Autosomal Dominant Polytechnic Kidney Disease ADPKD [First Edition] 9789354664335

Table of contents :
Cover
Half Title Page
Title Page
Copyright
Dedication
Contributors
Foreword by Prof Rajeev TP
Foreword by Prof Anant Kumar
Preface
Contents
1. Genetics of Autosomal Dominant Polycystic Kidney Disease
Genes
Types of Protein Anomalies
Detection Strategies
2. Pathophysiology of Autosomal Dominant Polycystic Kidney Disease
Molecular Basis: Proposed Models of Cystogenesis
Mechanisms of Ciliopathy and Cellular Abnormalities
3. Clinical Presentations of Autosomal Dominant Polycystic Kidney Disease
Renal Manifestations
Extrarenal Manifestations
4. Complications of Autosomal Dominant Polycystic Kidney Disease
Infections in ADPKD
Nephrolithiasis in ADPKD—Dilemmas
ADPKD Miscellaneous Complications
Hypertension in ADPKD
5. Imaging in Autosomal Dominant Polycystic Kidney Disease
Ultrasonography
Computerized Tomography
6. Renal Transplantation in Autosomal Dominant Polycystic Kidney Disease
Live Donor Evaluation
Recipient Evaluation
7. Laparoscopy in Autosomal Dominant Polycystic Kidney Disease
Preoperative Preparation
Open Access/Hasson’s Technique
Left-Sided ADPKD Laparoscopic Nephrectomy
8. Current Trends in Medical Management of Autosomal Dominant Polycystic Kidney Disease
Poor Prognostic Indicators
Management of Hypertension in ADPKD
Salt Restriction
Fluid Intake
mTOR Inhibitors
Statins
Index
Back Cover

Citation preview

Autosomal Dominant Polycystic Kidney Disease

ADPKD

Autosomal Dominant Polycystic Kidney Disease

ADPKD Editors

Arvind P Ganpule MS DNB MNAMS

Sishir D Gang MD DM DNB

Vice Chairman Department of Urology Muljibhai Patel Urological Hospital Nadiad, Gujarat, India

Chairman Department of Nephrology Muljibhai Patel Urological Hospital Nadiad, Gujarat, India

Gopal R Tak MS DNB

Abhijit Konnur MD DNB

Consultant Urologist Department of Urology Muljibhai Patel Urological Hospital Nadiad, Gujarat, India

Consultant Nephrologist Department of Nephrology Muljibhai Patel Urological Hospital Nadiad, Gujarat, India

CBS Publishers & Distributors

Pvt Ltd

New Delhi • Bengaluru • Chennai • Kochi • Kolkata • Lucknow • Mumbai Hyderabad • Jharkhand • Nagpur • Patna • Pune • Uttarakhand

Disclaimer Science and technology are constantly changing fields. New research and experience broaden the scope of information and knowledge. The authors have tried their best in giving information available to them while preparing the material for this book. Although, all efforts have been made to ensure optimum accuracy of the material, yet it is quite possible some errors might have been left uncorrected. The publisher, the printer and the authors will not be held responsible for any inadvertent errors, omissions or inaccuracies. eISBN: xxxx Copyright © Authors and Publisher First eBook Edition: 2022 All rights reserved. No part of this eBook 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 authors and the publisher. Published by Satish Kumar Jain and produced by Varun Jain for CBS Publishers & Distributors Pvt. Ltd. Corporate Office: 204 FIE, Industrial Area, Patparganj, New Delhi-110092 Ph: +91-11-49344934; Fax: +91-11-49344935; Website: www.cbspd.com; www.eduport-global.com; E-mail: [email protected]; [email protected] Head Office: CBS PLAZA, 4819/XI Prahlad Street, 24 Ansari Road, Daryaganj, New Delhi-110002, India. Ph: +91-11-23289259, 23266861, 23266867; Fax: 011-23243014; Website: www.cbspd.com; E-mail: [email protected]; [email protected].

Branches Bengaluru: Seema House 2975, 17th Cross, K.R. Road, Banasankari 2nd Stage, Bengaluru - 560070, Kamataka Ph: +91-80-26771678/79; Fax: +91-80-26771680; E-mail: [email protected] Chennai: No.7, Subbaraya Street Shenoy Nagar Chennai - 600030, Tamil Nadu Ph: +91-44-26680620, 26681266; E-mail: [email protected] Kochi: 36/14 Kalluvilakam, Lissie Hospital Road, Kochi - 682018, Kerala Ph: +91-484-4059061-65; Fax: +91-484-4059065; E-mail: [email protected] Mumbai: 83-C, 1st floor, Dr. E. Moses Road, Worli, Mumbai - 400018, Maharashtra Ph: +91-22-24902340 - 41; Fax: +91-22-24902342; E-mail: [email protected] Kolkata: No. 6/B, Ground Floor, Rameswar Shaw Road, Kolkata - 700014 Ph: +91-33-22891126 - 28; E-mail: [email protected]

Representatives Hyderabad Pune Nagpur Manipal Vijayawada Patna

to our patients and our families for their unstinted support, love and affection

Contributors Abhijit Konnur MD DNB (Nephrology)

Gopal R Tak MS DNB (Urology)

Consultant Nephrologist Muljibhai Patel Urological Hospital Nadiad, Gujarat, India

Consultant Urologist Department of Urology Muljibhai Patel Urological Hospital Nadiad, Gujarat, India

Abhijit Patil MS MC+h DNB (Urology) Consultant Urologist Department of Urology Muljibhai Patel Urological Hospital Nadiad, Gujarat, India

Abhishek Singh MS MCh DNB (Urology) Consultant Urologist Department of Urology Muljibhai Patel Urological Hospital Nadiad, Gujarat, India

Anant Kumar MS MCh (Urology) Chairman Department of Urology Robotics and Kidney Transplantation Max Superspeciality Hospital Saket, New Delhi

Arvind P Ganpule MS DNB MNAMS (Urology) Vice Chairman Department of Urology Muljibhai Patel Urological Hospital Nadiad, Gujarat, India

Hardik Patel MD DNB (Nephrology) Consultant Nephrologist Muljibhai Patel Urological Hospital Nadiad, Gujarat, India

Mital Parikh MD DNB (Nephrology) Consultant Nephrologist Pramukhswami Medical College and Shree Krishna Hospital Karamsad, Gujarat, India

Pranav Gwalani MBBS MPH Student Department of Epidemiology Mailman School of Public Health Columbia University, New York, United States

Rakhul LR MS MCh (Urology) Assistant Professor Department of Urology Trivandrum Medical College Trivandrum, Kerala

Avinash Rao MD DNB

Ravindra B Sabnis MS MCh (Urology)

Fellowship in Nephrology Muljibhai Patel Urological Hospital Nadiad, Gujarat, India

Chairman, Department of Urology Muljibhai Patel Urological Hospital Nadiad, Gujarat, India

viii

Autosomal Dominant Polycystic Kidney Disease

Rohan Batra MS DNB (Urology) Consultant Urologist Department of Urology Muljibhai Patel Urological Hospital Nadiad, Gujarat, India

Sandhya Suresh MD (Medicine) Resident in Nephrology Muljibhai Patel Urological Hospital Nadiad, Gujarat, India

Sanika A Ganpule MBBS DMRE Consultant Radiologist Muljibhai Patel Urological Hospital Dr Virendra Desai Road, Nadiad, Gujarat, India

Sishir D Gang MD DM DNB (Nephrology) Chairman Department of Nephrology

Muljibhai Patel Urological Hospital Nadiad, Gujarat, India

Umapati Hegde MD DNB (Nephrology) Vice Chairman Department of Nephrology Muljibhai Patel Urological Hospital Nadiad, Gujarat, India

V Mohankumar DNB (Surgery) DNB (Urology) Consultant Urologist Department of Urology Apollo Hospitals Chennai, India

Veermani Muthu MS MCh (Urology) Consultant Urologist Department of Urology SRM Medical College Chennai, India

Foreword

T

ouching one’s life, being always open to receive as well as to give, to be passionate and extend a helping hand when in need—are the qualities of most of the amazing people I have come across. We as professionals in the service to humanity share the same core of extending the knowledge to our fellow colleagues and budding youngsters in general. The editor, Dr Ganpule is known to me for several years. The things that have caught my attention is his sincerity, gentleness and perfection in his work. This book on adult polycystic kidney disease gives a perfect, in-depth knowledge on this disease entity which will be of immense help to the trainees and practicing urologists. Living with a focus on others is not only just a nice goal but a way of life and leads to a life that is full, rich and fulfilling. I extend all my blessings to the contributors in their endeavor which is a tribute to the nephro-urology fraternity.

Prof Rajeev TP Past Secretary Urological Society of India Professor and Head Department of Urology Gauhati Medical College Gauhati, Assam

Foreword

A

utosomal Dominant Polycystic Kidney Disease (ADPKD) is not an uncommon condition encountered by urologists, nephrologists and transplant surgeons. In the last two decades, there have been interesting developments in genetic diagnosis, prognosticating and understanding of natural history and etiopathogenesis of this perplexing disease. It is a very appropriate time to bring out such a monograph on all aspects of ADPKD. Now we can even preserve the nephrons and delay the disease progression in a select group of patients. It is more perplexing to transplant surgeons and physicians when it comes to choosing a family donor. Some advancement has occurred in genetic tests to rule out future development of this disease in a potential live-related donor. Pharmacological intervention in the form of V2 receptor antagonist is a new development and found to be helpful in a particular cohort which can be identified. These polycystic kidneys are prone to various complications like stone disease, infection and hematuria. In this monograph all these problems are well discussed. When they achieve an enormous size, which is debilitating and may need removal of one of the kidneys. It is also removed before transplant if there is no space to transplant an allograft. Due to sheer size, more often than not these kidneys are removed by open methods but one can chose a case and remove it laparoscopically. This has been beautifully demonstrated in this monograph. This monograph has scientifically discussed all aspects of ADPKD and it will be a very useful handy reference for all of us. I congratulate the authors for doing a wonderful work.

Prof Anant Kumar Past President, Urological Society of India Chairman Department of Urology Robotics and Kidney Transplantation Max Superspeciality Hospital Saket, New Delhi

Preface

A

dult polycystic kidney disease, the commonest hereditary kidney disease known to mankind, poses a unique challenge to both patients and their treating physicians. The issues involved in the management of patients with polycystic kidney disease are manifold. Many of the patients are aware of the disease early in life due to employment or insurance screening or unrelated medical issues. Sadly they have to deal with chronic kidney disease and its sequelae during their most productive years of life. As this disease tends to affect multiple members of the family, it also involves socio-economic considerations. The management of patients with ADPKD requires a multidisciplinary multipronged strategy involving as team of treating physicians, nephrologists, urologists and the anesthetists alike. There has been void felt in the medical field with regards to ADPKD literature of a textbook approach regards management and therapy. We have tried to fulfil this gap by dwelling at length on various facets of polycystic kidney disease but at the same time tried to keep the text concise, precise and evidence based on current levels of best medical practises. In this volume, all aspects of ADPKD have been discussed which include the etiopathology, presentation and management. From a physician's perspective the evaluation of the recipient with ADPKD is unique as it involves multiple considerations. Of equal importance is the evaluation of the donor especially in the resource and organ limited scenario like India where majority of the prospective kidney donors are live and related unlike in the west where deceased donation is more prevalent. The authors have elaborately discussed the evaluation of the recipient and donors in such a situation. Minimally invasive surgery is the latest kid on the block, the chapter on pretransplant nephrectomy alludes to the nuances of this procedure in such a situation. We wish to thank all the authors who contributed to make this book and our own families who supported us. We are reminded of all our patients with polycystic kidney disease who have been a source of inspiration and joy when they overcome their disease with grit and determination and have been the reason for the genesis of this book. Last but not the least, we would like to thank CBS Publishers for extending their support and cooperation to make sure that this project sees the light of the day. We wish you a happy reading

Arvind P Ganpule Sishir D Gang Gopal R Tak Abhijit Konnur

Contents Contributors Foreword by Prof Rajeev TP Foreword by Prof Anant Kumar Preface

vii ix xi xiii

1. Genetics of Autosomal Dominant Polycystic Kidney Disease

1

Abhijit Konnur, Hardik Patel, Avinash Rao

• Genes 1 • Types of protein anomalies • Detection strategies 4

2

2. Pathophysiology of Autosomal Dominant Polycystic Kidney Disease

7

Hardik Patel, Avinash Rao

• Molecular basis: Proposed models of cystogenesis 7 • Mechanisms of ciliopathy and cellular abnormalities 8

3. Clinical Presentations of Autosomal Dominant Polycystic Kidney Disease

12

Abhijit Konnur, Mital Parikh

• Renal manifestations 12 • Extrarenal manifestations 16

4. Complications of Autosomal Dominant Polycystic Kidney Disease • • • •

Infections in ADPKD 23 Nephrolithiasis in ADPKD—dilemmas 29 ADPKD miscellaneous complications 35 Hypertension in ADPKD 45

23

Abhijit Konnur, Sandhya Suresh Anant Kumar, Rakhul LR Gopal R Tak Umapati Hegde

5. Imaging in Autosomal Dominant Polycystic Kidney Disease

54

Sanika A Ganpule, Arvind P Ganpule, Gopal R Tak, Pranav Gwalani

• Ultrasonography 54 • Computerized tomography 55

6. Renal Transplantation in Autosomal Dominant Polycystic Kidney Disease • Live donor evaluation 62 • Recipient evaluation 64

62

Ravindra B, Sabnis, Abhijit Patil Veermani Muthu, V Mohankumar

Autosomal Dominant Polycystic Kidney Disease

xvi

7. Laparoscopy in Autosomal Dominant Polycystic Kidney Disease

68

Abhishek Singh, Rohan Batra, Arvind P Ganpule

• Preoperative preparation 70 • Open access/Hasson’s technique 73 • Left-sided ADPKD laparoscopic nephrectomy

74

8. Current Trends in Medical Management of Autosomal Dominant Polycystic Kidney Disease

92

Umapati Hegde, Sandhya Suresh

• • • • • •

Poor prognostic indicators 94 Management of hypertension in ADPKD 96 Salt restriction 97 Fluid intake 97 mTOR inhibitors 99 Statins 100

Index

105

Genetics of Autosomal Dominant Polycystic Kidney Disease

1

1 Genetics of Autosomal Dominant Polycystic Kidney Disease Abhijit Konnur, Hardik Patel, Avinash Rao

to be less than half.4 Major chunk of affected population develops the disease between the age group of 20 and 40 years although sporadic cases have been reported from in utero onset to late adulthood.5 Renal cysts may have association with cysts in liver, spleen, pancreas, dysfunctional heart valves and aneurysms in brain.6 The genetics, types of protein anomalies and mutation detection strategies of ADPKD are discussed in this chapter.

