Pregnancy and Kidney Disease - ECAB 9788131223284, 9788131231968, 8131231968

Table of contents :
Cover
Title page
Copyright
ECAB Clincal Update: Nephrology
Pregnancy and Kidney Disease
About the Authors
Contents
Preface
Physiological Changes in the Kidney, Assessment of Proteinuria and GFR during Pregnancy
ABSTRACT
KEYWORDS
Abstract
Keywords
Introduction
Structural Changes in The Urinary Tract
Renal Hemodynamic Changes in Normal Human Pregnancy
Determinants and Change in Glomerular Filtration
Renal Autoregulation During Pregnancy
Responsiveness of The Renal Vasculature in Pregnancy; Renal Vasodilatory Capacity
Mechanism(s) Initiating The Gestational Increase in Glomerular Filtration Rate
Plasma Volume Expansion and Gestational Increase in Glomerular Filtration Rate
Renal Tubular Function in Pregnancy
Renal Regulation of Acid Base in Normal Pregnancy
Potassium Balance in Normal Pregnancy
Calcium Balance in Normal Pregnancy
Maintenance of Osmoregulation in Normal Pregnancy
Tubular Function, Sodium and Volume Homeostasis in Normal Pregnancy
Factors Affecting Tubular Sodium Excretion: Summary
Factors which Increase Sodium Excretion
Factors which Decrease Sodium Excretion
Volume Sensing Systems in Pregnancy
Clinical Relevance of Renal Alterations in Normal Pregnancy
Assessment of Renal Function in Normal Pregnancy
Creatinine Clearance in Clinical Practice/GFR Estimation in Clinical Practice
Changes in Plasma Uric Acid
Changes in Glucose Excretion
Proteinuria
Renal Function Tests in Pregnancy
Pregnancy in Women with Chronic Kidney Disease
ABSTRACT
KEYWORDS
Abstract
Keywords
Introduction
Effect of Pregnancy on Chronic Kidney Disease
Proteinuria and Hypertension
Effect of Pregnancy on CKD Stages 1 and 2
Pregnancy in CKD Stages 3-5
Specific Renal Disease in Pregnancy
Primary Glomerulonephritis
Autosomal Dominant Polycystic Kidney Disease
Vesicoureteral Reflux (VUR)
Nephrolithiasis
General Management of Pregnancy in CKD
Pregnancy in Lupus Nephritis
Exacerbation of Systemic Lupus Erythematosus
Renal Disease
Pre-eclampsia
Fetal Loss
Neonatal Lupus
Breast Feeding
Management of Lupus Nephritis during Pregnancy
Pregnancy in Women with Diabetic Nephropathy
Effect of Diabetic Nephropathy on Pregnancy
Effect of Pregnancy on Diabetic Nephropathy
General Principles of Management
Pregnancy in Dialysis Patients
Diagnosis of Pregnancy
Outcome of Pregnancy in Dialysis Patients
Maternal Complications
Principles of Management
Pre-eclampsia: Recent Advances
ABSTRACT
KEYWORDS
Abstract
Keywords
Introduction
Epidemiology and Risk Factors
Clinical Features
Placental Vascular Development and Pre-Eclampsia
Pathogenesis
Altered Angiogenic Balance
Placental Ischemia
Renin-Angiotensin System
Immunological Maladaptation
Genetics
Endothelium-derived Vasoconstrictor and Vasodilators and Oxidative Stress
HELLP Syndrome and Eclampsia
Future Outlook
Case Studies Pre-eclampsia: Recent Advances
Case 1
Case 2
Pregnancy in Kidney Transplant Recipients
ABSTRACT
KEYWORDS
Introduction
Physiology of Pregnancy in Kidney Transplantation
Kidney Function
Renal Morphology
Pre-Pregnancy Counseling
Timing of Pregnancy
Special circumstances that may impact the recommendations
Management Issues During Pregnancy
Immunosuppressive Drug Therapy
Prednisolone
Azathioprine (AZA)
Cyclosporine (CSA)
Tacrolimus
Mycophenolate Mofetil
M-TOR Inhibitors (Sirolimus and Everolimus)
Antihypertensive Medications
Diuretics
Antibiotics
Analgesics
Ante Partum Management
Antenatal Complications
Evaluation of Renal Function
Pre-eclampsia/Pregnancy-induced Hypertension
Infections
Cytomegalovirus (CMV)
Herpes Simplex Virus (HSV)
Intrapartum Management
Breast Feeding
Contraception
Intrauterine Devices
Oral Contraceptive Pills (OCPs)
Summary
Case 1
Comments
Case 2
Comments
Nutrition in Pregnancy and Kidney Disease, Counseling, and Contraception
ABSTRACT
KEYWORDS
Nutrition in Pregnancy With Chronic Kidney Disease
Energy and Protein Needs
Vitamins and Minerals
Other Considerations
Counseling of Women With Ckd
Contraception
Conclusion
Summary
ECAB Clinical Update:NephrologyOther Books in This Series
DISORDERS OF BONE & MINERALMETABOLISM
SYSTEMIC DISEASES AND RENALMANIFESTATIONS
CONTINUOUS AMBULATORYPERITONEAL DIALYSIS

Citation preview

ECAB Clinical Update: Nephrology

Pregnancy and Kidney Disease

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ECAB Clinical Update: Nephrology

Pregnancy and Kidney Disease SK Agarwal Vivekanand Jha Suman Kher Vijay Kher Ghulam Hassan Malik

Editor

Vijay Kher

Elsevier Clinical Update: Nephrology

A division of Reed Elsevier India Private Limited

Copyright © 2009 Elsevier Mosby, Saunders, Churchill Livingstone, Butterworth Heinemann and Hanley & Belfus are the Health Science imprints of Elsevier. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying recording or otherwise, without the prior permission of the copyright holder. Medical knowledge is constantly changing. As new information becomes available, changes in treatment, procedures, equipment, and the use of drugs become necessary. The authors, editors, contributors, and the publisher have, as far as possible, taken care to ensure that the information given in this text is accurate and up-to-date. However, readers are strongly advised to confirm that the information, especially with regard to drug dose/usage, complies with current legislation and standard of practice. Opinions expressed in this book are those of the authors and do not necessarily reflect those of Elsevier India Pvt. Ltd., the editors, or sponsors. Elsevier India Pvt. Ltd. assumes no liability for any material published herein. The publisher does not endorse the quality or value of the advertised/sponsored products described therein. Please consult full prescribing information before issuing prescriptions for any products mentioned in this publication. ISBN 978-81-312-2328-4 Published by: Elsevier, a division of Reed Elsevier India Private Limited 14th Floor, Building No. 10B, DLF Cyber City, Phase-II, Gurgaon, Haryana – 122002, India

Printed at Solar Print Process Pvt Ltd., New Delhi

ELSEVIER CLINICAL ADVISORY BOARD MEMBERS Dr. D.S. Rana MD MNAMS (Nephrology)

Dr. Bharat V. Shah MD DNB

Sr. Consultant - Nephrologist Chairman, Dept. of Nephrology Sir Ganga Ram Hospital, New Delhi.

Anil Clinic, B-4, Shilpa Apartment, A-G Link Road, Chakala, Andheri (E), Mumbai. Lilavati Hospital & Research Centre, Bandra Reclamation, Bandra (W), Mumbai. Nanavati Hospital, S.V. Road, Vile Parle (W), Mumbai.

Dr. S.C. Tiwari MD DM FAMS Director, Renal Sciences, Rockland Hospital, New Delhi Former Professor & HOD, Nephrology, All India Institute of Medical Sciences, New Delhi.

Dr. Amit Gupta MD DNB Professor, Department of Nephrology, SGPGI, Lucknow.

Dr. Vivekananda Jha MD DM Additional Professor of Nephrology, Coordinator, Stem Cell Research Facility, Postgraduate Institute of Medical Education and Research, Chandigarh.

Dr. Vijay Kher MD DM FAMS Director of Nephrology & Renal Transplant Medicine, Fortis Healthcare Flt. Lt. Rajan Dhall Hospital, New Delhi.

Dr. H. Sudarshan Ballal MD (Med) Board Certified in Medicine, Nephrology & Critical Care (USA) Head, Department of Nephrology. Director, Manipal Institute of Nephrology & Urology, Manipal Hospital, Bangalore. Clinical Professor of Medicine, Kasturba Medical College, Manipal and Mangalore, MAHE (Deemed University).

Dr. Sanjay Kr Agarwal MD FRCP DNB FIMSA MNAMS FISN FICP

Professor & Head Department of Nephrology, All India Institute of Medical Sciences, New Delhi.

CONTRIBUTORS Dr. SK Agarwal Dr. Vivekanand Jha Dr. Suman Kher

Dr. Vijay Kher Dr. Ghulam Hassan Malik

EDITOR Dr. Vijay Kher

ELSEVIER INDIA Clinical Education and Reference Division DIRECTOR Vidhu Goel

HEAD - MEDICAL SOCIETIES, AGENCY AND GOVT. RELATIONS Tarun Choudhry

HEAD, CLINICAL SPECIALTIES, SOUTH ASIA

CONTENT DESIGNERS AND EDITORS

Dr. Shveta Dhamija

Bobby Choudhury Shravan Kumar

EDITORIAL OFFICE Elsevier, a division of Reed Elsevier India Private Limited 14th Floor, Building No. 10B, DLF Cyber City, Phase-II, Gurgaon, Haryana – 122002, India. Telephone: + 91-124-4774444 Fax: + 91-124-4774100 E-mail: [email protected]

Dr. SK Agarwal is an excellent academician, a dedicated teacher and a recipient of many awards and fellowships. He has done his MBBS and MD Medicine from KGMC Lucknow and had been an exemplary student. He also has the fellowship of Royal College of Physicians (Edinburgh) 2007 and has been awarded the “Country Leader for Transplantation” by the World Transplantation Society since 2003. Dr Agarwal has reviewed book for NEJM 2005 and is the member of PROJECT REVIEW COMMITTEE of ICMR. Dr. Agarwal has to his credit a total of 144 publications, 21 extramural research projects, 16 chapters in books and has given about 100 invited lectures. Dr. Vivekanand Jha is the Additional Professor of Nephrology and incharge of the Stem Cell Research Facility at the Postgraduate Institute of Medical Education and Research, Chandigarh. He did his MBBS from Patna Medical College, and MD in Internal Medicine and DM in Nephrology from PGIMER. He joined the faculty of PGIMER in 1991. He worked at the Beth Israel Deaconess Medical Center and Harvard University, Boston as an ISN-ASN fellow from 1999 to 2001. Dr. Jha holds important positions in various professional societies and national and international policy making bodies. He is the Cochair of the Education Committee, and member of the Fellowship Committee and Committee for Prevention of Kidney Disease project of the Commission for Global Advancement of Nephrology of the International Society of Nephrology. He serves on the Board of Directors of the Kidney Disease: Improving Global Outcomes, a body set up by the National Kidney Foundation of USA dedicated to developing the Best Practice Guidelines for Kidney Disease Management around the world, and is a member of Steering Committee of the Asian Forum of Chronic Kidney Disease. He is a member of the Scientific Committee of the Indian Society of Nephrology. He is also in-charge of National Peritoneal Dialysis Registry. He is a member of several task forces of the Department of Biotechnology and Indian Council of Medical Research. In the past, he has served as a Councilor of the Asian Pacific Society of Nephrology and

