO-incompatible group compared with 96% and 92% in ABO-compatible group.77 Shishido et al. reported 94% and 86% GSR at 1 year and 10 years, respectively, in ABO-incompatible group compared with 95% and 88% in ABO-compatible group.78 It is interesting to see that the 10-year graft survival in ABO-incompatible group in this pediatric study was higher than 72.9% survival in the United States and 76.1% survival in the Japanese study.79

13.3.2 Antibody Sensitization PRA is a complement-fixating assay to test the ability of recipient’s serum to lyse a panel of T-cells from a group of potential donors.80 For a PRA of 20% 80%, there is 50% chance to be transplanted compared to nonsensitized patients while the chance is only 5% for PRA greater than 80%. Approximately 3% of sensitized children on the waiting list have a PRA above 80%.81 PRA detects only anti-HLA I antibodies and does not reflect all donors. A positive T-cell cross-match has a high-risk for hyper-acute rejection and is considered an absolute contraindication to kidney transplantation. A positive B-cell cross-match indicates the presence of anti-HLA I and/or II antibodies. The presence of anti-HLA II alloantibodies is associated with a high-risk of hyperacute rejection. In this aspect, solid phase assays in which purified HLA I or II antigen attaches to flow cytometry beads or enzymelinked immunosorbent assay plates can identify specific anti-HLA I or II antibodies.82 Therefore, combined solid phase and cross-match assays allow for specification and quantitation of anti-HLA antibodies. Donor-specific antibodies (DSA) are produced when nonimmunosuppressed recipients are exposed to foreign antigens such as HLA-I and -II, ABO antigens, and possibly endothelial monocyte antigens. These antibodies are the result of persistence of donor proteins in the recipient follicular dendritic cells by chimerism.83 Sensitization may occur after blood transfusion but the main cause is previous transplantation. Prevention of sensitization from multiple transfusions in transplant candidates is important. Cyclosporine coverage during transfusion has been suggested84 but it is not widely used because of hyperkalemia. MMF exposure in a 4-year-old sensitized recipient reduced anti-HLA antibodies.85 The use of leukocyte-poor blood in transplant candidates on sensitization rate is unknown. Plasmapheresis, intravenous immunoglobulin (IVIG), and rituximab in combination are commonly used for antibody desensitization. Splenectomy at the time of transplantation, in combination of rituximab, is reserved for recipients with a high-risk profile.86 The goal of plasmapheresis is the removal of DSA to achieve a negative cross-match assay before transplantation. In addition to blocking anti-HLA antibodies, IVIG has immunomodulatory effects including downregulation of B-cell differentiation and antibody production, inhibition of T-cell proliferation and complement system, suppression of dendritic cells, and anticytokine activity.87,88 Desensitization using plasmapheresis and low-dose IVIG before LD transplantation improves the 8-year survival in adult recipients89 but there is no consensus in pediatric desensitization protocols. Tyan et al. reported the successful use of IVIG in a 13-year-old boy.90 Three doses of 2 g/kg IVIG every 4 weeks did not reduce PRA in an 11-year-old child. Subsequently, plasmapheresis every other day for 2 weeks reduced PRA with a negative cross-match assay.91 In contrast, 500 mg/kg IVIG weekly for 3 consecutive weeks every 12 weeks after 40 months reduced PRA to zero in a 7-year-old girl with a failed graft.92 These reports suggest IVIG’s effect on pediatric desensitization is unpredictable. Rituximab is often given after plasmapheresis to prevent B-cell differentiation and antibody rebound. This regimen can be used in conjunction with IVIG, or alone if patients fail IVIG.91 Since rituximab does not inhibit antibody production by plasma cells, bortezomib has been used alone in anti-HLA-sensitized adult recipients but results were disappointing.93,94 The combination of bortezomib and plasmapheresis seems to be a better desensitizing treatment than IVIG plus plasmapheresis in adults.95 There is no report regarding the use of bortezomib on sensitized pediatric kidney transplant candidates although its successful use in combination

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with rituximab and plasmapheresis has been reported in a heart transplant recipient.96 An alternate strategy for antibody desensitization is a paired living-donor program. After transplantation, triple agents including MMF, steroids, and tacrolimus are usually employed as maintenance immunosuppression. Most patients require additional plasmapheresis and IVIG after transplantation, depending on DSA titer and graft function. Future multicenter controlled pediatric clinical trials are needed to determine the most efficacious protocols.97

13.4 TRANSPLANT IMMUNOSUPPRESSION While adult data guide pediatric practice, there has been significant progress in developing pediatric protocols and obtaining outcome data. In pediatrics special attention has been focused on minimizing or avoiding steroids or calcineurin inhibitor (CNI). As of 2017, there is no evidence that the various induction agents improve longterm outcomes, though survival may be increased in LD recipients.4,98

13.4.1 Induction Therapy The goal of induction therapy is to prevent T-cell activation. The approach to induction therapy varies widely among transplant centers.4,49 The immunosuppressive effects of antithymocyte globulins is mediated through the depletion of circulating T-cells by complement-mediated lysis as well as blockage of T-cell proliferation.99 Polyclonal antithymocyte globulins can be derived from horse (Atgam) or rabbit (thymoglobulin). In a singlecenter pediatric study, the incidence of acute rejection was lower in Thymoglobulin-treated recipients when compared to the historical Atgam-treated recipients.100 Thymoglobulin reduced the incidence of AR in pediatric recipients.101 It is usually given as 1.5 2 mg/kg/dose when the CD3 count exceeds 20 cells/mm.3,102 Alemtuzumab (Campath-1H) is a humanized anti-CD52 antibody. It depletes T- and B-cells, monocytes, and natural killer cells and its effects last for months. In 42 pediatric LD recipients who received pretransplant alemtuzumab and posttransplant tacrolimus monotherapy, the 4-year GSR and PSR were comparable to those reported for LD recipients in the US-transplant SRTR database.103 In 101 pediatric LD recipients who received the first dose of alemtuzumab 12 29 days prior to transplantation and the second dose intraoperatively, along with a low-dose CNI, their 3-year GSR and AR episodes were comparable to NAPRTCS data. However, the incidences of subclinical Epstein Barr virus (EBV) and cytomegalovirus (CMV) infections were high.104 In a retrospective study, alemtuzumab was given intraoperatively at 0.5 mg/kg to 25 pediatric DD recipients. Steroids were discontinued 4 days later. Tacrolimus monotherapy was started the day after transplantation while MMF was added only in cases of high immunological risk or prolonged delayed graft function. Over a mean follow-up of 2 years, tacrolimus monotherapy was maintained in 48% of children and steroids were avoided in 80%. Incidence of AR was 12% within the first year and 16% at 2 years but the incidence of BK or CMV infection was 16%.105 In another retrospective study on 21 pediatric DD recipients who received alemtuzumab intraoperatively and maintained on tacrolimus and MMF, PSR was 100% and GSR 95% after a mean follow-up of 33 months (range 1 6.5 years). None of the patients had CMV infection, posttransplant lymphoproliferative disorder (PTLD), or BK virus nephropathy.106 These studies suggest that alemtuzumab can be a candidate as induction agent for steroid avoidance but prospective studies are needed to confirm these findings. Basiliximab (Simulect) and daclizumab (Zenapax) act on the inducible alpha-H chain of the interleukin-2 (IL-2) receptors on the surface of the activated lymphocytes. They saturate the IL-2 receptors, acting as a competitive antagonism of IL-2-dependent T-cell proliferation. Data from NAPRTCS demonstrated their use was associated with a decreased risk of thrombosis.107 Both antibodies have been studied extensively in children and have been shown to be safe and effective but neither confers increased long-term graft or patient survival.108

13.4.2 Maintenance Therapy Pediatric maintenance agents usually comprise of CNI (tacrolimus, cyclosporine), cell cycle inhibitors (azathioprine, MMF), and steroids. The most common maintenance protocol consists of tacrolimus, MMF, and steroids, followed by a steroid-free protocol with tacrolimus and MMF, though this differs internationally.4,109 Tacrolimus is used more commonly than cyclosporine.49,110 The combination of CNI, rapamycin, and corticosteroids should be avoided due to the risk of PTLD.11

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Steroids have multiple adverse effects on children including growth retardation, cushingoid habitus, infection, impaired wound healing, aseptic bone necrosis, cataracts, glucose intolerance, hypertension, hyperlipidemia, gastric ulcer disease, obesity, behavioral changes, and acne. In addition, the negative cosmetic effect may play a role in poor adherence. Therefore there have been attempts to withdraw steroids earlier after transplantation. Alternate-day steroid therapy improved linear growth and did not increase rejection episodes or affect renal function in retrospective111 and prospective112 pediatric studies. In a single-center retrospective study of 60 children, a steroid-free protocol using Thymoglobulin induction and maintenance tacrolimus and MMF had a 93% PSR and 63% GSR at 10 years with improved linear growth.113 Analysis of United Network for Organ Sharing database from 2002 to 2009 showed pediatric recipients who received only tacrolimus and MMF immunosuppression had a lower risk of AR 6 months after renal transplantation and a better 5-year GSR compared to steroidbased protocols. However, this data analysis was limited by steroid withdrawal patients having less delayed graft function and pretransplant dialysis, less likely to be African American, and more frequently receiving a LD graft.114 The cooperative clinical trials in pediatric transplantation study of corticosteroid withdrawal in pediatric kidney transplantation was halted at 1 year due to an increased incidence of PTLD. However, those children whose corticosteroids were successfully withdrawn did not have a higher rate of later rejection, and their longterm graft survival was equivalent to the control group.115 In a randomized, multicenter trial, 130 children were randomized to steroid-free or steroid-based immunosuppression, with concomitant tacrolimus, MMF, and standard-dose daclizumab (Steroid-based group) or extended-dose daclizumab (Steroid-free group). At 3-year follow-up, both groups had comparable graft and patient survival but the Steroid-free group had better linear growth, lower systolic BP, and lower cholesterol levels.116 There is no evidence to date of a higher risk of DSA in steroid-free protocols after renal transplantation. Further studies are needed to determine the long-term benefits of steroid-free protocols. The dose of cyclosporine is higher in children due to a more rapid metabolism.117 Among the side effects of cyclosporine, hirsutism, facial dimorphisms, and gingival hyperplasia are the main concerns in children since they can affect compliance.118 Neoral is a microemulsion form of cyclosporine that has a more consistent intestinal absorption with fewer dose adjustments compared to Sandimmune.119 Tacrolimus shares similar side effects with cyclosporine except for cosmetic effects but it has more frequent neurologic symptoms.120 Posttransplant diabetes mellitus associated with tacrolimus occurs via diminished insulin secretion complicated by insulin resistance from concomitant steroid use.121 Tacrolimus is not associated with a higher risk of PTLD, likely due to the lower dose.122 Extended-release tacrolimus is a once-daily formulation with comparable efficacy to twice-daily tacrolimus. Long-term renal function is greater than with cyclosporine123 125 but there remains a concern with how it compares with the twice-daily tacrolimus in terms of dosage monitoring, benefits in compliance, and rejection episodes in children.126 There are numerous drug and food interactions with cyclosporine and tacrolimus through cytochrome p450 system 3a4. Grapefruit not only contains substrates that inhibit CYP3A4 but it also increases membrane transporter p-glycoprotein and interferes with intestinal absorption and tissue distribution of cyclosporine, tacrolimus, and possible sirolimus.127 Diarrhea can lead to an increased tacrolimus level.128 A higher dose of tacrolimus is needed for African Americans due to the fact that CYP3A*51 alleles are expressed in 90% of African Americans but only 5% of Whites.129 The clearance of tacrolimus can be affected by food, medications such as corticosteroids and antibiotics, hypoalbuminemia, anemia, and hepatic dysfunction.130 Azathioprine inhibits purine synthesis, preventing gene replication and cell division. This in turn blocks cellmediated immunity, inhibits primary antibody synthesis, and decreases circulating monocytes and granulocytes.131 The main side effect of azathioprine is myelosuppression. Other side effects include viral infection, hepatotoxicity, pancreatitis, alopecia, and neoplasia, most notably skin cancer.132 To date, azathioprine is no longer the first-line immunosuppression in pediatric recipients but is still useful in select patients such as patients with MMF-associated colitis. MMF is rapidly metabolized to mycophenolic acid, which blocks conversion of inosine IMP to guanosine IMP in purine biosynthesis pathway. The net result is a decrease in the number of functional B- and T-cells and the inhibition of their response to antigen challenges.131 Hematological and gastric symptoms are the main side effects. Neutropenia and thrombocytopenia can be reversed with the reduction in MMF dose but frequent reduction or withholding of the MMF dose can lead to impaired graft survival due to rejection.133 Frank esophagitis and gastritis with occasional GI hemorrhage occur in approximately 5% of patients.134 Colonoscopic findings of chronic diarrhea from MMF include nonspecific, inflammatory bowel disease-like, graft-versus-host disease-like, and ischemic-like colitis.135 The enteric coated mycophenolic acid, myfortic, has fewer gastrointestinal side effects and a faster intestinal absorption.133 MMF in combination with tacrolimus results in a higher blood level of

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MMF.136 The use of therapeutic drug target monitoring of MMF has been suggested in patients with high immunologic risk; noncompliance; renal, hepatic, or bowel dysfunction; reduced dose or withdrawal of CNI; or drug interaction137 but its role in long-term graft outcome remains controversial.137,138 The pharmacokinetics of MMF are different between adults and pediatric patients and there is a weak negative association between its clearance and age in pediatric patients.139 The mammalian target of the rapamycin (mTOR) is a cytosolic serine/threonine enzyme that exists in two distinct multiprotein complexes, mTORC1 and mTORC2. It triggers the differentiation and proliferation of lymphocytes after activation by cytokines from the antigen-activated lymphocytes. Sirolimus or everolimus complexes with the immunophilin FK-binding protein 12, which inhibits mTORC1. mTOR inhibitors also promote T-cell apoptosis140 and inhibit proliferation of vascular muscle cells.141 This dual immunosuppressive and antiproliferative effect can be beneficial to long-term graft outcome. mTOR inhibitors do not possess nephrotoxicity.142 They have fewer GI side effects than MMF.143 Everolimus is the 40-O-(2-hydroxyethyl) derivative of sirolimus with improved GI absorption but a shorter elimination half-life,144 making it a twice-daily dosing versus the daily dosing of sirolimus in adults. In younger children, however, sirolimus is usually given twice a day due to higher clearance.145 There is a competitive interaction between sirolimus and CNI for being a substrate for p-glycoprotein and cytochrome p450 isoenzymes,146 147 allowing for a smaller CNI dose and fewer side effects. In a retrospective pediatric study, addition of sirolimus to cyclosporine on a steroid-withdrawal protocol led to stable graft function at 1 year without steroid-related side effects.148 In pediatric patients with chronic allograft nephropathy (CAN) or high immunologic risk, conversion of CNI to sirolimus preserved short-term149 151 or long-term152 153 graft function while decreased short-term graft function was reported in another study.154 However, there were high incidences of proteinuria, hypercholesterolemia, oral ulcers, myalgia, infection, and leukopenia from sirolimus149 153 resulting in a high withdrawal rate.149,153,154 A prospective, single-arm trial of CNI-free immunosuppression with sirolimus and MMF in pediatric recipients had biopsy-proven AR episodes occurring in almost one in three patients and a high rate of sirolimus-related patient withdrawal.155 Another pediatric prospective study using basiliximab induction and sirolimus, cyclosporine, and steroids for maintenance immunosuppression was discontinued at 1 year due to a high incidence of PTLD.115 A prospective combination of everolimus, corticosteroids, and a 50% dose of cyclosporine in 19 pediatric recipients had good 3-year patient and graft survival but there was a high incidence of biopsy-proven AR, hyperlipidemia, and bacterial infection.156 This increased incidence of AR was not observed in 13 LD recipients in the same trial at 1 year157 or in another study with additional basiliximab induction.155 Therefore, evidence from studies of sirolimus replacing CNI as maintenance immunosuppression in pediatric recipients has not been encouraging and the use of everolimus to reduce CNI exposure awaits further controlled studies. Furthermore, long-term side effects of mTOR inhibitors on spermatogenesis or growth retardation have not been examined in pediatric recipients. CTLA-4 signaling pathway is critical for T-cell costimulation and the induction of acquired tolerance in vivo.158 Belatacept is a recombinant protein that contains the extracellular domain of CTLA-4 fused to an IgG heavy chain tail. In a randomized adult BENEFIT trial, 666 patients who received basiliximab induction and MMF plus corticosteroid immunosuppression were randomized to low- or high-dose belatacept or cyclosporine. Renal function was higher and the incidence of chronic rejection was lower at 12 months in the belatacept group compared to the cyclosporine group.159 At 5 years, the benefit on renal function was sustained and the concern for PTLD in EBV-negative patients in the earlier study was not observed.160 A pediatric study on belatacept is currently under investigation.

13.4.3 Acute Rejection The rejection process is initiated and maintained by interaction among CD4 and CD8 T-cells, B-cells, and macrophages. This interaction mediates activation and expression of proinflammatory molecules on intragraft endothelial cells, which in turn augments recruitment and activation of leukocytes. The binding of alloantibodies to the cytokine-activated endothelial cells is associated with complement C4d deposition, resulting in regional vasculitis and endothelial cell death.161 AR is characterized histologically by the necrosis of renal parenchyma with lymphocyte and macrophage infiltrates. Its time course includes hyperacute rejection (immediately after engraftment), accelerated AR (within 1 week after transplantation), early AR (within 6 months after transplantation), and late AR (more than 12 months after transplantation). Hyperacute rejection is characterized by rapid thrombotic occlusion of the graft within minutes of vascular anastomosis. The only treatment is surgical removal. Accelerated AR carries a poor prognosis and its risk factors include delayed graft function

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and presence of de novo DSA.162 Both hyperacute rejection and accelerated AR are rare now with the widespread use of cross-match assay. The incidence of AR is declining in pediatric recipients163 but it remains higher than that in adult recipients.4,164 AR can be acute cellular rejection (ACR) or acute antibody-mediated rejection but mixed rejection can occur. Continuous and diffuse C4d staining along peritubular capillaries is present in 30% of rejection biopsies, and DSA are present in 90% of C4d 1 cases.165 Surveillance biopsies may be useful in diagnosing subclinical AR but data on long-term outcome is lacking.166,167 AR is a risk factor for graft dysfunction and chronic rejection. The incidences of graft failure and patient death after AR are 5% 7%.4 Graft loss from AR at 5 years after transplantation is approximately 13%,109 with infants and young children having the best outcome among age groups.168 Risk factors for AR in LD and DD recipients are similar, including years of transplant, adolescent age, and African American race.49 An elevated percentage of circulating CD25 level169 or CD69 level170 or a five-gene set on peripheral blood171 has been proposed as a marker for AR in pediatric recipients. 13.4.3.1 Acute Cellular Rejection ACR is mainly a T-cell-mediated rejection that involves tubular, interstitial, and intimal infiltration of inflammatory cells. Tubulitis is essential for its diagnosis, while glomerular changes are limited to mesangial expansion. ACR is associated with de novo DSA production and the risk for future AMR and graft loss.172 Standard treatment is intravenous methylprednisolone 10 25 mg/kg pulse therapy for 3 days, followed typically by Thymoglobulin at 1.5 2 mg/kg/dose for 10 14 days. High-dose oral prednisone in children has an equivalent result to intravenous therapy in terms of the rate of rejection reversal.173 Alemtuzumab has been used in adult patients with ACR who were previously treated with OKT3 or Thymoglobulin174 or who were resistant to steroids or Thymoglobulin.175 NAPRTCS 2001 07 data showed that 53% LD and 47% DD recipients had complete reversal of rejection, 43% LD and 47% DD recipients had a partially reversed rejection, and 4% LD and 6% DD recipients lost the graft.49 Despite the decreasing AR frequency, the reversibility rate of AR in pediatric recipients has not improved since the 1990s. 13.4.3.2 Acute Antibody-Mediated Rejection The incidence of AAMR in children is not known. In adults, the incidence was less than 5% in unsensitized patients but between 40% and 90% in sensitized patients.176 The risk for AAMR in children includes HLA mismatches, AR, nonadherence to treatment, insufficient immune suppression, previous transplantation, and blood transfusion.177 179 De novo DSA has been detected in up to 24% of children with renal transplants, equally found in those with steroid-free or steroid-based regimen.180 They are usually anti-HLA II antibodies,181 which are associated with a worse prognosis than are anti-HLA I antibodies.182 In AAMR, alloantibodies preferentially attack the peritubular and glomerular capillaries183,184 through activation of classical complement pathway, resulting in C4d binding to tissue and depositing in peritubular capillaries.185 The 2007 Banff criteria for AAMR included circulating DSA, diffuse deposition of C4d in more than 50% peritubular capillaries, acute tissue injury, and clinical evidence of graft dysfunction. The acute tissue injury includes acute tubular injury; neutrophils or monocytes in the peritubular capillaries or glomeruli; and intimal, intramural, or transmural inflammation or fibrinoid necrosis of the arteries.186 AAMR has been described in C4d-negative grafts. In such cases microcirculatory injury and the presence of Class II DSA indicate a worse outcome. For this reason, the updated 2013 Banff AMR criteria did not preclude a negative C4d staining.187 188 Since not all patients with anti-HLA antibodies have AR or graft loss, assays for C1q-binding DSA have been developed and C1q-positive DSA are associated with short- or long-term graft loss.172 189 There is evidence that non-HLA antibodies are also associated with the development of AAMR since it was reported in identical HLA recipients. These non-HLA antigens include polymorphic antigens of endothelial cells, the major histocompatibility complex class one-related chain A (MICA) on endothelial surface, the angiotensin II type 1 receptor, and vimentin.190 AAMR in general has a worse prognosis than ACR in adults.179 There are no agreed-upon pediatric protocols to treat AMR but commonly employed treatments alone or in combination include IVIG, plasmapheresis/immunoadsorption, rituximab, and an enhancement of existing immunosuppression with or without steroids.191 193 Other treatment has been reported in pediatric cases. Three pediatric recipients with AAMR who failed IVIG, rituximab, plasmapheresis, and steroid pulse therapy were treated with one dose of 900 or 1200 mg eculizumab but only one patient responded.194 Successful treatment with plasmapheresis, IVIG, and eculizumab was reported in a 7-year-old child who developed AMR at day 4 after transplantation.195 A recent retrospective study in 4 children with AAMR who received 4 doses of bortezomib (1.3 mg/m2) at days 1, 4, 8, and 11 and various combinations of rituximab, steroids, plasmapheresis, and IVIG suggested bortezomib therapy is an effective and

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safe method for rapid reduction in DSA levels.196 Because of the prolonged need for increased immunosuppression treatment, patients have increased risk of infectious and malignant complications.

13.4.4 Chronic Renal Allograft Injury Chronic renal allograft injury is characterized clinically by a progressive decrease in allograft function, usually accompanied by proteinuria and hypertension, and pathologically by interstitial fibrosis and tubular atrophy with or without mononuclear infiltration. It is the end result from a variety of etiologies including nonimmune causes such as CNI toxicity, arterial hypertension, chronic urinary obstruction, viral and bacterial infection, and immune causes such as chronic antibody-mediated rejection and chronic cellular rejection.197 CAMR is a chronic injury to the glomerular and tubular basement membrane as a result of capillary injury.198 Clinically it presents as proteinuria, hypertension, and declining graft function over time. The glomerular lesion is characterized by reduplication and lamination of glomerular basement membrane (transplant glomerulopathy). There are tubular basement membrane multilayers with margination of mononuclear leukocytes. Eventually these lesions lead to tubular atrophy and interstitial fibrosis.199 C4d deposition may or may not be present and DSA levels usually fluctuate, suggesting additional complement-independent mechanisms mediating the injury from antibodies against endothelial HLA antigens. Patients with positive DSA and untreated or inadequately treated AMR have a higher risk for CAMR.200,201 Surveillance biopsies may facilitate early detection of CAMR, which could lead to more prompt treatment and improved outcomes.200 Twenty pediatric recipients with CAMR were prospectively treated with 4 weekly IVIG (1 g/kg) and 1 dose of rituximab (375 mg/m2) at 1 week after the last IVIG infusion. Response to treatment was defined as a reduction of the rate of functional loss by at least 30% within 6 months compared with the period 6 months prior to treatment. After 2 years of follow-up, all 9 patients without transplant glomerulopathy (100%) and 5 of 11 patients with transplant glomerulopathy (45%) responded.177 CCR is incompletely described in pediatric transplant recipients and is usually comprised of intimal inflammation with intercurrent chronic allograft arteriopathy.202 A low-dose CNI in combination with a low-dose of sirolimus or everolimus in prospective pediatric studies improves graft function.203,204

13.5 METABOLIC COMPLICATIONS AFTER TRANSPLANTATION Despite the improvement in patient survival since the advent of pediatric renal transplantation, there remain significant deleterious effects on a patient’s metabolism, leading to poor cardiovascular, endocrine, musculoskeletal, and developmental outcomes. Contributing factors include medication side effects, complications from prior procedures, sequel from the underlying disease, and declining allograft function.

13.5.1 Cardiovascular Disease Children with ESRD have cardiovascular disease and while transplantation attenuates the risk factors, CVD remains a significant contributor to morbidity and mortality.4,205 207 Risk factors for CVD include hypertension, obesity, hyperglycemia, dyslipidemia, and anemia, and early interventions should focus on treatment of these conditions. Hypertension is a common posttransplant complication, especially with steroid and CNI use.208,209 Steroid avoidance improves BP.116 Appropriate lifestyle and pharmacologic management is critical. Adequate BP control can improve or stabilize end-organ damage such as left ventricular remodeling and carotid intima-media thickness.210,211 There is evidence angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers may protect and improve pediatric graft function over time.212 214

13.5.2 Endocrine Disorders Dyslipidemia, glucose intolerance, and DM are less common in pediatric recipients compared to adults but remain significant posttransplant complications. Posttransplant dyslipidemia improves over time and steroid avoidance improves cholesterol levels.116,206 Pediatric patients often have abnormalities in glucose metabolism. Glucocorticoids reduce peripheral insulin sensitivity by decreasing the binding of insulin to insulin receptors and by decreased glucose utilization. CNI and mTOR inhibitors reduce insulin secretion by pancreatic β-cells.215 Impaired glycemic control is associated with higher BP and being overweight and obese.216 In this aspect, the presence of metabolic syndrome in transplant patients has increased in the past few years.217 Insufficient or

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deficient 25-vitamin D levels have been reported in 76%218 to 92%219 of pediatric recipients. Vitamin D deficiency was associated with short stature and hyperparathyroidism219 but its association with posttransplantation proteinuria remains to be determined.

13.5.3 Growth Growth impairment occurs in patients with ESRD and in transplant recipients. Pretransplant growth deficits, posttransplant growth patterns, and final adult height improve dramatically across age groups after transplantation.4,220 Pubertal growth is maintained but catch-up growth during puberty typically does not occur. Steroid avoidance improves growth and graft function predicts growth.116 While improved growth is a desired outcome, obesity remains a significant issue. Most patients experience increases in BMI posttransplant, which in turn increases the risk of cardiovascular and metabolic disease.216,221

13.5.4 Metabolic Bone Disease There is improvement in metabolic bone disease posttransplant but the physiology does not return to normal.206,222 224 Pediatric recipients have increased loss of bone mass and strength and increased rates of fractures and avascular necrosis.225 228 Persistent posttransplant metabolic bone disease is a modifiable cardiovascular risk factor.229 Key interventions include maintaining normal graft function; targeting normal vitamin D, calcium, and phosphorus levels; and ensuring adequate nutrition and physical activity. Growth hormone may have a role in improving bone structure and final adult height.230 232

13.5.5 Development The metabolic complications of kidney disease and renal transplantation affect pediatric neurocognitive development. Patients with chronic kidney disease and ESRD have worse neurocognitive outcomes but this improves following renal transplantation.233 However, many patients have persistent developmental abnormalities and require some degree of educational and social support.234 Overall IQ, education levels, and social outcomes are normal to near-normal.235 237

13.6 RECURRENCE Disease recurrence accounts for 6.6% of primary allograft failure and 9.6% of subsequent allograft failure according to NAPRTCS 2010 data. The primary cause for disease recurrence in pediatric recipients is glomerular disease.