Autosomal dominant polycystic kidney disease (ADPKD) is a disease having renal and extrarenal manifestations. ADPKD is commonly associated with mutations in two primary genes; PKD1 on chromosome 16p13.3 and PKD2 on chromosome 4q21 (type II). There is an interaction of polycystin 1 and polycystin 2 (encoded on PKD1 and PKD2) located on the endoplasmic reticulum of cells lining the tubules. This is required for the mature polycystin complex to reach the cell surface. The two primary methods available for gene mutation are DNA linkage analysis and gene-based mutation screening. Linkage analysis involves highly informative microsatellite markers flanking PKD1 and PKD2. For the routine genetic screening of ADPKD direct DNA sequencing is employed.

Genes

PKD1, responsible for ADPKD type 1 is mapped on chromosome 16 (Fig. 1.1) 7 (16p13.3) and PKD2, responsible for ADPKD type 2 is mapped on chromosome 4q21. The PKD1 gene and gene for tuberous sclerosis (TSC2) are adjacently located. As per the available literature, approximately, PKD1 mutation affects 80–85% of ADPKD families, and 15–20% of the families are affected by PKD2 mutations.8 If a given patient is negative for PKD1 and PKD2 it is prudent to look for the mutations in gene GANAB located on chromosome 11q12.3 (Fig. 1.1). GANAB gene presents with autosomal dominant polycystic liver disese. The ADPKD component is not severe. It accounts for ~0.3% of total ADPKD.9 Similar to GANAB, four other genes, i.e.

INTRODUCTION

Polycystic kidney disease (PKD) refers to a variety of monogenic disorders characterized by the cyst formation in renal units with increase in size of these cysts. These changes lead to deterioration of renal function over the years.1 Among the different forms, autosomal dominant polycystic kidney disease (ADPKD) is common.2,3 As the disease is clinically silent in many individuals, the number of patients diagnosed during their lifetime is estimated 1

2

Autosomal Dominant Polycystic Kidney Disease

Fig. 1.1: Chromosome localization and genomic structure of PKD1, PKD2, and GANA genes and structure of polycystin 1 (PC1) and polycystin 2 (PC2).Schematic representation of chromosomes and genomic structure for the genes7

ALG8, SEC61B, SEC63, and PRKCSH, have been identified.10, 11 With the use of whole genome sequencing (WGS), an additional new gene, DNAJB11, has been identified recently, which presents with small renal cysts, nonenlarged kidneys, liver cysts and progressive renal failure.12

Types of Protein Anomalies

PKD1 and PKD2 encode proteins, polycystin 1 (PC1) and polycystin 2 (PC2) respectively (Fig. 1.2).13, 15 Polycystin 1 (PC1) is characterized by a 11-transmembrane domain. Majority of the protein is in the extracellular region. The

Fig. 1.2: Representation of PKD1 and PKD2 protein products: PC1 and PC27

Genetics of Autosomal Dominant Polycystic Kidney Disease

NH2 terminal of the extracellular domain is important in protein-protein interactions. NH2 terminal has a GPCR proteolytic site (GPS domain) and 12 PKD domains. 16,18 Among the several cleavage events, polycystin 1 undergoes, cleavage event at a juxtamembrane G protein-coupled receptor (GPCR) is significant. This is “Cis-autoproteolysis”, as it occurs in the absence of any exogenous protease. Two non-covalently associated fragments by cleavage at the GPS domain (Fig. 1.3).19 The importance of this cleavage event is that, it is fundamentally essential to maintain renal tubular morphology and mutation at the GPS site results in ADPKD with cysts primarily affecting the collecting duct as evidenced by knock-in mouse model with a mutation.16,20 Polycystin 2 (PC2) is a member of family of nonselective cation channels.21 Morphologically, PC2 is characterized by a short N-terminal cytoplasmatic region, six transmembrane domains that are homologous with a portion of the transmembrane domain of PCI, and a short C-terminal fragment. A tetrameric structure is formed by four polycystin 2 channels with a voltage-sensing domain and

3

a novel “TOP” domain comprised of the large extracellular loop between TM1 and TM2. The TOP domain is a hotspot for missense diseasecausing variants and is important for channel assembly and/or function.22, 23 Polycystins are membrane proteins situated in plasma membranes and primary cilium. They are localized in renal tubular epithelia, pancreatic ducts and hepatic bile ductules.24 The interaction of PC1 and PC2 in the endoplasmic reticulum is required for the mature polycystin complex to reach the cell surface, including the cilium. PC1 is involved in multiple cellular and matrix interactions.25 Polycystin 2, located in endoplasmic reticulum, is involved in calcium signaling. PC1 and PC2 interact in a common signaling pathway which results in identical clinical manifestation of ADPKD1 and ADPKD2.21 Genotype–Phenotype Relationship

The molecular diagnosis of the mutations associated with ADPKD is important in prognostication of the disease. Patients with PKD1 mutations have larger kidneys and early onset of the disease than in patients with PKD2 mutations.26, 27 GANAB mutation is associated

Fig. 1.3: Cleavage in extracellular and intracellular regions of polycystin 1 protein19

4

Autosomal Dominant Polycystic Kidney Disease

with a mild renal phenotype. 9 Truncated PKD1 mutations have a more serious disease. Milder form of disease is associated with nontruncated PKD1 mutations or mutations in PKD2. Truncating PKD1 mutations are associated with larger kidneys and that too in men, in women they manifest with liver disease.27, 28 Genetic interaction and epistasis is a variation in the modifier gene, this leads to difference in the presentation as regards to progression of the disease in members of same family with same mutation.29 The PRO-PKD score, a prognostic index, developed by Cornec-Le Gall et al, is based on both, genetic and clinical data.30 Detection Strategies

DNA linkage analysis along with gene-based mutation screening are the two primary methods available for the detection of the mutations.31 Haplotype reconstruction can be used to predict the status of other members of the family by performance of linkage analysis. This method may be considered in situations such as prenatal testing in which the mutation is unknown and for pre-implantation genetic diagnosis (PGD).32 Mutation screening for PKD genes using DNA or mRNA is the other method of detection currently used. Complete gene sequencing remains the gold standard for mutation analysis, but has the disadvantage of being highly expensive and time-consuming. For the routine genetic screening of ADPKD direct DNA sequencing is employed. In order to lower testing costs and minimize turnaround time, several mutation screening tools are available such as denaturing gradient gel electrophoresis (DGGE), single-strand conformation polymorphism (SSCP), DNA high-pressure liquid chromatography (DHPLC) screening method and multiplex ligation dependent probe assay (MLPA).33–39 But, these methods have lower definite mutation detection rates. Presently, longrange polymerase chain reaction (PCR)

strategy with specific primers are considered as a key strategy of gene mutation detection, as it has faster turnaround time, cost saving and reliable in the genetic diagnosis of ADPKD.40, 41 REFERENCES 1. Lee K, Battini L, Gusella GL. Cilium, centrosome and cell cycle regulation in polycystic kidney disease. Biochimicaet Biophysica Acta (BBA)— Molecular Basis of Disease. 2011 Oct 1;1812 (10):1263–71. 2. Davies F, Coles GA, Harper PS, Williams AJ, Evans C, Cochlin D. Polycystic kidney disease reevaluated: a population-based study. QJM: An International Journal of Medicine. 1991 Jun 1;79(3):477–85. 3. Grantham JJ. Autosomal dominant polycystic kidney disease. New England Journal of Medicine. 2008 Oct 2;359(14):1477–85. 4. Lanktree MB, Haghighi A, Guiard E, Iliuta IA, Song X, Harris PC, Paterson AD, Pei Y. Prevalence estimates of polycystic kidney and liver disease by population sequencing. Journal of the American Society of Nephrology. 2018 Oct 1;29(10):2593–600. 5. Loftus H, Ong AC. Cystic kidney diseases: many ways to form a cyst. Pediatric nephrology. 2013 Jan 1;28(1):33–49. 6. Peltola P, Lumiaho A, Miettinen R, Pihlajamaeki J, Sandford R, et al. Genetics and phenotypic characteristics of autosomal dominant polycystic kidney disease in Finns. J Mol Med. 2005;83: 638–646. 7. Cordido A, Besada-Cerecedo L, García-González MA. The genetic and cellular basis of autosomal dominant polycystic kidney disease—a primer for clinicians. Frontiers in pediatrics. 2017 Dec 18;5:279. 8. Cornec-Le Gall E, Audrézet MP, Renaudineau E, Hourmant M, Charasse C, Michez E, Frouget T, Vigneau C, Dantal J, Siohan P, Longuet H. PKD2related autosomal dominant polycystic kidney disease: Prevalence, clinical presentation, mutation spectrum, and prognosis. American Journal of Kidney Diseases. 2017 Oct 1;70(4): 476–85. 9. Porath B, Gainullin VG, Cornec-Le Gall E, Dillinger EK, Heyer CM, Hopp K, Edwards ME,

Genetics of Autosomal Dominant Polycystic Kidney Disease Madsen CD, Mauritz SR, Banks CJ, Baheti S. Mutations in GANAB, encoding the glucosidase II subunit, cause autosomal-dominant polycystic kidney and liver disease. The American Journal of Human Genetics. 2016 Jun 2;98(6):1193–207. 10. Fedeles SV, Gallagher AR, Somlo S. Polycystin 1: a master regulator of intersecting cystic pathways. Trends in molecular medicine. 2014 May 1;20(5):251–60. 11. Besse W, Dong K, Choi J, Punia S, Fedeles SV, Choi M, Gallagher AR, Huang EB, Gulati A, Knight J, Mane S. Isolated polycystic liver disease genes define effectors of polycystin 1 function. The Journal of clinical investigation. 2017 May 1;127(5):1772–85. 12. Cornec-Le Gall E, Olson RJ, Besse W, Heyer CM, Gainullin VG, Smith JM, Audrézet MP, Hopp K, Porath B, Shi B, Baheti S. Monoallelic mutations to DNAJB11 cause atypical autosomal-dominant polycystic kidney disease. The American Journal of Human Genetics. 2018 May 3;102(5):832–44. 13. Ward C, Peral B, Hughes J, Thomas S, Gamble V, MacCarthy A, Sloane-Stanley J, Buckle P, Kearney P, Higgs D, Ratcliffe C. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell. 1994 Jun 17;77(6):881–94. 14. International Polycystic Kidney Disease Consortium. Polycystic kidney disease: the complete structure of the PKD1 gene and its protein. Cell. 1995 Apr 21;81(2):289–98. 15. Geng L, Segal Y, Peissel B, Deng N, Pei Y, Carone F, Rennke HG, Glücksmann-Kuis AM, Schneider MC, Ericsson M, Reeders ST. Identification and localization of polycystin, the PKD1 gene product. The Journal of clinical investigation. 1996 Dec 15;98(12):2674–82. 16. Qian, F, Boletta, A., Bhunia, A.K., Xu, H., Liu, L., Ahrabi, A.K., Watnick, T.J., Zhou, F. and Germino, G.G., 2002. Cleavage of polycystin 1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1-associated mutations. Proceedings of the National Academy of Sciences, 99(26), pp.16981– 16986. 17. Bycroft M, Bateman A, Clarke J, Hamill SJ, Sandford R, Thomas RL, Chothia C. The structure of a PKD domain from polycystin 1: implications for polycystic kidney disease. The EMBO journal. 1999 Jan 15;18(2):297–305.