ECAB Clinical Update: Nephrology    n   About the Authors

Executive Committee member of the Indian Society of Nephrology. He has been the Associate Editor of Indian Journal of Nephrology for several years and is currently its Deputy Editor. He has conducted several pivotal trials in the field of kidney disease and transplantation. Dr. Jha has published over 125 research papers in leading journals around the world and has written chapters about various aspects of kidney diseases in leading medical and nephrology textbooks read globally. He has been invited to deliver lectures and talks at several national and international fora. He has been involved in several projects aimed at highlighting the emergence of chronic kidney disease epidemic in the developing world and started community awareness and prevention programs. Dr. Suman Kher is a Senior Consultant & Head, Department of Obstetrics & Gynecology at Apollo Hospital, NOIDA. An alumnus of Lady Hardinge College and PGIMER, Chandigarh, she did a fellowship in Gyne-oncology at Jewish Hospital, University of Cincinnati, Ohio, USA and diploma in advanced pelvic endoscopy from Kiel, Germany. She has held positions of Senior Consultant & Head, Department of Obstetrics & Gynecology at SGPGI, Lucknow; and Holy Family Hospital, New Delhi. Her areas of interest are: High-risk Pregnancy and Gyneendocrinology. Dr. Vijay Kher is the Director of Nephrology & Renal Transplant Medicine at Fortis Healthcare Ltd. He joined Fortis after 10 distinguished years as Senior Consultant & Academic Co-coordinator with Indraprastha Apollo Hospitals in New Delhi, bringing with him more than 25 years’ experience. He has worked internationally with Henry Ford Hospital, Detroit, USA and University of Cincinnati Medical Center, Ohio, USA and domestically with the Sher-i-Kashmir Institute of Medical Sciences, Srinagar, J&K; Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow; and PGIMER, Chandigarh. Dr. Kher, a Doctorate in Medicine (DM) in Nephrology, is recognized as an expert in the fields of Nephrology and Renal Transplant Medicine. His areas of expertise and special focus include: l Prevention and attenuation of progression of chronic kidney disease l Kidney transplantation improving outcomes

About the Authors    n   ECAB Clinical Update: Nephrology l

Hepatitis and kidney disease He is one of the first physicians to practice the concept of preemptive kidney transplantation in India. He has successfully completed more than 1500 transplants, for patients from all around the world. Regionally, he is considered to be one of the pre-eminent transplant physicians in Asia. Dr. Kher has published 70 international and 60 national publications and authored more than 20 textbook chapters. Dr. Kher is a fellow of National Academy of Medical Sciences and Indian Society of Nephrology. He is a member of an expert panel to select faculty at various prestigious national medical institutes and a Diplomate National Board Examiner for more than 15 years. Dr. Ghulam Hassan Malik, a well-known Nephrologist in Kashmir, has been associated with many Nephrology related organizations like Indian Society of Nephrology, Indian Society of Organ Transplantation, Peritoneal Dialysis Society of India, Indian Academy of Nephrology, International Society of Nephrology, and northern chapter of Indian Society of Nephrology. He has taught graduate and postgraduate students at Govt. Medical College and Sher-i-Kashmir Institute of Medical Sciences, Srinagar for around thirteen years He is also an examiner of the studies conducted by the Saudi Medical Council and King Khalid University, Riyadh, Saudi Arabia and a reviewer for Saudi Journal of Kidney Disease and Transplantation. Dr. Malik has delivered lectures and presented abstracts at various national and international meetings. He has published around sixty papers in various journals of national and international repute.

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ECAB Clinical Update Information.......................................... i Preface���������������������������������������������������������������������������������������v Dr. Vijay Kher

Physiological Changes in the Kidney, Assessment of Proteinuria and GFR during Pregnancy��������������������������������������1 Dr. SK Agarwal

Pregnancy in Women with Chronic Kidney Disease�����������������20 Dr. Ghulam Hassan Malik

Pre-eclampsia: Recent Advances���������������������������������������������52 Dr. Vivekanand Jha

Pregnancy in Kidney Transplant Recipients������������������������������85 Dr. Suman Kher and Dr. Vijay Kher

Nutrition in Pregnancy and Kidney Disease, Counseling, and Contraception����������������������������������������������103 Dr. Vijay Kher

Summary�������������������������������������������������������������������������������117 Other Books in This Series�����������������������������������������������������119

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ELSEVIER CLINICAL ADVISORY BOARD (ECAB) INDIA ECAB is an endeavor of Elsevier, the leading publishing house worldwide in health sciences, with an aim to develop relevant content in clinical specialties and make them easily available to the medical professionals of India. In the first year of its inception, ECAB included clinical specialties like diabetes, cardiology, gastroenterology, and obstetrics & gynecology. In the second phase, ECAB extended its endeavor to four more clinical specialties, i.e., orthopedics, pediatrics, nephrology, and medicine. The aim of this concept is to explore the experience and learning of some of the eminent medical professionals of India and south-east Asia in their respective fields in addition to Elsevier’s own existing resources to create content, which is available in the form of various products and services for utilization by the Indian clinical practitioners. This concept is the first of its kind in the Indian medical scenario, and ECAB will extend this to every clinical discipline in the near future to serve the information needs of the Indian medical fraternity.

STATEMENT OF NEED Nephrology is a superspecialty that requires knowledge of a wide range of clinical presentations. Because of the involvement and interrelation of the various organ systems, it takes longer to acquire the pattern recognition and to be able to recognize rare presentations of common conditions and rare conditions that may be serious and difficult to diagnose. In this age where at times, there seems to be an overabundance of information, it is important for the practising clinician to have an authoritative source of quality advice and genuine practice wisdom. Keeping in mind the requirements of the society, the practitioners need i

ECAB Clinical Update: Nephrology    n   Information

to update themselves on the current approach and the wide variety of choices now available. India has a distinct need for comprehensive programs that fit into the Indian context of the situation. It has to be a continuous process, which approaches the problem on the basis of the experience of the specialists in India who are among the stalwarts in this field. In its quest to better approach the topic, Elsevier has pooled its existing resources with those of the internationally acclaimed nephrologists of India who have chosen to apply their rich clinical knowledge and expertise to serve the Indian patients. This book provides a useful basis to view new perspectives in nephrology, coupled with the more traditional protocols. It will be a valuable learning tool and reference point for the many professionals engaged in nephrology practice.

Pregnancy and Kidney disease There are certain structural and functional changes that develop in the urinary tract during normal pregnancy, which are significantly different than non-pregnant normal females. During pregnancy in women with underlying chronic kidney disease (CKD), the adaptation to these changes may not be optimal. Under these circumstances, the pregnancy outcome as well as maternal CKD may be affected. The issue focuses on the physiological changes in the kidney and assessment of proteinuria and GFR during pregnancy. The current update also details the cases of pregnancy in the setting of CKD describing the effect of CKD on pregnancy as well as effect of pregnancy on CKD. The chapter on pregnancy-induced hypertension―Pre-eclampsia focuses on the prevention and management of complications in the patient. The authors also give an insight into the pregnancy in cases after kidney transplantation.

TARGET AUDIENCE This book is intended for the Indian Nephrologists, advanced

practitioners, and other healthcare professionals interested in the treatment of kidney and related disorders. ii

Information    n   ECAB Clinical Update: Nephrology

EDUCATIONAL OBJECTIVES Readers will find the contents of this book helpful to understand: •

Various physiological changes in the kidney during pregnancy.

•

Recent advances in the approach and management of pre-eclampsia.

•

Pregnancy outcomes in a patient with chronic kidney disease.

•

Pregnancy outcomes in renal transplant patients.

DISCLAIMER The content and views presented in this educational activity are those of the contributors and do not necessarily reflect the opinions or recommendations of the whole ECAB or Elsevier. The content has been prepared based on a review of multiple sources of information, but is not exhaustive of the subject matter. Readers are advised to critically evaluate the information presented, and are encouraged to consult the available literature on any product or device mentioned in the content.

DISCLOSURE OF UNLABELED USES This educational activity may contain discussion of published and/or investigational uses of agents that are not approved by the Food and Drug Administration. Please consult relevant literature for information about approved uses.

DISCLOSURE OF FINANCIAL RELATIONSHIPS WITH ANY COMMERCIAL INTEREST As a provider of credible content, Elsevier requires that everyone is in a position to: control the content of an educational activity, disclose all relevant financial relationships with any commercial interest, and identify and resolve all conflicts of interest prior to the educational activity. The ECAB defines “relevant financial relationships” as any amount occurring within the past 12 months. Financial relationships are those relationships in which the individual benefits by receiving a salary, royalty, intellectual property rights, consulting fee, honoraria, ownership interest (e.g., stocks, stock options, or other ownership iii

ECAB Clinical Update: Nephrology    n   Information

interest, excluding diversified mutual funds), or other financial benefit. Financial benefits are usually associated with roles such as employment, management position, independent contractor (including contracted research), consulting, speaking and teaching, membership on advisory committees or review panels, board membership, and other activities for which remuneration is received or expected. The ECAB considers relationships of the person involved in the educational activity to include financial relationships of a spouse or partner. For an individual with no relevant financial relationship(s), the participants must be informed that no relevant financial relationship(s) exist.

RESOLUTION OF CONFLICT OF INTEREST The ECAB has implemented a process to resolve conflict of interest for each book. In order to help ensure content objectivity, independence, and fair balance, and to ensure that the content is aligned with the interest of the intended audience, the ECAB has the evaluation of content done by those members of ECAB who are not directly involved in the project.