13.6.1 Focal Segmental Glomerulosclerosis FSGS recurs in 20% 50% of primary pediatric transplants with equally high incidence of graft loss.4,238 Risk factors for its recurrence include early onset of nephrotic syndrome, rapid progression to ESRD (less than 3 years), resistant to treatment, White or Asian race, and recurrence in previous transplant.239,240 For unclear reasons, familiar FSGS does not seem to recur in a graft. The recurrence can occur within the first 24 hours after the graft is reperfused or several months later. The presence of circulating permeability factors has been suggested in recurrent FSGS.241 There is no benefit to LD transplantation in children with recurrent FSGS. Treatment includes plasmapheresis242 and high-dose CNI,243 but there are mixed results with rituximab.244

13.6.2 Alport Syndrome In individuals with X-linked Alport syndrome or hereditary nephritis, antiglomerular basement membrane disease may develop after transplantation leading to allograft failure in 3% 5% of male cases,245 especially when there is an associated vascular rejection.246 The risk is higher in subsequent transplants and does not typically respond to treatment.

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13.6.3 Membranoproliferative Glomerulonephritis Membranoproliferative glomerulonephritis is characterized by subendothelial and mesangial deposits of immune complexes. It has been recently reclassified into immunoglobulin-positive MPGN caused by chronic infection or autoimmune disease and immunoglobulin-negative MPGN, which consists of dense deposit disease and C3 glomerulopathy.247 The latter is more common in pediatric patients, although still a relatively rare cause of glomerular disease in children. MPGN can recur in 20% 30% of cases in what is classically termed MPGN type 1. In cases of dense deposit disease (classically referred to as MPGN type 2), it can recur in up to 90% of cases.248 In a study based on NAPRTCS data, recurrence of MPGN type 2 resulted in allograft failure in 15% of children by 5 years after kidney transplantation249 and there is no evidence of effective treatment.250

13.6.4 IgA Nephropathy IgA nephropathy can recur but graft survival is not different from that in other glomerular diseases.238 However, there were case reports that it can present with crescentic lesions leading to deterioration of graft function.250

13.6.5 Hemolytic Uremic Syndrome Shiga toxin associated hemolytic uremic syndrome is unlikely to recur after kidney transplantation. Atypical HUS is a genetic disorder of complement pathway such as Factor H, B, or I deficiency, a genetic mutation resulting in deficiency of von Willebrand factor cleaving protease, ADAMTS13, and other metabolic disorders.251 Atypical HUS is highly likely to recur after transplantation, between 20% and 80%.251 ADAMTS13 deficiency is associated with high mortality and few patients undergo transplantation, with those that do having high rates of allograft failure from vascular thrombosis or disease recurrence. In patients with Factor H, I, or membrane cofactor protein mutations, recurrence is 67% 76%.252 Plasmapheresis is the main treatment and prophylactic plasmapheresis has some benefit compared to plasmapheresis after recurrence.253 There have been several successful simultaneous liver kidney transplants for patients with Factor H deficiency using presurgery plasmapheresis plus fresh frozen plasma infusion pre- and intraoperatively.252 Recently, weekly eculizumab starting 1 month prior to transplantation in a pediatric LD recipient with Factor H deficiency maintained graft function after 1 year of follow-up.254

13.6.6 Membranous Nephropathy Unlike in adult kidney transplant recipients, recurrence of primary membranous nephropathy is rare in children and does not impact graft function. De novo membranous nephropathy can occur but does not usually affect graft function or outcome.

13.6.7 Systemic Lupus Erythematosus The risk of recurrence in patients with lupus nephritis is low, likely from adequate maintenance immunosuppression.255 Patients with antiphospholipid syndrome have a higher risk of thrombotic complications. Recurrence in pediatric patients is not clinically significant and does not affect allograft outcome.238 In pediatric patients, allograft survival is not different from that in nonlupus renal disease, but patient survival is worse.256

13.6.8 ANCA-Associated Vasculitis/Pauci-Immune Glomerulonephritis Recurrence of ANCA-associated vasculitis and pauci-immune glomerulonephritis is rare due to adequate maintenance immunosuppression. If it recurs, it can be managed with cyclophosphamide, corticosteroids, and sometimes plasmapheresis.257 It is preferable that patients maintain remission without systemic signs or active nephritis for at least 6 months prior to transplantation.

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13.7 METABOLIC DISEASES Primary hyperoxaluria type I is secondary to a deficiency of hepatic alanine glyoxylate aminotransferase leading to excess production of oxalate and deposition in kidneys with associated renal injury. As kidney function declines there is reduced oxalate excretion and calcium oxalate is deposited in other tissue and organs. The recurrence is nearly 100% shortly after kidney transplantation. Treatment with intense plasmapheresis after kidney transplantation is needed to reduce the body load of oxalates. Therefore, a preemptive combined liver kidney transplant is preferred.258,259 For patients with long-term ESRD, sequential liver kidney transplantation with hemodialysis after liver transplantation may be beneficial to reduce total body oxalate levels.260 Patients with the Gly170Arg AGXT mutation may respond to pyridoxine, which allows them to receive an isolated kidney transplant with long-term pyridoxine supplementation.260 Patients with methylmalonic acidemia develop ESRD due to interstitial nephritis. It may be partially ameliorated by kidney transplantation, but methylmalonic acid continues to be produced after kidney transplantation so combined liver kidney transplantation has been suggested in selected cases.261 Kidney transplantation and cysteine-depleting therapy with cysteamine extends the life expectancy to the fifth decade and beyond for children with nephropathic cystinosis.262,263 Patients need to take cysteamine posttransplant since transplant does not correct or prevent nonrenal morbidity such as visual impairment, hypothyroidism, myopathy, central nervous system disease, and pancreatic insufficiency.262,264 Although cystine may accumulate in the interstitium of the renal graft, it does not cause graft failure. There is no risk of recurrence of primary disease in the renal graft.

13.8 CANCER AFTER KIDNEY TRANSPLANTATION Cancer accounts for 11% of mortality in pediatric recipients.4 It occurs in 2% 9% of pediatric recipients265 267 and its incidence increases with years of transplantation.267 PTLD accounts for 82% of pediatric cancer cases.2 The second most common cancer in pediatric recipients is skin cancer, which includes squamous cell carcinoma, basal cell carcinoma, lip cancer, and melanoma.268 Skin cancer usually develops 12 15 years after transplantation269 and so only a few cases are reported during childhood. Treatment of skin cancer relies on surgical excision with adequate margins, reduction of immunosuppression, and a change to mTOR inhibitors.270 Anogenital cancers involving the vulva, scrotum, penis, perianal skin, and anus are the third most frequent malignancy (4%) in pediatric recipients.271 They occur on average 12 years after transplantation268 and are associated with human papilloma virus infection. Kaposi’s sarcoma accounts for 3.2% of cancer in pediatric recipients271 and is associated with human herpes virus-8 infection. Its treatment includes surgical excision, chemotherapy, and a change to mTOR inhibitors.272 Renal carcinoma, mostly renal cell carcinoma in native kidneys, accounts for 0.6% of cancer in pediatric recipients.267,273 Surgery is the main therapy.274

13.8.1 Epstein Barr Virus and Posttransplant Lymphoproliferative Disorder Pediatric recipients are at increased risk of primary EBV infection due to the fact that up to 50% are EBV seronegative at time of transplant.275 EBV-related PTLD can be the result of reactivation or primary infection. Young children are at higher risk compared to their adult counterparts, especially in the setting of an EBV-positive donor. The incidence of PTLD in pediatric kidney transplant recipients is 1% 6%,4,276 below the reported 33% incidence in combined liver kidney, 15% in heart, and 10% in liver transplants.277 It follows a bimodal distribution, with the first peak occurring during the first year and the second within the third year after transplantation.278 EBV infection and, to a lesser extent, CMV infection, are involved in the pathogenesis of the majority of cases.279 The development of PTLD after EBV infection relies on the equilibrium between EBV-infected B-cells and EBVspecific, CD8-positive cytotoxic T-cells.280 Hence, the degree of immunosuppression,266 HLA mismatching,281 and the absence of EBV-specific cytotoxic T cells282 are major risk factors for PTLD. Recent large-scale data analysis does not support earlier reports that the use of Thymoglobulin283 or prior therapy of recombinant growth hormone284 increases the risk of PTLD. EBV-negative PTLD can be associated with T-cell, B-cell, or plasma-cell clonality.285 The World Health Organization (WHO) has classified PTLD into four categories: early lesion,

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polymorphic, monomorphic, and classical Hodgkin’s lymphoma. Pediatric EBV-related PTLD are mostly of the early or polymorphic type.286 PTLD can be insidious and patients often present with nonspecific symptoms such as fever, malaise, graft dysfunction, peripheral adenopathy, hepatosplenomegaly, and diarrhea. Thus, diagnosis requires a strong clinical suspicion. Routine monitoring of quantitative EBV blood PCR has been utilized as a screening tool. Its role in predicting and monitoring PTLD remains controversial. An increased EBV viral load has been shown to correlate with the development of PTLD or EBV-associated symptoms in pediatric solid organ transplant PTLD277,287 or renal transplant.288 290 However, not every case of EBV-related PTLD is associated with elevated EBV viral load.265 A chronically elevated viral load is not predictive of PTLD289,291 or EBV-associated symptoms.292 This controversy may be explained by variations in PCR assay methods, cut-offs of positivity, blood samples being used (peripheral blood lymphocytes, whole blood, or plasma), different primer sets and target genes, report of PCR results (genome copies/105 PBL, genome copies/mL, or genome copies/μg DNA), definition of viral loads, study design (prospective vs retrospective), and EBV serostatus at the time of transplantation.293 Therefore, vigilant monitoring, aggressive radiologic testing, and tissue biopsy are key steps in following renal transplant children with EBV infection.294 Consensus is lacking on treatment of PTLD, but the first step is usually reduction in immunosuppression, whether it is associated with EBV infection or not.295 How to reduce immunosuppression is center-specific. However, it has been demonstrated that different immunosuppression agents have different effects on different viruses.296 MMF inhibits the proliferation of newly EBV-infected B-cells in vitro297 and potentiates the effect of anti herpes virus drugs.298 A higher MPA concentration is associated with a lower risk of EBV infection in pediatric renal transplant.292 Therefore, studies examining the steps of immunosuppression are needed in pediatric renal transplantation. Early lesion in children usually responds to reduction of immunosuppression but only 50% of pediatric polymorphic PTLD respond.299 Those who failed reduction of immunosuppression carry a mortality rate of 50% 90%.300 Rituximab is routinely used for CD20-positive PTLD. A combination therapy with rituximab, low-dose cyclophosphamide, and prednisolone improved the 2-year PTLD-free GSR to 80%.301 Additional radiotherapy and surgery are used for those who failed combined rituximab and chemotherapy and those with central nervous system involvement, T-cell non-Hodgkin’s lymphoma, or Hodgkin’s disease.286 Therapy with the EBVspecific cytotoxic T-lymphocytes from immunocompetent donors who are challenged with EBV-transformed Blymphoblastoid cell lines is currently under investigation.302

13.9 INFECTION There is increased infection risk in pediatric recipients due to chronic immunosuppression. The infection risk is highest in the immediate posttransplant period due to higher degree of immunosuppression. Pediatric recipients are at risk for common community-acquired infections and UTI. They are also at risk for opportunistic infections such as Pneumocystis jiroveci and fungal infections. Prophylaxis against P. jiroveci with trimethoprimsulfamethoxazole or pentamidine in individuals with sulfa allergy is a common practice among most pediatric transplant centers. The most common opportunistic viral infections in pediatric transplant are BK virus, CMV, and EBV.

13.9.1 BK Virus BK virus belongs to the family Polyomaviridae of small nonenveloped DNA viruses. BK virus subtype I is the most commonly identified subtype in BKV nephropathy (BKVN), although types II and III have been reported.303 BK virus infection usually presents as a nonspecific viral illness in those with intact immunity and occurs mainly during childhood, with greater than 90% of adults being seropositive. After primary infection, renal tubular epithelial cells and the uroepithelial cell layer are the main sites of viral latency or replication.304 Immunosuppression, age, White race, male sex, HLA mismatch, seroconversion, and history of allograft rejection are risk factors for the development of BKVN with a high graft loss rate.305 308 The incidence of BKVN was 4.6%, with a rate of graft loss of 24% within 2 years after diagnosis, in pediatric transplant recipients according to 2007 NAPRTCS registry.309 In pediatric patients, primary BKV infection from seropositive kidney graft is common.306 There is still a debate as to the screening method for BKVN. Urine screening has a high negative predictive value and a lower inhibitory effect on PCR method and it can be assessed for decoy cells. However, a positive urine

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screening requires the confirmation of viremia. BKVN with a negative viremia has been reported.310 Therefore, the diagnosis of BKVN requires the demonstration of polyomavirus cytopathic changes and interstitial nephritis.311 In pediatric centers with an established BK virus screening protocol, the incidence of viremia ranges 16% 26% during the first 3 years after transplantation.312 314 Reduction of immunosuppression in patients without AR resulted in the clearance of viremia in 20%314 to as high as 83% 100%.312,313 For patients not responding to reduction of immunosuppression, cidofovir, a cytosine nucleoside analog, has had mixed results in uncontrolled pediatric reports315 317 but its direct tubular toxicity is a major concern.318 As reported in 2014, CMX001, a lipophilic nucleotide analog formed by covalently linking 3-(hexasecycloxy)propan-L-ol to cidofovir, successfully treated a young child with BKVN.319 Leflunomide is an inhibitor of pyrimidine synthesis with case reports of its success in treating BKVN without nephrotoxicity.320,321 A 2-month ciprofloxacin treatment, followed by leflunomide if there was no significant decrease in BK viremia, and a small reduction in immunosuppression reduced the incidence of BKVN to 1% in 19 pediatric transplant patients.322

13.9.2 Cytomegalovirus CMV infection can lead to symptoms of fever, hepatitis, leukopenia, thrombocytopenia, pneumonia, and gastrointestinal disease. CMV can lead to opportunistic infections such as P. jiroveci, fungal infections, and bacterial infections. CMV can also increase risk of allograft rejection and PTLD due to dysregulation of the immune system including altered T-cell function and upregulation of cytokines and proinflammatory markers. It is the practice of most pediatric transplant centers to implement viral prophylaxis with valgancyclovir or ganciclovir for a period of time (usually 6 months) posttransplant, particularly for CMV seronegative recipients in the setting of a CMV seropositive donor. There are no prospective, randomized, controlled trials providing clear indications as to whether preemptive or prophylactic treatment is the optimal approach. It is still recommended in pediatric patients to use intravenous ganciclovir for treatment of active CMV infection due to the lack of efficiency data on oral therapy. Viral load is a good predictor of response to treatment.323

13.10 TRANSITION The rate of improvement in pediatric graft and patient survival over the past 25 years was attenuated in recipients transplanted at 13 17 years old.5 The American OPTN 1987 2010 data indicated recipients who received their first kidney transplant at age 14 16 years were at the highest risk of graft loss, with inferior outcomes starting at 1 and amplifying at 3, 5, and 10 years after transplantation.324 Other studies also reported a higher risk of graft loss seen during late adolescence and early adulthood.325,326 These findings have been attributed to poor adherence to immunosuppressive drugs,327 331 alterations in health insurance coverage,332,333 or difficulties with transition between pediatric and adult posttransplant care.334 337 It should be noted that during early adulthood, notably between 18 and 25 years, patients become independent while facing a transition from childhood to adulthood. This age period denotes a developmental stage that has been conceptually termed “emerging adulthood.”338 Adherence to immunosuppressive medication is associated with a longer graft survival in pediatric renal transplant recipients.339 In pediatric solid organ transplant recipients, the rate of poor adherence among adolescents was three times higher than younger children327 and 60% higher than adults between 24 and 44 years old.331 Greater family dysfunction,327 risk-taking behavior,340,341 brain immaturity,342 344 neurocognitive impairment from chronic renal failure345 or young age at onset of ESRD,346 developmental delays at young age,347 and lower attention and executive function348 are associated with nonadherence during adolescence and emerging adulthood. In addition, adherence to general care such as clinic appointments and routine blood monitoring deteriorates during adolescence and emerging adulthood in renal transplant recipients.349 Greater frequency of visiting in young liver transplant recipients350 or a strong relationship with providers in adult renal transplant recipients351 improved the adherence but more studies are needed in this area. The transfer from pediatric to adult-oriented care is associated with adverse outcomes in pediatric renal transplant recipients. The graft failure rate was 35% within 3 years of transfer to adult service.352 The risk of graft failure was highest immediately following transfer.335 In 2008, through the initiative of the Pediatric Committee of the American Society of Transplantation, a jointly sponsored international consensus conference on Adolescent Transition to Adult Care in Solid Organ Transplantation recommended a transition process incorporating the developmental aspect of adolescents with solid organ transplant.353 In 2011 the International Society of Nephrology and

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International Pediatric Nephrology Institution released a consensus statement on the transition of children with renal disease and suggested interventions at all levels of adherence.354 However, these recommendations did not address the key factor, the self-management skill, in the readiness for transition.355,356 Setup of a multidisciplinary transition clinic improved graft survival357,358 or adherence and renal function.359 In addition, since those who were transferred before 21 years old had a higher graft failure rate than those who were transferred after 21 years old,337 it has been suggested to extend traditional pediatric care to the emergent adulthood group.360

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Long term results of liver-kidney transplantation in children with primary hyperoxaluria. Pediatr Nephrol 2001;16(12):946 50. 259. Ellis SR, Hulton SA, McKiernan PJ, et al. Combined liver-kidney transplantation for primary hyperoxaluria type 1 in young children. Nephrol Dial Transpl 2001;16(2):348 54. 260. Cochat P, Liutkus A, Fargue S, et al. Primary hyperoxaluria type 1: still challenging!. Pediatr Nephrol 2006;21(8):1075 81. 261. Van Calcar SC, Harding CO, Lyne P, et al. Renal transplantation in a patient with methylmalonic acidaemia. J Inherit Metab Dis 1998; 21(7):729 37. 262. Nesterova G, Gahl W. Nephropathic cystinosis: late complications of a multisystemic disease. Pediatr Nephrol 2008;23(6):863 78. 263. Langlois V, Geary D, Murray L, et al. Polyuria and proteinuria in cystinosis have no impact on renal transplantation. A report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Nephrol 2000;15(1 2):7 10. 264. Ueda M, O’Brien K, Rosing DR, et al. Coronary artery and other vascular calcifications in patients with cystinosis after kidney transplantation. Clin J Am Soc Nephrol 2006;1(3):555 62. 265. Axelrod DA, Holmes R, Thomas SE, et al. Limitations of EBV-PCR monitoring to detect EBV associated post-transplant lymphoproliferative disorder. Pediatr Transplant 2003;7(3):223 7. 266. Dharnidharka VR, Sullivan EK, Stablein DM, et al. North American pediatric renal transplant cooperative study, risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the north american pediatric renal transplant cooperative study (NAPRTCS). Transplantation 2001;71(8):1065 8. 267. Koukourgianni F, Harambat J, Ranchin B, et al. Malignancy incidence after renal transplantation in children: a 20-year single-centre experience. Nephrol Dial Transplant 2010;25(2):611 16. 268. Euvrard S, Kanitakis J, Cochat P, et al. Skin cancers following pediatric organ transplantation. Dermatol Surg 2004;30(4 Pt 2):616 21. 269. Coutinho HM, Groothoff JW, Offringa M, et al. De novo malignancy after paediatric renal replacement therapy. Arch Dis Child 2001; 85(6):478 83.

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270. Euvrard S, Morelon E, Rostaing L, et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med 2012;367(4):329 39. 271. Penn I. De novo malignances in pediatric organ transplant recipients. Pediatr Transplant 1998;2(1):56 63. 272. Riva G, Luppi M, Barozzi P, et al. How I treat HHV8/KSHV-related diseases in posttransplant patients. Blood 2012;120(20):4150 9. 273. Simard JF, Baecklund E, Kinch A, et al. Pediatric organ transplantation and risk of premalignant and malignant tumors in Sweden. Am J Transplant 2011;11(1):146 51. 274. Tsaur I, Obermuller N, Jonas D, et al. De novo renal cell carcinoma of native and graft kidneys in renal transplant recipients. BJU Int 2011;108(2):229 34. 275. Matas AJ, Smith JM, Skeans MA, et al. OPTN/SRTR 2011 Annual Data Report: kidney. Am J Transplant 2013;13(Suppl. 1):11 46. 276. Collins MH, Montone KT, Leahey AM, et al. Post-transplant lymphoproliferative disease in children. Pediatr Transplant 2001;5(4):250 7. 277. Holmes RD, Sokol RJ. Epstein-Barr virus and post-transplant lymphoproliferative disease. Pediatr Transplant 2002;6(6):456 64. 278. Schober T, Framke T, Kreipe H, et al. Characteristics of early and late PTLD development in pediatric solid organ transplant recipients. Transplantation 2013;95(1):240 6. 279. Opelz G, Daniel V, Naujokat C, et al. Epidemiology of pretransplant EBV and CMV serostatus in relation to posttransplant non-Hodgkin lymphoma. Transplantation 2009;88(8):962 7. 280. Merlo A, Turrini R, Dolcetti R, et al. The interplay between Epstein-Barr virus and the immune system: a rationale for adoptive cell therapy of EBV-related disorders. Haematologica 2010;95(10):1769 77. 281. Opelz G, Dohler B. Pediatric kidney transplantation: analysis of donor age, HLA match, and posttransplant non-Hodgkin lymphoma: a collaborative transplant study report. Transplantation 2010;90(3):292 7. 282. Dharnidharka VR, Harmon WE. Management of pediatric postrenal transplantation infections. Sem Nephrol 2001;21(5):521 31. 283. Hertig A, Zuckermann A. Rabbit antithymocyte globulin induction and risk of post-transplant lymphoproliferative disease in adult and pediatric solid organ transplantation: an update. Transplant Immunol 2015;32(3):179 87. 284. Longmore DK, Conwell LS, Burke JR, et al. Post-transplant lymphoproliferative disorder: no relationship to recombinant human growth hormone use in Australian and New Zealand pediatric kidney transplant recipients. Pediatr Transplant 2013;17(8):731 6. 285. Nelson BP, Nalesnik MA, Bahler DW, et al. Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity? Am J Surg Pathol 2000;24(3):375 85. 286. Mucha K, Foroncewicz B, Ziarkiewicz-Wroblewska B, et al. Post-transplant lymphoproliferative disorder in view of the new WHO classification: a more rational approach to a protean disease? Nephrol Dial Transplant 2010;25(7):2089 98. 287. Rowe DT, Qu L, Reyes J, et al. Use of quantitative competitive PCR to measure Epstein-Barr virus genome load in the peripheral blood of pediatric transplant patients with lymphoproliferative disorders. J Clin Microbiol 1997;35(6):1612 15. 288. Shroff R, Trompeter R, Cubitt D, et al. Epstein-Barr virus monitoring in paediatric renal transplant recipients. Pediatr Nephrol 2002; 17(9):770 5. 289. Ishihara M, Tanaka E, Sato T, et al. Epstein-Barr virus load for early detection of lymphoproliferative disorder in pediatric renal transplant recipients. Clin Nephrol 2011;76(1):40 8. 290. Wagner HJ, Wessel M, Jabs W, et al. Patients at risk for development of posttransplant lymphoproliferative disorder: plasma versus peripheral blood mononuclear cells as material for quantification of Epstein-Barr viral load by using real-time quantitative polymerase chain reaction. Transplantation 2001;72(6):1012 19. 291. Tanaka E, Sato T, Ishihara M, et al. Asymptomatic high Epstein-Barr viral load carriage in pediatric renal transplant recipients. Pediatr Transplant 2011;15(3):306 13. 292. Hocker B, Fickenscher H, Delecluse HJ, et al. Epidemiology and morbidity of Epstein-Barr virus infection in pediatric renal transplant recipients: a multicenter, prospective study. Clin Infect Dis 2013;56(1):84 92. 293. Green M, Webber SA. EBV viral load monitoring: unanswered questions. Am J Transplant 2002;2(10):894 5. 294. Comoli P, Ginevri F. Monitoring and managing viral infections in pediatric renal transplant recipients. Pediatr Nephrol 2012;27(5):705 17. 295. Frey NV, Tsai DE. The management of posttransplant lymphoproliferative disorder. Med Oncol 2007;24(2):125 36. 296. Brennan DC, Aguado JM, Potena L, et al. Effect of maintenance immunosuppressive drugs on virus pathobiology: evidence and potential mechanisms. Rev Med Virol 2013;23(2):97 125. 297. Alfieri C, Allison AC, Kieff E. Effect of mycophenolic acid on Epstein-Barr virus infection of human B lymphocytes. Antimicrob Agents Chemother 1994;38(1):126 9. 298. Neyts J, Andrei G, De Clercq E. The novel immunosuppressive agent mycophenolate mofetil markedly potentiates the antiherpesvirus activities of acyclovir, ganciclovir, and penciclovir in vitro and in vivo. Antimicrob Agents Chemother 1998;42(2):216 22. 299. Tsao L, Hsi ED. The clinicopathologic spectrum of posttransplantation lymphoproliferative disorders. Arch Pathol Lab Med 2007; 131(8):1209 18. 300. Taylor AL, Marcus R, Bradley JA. Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation. Crit Rev Oncol Hematol 2005;56(1):155 67. 301. Gross TG, Orjuela MA, Perkins SL, et al. Low-dose chemotherapy and rituximab for posttransplant lymphoproliferative disease (PTLD): a Children’s Oncology Group Report. Am J Transplant 2012;12(11):3069 75. 302. Bollard CM, Rooney CM, Heslop HE. T-cell therapy in the treatment of post-transplant lymphoproliferative disease. Nat Rev Clin Oncol 2012;9(9):510 19. 303. Kapusinszky B, Chen SF, Sahoo MK, et al. BK polyomavirus subtype III in a pediatric renal transplant patient with nephropathy. J Clin Microbiol 2013;51(12):4255 8. 304. Hirsch HH, Steiger J, Polyomavirus BK. Lancet Infect Dis 2003;3(10):611 23. 305. Ali AM, Gibson IW, Birk P, et al. Pretransplant serologic testing to identify the risk of polyoma BK viremia in pediatric kidney transplant recipients. Pediatr Transplant 2011;15(8):827 34. 306. Smith JM, McDonald RA, Finn LS, et al. Polyomavirus nephropathy in pediatric kidney transplant recipients. Am J Transplant 2004; 4(12):2109 17.