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18. Gunaratne HJ, Moy GW, Kinukawa M, Miyata S, Mah SA, Vacquier VD. The 10 sea urchin receptor for egg jelly proteins (SpREJ) are members of the polycystic kidney disease 1 (PKD1) family. BMC genomics. 2007 Dec 1;8(1):235. 19. Low SH, Vasanth S, Larson CH, Mukherjee S, Sharma N, Kinter MT, Kane ME, Obara T, Weimbs T. Polycystin 1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease. Developmental cell. 2006 Jan 1;10(1):57–69. 20. Yu S, Hackmann K, Gao J, He X, Piontek K, GarcíaGonzález MA, Menezes LF, Xu H, Germino GG, Zuo J, Qian F. Essential role of cleavage of polycystin 1 at G protein-coupled receptor proteolytic site for kidney tubular structure. Proceedings of the National Academy of Sciences. 2007 Nov 20;104(47):18688–93. 21. Hanaoka K, Qian F, Boletta A, Bhunia AK, Piontek K, Tsiokas L, Sukhatme VP, Guggino WB, Germino GG. Co-assembly of polycystin 1 and 2 produces unique cation-permeable currents. Nature. 2000 Dec;408(6815):990–4. 22. Shen PS, Yang X, DeCaen PG, Liu X, Bulkley D, Clapham DE, Cao E. The structure of the polycystic kidney disease 2 (PKD2) channel in lipid nanodiscs. Cell. 2016 Oct 20;167(3):763–73. 23. Grieben M, Pike AC, Shintre CA, Venturi E, ElAjouz S, Tessitore A, Shrestha L, Mukhopadhyay S, Mahajan P, Chalk R, Burgess-Brown NA. Structure of the polycystic kidney disease TRP channel polycystin 2 (PC2). Nature structural and molecular biology. 2017 Feb;24(2):114–22. 24. Berbari NF, O’Connor AK, Haycraft CJ, Yoder BK. The primary cilium as a complex signaling center. Current Biology. 2009 Jul 14;19(13):R526–35. 25. Ibraghimov-Beskrovnaya O, Dackowski WR, Foggensteiner L, Coleman N, Thiru S, Petry LR, Burn TC, Connors TD, Van Raay T, Bradley J, Qian F. Polycystin: in vitro synthesis, in vivo tissue expression, and subcellular localization identifies a large membrane-associated protein. Proceedings of the National Academy of Sciences. 1997 Jun 10;94(12):6397–402. 26. Harris PC, Bae KT, Rossetti S, Torres VE, Grantham JJ, Chapman AB, Guay-Woodford LM, King BF, Wetzel LH, Baumgarten DA, Kenney PJ. Cyst number but not the rate of cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease. Journal of the American Society of Nephrology. 2006 Nov 1;17(11):3013–9.

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27. Heyer CM, Sundsbak JL, Abebe KZ, Chapman AB, Torres VE, Grantham JJ, Bae KT, Schrier RW, Perrone RD, Braun WE, Steinman TI. Predicted mutation strength of nontruncating PKD1 mutations aids genotype–phenotype correlations in autosomal dominant polycystic kidney disease. Journal of the American Society of Nephrology. 2016 Sep 1;27(9):2872–84. 28. Hwang YH, Conklin J, Chan W, Roslin NM, Liu J, He N, Wang K, Sundsbak JL, Heyer CM, Haider M, Paterson AD. Refining genotype–phenotype correlation in autosomal dominant polycystic kidney disease. Journal of the American Society of Nephrology. 2016 Jun 1;27(6):1861–8. 29. Bergmann C, von Bothmer J, Brüchle NO, Venghaus A, Frank V, Fehrenbach H, Hampel T, Pape L, Buske A, Jonsson J, Sarioglu N. Mutations in multiple PKD genes may explain early and severe polycystic kidney disease. Journal of the American Society of Nephrology. 2011 Nov 1;22(11):2047–56. 30. Cornec-Le Gall E, Audrézet MP, Rousseau A, Hourmant M, Renaudineau E, Charasse C, Morin MP, Moal MC, Dantal J, Wehbe B, Perrichot R. The PROPKD score: a new algorithm to predict renal survival in autosomal dominant polycystic kidney disease. Journal of the American Society of Nephrology. 2016 Mar 1;27(3):942–51. 31. Pei Y. Diagnostic approach in autosomal dominant polycystic kidney disease. Clinical Journal of the American Society of Nephrology. 2006 Sep 1;1(5):1108–14. 32. De Rycke M, Georgiou I, Sermon K, Lissens W, Henderix P, Joris H, Platteau P, Van Steirteghem A, Liebaers I. PGD for autosomal dominant polycystic kidney disease type 1. Mol. Hum. Reprod. 2005;11;65–71. 33. Perrichot RA, Mercier B, Simon PM, Whebe B, Cledes J, Ferec C. DGGE screening of PKD1 gene reveals novel mutations in a large cohort of 146 unrelated patients. Human genetics. 1999 Sep 1;105(3):231–9.

34. Perrichot R, Mercier B, Quere I, Carre A, Simon P, Whebe B, Cledes J, Ferec C. Novel mutations in the duplicated region of PKD1 gene. European Journal of Human Genetics. 2000 May;8(5):353–9. 35. Veldhuisen B, Saris JJ, De Haij S, Hayashi T, Reynolds DM, Mochizuki T, Elles R, Fossdal R, Bogdanova N, Van Dijk MA, Coto E. A spectrum of mutations in the second gene for autosomal dominant polycystic kidney disease (PKD2). The American Journal of Human Genetics. 1997 Sep 1;61(3):547–55. 36. Watnick T, Germino GG. Molecular basis of autosomal dominant polycystic kidney disease. Seminars in nephrology July 1999;19(4):327–43. 37. Rossetti S, Chauveau D, Walker D, Saggar-Malik A, Winearls CG, Torres VE, Harris PC. A complete mutation screen of the ADPKD genes by DHPLC. Kidney International. 2002 May 1;61(5):1588–99. 38. Kozlowski P, Bissler J, Pei Y, Kwiatkowski DJ. Analysis of PKD1 for genomic deletion by multiplex ligation-dependent probe assay: absence of hot spots. Genomics. 2008 Feb 1;91(2):203–8. 39. Consugar MB, Wong WC, Lundquist PA, Rossetti S, Kubly VJ, Walker DL, Rangel LJ, Aspinwall R, Niaudet WP, Özen S, David A. Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome. Kidney International. 2008 Dec 1;74(11):1468–79. 40. Garcia-Gonzalez MA, Jones JG, Allen SK, Palatucci CM, Batish SD, Seltzer WK, Lan Z, Allen E, Qian F, Lens XM, Pei Y. Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease. Molecular genetics and metabolism. 2007 Sep 1;92(1–2):160–7. 41. Renkema KY, Stokman MF, Giles RH, Knoers NV. Next generation sequencing for research and diagnostics in kidney disease. Nature Reviews Nephrology. 2014 Aug;10(8):433.

Pathophysiology of Autosomal Dominant Polycystic Kidney Disease

7

2 Pathophysiology of Autosomal Dominant Polycystic Kidney Disease Hardik Patel, Avinash Rao

The polycystic kidney disease is the end result of ciliary dysregulation secondary to targeted inactivation of ciliary genes. The two-hit and three-hit models involving defective genetic make-up with secondary somatic mutation triggered by episodes of renal tubular cell injury has been put forth as a cause for ADPKD. Experimental models have suggested that either altered maturation or assembly of the PC complex due to mutations in PKD (PKD1 and PKD2) genes is the cause behind the PKD pathology.

In this chapter, the molecular basis, mechanisms of ciliopathy and cellular mechanisms have been discussed. Molecular Basis: Proposed Models of Cystogenesis Two-hit and Three-hit Models for ADPKD

This model was proposed in 1990s in orthologous mouse models.4, 5 According to this model, there is already an inherent mutated gene, resulting in an abnormal allele, present in the affected individuals, which is termed “first hit”, although this alone cannot cause the disease manifestation. This first hit affects all the body cells including the renal tubular epithelium. The “second hit” which is due to a somatic mutation, during any age of an individual, inactivates the normal PKD alleles, resulting in the multiplication of the tubular epithelia finally resulting in the cystogenesis.6,7 The cystic disease in induction murine model can be accelerated by renal injury called the “third hit”.8 There could be more than 1000 cysts in the ADPKD kidneys.9 Within the tubules, the cystic dilatation is usually focal and cysts form in 15 cm are associated with back pains6. Normally adult human kidneys weigh about 1% of a person’s total body weight. In ADPKD, post-bilateral nephrectomy specimens weighing up to 22 kg or 20% of adult body weight have been noted.7 Normal renal tubules which are 40 µm in diameter enlarge to form cysts that measure centimeters in diameter in patients with ADPKD.8 Pain is a common manifestation of ADPKD.9 Low back pain (71.3%) followed by abdominal pain (61.4 %) was the most common discomfort followed by abdominal pain reported by patients with PKD during the course of their disease. Usual reasons include: Cyst hemorrhage, nephrolithiasis, cyst infection, and, rarely, tumor. Mild discomfort, to severe pain along with feeling of flank fullness may be present due to renal enlargement and shape distortion by cysts. Gross hematuria and passage of clots can also be a source of pain. Cyst hemorrhage associated with fever can be due to secondary cyst infection. Usually the pain is self-limited and resolves within 2–7 days. Rarely, retroperitoneal bleeding may lead to pain that may be severe and require transfusion. Hypertension

Larger kidney sizes are associated with hypertension10. Pain and hypertension disappear with cyst decompression/deroofing procedures.11,12 Patients with ADPKD and hypertension develop renal dysfunction 20 years earlier than those who are normotensive.10 Hypertensive males fare the worst and normotensive females the best. Hypertension usually develops before any decline in GFR.

13

It is characterized by the following:13 • An increase in renal vascular resistance and filtration fraction • Normal or high peripheral plasma renin activity • Resetting of the pressure–natriuresis relationship • Salt sensitivity • Normal or increased extracellular fluid volume, plasma volume, and cardiac output • Partial correction of renal hemodynamics and sodium handling by converting enzyme inhibition. Hypertension follows the iceberg phenomenon and unfortunately is often diagnosed much later than when it first occurs in individuals with ADPKD. Twenty-four-hour monitoring of ambulatory blood pressure of children or young adults may reveal elevated blood pressure, attenuated decrease in nocturnal blood pressure, and exaggerated blood pressure response during exercise, which may be accompanied by left ventricular hypertrophy and diastolic dysfunction.14 The renal concentrating capacity is decreased in about half of the patients and is linked to BP. Decreased renal concentrating capacity should be considered as an early marker of functional impairment in ADPKD and a further risk factor for hypertension.14 There is high prevalence of hypertension in children with autosomal dominant polycystic kidney disease starting at young ages and hence monitoring of blood pressure in children at risk for ADPKD is recommended.15 Early detection and treatment of hypertension in ADPKD is important because cardiovascular disease is the primary cause of death and controlled high blood pressure predisposes these susceptible patients to increased risk of:13 • Proteinuria, hematuria, and a faster decline of renal function. • Morbidity and mortality from valvular heart disease and aneurysms. • Fetal and maternal complications during pregnancy.

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Autosomal Dominant Polycystic Kidney Disease

Renal Functional Abnormalities

Hematuria

Renal concentrating defect: It is the earliest functional abnormality detected especially in children. Usually asymptomatic, it may occasionally present as polyuria and polydipsia. The maximum urinary concentrating ability is significantly lower for children with >10 cysts than for unaffected siblings and normal controls {823+–54 mOsm, 940+–22 mOsm, 945+–21 mOsm respectively}.2 This decline in urinary concentrating ability increases with cysts size into adulthood {640+– 14 mOsm vs 812+–23 mOsm}. An important site of cyst formation appears to be the collecting duct at the corticomedullary junction. Thus, the more cysts present in a kidney, the more likely it is that the medullary architecture and countercurrent mechanisms that are vital in producing a maximally concentrated urine are disturbed.16 The renal cysts disrupt and destroy the urinary tubular concentrating functions and is one of the reasons for the decreased medullary trapping of ammonia and resultant decreased ammonia excretion.17 The reduction of urinary excretion of ammonia may contribute to the development of uric acid and calcium oxalate stones, which, in association with low urine pH values and hypocitric aciduria, occur with increased frequency in individuals with ADPKD.17 Studies suggest that the urinary concentrating defect and elevated serum concentration of vasopressin may contribute to cystogenesis.18 Water intake that is sufficient to cause persistent water diuresis suppresses B-Raf/MEK/ERK renal tubular epithelial cell growth factor activity and decreases cyst and renal volumes in PCK rats. This implies that by limiting surges of serum AVP levels by increased water intake may be beneficial to some patients with PKD. Elevated AVP levels may also contribute to the glomerular hyperfiltration seen in children and young adults, development of hypertension, and progression of chronic kidney disease.19

Microscopic or gross is related to worse outcomes at any age.22 Gross hematuria can occur in association with complications such as cyst hemorrhage and nephrolithiasis or as an isolated event. Cyst hemorrhage is a frequent cause of hematuria in ADPKD while other differential diagnoses include cyst infection, urinary tract infection, renal stones and an underlying malignancy.23 Renal Failure

GFR tends to be stable initially but then declines steeply. PKD1 mutations in patients induced a much steeper GFR decline than patients with PKD2 mutations or those without any detected mutation. Despite being nonlinear, the GFR decline in adulthood can be predicted from a single measurement of kidney volume. These GFR kinetic models are used for clinical prognostication, clinical trial design and patient selection for clinical interventions. MRI based renal volume and GFR analysis have proved a definite causal association between growth in total kidney volume and GFR decline.20 Interestingly, reduction in renal blood flow is an early functional abnormality, which can be detected in young individuals (even when systolic and diastolic blood pressures are still normal) and precedes the onset of hypertension.21 Renal blood flow reduction parallels total kidney volume (TKV) increase, precedes GFR decline and predicts structural and functional disease progression.21 The following variables were independently associated with worse mean renal function at a given age:22,24 • PKD1 gene • Younger age at diagnosis • Male gender • Hypertension • Left ventricular hypertrophy • Liver cysts in women • Three or more pregnancies