CONTENT DEVELOPMENT COMMITTEE Dr. SK Agarwal, MD, FRCP, DNB, FIMSA, MNAMS, FISN, FICP Dr. Vivekanand Jha, MD, DM, FRCP Dr. Suman Kher MD Dr. Vijay Kher MD, DM, FAMS, FRCPE Dr. Ghulam Hassan Malik, MD, DM, FISN, FACP Dr. Shveta Dhamija, MBBS Ms. Bobby Choudhury

ENQUIRIES For content related enquiries, please contact us at [email protected].

iv

Preface

ECAB Clinical Update: Nephrology      Preface

Nephrologists are frequently called to diagnose and treat kidney disorders in pregnant women and obstetricians are frequently challenged to manage pregnancy in patients with kidney disease and hypertension. Marshal Lindheimer, an obstetrician and Adrian Katz, a physician, who have had huge experience of such patients, opined that it is important for nephrologist to think like an obstetrician and the obstetrician to be like a nephrologist if one has to see successful outcome of such pregnancies. There are structural as well as physiological alterations in the kidney and urinary tract during normal pregnancy leading to changes in the parameters commonly utilized for measurement of kidney function which has clinical implications. Alterations in the structure of the kidney and the urinary tract might persist for 12–16 weeks post-delivery and need to be kept in mind while managing these patients. Increase in glomerular filtration rate (GFR) during pregnancy lowers serum creatinine and urea. Thus, normal non-pregnant serum creatinine and urea levels may indicate renal dysfunction during pregnancy. Modification of diet in renal disease (MDRD) formula for estimation of GFR in pregnancy with normal GFR has not been found to be accurate and there is no data on the accuracy of MDRD formula in pregnant women with GFR < 60 ml/min. Thus 24-hr urine collection for creatinine clearance remains the gold standard for GFR estimation in pregnancy. Spot urine protein to creatinine ratio has a linear relationship to 24hr urine protein in non-pregnant healthy individuals as well as patients of chronic kidney disease (CKD). Spot urine protein and creatinine ratio has been documented to be reliable and reproducible for diagnosis of pre-eclampsia. 24-hr urine protein estimation should be done only when results are equivocal. The literature on pregnancy in women with CKD is dominated by single-center, retrospective and often uncontrolled studies. Women with only mild renal impairment, controlled blood pressure with little/no proteinuria have usually good maternal and fetal outcomes without any or little risk for accelerated progression towards ESRD or preterm delivery. However, moderate to severe CKD results in increased risk for pregnancyv

ECAB Clinical Update: Nephrology      Preface

related maternal complications and neonatal morbidity. Patient with prepregnancy GFR < 40 ml/min and proteinuria >1 g/24 hrs have high rate of renal loss as well as pregnancy complications and pregnancy should be avoided in such patients. Last 5 years have seen new developments in our understanding of pathogenesis of pre-eclampsia and the central role of placental anti-angiogenic factors like soluble forms like tyrosine kinase (s-Flt 1) and endoglin. This new understanding might change the way the diagnosis of pre-eclampsia is going to be made. High s-Flt 1 and endoglin levels in the plasma predate by many weeks before hypertension, proteinuria and other overt manifestations of pre-eclampsia. A screening tool for pre-eclampsia will have the greatest impact in clinical outcomes when effective prevention or treatment becomes available. Fertility rates increase early and dramatically after kidney transplantation in women with kidney failure. There is a high incidence of successful pregnancies in kidney transplant recipients if monitored carefully and managed by combined skills of high-risk pregnancy specialist obstetrician and transplant physician. Managing nutrition in pregnant patients with CKD is challenging and many patients of CKD who want to be pregnant require lot of counseling and guidance. A chapter on this has been written for this very purpose. I do hope that greater understanding of the subject ‘Pregnancy and Kidney Disease’ as presented will translate into better management of these patients.

Dr. Vijay Kher

vi

Physiological Changes in the Kidney, Assessment of Proteinuria and GFR during Pregnancy Dr. SK Agarwal

MD, FRCP, DNB, FIMSA, MNAMS, FISN, FICP

Professor & Head Department of Nephrology All India Institute of Medical Sciences, New Delhi

ABSTRACT:  There  are  certain  structural  and  functional  changes  that  develop  in  the  urinary  tract  during  normal  pregnancy,  which  are  significantly  different  than  non‐pregnant  normal  females.  It  is  important  to  know  these  changes  in  order  to better interpret the abnormalities in pregnancy. In the normal  pregnant  woman,  effective  renal  plasma  flow  increases  by  70– 80%  between  conception  and  mid‐pregnancy  and  returning  to  near normal close to term, but still remaining above the value in  non‐pregnant  woman.    The  gestational  increase  in  glomerular  filtration  rate  (GFR)  in  pregnancy  is  due  to  the  renal  vasodilatation  and  increased  renal  plasma  flow.  However,  despite  the  hemodynamic  changes  of  normal  pregnancy  the    

1a

renal autoregulatory ability is intact. In late‐pregnancy, when the  gestational  reduction  in  blood  pressure  has  occurred,  there  is  some  indication  of  a  downward  resetting  in  the  threshold  for  renal  autoregulation  of  blood  flow.  This  may  represent  a  protective mechanism whereby late pregnancy is protected from  periods  of  renal  hypoperfusion.  Increase  in  excretion  of  many  substances  as  a  result  of  the  increased  GFR  is  antagonized  by  increases  in  tubular  re‐absorption,  which  ultimately  results  in  less depletion. Plasma creatinine and blood urea decreases from  a  non‐pregnant  value  in  successive  trimesters.  Familiarity  with  the  changes  is  vital,  because  values  considered  normal  in  non‐ pregnant  women  may  signify  decreased  renal  function  in  pregnancy.  As  a  rough  guide,  values  of  plasma  creatinine  and  urea  >0.8  mg/dL and of 20 mg/dL,  respectively  should  alert  the  clinician to assess renal function further.   

KEYWORDS:  Gestational  increase  in  GFR,  24‐hour  creatinine  clearance, protein excretion, glycosuria, plasma osmolality, atrial  natriuretic  peptide,  tubular  Function,  sodium  homeostasis,  volume  homeostasis,  human  chorionic  gonadotropin,  osmoregulation, antidiuretic hormone.   

1b

Physiological Changes in the Kidney, Assessment of Proteinuria and GFR during Pregnancy Dr. SK Agarwal

MD, FRCP, DNB, FIMSA, MNAMS, FISN, FICP

Professor & Head Department of Nephrology All India Institute of Medical Sciences, New Delhi

INTRODUCTION There are certain structural and func onal changes that develop in the urinary tract during normal pregnancy, which are significantly different than non-pregnant normal females. It is important to know these changes in order to be er interpret the abnormali es in pregnancy. The changes have been understood from animal studies and clinical prac ce.

STRUCTURAL CHANGES IN THE URINARY TRACT There is enlargement of kidneys predicted by standard height and weight nomography in pregnancy because both increase in vascular volume (approximately 70%) and inters al space. Increase in size is approximately 1 cm. There is dilata on of the calyces, renal pelvis, and ureter invariably more prominent on the right side, some mes seen in the first trimester but by the third trimester, is present in 90% of women.1 There is controversy regarding cause of dilata on from hormonal effects 1

ECAB Clinical Update: Nephrology

to obstruc on by enlarged uterus. Dilata on terminates as the ureter crosses the iliac artery, and at this point a filling defect termed the iliac sign can be demonstrated. There is no reason to think loss of tonicity of ureter to be cause of ureteric dilata on. These structural changes have the following important clinical implica ons: 1.

Dilata on of the urinary tract may lead to error in collec on of urine and thus tests based on med urine volume. This error may be minimized if the pregnant woman is adequately hydrated to give a high urine flow and/or if she lies down on her side for an hour before and at the end of the collec on.

2.

Acceptable norms of kidney size should be increased by 1 cm

3.

Dilata on of the ureter may persist un l the 16th post-partum week, and elec ve intravenous urography (IVU) during this period should be deferred

4.

Urinary stasis within the ureter may become a risk for development of frank pyelonephri s in women with asymptoma c bacteriuria.

RENAL HEMODYNAMIC CHANGES IN NORMAL HUMAN PREGNANCY In the normal pregnant woman, effec ve renal plasma flow increases by 70–80% between concep on and mid-pregnancy and returning Late pregnancy is associated with an increase in filtration fraction to values similar to those of the non-pregnant normal women.

to near normal close to term, but s ll remaining above the value in non-pregnant woman. It is generally accepted that inulin clearance increases by about 50% during pregnancy, reaching a maximum at the end of the first trimester and being maintained at this level un l at least the 36th gesta onal week. Filtra on frac on decreases as glomerular filtra on rate (GFR) increases less than renal plasma flow during early pregnancy. Late pregnancy is associated with an increase in filtra on frac on to values similar to those of the non-pregnant normal women. As against inulin clearance, 24-h crea nine clearance increases by 25% by 4 weeks a er the last menstrual period and by 45% at 9 weeks. 2

Assessment of Proteinuria and GFR during Pregnancy

„

Agarwal

During the third trimester, a decrease towards non-pregnant values precedes delivery, with a small increase during the first few days of the puerperium. Values for GFR es mated from 24-h crea nine clearances are consistently less than those obtained from inulin clearances.

DETERMINANTS AND CHANGE IN GLOMERULAR FILTRATION There are a number of determinants of glomerular filtra on rate in an individual. The determinant and its change associated with net effect in pregnancy is shown in Table 1.

Table 1. Determinant, Its Change and Effect on Glomerular Filtration Rate in Normal Pregnancy Determinant

Change in Pregnancy

Effect

Glomerular number

No change

No effect

Single nephron GFR

Increased to 30–40% in mid-pregnancy

GFR increased

Glomerular capillary permeability coefficient

Remains normal

No change in GFR

Filtration pressure

Normal

No change in GFR

Renal plasma flow

Increased

GFR increased

Filtration surface area

Pregnancy is a state in which the kidneys have vasodilata on for longer period. Although pregnancy is a physiological condi on, which proceeds without loss of nephron number or underlying disease and is reversible. Also, there is no sustained increase in glomerular blood pressure during a single gesta on period because of the parallel falls in pre- and postglomerular arteriolar resistances. In humans, the evidence also argues against glomerular injury resul ng from normal pregnancy. Therefore, the gesta onal increase in GFR in pregnancy is en rely due to renal vasodilata on with consequent increases in renal plasma flow. 3

ECAB Clinical Update: Nephrology

RENAL AUTOREGULATION DURING PREGNANCY The normal kidney maintains blood flow and GFR over a range of systemic blood pressure, which means it autoregulates its GFR, and change in pre-glomerular arteriolar tone is the main mechanism of this autoregulatory mechanism. Despite the hemodynamic changes of normal pregnancy, renal autoregulatory ability is intact in pregnancy. Thus, pregnancy related renal vasodilata on does not alter intrinsic renal autoregula on ability. In late-pregnancy, when the gesta onal reduc on in blood pressure has occurred, there is some indica on of a downward rese ng in the threshold for renal autoregula on of blood flow. This may represent a protec ve mechanism whereby latepregnancy is protected from periods of renal hypoperfusion. There has been no direct assessment in pregnant women but the rou nely Despite the hemodynamic changes of normal pregnancy, renal autoregulatory ability is intact in pregnancy.

elevated GFR of normal pregnancy makes it likely that autoregula on is well maintained. Renal autoregula on involves a tubuloglomerular feedback component as well as a myogenic component. In mid-term pregnancy, tubuloglomerular feedback ac vity is normal, having reset to recognize the elevated single nephron GFR as normal, thus this component of the autoregulatory response is intact.