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307. Ramos E, Drachenberg CB, Wali R, et al. The decade of polyomavirus BK-associated nephropathy: state of affairs. Transplantation 2009; 87(5):621 30. 308. Vasudev B, Hariharan S, Hussain SA, et al. BK virus nephritis: risk factors, timing, and outcome in renal transplant recipients. Kidney Int 2005;68(4):1834 9. 309. Smith JM, Dharnidharka VR, Talley L, et al. BK virus nephropathy in pediatric renal transplant recipients: an analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry. Clin J Am Soc Nephrol 2007;2(5):1037 42. 310. Vats A, Shapiro R, Singh Randhawa P, et al. Quantitative viral load monitoring and cidofovir therapy for the management of BK virusassociated nephropathy in children and adults. Transplantation 2003;75(1):105 12. 311. Hirsch HH, Brennan DC, Drachenberg CB, et al. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation 2005;79(10):1277 86. 312. Zarauza Santovena A, Garcia Meseguer C, Martinez Mejia S, et al. BK virus infection in pediatric renal transplantation. Transplant Proc 2015;47(1):62 6. 313. Ginevri F, Azzi A, Hirsch HH, et al. Prospective monitoring of polyomavirus BK replication and impact of pre-emptive intervention in pediatric kidney recipients. Am J Transplant 2007;7(12):2727 35. 314. Hymes LC, Warshaw BL. Polyomavirus (BK) in pediatric renal transplants: evaluation of viremic patients with and without BK associated nephritis. Pediatr Transplant 2006;10(8):920 2. 315. Pallet N, Burgard M, Quamouss O, et al. Cidofovir may be deleterious in BK virus-associated nephropathy. Transplantation 2010; 89(12):1542 4. 316. Hymes L. BK virus nephropathy: a pediatric nephrologist’s perspective. Transplant Rev 2010;24(1):28 31. 317. Araya CE, Lew JF, Fennell RS, et al. Intermediate dose cidofovir does not cause additive nephrotoxicity in BK virus allograft nephropathy. Pediatr Transplant 2008;12(7):790 5. 318. Izzedine H, Launay-Vacher V, Deray G. Antiviral drug-induced nephrotoxicity. Am J Kidney Dis 2005;45(5):804 17. 319. Reisman L, Habib S, McClure GB, et al. Treatment of BK virus-associated nephropathy with CMX001 after kidney transplantation in a young child. Pediatr Transplant 2014;18(7):E227 31. 320. Jung YH, Moon KC, Ha JW, et al. Leflunomide therapy for BK virus allograft nephropathy after pediatric kidney transplantation. Pediatr Transplant 2013;17(2):E50 4. 321. Araya CE, Garin EH, Neiberger RE, et al. Leflunomide therapy for BK virus allograft nephropathy in pediatric and young adult kidney transplant recipients. Pediatr Transplant 2010;14(1):145 50. 322. Zaman RA, Ettenger RB, Cheam H, et al. A novel treatment regimen for BK viremia. Transplantation 2014;97(11):1166 71. 323. Sanghavi SK, Abu-Elmagd K, Keightley MC, et al. Relationship of cytomegalovirus load assessed by real-time PCR to pp65 antigenemia in organ transplant recipients. J Clin Viro 2008;42(4):335 42. 324. Andreoni KA, Forbes R, Andreoni RM, et al. Age-related kidney transplant outcomes: health disparities amplified in adolescence. JAMA Int Med 2013;173(16):1524 32. 325. Foster BJ, Dahhou M, Zhang X, et al. Association between age and graft failure rates in young kidney transplant recipients. Transplantation 2011;92(11):1237 43. 326. Van Arendonk KJ, James NT, Boyarsky BJ, et al. Age at graft loss after pediatric kidney transplantation: exploring the high-risk age window. Clin J Am Soc Nephrol 2013;8(6):1019 26. 327. Dew MA, Dabbs AD, Myaskovsky L, et al. Meta-analysis of medical regimen adherence outcomes in pediatric solid organ transplantation. Transplantation 2009;88(5):736 46. 328. Dobbels F, Ruppar T, De Geest S, et al. Adherence to the immunosuppressive regimen in pediatric kidney transplant recipients: a systematic review. Pediatr Transplant 2010;14(5):603 13. 329. Rianthavorn P, Ettenger RB. Medication non-adherence in the adolescent renal transplant recipient: a clinician’s viewpoint. Pediatr Transplant 2005;9(3):398 407. 330. Shaw RJ, Palmer L, Blasey C, et al. A typology of non-adherence in pediatric renal transplant recipients. Pediatr Transplant 2003;7(6):489 93. 331. Pinsky BW, Takemoto SK, Lentine KL, et al. Transplant outcomes and economic costs associated with patient noncompliance to immunosuppression. Am J Transplant 2009;9(11):2597 606. 332. Willoughby LM, Fukami S, Bunnapradist S, et al. Health insurance considerations for adolescent transplant recipients as they transition to adulthood. Pediatr Transplant 2007;11(2):127 31. 333. White PH. Access to health care: health insurance considerations for young adults with special health care needs/disabilities. Pediatrics 2002;110(6 Pt 2):1328 35. 334. Chaturvedi S, Jones CL, Walker RG, et al. The transition of kidney transplant recipients: a work in progress. Pediatr Nephrol 2009; 24(5):1055 60. 335. Samuel SM, Nettel-Aguirre A, Hemmelgarn BR. Pediatric Renal Outcomes Canada Group, Graft failure and adaptation period to adult healthcare centers in pediatric renal transplant patients. Transplantation 2011;91(12):1380 5. 336. Watson AR, Harden P, Ferris M, et al. Transition from pediatric to adult renal services: a consensus statement by the International Society of Nephrology (ISN) and the International Pediatric Nephrology Association (IPNA). Pediatr Nephrol 2011;26(10):1753 7. 337. Foster BJ, Platt RW, Dahhou M, et al. The impact of age at transfer from pediatric to adult-oriented care on renal allograft survival. Pediatr Transplant 2011;15(7):750 9. 338. Arnett JJ. Emerging adulthood. A theory of development from the late teens through the twenties. Am Psychol 2000;55(5):469 80. 339. Chisholm-Burns MA, Spivey CA, Rehfeld R, et al. Immunosuppressant therapy adherence and graft failure among pediatric renal transplant recipients. Am J Transplant 2009;9(11):2497 504. 340. Reyna VF, Farley F. Risk and rationality in adolescent decision making: implications for theory, practice, and public policy. Psychol Sci Public Interest 2006;7(1):1 44. 341. Casey BJ, Getz S, Galvan A. The adolescent brain. Devel Rev 2008;28(1):62 77.

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342. Casey BJ, Tottenham N, Liston C, et al. Imaging the developing brain: what have we learned about cognitive development? Trends Cogn Sci 2005;9(3):104 10. 343. Rubia K, Smith AB, Woolley J, et al. Progressive increase of frontostriatal brain activation from childhood to adulthood during eventrelated tasks of cognitive control. Hum Brain Mapp 2006;27(12):973 93. 344. Casey BJ, Jones RM, Hare TA. The adolescent brain. Ann N York Acad Sci 2008;1124:111 26. 345. Gipson DS, Hooper SR, Duquette PJ, et al. Memory and executive functions in pediatric chronic kidney disease. Child Neuropsychol 2006;12(6):391 405. 346. Johnson RJ, Warady BA. Long-term neurocognitive outcomes of patients with end-stage renal disease during infancy. Pediatr Nephrol 2013;28(8):1283 91. 347. Gipson DS, Duquette PJ, Icard PF, et al. The central nervous system in childhood chronic kidney disease. Pediatric nephrology 2007; 22(10):1703 10. 348. Hooper SR, Gerson AC, Butler RW, et al. Neurocognitive functioning of children and adolescents with mild-to-moderate chronic kidney disease. Clin J Am Soc Nephrol 2011;6(8):1824 30. 349. Zelikovsky N, Schast AP, Palmer J, et al. Perceived barriers to adherence among adolescent renal transplant candidates. Pediatr Transplant 2008;12(3):300 8. 350. Shemesh E, Annunziato RA, Shneider BL, et al. Improving adherence to medications in pediatric liver transplant recipients. Pediatr Transplant 2008;12(3):316 23. 351. Chisholm MA, Lance CE, Mulloy LL. Patient factors associated with adherence to immunosuppressant therapy in renal transplant recipients. Am J Health Syst Pharm 2005;62(17):1775 81. 352. Watson AR. Non-compliance and transfer from paediatric to adult transplant unit. Pediatr Nephrol 2000;14(6):469 72. 353. Bell LE, Bartosh SM, Davis CL, et al. Adolescent transition to adult care in solid organ transplantation: a consensus conference report. Am J Transplant 2008;8(11):2230 42. 354. Watson AR, Harden PN, Ferris ME, et al. Transition from pediatric to adult renal services: a consensus statement by the International Society of Nephrology (ISN) and the International Pediatric Nephrology Association (IPNA). Kidney Int 2011;80(7):704 7. 355. Sawyer SM, Aroni RA. Self-management in adolescents with chronic illness. What does it mean and how can it be achieved? Med J Aust 2005;183(8):405 9. 356. Dobbels F, Van Damme-Lombaert R, Vanhaecke J, et al. Growing pains: non-adherence with the immunosuppressive regimen in adolescent transplant recipients. Pediatr Transplant 2005;9(3):381 90. 357. Prestidge C, Romann A, Djurdjev O, et al. Utility and cost of a renal transplant transition clinic. Pediatr Nephrol 2012;27(2):295 302. 358. Harden PN, Walsh G, Bandler N, et al. Bridging the gap: an integrated paediatric to adult clinical service for young adults with kidney failure. BMJ 2012;344:e3718. 359. McQuillan RF, Toulany A, Kaufman M, et al. Benefits of a transfer clinic in adolescent and young adult kidney transplant patients. Canad J Kidney Health Dis 2015;2:45. Available from: http://dx.doi.org/10.1186/s40697-015-0081-6. 360. Foster BJ. Heightened graft failure risk during emerging adulthood and transition to adult care. Pediatr Nephrol 2015;30(4):567 76.

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C H A P T E R

14 Indications for Renal Transplantation: Evaluation of Transplant Candidates Opas Traitanon1,2 and Lorenzo Gallon1 1

Northwestern University, Chicago, IL, United States 2Thammasart University Hospital, Pathumthani, Thailand

14.1 INTRODUCTION Kidney transplantation, at this time, provides the best treatment option for end stage renal disease (ESRD) patients. However, while the incidence of treated ESRD has almost doubled over the last decade, the number of potential donor kidneys has not shown the same type of substantial growth. Consequently, the median waiting time for patients receiving a kidney allograft has steadily increased (Fig. 14.1). Data from the United States Renal Data System (USRDS) in 2014 showed that the average wait time for newly listed transplant candidates currently ranges from 3 to 5 years (Fig. 14.2). In order to ensure that the limited and vital resources we have are used optimally, all transplant candidates should undergo pretransplant evaluation to ensure that they are fit for anesthesia and operation. All the candidates in the transplant waiting list should be capable of surviving the current waiting time for transplant, and should also have a reasonable life expectancy as well as an expected greater quality of life after the procedure.

Transplant rate 10

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FIGURE 14.1

Percent of dialysis patients waitlisted versus unadjusted transplant rates.

Kidney Transplantation, Bioengineering, and Regeneration. DOI: http://dx.doi.org/10.1016/B978-0-12-801734-0.00014-X

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© 2017 Elsevier Inc. All rights reserved.

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Counts: subsequent listings Wait time: subsequent listings

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FIGURE 14.2 Kidney waiting list counts versus waiting time.

14.2 INDICATIONS AND CONTRAINDICATIONS 14.2.1 Potential Indications for Kidney Transplantation Renal transplantation is the treatment of choice in most patients with ESRD. In the past decade, significant improvements in transplant management now allows most patients with ESRD to be considered for kidney transplantation, unless there is an apparent contraindication. Although there is increased risk of death in the first few months following transplant, the long-term survival and quality of life are significantly higher in patients having had a kidney transplantation compared to those patients on dialysis.1 5 Potential kidney transplant candidates should be referred to a transplant program for evaluation when their glomerular filtration rate falls below 20 30 mL/minute or when initial renal replacement therapy is expected in the following 12 months.6 8 For patients already on chronic dialysis, the transplant option should be offered and discussed with them when all other medical conditions have stabilized.

14.2.2 Contraindications for Kidney Transplantation There are certain contraindications to renal transplantation: • • • • •

Advanced stage or untreated cancer with short life expectancy Untreated active infection Severe psychiatric disease Unresolvable psychosocial problems Persistent substance abuse

The following conditions require careful evaluation or possibly correction before proceeding to transplantation. Some conditions might be a contraindication in one transplant center but not in another. • Unreconstructable coronary artery disease or refractory congestive heart failure (may be a candidate for combined organ transplantation). • History of malignancy. The cancer-free interval required is varied depending on the stage and type of cancer (the detailed discussions follow).

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All

0–17

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Waiting list or transplantation among incident ESRD patients by age (0 74 years) (USRDS 2014).

• Substance abuse history. Patients must present evidence of involvement in at least 12 months of drug-free rehabilitation. This includes written documentation of participation in rehabilitation including negative random toxicologic screens. • Active hepatitis or chronic liver disease. Candidates with chronic hepatitis B or C or persistently abnormal liver function testing should be evaluated by a hepatologist. Patients may be candidates for combined liver and kidney transplantation. • Structural genitourinary abnormality or recurrent urinary tract infection. Urologic consultation is required prior to transplantation. • Treated and controlled active infection. • Proven noncompliance patients. • Severe malnutrition. • Severe hyperparathyroidism. • Past psychosocial abnormality that might interfere with posttransplant compliance. • Cerebrovascular disease with significant disabilities. • Aortoiliac disease. Patients with abnormal femoral pulses or disabling claudication, rest pain, or gangrene should be evaluated by a vascular surgeon prior to consideration. Patients with significant aortoiliac occlusive disease may require angioplasty or aortoiliac grafting prior to transplantation. Advanced age alone should not be considered a contraindication if the patients are medically and surgically suitable for kidney transplantation, although it is still unclear whether the benefits of transplantation are sufficient enough to consider transplantation over chronic dialysis. Data from USRDS 2014 showed a gradual increase of patients over age 65 in the transplant waiting list in the past decade (Fig. 14.3), meaning there is an increasing number of patients over 65 years of age who require chronic dialysis and kidney transplantation. Most published studies show better survival of elderly patients with kidney transplantation in comparison to patients with chronic dialysis.1,9,10 However, the recipients in the studies could be a sample of cases that do not perfectly represent the population of all elderly patients. Elderly candidates should have a reasonable expectancy beyond the current waiting time for transplantation and should have an expected improved quality of life after transplantation.

14.3 PRETRANSPLANT EVALUATION FOR TRANSPLANT CANDIDATES 14.3.1 Initial Evaluation The first step for pretransplant evaluation is to inform the patients and/or family members about the ESRD treatment options available and the risks and benefits of kidney transplantation compared to the patients’ current treatment. If the patients decide to proceed with kidney transplantation, the physician should carefully review the medical history, underlying renal diseases, previous nonrenal illnesses, and other comorbidities of the

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14. PRETRANSPLANT RECIPIENT EVALUATION

Initial Diagnostic Studies for Kidney Transplant Candidates

• Complete blood count, Blood group, PT/PTT/INR • Human leukocyte antigen (HLA typing) and panel reactive antibody testing (PRA) • Blood chemistry & metabolic profile: BUN, creatinine, uric acid, electrolytes, calcium, phosphate, liver function test, albumin, globulin, parathyroid hormone (PTH), lipid profile • Urinalysis • Serology: hepatitis B and C, human immunodeficiency virus (HIV), cytomegalovirus (CMV), Epstein Barr virus (EBV), varicella virus, herpes simplex virus, rapid plasma regain (RPR) • Pregnancy test for fertile women • Chest X-ray • Electrocardiogram • Prostatic specific antigen in elderly men • Pap smear (all women), mammography (elderly women) • Screening colonoscopy (elderly patients)

patient. A detailed history of cardiovascular disease including family history should be obtained. Physical examination should include checking for signs of congestive heart failure, carotid artery disease, or peripheral vascular disease. Elderly patients should also be examined for common malignancy such as prostate, breast, and cervical cancer. The initial testing is summarized in Table 14.1.

14.3.2 Cardiovascular Disease Cardiovascular disease is the greatest cause of death of both dialysis and transplant patients. Data from USRDS 2014 showed the rate of death from cardiovascular disease is 3.6 per 1000 patients per year, almost double compared to the rate of death by infection and malignancy; cardiovascular disease is also the leading cause of death with a functioning graft. Transplant candidates should be assessed for cardiovascular risk to ensure that they are fit to undergo the anesthesia and transplant surgery. However, extensive cardiovascular evaluation in the transplant candidates still remains controversial since many patients may be subjected to numerous unnecessary screening procedures and sometimes receive false-positive results from such screenings. There is little evidence that screening asymptomatic transplant candidates for cardiac diseases will improve posttransplant outcomes. Screening could also lead to rejection of a transplant candidate who otherwise might benefit from transplantation, or could delay the transplant procedure, which could lead to increased costs and complications.11 Furthermore, recent metaanalysis also showed that noninvasive cardiac tests (myocardial perfusion scintigraphy, dobutamine stress echocardiography) are as effective as coronary angiography at predicting future adverse cardiovascular events in cases of advanced chronic kidney disease.12 Although there has been no consensus about the best way to perform cardiac evaluation in the transplant candidates, most transplant centers still do the screening for cardiac diseases. The goal of this screening is to identify those patients who might benefit from cardiac intervention and risk factor modification before undergoing kidney transplantation. For most transplant candidates, examining the medical history carefully, conducting a physical examination, a chest X-ray and a 12-lead electrocardiogram (EKG) are the standard initial noninvasive tests. Echocardiograms may be performed to assess the structural abnormalities, left ventricular functions, and valvular abnormalities. In asymptomatic low cardiovascular risk patients, the initial evaluation (medical history, physical examination, basic EKG, chest X-ray 6 echocardiography) has a very high negative predictive value13 and should be appropriate. Patients with negative test results may be placed on the transplant waitlist. In cases of patients with high cardiovascular risk (elderly patients, diabetes mellitus, history of cardiovascular disease, family history of cardiovascular disease), additional stress testing should be performed. These additional stress tests, such as the dobutamine stress echocardiography, myocardial perfusion scintigraphy, or exercise stress electrocardiography, can be performed in select patients. Although exercise stress electrocardiography is more physiologic and does not require any injection, it may not be suitable for some dialysis patients who might have low exercise tolerance and motor disability. Dobutamine stress echocardiography and myocardial perfusion scintigraphy were shown to have moderate sensitivity and specificity in detecting coronary artery stenosis in patients who are kidney transplant candidates (pooled sensitivity 0.79, pooled specificity 0.89 for dobutamine stress echocardiography; pooled sensitivity 0.74, pooled specificity 0.70 for myocardial perfusion scintigraphy).14 However, there is no clear evidence for superiority of one method of stress testing over the other.13 The selection of stress test should be based on the expertise of each center

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191

itself. High-risk patients with positive stress testing should undergo coronary angiography for further evaluation. Patients with significant coronary lesions should undergo a revascularization procedure. Patients with successful revascularization may proceed to be placed on the transplant waitlist after careful evaluation and should be reevaluated on a regular basis. Coronary CT angiography is also an emerging option to evaluate the obstructive coronary lesions in the transplant candidates.15 On the other hand, there is evidence that noninvasive cardiac tests may not be sufficient to detect the coronary artery disease especially in the diabetes patients with advanced chronic kidney disease.16 18 One study showed that myocardial perfusion scintigraphy could not detect half of the patients who had significant coronary lesions on angiography18; many transplant centers have a lower threshold for coronary angiography in high-risk diabetic patients. The decision tree for cardiovascular evaluation is given in Fig. 14.4. Patients with known ischemic heart disease should also be eligible for transplantation if they are low-risk asymptomatic patients with negative noninvasive tests. Patients who have undergone successful revascularization or patients who have noncritical diseases and are on appropriate medical therapy may also be candidates for kidney transplantation with careful evaluation.

14.3.3 Cerebrovascular Disease There is an increased incidence of atherosclerotic cerebrovascular disease in dialysis patients as well as in transplant patients.19 22 The mortality rate following stroke after transplantation is quite high so transplant

FIGURE 14.4

Suggested decision tree for cardiovascular evaluation. Source: Modified from ERBP Guideline.

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candidates should be carefully evaluated for evidence of carotid stenosis, especially elderly patients with high risk for cerebrovascular diseases (hypertension, smoking, dyslipidemia, history of cerebrovascular disease). Patients with a history of transient ischemic attack are considered at high risk and should be evaluated by a neurologist. CT scan or magnetic resonance imaging (MRI) and carotid Doppler or magnetic resonance angiography may be performed in these patients. It is also important to screen for cerebral aneurysms in high-risk patients with autosomal dominant polycystic kidney disease (ADPKD) although there is not enough evidence to support all ADPKD patients undergoing transplantation.6

14.3.4 Peripheral Vascular Disease Peripheral vascular disease is also an important part of pretransplant evaluation and can cause allograft ischemia in some transplant cases. Peripheral vascular disease is also associated with higher mortality posttransplantation.23 Diabetes, hypertension, dyslipidemia, smoking, and a history of vascular disease are among the risk factors for peripheral vascular disease. Patients with history of claudication, diabetes, and poor peripheral pulse by physical examination may be candidates for Doppler vascular screening.7 CT scan and CT angiography could also help in the evaluation of anatomical lesions and assess the flow. Patients with large uncorrectable abdominal aneurysms, severe occlusive common iliac disease, active gangrene, or recent atheroembolic events are not suitable candidates for kidney transplantation.6

14.3.5 Malignancy All transplant candidates should be carefully evaluated for the potential of occult malignancy. Chronic dialysis increases risk of some malignancies.24 High risks were observed for malignancy of the kidney, bladder, thyroid, and other endocrine organs although in cancers of the lung, colorectum, prostate, breast, and stomach the risks were not consistently increased.24 Younger patients were found to have higher risk than older patients on chronic dialysis and may benefit the most from cancer screening. Posttransplant immunosuppression may enhance the growth of malignant cells. Furthermore, chronic immunosuppression after transplantation has an impact on both viral and tumor surveillance of the recipient immune system and has been linked to the higher incidence of malignancy after transplantation. From the 2014 USRDS report, malignancy was the cause of death in 1.8 patients per 1000 patients per year, which is about the same rate as that of infection, and about half of that of cardiovascular disease. Active malignancy is generally an absolute contraindication for transplantation. However, patients who were successfully treated for malignancy can be suitable candidates for kidney transplantation. There is limited data available regarding the rate of recurrence after transplantation.25,26 One study showed that 53% of malignancy recurrence occurred within 2 years of successful treatment, 33% of recurrence occurred in patients treated between 2 and 5 years before transplantation, and only 13% of cases recurred if successfully treated for more than 5 years.25 Based on the available data, most published clinical guidelines recommend a waiting time of at least 2 5 years to minimize the risk of malignancy recurrence after transplantation.6,27,28 Breast carcinomas, symptomatic renal carcinomas, sarcomas, bladder carcinomas, nonmelanoma skin cancers and multiple myeloma are among the malignancies that have highest recurrence rates after transplantation. Some malignances such as basal cell carcinoma of the skin and superficial lesions of bladder carcinoma may not require the wait period after successful treatment of the lesions.27 However, patients with advanced breast cancer (stages III and IV) and patients with multiple myeloma should not undergo renal transplantation due to the very high risk of recurrence.6 The recommended wait times for some common cancers are summarized in Table 14.2. There are many clinical tools available to screen the transplant candidates for malignancies. Various transplant centers may have their own screening program, which may differ from one another based on the risk factor of patients and incidence of common malignancies in the local population. The evaluation should be individually considered based on patient’s age, sex, family history, and environmental exposures. Patients with high risk for renal and bladder cancer may be screened by renal ultrasound,29 urinalysis, urine cytology, and cystoscopy. All female candidates should undergo pelvic examination and cervical cytology to exclude occult cervical cancer. Breast examination should be performed as well as a screening mammogram in women over age 40. Male patients over age 50 should have digital rectal examination and prostatic specific antigen tested. Fecal occult blood, colonoscopy or double contrast barium enema X-ray may be performed in individuals with high risk of colorectal cancer. Patients with hepatitis B or C virus

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TABLE 14.2

193

Recommended Wait Times for Common Malignancies (Canadian Guidelines)

Type

Recommended wait time

Cervival cancer • localized cervical cancer • in situ cervical lesions • invasive cervical lesion Breast cancer

• 2 years • 2 years • No firm recommendation 5 years (2 years for early in situ lesions)

Bladder cancer

2 years

Renal cell carcinoma

2 years

Colorectal cancer

5 years

Hodgkin’s disease, non-Hodgkin’s lymphoma, posttransplant lymphoproliferative disorder or leukemia

2 years

Lung cancer

2 years

Melanoma

5 years

Prostate cancer

2 years

Thyroid cancer

2 years

Testicular cancer

2 years

infection should be screened for hepatocellular carcinoma using alpha-fetoprotein, liver ultrasonography, CT scan, or MRI.

14.3.6 Infection All transplant candidates should be free from active infection and should receive immunizations for prevalent or life-threatening infections. The pretransplant vaccinations should include hepatitis B (if nonimmune), influenza (annually), pneumococcal vaccine (every 5 years), and the varicella vaccine (if negative for varicella-zoster antibodies).6,13 Vaccination should be administered early in the course of disease since the response rate may be reduced in patients with worse kidney function.30 Serologic status of hepatitis B and C virus, cytomegalovirus (CMV) and Epstein Barr virus (EBV) should be obtained in all transplant candidates. Patients with evidence of chronic hepatitis B or C infection require consultation with a hepatologist for possible treatment options prior to transplantation. All patients should be assessed for a history of tuberculosis exposure (direct contact from friends or family and travel history) especially in the endemic area such as south/southeast Asia and Africa. Purified protein derivatives (PPD) skin test or quantiferon assay may be useful in cases with questionable chest X-ray’s although the PPD skin test might give negative results in ESRD patients. Patients with active or latent tuberculosis should be treated before undergoing transplantation.31 HIV infection is not a contraindication for kidney transplantation. The rapid advancement of highly active antiretroviral therapy has led to markedly improved survival and quality of life of HIV infected patients.32 The estimated prevalence of HIV infection in advance stage kidney disease is around 0.5% 1.5% and that number is expected to gradually increase in the future.33,34 Many transplant centers now routinely perform kidney transplantation in well-controlled HIV infected patients. Recent data has shown that the long-term outcomes of HIV patients who received kidney transplantation are similar to non-HIV-infected patients and significantly better than HCV-infected or HIV/HCV coinfected recipients.35,36 Kidney transplantation from HIV positive donors to HIV positive recipients is also a suitable option. Data on carefully selected patients show that the patient and graft survival are good for up to 5 years posttransplant, with more than 80% graft survival and more than 70% patient survival at 5 years.37 The HIV-infected patients should be carefully selected and evaluated before transplantation. The patients should have undetectable HIV viral load with CD4 counts more than 200/µL and have been stable for at least 3 months. The patients should be free from any opportunistic infections for at least 6 months and show no signs of possible progressive multifocal leukoencephalopathy, chronic intestinal cryptosporidiosis, or lymphoma.13

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14.4 PRETRANSPLANT RENAL AND SYSTEMIC DISEASES 14.4.1 Glomerulonephritis Glomerulonephritis is the primary cause of ESRD in about 30% 50% of kidney transplant recipients.38 Recurrent glomerular disease after transplantation is quite common (5% 20% of recipients)8,27,39 and is the third most leading cause of posttransplant graft loss after chronic rejection and death with functioning graft.38,40 Despite the risk of recurrent glomerular disease, there is no contraindication to the first kidney transplant in patients with ESRD due to primary glomerulonephritis. The most common form of recurrent disease is IgA nephropathy although it is not the dominant glomerulopathy responsible for graft loss. Primary focal segmental glomerulosclerosis (FSGS) frequently recurs after kidney transplantation (30% 50%),38,41 44 and graft loss occurs in 30% 50% of patients with recurrence. If the patients lose their graft due to FSGS recurrence, the risk of recurrence in the second transplant is very high.45 Recurrence usually occurs early after transplantation, even as early as the first day after transplantation. Late recurrence can occur but tends to be a slower process with less proteinuria.40 The patients and the donors (in living donation) should be informed about the risk of recurrence and graft loss. Secondary FSGS, however, does not recur after transplantation. Membranoproliferative glomerulonephritis (MPGN) type 2 also has a high recurrent rate (more than 80%) after transplant and the risk of graft loss is also high. The risk of recurrence and risk of graft loss after recurrence in primary glomerulonephritis are summarized in Table 14.3. To date there is no evidence that any specific immunosuppressive regime or induction agent affects the risk of recurrent glomerular disease, and therefore, preoperative counseling regarding the risks of graft loss is critical.