Clinical Presentations of Autosomal Dominant Polycystic Kidney Disease

• Gross hematuria • Urinary tract infections in men • Total kidney volume The following were not associated significantly with the course of renal function:22, 24 • Gender of affected parent • Mitral valve prolapse • Intracranial aneurysms • Hepatic cysts in men • Urinary tract infections in women Progressive renal failure is seen in ADPKD patients.25,26 Approximately 50% of individuals with ADPKD have ESRD by age 60 years. Mechanisms responsible for the decline in renal function include: Compression of the normal renal parenchyma by expanding cysts, vascular sclerosis, interstitial inflammation and fibrosis, and apoptosis of the tubular epithelial cells. ADPKD patients were more likely to receive a kidney transplant, use home HD, dialyze with an AVF, and have better survival relative to non-ADPKD patients. Conversely, they were less likely to receive PD either as initial therapy or anytime during ESKD.27 While outcomes on dialysis are better for ADPKD than for non-ADPKD patients, access to predialysis nephrology care and nondeclining ESRD rates may be a cause for concern.28 The CRISP study (consortium of imaging studies to assess the progression of polycystic kidney disease) was a prospective study of 241 nonazotemic ADPKD patients. Annual MRI examinations showed that total kidney volume (TKV) and cyst volumes increased exponentially. TKV was 1,060 ± 642 ml at baseline with mean increase of 204 ml over 3 years or 5.3% per year. The baseline TKV predicted the subsequent rate of increase in renal volume meaning that the larger the kidney, the faster the rate of renal enlargement over time and also the more rapid the rate of decline of GFR. Baseline TKV above 1,500 ml was associated with progressive decline of

15

GFR.19 Kidney size has been shown to be a strong predictor of subsequent decline in renal function with an ht TKV of  600 ml/m showing a high predictive value for the individual to develop renal insufficiency within 8 years.29 PKD1-related ADPKD is associated with larger kidneys and more cysts than individuals with PKD2-related ADPKD. A very important point is that the rates of cyst growth is not different in ADPKD1 and -2 indicating that PKD1-related ADPKD is more severe only because more cysts develop earlier, not because they grow faster.30 Occasionally, enlarged and echogenic kidneys with or without renal cysts are detected prenatally in a fetus at risk for ADPKD.31 Not surprisingly, the prognosis in these individuals is often more favorable than expected despite the large kidney size as a decrease in volume translates to no decline in renal function at least during childhood. However, ESRD develops earlier in very early onset than non-very early onset PKD. Biallelic PKD1 or PKD2 pathogenic variants have been reported in individuals with very early-onset ADPKD.32 Nephrolithiasis

The prevalence of renal stone disease in individuals with ADPKD is approximately 20%. The majority of stones are composed of uric acid and/or calcium oxalate.33 Computed tomography is the most sensitive imaging technique for detection of stones or calcifications, whereas intravenous urography is the most sensitive for visualization of the intrarenal collecting system. Urinary stasis occurs due to distorted renal anatomy and metabolic factors are also implicated in the pathogenesis. Metabolic abnormalities linked to distal tubular acidification defects, abnormal transport of ammonium, low urine pH, and hypocitruria are usually seen. Larger kidneys from patients with ADPKD were more prone to develop stones, irrespective of the presence of metabolic disturbances.34

16

Autosomal Dominant Polycystic Kidney Disease

Urinary tract infection and cyst infection. In the past, the increased presence of sterile pyuria leads to an erroneous overestimation of the incidence of urinary tract infection in individuals with ADPKD. Reflecting trends usually seen in general population, females experience urinary tract infections more frequently than males with the majority of infections due to E. coli and other Enterobacteriaceae. Retrograde infection from the bladder may lead to pyelonephritis or cyst infection. Renal cyst infections are responsible for nearly 9% of hospitalizations in individuals with ADPKD.35 High serum WBC, isolation of atypical pathogens and early infection after transplantation are factors that increase the risk of escalation of care in hepatic and renal cyst infection patients. 36 On CT imaging, 90.2% infected cysts are located in the subcapsular region. Most infected cysts showed lobulated, focal bulging or irregular shape. Discernible wall thickening (84.1%) was the most frequently found imaging feature of infected cysts followed by relatively higher intracystic attenuation and pericystic fat infiltration. Fluid/fluid level and intracystic gas was found in approx. 5% infected cysts. 85% infected cysts on US showed heterogeneous echogenicity.37 Renal cell carcinoma (RCC) does not occur more frequently in individuals with ADPKD than in the general population. However, renal cell cancers in ADPKD have atypical presentations with earlier age of presentation, increased frequency of constitutional symptoms and a higher incidence of sarcomatoid, bilateral, multicentric, and metastatic tumors. Males and females with ADPKD are equally likely to develop RCC. Usual imaging findings include solid mass on ultrasound; speckled calcifications on CT examination; and contrast enhancement, tumor thrombus, and regional lymphadenopathies on CT or MRI. There is up to 3 times increased risk for RCC in individuals with ADPKD who are on dialysis for ESRD than ESRD alone. 38 A

retrospective study of 40,821 medicare primary renal transplant recipients transplanted from January 1, 2000 to July 31, 2005 (excluding those with pre-transplant nephrectomy), demonstrated that acquired renal cystic disease pre-transplant, but not ADPKD, and was associated with posttransplant RCC. When age and other co-variants were taken into consideration, the rate of all cancers in individuals with ADPKD after kidney transplantation was reported to be lower than in kidney transplant recipients who did not have ADPKD. 39 Other: Massive renal enlargement can cause complications resulting from compression of local structures, such as inferior vena cava compression and gastric outlet obstruction mainly caused by cysts of the right kidney. Extrarenal Manifestations

Extrarenal manifestations in ADPKD include cysts in other epithelial organs such as liver, pancreas, prostate, uterus and pericardium.40 ADPKD patients also show connective tissue defects such as intracranial aneurysms, arachnoid cysts, cardiac valve abnormalities, aortic dissection and abdominal wall hernias.41, 42 In the liver, it can result in severe polycystic liver disease (PLD) requiring surgical intervention. Other notable phenotypes in ADPKD involve the vasculature, with intracranial aneurysms approximately five times more common than in the general population and significant morbidity/mortality associated with aneurysmal rupture. 42 Syndromic forms of PKD are ciliopathies. The pleiotropic phenotypes in these syndromic disorders can likely be linked to defects in ciliary function. Polycystic liver disease (PLD) is the most common extrarenel manifestation of ADPKD. Hepatic cysts are rarely seen in children and its frequency increases with age. Their

Clinical Presentations of Autosomal Dominant Polycystic Kidney Disease

prevalence was 58% in participants age 15– 24 years, 85% in those age 25–34 years, and 94% in those age 35–46 years in the CRISP study.43 PLD tends to develop at a younger age in women than men and is more severe in women who have had multiple pregnancies. Estrogen replacement therapy use after menopause was shown to increase liver cyst size suggesting that estrogens have a proliferative effect on the progression of PLD and naturally cysts showed regression after menopause.44, 46 Analysis of individuals with severe PLD, defined as a height-adjusted total liver volume of 1.8 liters, showed no difference in frequency among those with truncating PKD1 variants, non-truncating PKD1 variants, and PKD2 pathogenic variants, suggesting that other factors are primarily responsible for the severity of PLD.45 Liver cysts are generally asymptomatic and usually are not associated with liver failure. Symptoms are mainly due to mass effects like pain and abdominal distention, early satiety, dyspnea, and low back pain. Liver cysts can also cause extrinsic compression of the inferior vena cava (IVC), hepatic veins, or bile ducts.47 The liver cyst epithelia produce and secrete carbohydrate antigen 19-9 (CA19-9), a tumor marker for gastrointestinal cancers. The concentration of CA19-9 is increased in the serum of patients with PLD and is markedly elevated in hepatic cyst fluid. Serum CA19-9 levels correlate with polycystic liver volume.48, 49 Elevations of CA19-9 can also be elevated in acute cholangitis or diverticulitis. Complications of PLD are similar to renal cysts and include cyst hemorrhage, infection, or rupture. Hemorrhagic cysts may cause febrile illness mimicking cholecystitis or cyst infection. Cyst infections are usually caused by enterobacteriaceae, presenting with localized pain or tenderness, fever, leukocytosis, elevated erythrocyte sedimentation rate, and high serum concentration of alkaline phosphatase and CA19-9. CT and MRI are

17

helpful in the diagnosis of cyst infection but have low specificity. Signs of cyst infection on CT examination include fluid-debris levels within cysts, cyst wall thickening, intracystic gas bubbles, and heterogeneous or increased density. Indium-labeled white blood cell scans are more specific for abscess formation. 18 Ffluorodeoxyglucose positron emission tomography examination is the most sensitive technique for diagnosis of infected cysts. The rupture of a hepatic cyst can cause acute abdominal pain and ascites.50 • For hepatic cysts, 80% infected cysts showed pericystic hyperemia. Intracystic attenuation was significantly higher in infected cysts. Other Liver Disease Presentations

• Cholangitis due to dilatation of biliary ducts • Congenital hepatic fibrosis is rarely seen in individuals with ADPKD. • Cholangiocarcinoma is rarely associated with ADPKD. • Case reports of adenomas of the ampulla of Vater. Pancreatic Lesions

Pancreatic cysts occurrence is rare and is seen in approximately 8% of individuals with ADPKD. Almost always asymptomatic pancreatic cysts have been rarely associated with recurrent pancreatitis.51Although intraductal papillary mucinous tumors have been reported with increased frequency, their prevalence and prognosis in ADPKD is of uncertain importance. 52 An association between ADPKD and pancreatic carcinomas may represent a chance association of two common disorders.53 Cysts in Other Organs

• Seminal vesicle cysts may be noted in 40% of males but rarely result in infertility. Defective sperm motility is another cause of male infertility in ADPKD.54

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Autosomal Dominant Polycystic Kidney Disease

• Arachnoid membrane cysts, present in 8% of affected individuals, are usually asymptomatic, but may increase the risk for subdural hematomas.55,56 • Spinal meningeal diverticula may occur with increased frequency and individuals may present with intracranial hypotension secondary to cerebrospinal fluid leak.57,58 • Ovarian cysts are not associated with ADPKD.13 Vascular and Cardiac Manifestations

Some of the most important noncystic manifestations of ADPKD are vascular malformations like presence of intracranial and other arterial aneurysms and more rarely, dolichoectasias, dilatation of the aortic root, dissection of the thoracic aorta and cervicocephalic arteries, abnormalities of the cardiac valves, and, possibly, coronary artery aneurysms.42, 59 There are described case series of familial clustering of thoracic aortic dissections in ADPKD. Intracranial aneurysms are found in approximately 10% of individuals with ADPKD.60 A positive family history is present in individuals with intracranial or subarachnoid hemorrhage (22%) than in those without such a family history (6%). The majority of intracranial aneurysms are asymptomatic. 54% of the patients still have a normal renal function at that time, and 26% had a BP within the normal range before rupture.61 Focal findings, such as cranial nerve palsy or seizure, may result from compression of local structures by an enlarging aneurysm. The mean age of rupture of intracranial aneurysms is lower in individuals with ADPKD than in the general population (39 years vs 51 years). The risk of rupture of asymptomatic intracranial aneurysms depends on the history of rupture from a different site.62 With no previous history of rupture at another site, the risk for rupture is as follows: • 0.05% per year for aneurysms 50 mg/L, abdominal pain (palpable site of liver/renal tenderness) and absence of any significant recent intracystic bleeding or any other cause of fever.4,5 Recent intracystic bleed can be ruled out from absence of CT augmentation indicated by spontaneous intracystic density greater than 25 HU. 5 However, except for cyst aspiration, none of these criteria are specific for the diagnosis of cyst infection or pyocyst. They are not useful for identifying location of cyst or for distinguishing from cyst hemorrhage with superadded infection. Based on the study by Lantinga et al which was framed to evaluate various diagnostic criteria, it was found that fever (median 39.0°C), abdominal pain (89%) and raised CRP (median 226 mg/L) were indicators for cyst infection and should be part of diagnostic criteria. Cyst aspiration showing infection is considered the gold standard for diagnosis. In absence of cyst aspirate, it was suggested to diagnose cyst infection from a combination of clinical, biochemical and imaging findings preferably including 18FDGPET/CT.9 Diagnosis

The major objectives for diagnostic testing in ADPKD patients with suspected cyst infection are as follows: (a) To rule out non-cyst infections, (ii) to identify location of infected cysts, (iii) to find the causative microorganism and its sensitivity pattern, and (iv) to rule out associated conditions, such as obstruction or calculi. URINALYSIS AND MICROBIOLOGY

Approach to diagnosis of renal infections in ADPKD is similar to the approach in patients without ADPKD. Complete physical examination, urinalysis, urine culture and sensitivity and blood culture should be done in all suspected cases of UTI in ADPKD. Findings