RESPONSIVENESS OF THE RENAL VASCULATURE IN PREGNANCY; RENAL VASODILATORY CAPACITY The normal mid-term pregnancy, which exhibits the maximal gesta onal renal vasodilata on, responds to an acute amino acid infusion with further significant increases in both GFR and single nephron GFR, due solely to further increases in plasma flow. To date, studies in normal women have been conflic ng. In response to intravenous amino acids, however, normal pregnant women show a marked renal vasodilatory response. It is interes ng that in women with single kidney, where 4

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Table 2. Changes and Effect of Various Biochemicals in Normal Pregnancy Determinant Renin-angiotensin system

Change in Pregnancy Increase in plasma renin activity

Effect No significant effect

Decreased response to vasopressure action including angiotensin Downregulation of angiotensin II receptor Prostaglandins

Increased renal synthesis

No direct effect of its own

Dopamine

Increased urinary dopamine

No confirmed effect

Atrial natriuretic peptide (ANP)

Moderate increase in plasma ANP

No confirmed effect

Nitric oxide

Increased nitric oxide activity

Causes renal vasodilatation

Ovarian relaxin

Not much data

No definite information

compensatory renal hypertrophy has already occurred, pregnancy s ll causes a significant augmenta on of renal hemodynamics, unmasking renal reserve. Overall, the kidney in pregnancy exhibits significant renal vasodilatory reserve capacity.

MECHANISM(S) INITIATING THE GESTATIONAL INCREASE IN GLOMERULAR FILTRATION RATE In women, marked renal and peripheral vasodilata on is evident early in pregnancy prior to complete placenta on. Similar changes occur in non-pregnant women in the luteal phase of the menstrual cycle. These studies suggest that the fetoplacental unit is not necessary for the increase in GFR of pregnancy and indicate that some maternal s mulus must ini ate these gesta onal changes. Although the placenta is not 5

ECAB Clinical Update: Nephrology

involved in the ini a on of the gesta onal increase in GFR, there may be some role for placental factors in maintenance of the elevated GFR later in pregnancy, since removal of the placenta from mid-term pregnancy leads to reduc on in GFR and renal plasma flow.

Plasma Volume Expansion and Gestational Increase in Glomerular Filtration Rate Plasma volume expansion will cause renal vasodilata on with resultant increases in renal plasma flow and GFR.2 A cumula ve volume expansion occurs during pregnancy such that, close to term, plasma volume is enormously expanded. There is, however, dissocia on between the plasma volume increase and the eleva on in renal plasma flow and A cumulative volume expansion occurs during pregnancy such that, close to term, plasma volume is enormously expanded.

GFR in pregnancy well before the maximum increase in plasma volume. It therefore seems that the plasma volume expansion of pregnancy is not the primary determinant of the gesta onal increase in GFR.

RENAL TUBULAR FUNCTION IN PREGNANCY The physiological plasma volume expansion of pregnancy results in decreased plasma concentra on of many plasma cons tuents but s ll their filtered load increases due to the large increases in GFR. Increase in excre on of many substances is antagonized by increases in tubular reabsorp on, which ul mately results in less deple on. The renal handling of a number of solutes is altered in normal pregnancy, as discussed below.3

Renal Regulation of Acid Base in Normal Pregnancy In pregnancy, the daily amount of acid generated is increased both due to an increased basal metabolism and greater food intake. Despite this increased acid load, the blood concentra ons of hydrogen ions decrease by 4 mmol/l early in pregnancy and con nue ll term. Arterial pH 6

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Table 3. Renal Handling of Substances Tubular handling Uric acid

↓ in net tubular absorption Maximum in 1st trimester

Glucose

Overall change 25% ↓ serum value Value not much low in multiple fetus

Glycosuria is often seen

Serum values are practically unaffected

↓ net glucose tubular absorption

Overall benign state

TmG is decreased Protein

↑ Total protein and albumin excretion More after 20 weeks

Amino acid

Tubular excretion of most amino acid ↑ due to ↓ absorption

Urinary protein increases Some ↑ is due to ↑ glomerular capillary permeability and ↑ GFR Amino acid blood concentration decreases

Most ↑ is in early pregnancy Water soluble vitamins

↓ Folic acid tubular absorption ↑ Other water soluble vitamin excretion

Serum value decreases There is need of supplementation

averages 7.44 in pregnant women, compared to 7.40 in non-pregnant women. This mild alkalemia is respiratory in origin, since pregnant women normally hyperven late and their arterial PCO2 decreases from approximately 39 mmHg when non-pregnant to approximately 31 mmHg in pregnancy. A secondary, compensatory fall in plasma bicarbonate concentra on occurs so that values between 18 mmol/l and 22 mmol/l are normal. The renal capacity to reabsorb bicarbonate and excrete H+ is unchanged by pregnancy, but the pregnant woman is at a disadvantage when threatened by sudden metabolic acidosis, such as lac c acidosis in pre-eclampsia, and acute renal failure. 7

ECAB Clinical Update: Nephrology

Potassium Balance in Normal Pregnancy Despite the high aldosterone values and rela vely alkaline urine of pregnancy, potassium excre on is decreased during gesta on. Together with the increased potassium intake, this leads to significant net potassium reten on of approximately 350 mmol. Majority of potassium enters the enlarging ssues of mother and fetus. Furthermore, pregnant women are resistant to the kaliure c effects of a combina on of exogenous mineralocor coid and a high sodium intake. The gesta onal tendency to conserve potassium despite increased concentra ons of mineralocor coid has been a ributed to the an -mineralocor coid effect of the increased progesterone of pregnancy. The tubular handling of potassium is complex and the final urinary potassium excre on is independent of the filtered load of potassium and is determined largely by the magnitude of potassium secre on in Renal resistance to kaliuretic stimuli in women with underlying disorders impairing potassium excretion could jeopardize pregnancy.

the distal nephron. Probably, inhibi on of potassium secre on in the collec ng duct, and/or enhanced potassium recycling, provides the final mechanism of urinary potassium conserva on by the pregnant lady. Renal resistance to kaliure c s muli in women with underlying disorders impairing potassium excre on could jeopardize pregnancy.

Calcium Balance in Normal Pregnancy Due to increase in GFR, there is an increase in the filtered load of calcium and there is associated increase in tubular reabsorp on of calcium but s ll urinary calcium excre on increases two- to threefold during pregnancy. The hypercalciuria is explained due to increased plasma 1,25-dihydroxyvitamin D3, which increases intes nal reabsorp on of calcium and is known to cause hypercalciuria. Calcitriol can suppress serum parathyroid hormone such that renal calcium reabsorp on is reduced in the thick ascending limb of the loop of Henle. Associated with increased calcium excre on in pregnancy, urinary supersatura on is increased, predisposing to the forma on of 8

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calcium stones. However, magnesium and citrate, known inhibitors of calcium kidney stones, also increase and thus counterbalance against nephrolithiasis. In addi on, during pregnancy there is increased excre on of acidic glycoproteins, including Tamm-Horsfall protein and nephrocalcin, which inhibit calcium oxalate stone forma on. Thus, overall calcium stone forma on tendency does not increase.

Maintenance of Osmoregulation in Normal Pregnancy Very early in pregnant women, plasma osmolality decreases by about 10 mOsm/kg below the non-pregnant norm due to a reduc on in plasma sodium and associated anions. This hypo-osmolality normally inhibits an diure c hormone (ADH) release in non-pregnant individuals, leading to a state of con nuous diuresis. However, this does not happen in pregnancy because the osmo c thresholds for ADH release and thirst Human chorionic gonadotrophin may influence decrease in the osmotic thresholds for thirst and ADH secretion.

also decrease during the ini al weeks of pregnancy. The decrease in thirst threshold may precede that for hormone release, resul ng in mild transient polyuria early in pregnancy. Human chorionic gonadotrophin (hCG) may influence decrease in the osmo c thresholds for thirst and ADH secre on. Osmoregula on may also be affected by changes in ADH metabolism which are apparent by mid-pregnancy.4 The metabolic clearance rate of ADH is similar to non-pregnant values in early pregnancy, but increases fourfold during the second and third trimesters. The blood of pregnant women contains a cys ne amino pep dase enzyme (vasopressinase) of placental origin, capable of inac va ng large quan es of ADH. Increments in the metabolic clearance rate of ADH correlate well with the appearance and increase in plasma vasopressinase a er mid-pregnancy, sugges ng that the placental vasopressinase is ac ve. Furthermore, the metabolic clearance rate of 1-desamino-(8-D-arginine) vasopressin, an ADH analog resistant to in vitro degrada on by vasopressinase does not increase during human gesta on. In addi on, the placenta can degrade ADH in situ, 9

ECAB Clinical Update: Nephrology

and studies with in vitro perfusion of term placentas suggest that this organ may be responsible for at least one-third of the increased hormonal disposal rates during pregnancy. Volume status is a separate, non-osmo c determinant of ADH release. Any hypovolemia s mulates ADH secre on, and although this is much less sensi ve than the osmo c control, when ac vated (by greater than about 10% volume loss), volume deple on provides a powerful s mulus to ADH release. Absolute blood volume increases significantly in pregnancy, but how effec ve volume is sensed is controversial, and it has been postulated that the osmoregulatory changes are due to underfilling of the dilated intravascular compartment. Hypovolemia can diminish osmo c thresholds for ADH release and thirst.