14.4.2 Autoimmune Diseases Although significant improvement has been made in the past decades, some patients still experience ESRD from autoimmune diseases. Patients with clinically active systemic lupus erythematosus (SLE) should wait until the disease is quiescent for at least 6 months off cytotoxic agents.46 SLE recurs in 10% 30% of patients but rarely leads to graft failure.27,47,48 Scleroderma patients should wait for at least 6 months off cytotoxic agents and have limited extrarenal diseases.46 Patients with vasculitis (Wegener’s granulomatosis, microscopic polyangiitis, pauciimmune necrotizing glomerulonephritis, and Henoch Schonlein purpura) develop recurrent diseases in about 20% of cases posttransplantation, which rarely leads to graft loss.27,38 Patients with vasculitis should have quiescent disease for at least 12 months off immunosuppressive agents.46

14.4.3 Primary Hyperoxaluria Primary hyperoxaluria is a rare condition characterized by the overproduction of oxalate due to the shortage of an enzyme that normally prevents oxalate accumulation. Deposits of calcium oxalate can lead to kidney damage, kidney failure, and injury to other organs.49 Screening for primary hyperoxaluria should be considered for all young patients with ESRD secondary to stones. Patients with kidney failure from primary hyperoxaluria type 1 should not undergo kidney transplantation alone due to the very high risk of recurrence.50,51 Combined liver and kidney transplantation is the treatment of choice.52 54 Sequential transplantation (liver transplantation followed by kidney transplantation) may allow the clearance of oxalate from the patients and protect the new kidney that will be transplanted later.55 57 TABLE 14.3

Risk of Recurrence and Risk of Graft Loss After Recurrence in Primary Glomerulonephritis

Type

Risk of recurrent

Risk of graft loss

Primary FSGS

30% 50%

High

MPGN Type 1

20% 50%

Moderate

MPGN Type 2

80% 100%

High

Membranous nephropathy

10% 40%

Moderate

IgA nephropathy

Up to 100%

Low

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14.4.4 Hemolytic Uremic Syndrome Transplant candidates with proven shiga-toxin Escherichia coli-associated hemolytic uremic syndrome have very low risk of recurrence after transplantation and can proceed with either deceased or living donor kidney transplantation.11,58 60 Atypical hemolytic uremic syndrome (aHUS) is a rare condition characterized by dysregulation of the alternate complement pathway. aHUS can present as familial (,20%) but most often the cases are of the sporadic type. Most common genetic abnormalities include the mutation of complement factor H (CFH, 20% 30%), membrane cofactor protein (MCP, 10% 15%), complement factor I (CFI, 5% 10%), complement C3 (2% 10%), thrombomodulin (THBD, 3% 5%), and complement factor B (CFB, 1% 4%).61,62 About 10% of the patients may have combined mutations. Antibodies to CFH have been identified in about 6% of patients with sporadic aHUS.61 aHUS with CFH, CFI, and CFB mutations have high recurrent rates (70% 100%) after kidney transplantation, and graft failure after recurrence is high (80% 90%).61,63 65 However, aHUS with MCP mutation has less than 20% recurrent rate (unless associated with other mutations).61 65 The recurrence of aHUS usually occurs within the first year posttransplant. Ischemia-reperfusion injury, immunosuppressive drugs, and infections are among the triggering factors of posttransplant aHUS recurrence. In the past, kidney transplantation was not recommended for the patients with aHUS, however, with the improvement in aHUS management over the past decades, isolated kidney transplantation can be safely done in aHUS patients in centers with experience managing this condition. Eculizumab, a humanized monoclonal anti-C5 antibody recently approved for aHUS treatment, has been used as a prophylactic treatment in aHUS patients who have undergone kidney transplantation with promising results.66 68 Combined liver and kidney transplantation can correct the genetic defects and offer a curative treatment for aHUS, but earlier reports were disappointing.69,70 Nevertheless, recent reports with the use of preoperative eculizumab or plasma therapy with combined liver and kidney transplantation have demonstrated good results, with 80% success rate,71 the newer therapy has allowed isolated kidney transplantation as a more preferable option.

14.5 REEVALUATION AFTER WAITLISTING The growing number of patients on the transplant waiting list and the shortage of kidneys available for transplantation have consequently led to a steady increase in the current wait time for the patients on the list. The transplant candidates on the waiting list should be reevaluated by the transplant nephrologist in order to keep their health status up to date. The timing and frequency of such evaluations should depend on the age and comorbid conditions of the patients. Patients with advanced age, high risk for cardiovascular disease, and diabetes should be periodically reassessed for cardiovascular status. Patients who experience a major comorbidity (such as major cardiovascular events) while on the transplant waiting list should be carefully reassessed after the conditions are successfully treated.

References 1. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. New Engl J Med 1999;341(23):1725 30. 2. Rabbat CG, Thorpe KE, Russell JD, Churchill DN. Comparison of mortality risk for dialysis patients and cadaveric first renal transplant recipients in Ontario, Canada. J Am Soc Nephrol 2000;11(5):917 22. 3. Meier-Kriesche HU, Ojo AO, Port FK, Arndorfer JA, Cibrik DM, Kaplan B. Survival improvement among patients with end-stage renal disease: trends over time for transplant recipients and wait-listed patients. J Am Soc Nephrol 2001;12(6):1293 6. 4. Schnuelle P, Lorenz D, Trede M, Van Der, Woude FJ. Impact of renal cadaveric transplantation on survival in end-stage renal failure: evidence for reduced mortality risk compared with hemodialysis during long-term follow-up. J Am Soc Nephrol 1998;9(11):2135 41. 5. Oniscu GC, Brown H, Forsythe JL. Impact of cadaveric renal transplantation on survival in patients listed for transplantation. J Am Soc Nephrol 2005;16(6):1859 65. 6. Knoll G, Cockfield S, Blydt-Hansen T, Baran D, Kiberd B, Landsberg D, et al. Canadian Society of Transplantation: consensus guidelines on eligibility for kidney transplantation. CMAJ 2005;173(10):S1 25. 7. Bunnapradist S, Danovitch GM. Evaluation of adult kidney transplant candidates. Am J Kidney Dis 2007;50(5):890 8. 8. European Best Practice Guidelines for Renal Transplantation (part 1). Nephrol Dial Transpl 2000;15(Suppl. 7):1 85. 9. Rao PS, Merion RM, Ashby VB, Port FK, Wolfe RA, Kayler LK. Renal transplantation in elderly patients older than 70 years of age: results from the Scientific Registry of Transplant Recipients. Transplantation 2007;83(8):1069 74. 10. Oniscu GC, Brown H, Forsythe JL. How great is the survival advantage of transplantation over dialysis in elderly patients? Nephrol Dial Transpl 2004;19(4):945 51.

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11. European Renal Best Practice Transplantation Guideline Development G. ERBP guideline on the management and evaluation of the kidney donor and recipient. Nephrol Dial Transpl 2013;28(Suppl. 2):ii1 71. 12. Wang LW, Masson P, Turner RM, Lord SW, Baines LA, Craig JC, et al. Prognostic value of cardiac tests in potential kidney transplant recipients: a systematic review. Transplantation 2015;99(4):731 45. 13. Abramowicz D, Cochat P, Van Biesen W, Vanholder R. ERBP guideline on the management and evaluation of the kidney donor and recipient. Nephrol Ther 2014;10(6):427 32. 14. Wang LW, Fahim MA, Hayen A, Mitchell RL, Lord SW, Baines LA, et al. Cardiac testing for coronary artery disease in potential kidney transplant recipients: a systematic review of test accuracy studies. Am J Kidney Dis 2011;57(3):476 87. 15. Winther S, Svensson M, Jorgensen HS, Bouchelouche K, Gormsen LC, Pedersen BB, et al. Diagnostic performance of coronary CT angiography and myocardial perfusion imaging in kidney transplantation candidates. J Am Coll Cardiol Img 2015;8(5):553 62. 16. Pilmore H. Cardiac assessment for renal transplantation. Am J Transpl 2006;6(4):659 65. 17. Holley JL, Fenton RA, Arthur RS. Thallium stress testing does not predict cardiovascular risk in diabetic patients with end-stage renal odisease undergoing cadaveric renal transplantation. Am J Med 1991;90(5):563 70. 18. Welsh RC, Cockfield SM, Campbell P, Hervas-Malo M, Gyenes G, Dzavik V. Cardiovascular assessment of diabetic end-stage renal disease patients before renal transplantation. Transplantation 2011;91(2):213 18. 19. Seliger SL, Gillen DL, Longstreth Jr. WT, Kestenbaum B, Stehman-Breen CO. Elevated risk of stroke among patients with end-stage renal disease. Kidney Int 2003;64(2):603 9. 20. Oliveras A, Roquer J, Puig JM, Rodriguez A, Mir M, Orfila MA, et al. Stroke in renal transplant recipients: epidemiology, predictive risk factors and outcome. Clin Transplant 2003;17(1):1 8. 21. Kawamura M, Fijimoto S, Hisanaga S, Yamamoto Y, Eto T. Incidence, outcome, and risk factors of cerebrovascular events in patients undergoing maintenance hemodialysis. Am J Kidney Dis 1998;31(6):991 6. 22. Adams Jr HP, Dawson G, Coffman TJ, Corry RJ. Stroke in renal transplant recipients. Arch Neurol 1986;43(2):113 15. 23. Snyder JJ, Kasiske BL, Maclean R. Peripheral arterial disease and renal transplantation. J Am Soc Nephrol 2006;17(7):2056 68. 24. Maisonneuve P, Agodoa L, Gellert R, Stewart JH, Buccianti G, Lowenfels AB, et al. Cancer in patients on dialysis for end-stage renal disease: an international collaborative study. Lancet 1999;354(9173):93 9. 25. Penn I. Evaluation of transplant candidates with pre-existing malignancies. Ann Transplant 1997;2(4):14 17. 26. Chapman JR, Sheil AG, Disney AP. Recurrence of cancer after renal transplantation. Transplant Proc 2001;33(1 2):1830 1. 27. Kasiske BL, Cangro CB, Hariharan S, Hricik DE, Kerman RH, Roth D, et al. The evaluation of renal transplantation candidates: clinical practice guidelines. Am J Transplant 2001;1(Suppl. 2):3 95. 28. Kasiske BL, Ramos EL, Gaston RS, Bia MJ, Danovitch GM, Bowen PA, et al. The evaluation of renal transplant candidates: clinical practice guidelines. Patient Care and Education Committee of the American Society of Transplant Physicians. J Am Soc Nephrol 1995;6(1):1 34. 29. Gulanikar AC, Daily PP, Kilambi NK, Hamrick-Turner JE, Butkus DE. Prospective pretransplant ultrasound screening in 206 patients for acquired renal cysts and renal cell carcinoma. Transplantation 1998;66(12):1669 72. 30. Soni R, Horowitz B, Unruh M. Immunization in end-stage renal disease: opportunity to improve outcomes. Semin Dialysis 2013;26(4):416 26. 31. British Thoracic Society Standards of Care C, Joint Tuberculosis C, Milburn H, Ashman N, Davies P, Doffman S, et al. Guidelines for the prevention and management of Mycobacterium tuberculosis infection and disease in adult patients with chronic kidney disease. Thorax 2010;65(6):557 70. 32. Mills EJ, Barnighausen T, Negin J. HIV and aging--preparing for the challenges ahead. New Engl J Med 2012;366(14):1270 3. 33. Trullas JC, Cofan F, Tuset M, Ricart MJ, Brunet M, Cervera C, et al. Renal transplantation in HIV-infected patients: 2010 update. Kidney Int 2011;79(8):825 42. 34. Gomez V, Fernandez A, Galeano C, Oliva J, Diez V, Bueno C, et al. Renal transplantation in HIV-infected patients: experience at a tertiary hospital in Spain and review of the literature. Transplant Proc 2013;45(3):1255 9. 35. Locke JE, Mehta S, Reed RD, MacLennan P, Massie A, Nellore A, et al. A National Study of Outcomes among HIV-Infected Kidney Transplant Recipients. J Am Soc Nephrol 2015. Mar 19. pii: ASN.2014070726. 36. Sawinski D, Forde KA, Eddinger K, Troxel AB, Blumberg E, Tebas P, et al. Superior outcomes in HIV-positive kidney transplant patients compared with HCV-infected or HIV/HCV-coinfected recipients. Kidney Int 2015. Available from: http://dx.doi.org/10.1038/ki.2015.74. 37. Muller E, Barday Z, Mendelson M, Kahn D. HIV-positive-to-HIV-positive kidney transplantation--results at 3 to 5 years. New Engl J Med 2015;372(7):613 20. 38. Briganti EM, Russ GR, McNeil JJ, Atkins RC, Chadban SJ. Risk of renal allograft loss from recurrent glomerulonephritis. New Engl J Med 2002;347(2):103 9. 39. Cosio FG, Alamir A, Yim S, Pesavento TE, Falkenhain ME, Henry ML, et al. Patient survival after renal transplantation: I. The impact of dialysis pretransplant. Kidney Int 1998;53(3):767 72. 40. Fairhead T, Knoll G. Recurrent glomerular disease after kidney transplantation. Curr Opin Nephrol Hypertens 2010;19(6):578 85. 41. Canaud G, Dion D, Zuber J, Gubler MC, Sberro R, Thervet E, et al. Recurrence of nephrotic syndrome after transplantation in a mixed population of children and adults: course of glomerular lesions and value of the Columbia classification of histological variants of focal and segmental glomerulosclerosis (FSGS). Nephrol Dial Transpl 2010;25(4):1321 8. 42. Fuentes GM, Meseguer CG, Carrion AP, Hijosa MM, Garcia-Pose A, Melgar AA, et al. Long-term outcome of focal segmental glomerulosclerosis after pediatric renal transplantation. Pediatr Nephrol 2010;25(3):529 34. 43. Hickson LJ, Gera M, Amer H, Iqbal CW, Moore TB, Milliner DS, et al. Kidney transplantation for primary focal segmental glomerulosclerosis: outcomes and response to therapy for recurrence. Transplantation 2009;87(8):1232 9. 44. Pardon A, Audard V, Caillard S, Moulin B, Desvaux D, Bentaarit B, et al. Risk factors and outcome of focal and segmental glomerulosclerosis recurrence in adult renal transplant recipients. Nephrol Dial Transpl 2006;21(4):1053 9. 45. Ponticelli C. Recurrence of focal segmental glomerular sclerosis (FSGS) after renal transplantation. Nephrol Dial Transpl 2010;25(1):25 31. 46. Knoll G, Cockfield S, Blydt-Hansen T, Baran D, Kiberd B, Landsberg D, et al. Canadian Society of Transplantation consensus guidelines on eligibility for kidney transplantation. CMAJ 2005;173(10):1181 4.

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47. Lionaki S, Skalioti C, Boletis JN. Kidney transplantation in patients with systemic lupus erythematosus. World J Transpl 2014;4(3):176 82. 48. Goral S, Ynares C, Shappell SB, Snyder S, Feurer ID, Kazancioglu R, et al. Recurrent lupus nephritis in renal transplant recipients revisited: it is not rare. Transplantation 2003;75(5):651 6. 49. Hoppe B. An update on primary hyperoxaluria. Nat Rev Nephrol 2012;8(8):467 75. 50. Harambat J, van Stralen KJ, Espinosa L, Groothoff JW, Hulton SA, Cerkauskiene R, et al. Characteristics and outcomes of children with primary oxalosis requiring renal replacement therapy. Clin J Am Soc Nephrol 2012;7(3):458 65. 51. Cochat P, Rumsby G. Primary hyperoxaluria. New Engl J Med 2013;369(7):649 58. 52. Rumsby G, Cochat P. Primary hyperoxaluria. New Engl J Med 2013;369(22):2163. 53. Bergstralh EJ, Monico CG, Lieske JC, Herges RM, Langman CB, Hoppe B, et al. Transplantation outcomes in primary hyperoxaluria. Am J Transpl 2010;10(11):2493 501. 54. Lorenzo V, Alvarez A, Torres A, Torregrosa V, Hernandez D, Salido E. Presentation and role of transplantation in adult patients with type 1 primary hyperoxaluria and the I244T AGXT mutation: single-center experience. Kidney Int 2006;70(6):1115 19. 55. Malla I, Lysy PA, Godefroid N, Smets F, Malaise J, Reding R, et al. Two-step transplantation for primary hyperoxaluria: cadaveric liver followed by living donor related kidney transplantation. Pediatric Transpl 2009;13(6):782 4. 56. Sasaki K, Sakamoto S, Uchida H, Shigeta T, Matsunami M, Kanazawa H, et al. Two-step transplantation for primary hyperoxaluria: a winning strategy to prevent progression of systemic oxalosis in early onset renal insufficiency cases. Pediatric Transpl 2015;19(1):E1 6. 57. Mor E, Nesher E, Ben-Ari Z, Weissman I, Shaharabani E, Eizner S, et al. Sequential liver and kidney transplantation from a single living donor in two young adults with primary hyperoxaluria type 1. Liver Transpl 2013;19(6):646 8. 58. Artz MA, Steenbergen EJ, Hoitsma AJ, Monnens LA, Wetzels JF. Renal transplantation in patients with hemolytic uremic syndrome: high rate of recurrence and increased incidence of acute rejections. Transplantation 2003;76(5):821 6. 59. Ferraris JR, Ramirez JA, Ruiz S, Caletti MG, Vallejo G, Piantanida JJ, et al. Shiga toxin-associated hemolytic uremic syndrome: absence of recurrence after renal transplantation. Pediatr Nephrol 2002;17(10):809 14. 60. Loirat C, Niaudet P. The risk of recurrence of hemolytic uremic syndrome after renal transplantation in children. Pediatr Nephrol 2003; 18(11):1095 101. 61. Alasfar S, Alachkar N. Atypical hemolytic uremic syndrome post-kidney transplantation: two case reports and review of the literature. Front Med 2014;1:52. 62. Bresin E, Daina E, Noris M, Castelletti F, Stefanov R, Hill P, et al. Outcome of renal transplantation in patients with non-Shiga toxin-associated hemolytic uremic syndrome: prognostic significance of genetic background. Clin J Am Soc Nephrol 2006;1(1):88 99. 63. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010;5(10):1844 59. 64. Lahlou A, Lang P, Charpentier B, Barrou B, Glotz D, Baron C, et al. Hemolytic uremic syndrome. Recurrence after renal transplantation. Groupe Cooperatif de l’Ile-de-France (GCIF). Med 2000;79(2):90 102. 65. Zuber J, Le Quintrec M, Sberro-Soussan R, Loirat C, Fremeaux-Bacchi V, Legendre C. New insights into postrenal transplant hemolytic uremic syndrome. Nat Rev Nephrol 2011;7(1):23 35. 66. Weitz M, Amon O, Bassler D, Koenigsrainer A, Nadalin S. Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome. Pediatr Nephrol 2011;26(8):1325 9. 67. Zuber J, Le Quintrec M, Krid S, Bertoye C, Gueutin V, Lahoche A, et al. Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation. Am J Transpl 2012;12(12):3337 54. 68. Matar D, Naqvi F, Racusen LC, Carter-Monroe N, Montgomery RA, Alachkar N. Atypical hemolytic uremic syndrome recurrence after kidney transplantation. Transplantation 2014;98(11):1205 12. 69. Loirat C, Saland J, Bitzan M. Management of hemolytic uremic syndrome. Presse Med 2012;41(3 Pt 2):e115 35. 70. Remuzzi G, Ruggenenti P, Colledan M, Gridelli B, Bertani A, Bettinaglio P, et al. Hemolytic uremic syndrome: a fatal outcome after kidney and liver transplantation performed to correct factor h gene mutation. Am J Transpl 2005;5(5):1146 50. 71. Saland J. Liver-kidney transplantation to cure atypical HUS: still an option post-eculizumab? Pediatr Nephrol 2014;29(3):329 32.

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15 Early Postoperative ICU Care of the Kidney Transplant Recipient Xavier Wittebole, Diego Castanares-Zapatero, Michel Mourad, Virginie Montiel, Christine Collienne and Pierre-Franc¸ois Laterre St Luc university Hospital, Universite´ Catholique de Louvain (UCL), Brussels, Belgium

15.1 INTRODUCTION In 2009, the Kidney Disease Improving Global Outcomes (known as KDIGO) published clinical practice guidelines on the posttransplant care of kidney transplant recipients.1,2 Those extensive guidelines (more than 150 pages, more than 900 references) address immunosuppression therapy (induction, initial and long-term maintenance of immunosuppressive drugs, acute and chronic rejection), graft monitoring and infections (kidney function monitoring, graft biopsy, vaccination, viral and other infections), associated cardiovascular risk factors and diseases, malignancies, and other chronic disorders such as transplant bone disease, hematological complications, and metabolic and endocrine disorders such as gout. However, there is very little information on how to manage the kidney transplant recipient in the first hours or days after surgery. The European Best Practice Guideline Group (EBPG) published guidelines on the evaluation and selection of kidney transplant donor and recipient, as well as posttransplant care, in 2000 and 2002. While this group endorsed the KDIGO guidelines, they recently updated their own guidelines, mainly on patient and donor selection, and perioperative care, in order to avoid redundancies with the KDIGO work.3,4 In those guidelines, a whole chapter is dedicated to the perioperative care of patients undergoing kidney transplantation. The role of preoperative dialysis, the use of central venous pressure (CVP) monitoring, the type of fluid as well as the use of dopaminergic agents and antithrombotic agents, and timing of bladder catheter removal are discussed. We will review and further discuss some of those recommendations.

15.2 FLUID THERAPY Patients undergoing kidney transplantation should be properly hydrated in order to avoid intravascular volume deficit and hypovolemia as precipitating factors for postoperative kidney injury. Hence, fluid therapy to maintain adequate organ perfusion is mandatory. Fluid therapy may also be required as maintenance solution, specifically given to cover the patient’s daily basal requirements of water and electrolytes, or as replacement solutions to correct or prevent deficits that cannot be compensated by oral intakes.5 There are increasing data, mainly coming from the critical care area and septic patients studies, demonstrating that the type of fluid may be of importance in avoiding worsening acute kidney injury. The mechanisms proposed to explain fluid-induced kidney injury include activation of the tubuloglomerular feedback, increased intravascular oncotic pressure, osmotic nephrosis, and kidney parenchymal edema and/or venous congestion.6 Two major debates have taken place since the 1990s: colloid versus crystalloid solutions, and balanced versus

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unbalanced solutions. Both debates mainly focus on the use of resuscitation fluids for correction of the intravascular volume status in various clinical settings, including perioperative and postoperative care.