Complications of Autosomal Dominant Polycystic Kidney Disease

may be nonspecific but may help to differentiate cyst infection from acute pyelonephritis. As the cysts may not be in communication with the collecting system, urinalysis may not show pyuria and urine culture may be negative in cyst infections. Acute pyelonephritis is more commonly associated with pyuria and a positive urine culture. Positive blood cultures may be found in both. In a study done with 36 patients of ADPKD who had 41 episodes of renal or liver cyst infection, urine culture was positive in 39% of episodes and blood culture was positive in 24% of cases and cyst fluid culture was positive in 12% of cases.4 Gram-negative enteric organisms were commonly implicated in cyst infections with Escherichia coli being the most common organism isolated. This further indicates ascending mechanism of cyst infection. Liver cyst infection was associated with bacteria generally found in the digestive system. However, bacteria less commonly found in the urinary tract such as Staphylococcus aureus, Lactobacillus, Enterococcus species and anaerobic bacteria were also found in 15% of all cyst infections. SERUM MARKERS

CRP level more than 50 mg/L may be used as a useful indicator of cyst infection. Median CRP level was 205 mg/L in patients with definite cyst infection in the study by Sallée et al.4 The utility of CRP as a diagnostic marker in patients with ADPKD on hemodialysis is questionable in view of the elevation of CRP due to other reasons in this group of patients.7 Serum levels of CA19-9 may be useful in the diagnosis of liver cyst infections.5 CA19-9 is probably secreted by the biliary epithelial cyst lining. In ADPKD patients with liver cyst infection, cyst fluid CA19-9 was high and serum CA19-9 was markedly higher than that found in asymptomatic patients with ADPKD and in controls. It may potentially be useful as a diagnostic marker of hepatic cyst infections.10 However, that serum cut-off level

25

with optimum sensitivity and specificity for diagnosis has not been specified. USG, CT AND MRI

ADPKD is associated with profound alteration of the anatomy of the liver and kidney and therefore, cyst infections may not be identified by conventional imaging techniques. Ultrasonography (USG) was considered suggestive of likely renal or liver cyst infection in case of presence of a thick walled cyst with debris and/ or at least one cyst showing distal acoustic enhancement. CT and MRI were considered indicative of likely cyst infection in the presence of enhanced wall thickening or perilesional inflammation in at least one cyst.4 Heterogenous content also indicated cyst infection but intracystic debris had poor specificity in differentiating infected and non-infected cysts. Cyst wall enhancement could also be seen in both inflammation and presence of residual functioning renal parenchyma. There is also a limitation in ADPKD patients with chronic kidney disease (CKD) with use of radiological contrast being contraindicated.5,11 dwMRI (diffusion weighted MRI) may help in identifying infected cysts from decreased ADC (apparent diffusion coefficient) value.12 In the study by Salée et al, USG, CT and MRI did not detect cyst infection in 94, 82 and 60% cases respectively and yielded negative results in over half the patients with definite cyst infections.4 RADIOLABELED LEUKOCYTE SCINTIGRAPHY

Radiolabeled leukocytes may be utilized with conventional imaging to localize cyst infections. Gallium scans or 111In leukocyte scanning can identify cyst infections. HMPAO (hexamethylpropylene amine oxime) aids in 99m Tc (technetium 99m) labeling of leukocytes.5 18

FDG-PET/CT

18

FDG-PET/CT is a reliable modality for detecting tissue infection due to the raised

26

Autosomal Dominant Polycystic Kidney Disease

metabolic activity and increased uptake by inflammatory cells of 18 FDG, a glucose analogue. The advantage of 18FDG is the absence of nephro- or hepatotoxicity and safety for use in patients with ESRD. Metabolic data from 18 FDG-PET is combined with anatomical data from CT for better localization of cyst infections. Positive PETCT result for cyst infection was considered in case of focally increased uptake of 18FDG at least around one cyst when compared to physiological accumulation in renal parenchyma and it was situated away from the pelvicalyceal system. 5 18FDG-PET/CT identified cyst infection successfully in 85% of cases.13 PET-CT would also identify other sources of infection especially in the setting of pyrexia of unknown origin. Other advantages of PET-CT include fast imaging, good interobserver agreement and lack of need for contrast injection. Limitations include cost, limited availability in low-resource settings and difficulty in distinguishing infections from other non-infective inflammatory conditions and malignancy. PET scan is yet to be evaluated in cyst hemorrhage which is the major differential diagnosis for cyst infection. However, significant cyst hemorrhage can be easily ruled out from the CT imaging. It is therefore now suggested to use 18FDG-PET as a first-line tool for the diagnosis of cyst infections in ADPKD and also for patient follow-up after antibiotic therapy. New diagnostic criteria for cyst infection including PET/CT need to be defined. The sensitivity and specificity and costbenefit ratio also need to be established.4, 5 Differential Diagnosis of Renal Infections

The major diagnostic dilemma in renal infections is distinguishing pyelonephritis and pyocysts from cyst hemorrhage. Bleeding into cyst usually presents with sudden onset flank pain and transient fever in the absence of LUTS, dysuria or pyuria. Cultures are usually negative in cyst hemorrhage.

MANAGEMENT OF CYST INFECTIONS Antibiotic Therapy

Patients with ADPKD with systemic symptoms of infection should be admitted and after relevant investigations, must be started on empirical antibiotic therapy if renal infection is suspected. Initial empirical antibiotic therapy should cover both pyelonephritis and cyst infection. Diagnosing pyocyst is important due to implications on antibiotic selection, duration of therapy and possible need for surgical drainage. Large cysts >2 cm are usually not connected to the glomerulus and antibiotics administered cannot reach the cyst through glomerular filtration. Antibiotics enter into cysts either through passive diffusion or active transepithelial transport. Drugs that can be detected in cysts include lipid soluble (lipophilic) drugs, those that undergo tubular secretion or have high pKa.14 Drugs that have good permeability into cysts and therefore achieve therapeutic intracyst concentrations include metronidazole, clindamycin, trimethoprim-sulfamethoxazole, vancomycin, cefotaxime and erythromycin. Trimethoprim has good penetration but sulfamethoxazole may not reach therapeutic concentrations in cysts. Aminoglycosides and penicillins have poor penetration into cysts. Chloramphenicol and fluoroquinolones like ciprofloxacin and levofloxacin have good penetration into cysts. One study demonstrated poor penetration of meropenem into cysts but the intracyst level was higher than the MIC for the microorganism.4,14–18 Diffusion of antibiotics may be altered by the inflammation and hyperpermeability in the cyst wall vessels in the presence of cyst infection. First-line agents used include fluoroquinolones and third generation cephalosporins which were used as initial therapy in 95% of patients with cyst infections in a retrospective study. Fluoroquinolones are favored due to lipophilic property, good cyst penetration and bactericidal action against

Complications of Autosomal Dominant Polycystic Kidney Disease

enteric gram-negative pathogens. Clinical efficacy of antibiotic therapy was 71% in the study by Sallée et al with higher efficacy for quinolones alone (66%) compared to betalactam antibiotics (33%). Combination therapy with 2 agents was also superior to monotherapy.4 However, due to increasing quinolone resistance, quinolones may not be useful as initial empirical therapy. Third generation cephalosporin like cefotaxime or a combination of beta-lactamine like ampicillin with aminoglycoside like gentamicin may be more useful as initial therapy. In case of suspicion of staphylococcal or other grampositive infection, vancomycin may be considered. Levofloxacin has good activity against group A Streptococcus. If anaerobic infections are suspected, metronidazole or clindamycin should be added. Initial antibiotic therapy in cyst infection has high failure rate (61%) and long-term antibiotic therapy may be required. There is limited clinical evidence on optimum duration of antibiotic therapy in cyst infection but the study by Lantinga et al showed that duration of antibiotic therapy was significantly shorter in the treatment failure group (median 7 days) compared to the treatment success group (median 28 days). In addition, cysts larger than 5 cm diameter, obstruction and urolithiasis were associated with treatment failure. 19 Acute pyelonephritis is usually treated with IV antibiotics for at least 10 to 14 days. Cyst infections may require longer treatment for 4–6 weeks. In cases of recurrence of infection, the patient may require antibiotics for longer period of two to three months.20 Outcome of treatment was assessed from clinical improvement of patient. Resolution of fever, decline in CRP levels and negative repeat blood and urine cultures are to be used to follow the patient. In case of no response after 72 hours after initiating appropriate therapy or persistence of fever for more than 1 week, imaging with CT should be done to rule out calculi or obstruction and to detect

27

large infected cysts or perinephric abscess. Possible other causes of fever should also be considered.19 SURGICAL INTERVENTION

Percutaneous or surgical drainage must be considered for large cysts (5 cm or more in diameter) which are unlikely to respond to medical management and cyst infections not responding to initial antibiotic therapy. Drainage is also required for perinephric abscesses. However, there is no randomized control trial comparing medical management and interventional therapy. Hepatic cysts require early drainage and a combination of medical therapy with drainage is superior to antibiotics alone in liver cysts.4, 21 Nephrectomy is usually considered as last-resort procedure. It may be considered in infections with gas-forming organisms like Clostridium difficile and patients with staghorn calculi in a non-functioning kidney. Pretransplant nephrectomy may be considered in patients with recurrent, refractory and recent infections. It is not routinely recommended in patients without recurrent UTI as posttransplant UTI rates are not altogether higher in the non-nephrectomised bunch contrasted with the nephrectomised bunch.22, 23 REFERENCES 1. Delaney VB, Adler S, Bruns FJ, Licinia M, Segel DP, Fraley DS. Autosomal dominant polycystic kidney disease: presentation, complications, and prognosis. American Journal of Kidney Diseases. 1985 Feb 1;5(2):104–11. 2. Sklar AH, Caruana RJ, Lammers JE, Strauser GD. Renal infections in autosomal dominant polycystic kidney disease. American Journal of Kidney Diseases. 1987 Aug 1;10(2):81–8. 3. Stiasny B, Ziebell D, Graf S, Hauser IA, Schulze BD. Clinical aspects of renal transplantation in polycystic kidney disease. Clinical nephrology. 2002 Jul;58(1):16–24. 4. Sallée M, Rafat C, Zahar JR, Paulmier B, Grünfeld JP, Knebelmann B, Fakhouri F. Cyst infections in patients with autosomal dominant polycystic

28

5.

6.

7. 8.

9.

10.

11.

12.

13.

14.

Autosomal Dominant Polycystic Kidney Disease

kidney disease. Clinical Journal of the American Society of Nephrology. 2009 Jul 1;4(7):1183–9. Jouret F, Lhommel R, Devuyst O, Annet L, Pirson Y, Hassoun Z, Kanaan N. Diagnosis of cyst infection in patients with autosomal dominant polycystic kidney disease: attributes and limitations of the current modalities. Nephrology Dialysis Transplantation. 2012 Oct 1;27(10):3746–51. Montero N, Sans L, Webster AC, Pascual J. Interventions for infected cysts in people with autosomal dominant polycystic kidney disease. Cochrane Database of Systematic Reviews. 2014(1). Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858. CD010946/full Alam A, Perrone RD. Managing cyst infections in ADPKD: an old problem looking for new answers. Christophe JL. van Ypersele de Strihou C, Pirson Y. Complications of autosomal dominant polycystic kidney disease in 50 haemodialysed patients. A case-control study. The UCL Collaborative Group. Nephrol Dial Transplant. 1996 Jul;11(7):1271-6. Lantinga MA, Drenth JP, Gevers TJ. Diagnostic criteria in renal and hepatic cyst infection. Nephrology Dialysis Transplantation. 2015 May 1;30(5):744–51. Kanaan N, Goffin E, Pirson Y, Devuyst O, Hassoun Z. Carbohydrate antigen 19–9 as a diagnostic marker for hepatic cyst infection in autosomal dominant polycystic kidney disease. American journal of kidney diseases. 2010 May 1;55(5):916–22. Gupta S, Seith A, Dhiman RK, Chawla YK, Sud K, Kohli HS, Sakhuja V, Suri S. CT of liver cysts in patients with autosomal dominant polycystic kidney disease. Acta Radiologica. 1999 Jan 1;40(4):444–8. Ichioka K, Saito R, Matsui Y, Terai A. Diffusionweighted magnetic resonance imaging of infected renal cysts in a patient with polycystic kidney disease. Urology. 2007 Dec 1;70(6):1219. Jouret F, Lhommel R, Beguin C, Devuyst O, Pirson Y, Hassoun Z, Kanaan N. Positron emission computed tomography in cyst infection diagnosis in patients with autosomal dominant polycystic kidney disease. Clinical Journal of the American Society of Nephrology. 2011 Jul 1;6(7):1644–50. Bennett WM, Elzinga L, Pulliam JP, Rashad AL, Barry JM. Cyst fluid antibiotic concentrations in autosomal-dominant polycystic kidney disease. American Journal of Kidney Diseases. 1985 Dec 1;6(6):400–4.