TUBULAR FUNCTION, SODIUM AND VOLUME HOMEOSTASIS IN NORMAL PREGNANCY In normal pregnancy, the average weight gain is 10–15 kg, of which majority is water, since total body water increases by 6–8 l, of which 4–6 l is extracellular water. There is an increase in plasma volume During normal pregnancy, there is a gradual cumulative retention of about 900 mmol of sodium, distributed between the products of conception and maternal extracellular space.

(maximum during the second trimester and approaching 50% above non-pregnant values), and fluid accumulates within the fetal and maternal inters al spaces. During normal pregnancy, there is a gradual cumula ve reten on of about 900 mmol of sodium, distributed between the products of concep on and maternal extracellular space. In pregnant women, the filtered sodium load increases from about 20,000 mmol/day to about 30,000 mmol/day, due to increases in GFR. However, it is associated with mild reduc on in plasma sodium concentra on. The adap ve increment in renal tubular reabsorp on not only equals the increase in filtered load, but an addi onal 2–6 mmol of sodium is reabsorbed daily for fetal and maternal stores. 10

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Nevertheless, it is common for sodium excre on to increase during pregnancy because of increase in intake. The pregnant woman handles ingested salt same as non-pregnant woman. Sodium handling in an individual nephron segments during pregnancy is not clear. Studies in normal women indicate increased sodium reabsorp on in the proximal tubule and distal nephron segments in late pregnancy. The reason for the net renal sodium reten on in pregnancy is not known and, in fact, sodium homeostasis in pregnancy remains an enigma. There are many factors opera ng to There are many factors operating to both increase and to decrease sodium excretion, and exactly how the normal balance of net retention is achieved remains a mystery.

both increase and to decrease sodium excre on, and exactly how the normal balance of net reten on is achieved remains a mystery.

Factors Affecting Tubular Sodium Excretion: Summary Factors which Increase Sodium Excretion 1. Progesterone: Progesterone increases by 10- to 100-fold and these concentra ons are potently natriure c, and cause a natriuresis by an an mineralocor coid effect as well as a direct inhibitory effect on proximal tubular reabsorp on. 2. ANP: Atrial natriure c pep de and its metabolic clearance increase in human pregnancy, although plasma ANP increments are small rela ve to the marked intravascular volume expansion. This increases sodium excre on. 3. Increased GFR leads to increased filtra on of sodium, which will increase sodium excre on. 4. Decreases in plasma albumin concentra on and the increment in effec ve renal plasma flow during pregnancy will also enhance sodium excre on by inhibi ng tubular sodium reabsorp on. The slightly decreased filtra on frac on and consequent reduc on in postglomerular and thus renal inters al colloid osmo c (onco c) pressure in pregnant women will reduce proximal tubular sodium reabsorp on via a direct ac on on the tubule. 11

ECAB Clinical Update: Nephrology

Factors which Decrease Sodium Excretion 1. ADH hormones: ADH is increased and it decreases sodium excre on. 2. Angiotensin: There is marked increase in plasma angiotensin ac vity in normal pregnancy. In addi on to s mula ng aldosterone release, physiological concentra ons of angiotensin II act directly on the proximal tubule to increase sodium reabsorp on. However, refractoriness develops to the vascular and possibly tubular ac ons of angiotensin II in normal pregnancy, which may nullify any net sodium reten on by this mechanism. 3. Aldosterone: Aldosterone is elevated and serves as homeosta c func on in pregnancy, and since sodium deple on results in further increases in aldosterone, while expansion of body fluid volume decreases, the concentra on of aldosterone is appropriate. 4. DesoxycorƟcosterone: Concentra ons increase con nuously throughout normal pregnancy, but most markedly in the third trimester. This pa ern of change is similar to that for aldosterone, progesterone, and estradiol. In this respect, both urinary free Some of the increased desoxycorticosterone during pregnancy may be from a fetal source, but the current view is that most arises by extra-adrenal 21-hydroxylation of circulating progesterone.

5. 6.

12

desoxycor costerone and the free desoxycor costerone in plasma are substan ally increased during gesta on. Some of the increased desoxycor costerone during pregnancy may be from a fetal source, but the current view is that most arises by extraadrenal 21-hydroxyla on of circula ng progesterone. This causes increased sodium absorp on and decreases excre on. Estrogens ProlacƟn and Placental Lactogen’s role in decreasing sodium excre on s ll needs to be clarified. Increased Ureteric Pressure and Upright Posture: Elevated intraureteral pressure (in the upright or supine posi ons) and the presence of the newly formed uterine vasculature, which has been likened to an arteriovenous shunt influencing sodium handling during pregnancy. Supine and upright posi ons are strongly

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an natriure c and standing may decrease sodium excre on more in a pregnant than in a non-pregnant woman. Finally, the decrease in mean arterial blood pressure that also occurs in normal pregnancy is an natriure c. It is evident from above literature that there are many conflic ng s muli to sodium excre on in pregnancy but net sodium reten on and marked plasma volume expansion is the norm. In fact, there is a strong posi ve correla on between the maternal plasma volume expansion and a successful obstetrical outcome. In the normal non-pregnant steady state, plasma volume expansion and renal sodium reten on cannot co-exist, but pregnancy is not a steady state, and the volume sensing and regulatory systems are drama cally readjusted throughout pregnancy to accommodate and maintain the volume expansion.

Volume Sensing Systems in Pregnancy Volume sensing and control in pregnancy is different from that in non-gravid states. Despite the progressive extracellular fluid volume expansion of normal pregnancy, the volume receptors sense these It is unclear exactly how the changes in the renin angiotensin system during pregnancy are associated with the alterations in volume homeostasis.

large gains as normal and when diure cs or salt restric on limit volume expansion, the maternal response is similar to that observed in saltdepleted non-pregnant women. Plasma renin ac vity, concentra on and substrate, as well as plasma angiotensin II, increase markedly in pregnancy, and pregnant women are resistant to the pressor and renal effects of infused angiotensin II. In non-pregnant women, increased plasma renin, angiotensin II, and aldosterone are associated with volume deple on, whereas in pregnancy, elevated renin, angiotensin II, and aldosterone co-exist with an expanded plasma volume. It is unclear exactly how the changes in the renin angiotensin system during pregnancy are associated with the altera ons in volume homeostasis. Baseline renin ac vity, already elevated despite increased effec ve renal plasma flow and absolute blood volume, is 13

ECAB Clinical Update: Nephrology

increased further by sodium restric on or assump on of the supine or upright posture and is decreased by volume expansion, sugges ng a new set point in the system. Further, it has been suggested that the enhanced renin secre on in pregnancy is secondary to increments in vasodilatory prostaglandins, which originate from both the uterus and vascular endothelium. The prostaglandins could contribute to the decreased blood pressure and dilated vascular compartment of normal pregnancy, and both the vasodilata on and the direct ac on of increased prostacyclin concentra on could lead to compensatory s mula on of the renin angiotensin system. This might explain why angiotensin and aldosterone values are increased despite the absolute hypervolemic of pregnancy. Indeed, increased renin/angiotensin in pregnancy has been cited as evidence that pregnancy is actually a state Both osmotic and non-osmotic control of ADH release are dramatically altered in normal pregnancy in a manner indicating that the expanded volume of pregnancy is sensed as normal.

of underfill, subop mal effec ve blood volume despite the marked increase in blood volume that occurs in absolute terms. This view is supported by the observa on that in early pregnancy an infusion of angiotensin-conver ng enzyme inhibitors leads to exaggerated decrements in blood pressure, while graded infusions of angiotensin II lead to greater increments in aldosterone than similar doses that evoke in non-pregnant individuals. In contrast, and as discussed in detail above, both osmo c and non-osmo c control of ADH release are drama cally altered in normal pregnancy in a manner indica ng that the expanded volume of pregnancy is sensed as normal. The ANP system is ac vated in response to increased extracellular fluid volume. Plasma ANP increases slightly in late-pregnant women, but this is unlikely to reflect a physiological response to volume expansion because atrial size does not change during normal pregnancy; plasma ANP remains elevated long a er delivery; and even greater increases in ANP are seen in pre-eclamp c pregnancies, which also exhibit volume contrac on. Thus, the ANP system appears to recognize the expanded volume in pregnancy as normal. The tubuloglomerular feedback system 14

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also func ons as an intrarenal volume sensing and regulatory system, in which the delivery of tubular fluid is sensed by the macula. When fluid delivery increases, a signal is sent to the parent glomerulus, resul ng in vasoconstric on with a consequent reduc on in single nephron GFR and thus, restora on of early distal fluid delivery. In some states of chronic volume expansion, tubuloglomerular feedback ac vity is suppressed, an adapta on which allows the volume-expanded organism to excrete the excess volume load efficiently. However in pregnancy, the tubuloglomerular feedback system is not suppressed but is reset to recognize the expanded volume and increased GFR as normal. Taken in conclusion, the various volume sensing and control systems are drama cally altered in normal pregnancy. Despite clear evidence of an absolute expansion in the plasma volume, the majority of bodyvolume sensor systems perceive the maternal plasma volume as normal Despite clear evidence of an absolute expansion in the plasma volume, the majority of body-volume sensor systems perceive the maternal plasma volume as normal or contracted.

or contracted. This raises the issue of effec ve rather than absolute vascular volume. In normal pregnancy, the peripheral vasculature is markedly vasodilated and this is the only mechanism by which the elevated cardiac output of pregnancy could be accommodated without increasing arterial blood pressure. This vasodilata on produces pooling of blood in the venous side of the circula on, which means arterial volume receptors sense the effec ve blood volume as less expanded. Also, the presence of an arteriovenous fistula causes renal sodium reten on, sugges ng that the effec ve blood volume may be sensed as reduced.

CLINICAL RELEVANCE OF RENAL ALTERATIONS IN NORMAL PREGNANCY The altered milieu of pregnancy means that hemodynamic and biochemical markers of normal func ons are substan ally altered. Table 4 summarizes that the common normal values are altered by pregnancy. 15

ECAB Clinical Update: Nephrology

Table 4. Altered Hemodynamic and Biochemical Markers of Normal Pregnancy Parameter

Non-pregnant women

Pregnancy

Hematocrit (vol/dl)

41

33

Plasma protein (g/dl)

7.0

6.0

Plasma osmolality (mOsm/Kg)

285

275

Plasma Na (mEq/L)

140

135

Serum creatinine (mg/dl)

0.8

0.5

Blood urea (mg/dl)

27

20

7.40

7.44

PCO2 (kPa)

40

30

Serum HCO3 (mEq/L)

25

20

Serum uric acid (mg/dl)

0.40

0.32

Systolic blood pressure (mmHg)

115

105

Diastolic blood pressure (mmHg)

70

60

pH

Assessment of Renal Function in Normal Pregnancy Plasma crea nine and blood urea decreases from a non-pregnant value in successive trimesters. Familiarity with the changes is vital, because values considered normal in non-pregnant women may signify decreased renal func on in pregnancy. As a rough guide, values of plasma crea nine and urea >0.8 mg/dl and of 20 mg/dl, respec vely should alert the clinician to assess renal func on further.