15.2.1 Colloids Colloid solutions include albumin solutions, available in two different preparations (the isooncotic 4% or 5% and the concentrated 20% 25% solutions) and synthetic solutions such as hydroxyethyl starches (HES) derived from maize or potato, gelatins derived from bovine collagen, and dextrans (polysaccharide) solutions. Despite major modifications in their structure (molecular weight, degree of molar substitution that is the number of hydroxyethyl residues per glucose unit) over time, leading to faster clearance from the body,7 starches should certainly be avoided as fluid therapy. Indeed, there are at least 4 large randomized controlled trials that specifically confirmed an increased risk for acute kidney injury and need for renal replacement therapy with starch solutions when compared to balanced or unbalanced crystalloid solutions in either severe sepsis patients or general ICU patients. In a French study involving 129 patients with severe sepsis, the use of HES was found, in a multivariate analysis, to be an independent risk factor for renal failure when compared to a gelatin solution.8 In the German VISEP study, the use of HES was associated with a significantly higher rate of acute renal failure (34.9% vs 22.8%, P 5 .002), a significantly higher number of days on renal replacement therapies (18.3% vs 9.2%) and a trend toward increased mortality at day 90 compared to Ringer lactate solution in patients with severe sepsis.9 A dose effect was clearly demonstrated in this study, with higher dose of HES leading to a significant increase in mortality when compared to lower dose. Likewise, in the Scandinavian 6S study, the primary outcome of death or need for dialysis at day 90 was significantly higher in the group of septic patients receiving HES as compared to Ringer lactate solution.10 Similarly to the German study, the use of HES was also associated with an increased need for renal replacement therapy during the ICU stay. Finally, the Australian and New Zealand CHEST study confirmed, in a large general ICU population (about 7000 patients), a significantly increased need for renal replacement therapy in those patients who received HES as compared to those treated with normal saline solution (NS).11 However, there was no difference in mortality in that particular study. Those data on deleterious side effects on kidney function were confirmed in various metaanalyses, and some authors proposed alternate volume replacement should be used in place of HES products.12 With those data in mind, both the United States Food and Drug Administration and the European Medicines Agency issued, in 2013, warnings on the use of HES in septic patients, leaving the debate open for the perioperative setting. This led to various publications with some conflicting results. In the particular setting of kidney transplantation, Legendre et al. already raised concerns, back in the early 1990s, on the use of HES in the management of brain dead kidney donors, as it could induce osmotic nephrosis-like lesions.13 To confirm the impact of these histopathological findings, the same group prospectively studied 47 kidney recipients.14 They demonstrated a potential for nephrotoxicity with HES as there were significantly more dialysis requirements in those patients receiving a kidney from an HES-treated donor and the evolution of the creatinine value after transplantation was better in those patients receiving a kidney from a gelatin-treated donor. However, the long-term effect at 5 years was not different between groups in terms of serum creatinine value.15 Other authors did not confirm the relationship between osmosis-like lesions in the kidney recipient and the use of HES as other confounding factors could have influenced the results.16 Some authors also did not confirm any difference in outcome between patients receiving a kidney from a donor treated with HES or another type of solution such as crystalloid17,18 while others even observed an improved outcome with 3rd-generation HES solutions on renal function of kidney recipients.19 However, those studies were retrospective and the latest one19 compared two different types of HES solutions without any other control solution. Finally, a large prospective observational study to assess the effect of HES, given to the kidney donor, on graft function in the recipient was conducted in Los Angeles.20 Data were completed for 986 kidneys transplanted from 529 donors. In this study, HES use was associated with a 41% increased risk of delayed graft failure in the kidney transplant recipient. Those latest data certainly reinforce the statement by the EBPG, which already raised caution on the use of starches in kidney donor management and kidney recipient patients, 2 years before this latest study was published.3,4 Other synthetic colloid solutions were certainly not studied to the extent of starch. Gelatins exist in three different solutions (succinilated, urea-linked, or oxypolygelatin), are eliminated by glomerular filtration, and are known to induce allergic reactions. In a well-known animal model of peritonitis (cecal ligature and punction or CLP) gelatins were shown to increase markers of renal failure (urea and creatinine) and kidney damage (NGAL), and induce structural changes as seen with starches.21 In humans, data on the use of gelatins in adequately powered randomized trials are scarce. Such a trial is planned in Germany (the GENIUS study for gelatin in ICU and

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sepsis; EudraCT 2015-000057-20), but this study will evaluate the safety of gelatins in critically ill septic patients, as compared to a crystalloid solution. In a study comparing the use of crystalloids and colloids, there was a trend toward increased kidney injury (as assessed by the RIFLE score R), a significant increase in the use of renal replacement therapy, and a prolonged ICU stay with gelatins,22 confirming to a large extent a previous trial.23 Likewise, in a similar large before-and-after study, gelatins were shown to increase the need for renal replacement therapy as compared to crystalloids without achieving any better hemodynamic outcome in cardiac surgery patients.24 Hence, the use of gelatins at the present time remains questionable. Dextrans are polysaccharides that are mainly eliminated by glomerular filtration and the digestive tract system, while cellular uptake and storage has also been described. In a canine model of kidney transplantation, the use of dextran was associated with decreased renal function and histopathological features of osmotic nephrosis-like lesions.25 Some case reports, reviewed elsewhere26 also describe such lesions associated with kidney failure in humans. On top of those potential kidney side effects, dextrans may also induce severe allergic reactions and compromise hemostasis, which makes their use difficult to justify in the ICU setting or in kidney transplant patients. From a theoretical point of view, albumin contained in natural colloid albumin solutions would be of great interest and show major advantages such as the major determinant of plasma colloid pressure, an ability to bind and transport various molecules including drugs, free radicals scavenging, and the protection of the endothelial surface layer. However, they are not equivalent in terms of sodium and chloride content; indeed the 4% or 5% solution displays sodium and chloride concentrations at 140 160 mmol/L and 100 130 mmol/L respectively while the 20% and 25% solutions contain 100 125 mmol/L sodium and 20 25 mmol/L chloride. Since this difference could account for different effects on the kidney (see the balanced unbalanced solution debate later in the chapter), results from a particular study would probably not extend to other studies. In the critical care setting, albumin was not demonstrated to be superior in term of renal failure, need for renal replacement therapy, or mortality when compared to crystalloids.27,28 In the Saline versus Fluid Evaluation or SAFE study,27 4% albumin was compared to 0.9% saline and did not result in any better outcome, including for the kidney. In the Albumin Italian Outcome Study or ALBIOS study,28 a 20% albumin solution was prescribed to target a plasma albumin level of 30 g/L. Again, the various outcomes including the incidence of acute kidney injury were not affected by the treatment. Various factors such as the high chloride content of the albumin solution in the SAFE study or the high oncotic pressure in the ALBIOS study could explain the nonpositive results since those two characteristics could lead to renal failure (see previous). Furthermore, the cost of albumin solutions (in the absence of clear benefit in the general ICU population) prevents its generalized use. The situation is slightly different for kidney transplant patients. Indeed, in this context, observational studies showed albumin solution was associated with increased urine output, graft renal function and 1-year graft survival.29 31 In a large series of 438 patients transplanted with kidneys from cadaveric donors, there was even a linear dose effect with albumin, the higher dose (1.2 1.6 g/kg body weight) achieving the better outcomes in term of urine volume, serum creatinine and glomerular filtration rate, delayed graft failure, and graft function at 1 year.32 Because of the design of those studies, other factors (such as concomitant medications and the use of mannitol) may have affected the results. In a recent retrospective study on about 2000 kidney-transplanted patients over a 20-year period, the use of albumin was found to be an independent factor of protection for acute rejection and chronic graft dysfunction.33 Beyond the fact this study was retrospective, the importance of the results are weakened by the very limited number of patients (91) treated with albumin. Controlled clinical data investigating the effect of albumin in kidney transplant patients were not available until recently. A first study on 44 patients assessed the outcome of patients receiving intraoperative 20% albumin and 0.9% saline versus 0.9% saline alone to target a CVP between 10 and 15 mmHg.34 There was no difference between groups at baseline. The volume infused during surgery was equivalent (roughly 4 L). Neither urine output nor the various creatinine values at days 1, 3, and 5 were different between groups. Another study analyzed intraoperative 20% albumin versus 0.9% saline, to target a CVP of 12 15 mmHg, on the outcome of kidney graft function in 80 patients.35 Groups were well balanced apart from a trend towards an increased kidney donor age in the albumin group (49 vs 45; P 5 .051). None of the outcomes (hemodynamic parameters, creatinine serum value and urine output) was affected by the treatment group. Hence, the authors concluded albumin solution should be used rationally, considering its risk benefit and cost benefit ratios.

15.2.2 Crystalloids As demonstrated in the various studies in the section on colloids, crystalloids perform better than, or at the worst are equivalent to, colloid solutions. However, there is a major debate on which type of crystalloid solution

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should be used: Unbalanced (with a high sodium and chloride content) or balanced (with a composition that mimics more the plasma content). Beyond its well-known effects on metabolic acidosis,36,37 chloride-rich solutions induce the so-called glomerulo-tubulo-feedback mechanism: the increased delivery of chloride to the macula densa cells located in the distal part of the nephron induces the release of various vasoactive mediators, which in turn promote vasoconstriction of the afferent arteriole and finally a reduced glomerular filtration rate. This is supported by both animal and human studies.38,39 There are many observational and retrospective studies assessing the effect of chloride-poor solution on renal function. While not always consistent, most of those studies report on decreased acute kidney injury, decreased need for renal replacement therapy and improved urine output with chloride-poor solutions. The largest retrospective study, on 53,448 patients treated for sepsis in an intensive care unit, demonstrated, in a propensitymatched cohort, that those who received balanced solutions (3396 patients or 6.4% of the total cohort) had a decreased mortality.40 In this study, renal failure, ICU, and hospital length of stay were not affected by the type of crystalloid solution. There are also some prospective randomized controlled trials on that topic. In a prospective, before-andafter study, the implementation of a chloride-restrictive policy led to a significant decrease in the incidence of acute kidney injury and need for renal replacement therapy.36 Likewise, in this study involving 1644 ICU admissions in 1533 patients, the chloride-restrictive strategy was associated with a significantly lower increase in serum creatinine, while mortality and need for RRT at 3 months were not affected. A large prospective randomized controlled trial comparing 0.9% saline and a balanced solution was started on April 1, 2014.41,42 The SPLIT study (Saline vs Plasma-Lyte 148 for Intensive care fluid Therapy) planned to recruit 2300 patients in four New Zealand tertiary ICUs. Results of this particular study are supposed to be published by the end of 2015. While awaiting those results, a panel of experts proposed balanced solutions may be a reasonable default choice.43 In the particular setting of kidney transplantation, there are few studies evaluating the effect of “normosaline” solution (NS) versus balanced solutions. In a study involving 74 patients during living donation kidney transplantation, the use of Ringer’s lactate solution resulted in lower metabolic acidosis and hyperkalemia than the use of NS.44 This recent study confirmed the results of another trial that was stopped prematurely, after the safety analysis of 51 patients, because of increased incidence of metabolic acidosis and hyperkalemia with the use of NS.45 Kidney function was not affected by the type of solution. The study by Kim et al. evaluated the effect of NS versus Plasmalyte in 60 patients undergoing living donor kidney transplantation.46 While postoperative serum creatinine, urine output, and incidence of graft failure were unaffected by the type of crystalloid, Plasmalyte better maintained the acid base and electrolyte balances. The better metabolic profile with Plasmalyte as compared to NS or even Ringer’s lactate solution was confirmed in a large recent metaanalysis.47 In summary, and awaiting some new data, it seems reasonable to avoid synthetic colloid when fluid therapy is required in kidney recipient patients. Concentrated 20% albumin (with low chloride content) and balanced crystalloids are probably preferable to normal saline because of its high chloride content, which may be deleterious for the kidney function as well as the metabolic status since it induces acidosis as confirmed by a recent metaanalysis.48 Furthermore, the high cost of albumin solutions makes its cost benefit ratio below that of balanced crystalloid solution.

15.3 CENTRAL VENOUS PRESSURE MONITORING CVP is the measurement of pressures within the thorax in the superior vena cava; it normally provides some estimates of the volume status of the systemic circulation, as it is a surrogate for the right atrial pressure. It does not provide any information on cardiac output nor on the volume status of the pulmonary circulation in the presence of left ventricular dysfunction. For this purpose, pulmonary artery catheters were frequently placed in patients, until large studies and metaanalysis were unable to confirm a benefit on mortality with its use.49 51 Likewise, apart from cardiac surgery patients,52 data on how CVP monitoring affects outcome are lacking. Furthermore, a single value of CVP does not preclude if a patient will respond to fluid challenge and increase its cardiac output.53 Hence, many studies questioned the interest in CVP and many other parameters such as stroke volume variation, pulse pressure variation, and inferior vena cava diameter assessed by ultrasound were proposed in critically ill patients as well as in the operating room. The EBPG recommend to measure and correct CVP values in order to decrease the incidence of hypovolemia and delayed graft function (recommendation grade 2D).3,4 They base their recommendation on small trials. In a

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retrospective analysis assessing potential risk factors for graft failure, a CVP value below 8 mmHg at awakening was significantly associated with delayed graft failure.54 Othman and colleagues demonstrate in 40 patients that perioperative infusion of sodium chloride targeting a CVP above 15 mmHg was associated with earlier onset of diuresis and better graft outcome.55 Some new studies, published after the ERBP guidelines, confirmed the positive impact of CVP monitoring.56 As already mentioned, some authors questioned the role of routine CVP monitoring and proposed some other tools to assess the volume status of the patient.57,58 However, the PVC monitoring may easily be maintained after surgery (as opposed to transesophageal Doppler) and it may help in diagnosing conditions known to worsen kidney function such as renal venous hypertension59 and the abdominal compartment syndrome (ACS) (see the following).

15.4 DOPAMINE AND OTHER MEDICATIONS The use of dopamine to improve renal function after various insults was a matter of debate for more than 20 years. Dopamine is the immediate precursor of norepinephrine and its effects are dose-dependent: small doses (0.3 up to 3 5 mcg/kg/minute) activate dopamine and beta-receptors, while at higher doses, alpha-receptorrelated effects are observed. In summary, the various effects of dopamine on the kidney could be described as increase in renal blood flow, increase in natriuresis through direct effects on renal tubules, and increase in free water clearance through a stimulation of the E2 prostaglandin synthesis, which antagonizes the antidiuretic hormone.60 However, dopamine effects on renal blood flow could potentially also be detrimental, since it induces vasodilation in the cortex and inner medulla while it decreases blood flow from the outer medulla, shunting blood away from it. Some old physiological studies performed in healthy volunteers demonstrated that low-dose dopamine (LDD) increased renal blood flow and promoted natriuresis and diuresis.61,62 Based on its potential beneficial effects, dopamine has been extensively used at the so-called “renal dose” for years in critical care in order to improve renal function. While LDD improved hemodynamic and renal parameters in patients with septic shock,63 others were not able to demonstrate any benefit from LDD apart from its effect on diuresis.64 A large randomized controlled trial did not confirm positive effect of such treatment in 324 patients with signs of systemic inflammatory response syndrome and early renal dysfunction.65 None of the evaluated outcomes (peak value and increase from baseline value of serum creatinine concentration, number of patients with a creatinine value above 300 micromol/L, need for renal replacement therapy, ICU and hospital length of stay) were affected by treatment.65 Observational66 and prospective randomized67 studies in shock patients even raised some concern on the use of dopamine as vasopressor. The many studies performed in this area were evaluated in various metaanalyses. The renal protective effect was not confirmed in critically ill patients68 and, as mentioned, dopamine was even found deleterious when used as a vasopressor in septic shock patients because of increased side-effect events.69 Dopamine has also extensively been studied in kidney transplantation as an agent that might improve graft function when given to the kidney donor, during surgery or in the kidney recipient. A retrospective observational analysis of a 152 consecutive kidney transplantation database found that donor catecholamine treatment was associated with improved graft survival.70 This was later confirmed in a larger database.71 This was further studied in a rodent model of brain death.72 The use of dopamine in the donor was associated with better serum creatinine value in the recipient. Interestingly, 10 days after transplantation, dopamine treatment also decreased monocyte infiltration and cytokine mRNA expression, confirming a potential role of dopamine as an immunemodulatory agent.73 Finally, small-dose dopamine (4 mcg/kg/minute) given for a median time of 344 minutes (IQR: 215 minutes) to heart-beating donors was further evaluated in a randomized controlled trial. The need for dialysis was evaluated in the 487 subsequent recipients.74 The main outcome of dialysis was significantly reduced in patients receiving a dopamine-treated graft. In the subsequent multivariate analysis, the use of dopamine remained statistically significant; other risk factors for graft failure included cold ischemic time and recipient body weight. To enhance urine output and prevent arterial vasospasm and acute tubular necrosis, LDD has frequently been used in kidney recipients. Despite its general use, results from clinical studies were conflicting. Some studies reported on some beneficial effects such as slightly better creatinine clearance and improved urine output.75,76 In a short-course treatment study (3 hours infusion) with LDD, Dalton demonstrated that during the period of time the kidneys were exposed to LDD, urine flow rate, effective renal plasma flow, creatinine clearance, and urinary sodium excretion were improved.77 Clinical consequences were not evaluated. Others could

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not confirm those positive results. DeLosAngeles was not able to demonstrate that a combined infusion of dopamine (3 mcg/kg/minute) with furosemide improved creatinine clearance in 20 patients as compared to 20 others not receiving the treatment.78 Cardiac arrhythmias, however, were increased in the dopamine group. Resistive index, renal blood flow velocity, and vascular resistance assessed by Doppler ultrasound were evaluated in a prospective study.79 None of these indices were modulated by LDD infusion. The authors hypothesized that the denervated kidney might not respond the same way as normal kidneys in healthy persons. In a retrospective study of 105 patients, Ciapetti and colleagues compared 57 patients kidney recipients receiving dopamine (0.5 2.5 mcg/kg/minute) to 48 controlled patients.80 While kidney donor characteristics, intraoperative procedure, and kidney recipient characteristics were similar, patients treated with LDD had an increased heart rate and ICU length of stay (20.4 vs 29 hours, P , .05). Kidney function parameters and urine output as well as graft rejection at day 28 were equivalent in both groups. Mortality at 6 months was also increased in the dopamine-treated patients, but the small number of patients analyzed in the study limit the interpretation of this data. Taking all those data together, the use of dopamine as a renoprotective agent in kidney recipient patients is certainly not supported outside of prospective randomized trial. This is actually confirmed by the ERBP guidelines.3 Fenoldopam is a synthetic benzazepine derivate that acts as a selective dopaminergic 1 receptor agonist, causing vasodilation of both systemic and renal vessels. It also promotes sodium excretion.81 A metaanalysis, gathering data on 1290 critically ill patients, suggested fenoldopam reduced the risk for acute kidney injury and mortality while the risk for hypotension was clinically acceptable.82 However, a later randomized controlled study in cardiac surgery patients was stopped early because of futility.83 While need for renal replacement therapy and mortality were equivalent between both groups, hypotension was significantly more frequent in treated patients. Fenoldopam was evaluated in kidney- transplanted recipients. Oral treatment in 6 patients evaluated 3 6 months after transplantation was assessed using a loading dose of 100 mg and after 3 weeks of treatment, 100 mg thrice daily.84 Despite those patients being on oral cyclosporine (a potent renal vasoconstrictor), the administration of fenoldopam improved mean effective renal plasma flow. However, the other variables such as glomerular filtration rate, urine output, and fractional excretion of sodium were not significantly ameliorated. Curiously, despite the conflicting results with dopamine (see previous), there are two studies comparing, in kidney recipient, the effect of fenoldopam with dopamine.85,86 In the first study, a continuous infusion of fenoldopam at a dose of 0.05 mcg/kg/minute for 48 hours did not significantly improve urine output, the first postoperative day creatinine value, or the renal vascular resistive index assessed by Doppler ultrasound.85 In the second study, Sorbello and colleagues showed that fenoldopam for a 2-hour continuous infusion treatment at a dose of 0.1 mcg/kg/minute increased urine sodium concentration and decreased urine potassium concentration.86 There was no observed effect on urine output. A recent study in liver transplant recipients showed however some promise on the use of fenoldopam87 but data are certainly too weak in the kidney transplant literature to recommend the use of fenoldopam as a nephroprotective agent. Medications aimed at increasing the urine output such as diuretics or mannitol are often used in patients during or after kidney transplantation. For instance mannitol was reported to be used, as an antioxidant or diuretic, or both, in about 65% of centers performing living donor nephrectomy.88 Positive effects are indeed reported in the literature with mannitol prescribed to the donor89 or recipient90 or even used in the storage solution91 but those studies involved a very limited number of patients and drawing any conclusion is therefore of limited value. A recent systematic review and metaanalysis concluded mannitol does not convey any additional benefit in preventing acute kidney injury.92 The authors proposed that a large well-conducted randomized controlled trial should be undertaken in kidney recipients. Likewise, the use of diuretics resulted in conflicting data with some studies unable to demonstrate any positive effect.93 Actually, it is clearly reported that diuretics are ineffective in preventing acute kidney injury and might even be detrimental.94,95 Therefore the prescription of diuretics should be restricted to those patients with limited diuresis and clear evidence of volume overload. Furthermore, the use of diuretics (or mannitol) should not induce hypovolemia since it could worsen kidney injury. One exception might be spironolactone. Indeed there are some very interesting experimental data showing that spironolactone was of great interest in models of ischemia-reperfusion kidney injury.96,97 This, however, has to be translated into clinical studies and practice. Many other medications aimed at decreasing the oxidative stress induced by the transplant procedure related ischemia-reperfusion have been evaluated in experimental models as well as in clinical practice. For instance, N-acetyl-cysteine was studied as a renal protective agent when given to the donor98 or the recipient.99 Results of these two studies, which did not show any positive impact on the various parameters of kidney

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function, did not confirm the positive results observed in another study that suggested NAC reduced oxidative stress assessed by levels of thiobarbituric acid reactive substances and improved kidney function up to 1 year after transplantation.100 Other molecules studied in experimental models or clinical practice included calcium channel blockers, atrial natriuretic peptide, brain natriuretic peptide, vitamin E, and nitric oxide generators. However, strong clinical evidence is still lacking and none of these molecules should be recommended at the present time.101 Future research should certainly focus on the role of the innate system activation in ischemia-reperfusion injury as inhibition of toll-like receptor was demonstrated of benefit in a model of ischemic heart injury.102

15.5 ABDOMINAL COMPARTMENT SYNDROME AND RENAL ALLOGRAFT COMPARTMENT SYNDROME Increased pressure within the abdominal cavity leads to intraabdominal hypertension (IAH) when intraabdominal pressure is above 12 mmHg and ACS when the rise in pressure constantly exceeds 20 mmHg, and is accompanied by a new onset of organ failure within or outside of the abdominal cavity.103 Many conditions, such as decreased abdominal wall compliance, increased abdominal content, capillary leak and others are associated with the development of this syndrome.103 The relationship between increased intraabdominal pressure and kidney function was already described by Wendt in 1876. The different mechanisms involved in the pathophysiology of ACS-induced renal failure were reviewed in 2011.104 Beyond the effects of ACS on hemodynamics, which lead to decreased cardiac output, local arterial inflow to the kidney is also impaired. Likewise, the IAH-induced increase in venous pressure decreases venous blood flow. While compression of the ureter does not seem relevant to postrenal kidney injury, direct compression of the kidney parenchyma, as it was demonstrated in ischemia-reperfusion models,105 certainly is an important contributor to renal failure. In a surgical population, the level of IAH was demonstrated to be an independent risk factor with worsening renal failure associated with increased IAH values.106 This was confirmed in liver-transplanted patients; higher value of IAH ( . 25 mmHg) was associated with higher creatinine value, greater need for diuretics, increased incidence of renal failure, and worse outcome.107 Initially described by Humar,108 the terminology of renal allograft compartment syndrome (RACS) was proposed by Ball and colleagues to define this subtype of secondary ACS.109 Actually two different scenarios may occur: Renal failure due to classical intraabdominal hypertension with increased pressure within the whole abdominal cavity and retroperitoneal space, and, renal failure related to compression of the parenchyma within the kidney capsule, as met in the ischemia-reperfusion model described previously.105 Indeed, transplantation induces ischemia-reperfusion injury and inflammation in the kidney with activation of the innate immune system, leading to swelling within a closed space (capsule).101 Risk factors for RACS include weight discrepancy between the donor and the recipient, child recipient, and a noncompliant retroperitoneal space, which is limited laterally by the pelvic sidewall, posteriorly and medially by the peritoneum and its contents, and anteriorly by the abdominal wall musculature.109 Allograft width and length were also proposed as potential risk factor.110 Diagnosis is made upon clinical assumption and ultrasound. Reversed diastolic blood flow in interlobar and segmental renal arteries, in conjunction with minimized venous flow, defines the sonographic criteria for RACS.109 RACS is rarely reported in the literature. Pertek described three cases of posttransplant renal failure due to occult bleeding related retroperitoneal hematoma; evolution was excellent after abdominal decompression.111 Fontana reported on a case where RACS was induced by the presence of a large amount of ascites.112 While intraabdominal pressure was moderately elevated (14 mmHg), paracenthesis allowed recovery of kidney function. Decoster observed RACS in a patient who underwent simultaneous pancreas kidney transplantation.113 Again, in this case report, the IAP was only moderately increased; surgical decompression resulted in immediate recovery of kidney function. Pediatric cases were also reported.114 After early recognition, initial management includes the treatment of the precipitating factor and surgical decompression is usually required; this allows dramatic improvement of graft function.109 A particular technique of mesh hood fascial closure may apply to prevent and treat RACS.115 Various types of mesh are used to close the abdominal wall (porcine collagen graft, prosthetic mesh (PTFE), polypropylene assisted mesh). Interestingly this procedure does not preclude biopsy procedure or imaging of the renal graft postoperatively.116 Subcutaneous placement of the kidney graft and intraperitoneal placement of the graft117 have also been proposed.

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15.6 OTHER CONSIDERATIONS The ERBP Guidelines also recommend on dialysis session prior to transplantation, the use of antithrombotic agents in the perioperative period, the placement of a ureteral catheter (JJ stent), and the optimal timing of bladder catheter removal.3,4 Routine hemodialysis sessions should not be performed before the surgical procedure as there are no demonstrated benefits (recommendation 1 C). It could even delay the surgical procedure and increase the cold ischemia time. Actually, this procedure should be restricted to those patients with severe metabolic disorders such as hyperkalemia. Likewise, hemofiltration should be performed only if fluid overload is evident. Antithrombotic agents are not recommended for the prevention of graft thrombosis and bladder catheter should be removed as soon as possible, balancing the risk between infection and urinary leak. However, the authors propose to monitor adverse rate in each transplant center in order to help in the decision of catheter removal. Curiously, the guidelines do not approach the need for specific biologic monitoring or noninvasive techniques to assess graft functioning. Usual kidney function tests (urea or BUN, creatinine serum values) should be performed routinely after kidney transplantation and urine output monitoring is certainly warranted. The use of other kidney function markers such as neutrophil gelatinase-associated lipocalin (NGAL), KIM-1, or others might be reliable markers of early and delayed graft failure.118 However, their routine use at the present time does not add to the usual blood test as it was demonstrated for NGAL, for instance, that it was not able to compete with markers used in clinical practice.119 Postoperative graft function may also be assessed with ultrasound or nuclear imaging techniques. Ultrasound may help diagnose vascular complications (arterial stenosis, arterial and venous thrombosis, pseudoaneurysm formation), urological complications (urinary obstruction and leaks), and collections.120,121 Renal scintigraphy has also been proposed by some authors to assess kidney function as well as posttransplant complications such as vascular compromise, acute tubular necrosis, and urine leak.122 Finally, some specificities for the management of children after kidney transplantation are also described in the literature.123

15.7 CONCLUSIONS Above usual postoperative care, management of the kidney-transplanted patient warrants particular attention to avoid anything that could compromise the kidney function in this particular ischemia-reperfusion period. On top of avoiding usual nephrotoxic agents, patient care should include adequate maintenance of volume and hemodynamic status with fluid therapy with balanced solutions. There are no specific medications at the present time that might help graft function recovery, and, in case of persistent renal failure, adequate work-up with ultrasound, scintigraphic imaging, and measurement of the intraabdominal pressure may help the physician. Finally, care of the donor is of importance as it was demonstrated in 2015 that mild hypothermia in the donor might improve graft function after kidney transplantation.124 This is however beyond the scope of this chapter.

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C H A P T E R

16 Approaches to Minimize Delayed Graft Function in Renal Transplantation Maria Francesca Egidi and Domenico Giannese University of Pisa, Pisa, Italy

ABBREVIATIONS ACR AKI AMR ATN BMI CIT CNI DBD DCD DGF ECD GFR GI HD HMP IRI IS NGAL PD SCD s.creat. Thymo US

acute cellular rejection acute kidney injury antibody-mediated rejection acute tubular necrosis body mass index cold ischemia time calcineurin inhibitor donation after brain death donation after cardiac death delayed graft function extended criteria donor glomerular filtration rate graft index hemodialysis hypothermic machine perfusion ischemia-reperfusion injury immunosuppressive regimens neutrophil gelatinase-associated lipocalin peritoneal dialysis standard criteria donor serum creatininemia Thymoglobulin ultrasonography

16.1 INTRODUCTION In the present chapter the authors attempt to give a comprehensive picture of delayed graft function (DGF) in relation to different definitions, causes, and the impact on graft outcomes. DGF is a complication in the immediate posttransplant (TX) period that not only increases morbidity, length of hospitalization, and health care costs, but more importantly enhances immunogenicity, chronic allograft damage, and decreased long-term patient and graft survival.1,2 Therefore DGF is a relevant prognostic indicator. Risk factors for DGF derive from the donor and the recipient.3 Although the incidence of DGF has remained unchanged over the past decades, it is crucial to stress that in the current era this post-TX complication requires major endeavor with its prevention and Kidney Transplantation, Bioengineering, and Regeneration. DOI: http://dx.doi.org/10.1016/B978-0-12-801734-0.00016-3

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management. In particular, the imbalance between organ demand and supply has induced the increasing use of “suboptimal donors,” defined as extended criteria donor (ECD) and donor after cardiac death (DCD) whose grafts will suffer more from DGF impact when compared to standard criteria donors (SCD).4 6 There is no effective treatment for DGF; however, early diagnosis and therapeutic interventions may improve short and long-term results. In order to prevent or reverse the initial kidney injury and the deleterious consequences several biomarkers and new immunosuppressive regimens (IS) are under investigation.