15. Elzinga LW, Golper TA, Rashad AL, Carr ME, Bennett WM. Ciprofloxacin activity in cyst fluid from polycystic kidneys. Antimicrobial agents and chemotherapy. 1988 Jun 1;32(6):844–7. 16. Hiyama L, Tang A, Miller LG. Levofloxacin penetration into a renal cyst in a patient with autosomal dominant polycystic kidney disease. American Journal of Kidney Diseases. 2006 Jan 1;47(1):e9–13. 17. Schwab SJ, Weaver ME. Penetration of trimethoprim and sulfamethoxazole into cysts in a patient with autosomal-dominant polycystic kidney disease. American Journal of Kidney Diseases. 1986 May 1;7(5):434–8. 18. Hamanoue S, Suwabe T, Ubara Y, Kikuchi K, Hazue R, Mise K, Ueno T, Takaichi K, Matsumoto K, Morita K. Cyst infection in autosomal dominant polycystic kidney disease: penetration of meropenem into infected cysts. BMC nephrology. 2018 Dec 1;19(1): 272. 19. Lantinga MA, Casteleijn NF, Geudens A, de Sevaux RG, van Assen S, Leliveld AM, Gansevoort RT, Drenth JP, DIPAK Consortium. Management of renal cyst infection in patients with autosomal dominant polycystic kidney disease: a systematic review. Nephrology Dialysis Transplantation. 2017 Jan 1;32(1):144–50. 20. Gabow PA, Bennett WM. Renal manifestations: complication management and long-term outcome of autosomal dominant polycystic kidney disease. InSeminars in nephrology 1991 Nov 1 (Vol. 11, No. 6, pp. 643–652). Elsevier. 21. Telenti A, Torres VE, Gross Jr Jb, Van Scoy RE, Brown Ml, Hattery RR. Hepatic cyst infection in autosomal dominant polycystic kidney disease. In Mayo Clinic Proceedings 1990 Jul 1; 65(7): 933– 94 Elsevier. 22. Salehipour M, Jalaeian H, Salahi H, Bahador A, Davari HR, Nikeghbalian S, Sagheb MM, RaissJalali GA, Roozbeh J, Behzadi S, Janghorban P. Are large nonfunctional kidneys risk factors for posttransplantation urinary tract infection in patients with end-stage renal disease due to autosomal dominant polycystic kidney disease? InTransplantation proceedings 2007 May 1; 39(4): 887–888. Elsevier. 23. Rozanski J, Kozlowska I, Myslak M, Domanski L, Sienko J, Ciechanowski K, Ostrowski M. Pretransplant nephrectomy in patients with autosomal dominant polycystic kidney disease. InTransplantation proceedings 2005 Mar 1; 37(2): 666–668. Elsevier.

Complications of Autosomal Dominant Polycystic Kidney Disease

29

NEPHROLITHIASIS IN ADPKD—DILEMMAS Anant Kumar, Rakhul LR

In an ADPKD patient, treatment options for symptomatic urolithiasis should not differ from those in normal kidneys. Special emphasis should be given for preoperative imaging to delineate the collecting system anatomy and plan accordingly. With adequate preoperative planning and modifications in standard treatment approaches, satisfactory stone clearance rates can be achieved without significant morbidity. INTRODUCTION

Nephrolithiasis occurs more frequently in patients with ADPKD 1,2 with a reported incidence of 8–36%.2–4 When compared to general population, the relative risk for stone formation is 2–10 times higher in this group.2, 5 Frequency of stone formation is similar in men and women.2 Age at presentation of nephrolithiasis is 39+/–14 years for symptomatic cases and 42+/–12 for asymptomatic cases.2 25–50% of patients are symptomatic. 2, 6 Presence of nephrolithiasis can have an adverse effect on the polycystic kidneys, it leads to the commencement of kidney failure, infection as well.7, 8 The combination of both anatomic and metabolic factors prevalent in polycystic kidneys itself explain the higher occurrence of urolithiasis in these kidneys. a. Anatomical factors: The enlarging cysts exert compression on the collecting system, which in turn leads to urinary stasis and stone formation.9, 10 Those ADPKD patients with stone were found to have significantly greater total number of cysts and predominant cyst size.10 This relation shows that, as the disease progresses, there is more distortion of the collecting system and more urinary stasis, which forms a favorable milieu for stone formation.9, 10 This in turn progressively affect the medullary archi-

tecture as well and result in abnormal tubular function in the form of impaired ammonia handling and excretion by the renal unit, resulting in lower urinary pH.11 b. Metabolic factors: Elegant studies by Torres et al and Grampass et al and various others have shown mainly two types of metabolic anomalies in the urine of ADPKD patients.2, 10, 11 i. Hypocitraturia ii. Low urine pH Surprisingly, the usual metabolic abnormalities seen in non-PKD stone formers like hypercalciuria, hyperoxaluria and hyperuricosuria were seen infrequently in this group.4,9 These metabolic abnormalities also explains the type of stones formed in ADPKD patients— majority are uric acid stones (secondary to low pH) and calcium oxalate monohydrate stones (due to hypocitraturia). The cause for low urine pH is postulated due to defective ammonia excretion in the distal tubules.4 Exact cause of hypocitraturia is not known, but it is not due to distal renal tubular acidosis as once thought. Other contributive metabolic factors include low urinary levels of magnesium, phosphate and potassium4,6 and also reduced urine volume (these patients typically produce up to 30% lower volume of urine compared to general population). Knowledge of these factors explained the widespread use of potassium citrate in the treatment of PKD patients with nephrolithiasis. Various conditions associated with ADPKD like uric acid lithiasis, hypocitraturia, calcium oxalate lithiasis, and distal acidification defects are effectively and efficiently treated with potassium citrate.4, 12 Symptoms

Flank pain and hematuria are the most important manifestations of ADPKD. But

30

Autosomal Dominant Polycystic Kidney Disease

these may result from a variety of complications like urolithiasis, cyst hemorrhage, cyst infection, or cyst neoplasm. 13 Differentiation among these causes is important. Low back pain had also been reported much more frequently in ADPKD patients with stones.14 Approximately half the number of patients will have symptoms, but it is the other half that is a concern, their renal function can silently deteriorate. Investigations

Basic blood and urine investigations, renal function and urine cultures should be done in all. Imaging plays the major role in planning management. Abdominal Imaging

All the routine diagnostic imaging modalities can be used in a case of PKD with stones, but certain special points are to be considered. We will discuss the pros and cons of each. 1. X-ray KUB: Highly unreliable examinations to screen/analyze stones in PKD, as the vast majority of them are uric acid stones and characteristically radiolucent. Moreover, X-ray cannot differentiate between cyst/ parenchymal calcification and stones. 2. Ultrasonography: It is good screening investigation with 90% specificity for detecting stones but sensitivity is as low as 24%.15 Cannot reliably differentiate stones from calcifications and also operator dependent, multiple cysts may obscure visualization of calculi and other important findings.14 3. CT scan: This is the most sensitive and specific modality to identify kidney stones all in all14 and those in ADPKD specifically. Sensitivity and specificity of CT in detecting urolithiasis in ADPKD is 63% and 81% respectively. CT reliably diagnoses renal stones, also delineates the kidney architecture, orientation of the collecting system and cysts, amount of distortion and compression of the PCS caused by the cysts. It will also show cyst hemorrhages,

calcification, rupture, neoplasm, etc. CT has the added benefit of screening the rest of the abdominal viscera for the extrarenal manifestations of the disease.16 To differentiate uric acid stones from calcium containing stones newer modalities like dual energy CT scan is highly valuable; also it guides in the management.17 Stone Analysis and Metabolic Evaluation

Stone analysis should be incorporated into the diagnostic armamentarium as it can point to various pathologies. Most of the stones in PKD patients consist of uric acid and a smaller number of calcium oxalate monohydrate stones.2,14 Any other type of stones if encountered should raise the suspicion of an underlying metabolic problem or infection depending on the stone composition. Because of raised risk of recurrent stone formation; a thorough metabolic evaluation in stone forming PKD patients is imperative. If any correctable metabolic abnormalities are detected; early in the disease course, will definitely help to decrease the morbidity by avoiding stone formation in future. The most commonly observed anomalies include hypocitraturia, low urine pH, and reduced urine volume.6,11 Most patients with ADPKD will have a urine pH less than 5.5 either in the normal state or after acid load, ruling out the possibility of distal RTA.4,13,14 Such patients would benefit from adequate oral hydration and alkalinization with oral potassium citrate, which will prevent uric acid crystallization and reduce calcium oxalate supersaturation. Various Surgical Options for Stone Removal (Fig. 4.1) ESWL in the Management of Urolithiasis in ADPKD Patients

Since the article by Dimitrios et al in 199718 and various others19, presence of renal cysts is no longer considered a contraindication for SWL. Initially there had been concerns

Complications of Autosomal Dominant Polycystic Kidney Disease

31

Fig. 4.1: Various surgical options for stone removal in ADPKD (based on size and density of stone)

regarding cyst hemorrhage but many of the later studies did not show any significantly increased incidence of this complication.18–20 However, it is advisable to subject the kidneys to lesser number of shocks as far as possible. Stone clearance rates following SWL are uniformly low when compared to normal kidneys. 18,19 The anatomical obstruction caused by the cysts on the PCS impairing the drainage of stone fragments is the likely cause.19 Complete stone clearance in various published series vary from 0 to 80%.18, 19, 21 The clearance rate is inversely proportional to the number of cysts, more number of cysts–more

PCS distortion–more obstruction–more retained fragments.19 Likewise, renal pelvic stones have had better clearance than calyceal stones, as one may expect.21 SWL is not without complications—these include hemorrhage into the cyst, cyst ruptures, perirenal hemorrhages and cyst infections. But these are remarkably rare in modern day series 18, 19, 21 and when the procedure is properly performed. Incomplete clearance remains the single most important problem and multiple SWLs or auxiliary procedures are required in unfavorable cases. 18 Routine stenting of ureter is not

32

Autosomal Dominant Polycystic Kidney Disease

recommended and unnecessary during SWL in general 22, 23 (phone screen). But some authors do recommend pre-procedure DJ stent insertion in polycystic kidneys, since obstruction in these susceptible kidneys can have delirious effects like worsening of kidney function and infection as well.18 Nephrolithiasis Management in ADPKD with RIRS

The introduction of flexible ureterorenoscopes and miniaturization of instruments has made retrograde access into collecting system possible. But in case of cystic kidneys performing RIRS is challenging because of the abnormal calyceal architecture caused by compressing cysts. Infundibulae become long and slender making it extremely difficult for the endoscopist to negotiate the scope through. Moreover, the residual fragments will not pass spontaneously unless they are finely dusted to navigate through long narrow infundibulum. This is especially true in cases of lower calyceal stones.24 Most of the published series describe more than one sitting for complete clearance. Thus, RIRS has to be offered only to select group of patients with low stone burden and favorable calyceal anatomy, and always be prepared for multiple sittings or auxiliary procedures.21, 24, 25 PCNL in ADPKD

Performing PCNL in patients with ADPKD could be challenging due to abnormal calyceal anatomy and presence of multiple cysts. 5 Narrow and elongated interferes with the proper puncture and dilation. 8 The compressive effect of the cysts is more important than their size and location. Furthermore, the patients could have varying degrees of chronic renal impairment with a coagulation defect. Both efficacy and safety of PCNL in ADPKD patients had been well established.5, 8, 12, 26 The initial puncture can be done using fluoroscopy or USG. US-guided puncture

could be difficult due to the interference of multiple cysts and compressed calyces, but it helps to avoid cyst punctures.21 Most of the authors used fluoroscopic punctures.5, 8, 12, 26 except a few.21, 27 Confirmation of calyceal puncture may be difficult due to aspirated cyst fluid mimicking urine. Al-kandari et al suggested retrograde instillation of blue dye into PCS, aspiration of which confirms PCS entry.8 Normal saline alone can also be used5, 21 the gush of which confirms proper entry. Wang et al reported US-guided punctures with retrograde instillation of contrast to create turbulence and easy identification of calyces.27 Cyst aspiration may be done to facilitate calyceal localization.12 Some authors prefer puncture by interventional radiologists.12 The calyx for puncture is chosen depending on the stone location and the width of the target calyx. One should not try to forcibly dilate a narrow calyx, instead choose another, wider, calyx to access most of the stone bulk, and use flexible nephroscope to access the rest. Tract can be dilated to 28 Fr but be careful not to overdilate as the calyces are narrow and parenchyma is thin. Extra-long nephroscopes are usually not required, but slender scopes would be of help in narrow calyces.12 Multiple punctures are not contraindicated, but better to avoid in those with marginal renal functions for the fear of nephron loss. Puncture wash can be done instead.21 All the published series support the use of nephrostomy tubes and double J stents.5, 8, 12, 21, 25–27

It is advisable to do imaging before removal of nephrostomy tube to confirm stone clearance26, either nephrostogram12 or even better, a CT. 5, 8 Successful treatment is— complete removal of the targeted stones or presence of insignificant fragments only (less than 4 mm). A relook PCNL was performed in those with clinically significant residual fragments. ESWL can also be used as an alternative.