Creatinine Clearance in Clinical Practice/GFR Estimation in Clinical Practice Although plasma creatinine, its reciprocal, or its logarithm is often used to estimate GFR, this approach has been questioned for 16

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pregnancy, where in any case it is not ideal, because body weight or size do not reflect kidney size. Ideally, evaluation of renal function in pregnancy should be based on the clearance rather than the plasma concentration of creatinine. To overcome such problems as washout from changes in urine flow, and to avoid difficulties caused by diurnal variations, 24-h urine samples should be used for clearances. Many methods of determining creatinine concentration in plasma also measure non-creatinine chromogens, leading to overestimates that must be taken into consideration when calculating creatinine clearances. The modification of diet in renal disease (MDRD) formula is often used to calculate GFR in non-pregnant renal states. The accuracy of MDRD formula in pregnancy was evaluated in two prospective studies.5 In these studies it was found that Cockroft and Gault formula overestimated GFR by approximately 40 ml/min whereas MDRD formula underestimated GFR by approximately 20 ml/min for full MDRD and 13 ml/min for modified MDRD. Given these issues, 24-hr urine collections for creatinine clearance is the gold standard for estimating GFR in pregnancy.

Changes in Plasma Uric Acid From the clinical viewpoint, it is of interest that plasma uric acid concentra on and renal absorp on are significantly greater in pregnancies complicated by pre-eclampsia or intrauterine growth retarda on. At a cri cal blood value of >5.5 mg/dl, there is significant perinatal mortality in hypertensive pa ents, and serial measurements can be used to monitor progress in pre-eclampsia. It must be remembered that there is diurnal varia on in plasma concentra ons and that variability is such that some healthy women have hyperuricemia without problems, that single random measurements are of no use clinically, and that concentra ons tend to be greater with mul ple pregnancies.

Changes in Glucose Excretion Glycosuria of pregnancy reflects alteration in renal function rather than alteration in carbohydrate metabolism. The testing of random urine samples during pregnancy is unhelpful in the diagnosis or 17

ECAB Clinical Update: Nephrology

control of diabetes mellitus and unrepresentative as to the degree of glycosuria present.

Proteinuria Urine flow normally varies over a wide range from moment to moment so that the protein concentration of a random specimen can give only a semiquantitative appraisal. In normal pregnancy proteinuria may well be up to 500 mg in 24 h (twice the upper limit in non-pregnancy), but for the purposes of definition 300 mg in 24 h is considered abnormal.6 Likewise spot urine protein/creatinine ratios >30 mg protein/mmol creatinine being the optimal discriminate value for true proteinuria, with sensitivity 93%, specificity 92%, positive predictive value 95%, and negative predictive value 90%. There is debate about the independent effect of normal pregnancy on long-term renal function, using microalbuminuria to detect any damage. However the consensus is that pregnancy does not damage the kidney, and in many cases, better markers are needed than albumin excretion alone. Several studies have compared urine protein-creatinine ratio with 24-hr urine collection in the setting of pre-eclampsia. A meta-analysis of 974 pregnant women for 10 studies showed a pooled sensitivity of 90% and specificity of 78% using protein-creatinine ratio. Hence, it is reasonable to use urine protein-creatinine ratio for diagnosis of proteinuria in pre-eclampsia.7

Renal Function Tests in Pregnancy Serial data on renal func on are o en needed to supplement rou ne antenatal observa ons. Tests available for use in rou ne clinical prac ce include the es ma on of blood urea and electrolytes, crea nine clearance determina on, and urinary concentra on and dilu on assessment. Serial surveillance of 24-h crea nine clearance and protein excre on (24-h collec ons and protein/crea nine ra os) should be performed and, wherever possible, compared with nonpregnant values. Near term, a decrease in func on of 15% (which affects plasma crea nine minimally) is probably normal. Thus, we can conclude that there are significant anatomical and physiological changes in normal pregnancy and clinician must be aware 18

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of this to be sure of when a func on should be taken as abnormal in pregnancy.

REFERENCES 1. 2.

3.

4.

5.

6.

7.

Brown MA. Urinary tract dilatations in pregnancy. American Journal of Obstetrics and Gynecology 1990;164:641–3. Brown MA, Gallery EDM. Volume homeostasis in normal pregnancy and pre-eclampsia: physiology and clinical implications. Clinical Obstetrics and Gynecology 1994;287:310. Davison JM, Dunlop W. Changes in renal haemodynamic and tubular function induced by normal human pregnancy. Seminars in Nephrology 1984;4:198–207. Durr JA, Stamoutsos B, Lindheimer MD. Osmoregulation during pregnancy in the rat: evidence for resetting of the threshold for vasopressin secretion during gestation. Journal of Clinical Investigation 1981;68:337–46. Smith MC, Moran P, Ward MK, Davison JM. Assessment of glomerular filtration rate during pregnancy using the MDRD formula. BJOG 2008;115: 109–12. Higby K, et al. Normal values of urinary albumin and total protein excretion during pregnancy. American Journal of Obstetrics and Gynecology 1994;171:984–9. Rodriguez Thompson D, Lieberman ES. Use of a random urinary protein-tocreatinine ratio for the diagnosis of significant proteinuria during pregnancy. Am J Obstet Gynecol 2001;185:808–11.

19

Pregnancy in Women with Chronic Kidney Disease Dr. Ghulam Hassan Malik

MD, DM, FISN, FACP

Director and Senior Consultant Nephrologist Well Care Medical Center Soura, Srinagar, Kashmir

ABSTRACT:  In  normal  pregnancy  there  are  significant  renal  changes  both  anatomical  (increase  in  kidney  size)  and  physiological  (hemodynamic,  tubular,  and  hormonal).  During  pregnancy  in  women  with  underlying  chronic  kidney  disease  (CKD),  the  adaptation  to  these  changes  may  not  be  optimal.  Under  these  circumstances,  the  pregnancy  outcome  as  well  as  maternal  CKD  may  be  affected.  Women  with  moderate  renal  dysfunction  exhibit  increased  creatinine  clearance  and  plasma  volume expansion during gestation, whereas women with severe  renal dysfunction do not. This chapter addresses the influence of  pregnancy on the underlying kidney disease and the effect of the  kidney disease on the outcome of pregnancy.   

KEYWORDS: 

Pre‐eclampsia,  proteinuria,  maternal  hypertension,  hypocomplementemia,  antiphospholipid  antibodies, microalbuminuria, pregnancy in dialysis patients.   

20a

Pregnancy in Women with Chronic Kidney Disease Dr. Ghulam Hassan Malik

MD, DM, FISN, FACP

Director and Senior Consultant Nephrologist Well Care Medical Center Soura, Srinagar, Kashmir

INTRODUCTION In normal pregnancy there are significant renal changes both anatomical (increase in kidney size) and physiological (hemodynamic, tubular and hormonal). During pregnancy in women with underlying chronic kidney disease (CKD), the adapta on to these changes may not be op mal. Under these circumstances, the pregnancy outcome as well as maternal CKD may be affected.1 Women with moderate renal dysfunc on exhibit increased crea nine clearance and plasma volume expansion during gesta on whereas women with severe renal dysfunc on do not.2 The incidence of CKD in pregnancy was 0.03–0.2% of all pregnancies from two US popula on-based and registry studies.3 Two aspects need to be addressed: 1.

The influence of pregnancy on the underlying kidney disease.

2.

The kidney disease affec ng the outcome of pregnancy.

Some obstetric defini ons need to be recapitulated as also their incidence in general popula on. Spontaneous aborƟon: Loss of pregnancy without outside interven on before 22 weeks of gesta on. Of clinically recognized pregnancies, 10–15% end up with spontaneous abor on.4 Perinatal mortality (PM): Death of a viable fetus a er 22 weeks of gesta on or within 4 weeks of delivery (includes s llbirth). In the USA it was 6.9/1000 births in 2001.5 20

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Preterm delivery: Delivery before 37 weeks of gesta on―occurs in 12.5% of all pregnancies.5 Low birth weight (LBW): Baby weighing 2.3 mg/dl.1,7,8

Proteinuria and Hypertension Proteinuria >500 mg/day in the first half of pregnancy usually indicates pre-exis ng CKD and increases the risk of pre-eclampsia by 30% and higher with associated chronic hypertension.9 The degree of proteinuria increases by 50% and hypertension develops or worsens in about 25%.10–13 Severe hypertension can lead to maternal injury, premature delivery or poor fetal outcome and remains the greatest threat to the pregnant pa ent with CKD.14 Blood 21

ECAB Clinical Update: Nephrology

pressure control remains the cornerstone of successful treatment of CKD in pregnancy. Massive proteinuria in general, does not indicate an increased risk for mother or fetus.15 In a study of 51 pregnancies in women with CKD in a ter ary referral center in India, hypertension at concep on was a significant factor influencing the gesta onal age at delivery. Hypertension worsened in 16 (35.5%) women during pregnancy, of which 13 had to be terminated preterm because of uncontrolled hypertension. The risk of prematurity was significantly increased when diastolic blood pressure was 90 mmHg or more at concep on. All pa ents with diastolic blood pressure >100 mmHg delivered preterm. Serum crea nine increased Blood pressure control remains the cornerstone of successful treatment of chronic kidney disease in pregnancy.

during pregnancy in 32.5% and this increase was inversely related to the baseline crea nine clearance.16

Effect of Pregnancy on CKD Stages 1 and 2 With ini al normal or mildly impaired renal func on (serum crea nine 50 ml/min, there may be a transient decline in renal func on during pregnancy and 1.5 mg/dl). In this se ng, the plasma crea nine tends to decline in the first half of pregnancy as in normal pregnancy in which increase in GFR up to 50% above baseline is noted.22 This may rise above baseline as pregnancy progresses.23 There may be an accelerated decline in renal func on during pregnancy. Pre-exis ng hypertension and proteinuria both increase the risk.24 Women who ini ated pregnancy with a serum crea nine of >2 mg/dl had a high (33%) likelihood of an accelerated decline in renal 23

ECAB Clinical Update: Nephrology

func on during or following pregnancy.25 More than 70% of women who become pregnant with more than 2.5 mg/dl will have preterm delivery and more than 40% develop pre-eclampsia.25,26 Current consensus suggests the degree of renal insufficiency rather than the underlying renal disease as the primary determinant of outcome.27 In a prospec ve study by Imbascia et al in women with stages 3–5 CKD, women with es mated GFR < 40 ml/min/1.73 m2 and proteinuria more than 1 g/day before pregnancy showed an accelerated decline in renal func on in pregnancy with poor fetal and maternal outcome.28 Similar observa ons have been made in other studies.29–32 Kidney disease has been suggested as an independent risk factor for unfavorable outcome for both mother and child.33 A large number of women with moderate renal insufficiency may have an irreversible decline in GFR greater than predicted in the natural course of the disease; about one third may experience an irreversible decline.23,34,35 The risk of an irreversible decline may be more than 50% if uncontrolled hypertension is also present.35 Current consensus suggests the degree of renal insufficiency rather than the underlying renal disease as the primary determinant of outcome.