16.2 DEFINITIONS DGF can affect 20% 50% of recipients of cadaveric TX and 4% 10% of living donors. This large variability is related to the various definitions of DGF, most of them based on dialysis requirement or serum creatinine (s. creat.) values.7 9 This lack of consensus complicates the interpretation of the results on patient and graft outcomes and also generates discrepancies from the literature data. One systematic review by Yarlagadda reported 18 definitions and at least 10 different techniques for DGF diagnosis, based on need for dialysis, histological findings, urinary output and s.creat.7 The need for dialysis in the first week after TX is the most commonly used definition for DGF and has shown high specificity and sensitivity for predicting graft outcome.10 However, there is an important selection bias: The indication for dialysis can be subjective, being a clinician decision, and depends on single-center experience and policy. Furthermore, patients with a residual urinary output and glomerular filtration rate (GFR), such as the candidates for a preemptive TX, may not require post-TX dialysis despite a suboptimal graft function. These circumstances are reasons to underestimate the real DGF incidence.7 Aitken et al.10 assumed that DGF is a syndrome with different variety of etiologies and after a retrospective analysis of data collected in 762 recipients in the first 30 days post-TX, described 4 distinct patterns of DGF: 1. A prolonged hemodialysis: a prolonged period of hemodialysis, then a fall in s.creat. 2. A single hemodialysis: a single session of hemodialysis required, then be s.creat. fell. 3. A slow decline: immediate reduction in s.creat; however, s.creat. took a long time to reach baseline and .1 week for the s.creat to half. 4. A slow rise, then a gradual decline: s.creat. initially rose, then declined slowly with .1 week for s.creat. to half. No dialysis required. Although the number of patients who suffered DGF was limited (24.9%), this classification is relevant and could reflect the potential injuries incurred by the kidneys including the type and the length of the ischemia. In fact, cold ischemia time (CIT) or acute kidney injury (AKI) correlate with the need for dialysis, whereas the rate of decline of s.creat. may be influenced by warm ischemia and ischemia-reperfusion injury (IRI). Recipients of marginal kidneys could be consistent with this observation, as ECD kidneys are more likely to require dialysis than DCD kidneys, which conversely show a slower decline in s.creat. to the ultimate baseline. This classification focuses on the renal function recovering rate and could be a reliable predictor of medium-long term graft outcomes.9 The DGF definitions do not allow the differentiation from the other concomitant causes of nonfunctioning graft. It has been clearly documented that IRI activates an immunological cascade but its relationship with acute cellular rejection (ACR) or antibody-mediated rejection (AMR) can be proven only by renal biopsy. Besides irreversible thrombotic events, other possible etiologies such as calcineurin inhibitors (CNI) acute toxicity and/or thrombotic microangiopathy should be taken under consideration, not only for diagnostic approach but for pharmacological management. The induction strategies, in particular with the antithymocyte globulin Thymoglobulin (Thymo), have been designed not only to minimize CNI nephrotoxicity but also to ensure an immunological protection of the graft during DGF.11,12

16.3 PATHOPHYSIOLOGY The etiology of DGF is multifactorial and involves different risk factors including CIT and AKI, which perhaps play the major role in the inflammatory and immunological cascade. The development of immune response and the presentation of intra- or extracellular antigens result in poor long-term outcome of the graft.13,14 After the organ procurement, the cellular components of the kidney, despite storage in hypothermic solution, change their metabolic pathways from aerobic to anaerobic. This hypoxic status during the ischemic period causes the loss of osmotic equilibrium and increases the permeability of cellular membranes, with

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consequent cell necrosis and further irreversible damage. The endothelial and tubular epithelial cells, because of the great number of metabolic processes, are extremely vulnerable to the toxic effects of the ischemia. The following reperfusion phase induces the restoration of the metabolic processes but concomitantly triggers the expression of inflammatory cytokines and adhesion molecules that play an integral role in DGF development.15 18 These events stimulate interactions among leukocytes, platelets, and erythrocytes that plug the capillaries and create a low-flow condition with tubular obstruction and detrimental intraluminal pressure.19 The immune system activation and DGF coexist, interact, and lead to a complex interaction that involves different mediators, dendritic cells, and complement components. Acute tubular necrosis (ATN) is the corresponding histological picture of DGF that can also be associated to ACR or AMR. ATN shows different degrees of severity that range from the dilatation and loss of tubular epithelial cells to the significant damage of the microvascular epithelium. The tubular repair process is often associated with multiple mitosis. On the other side, the persisting damage induces an early and irreversible tubule-interstitial fibrosis with poor outcome of the graft.13 The incidence of ATN is increased by CIT longer than 24 hours, the presence of preformed antibodies, the type of pre-TX dialysis and the poor quality of the donor.20,21 Associations among gene polymorphism, DGF, and ACR or AMR are under investigation. Some genes appear to play a minor role in DGF pathogenesis but can be strongly related to ACR.22 Recent studies have shown that CC genotype (CX3CR1 gene V2491) appear to be an independent and significant predictor of higher risk for DGF.23 It has not yet been determined what, if any, are the potential repair mechanisms possibly linked to the genetic asset of the recipient.

16.4 IMAGING As described in the previous section, the definition of DGF is based on clinical features, but imaging could be a worthwhile aid. Ultrasonography (US) is the noninvasive approach used in every TX phase and is the primary imaging technique for the evaluation of an early diagnosis of DGF. Several reports agree that indexes of perfusion and elevated resistive index (RI) differ in patients with DGF when compared to a control group.24 An US evaluation performed in 79 patients in the early post-TX period showed higher RI of upper and middle segments in cases of DGF. Also a multivariate analysis evidenced that older donors and high final s.creat. correlate with the risk for DGF.25 In agreement with those data are the findings of a contrast-enhanced US study where the inflow was significantly delayed, and lower, in patients with DGF. The renal biopsies performed in this latter group showed a picture of ACR or ATN respectively. As expected, the inflow time to the cortex and the pyramids was longer in ACR than in ATN.26 Two studies performed after 2 4 weeks post-TX identified particular features in patients with increase of RI and pulsatility. Both investigations evidenced that graft and recipient characteristics such as age, diabetes, and DGF had significant impact in abnormal US findings. However, the second study reported that donor features such as hypotension, use of catecholamines, HLA mismatch, and impaired central venous pressure were also relevant.27 Scintigraphy with 99 m Tc-DTPA is another imaging technique useful for diagnosis of DGF and appears to be more accurate and sensitive than US. Yazici28,29 described a formula defined as the graft index. In 179 patients who underwent a renal scintigraphy after 2 days from TX, this index was the most accurate parameter for DGF identification.30 The obvious limitations of this imaging are the exposure of the patient to radionuclides and the involved costs. Magnetic resonance imaging is free from radioactive risk, has proven reliability in detecting perfusion impairment during DGF, and correlates well with GFR, RI, and CIT.31 Noninvasive tests are more and more sophisticated and well equipped in terms of sensitivity. Therefore, radiology imaging should be considered an important and complementary tool for the detection of renal dysfunction, including DGF.

16.5 NEW BIOMARKERS AND PREDICTIVE MODELS In recent years, new markers of kidney injury have acquired an important role. There are emerging and promising markers able to predict DGF, but the complexity of AKI pathophysiology has low probability to detect one specific biomarker rather than a full panel. Biomarkers can be found not only in urine but in serum as well. This is relevant as DGF induces oligo-anuria in most cases. As of 2017, studies are based on a small number of patients due to the limitations for the high costs of production and validation of the laboratory through standardized techniques. Basically, the new biomarkers correspond to the different functional components of the kidney.

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Neutrophil gelatinase-associated lipocalin (NGAL), a small protein expressed in various epithelial cells (e.g., kidney, gastrointestinal tract, lungs), filtered through the glomerulus and secreted in tubular cells is greatly increased in the serum and urine of patients with AKI.32 34 Different studies have shown that high urine and serum NGAL levels shortly after TX are predictors of DGF and are associated with reduced graft function at 1 year.35 38 Recent reports have shown that clusterin and interleukin 18 can predict DGF.39 Leptin, an adipocytokine whose circulating levels are increased in chronic kidney diseases, appears to be a good marker for DGF. In recipients with DGF, leptin values, just after 1 day, were approximately two times higher than in patients with immediate graft function. After correcting for gender and body mass index (BMI), day-1 leptin predicted DGF with a performance slightly better than s.creat.40 Assessments conducted on gene expression during DGF show a correlation with some potential inflammatory and protective molecules. For instance genes for IL-1R1, IL10, IFNA1 during DGF seem to promote and upregulate inflammation, whereas the gene for TGF-beta is downregulated.41 As a consequence, the absence of the immunomodulatory effect of TGF-beta activates immunity and triggers inflammation that result in chronic damage.42 The interleukin 2 (IL2), is under investigation for a possible link with DGF because of an established role in the immunological response. Nevertheless, the correlation between rs6822844 gene polymorphism in the IL2-IL21 region and graft function did not show any statistically significant difference between the patients who developed DGF and the group with rapid recovery.43 In a swine model of IRI, Castellano,44 after the discovery of a remarkable decrease of Klotho produced by the tubular cells, analyzed kidney biopsies from cadaveric donors at the implantation time. If compared with patients with immediate graft function, patients with DGF showed downregulation of Klotho. Interestingly in this latter group, Klotho levels continued to be lower up to 2 years after TX. Taken together these data support the hypothesis that a persistent deficiency of Klotho, with its antisenescence and antifibrotic effects, may contribute to chronic allograft dysfunction in DGF patients. In order to prevent or reduce the severe consequences and complications of DGF, several predictive models have been proposed. Irish and coworkers45,46 defined a model in 2003 and later revised in 2010, based on 18 parameters that included: recipient’s ethnicity, gender, BMI, diabetes, previous TX, preformed antibodies, pre-TX transfusions, HLA mismatches, duration of dialysis, and donor’s age, s.creat., weight, age, hypertension, causes of death, DCD, CIT, and warm ischemia time. Jeldres and Chapal47,48 proposed a model based on 5 6 parameters. In 2015, Zaza49 identified a preoperative predictive model for DGF by the analysis of pre-TX variables detected in 2755 patients transplanted between 1984 and 2012. Recipients’ characteristics at the time of TX such as age, body weight, modality, and duration of dialysis were statistically associated with DGF development. Finally, Decruyenaere et al.50 combined into a single metaanalysis model based upon the four existing predictive models and studied parameters not included in previous analyses. The main purpose of the study was to achieve a better degree of calibration without overestimating the risk of DGF. The study resulted in the identification of two relevant parameters not included in the previous models: cardiac function and preoperative blood pressure.

16.6 PROGNOSTIC IMPACT DGF has short- and long-term consequences with significant reduction of patient and graft survival.51,52 The impact on the immediate post-TX period not only prolongs hospitalization but increases morbidity and health care costs. It is well documented that DGF can induce ACR/AMR and chronic allograft dysfunction but there is not complete agreement about the role of DGF alone on graft survival because of possible unrecognized rejection or poor intrinsic graft quality.53 55 The diagnosis of rejection, often based on clinical findings rather than graft biopsies, might have led to its underestimation. Data from 2012 based on biopsy-proven ACR during DGF condition have documented a clear relationship between these complications.56 The link between DGF and ACR/AMR may have changed over time due to new IS, including the induction with Thymo, a strategy for protecting the kidney from the immunological cascade and for minimizing the nephrotoxic effects of CNI.57 As reported by several studies, there are three different pictures based on the presence or absence of DGF and rejection: DGF-ACR-; DGF 1 ACR-; and DGF 1 ACR 1 . Patient survival up to 10 years was similar in all the groups with the exception that in case of DGF 1 ACR 1 , graft survival, even at 1 year post-TX, was always significantly lower.13,51 Finally, since biopsies are performed infrequently in the early post-TX phases, it is difficult to establish the scenario of possible ACR/AMR without DGF because the majority of rejections have ATN, a basic component of DGF. DGF is particularly frequent in the ECD group, and results in higher number of premature deaths due to severe complications. In an attempt to limit the onset of DGF or ACR triggered by DGF, these recipients might receive more IS with an increased risk for lethal infections.6,10,57

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16.7 INTERVENTIONS AND APPROACHES TO THE PATIENT WITH DGF In recent years several attempts have been made to limit the incidence of DGF, especially in grafts of donors with more risk factors such as ECD, DCD, major trauma, etc. During the final phases of establishing brain death, the donor has a nonphysiological status with metabolic and inflammatory abnormalities that impact the quality of retrievable organs and compromise the recipient and graft survival. The first step for avoiding DGF is to optimize the donor’s care. Ethical and legal issues do not allow specific donor pretreatment strategies. The approaches for organ protection can be attempted only after the death and the consent for donation. Interventions have been directed to improve perfusion, to reduce CIT, to fight the oxidative damage caused by IRI, and, finally, to ameliorate the repair process. The first point of concern is that CIT is probably the most important determinant for the severity of IRI; therefore, the use of cold preservation solutions containing antioxidants and a careful hemodynamics during surgery are crucial.58 In the ECD era, an important aid comes from the possibility to use hypothermic machine perfusion (HMP). This device allows more stabilized conditions than the cold storage solution. In an animal model, after 1-hour vascular clamping, canine kidneys were stored for 24 hours and then biopsied. The kidneys stored in cold solution were available to 40% according to established biopsy criteria, as opposed to those saved in HPM, which were available to 100%.59 In humans, the incidence of DGF is less if the kidney is kept in these devices.60 The organs preserved in HMP reduce the duration of DGF with a faster drop in s.creat. during the recovery phase.61,62 The use of HMP increased 1-year ECD graft survival whereas DCD grafts did not show a statistically significant difference. The best results occur with pulsatile rather than continuous kidney perfusion flow.59 HMP allows the evaluation of the different components of the perfusion fluid and monitoring of kidney status during the time between organ procurement and TX procedure. Concerning the economic impact, the use of HMP per se entails an increase in the costs but its use saves resources by reducing DGF, primary nonfunctioning grafts, and length of hospitalization.63 Three main factors should be addressed for preventing or at least minimizing IRI: The preservation of the microcirculatory fluidity, the inhibition of oxygen radicals with antioxidants and the block of inflammatory cells.64,65 Drug regimens consisting of prostaglandin E, dopamine, and vasodilator agents able to increase nitric oxide synthesis, in addition to isovolemic hemodilution and hypertonic solutions, have been shown to also be beneficial for edema prevention.66,67 During the implantation, the incidence of DGF can be reduced by administration of mannitol, which minimizes CIT effects.68 Different antioxidant agents have been unsuccessfully tested, including N-acetylcysteine, alone or in association with vitamin C.69,70 During the TX procedure, the administration of high doses of erythropoietin showed a slight tendency to DGF reduction but this event was not statistically significant.71,72 In a recent paper, the authors analyzed by logistic regression the classic risk factors for DGF along with two novel ones, the recipient’s residual diuresis and the perioperative saline load. These two strategies resulted in an efficacious IRI prevention. The simplistic but intriguing conclusion from the study, retrospectively performed on 1784 kidney TX recipients, was that the susceptibility to rejection enhanced by IRI decreased and impacted positively patient and graft outcomes.73 Prolonged cold storage and rewarming induce stress and nutrient deprivation mainly in the renal tubular epithelium and may induce apoptosis and autophagy. However attempts focused on autophagy blockage did not seem to be protective for the development of DGF.74,75 Monoclonal antibodies against ICAM-1 or CTLA4 designed for inhibiting the interaction between neutrophils and endothelial cells and T-cell activation, have been explored with discordant results in animal models.76 78 Few preclinical studies have shown that thiazolidinediones, although designed with the purpose of enhancing glucose sensitivity and improving free fatty acid metabolism, have instead shown efficacy in reducing IRI because of downregulation of specific antiinflammatory genes in endothelial and myeloid cells. Experimental and clinical data suggest that Thymo might ameliorate IRI, and consequently reduce the incidence of DGF. The mechanisms of the effects of Thymo are multiple such as a direct block of cell cell interaction, reduction of leukocyte rolling and adhering along endothelial surface, downmodulation of adhesion molecules, reduction of inflammatory mediations and chemokine receptors.79,80,85 During the repair phases, the tubular regeneration is well documented whereas the potential regrowth of the endothelial cells is probably limited. This has generated interest in the hematopoietic progenitor cells and their ability to differentiate into mature cells of the microvascular system.87 Mesenchymal stromal cells and growth factors are still under deep investigation. However, the need for a mixture of growth elements rather than a single one and the association with tumorogenesis have limited this approach.88 There are no effective treatments for DGF; however, early diagnosis and some possible therapeutic interventions may improve the TX outcomes. Markers for detecting AKI and DGF are crucial and in continuous development but so far the only reliable diagnostic approach is sustained by the clinical findings of

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anuria, oliguria, renal dysfunction, increased RI, and the patient’s conditions. The main reason to avoid excessive ultrafiltration is to allow some degree of diuresis that will be further impaired by intravascular fluid depletion. This last condition can induce hypotension, a condition that generates low perfusion of the graft and worsens the lesions secondary to ATN. Different IS regimens have been proposed during DGF phases. In order to prevent further vasoconstriction, CNI minimization or avoidance in the early post-TX period have been studied in several trials.89 Most of these studies have reached similar conclusions and aimed Thymo or anti-IL-2 receptor antibody induction (basilixamab or the no longer available daclizumab). The literature reports very few experiences with the initial use of m-TOR inhibitors (Sirolimus and Everolimus) that despite the lack of nephrotoxicity, have been avoided because of their antifibroblastic property and consequently impaired wound healing. However, with particular interest for ECD kidneys, the m-TOR inhibitors have been revisited and utilized in combination with a short Thymo course.90

16.7.1 Center Features According to the literature, the risk for AKI increases 3% for each hour of CIT.91 Thirty-six hours is an acceptable time to prevent long-term injury.13 Some TX centers have established a policy to discard organs from marginal donors and prolonged CIT.5 The impact of CIT is more noticeable in DCD kidneys who show higher percentage of DGF.6,8,9 For these reasons, the introduction of CNI in DCD grafts should be delayed and eventually introduced at low doses after induction therapy with Thymo. The need of activating health personnel during the nighttime prolongs CIT. This situation does not increase surgical complications, but it can increase CIT and the possibility of developing DGF.92 The minimally invasive and robotic surgery reduce surgical complications and hospitalization and improve short- and long-term graft survival.93

16.7.2 Recipient Features There are some recipient features that increase the incidence of DGF3,94: these include pre-TX anuria, mannitol, hemodynamic instability and absence of diuresis during surgery, low quality of reperfusion, old age of the recipients, duration of pre-TX dialysis and obesity. This last feature is strongly linked to DGF after correction for recipient’s age, gender and years of dialysis.4 In fact a BMI greater than 30 predisposes to the development of DGF.3,57,94 Increased risks for DGF up to 8.7% are generated by each point of body BMI and also by increased triceps skinfold thickness.94,95 This link between obesity and DGF is related to a difficult and prolonged surgery. The obesity induces the rise of prothrombotic events with endothelial damage. Post-TX micro- thrombotic complications are known to increase the risk for DGF.94 Finally, in obese recipients there is an over activation of the sympathetic system and a greater renal vasoconstriction, conditions that can further increase the CNI related ischemic damage and the risk for DGF.96

16.7.3 Donor Features Donor features that increase the incidence of DGF are: Age over 60 years, s.creat. above 1.36 mg/dL, long time of CIT, causes of death, ECD and DCD, AKI, hypertension, diabetes mellitus, and arteriosclerosis.3,7,41,51,57,94 Today the use of ECD is raised by the need to find an increasing number of organs for TX. In order to minimize the incidence of DGF, the graft of donor of .60 years old requires more invasive interventions that unfortunately may result in an early post-TX mortality.57 The grafts from AKI donors have a chance to develop DGF almost double compared to SCD (68% vs 36%). However, the data of mortality and long-term graft survival collected are similar to SCD transplants. This reassures about the safety of this type of donor.51 The comparison between SCD and DCD favors the former as shown by biopsies performed pre-TX: in DCD there are more hypoxic injuries and complement activated coagulation cascade that will enhance DGF and immune response.97

16.8 CONCLUSIONS DGF is a common post-TX complication induced by immunologic and nonimmunologic events mainly related to IRI. The real incidence of DGF has to be determined because of different definitions and diagnostic criteria. Risk factors for DGF are associated with recipient’s and donor’s characteristics. In particular, for the urgent

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demand for organs, more and more marginal donors are used with a consequent impact on renal function in short- and long-term follow up. There are no effective and standardized treatments for DGF; however, an early diagnosis with novel biomarkers, procurement, and preservation techniques offer promising results.

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Aitken E, Cooper C, Dempster N, et al. Delayed graft function is a syndrome rather than a diagnosis. Exp Clin Transplant 2015;13:19 25. 11. Wang CJ, Tuffaha A, Shang D, et al. A CD3 1 count-based thymoglobulin induction regimen permits delayed introduction of calcineurin inhibitors in kidney transplantation. Clin Transplant 2012;26:900 9. 12. Murad G, Morelon E, Noel C, et al. The role of thymoglobulin induction in kidney transplantation: an update. Clin Transplant 2012;26:e450 64. 13. Ponticelli CE. The impact of cold ischemia time on renal transplant outcome. Kidney Int 2015;87:272 5. 14. Malyszko J, Lukaszyk E, Glowinska I, et al. Biomarkers of delayed graft function as a form of acute kidney injury in kidney transplantation. Sci Rep 2015;5:11684. 15. Lang P, Pardon A, Audard V. Long-term benefit of mycophenolate mofetil in renal transplantation. Transplantation 2005;79:S47 8. 16. Laskowski I, Pratschke J, Wilhelm MJ, et al. 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Perit Dial Int 2009;29 (Suppl. 2):117 22. 22. Israni AK, Li N, Cizman BB, et al. Association of donor inflammation and apoptosis-related genotypes and delayed allograft function after kidney transplantation. Am J Kidney Dis 2008;52:331 9. 23. Dabrowska-Zamojcin E, Dziedziejko V, Sadranow K, et al. Association between the CX3CR1 gene V249I polymorphism and delayed kidney allograft function. Transpl Immunol 2015;32:172 4. 24. Liang WX, Cai MJ, Jiang L, et al. Ultrasonic imaging characteristics of transplanted kidney with delayed graft function. Genet Mol Res 2014;13:6878 84. 25. Contti MM, Garcia PD, Kojima CA, et al. Quantified power Doppler as a predictor of delayed graft function after renal transplantation. Int Urol Nephrol 2015;47:405 12. 26. Grzelak P, Szymczyk K, Strzelczyk J, et al. Perfusion of kidney graft pyramids and cortex in contrast-enhanced ultrasonography in the determination of the cause of delayed graft function. Ann Transplant 2011;16:48 53. 27. Rodrigo E, Lopez-Rasines G, Ruiz JC, et al. Determinants of resistive index shortly after transplantation: independent relationship with delayed graft function. Nephron Clin Pract 2010;1113:178 86. 28. Yazici B, Yazici A, Oral A, et al. Comparison of renal transplant scintigraphy with renal resistance index for prediction of early graft dysfunction and evaluation of acute tubular necrosis and acute rejection. Clin Nucl Med 2013;38:931 5. 29. Yazici B, Oral A, Gokalp C, et al. A new quantitive index for baseline renal transplant scintigraphy with 99m Tc-DTPA in evaluation of delayed graft function and prediction of 1-year graft function. Clin Nucl Med 2015;40:548 52. 30. Obeidat MA, Luyckx VA, Grebe SO, et al. Post-transplant nuclear scans correlate with renal injury biomarkers and early allograft outcomes. Nephrol Dial Transplant 2011;26:3038 45. 31. Hueper K, Gueler F, Brasen JH, et al. Functional MRI detects perfusion impairment in renal allografts with delayed graft function. 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32. Mishra J, Dent C, Tarabishi R, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005;365:1231 8. 33. Makris K, Markou N, Evodia E, et al. Urinary neutrophil gelatinase-associated lipocalin (NGAL) as an early marker of acute kidney injury in critically ill multiple trauma patients. Clin Chem Lab Med 2009;47:79 82. 34. Bennett M, Dent CL, Ma Q, et al. Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study. Clin J Am Soc Nephrol 2008;3:665 73. 35. Hollmen ME, Kyllo¨nen LE, Merenmies J. Serum neutrophil gelatinase-associated lipocalin and recovery of kidney graft function after transplantation. BMC Nephrol 2014;15:123. 36. Bataille A, Abbas S, Semoun O, et al. Plasma neutrophil gelatinase-associated lipocalin in kidney transplantation and early renal function prediction. Transplantation 2011;92(9):1024 30. 37. Buemi A, Musuamba F, Frederic S, et al. Is plasma and urine neutrophil gelatinase-associated lipocalin (NGAL) determination in donors and recipients predictive of renal function after kidney transplantation? Clin Biochem 2014;47:68 72. 38. Van den Akker EK, Hesselink DA, Manintveld OC, et al. Neutrophil gelatinase-associated Lipocalin, but not kidney injury marker 1, correlates with duration of delayed graft function. Eur Surg Res 2015;55:319 27. 39. Hall IE, Yarlagadda SG, Coca SG, et al. IL-18 and urinary NGAL predict dialysis and graft recovery after kidney transplantation. J Am Soc Nephrol 2010;21:189 97. 40. Fonseca I, Oliveira JC, Santos J, et al. Leptin and adiponectin during the first week after kidney transplantation: biomarkers of graft dysfunction? Metabolism 2015;64:202 7. 41. Pribylova-Hribova P, Kotsch K, Lodererova A, et al. TGF-β1 mRNA upregulation influences chronic renal allograft dysfunction. Kidney Int 2006;69:1872 9. 42. Guerrieri D, Re L, Petroni J, et al. Gene expression profile in delay graft function: inflammatory markers are associated with recipient and donor risk factor. Mediators Inflamm 2014;167361. 43. Kwiatkowska E, Domanski L, Kloda K, et al. IL2-IL21 gene cluster polymorphism is not associated with allograft function after kidney transplantation. Nephrology 2014;46:2415 20. 44. Castellano G, Intini A, Stasi A, et al. Complement modulation of anti-aging factor Klotho in ischemia/reperfusion injury and delayed graft function. Am J Transplant 2015. Available from: http://dx.doi.org/10.1111/ajt.13415. 45. Irish WD, McCollum DA, Tesi RJ, et al. Normogram for predicting the likelihood of delayed graft function in adult cadaveric renal transplant recipients. J Am Soc Nephrol 2003;14(11):2967 74. 46. Irish WD, Ilsley JN, Schnitzler MA, et al. A risk prediction model for delayed graft function in the current era of deceased donor renal transplantation. Am J Transplant 2010;10(10):2279 86. 47. Jeldres C, Cardinal H, Duclos A, et al. Prediction of delayed graft function after renal transplantation. Can Urol Assoc J 2009;3(5):377 82. 48. Chapal M, Le Borgne F, Legendre C, et al. A useful scoring system for the prediction and management of delayed graft function following kidney transplantation from cadaveric donors. Kidney Int 2014;86(6):1130 9. 49. Zaza G, Ferraro PM, Tessari G, et al. Predictive model for delayed graft function based on easily available pre-renal transplant variables. Intern Emerg Med 2015;10(2):135 41. 50. Decruyenaere A, Decruyenaere P, Peeters P, et al. Validation in a single-center cohort of existing predictive models for delayed graft function after kidney transplantation. Ann Transplant 2015;20:544 52. 51. Molina M, Apaza J, Gonzalez ME, et al. Results of kidney transplantation from deceased donors with acute kidney injury. Transplant Proc 2015;47:42 4. 52. Almond PS, Troppmann C, Escobar F, et al. Economic impact of delayed graft function in cadaveric renal transplantation. Transplant Proc 1991;23:1304. 53. Rosenthal JT, Danatovich GM, Wilkinson A, et al. The high costs of delayed graft function in cadaveric renal transplantation. Transplantation 1991;51:1115 18. 54. Raimundo M, Guerra J, Teixeira C, et al. Intermediate early graft function is associated with increased incidence of graft loss and worse long-term graft function in kidney transplantation. Transplant Proc 2013;45:1070 2. 55. Wu WK, Famure O, Li Y, et al. Delayed graft function and the risk of acute rejection in the modern era of kidney transplantation. Kidney Int 2015;88:851 8. 56. Requia˜o-Moura LR, Ferraz E, Matos AC, et al. Comparison of long-term effect of thymoglobulin treatment in patients with a high risk of delayed graft function. Transplant Proc 2012;44:2428 33. 57. Tanrisev M, Ho¸sco¸skun C, A¸sc¸ G, et al. Long-term outcome of kidney transplantation from elderly living and expanded criteria deceased donor. Ren Fail 2015;37:249 53. 58. Andrews PM, Cooper M, Verbesey J, et al. Mannitol infusion within 15 min of cross-clamp improves living donor kidney preservation. Transplantation 2014;98:893 7. 59. Lindell LS, Muir H, Brassil J, et al. Hypothermic machine perfusion preservation of the DCD kidney: machine effects. J Transplant 2013;802618. 60. Forde JC, Shields WP, Azhar M, et al. Single centre experience of hypothermic machine perfusion of kidneys from extended criteria deceased heart-beating donors: a comparative study. Ir J Med Sci 2014;14(4):109 12. 61. Burgos Revilla FJ, Hevia V, Diex V, et al. Machine perfusion: initial results in an expanded criteria donor kidney transplant program. Transpl Proc 2015;47:19 22. 62. Oliver E, Lopez-Delgado JC, Gil-Vernet S, et al. Machine perfusion for preservation of kidneys from expanded criteria donors after brain death improves transplantation results. Org Tiss Cells 2013;16:99 105. 63. Go´mez V, Galeano C, Diez V, et al. Economic impact of the introduction of machine perfusion preservation in a kidney transplantation program in the expanded donor era: cost-effectiveness assessment. Transplant Proc 2012;44:2521 4. 64. Aydin Z, van Zonneveld AJ, de Fijter JW, et al. New horizons in prevention and treatment of ischaemic injury to kidney transplants. Nephrol Dial Transplant 2007;22:342 6.