Complications of Autosomal Dominant Polycystic Kidney Disease

The success rates in terms of stone free rate in various series are as follows Year of publication

Authors

Stone clearance (after first PCNL)

Stone clearance (after 2nd procedure— PCNL/ ESWL)

2009

Al-Kandari et al8

NA

89.4%

2010

Umbreit et al12

82%

100%

2011

Srivastava et al5

88%

96%

67%

100%

82.1%

92.85%

83%

100%

2012 2013 2019

Baishya et al Singh et al

21

26

G. Singh et al

25

These data are comparable with the stone clearance rates in non-PKD patients undergoing PCNL. Complications of PCNL in PKD Patients 1. Bleeding requiring transfusion

Incidence varied from 0 to 13% in most series5, 8,12,27, comparable to non-PKD-PCNL cases (0–17.5%8). All of them were managed by transfusion and none required angioembolization or open surgery. 2. Postoperative fever due to cyst infection

Incidence of fever varies from 0 to 18%. Urine cultures can be sterile and because of poor penetration of antibiotics into the cyst itself, even with antibiotic treatment; patients get the fever. Renal USG or CT can guide in aspiration of infected cyst material and appropriate antibiotic therapy.6, 26, 28 Long-term treatment with cyst penetrating lipophilic antibiotics may be required. 3. Deterioration of renal function

None of the available evidence show any persistent deterioration in renal function after PCNL in ADPKD. It remained nearly stable or improved.5, 8 Three of the patients in Singh et al series showed transient worsening of

33

function in immediate postoperative period, which improved with conservative measures. 4. Other complications

Rest of the complications like collecting system and visceral injuries, chest and neuromusculoskeletal complications, etc. are similar to non-PKD patients In summary, PCNL in ADPKD gives satisfactory stone-free rate with acceptable morbidity. The approach to such renal units slightly differs from usual PCNL. Also, multiple procedures may be required for complete clearance. The outcome and complications are comparable to kidneys with normal anatomy. PCNL is the modality of choice for the management of ADPKD patients with large stone burden, whenever possible. Open Surgery

In the past, most of the ADPKD patients underwent pyelolithotomies for stone removal. It was associated with high morbidity. In present day practice most patients can be managed via minimally invasive methods. Occasional patient with unfavorable anatomy and large stone burden may still be a candidate for this time-tested procedure. Nonsalvageable renal units with infection and stone may have to be removed in toto. Laparoscopic nephrectomy can be challenging in such cases and open surgery is to be preferred. Medical Management of Lithiasis in ADPKD

Since most of the stones in cystic kidneys are made of uric acid and the basic metabolic abnormalities include low urine pH and hypocitraturia, medical dissolution therapy with potassium citrate may be tried in “small” asymptomatic stones. But the threshold stone size for surgical intervention is not defined. It was probably the only option available in the past for stones not big enough to undergo a

34

Autosomal Dominant Polycystic Kidney Disease

pyelolithotomy. A reasonable approach today will be to use potassium citrate as a method to prevent stone formation and to treat asymptomatic small nonobstructing uric acid renal calculi in cystic kidneys with normal renal function. REFERENCES 1. Delaney VB, Adler S, Bruns FJ, Licinia M, Segel DP, Fraley DS. Autosomal dominant polycystic kidney disease: presentation, complications, and prognosis. American Journal of Kidney Diseases. 1985;5(2):104–11. 2. Torres V, Erickson S, Smith L, Wilson D, Hattery R, Segura J. The association of nephrolithiasis and autosomal dominant polycystic kidney disease. American Journal of Kidney Diseases. 1988;11(4): 318–25. 3. Idrizi A, Barbullushi M, Gjata M, Koroshi A, Roshi E, Backa T, et al. Prevalence of nephrolithiasis in polycystic kidney disease. Central European Journal of Medicine. 2011;6(4):497. 4. Torres VE, Wilson DM, Hattery RR, Segura JW. Renal stone disease in autosomal dominant polycystic kidney disease. American Journal of Kidney Diseases. 1993;22(4):513–9. 5. Srivastava A, Bansal R, Srivastava A, Chaturvedi S, Ranjan P, Ansari M, et al. Percutaneous nephrolithotomy in polycystic kidney disease: is it safe and effective? International urology and nephrology. 2012;44(3):725–30. 6. Mufti UB, Nalagatla SK. Nephrolithiasis in autosomal dominant polycystic kidney disease. Journal of endourology. 2010;24(10):1557–61. 7. NG CS, YOST A, STREEM SB. Nephrolithiasis associated with autosomal dominant polycystic kidney disease: contemporary urological management. The Journal of urology. 2000;163(3):726-9. 8. Al-Kandari AM, Shoma AM, Eraky I, El-Kenawy MR, Al-Eezi H, El-Kappany HA. Percutaneous nephrolithotomy for management of upper urinary tract calculi in patients with autosomal dominant polycystic kidney disease. Urology. 2009;74(2): 273–7. 9. Gambaro G, Fabris A, Puliatta D, Lupo A. Lithiasis in cystic kidney disease and malformations of the urinary tract. Urological research. 2006;34(2): 102–7.

10. Grampsas SA, Chandhoke PS, Fan J, Glass MA, Townsend R, Johnson AM, et al. Anatomic and metabolic risk factors for nephrolithiasis in patients with autosomal dominant polycystic kidney disease. American journal of kidney diseases. 2000;36(1):53–7. 11. Mao Z, Xie G, Ong AC. Metabolic abnormalities in autosomal dominant polycystic kidney disease. Nephrology Dialysis Transplantation. 2014;30(2): 197–203. 12. Umbreit EC, Childs MA, Patterson DE, Torres VE, LeRoy AJ, Gettman MT. Percutaneous nephrolithotomy for large or multiple upper tract calculi and autosomal dominant polycystic kidney disease. The Journal of urology. 2010;183(1):183–7. 13. Levine E, Grantham JJ. Calcified renal stones and cyst calcifications in autosomal dominant polycystic kidney disease: clinical and CT study in 84 patients. AJR American journal of roentgenology. 1992;159(1):77–81. 14. Nishiura JL, Neves RF, Eloi SR, Cintra SM, Ajzen SA, Heilberg IP. Evaluation of nephrolithiasis in autosomal dominant polycystic kidney disease patients. Clinical Journal of the American Society of Nephrology. 2009;4(4):838–44. 15. Fowler KA, Locken JA, Duchesne JH, Williamson MR. US for detecting renal calculi with nonenhanced CT as a reference standard. Radiology. 2002;222(1):109–13. 16. Hoppe H, Studer R, Kessler TM, Vock P, Studer UE, Thoeny HC. Alternate or additional findings to stone disease on unenhanced computerized tomography for acute flank pain can impact management. The Journal of urology. 2006; 175(5):1725–30. 17. Chapman AB, Devuyst O, Eckardt K-U, Gansevoort RT, Harris T, Horie S, et al. Autosomaldominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney international. 2015;88(1):17–27. 18. Delakas D, Daskalopoulos G, Cranidis A. Extracorporeal shockwave lithotripsy for urinary calculi in autosomal dominant polycystic kidney disease. Journal of endourology. 1997;11(3): 167–70. 19. Deliveliotis C, Argiropoulos V, Varkarakis J, Albanis S, Skolarikos A. Extracorporeal shock wave lithotripsy produces a lower stone-free rate in patients with stones and renal cysts. International journal of urology. 2002;9(1):11–4.

Complications of Autosomal Dominant Polycystic Kidney Disease 20. Cass A. Extracorporeal shock wave lithotripsy for renal stones with renal cysts present. The Journal of urology. 1995;153(3):599–601. 21. Baishya R, Dhawan DR, Kurien A, Ganpule A, Sabnis RB, Desai MR. Management of nephrolithiasis in autosomal dominant polycystic kidney disease—a single center experience. Urology annals. 2012;4(1):29. 22. Kirkali Z, Esen AA, Akan G. Place of double-J stents in extracorporeal shock wave lithotripsy. European urology. 1993;23:460–2. 23. Low RK, Stoller ML, Irby P, Keeler L, Elhilali M. Outcome assessment of double-J stents during extracorporeal shockwave lithotripsy of small solitary renal calculi. Journal of endourology. 1996;10(4):341–3. 24. Yili L, Yongzhi L, Ning L, Dongwei X, Chunlai L, Suomin L, et al. Flexible ureteroscopy and holmium laser lithotripsy for treatment of upper urinary tract calculi in patients with autosomal dominant polycystic kidney disease. Urological research. 2012;40(1):87–91.

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25. Singh AG, Jairath A, Balaji SS, Tak G, Ganpule AP, Vijayakumar M, et al. Changing trends in the endourological management of urolithiasis in anomalous kidneys. BJU international. 2019; 123(2):318–27. 26. Singh V, Sinha RJ, Gupta DK. Percutaneous nephrolithotomy in autosomal dominant polycystic kidney disease: is it different from percutaneous nephrolithotomy in normal kidney? Current urology. 2013;7(1):7–13. 27. Wang X, Yang X, Zhong X, Wang Z, Xue S, Yu W, et al. Percutaneous nephrolithotomy under ultrasound guidance in patients with renal calculi and autosomal dominant polycystic kidney disease: a report of 11 cases. Advances in urology. 2017;2017. 28. Bennett WM, Elzinga L, Pulliam JP, Rashad AL, Barry JM. Cyst fluid antibiotic concentrations in autosomal-dominant polycystic kidney disease. American Journal of Kidney Diseases. 1985; 6(6):400–4.

ADPKD MISCELLANEOUS COMPLICATIONS Gopal R Tak

Pain in ADPKD which must be evaluated with proper history, examination, relevant investigations and after proper diagnosis; should be managed accordingly as mentioned below. Incidence of RCC in ADPKD is same as that of general population. However, may have earlier age of presentation with frequent constitutional symptoms and a higher proportion of sarcomatoid, bilateral, multicentric, and metastatic tumors. CT without and after IV contrast material, with thin (5 mm) slices through areas of interest, is the primary imaging modality for the evaluation of patients with ADPKD who may have RCC. Hematuria in ADPKD, though mostly benign, should be evaluated with high index of suspicion to rule out malignancy. Early diagnosis and treatment can be very beneficial for the patient. Further genetic and molecular studies may be needed to reveal which subset of patients with ADPKD may be having a greater risk of malignancy.1

INTRODUCTION

Primary health care providers or the hospital staff should be aware of the diagnostic dilemma while attending the ADPKD patient who has developed complications. Three main complications of ADPKD, namely pain, hematuria, malignancy. Flash pain events are common in ADPKD. ADPKD patients complain of pain quite often. The pain tends to occur during initial course of disease and majority of times give clue to diagnosis. Mostly pain can be tackled effectively with conservative methods. Certain patients develop chronic pain which may lead to anxiety, depression, fatigue, negatively affect social relations and ability to function as well. Another common complication of ADPKD is macroscopic hematuria. About 50% of patients suffer from episodic hematuria during their lifetime, which is mostly having benign etiology. However, sometimes hematuria may have an unrelated cause which needs proper evaluation and management.

36

Autosomal Dominant Polycystic Kidney Disease

As compared to the general population there is an increased risk of skin and renal neoplasm in patients with ADPKD on dialysis, or after transplantation, but not to other patients on renal replacement therapy without ADPKD. Recently one study had shown that ADPKD patients were slightly at greater risk of post-transplant malignancies as compared to end stage renal disease unrelated to ADPKD. One by one the important complications of ADPKD are discussed in detail. PAIN

In addition to the flank heaviness (not a pain as such) patients can present with flank, abdominal or back pain as chief complain. The pain may vary from dull aching to severe pain which needs thorough evaluation. Renal as well nonrenal origin of pain must be differentiated since the conditions like abdominal wall hernias, colon diverticulitis, and possibly abdominal aneurysms, which can co-exist frequently with ADPKD.1 ACUTE PAIN FROM ADPKD Pain Assessment in ADPKD

Comprehensive history taking focusing on location of pain, onset, duration, aggravating, relieving factors, and symptoms associated is imperative. This will differentiate whether pain relates directly or indirectly (mechanical backache related to renomegaly) to cystic disease or if it is a manifestation of extrarenal associations of the disease.1 Kidney Pain Acute

Urinary tract infection, a burst or bleeding cyst, kidney stones, problems, like a slipped disc (this entity has association with postural change) these are some common reasons of temporary or persistent pain in patients with ADPKD. There is definite correlation between the size of the kidneys and the frequency of cyst hemorrhage, gross hematuria, and nephrolithiasis.

Cyst Hemorrhage

One of the common and important causes of pain is cyst hemorrhage. The pain due to cyst hemorrhage is usually sharp, localized and sudden in onset. The reason behind such pain is acute expansion of cyst and distension of renal capsule. Gross hematuria and passage of clots leading to renal colic is frequent association with cyst hemorrhage. Cyst hemorrhage may occasionally lead to subcapsular, and retroperitoneal hemorrhage or hemoperitoneum.1 The cystic epithelium produces vascular endothelial growth factor (VEGF), promoting angiogenesis leading to increased risk of cyst hemorrhage and gross hematuria. Symptomatic events usually underestimate the frequency of cyst hemorrhage. This is because above 90% of ADPKD patients have cysts which are hyperdense (on computed tomography [CT] scan) or high signal (on magnetic resonance imaging [MRI]) suggestive of blood or high protein content.1 Majority of the times such hemorrhages resolve within 2 to 7 days (self limiting). It is necessary to exclude neoplasm if hematuria persists for greater than 1 week of first episode at the age above 50 years. Both plain and contrast CT (if renal function permits) are required to make diagnosis with accuracy and to differentiate other complications affecting ADPKD patients. Physician should warn the patients about pain episodes associated with cyst hemorrhage and educate them regarding the necessary measures to be taken.1 Cyst Infection and Pyelonephritis

Women have more chance to get urinary tract infections (UTI) as compared to men. Acute pyelonephritis and cyst infections are quite common in ADPKD patients. One has to immediately obtain the urine for gram stain and culture findings to immediately commence the appropriate antibiotic therapy in patients with ADPKD with suspicion of UTI.