In pregnancy with normal or mildly impaired renal func on (CKD stages 1 and 2) and well controlled blood pressure live birth rate is above 90% but fetal survival is lower if BP is uncontrolled.14,34,35 The risk of prematurity is increased with baseline serum crea nine above 1.4 mg/dl compared to general popula on (59% versus 10%, respec vely). Preterm delivery is mostly related to interven on for pre-eclampsia and intrauterine growth restric on.25,36 The risk of pre-eclampsia is significantly increased in CKD with increased fetal and maternal morbidity and mortality. Diagnosis of pre-eclampsia in CKD may be difficult in presence of CKD. However, worsening of hypertension with hyperreflexia favor the diagnosis of pre-eclampsia.37 The occurrence of elevated liver enzymes, thrombocytopenia and microangiopathic hemoly c anemia in severe pre-eclampsia make the diagnosis easy.37 The dis nguishing features between pre-eclampsia and pre-exis ng renal disease are given in Table 1. 24

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Table 1. Differential Diagnosis of Pre-eclampsia and Primary Renal Disease in Pregnancy.1 During pregnancy

Pre-eclampsia

Proteinuria

After 20 weeks’ gestation

Hematuria Casts Hypertension

— Rarely seen After 20 weeks’ gestation

Thrombocytopenia

Occurs in moderate and severe pre-eclampsia Occur in moderate and severe pre-eclampsia

Elevated hepatic transaminases

Pre-existing renal disease May occur before 20 weeks May occur Often seen May occur before 20 weeks Not usually seen Not usually seen

The diagnosis of pregnancy in end stage renal disease is difficult since raised levels of beta human chorionic gonadotropin are found in the range indica ng pregnancy.38 Ultrasonography will confirm the diagnosis. To summarize, in CKD with normal or mildly impaired renal func on (serum crea nine 90% but there may be worsening of renal func on especially in presence of uncontrolled hypertension. Proteinuria >1.0 g/day along with hypertension worsens the prognosis for mother.

Specific Renal Disease in Pregnancy Most inves gators have observed that baseline renal func on, presence of hypertension, proteinuria and urinary tract infec on are the determining factors for pregnancy outcome and not the e ology except lupus nephri s (LN).35,36,39

Primary Glomerulonephritis Accelerated progression was noted in membranoprolifera ve and focal segmental glomerulosclerosis in some studies.12,35 However, the outcome 25

ECAB Clinical Update: Nephrology

of pregnancy and the reciprocal effect on the course of renal disease in CKD was comparable to normal pregnancy in women who underwent repeated pregnancies in different histological types of glomerulonephri s including focal and segmental glomerulosclerosis.19–21

Autosomal Dominant Polycystic Kidney Disease Women with autosomal dominant polycys c kidney disease (ADPKD) with normal renal func on and blood pressure have successful pregnancy. Pre-exis ng hypertension however, increases chances of pre-eclampsia and prematurity.40

Vesicoureteral Reflux (VUR) Reflux nephropathy may be associated with impaired renal func on, hypertension and proteinuria. Pre-existing hypertension increases chances of pre-eclampsia and prematurity.

Pregnancy in VUR is complicated by superimposed pre-eclampsia, recurrent urinary tract infec on, deteriora on of renal func on and gesta onal ureteral obstruc on. Fetal morbidity and mortality are related to hypertension and level of renal func on at concep on.41,42 To prevent recurrent urinary tract infec on, an bio c prophylaxis following an a ack of pyelonephri s is indicated.

Nephrolithiasis Symptoma c renal stone disease during pregnancy is seen in 1 in 244 pregnancies―same as in general popula on. Renal colic is common in the second and third trimesters.43 Urinary tract infec on associated with renal stones should be treated longer followed by prophylaxis.43 Ultrasound will diagnose the calculus in half of the cases. Magne c resonance urography may be needed to differen ate physiological hydronephrosis from hydronephrosis due to calculi.

General Management of Pregnancy in CKD Pa ents of CKD during pregnancy should be managed jointly by a 26

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nephrologist and an obstetrician familiar with the effects of renal disease on pregnancy (Fig. 1). General principles of management are as follows: 1.

If the pregnancy is planned angiotensin conver ng enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) should be discon nued once pregnancy is confirmed. Folic acid 0.5 mg daily should be prescribed un l 12 weeks of gesta on. Low dose aspirin 50–150 mg daily should be commenced and con nued ll delivery.

2.

Antenatal visits should be every 2 weeks un l third trimester and then weekly.

3.

Early detec on and treatment of asymptoma c bacteriuria.

4.

Serial monitoring (at least monthly) of maternal renal func on

5.

Close monitoring for the development of pre-eclampsia.

6.

Fetal surveillance with ultrasound and fetal heart rate monitoring to assess the fetal growth and well being.

Patients of chronic kidney disease during pregnancy should be managed jointly by a nephrologist and an obstetrician familiar with the effects of renal disease on pregnancy.

7.

Treatment of maternal hypertension. Blood pressure should be maintained at 140/90 mmHg or lower throughout pregnancy. An hypertensive medica ons in CKD with pregnancy are methyldopa, labetolol, calcium channel blockers and alfa blockers. In general all an hypertensive medica ons except ACEI or ARBs can be used safely.

8.

Preterm interven on may be necessary in the presence of deteriora ng renal func on, severe pre-eclampsia, intrauterine fetal growth restric on or distress.

Pregnancy in Lupus Nephritis Systemic lupus erythematosus (SLE) predominantly occurs in women in childbearing age. Pregnancies in LN are high risk and associated with both maternal and fetal problems. The outcome of pregnancy has improved with a significant fall in fetal loss in the last 40 years from 40% in 1960–65 to 17% in 2000–03.44 27

ECAB Clinical Update: Nephrology

Prepregnancy

• Discontinue ACEI and ARBs • Folic acid 0.5 mg daily until 12 weeks of gestation • Low dose aspirin (50–150 mg daily) till delivery • Low dose heparin, if antiphospholipid antibodies are present or proteinuria more than 3 g/day

Antenatal visits

• Every 2 weeks until first 2 trimesters, weekly—third trimester • Early detection and treatment of asymptomatic bacteriuria • Serial monitoring (monthly) of maternal renal function • Close monitoring for the development of pre-eclampsia • Fetal growth assessment―ultrasound and fetal heart monitoring • Treatment of maternal hypertension―Methyldopa, labetalol, calcium channel blocks and alfa-blockers

Delivery

• Preterm intervention in presence of deteriorating renal function, severe pre-eclampsia, IUGR or fetal distress

Post-delivery

• Close monitoring of BP • Continue aspirin/low dose heparin for 6 weeks • Return to nonpregnant medication regimen

Figure 1. Management of women with chronic kidney disease during pregnancy. ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; IUGR: intrauterine growth restriction.

The major issues concerning pregnancy in LN are exacerba on (flare), renal disease, pre-eclampsia, abor on, placental insufficiency, intrauterine growth restric on, preterm delivery, cesarean sec on, neonatal lupus and breas eeding.

Exacerbation of Systemic Lupus Erythematosus There are conflic ng reports about exacerba on of SLE during pregnancy. Some studies have shown flares during pregnancy up to 60%. Flares present most commonly as cons tu onal symptoms, renal disease and/or involvement of skin joints.45,46 Other studies have shown no increase in flare rate during pregnancy.47,48 Renal flare may 28

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be related to the ac vity of LN at the me of concep on and such pregnancies are also associated with an increased maternal and fetal risk.49,50 The improved outlook may reflect be er management and control of disease ac vity before pregnancy.51

Renal Disease Pregnancy in women with LN is associated with an increased risk of fetal loss (up to 75%) and worsening of renal and extra-renal manifesta ons.52–55 The frequency of exacerba on varies with the state of disease ac vity ranging from 7% to 33% in women who have been in remission for at least 6 months and from 61% to 67% in women who have ac ve disease at the me of concep on.52,53 Thus, women should be counseled to delay pregnancy un l the disease is inac ve for at least 6 months. Women with renal impairment are likely to have more progressive disease24 and such women are likely to have adverse pregnancy outcome―pre-eclampsia, pre-term delivery and intrauterine growth restriction.56 Hypertension is an independent risk factor There are conflicting reports about exacerbation of systemic lupus erythematosus during pregnancy.

of fetal death in LN.49 Proteinuria, hypertension and positivity of antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies) have been found to be independent risk factors for fetal outcome.57 Patients with SLE and antiphospholipid antibodies are at increased risk for spontaneous abortion typically second trimester. A review of 10 studies of 554 women with SLE found that fetal loss was more common in those with antiphospholipid antibodies (38– 59%) versus 16–20% in those without such antibodies. 58 In another study Moroni et al noted that pregnancies in women with antiphospholipid antibodies resulted in 76% fetal loss versus 13% in antibody negative pregnancies.57 In the absence of proteinuria, the probability of a successful pregnancy was 91%, whereas proteinuric pa ents had only 43% successful pregnancy.57 29