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65. Yates PJ, Hosgood SA, Nicholson ML. A biphasic response to nitric oxide donation in an ex vivo model of donation after cardiac death renal transplantation. J Surg Res 2012;175:316 21. 66. Brauer RB, Marx T, Ulm K, et al. Effect of perioperative administration of a drug regimen on the primary function of human renal allografts. Transplant Proc 2010;42:1523 5. 67. McCune TR, Wombolt DG, Whelan TV, et al. Vasodilatation vs. immunotherapy to prevent delayed graft function: delayed graft function as an indication of immune activation. Int Immunopharmacol 2005;5:85 92. 68. Andrews PM, Cooper M, Verbesey J, et al. Mannitol infusion within 15 min of cross-clamp improves living donor kidney preservation. Transplantation 2015;98:893 7. 69. Orban JC, Quintard H, Cassuto E, et al. Effect of N-acetylcysteine pretreatment of deceased organ donors on renal allograft function: a randomized control trial. Transplantation 2015;99:746 53. 70. Sahraei Z, Salamzadeh J, Nafar M. Effect of N-acetylcysteine and vitamin C on kidney allograft function biomarkers interleukin-18 and neutrophil gelatinase-associated lipocalin. Transplantation 2015;9:56 62. 71. Coupes B, de Freitas DG, Roberts SA, et al. rhErythropoietin-b as a tissue protective agent in kidney transplantation: a pilot randomized controlled trial. BMC Res Notes 2015;8:21. 72. Xin H, Ge YZ, Wu R, et al. Effect of high-dose erythropoietin on graft function after kidney transplantation: a meta-analysis of randomized controlled trials. Biomed Pharmacother 2015;96:29 33. 73. Chaumont M, Racape´ J, Broeders N, et al. Delayed graft function in kidney transplants: time evolution, role of acute rejection, risk factors, and impact on patient and graft outcome. J Transplant 2015;163757. 74. Jain S, Keys D, Nydam T, et al. Inhibition of autophagy increases apoptosis during re-warming after cold storage in renal tubular epithelial cells. Transpl Int 2014;28:214 23. 75. Salahudeen AK, Joshi M, Jenkins JK, et al. Apoptosis versus necrosis during cold storage and rewarming of human renal proximal tubular cells. Transplantation 2001;72(5):798 804. 76. Kelly KJ, Williams Jr. WW, Colvin RB, et al. Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. J Clin Invest 1996;97(4):1056 63. 77. Ichikawa H, Flores S, Kvietys PR, et al. Molecular mechanisms of anoxia/reoxygenation-induced neutrophil adherence to cultured endothelial cells. Circul Res 1997;81:922 31. 78. Aydin Z, van Zonneveld AJ, de Fijter JW, et al. New horizons in prevention and treatment of ischaemic injury to kidney transplants. Nephrol Dial Transplant 2007;22(2):342 6. 79. Pre´ville X, Flacher M, LeMauff B, et al. Mechanisms involved in antithymocyte globulin immunosuppressive activity in a nonhuman primate model. Transplantation 2001;71:460 8. 80. Beiras-Fernandez A, Thein E, Chappel D, et al. Polyclonal anti-thymocyte globulins influence apoptosis in reperfused tissues after ischaemia in a non-human primate model. Transpl Int 2004;17:453 7. 81. Goggins WC, Pascual MA, Powelson JA, et al. A prospective, randomized, clinical trial of intraoperative versus postoperative Thymoglobulin in adult cadaveric renal transplant recipients. Transplantation 2003;76:798 802. 82. Cravedi P, Codreanu I, Satta A, et al. Cyclosporine prolongs delayed graft function in kidney transplantation: are rabbit anti-human thymocyte globulins the answer? Nephron Clin Pract 2005;101:c65 71. 83. Chappell D, Beiras-Fernandez A, Hammer C, et al. In vivo visualization of the effect of polyclonal antithymocyte globulins on the microcirculation after ischemia/reperfusion in a primate model. Transplantation 2006;81:552 8. 84. Aydin Z, van Zonneveld AJ, de Fijter JW, et al. New horizons in prevention and treatment of ischaemic injury to kidney transplants. Nephrol Dial Transplant 2007;22:342 6. 85. Mehrabi A, Mood Zh A, Sadeghi M, et al. Thymoglobulin and ischemia reperfusion injury in kidney and liver transplantation. Nephrol Dial Transplant 2007;22(Suppl. 8):viii54 60. 86. Patel SJ, Duhart Jr BT, Krauss AG, et al. Risk factors and consequences of delayed graft function in deceased donor renal transplant patients receiving antithymocyte globulin induction. Transplantation 2008;86:313 20. 87. Rabelink TJ, de Boer HC, de Koning EJ, et al. Endothelial progenitor cells: more than an inflammatory response. Arterioscler Thromb Vasc Biol 2004;24(5):834 8. 88. Devarajan P. Has HGF met other partners? Met-independent epithelial morphogenesis induced by HGF. focus on “Hepatocyte growth factor induces MDCK cell morphogenesis without causing loss of tight junction functional integrity.” Am J Physiol Cell Physiol 2004;286(3): C475 7. 89. House AA, Nguan CY, Luke PP, et al. Sirolimus use in recipients of expanded criteria donor kidneys. Drugs 2008;68(Suppl. 1):41 9. 90. Tahir W, Hakeem A, Dawrant M, et al. Early sirolimus conversion as rescue therapy in kidneys with prolonged delayed graft function in deceased donor renal transplant. Transplant Proc 2015;47(6):1610 15. 91. Frei U, Noeldeke J, Machold-Fabrizii V, et al. Prospective age-matching in elderly kidney transplant recipients--a 5-year analysis of the Eurotransplant Senior Program. Am J Transplant 2008;8(1):50 7. 92. Fockens MM, Alberts VP, Bemelman FJ, et al. Renal transplantation at night. Ned Tijdschr Geneeskd 2014;158:a7779. 93. Sood A, Ghosh P, Jeong W, et al. Minimally invasive kidney transplantation: perioperative considerations and key 6-month outcomes. Transplantation 2015;99(2):316 23. 94. Tsirigoti L, Kontogianni MD, Darema M, et al. Exploring associations between anthropometric indices and graft function in patients receiving renal transplant. J Hum Nutr Diet 2014. Available from: http://dx.doi.org/10.1111/jhn.12289. 95. Weissenbacher A, Jara M, Ulmer H, et al. Recipient and donor body mass index as important risk factors for delayed graft function. Transplantation 2012;93:524 9. 96. Lambert E, Sari CI, Dawood T, et al. Sympathetic nervous system activity is associated with obesity-induced subclinical organ damage in young adults. Am J Kidney Dis 2010;54:1043 51. 97. Damman J, Bloks VW, Daha MR, et al. Hypoxia and complement-and-coagulation pathways in the deceased organ donor as the major target for intervention to improve renal allograft outcome. Transplantation 2014;99(6):1293 300.

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C H A P T E R

17 Histocompatibility Testing in the Transplant Setting Michael D. Gautreaux Wake Forest School of Medicine, Winston-Salem, NC, United States

17.1 INTRODUCTION There are two basic systems of defense that animals use against pathogens or invaders: innate and adaptive. Innate defenses, as the name suggests, are defenses one is born with. Innate immune responses are not specific to a particular pathogen. Innate immunity includes external barriers (e.g., intact skin, mucus membranes), secretory components (e.g., enzymes, histamine, oxygen radicals, etc.), and certain leukocytes (such as phagocytes, NK cells, platelets). A hallmark of innate immunity is that there is no increase in strength after exposure. Innate immune responses have been found among both vertebrates and invertebrates, as well as in plants, and the basic mechanisms that regulate them are conserved.1 Adaptive immunity, also known as acquired immunity, is generally referred to as the “immune system.”2 The adaptive immune system is composed of highly specialized cells and processes that eliminate or prevent pathogen growth. In addition, the adaptive immune system can potentiate the effects of certain parts of the innate immune system. The adaptive immune system performs three basic functions: (1) to discriminate between “self” and “nonself”; (2) generate a specific response to what is perceived as nonself antigens and facilitate the clearance of such antigens; and (3) develop specific memory to such antigens to facilitate a quicker and greater response to such antigens in the future. The pioneering work of Medawar3 demonstrated that rejection to transplants is a form of adaptive immunity. Two factors play a strong role in the speed in which rejection occurs: The degree of presensitization and the magnitude of the HLA mismatch between a donor and recipient. Mostly for historical reasons, graft rejection is usually classified on the basis of histopathology or time after transplant, rather than immune effector mechanisms. Subsequent research and clinical experience have shown three patterns of rejection based on clinical presentation and histological criteria. These types of rejection are hyperacute, acute, and chronic; each will be discussed separately in the following sections.

17.2 TYPES OF REJECTION 17.2.1 Hyperacute Rejection Hyperacute rejection is characterized by rapid endothelial cell disruption, platelet margination, complement activation, and thrombotic occlusion of the graft vasculature within minutes of vascular anastomosis. Hyperacute rejection is the only form of rejection that is exclusively mediated by a humoral mechanism, the remaining forms of rejection appear to have both cellular and humoral components. Preformed antibodies to histocompatibility antigens bind to the graft’s endothelial cells and activate complement causing endothelial cell injury.4 This

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process exposes subendothelial basement membrane proteins that activate platelets. As a result of these processes the organ suffers irreversible ischemic damage. Hyperacute rejection has been virtually eliminated in kidney transplantation because of the prospective crossmatch test. Prospective crossmatches are not the norm outside of the renal transplant setting because of the short ideal preservation time for hearts, lungs, and livers. Most crossmatches for these organs are done retrospectively. As a result, there are cases in which a transplant occurs across a positive crossmatch. Hyperacute rejection of a heart is extremely rare; however, it has been documented.5 More common, however, is significantly lower 1-year survival of a heart transplanted across a positive crossmatch.5,6

17.2.2 Acute Rejection Accelerated rejection and acute rejection are different names for the same basic process. The only difference between the two is the time of onset after the transplant has occurred. Accelerated rejection is said to occur within a week or two after transplant (sometimes as long as 1 month), and acute rejection is said to occur 2 weeks to several months after transplant. For the sake of simplicity, both types will be referred to as acute rejection. Acute rejection, from an effector standpoint, can actually happen at any time after a transplant and is considered an active immune response to the graft. Acute rejection can have humoral and/or cellular mechanisms of action.7,8 Acute humoral rejection is characterized by necrosis of graft endothelial cells. The histologic pattern is one of vasculitis rather than massive vascular thrombosis seen with hyperacute rejection. A more accurate name for this process is acute vascular rejection because the vascular endothelium is destroyed, primarily by antibody-mediated mechanisms. Lymphocytes (especially donor-specific CD8 1 T-cells) also appear to directly kill endothelial cells and, in addition, provide cytokines to stimulate inflammatory responses (primarily CD-4 1 T-cell mediated). Acute cellular rejection is mediated by lymphocytes and macrophages infiltrating into the parenchyma and lysing the parenchymal cells. The infiltrating lymphocytes are T-cells and NK cells. The recognition of donor HLA markers by alloreactive CD8 1 T-cells appears to be the most important mechanism in acute cellular rejection. This conclusion is supported by the finding that CD8 1 T-cells predominate in cellular infiltrates and by the knowledge that most graft vascular and parenchymal cells express class I HLA, which is recognized by CD8 1 T-cells; however, they are usually resistant to killing by NK cells and macrophages. Animal studies have demonstrated that adoptive transfer of cytotoxic T-cells (CD8 1 ) can eliminate tumor grafts.9 The realization that antibodies and CTLs are the primary effectors in the acute graft rejection response has led to the idea that this process is similar to the immune response to viruses. This is in contrast to the idea that chronic rejection (discussed in the next section) represents a variant of the wound healing process. The potential mechanisms by which the immune system can recognize foreign HLA will be discussed in the following.

17.2.3 Chronic Rejection Chronic rejection is a much more insidious process than acute rejection. The damage from chronic rejection slowly compromises organ function through two pathways: Parenchymal remodeling with fibrosis and graft vascular disease. Patchy interstitial inflammation can give way to fibrosis and parenchymal injury. The fibrosis seen with chronic rejection may represent wound healing following cellular necrosis due to acute rejection. Indeed, the incidence of chronic rejection is increased following severe or persistent acute rejection, perhaps due to insufficient or ineffective immunosuppression.10 The most common histologic manifestation of chronic rejection in heart and kidneys is a progressive narrowing of the graft’s arteries. This is referred to as obliterative arteriopathy (OA). OA can be likened to an accelerated form of atherosclerosis. In this form of chronic rejection, the vascular lumen is replaced by an accumulation of smooth muscle cells and connective tissue.11,12 This predisposes the graft to chronic ischemic damage and infarction. In lung allografts, destruction of the small bronchioles, termed obliterative bronchiolitis (OB), is the major manifestation of chronic rejection, while vascular disease is thought to be of lesser importance.13 Chronic rejection can begin within weeks to months after transplantation. Indeed, chronic and acute rejection can be occurring within the same graft at the same time. In general, the incidence of chronic rejection increases with time after rejection and, with the notable exception of the liver,14 eventually afflicts a majority of solid organ allografts. By 5 years posttransplant, chronic rejection affects up to 80% of lung transplants,15,16 60% of heart transplants,17 50% of kidney transplants,18 but only about 10% of liver allografts.19

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17.3 HISTOCOMPATIBILITY TESTING The goal of histocompatibility testing is to ensure that the transplanted organ remains viable in the recipient for the longest period of time. Three sets of tests are performed to accomplish this goal. The first is determining the human leukocyte antigen (HLA) types of the patient and donor. The second is determining the presence and identity of any anti-HLA antibodies by testing against a reference cell panel, otherwise known as panel-reactive antibody or panel-reactive antibody (PRA) testing. Lastly, donor-specific antibody response is measured in the crossmatch assay.

17.3.1 HLA Typing For transplantation, it is recommended that HLA typing and, more importantly, antibody testing be performed on all patients prior to transplant. Time constraints make a pretransplant crossmatch impractical for most heart and liver cases. The maximum preservation time for a kidney is 24 36 hours; whereas, the ideal preservation time for a heart is 4 6 hours, a liver 8 12 hours, and pancreas 12 18 hours.20 Unless there are sufficient reasons to believe a patient may have a positive crossmatch, such as a high PRA or identified antibody specificity, the crossmatch is usually performed retrospectively. These considerations will be addressed below. HLA matching is one of the major considerations for allocating kidneys from deceased donors. The stringent time constraints and lack of computerized algorithms from UNOS mean that HLA matching is not usually a consideration for either heart or liver allocation. However, several publications suggest that there may be sufficient benefits of HLA matching to warrant its consideration.21 26 17.3.1.1 HLA Typing Methods 17.3.1.1.1 Complement-Dependent Cytotoxicity Complement-dependent cytotoxicity (CDC) had been the predominant form of HLA testing until it was supplanted by molecular or DNA typing (discussed in the following). CDC or serological typing relies on HLAspecific antibodies, from characterized alloantisera or monoclonal antibodies, binding to the HLA molecules expressed on the surface of patient or donor cells. Complement is added to the reactions and if specific antibodies are bound on the cells the complement cascade is initiated and cell death occurs. Special stains are added to identify dead cells from live cells and the cells are visualized microscopically. The percentage of cell death in each reaction is noted and each well given a score. Multiple reactions are analyzed to determine a patient or donor’s phenotype. Indeed, for one complete HLA typing, 300 individual reactions or more may be analyzed in order to assign an HLA phenotype.27 The CDC typing test relies on allospecific antisera or monoclonal antibodies, which permit identification of HLA-A, HLA-B, and HLA-DR antigens recognized by the World Health Organization. If possible, private (split) specificities should be differentiated from public (broad) specificities. By way of example, A9 is considered a broad antigen. As better-defined antisera became available, it was realized that two separate antigens were recognized by the original anti-A9 antisera. These new specificities, A23 and A24, are considered private specificities. Fig. 17.1 gives an overview of the CDC tests. Peripheral blood lymphocytes are separated into T-cell and Bcell-enriched fractions. In the case of the figure, superparamagnetic beads with pertinent monoclonal antibodies to either T-cell antigens or B-cell antigens are incubated with the buffy coat of a peripheral blood prep or a single-cell suspension derived from a peripheral lymph node or a piece of spleen. Once magnetically separated into either T-cells or B-cells, the cells are incubated with antisera with precharacterized antisera to various HLA specificities. Depending on the laboratory protocol, the cells/sera are then washed with buffer and then incubated with rabbit complement. A vital dye preparation is added (in the case of the figure acridine orange for green, denoting viable cells, and ethidium bromide to stain dead cells red). Each well is visualized and independently scored utilizing the ASHI scoring system (Fig. 17.2).28 The percentages of cell death are estimated and a score given appropriately. An example of a scoring sheet is given in Table 17.1. 17.3.1.1.2 Molecular Typing Molecular or DNA-based typing allows for the identification of HLA types independent of expression on the cell surface. Most molecular HLA typing procedures rely, in whole or part, on the polymerase chain reaction (PCR) process. The three most common forms of molecular HLA typing are sequence-specific primer (SSP) test, the sequence-specific oligonucleotide probe (SSOP) process, and the sequence-based typing (SBT) test.

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FIGURE 17.1 Schematic of a CDC-based HLA typing utilizing magnetic beads.

FIGURE 17.2 Diagram of the ASHI scoring system for CDC-based testing.

DNA-based typing has several benefits when compared to serological based typing: Less blood is required, viable cells are not essential, there is less cost, and the typing process can be performed faster because of greater reliability. An excellent primer for molecular typing for HLA typing purposes is “DNA Methods for HLA Typing: A Workbook for Beginners.”29 SSP relies on amplification of specific regions of the HLA molecule after binding of a specific piece of DNA as an initiator of DNA replication (Fig. 17.3).30 Once the DNA is amplified, an agarose gel is run with a special stain, such as ethidium bromide, in order to determine if a specific primer amplified the patient’s input DNA. If amplification has occurred, then the patient’s DNA reacted with the specific primers in a particular well. The reactivity of a particular set of primers in a well is scored as positive, negative, or no reaction (Fig. 17.4). The reaction pattern of the various sets of primers is then interpreted to provide the final typing. Recently, a modified form of SSP has gained a considerable following. Real-time or quantitative PCR, utilizes specific primers to amplify DNA with specific sequences. However, instead of relying upon gel electrophoresis for readout, fluorescent dyes are intercalated into the amplified DNA. Upon completion of amplification, a specialized melting curve is generated and the release of the fluorescent dye at a specific temperature, under controlled conditions, indicates the presence or absence of specific amplification.31

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TABLE 17.1 Scoring Sheet for CDC-Based HLA Testing Well

Specificity

Reaction

1A

Positive control

8

1B

Negative control

1

1C

A1

1

1D

A1,36

1

1E

A1,36,80

1

1F

A2

8

2F

A2

8

2E

A3

8

2D

A3

8

2C

A23,24

1

2B

A23

1

2A

A24

1

3A

A25,26,34,11

1

3B

A25,26

1

3C

A26

1

3D

A11

1

3E

A68,69

4

3F

A68,69,33,34

2

4F

A29

1

4E

A30

1

4D

A30,31

1

4C

A30,31

1

4B

A32

1

4A

A32,25,26,34,43

1

5A

A33,34

1

5B

A34

1

5C

B51,52

1

5D

B51,7801

1

5E

B7,8101

1

5F

B7,8101

1

6F

B8

1

6E

B8

1

6D

B44,45

1

6C

B44

1

6B

B45

1

7B

B64,65

1

7C

B64,65

1 (Continued)

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TABLE 17.1 (Continued) Well

Specificity

Reaction

7D

B62,63,75

8

7E

B62,63,75

8

7F

B62

8

8F

B38,39

1

8E

B38

1

8D

B39

1

8C

B57,58

1

8B

B57

1

8A

B18

8

9A

B18

8

9B

B49,50

1

9C

B49

1

9D

B54,55,56,42

1

9E

B55,42

1

9F

B56

1

10F

B27

1

10E

B27

2

10D

B35

1

10C

B35,53

1

10B

B51,52,53

1

10A

B37

1

11A

B60,61,48

1

11B

B60

1

11C

B41,42

1

11D

B42

1

11E

B70,62,50,35

1

11F

B70,35,50,75,56

1

12F

Bw4

1

12E

Bw6

8

12D

Cw1

1

12C

Cw2

8

12B

Cw3

8

12A

Cw4

8

SSOP relies on a specific piece of DNA that is labeled to act as a specific detector or probe for a particular HLA sequence.32 Similar to SSP, sequences of DNA specific to particular HLA types are utilized. However, instead of utilizing the specific sequence to initiate DNA amplification, the specific DNA is labeled with a particular compound and then allowed to bind to the DNA. The DNA sequence is used to probe the patient’s DNA. The pattern of reactivity for a series of probes is then interpreted to provide the HLA typing.

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FIGURE 17.3

Schematic of PCR-based HLA typing utilizing DNA primers.

FIGURE 17.4

A ethidium-bromide stained gel along with a legend to show how individual wells are to be considered negative or

positive.

SBT relies on DNA sequencing technology to determine the unique sequence of base pairs in a particular HLA allele.33 The input DNA is amplified with locus-specific primers. Then that DNA is used as a template for sequencing reactions with dye labeled dideoxynucleotides. The termination of the elongating DNA chain by the specific dideoxynucleotide provides the sequence by size separation through a capillary gel electrophoresis. The sequence from the reaction is then compared with an HLA sequence database in order to assign the HLA type. The level of typing resolution is not usually necessary for solid organ transplantation. However, the potential for allele-specific antibodies could necessitate knowing a patient and/or donor’s high-resolution HLA typing. The demand for high throughput and low cost has fueled a new method of sequencing DNA sequences, called next generation sequencing,34 which holds promise for making high-resolution HLA typing become the norm for all solid organ patients. Outside the cost of acquiring the next generation sequencers, the costs of actually performing the HLA typing are poised to drop to previously unimaginable levels.

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17.3.1.2 Specimen Requirements Individual laboratories may have their own preferred set of requirements for serological or molecular HLA typing and it is best to check an institution’s HLA laboratory to determine its requirements. The suggestions in this section reflect the general consensus of the HLA community. Complete serological HLA typing (HLA-A, B, and DR) generally requires 30 mL of anticoagulated blood. The anticoagulants of choice are acid citrate dextrose (ACD; yellow-top Vacutainer tubes) or sodium heparin (green-top Vacutainer tubes). The use of lithium heparin is strongly discouraged because of problems with cell viability and purity. Samples for serological typing must be kept at room temperature and should be delivered to the HLA laboratory as rapidly as possible. In general, these samples maintain useful viability for 12 24 hours with sodium heparin and 24 72 hours with ACD. HLA typing on donors can be performed on whole blood, lymph nodes, or spleen sections. Occasionally, whole blood may not be the optimal specimen due to the adverse effects of steroids and blood transfusions. For lymph nodes and spleens, it is imperative that these tissues not be placed in any type of fixative. It is recommended that 2 or 3 lymph nodes and a piece of spleen at least 2 cm2 be provided to the HLA lab for testing. More lymph nodes and spleen would be beneficial if the organ is exported to another center to allow for confirmation typing and crossmatching at that location. Donor tissue specimens should be placed in a complete tissue culture medium such as RPMI 1640. Saline and Ringer’s lactate are not complete media. Check with an HLA lab to determine its recommendation. Molecular HLA typing usually requires much less volume of sample than serological typing. Generally, a single 10-mL tube of anticoagulated blood is sufficient. The anticoagulants of choice for DNA typing are ACD (yellow-top Vacutainer tube) and EDTA (lavender-top Vacutainer tube). Once again, this is a guideline. 17.3.1.3 Interpretation HLA types are assigned based on the reactivities of the specific antisera in the CDC method or specific DNA sequences in the molecular assay. Since HLA antigens are codominantly expressed, the goal is to detect two antigens or alleles each for HLA-A, HLA-B, and HLA-DR. If only one antigen or allele is identified for a particular locus, it is designated as a blank. Blanks usually represent homozygosity at the particular locus but such homozygosity can only be proven by performing typings on additional family members to determine haplotype inheritance patterns. A blank can also indicate expression of a particular allele that is not identifiable by current technology. Current guidelines recommend that a patient be retyped every 5 years if any of their HLA loci have a blank locus or if they possess an antigen that can be split with more current tissue typing procedures.