Complications of Autosomal Dominant Polycystic Kidney Disease

It is necessary to start prophylactic antibiotics prior to any instrumentation since genitourinary instrumentation is associated with an increased risk of infection. The usual presentation of ADPKD with UTI is flank pain, fever, and leukocytosis. Sometimes, it becomes difficult to differentiate between cyst infection and acute pyelonephritis. Even after an appropriate course of antibiotics the patient fail to respond or symptoms reoccur after resolution then a diagnosis of cyst infection must be considered.1 Another differential will be the cyst hemorrhage which can also have presentation of flank pain and fever but the fever is usually without leukocytosis. Even though the urine and blood culture reports are negative it does not rule out cyst infection. Sometimes the diagnostic as well as therapeutic cyst aspiration and culture of complex cysts detected by imaging modalities may be indicated in appropriate clinical scenarios. There are certain diagnostic criteria for both renal and hepatic cysts infection as follows: Fever (temperature >38.5°C for >3 d), abdominal pain (particularly a palpable area of renal or liver tenderness), increased C reactive protein (CRP >50 mg/L), and the absence of any significant recent intracystic bleeding (based on the results of an abdominal computed tomography [CT] scan) or other causes of fever.1 Ultrasound of kidney and liver features of cyst infection are debris with a thick wall and/ or a distal acoustic enhancement is detected in at least one cyst. CT scan and magnetic resonance imaging (MRI) features suggestive of cyst infection are enhanced wall thickening and/or perilesional inflammation is detected in at least 1 cyst. Diffusion-weighted MRI or nuclear imaging ( 67 Ga or 111 In-labeled leukocyte scans) are helpful but limited by false-negative and false-positive results. For infected liver cysts particularly positron emission tomography scans may be helpful.1

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Nephrolithiasis

Around 20% of ADPKD patients have renal stones and often present with renal colic. These patients commonly have calcium oxalate or uric acid stones. Various factors play role for nephrolithiasis in ADPKD like anatomical factors (distorted renal anatomy leads to urinary stasis) and metabolic factors (decreased ammonia excretion, low urinary pH, and low urinary citrate concentration). Sometimes parenchymal calcification or cyst wall calcifications mimic the stones so closely that it is difficult to differentiate between them. Stones usually develop in ADPKD patients with larger kidneys. Whenever feasible a noncontrast CT scan can be most informative to rule out obstruction (e.g. because of large cysts near the pelvis or calculus). To relieve the obstruction promptly a urology or intervention radiology consultation should be considered.1 Renal Cell Carcinoma

A rare cause of pain in ADPKD can be renal cell carcinoma. (Discussed in detail in malignancy section.) Chronic Kidney Pain

A chronic pain is a pain occurring daily and lasting for more than 4–6 weeks. (3 months according to some authors.) Specific cystrelated pain is steady nagging discomfort aggravated by standing and walking. Patient can pinpoint the location of pain which is usually on anterior abdominal wall rather than localized back pain which may not correlate with the largest sized cysts seen on imaging.1 Mostly pain start with an acute episode and remain as chronic kidney pain once the eliciting underlying cause has been treated and resolved, which suggests sensitization. Otherwise, it develops slowly and becomes severe over several years. There might be discordance between the appearance of the kidneys and the gravity of chronic pain as the patients with moderate or even mild cystic

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Autosomal Dominant Polycystic Kidney Disease

disease may still have distressing pain. Thus, such circumstances are very disappointing to patients and physicians, since substantial testing of the serum and urine and imaging studies fail to indicate the precise-related findings which will explain the pain. It needs proper assessment to recognize nonrenal causes of pain; also evaluation by physician will help to rule out musculoskeletal causes of pain.1 Early Satiety

Sometimes patients with ADPKD may complain of early satiety usually because of the compression exerted by the large kidney cyst on the greater curvature of the stomach and/ or duodenal loop.1 Liver-related Pain

The hepatic cysts detection rate of MRI is around 94% between 35 and 46 age groups; even though hepatic cysts are present the function of liver is well preserved. Most of these patients are asymptomatic; but the patients with pronounced hepatomegaly may present with symptoms such as heaviness, mild ache, mechanical low back, and gastrointestinal problems. Acute episodes of pain may be because of cyst hemorrhage, rupture, torsion, and infection.1 These patients may rarely show blockage of hepatic venous outflow and compression of the inferior vena cava or portal vein or bile ducts.1 Pancreas-related Pain

It is highly unusual that pain is due to pancreatic disease. Even if it occurs, its due to pancreatitis secondary to pancreatic duct obstruction. Rate of detection of pancreatic cyst by ultrasound is around 5–9% which may be increased up to 19% by MRI in ADPKD patients. There are some case reports of an intraductal papillary mucinous neoplasm in ADPKD patients.1

Medical Management of Kidney Pain in ADPKD Cyst Hemorrhage

The pain episodes associated with cyst hemorrhage and gross hematuria are transient and self-limiting in most of the patients. Management includes limiting the physical activities or rest, use of acetaminophen or propoxyphene in appropriate doses till patient get relief from pain. Hydration and strict control of hypertension also play important role in management of cyst hemorrhage. Even after such conservative management the pain does not subside or if gross hematuria is persistent or recurrent, a detailed evaluation with CT scans or MRI is warranted. When hemorrhage is severe, extends into the retroperitoneal space, or cause urinary tract obstruction by clots or pain is severe; hospitalization may be required for close monitoring and control of pain. To stop the hemorrhage, interventions (embolization or surgery) may be required in rare cases.1 Cyst Infection

The disappearance of fever, optimum C-reactive protein level, and minimum 2 negative blood and/or urine cultures indicates the efficacy of antibiotic therapy and suppression of infection. This also holds true for hepatic cyst infection. If these measures fail then percutaneous or surgical drainage should be taken into account.1 Nephrolithiasis

Although, extracorporeal shock wave lithotripsy (ESWL) is safe in patients with ADPKD having stone, the higher (~50%) incidence of residual fragments (as compared to those patients without ADPKD) limits its use. Higher clearance rate can be achieved by percutaneous nephrolithotomy (PCNL) or retrograde intrarenal surgery (RIRS).1

Complications of Autosomal Dominant Polycystic Kidney Disease

Management of Acute Liver Pain Hepatic Cyst Infection

Hepatic cyst infection, particularly in large diameter cysts, can be treated effectively using drainage and antibiotic therapy together, rather than antibiotics alone. Management of Chronic Kidney Pain Noninvasive Techniques

Initial management includes the conservative management which comprises measures including heat, ice, whirlpool, massage, and the Alexander technique. Alexander Technique

In this technique the skill of self care is taught which help people identify, perceive, and avert poor habits that adversely impacts the posture and neuromuscular coordination by allowing spine decompression and posture enhancement. This technique is conducted by constantly assessing individual’s musculoskeletal posture and releasing undesirable tension in head, neck, and spinal muscle, directed by verbal instruction and hand contact.1 Transcutaneous Electrical Nerve Stimulation (TENS)

Majorly dorsal horn cells having renal inputs have accompanying somatic inputs enabling TENS to decrease the nociceptive stimuli. TENS electrode when placed on somatic receptive field of neurons on skin surface has decreased responsiveness to painful stimuli and reduced the dorsal horn cell responsiveness to C-fiber direct electrical stimulation to around 39% of control in experimental animals.1 In patients with chronic mild aching pain, sporadic use of a TENS unit is beneficial in dealing with the symptoms as well as manages renal colic.1 Nonopioid Analgesia

Acetaminophen which is a centrally acting and safe drug in patients with renal impairment is commonly used as the first-line pain

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medication. Those patients who do not achieve adequate pain control with acetaminophen the next group of analgesics are opioid analgesics (since nonsteroidal antiinflammatory drugs exhibit potential nephrotoxicity).1 Opioid Analgesia

For initial titration and control of pain the short acting opioids are agents of choice. Irrespective of the opioid regimen used, proper assessment of pain level and function before and after initiation of opioid therapy should be done. The patients should be supervised periodically for potential misuse or abuse of opioid drugs.1 As per American Society of Pain Physicians long-term opioid use has variable effectiveness in chronic noncancer pain and improving functional status for 6 months or longer. Transdermal fentanyl and sustained-release morphine are more efficacious (level II evidence); for oxycodone the level of evidence is II and the evidence for hydrocodone and methadone is level III. Pain specialist must be involved in the management of such cases because there is a chunk of evidence of misuse, abuse and toxicity of opioids.1 Adjuvant Analgesics

The use of adjuvant analgesics like clonidine, gabapentin, or pregabalin should also be considered for ADPKD patients with chronic kidney pain. Appraisal of adjuvant analgesics such as gabapentin, clonidine and pregabalin should be necessarily considered in patients with ADPKD and chronic renal pain. Complementary Medicine Acupuncture

Majority of the patients having mechanical low back pain due to large kidney size may ease the pain with acupuncture; however, no studies or literature support this alternate treatment modality.1

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Autosomal Dominant Polycystic Kidney Disease

Surgical Approaches Kidney Pain Kidney cyst(s) aspiration

The renal cyst aspiration with or without injection of sclerosant is the least invasive among the interventions for ADPKD-related pain. Aspiration alone is able to relieve pain; however, only one-third patients will remain without pain at 18 months.1 Surgical fenestration of kidney cysts

It can give good symptomatic relief in cases having large cysts and causing heavy distortion of kidney and compacting adjoining tissues. Immediate pain relief is obtained in 85–90% but over a period of 2 years the percentage of patients having pain relief reduces to 62–67%. It improves hypertension and provides long-term pain control.1 Renal denervation

Laparoscopic renal denervation (with or without nephropexy) or thoracoscopic renal denervation also gives favorable results for pain control.1 Nephrectomy

Those patients who did not benefit from other methods of pain control, nephrectomy is an ideal option for them. Some patients may choose nephrectomy option prior to dialysis or ESRD. Nephrectomy can be unilateral or bilateral when one or both kidneys are functioning at a very low level. Laparoscopic approach is safe with added advantages such as less complications, reduced postoperative pain, and a better cosmetic outcome.1 Transcatheter arterial embolization

Renal transcatheter arterial embolization (TAE) using intravascular coils, is another approach for patients of APDKD having developing abdominal distension and discomfort due to enlarged kidneys. To recognize the renal arteries at proximal location renal arteriography is necessary. Small subsets of

patients who have progressed to ESRD, are unstable, or unfit for surgery (for nephrectomy) are the ideal candidates for this procedure. Initially, stainless steel coils were choice of embolization agent that were placed into the renal arteries and were then subsequently advanced into the arteries. Thereafter the peripheral renal artery branches are obstructed using platinum microcoils. Nevertheless, if this technique is unsatisfactory then a gelatin sponge near the platinum microcoil is implemented. Though it does not have serious complications, minor complications like fever and flank pain were seen for the first postoperative week. In comparison with preintervention volumes this technique is able to shrink the kidney volume up to ~50% at 12 months.1 Liver surgery: Partial hepatic reduction and liver cyst fenestration surgery

Though the indications for and outcomes of hepatic volume reduction with partial hepatic resection and/or cyst fenestration have not been defined it can be considered for pain related to massive polycystic liver disease (PCLD).1 TAE

Transarterial embolization (chiefly used for hepatocellular carcinoma treatment) considerably decreases (~20%) both total liver and cyst volume in patients with symptomatic PCLD. In PCLD, hepatic arteries and portal veins course in a distinct style (in contrast to normal liver pattern, i.e. hepatic arterial and portal venous branches course in parallel in the same anatomic segment); nearly each hepatic arterial branch is fully matured, while portal venous branches in are swapped by multiple cysts. The interventional radiologist, under local anesthesia excellently marks the hepatic arterial branches that supply hepatic regions. It causes minimal damage to the remaining intact liver, and the majority of patients underwent embolization of 2 to 5 segments using platinum microcoils.1 It is useful in

Complications of Autosomal Dominant Polycystic Kidney Disease

treatment of symptomatic PCLD in selected patients of ADPKD with less serious adverse effects and if performed by the experienced surgeon. Some common adverse effects such as fever, vomiting, nausea and epigastric ache is likely to occur. The procedure requires a contrast material which restricts its usage in patients with renal insufficiency.1 MALIGNANCY

Renal cell carcinoma (RCC) can occur in ADPKD patients. Incidence of RCC in ADPKD is same as that of general population. However, may have earlier age of presentation with frequent constitutional symptoms and a higher proportion of sarcomatoid, bilateral, multicentric, and metastatic tumors. Features favoring RCC on imaging are the presence of a solid mass on ultrasonography, speckled calcifications on CT, contrast enhancement, tumor thrombus, or regional lymphadenopathy. Data for cancer incidence in patients with ADPKD on dialysis, or after transplantation, show an increased risk of neoplasm, mostly skin and kidney, when compared with the general population, but not to other patients on renal replacement therapy without ADPKD. However, a recent study found patients with ADPKD were at a slightly higher risk of having post-transplant malignancies, when compared with other patients with endstage renal disease not related to ADPKD.2 The association of RCC and ADPKD remains controversial. First, RCC in ADPKD has earlier age of presentation than that of the general population. A study depicted the median age of patients with ADPKD and RCC as 45 years that was remarkably less than that of Olmsted county patients with RCC who were diagnosed during 61 years; P