17.3.2 Serum Screening for HLA Antibodies The purpose of PRA screening is twofold. The first consideration is to determine the likelihood of a patient having a positive crossmatch with a random donor, i.e., a predictor of crossmatch compatibility. This is the reason that a percent score is given with antibody screening, e.g., a patient with a 5% PRA will likely have a positive crossmatch with 5% of the potential donors. The second, and more important, consideration for antibody screening is determination of the specificity of any alloreactive antibodies directed against particular HLA antigens. Federal regulations require a prospective crossmatch, whenever medically possible, for presensitized transplant recipients regardless of organ.35 Since serum screening is strongly recommended with the initial patient typing, the results of the serum screen may necessitate a prospective crossmatch in a cardiac transplant setting. The American Society of Histocompatibility and Immunogenetics (ASHI), the accrediting body for HLA laboratories, sets the definition of sensitized patient as having a greater than 15% PRA or having an identified allospecific antibody.36 UNOS standards reflect ASHI standards in the area of histocompatibility although transplant centers may have a certain amount of latitude in the definition of a “sensitized” patient. 17.3.2.1 Serum Screening Methods 17.3.2.1.1 Standard Panel Testing The patient’s sera are tested against a panel of lymphocytes from individuals whose HLA phenotypes have been predetermined. Ideally, the panel provides a spectrum of HLA antigens that are representative of the local population. Panels may be made by an individual laboratory from freshly isolated lymphocytes, frozen lymphocytes, or purchased from commercial sources. The use of frozen cells or commercially prepared panels eliminates the great concentration of personnel resources required to utilize fresh lymphocytes within the limited span of

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viability of these cells. Whatever the source of the panel lymphocytes, the actual assay is performed by the CDC process, in a manner very similar to the complement-based HLA typing described previously. 17.3.2.1.2 Solid-Phase Microarrays Solid-phase microarrays, better known as Luminex, serum screening utilizes solubilized and purified HLA antigens bound to a solid support, a microsphere. The purified HLA proteins serve as targets for HLA-specific antibodies that may exist in a patient’s serum. The presence of anti-HLA antibodies is detected by antihuman IgG conjugated to the fluorochrome FITC. A colorless substrate for the enzyme is added and a colored product develops if the antibody/enzyme complex is present. The absorbance of the colored product is then measured spectrophotometrically. The microspheres themselves have two dyes, a red dye and an infrared dye, at varying concentrations that allow for discrimination of the individual beads. Usually, a result is considered positive if the MFI of the FITC reading is above a cut-off value determined by the laboratory’s parameters. Solid-phase microarray serum screening offers several advantages over cell panel screening. First, the solidphase microarray is not dependent on viability of lymphocytes. Fresh lymphocytes maintain viability up to 72 hours and frozen lymphocytes may have lower viability because of the freezing and thawing process. The second and perhaps most important advantage is that only antibodies against HLA antigens are detected. Autolymphocytotoxic antibodies, which cause false positive reactions in the cell panel test and could subsequently confound the interpretation of such tests, do not react in the solid-phase microarrays system. 17.3.2.2 Specimen Requirements Serum derived from clotted whole blood is the specimen of choice for all antibody screening methods. It is vitally important that the specimen be collected in a plain tube with no additives (plain red-top Vacutainer tube). Specimen tubes with clot activators and serum separators are unacceptable because the additives can interfere with the serum screen assay. The serum from a full-draw 10-mL tube of clotted blood is sufficient for the serum screen assays. If a patient has a potential sensitizing event, such as a blood transfusion, it is best to wait 2 weeks from such an event prior to drawing a sample to allow for detection of any new anti-HLA specificities. 17.3.2.3 Interpretation A negative PRA test is indicative of a lack of anti-HLA antibodies. A positive result may indicate the presence of anti-HLA antibodies. Studies have demonstrated that sensitized patients have poorer outcomes in transplant when compared to unsensitized patients. In one study of 120 heart transplant patients, a PRA of 25% or greater was associated with a poorer outcome even in the presence of a negative crossmatch.33 In another study, patients with a T-cell PRA or a B-cell PRA greater than 11% had significantly poorer 3-year survival than patients with a PRA of less than 11%.37 Care must be taken in standard panel testing to determine if the antibodies present are anti-HLA in nature. Certain patients can develop autolymphocytotoxic antibodies that are usually of the IgM isotype. These react most often with B-cells, and are considered harmless to most kidney grafts.38 The best way to determine if a patient has an autoantibody is to perform an autocrossmatch. Some labs prefer to perform this at the time of the patient’s initial typing workup, while other labs perform autocrossmatches at the time of final crossmatch. Autoantibodies are not a problem with ELISA and the microarray serum screenings because these assays only have purified HLA antigens with which the serum may react. IgM antibodies directed against HLA have been demonstrated and are suspected of being harmful to a graft but there is little direct evidence to substantiate that fact.39 The serum screen assay allows the transplant team to determine if a prospective crossmatch is necessary. The crossmatch assay will be discussed in the next section. A PRA in excess of 15% indicates that a patient may have developed an anti-HLA antibody and is therefore considered sensitized. The serum screen may also determine if a patient has developed an antibody to a particular HLA antigen. If the medical situation allows, the safest course seems to be avoiding a transplant with a heart bearing a particular HLA antigen to which the potential recipient has been sensitized.

17.3.3 Crossmatching Because of the time constraints involved with both liver and cardiac transplantation, it is often necessary to perform such a transplant before the results of a crossmatch are known. As mentioned previously, a sensitized patient must have a prospective crossmatch prior to receiving any transplant, if medical circumstances permit.

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Crossmatch testing detects the presence of antibodies in the recipient that react specifically with the tissue of the donor. A positive crossmatch does not appear to directly lead to hyperacute rejection in the cardiac and liver transplant settings as it does in the renal setting, although cases of hyperacute rejection have been documented in both.40 42 More commonly, the presence of preformed donor-specific antibodies appears to lead to a dramatically lessened 1-year survival. Several studies have shown that a positive T-cell crossmatch can lead to a dramatically poorer clinical outcome. One study reported a 1-year survival rate of 73% when the crossmatch was negative but when the B-cell crossmatch was positive the survival rate was 62%. More significantly, when the T-cell crossmatch was positive the 1-year survival rate was 28%.43 Another study touched on the potential importance of positive B-cell crossmatches. In this study, about 9% of the patients with a negative T-cell crossmatch and a positive B-cell crossmatch were found to have an increased frequency of severe rejection when compared to crossmatch negative controls.44 The study did not focus on whether the antibodies were directed against HLA class I or HLA class II. In another report, the frequency of positive crossmatches in patients undergoing retransplantation was eightfold higher than the controls.45 It is important to determine the isotype of the antibody in the case of positive crossmatches since positive crossmatches caused by IgM antibodies have not been found to alter the outcome of cardiac transplantations.46 17.3.3.1 Crossmatch Methods 17.3.3.1.1 Complement-Dependent Cytotoxicity Crossmatch The standard crossmatch procedure is a CDC assay that detects the presence of antibodies in the recipient to antigens in donor lymphocyte preparations. There are many variations of this test depending on the target lymphocyte preparation, extension of incubation times, inclusion of wash steps, or utilization of antiglobulin reagents. The basic cytotoxicity crossmatch, called the NIH crossmatch because of its description by the NIH, consists of a 30-minute incubation with the serum followed by the addition of complement and an additional 60minute incubation. This is considered to be the least sensitive of the CDC crossmatch techniques. ASHI and UNOS guidelines require a crossmatch test that is more sensitive than the basic NIH crossmatch. Several modifications of the CDC crossmatch allow for greater sensitivity. Perhaps the simplest modification is the NIH extended technique, which calls for extended incubation time (120 minutes vs 60 minutes) after the addition of complement. The Amos modified crossmatch calls for the introduction of a wash step or steps prior to the addition of complement to wash away anticomplementary factors that may be present in the patient’s serum. Antiglobulin techniques call for several wash steps after the serum incubation followed by the addition of antihuman globulin (AHG; usually antikappa light chain antibody) and complement. Antiglobulin crossmatches are useful for identifying weak antibodies or anti-HLA antibodies of an isotype that does not fix complement. Another important consideration is the lymphocyte preparation that is used for the target of the crossmatch. The lymphocytes used as targets for the crossmatch can be an unseparated lymphocyte preparation containing both T-cells and B-cells or separate T-cell-enriched or B-cell-enriched preparations. Use of a separated T-cell or B-cell crossmatch may be more informative in determining the significance of a possible positive crossmatch. 17.3.3.1.2 Flow-Cytometric Crossmatch As mentioned in the serum screen section, flow-cytometric crossmatching is now considered to be the most sensitive type of crossmatch available. The flow-cytometric crossmatch relies on indirect immunofluorescence to detect the presence of antidonor antibodies in the serum of a potential recipient. With appropriate reagents, the flow-cytometric crossmatch can detect the presence of antibodies directed against donor T-cells or B-cells and the isotype of the reacting antibody.47 17.3.3.2 Specimen Requirements 17.3.3.2.1 Recipient Specimens Serum derived from clotted whole blood is the specimen of choice for all crossmatch methods. The serum should have been collected within the last 30 days prior to transplant with serum collected within 48 hours of transplant being ideal. Individual labs and transplant programs may have their own definition of what is considered to be a “current” sample. It is vitally important that the specimen be collected in a collection tube with no additives (plain red-top Vacutainer tube). Specimen tubes with clot activators and serum separators are unacceptable because the additives can interfere with the crossmatch assay. The serum from a full-draw 10-mL tube of clotted blood is

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sufficient for crossmatches. If a patient has a potential sensitizing event, such as a blood transfusion, it is best to wait, if possible, 2 weeks from such an event to allow for detection of any new anti-HLA specificities. In sensitized patients, previous sera representing peaks of reactivity (as determined by PRA testing) from within the last 6 24 months should also be included in a crossmatch. In regraft patients, it is also recommended that serum from the time of rejection of the previous allograft be included in a crossmatch. 17.3.3.2.2 Donor Specimens Donor lymphocytes for crossmatching can be isolated from whole blood, lymph nodes, or spleen sections. As mentioned previously, whole blood may not be optimal due to the adverse effects of steroids and blood transfusions on peripheral blood lymphocytes. If whole blood is to be used, 50 mL of anticoagulated blood is usually sufficient. The anticoagulant of choice is acid citrate dextrose (ACD; yellow-top Vacutainer tubes). As mentioned earlier, tissue specimens, such as lymph nodes and spleens, should not be placed into any type of fixative. 17.3.3.3 Interpretation A negative crossmatch is one predictor of a favorable transplant outcome. Data from several studies indicate that a positive crossmatch, especially a positive T-cell crossmatch, is an indicator of a poor clinical outcome. However, it must be recognized positive crossmatches in different crossmatch methodologies can indicate different levels of risk that certain transplant programs may feel more comfortable accepting.

17.4 CONCLUSION A great deal of insight has been gathered regarding the role of the immune system in acute and chronic rejection. Central to these advances has been the elucidation of the role of HLA as a target for antibodies and T-cells through both the direct and indirect pathways of allorecognition. Regardless of the direction that any of these areas of research may take, one thing that increases optimism is the near certainty that all of the great advances of the 2000s in defining the mechanisms of rejection will be outstripped by the advances in understanding that will come in the next decades.

References 1. Alberts B, Johnson A, Lewis J, et al. Molecular biology of the cell. Innate immunity. 4th edition New York: Garland Science; 2002. Available from: http://www.ncbi.nlm.nih.gov/books/NBK26846/. 2. Alberts B, Johnson A, Lewis J, et al. Molecular biology of the cell. Chapter 24, the adaptive immune system. 4th edition New York: Garland Science; 2002. Available from: http://www.ncbi.nlm.nih.gov/books/NBK21070/. 3. Medawar PB. The behaviour and fate of skin autografts and skin homografts in rabbits. J Anat 1944;78:176 99. 4. Kissmeyer-Nielson F, Olsen S, Peterson VP, Fjeldborg O. Hyperacute rejection of kidney allografts associated with pre-existing humoral antibody against donor cells. Lancet 1966;2:662 5. 5. Ratkovec RM, Hammond EH, O’Connell JB, et al. Outcome of cardiac transplant recipients with a positive donor-specific crossmatch-preliminary results with plasmapheresis. Transplantation 1992;54:651 5. 6. Zerbe TR, Arena VC, Kormos RL, Griffith BP, Hardesty RL, Duquesnoy RJ. Histocompatibility and other risk factors for histological rejection of human cardiac allografts during the first three months following transplantation. Transplantation 1991;52:485 90. 7. Abbas AK, Lichtman AH, Pober JS. Chapter 16: Immunity to tissue transplants. In: Abbas AK, Lichtman AH, Pober JS, editors. Cellular and Molecular Immunology. Philadelphia, PA: W.B. Saunders Co; 1991. 8. Mason DW, Morris PJ. Effector mechanisms in allograft rejection. Ann Rev Immunol 1986;4:119 45. 9. Engers HD, Glasebrook AL, Sorenson GD. Allogeneic tumor rejection induced by the intravenous injection of Lyt-2 1 cytotoxic T lymphocyte clones. J Exp Med 1982;156:1280 5. 10. Humar A, Kerr S, Gillingham KJ, Matas AJ. Features of acute rejection that increase risk for chronic rejection. Transplantation 1999;68:1200 3. 11. Demetris AJ, Murase N, Lee RG, et al. Chronic rejection. A general overview of histopathology and pathophysiology with emphasis on liver, heart and intestinal allografts. Ann Transplant 1997;2:27 44. 12. Pethig K, Heublein B, Wahlers T, Haverich A. Mechanism of luminal narrowing in cardiac allograft vasculopathy: inadequate vascular remodeling rather than intimal hyperplasia is the major predictor of coronary artery stenosis. Working Group on Cardiac Allograft Vasculopathy. Am Heart J 1998;135:628 33. 13. Griffith BP, Hardesty RL, Armitage JM, et al. A decade of lung transplantation. Ann Surg 1993;218:310 18. 14. Wiesner RH, Batts KP, Krom RA. Evolving concepts in the diagnosis, pathogenesis, and treatment of chronic hepatic allograft rejection. Liver Transpl Surg 1999;5:388 400. 15. Sundaresan S. Bronchiolitis obliterans. Semin Thorac Cardiovasc Surg 1998;10:221 6. 16. Haverich A. Experience with lung transplantation. Ann Thorac Surg 1999;67:305 12.

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17. Billingham ME. Pathology of graft vascular disease after heart and heart-lung transplantation and its relationship to obliterative bronchiolitis. Trans Proc 1995;27:2013 16. 18. Cecka M. Clinical outcome of renal transplantation: factors influencing patient and graft survival. Surg Clin North Amer 1998;78:133 48. 19. Wiesner RH, Batts KP, Krom RA. Evolving concepts in the diagnosis, pathogenesis and treatment of chronic hepatic allograft rejection. Liver Transpl Surg 1999;5:388 400. 20. http://optn.transplant.hrsa.gov/learn/about-transplantation/how-organ-allocation-works/. 21. Hosenpud JD, Edwards EB, Lin HM, Daily OP. Influence of HLA matching on thoracic transplant outcomes. Analysis from the UNOS/ ISHLT Thoracic Registry. Circulation 1996;94:170 4. 22. Leivestad T, Foerster A, Simonsen S, Bratlie A, Thasby E, Geiran O. HLA-DR matching reduces rejection rate in heart transplantation. Transpl Int 1996;9(Suppl. 1):S230 3. 23. Sheldon S, Yonan NA, Aziz TN, et al. The influence of histocompatibility on graft rejection and graft survival within a single center population of heart transplant recipients. Transplantation 1999;68:515 19. 24. Dyer PA, Claas FH. A future for HLA matching in clinical transplantation. Eur J Immunogenet 1997;24:17 28. 25. Smith J, Ellis H, Hunt D, Laylor R, Danskine A, Rose M, et al. Prospective HLA matching is feasible in thoracic organ transplantation. Transpl Proc 1997;29:1467 8. 26. Ketheesan N, Tay GK, Witt CS, Christiansen FT, Taylor RR, Dawkins RL. The significance of HLA matching in cardiac transplantation. J Heart Lung Transplant 1999;18:556 1230. 27. Amos D, Bashir H, Boyle W, MacQueen M, Tiilikainen A. A simple micro cytotoxicity test. Transplantation 1969;7:220 3. 28. Hopkins KA. The Basic Lymphocyte Microcytotoxicity Tests: Standard and AHG Enhancement. ASHI Laboratory Manual 4th Edition., 2000. 29. Hurley CK. DNA Methods for HLA Typing: A Workbook for Beginners. Available at www.ashi-hla.org/images/uploads/ DNAMethodsforHLATyping-Workbook.pdf, 2008. 30. Bunce M, Passey B. HLA typing by sequence-specific primersdoi:10.1007/978-1-62703-493-7_1 In: Zachary AA, Leffell MS, editors. Transplantation immunology: methods and protocols, second edition, methods in molecular biology, vol. 1034. Springer Science 1 Business Media, LLC; 2013. 31. Antovich ZR, Russnak NL, Quinto K, Frome M, Grumet FC. LinkSeq and SureTyper a new agile system for HLA typing. Tissue antigens 2011;77:473 4. 32. Trajanoski D, Fidler S. Immunogenetics: methods and applications in clinical practicedoi:10.1007/978-1-61779-842-9_1 In: Christiansen FT, Tait BD, editors. Methods in molecular biology, vol. 882. New York: Springer Science 1 Business Media; 2012. 33. Lazaro A, Tu B, Yang R, et al. Human leukocyte antigen (HLA) typing by DNA sequencing. Available from: http://dx.doi.org/10.1007/ 978-1-62703-493-7_1doi: In: Zachary AA, Leffell MS, editors. Transplantation immunology: methods and protocols, second edition, methods in molecular biology, vol. 1034. Springer Science 1 Business Media, LLC; 2013. 34. Trachtenberg EA, Holcomb CL. Next-generation HLA sequencing using the 454 GS FLX system. In: Zachary AA, Leffell MS, editors. Transplantation immunology: methods and protocols, second edition, methods in molecular biology, vol. 1034. Springer Science 1 Business Media, LLC; 2013. . p. 2013. Available from: http://dx.doi.org/10.1007/978-1-62703-493-7_1. 35. Department of Health and Human Services, Health Care Financing Administration. Medicare, Medicaid and CLIA Programs: Revision of Laboratory Regulations. Federal Register 1990; 55:9538 9610. 36. American Society for Histocompatibility and Immunogenetics. ASHI Standards for Histocompatibility Testing Revised October 2014. Accessed at www.ashi-hla.org/images/uploads/2014ASHIStandardsandGuidance.pdf. 37. Kobashigawa JA, Sabad A, Drinkwater D, et al. Pretransplant panel reactive antibody screens. Are they truly a marker for poor outcome after cardiac transplantation? Circulation 1996;94:294 7. 38. Ting A. The lymphocyte crossmatch test in clinical renal transplantation. Transplantation 1983;35:403 6. 39. Braun WE. Laboratory and clinical management of the highly sensitized organ transplant recipient. Hum Immunol 1989;26:245 60. 40. Loh E, Bergin JD, Couper GS, Mudge GH. Role of panel-reactive antibody cross-reactivity in predicting survival after orthotopic heart transplantation. J Heart Lung Transplant 1994;13:194 201. 41. Ratkovec RM, Hammond EH, O’Connell JB, et al. Outcome of cardiac transplant recipients with a positive donor-specific crossmatch-preliminary results with plasmapheresis. Transplantation 1992;54:651 5. 42. Zerbe TR, Arena VC, Kormos RL, Griffith BP, Hardesty RL, Duquesnoy RJ. Histocompatibility and other risk factors for histological rejection of human cardiac allografts during the first three months following transplantation. Transplantation 1991;52:485 90. 43. Smith JD, Danskine AJ, Laylor RM, Rose ML, Yacoub MH. The effect of panel reactive antibodies and the donor specific crossmatch on graft survival after heart and heart-lung transplantation. Transpl Immunol 1993;1:60 5. 44. Bunke M, Ganzel B, Klein JB, Oldfather J. The effect of a positive B-cell crossmatch on early rejection in cardiac transplant recipients. Transplantation 1993;56:1595 7. 45. Ensley RD, Hunt S, Taylor DO, et al. Predictors of survival after repeat heart transplantation. The Registry of the International Society for Heart and Lung Transplantation and Contributing Investigators. J Heart Lung Transpl 1992;11:S142 58. 46. Kerman RH, Kimball P, Scheinen S, et al. The relationship among donor-recipient HLA mismatches, rejection and death from coronary artery disease in cardiac transplant recipients. Transplantation 1994;57:884 8. 47. Bray RA. Lymphocyte crossmatching by flow cytometry. In: Zachary AA, Leffell MS, editors. Transplantation immunology: methods and protocols, second edition, methods in molecular biology, vol. 1034. Springer Science 1 Business Media, LLC; 2013. Available from: http://dx.doi. org/10.1007/978-1-62703-493-7_1In: Zachary AA, Leffell MS, editors. Transplantation immunology: methods and protocols, second edition, methods in molecular biology, vol. 1034. Springer Science 1 Business Media, LLC; 2013.

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18 The Immune Response to the Allograft Fiona Carty and Karen English National University of Ireland, Maynooth, Ireland

18.1 INTRODUCTION Despite the progress made in solid organ transplantation since the 1950s, alloimmunity remains the greatest barrier to successful graft survival. Tolerance of the transplanted organ by the recipient immune system is the goal in clinical transplantation; however, manipulation of the recipient immune response is crucial for successful clinical outcomes.1 3 Although 1-year survival rates for renal allografts have increased since the 1990s due to improved immunosuppression regimens, long-term outcomes have not significantly improved, suggesting that ameliorating acute rejection does not necessarily guarantee successful graft survival. In fact, these findings suggest that chronic rejection is still a major obstacle to successful renal transplantation.4 6 Herein we review current knowledge on the immune response to the allograft, and discuss the homeostatic proliferation following lymphopenia that contributes to allograft rejection.

18.2 ISCHEMIA REPERFUSION Ischemia reperfusion injury (IRI) is an unavoidable side effect of solid organ transplantation; however, the degree to which IRI occurs is a key factor affecting the clinical outcome of the transplant. Approximately onethird of transplants are significantly affected by IRI, and this increases to one half when donor organs are isolated after circulatory arrest of the donor.7,8 Twenty percent of kidney transplant patients suffer from acute kidney injury as a direct result of IRI, leading to delayed graft function (DGF), requiring dialysis within a week of transplantation. Others suffer from slow graft function (SGF) and both of these complications increase the likelihood of graft loss and acute rejection, while DGF increases the likelihood of chronic allograft dysfunction.9 IRI occurs when blood supply to tissue is interrupted, and the organ is subsequently exposed to hypoxic conditions. This causes mitochondrial damage, ATP depletion, necrosis, and vascular damage within the donor tissue. Reperfusion then triggers the release of free oxygen radicals causing further damage to the donor tissue, and also carries lymphocytes to the graft.10,11 This ischemic injury initiates the production of danger associated molecular patterns (DAMPs), activating both the complement system and innate immune cells through pattern recognition receptors (PRRs). DAMPs in this context are typically associated with cell damage and death. They include necrotic cells, cellular debris, heat shock proteins, tissue factor (TF), and high-mobility group protein box 1 (HMGB1). The importance of DAMPs in graft survival is apparent in islet transplantation, where it has been shown that the clinical outcome of graft survival directly correlates to TF expression.12,13 DAMPs activate PRRs on innate immune cells such as toll like receptors (TLRs), nucleotide-binding oligomerization domain (NOD) and NOD-like receptors, C type lectin receptors, receptors for advanced glycation end products (RAGE), and retinoic acid inducible gene 1 receptors. Signaling through these receptors activates the inflammasome and complement system, amplifying the inflammatory response. Proinflammatory cytokines, precoagulants, and chemoattractants are produced, subsequently causing recruitment of innate immune cells, and eventually recruitment of adaptive immune cells.1,14 Kidney Transplantation, Bioengineering, and Regeneration. DOI: http://dx.doi.org/10.1016/B978-0-12-801734-0.00018-7

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The complement system is activated upon tissue damage, and has a significant role in IRI. C3a and C5a are important initiators and regulators of the inflammatory response, and have been shown to induce production of proinflammatory cytokines by tubular epithelial cells (TECs) and macrophages, and activate endothelial cells in renal IR. In addition, complement mediates epithelial cell damage, leukocyte infiltration, and chemotaxis of interleukin (IL)-17 producing innate immune cells.15 The membrane attack complex (MAC) formed by C5b-C9 has also been shown to contribute to renal IRI. MAC forms pores in cell membranes, causing cell activation, inducing the expression of proinflammatory cytokines, adhesion molecules, and TF, further contributing to acute inflammation and renal IRI.7,16 Inflammasome activation, complement, and chemotactic factors guide neutrophils and γδ T cells to the ischemic tissue. Neutrophils and γδ T cells are among the first populations of cells to infiltrate the graft following IRI. These cells release significant amounts of IL-17, resulting in natural-killer T (NKT) cell activation, leukocyte recruitment, inflammatory cytokine production, chemokine production, enhanced tissue damage and allograft rejection.17 19 Activated NK cells subsequently migrate to the areas of ischemic damage and further contribute to tissue damage in the ischemic kidney. This is thought to be associated with NK cell mediated death of TECs.20 Elevated levels of stromal derived factor-1 (SDF-1) in the ischemic kidney induce the infiltration of macrophages that accumulate in early stages of IRI.21 TLR4 stimulation via hypoxia, glucose deprivation, and HMGB-1 activates macrophages, stimulating the production of IL-6, IL-23, IL-17, and TNF-α.22 24 Despite the significant contribution of macrophages to tissue damage and inflammatory responses in early IRI, macrophages can also play a reparative role in the late stages. Antiinflammatory macrophages mediate proreparative effects in IRI through growth factors and antiinflammatory cytokines.25,26 Infiltration of activated, effector memory CD41 and CD81 T lymphocytes via chemotaxis is observed following moderate and severe IRI. These activated T cells contribute to tissue damage, mediated by inflammatory cytokines and Fas/Fas ligand (FasL) interactions.8,14,27,28 Inhibition of NF-κB in T cells led to decreased CD41 T cell infiltration and leukocyte accumulation in a murine IRI kidney model. NF-κB inhibition in T cells also resulted in decreased levels of IL-1 and TNF-α, and improved survival.29,30 While systemic NF-κB inhibition has also been shown to attenuate IRI, it was not as successful as T cell specific NF-κB inhibition. This is consistent with studies demonstrating that NF-κB can also play a protective role in IRI, and suggests that the impaired T cell activation due to NF-κB inhibition is responsible for attenuation of IRI.30,31 It is widely accepted that regulatory T cells have protective effects in IRI.32 36 Many of these studies have shown that depleting Tregs exacerbates IRI, while adoptive transfer or recruitment of Tregs to damaged tissue ameliorates IRI. The protective effects of Tregs include impairing migration of innate immune cells to IRI areas and suppression of inflammatory cytokine production. These effects are mediated by Treg-derived IL-10 and PDL molecules.32,37

18.3 T CELLS AND MECHANISMS OF ALLORECOGNITION Heterodimeric T-cell receptors (TCR) expressed on the surface of T cells, consist of either the αβ or γδ chains. TCR diversity results from variations and diversity in these chains, which allow T cells to recognize a wide range of peptides expressed on major histocompatibility complex (MHC) by APCs. T cells go through a rigorous “education” process of positive and negative selection in the thymus, determined by the strength of interaction between TCR and self-peptide MHC complexes. The T cells that are unable to interact with self MHC complexes sufficiently are eliminated by apoptosis. T cells that interact with MHC-I complexes become CD81 T cells, while T cells that interact with MHC class II complexes become CD41 T cells. T cells displaying high levels of recognition with self-peptides on MHC complexes are eradicated to ensure that potentially self-reactive T cells do not survive. Following antigen recognition, naı¨ve CD41 and CD81 T cells are activated and undergo clonal expansion. During activation, costimulatory molecules and cytokines expressed by antigen presenting cells (APCs) dictate the phenotypic and functional fate of the T cell.38 Upon reperfusion of the transplanted organ, recipient leukocytes infiltrate the graft, while donor DCs migrate to the lymph nodes and spleen via CCL19 and CCL21. While the early innate immune response to the allograft associated with IRI is largely unspecific, and occurs even in syngeneic transplants, allorecognition by the adaptive immune response is considerably more specific.2,39 The first step in the adaptive immune response to the allograft is mediated by T cells. MHC complexes expressed by allogeneic tissue are the predominant target of the recipient immune system, though minor antigens

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FIG. 18.1 Pathways of allorecognition. The direct pathway (A) occurs when recipient CD41 T cells recognize foreign MHC II molecules presented by donor APCs. This is thought to be via the “high determinant density” model or the “multiple binary complex” model. In the indirect pathway (B) recipient APCs take up donor MHC molecules and present them as foreign peptides to recipient CD41 or CD81 T cells. In the semidirect pathway (C) intact donor MHC molecules are transferred to recipient APCs. Intact MHC I molecules can be presented to CD81 T cells, while at the same time, processed MHC molecules can be presented by recipient MHC II molecules to CD41 T cells.

such as ABO glycolipids expressed by red blood cells and endothe