ECAB Clinical Update: Nephrology

Pre-eclampsia The incidence of pre-eclampsia in patients with LN varies from 15% to 30% due to inconsistencies in definition and classification of these disorders in various studies.49,59–62 Women with LN are most susceptible owing to the association of pre-eclampsia with an underlying renal disease. Pre-eclampsia is also seen more often in association with antiphospholipid antibodies. 63 It may be difficult to distinguish pre-eclampsia from LN activity. Both can present with increasing proteinuria, hypertension and deterioration of renal function. 51 Laboratory tests may serve as useful parameters for distinction. LN is often associated with low complement levels whereas complement levels are normal or high in pre-eclampsia. Moreover, active urine sediment (red and white blood cells and casts) is seen in flare of LN. Thrombocytopenia, elevated liver enzymes and uric acid are more prominent in pre-eclampsia. Aspirin reduces the risk of pre-eclampsia and perinatal death, and increases the birth weight in those with The incidence of pre-eclampsia in patients with lupus nephritis varies from 15% to 30% due to inconsistencies in definition and classification of these disorders.

risk factors including renal disease. With positive antiphospholipid antibody, combination therapy with aspirin and heparin has been shown to be more effective.50,64–66

Fetal Loss Approximately 20–30% pregnancies with SLE result in a miscarriage which is higher that that in general population. Overall fetal loss may approach 50%.67,68 Even in recent studies fetal loss from 13% to 38% has been reported.50,51,63,69 In a case control study of 481 pregnancies in 203 patients with SLE, loss including spontaneous abortion, miscarriage or still birth was more common in SLE pregnancies (21%) than in pregnancies of friends (14%) or relatives (8%) of patients with SLE.68 Hypertension, LN, hypocomplementemia; elevated levels of an DNA an bodies or an phospholipid an bodies are associated with poor 30

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fetal outcome.46,70,71 In many studies, the presence of an phospholipid an bodies has been the single most sensi ve predictor of fetal death.59 In prospec ve studies with planned pregnancies in quiescent disease, live birth rates of 85–88% were noted50,63,72 whereas live birth rate was 64% in LN pregnancies in ac ve disease.73 Pa ents with SLE have preterm delivery rates three mes compared to pa ents without SLE. The causes are: hypertension, renal complica ons, an phospholipid an bodies, pre-eclampsia, premature rupture of membranes and cor costeroid use.74,75 Imbascia et al in a recent prospec ve study noted preterm deliveries and LBW babies in 31% and 34% pregnancies, respec vely.50

Neonatal Lupus Neonatal lupus is a passively transferred autoimmune disease of babies born to mothers with an -R O/SSA and/or La/SSB an bodies. Its incidence is low―1 in 15000 live births and in a small percentage Hypertension, lupus nephritis, hypocomplementemia; elevated levels of anti-DNA antibodies or antiphospholipid antibodies are associated with poor fetal outcome.

of lupus pregnancies.76,77 These an bodies cross the placenta and are associated with congenital complete atrioventricular heart block which occurs in approximately 2% of such pregnancies. Neonatal lupus accounts for 90–95% of complete heart block in neonates. Skin rash and rarely hematological abnormali es are other clinical manifesta ons. In a study of 62 pregnancies in 38 women with SLE cutaneous lupus was noted in 2 neonates.78 The skin lesions typically appear in the first week and may last up to 6 months.79

Breast Feeding Breast feeding is feasible in most women with SLE. Some medica ons may enter breast milk. Immunosuppressive agents are contraindicated and long-ac ng nonsteroidal an -inflammatory drugs (NSAIDs) are inadvisable. Short-ac ng NSAIDs, an malarials, low-dose prednisolone (up to 20 mg/day), warfarin and heparin are safe.80–82 31

ECAB Clinical Update: Nephrology

The following three cases of pregnancy in LN will illustrate the good outcome for mother and fetus in well controlled disease and fetal demise and rapid progression of LN in pregnancy in uncontrolled disease.

CASE 1 SSA, a 43-year-old female was seen in May 1995 in Rheumatology Clinic with history of polyarthralgia. On inves ga on, ESR was 128 mm, an nuclear an body (ANA) and an -DNA an body were posi ve, serum levels of C3 and C4 were llow, LE cells were posi ve. The pa ent was treated as SLE with steroids. On follow-up, proteinuria was detected and referred to Renal Clinic on 1-9-1996. Urinalysis revealed proteinuria 2+ and RBC 8–10/hpf, 24-hour proteinuria was 1.2 g, serum urea 19 mg/dl and serum crea nine 0.7 mg/dl. Renal biopsy showed LN WHO class IV and V and was planned for cyclophosphamide therapy (6 courses monthly and 6 courses 3 monthly) and prednisolone (0.3–0.5 mg/kg). First course of cyclophosphamide was given in October 1996. On follow-up on 17-6-97, proteinuria was 1.5 g/d, ANA was posi ve (1:160) an -DNA was nega ve, serum C3 and C4 were normal, and an -cardiolipin an body was nega ve. The follow-up inves ga ons are presented in Table 2. Last course of cyclophosphamide was completed on 28-9-98 and therapy changed to azathioprine 100 mg/day and low-dose prednisolone. She underwent 8 pregnancies: 4 before and 4 a er SLE (Table 3). Tubal liga on was performed a er last cesarean delivery. Maintenance therapy was con nued with prednisolone 10 mg and azathioprine 100 mg daily.

CASE 2 WN, a 24-year-old female had intrauterine fetal death (IUFD) and spontaneous vaginal delivery (SVD) in 1994. Was seen in another hospital 3 months earlier for skin rash and arthri s and treated with steroids for SLE. On 3-1-1995, she was admi ed with molar pregnancy of 10 weeks’ dura on and underwent dilata on and cure age. On renal biopsy in that hospital on 31-10-95, diagnosis of LN WHO class V was made. 32

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Table 2. Pregnancy in Lupus Nephritis—Follow-up Investigations (Case 1) 17-6-97

2-2-99

11-7-99

1-2-00

2.5

2.5

2.5

1.6

1.2

1.5

1:160

–

1:160

–

+

1:160

Anti-DNA

–

Negative

–

+

Negative

–

S. C3 (N = 0.55–1.2)

0.69

1.18

1.3

0.93

1.07

1.01

S. C4 (N = 0.2–0.5)

0.07

0.11

0.13

0.24

0.27

0.13

S. creatinine

0.76

0.72

0.68

–

0.76

0.82

–

–

–

–

–

Proteinuria (g/d) ANA

Anticardiolipin Negative

9-12-00 6-2-01

Admi ed in Rheumatology on 5-3-96 as gravida (G) 3 of 10 weeks with hypertension. Urinalysis showed protein 2+, RBC 8–10/F, serum urea 28 mg/dl, serum crea nine 1.0 mg/dl, serum C3 0.94 (N = 0.55– 1.20/L) serum C4 0.11 (N = 0.20–0.50/L), proteinuria 1.3 g/d, serum ANA posi ve (1:40) and serum an -DNA an body was nega ve Re-admi ed in Obstetrics/Gynecology (Ob/G) department on 10-996 with pre-eclampsia and intrauterine growth restric on (IUGR), she underwent LSCS at 34 weeks and baby weighed 2.0 kg. Re-admi ed on 14-1-98 in Ob/G department as G4 of 34 weeks. Blood pressure was 182/107, serum urea 20 mg/dl, serum crea nine 0.8 mg/dl serum ANA + (1:80), serum an -DNA + (1:40), an cardiolipin an body was nega ve, serum C3 and C4 levels were normal. Was diagnosed as intrauterine growth retarda on and LSCS was performed, baby weighed 1.5 kg. On renal biopsy on 6-10-98, diagnosis of membranous (WHO class V) LN was made and planned for cyclophosphamide therapy (6 + 6 courses) and prednisolone. A er comple ng 6 courses of monthly and 3 courses of 3-monthly cyclophosphamide, was admi ed on 17-7-2000 for 4th course of 3-monthly cyclophosphamide which was held because of pregnancy. Blood pressure was 140/90, serum urea 54 mg/dl, serum 33

ECAB Clinical Update: Nephrology

Table 3. Date, Mode and Timing of Delivery Before and After the Diagnosis of SLE (Case 1) Pregnancies Pre-SLE

Post-SLE

1. 1981 – SVD (FT)

5. 1994 – SVD (FT)

2. 1984 – SVD (FT)

6. 25-2-96 LSCS (35 weeks)

3. 1987 – SVD (FT)

7. 2000 abortion (12 weeks)

4. 1990 – LSCS (FT)

8. 27-4-2001 – LSCS (FT)

SVD: spontaneous vaginal delivery; FT: full term; LSCS: lower segment cesarean section.

crea nine 1.5 mg/dl, serum uric acid 8.2 mg/dl, 24-hour proteinuria 9.8 g/day, serum levels of ANA and an -DNA were nega ve, serum C3 and C4 levels were normal. Cyclophosphamide was changed to therapy with azathioprine 100 mg daily and prednisolone 15 mg daily. The pa ent was re-admi ed on 19-2-2001 as G5 of 36 weeks. Hemoglobin was 8.7 g/dl, serum urea 62 mg/dl, serum crea nine 2.3 mg/dl. LSCS was performed on 20-2-01, baby weighed 1.5 kg. On follow-up in the renal clinic on 9-4-01 proteinuria was 1.8 g/ day, serum urea 85 mg/dl, serum crea nine 2.4 mg/dl, serum ANA was posi ve (1:80), serum C3 and C4 levels were normal and an cardiolipin an body was nega ve. Admi ed on 3-2-02 as G6 of 34 weeks, the pa ent had preeclampsia, serum crea nine was 4.0 mg/dl, which increased to 6.0 mg/dl and hemodialysis was ini ated as per protocol (4–6 mes/ week) to maintain serum urea nitrogen 1.0 g/day are present. Low molecular weight (LMW) heparin is added. LN may flare postpartum but prophylaxis with steroids is generally avoided and treatment given only in those with disease ac vity.1 36

Pregnancy in Women with Chronic Kidney Disease

First visit

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• Physical examination—blood pressure • Urinalysis—urine protein/urine creatinine ratio • Serum urea, creatinine, uric acid • Complete blood count, anti-DNA, complement levels • Antiphospholipid antibodies—if positive start low-dose aspirin and may add low-dose heparin

Monthly during first and second trimester

• Complete blood count

End of each trimester

• 24-hr urine collection for calculation of GFR

• Serum urea, creatinine, uric acid

• Urine protein/urine creatinine ratio • Anti-phospholipid antibodies • Complement and anti-DNA antibodies

Weekly—last trimester

• Ultrasonography

Postpartum

• Urinalysis, urine protein/urine creatinine ratio

• Fetal heart monitoring

• Renal function―Serum urea, creatinine, uric acid • Complete blood count, anti-DNA antibodies, complement levels

Figure 2. Management of women with lupus nephritis during pregnancy.82

Pregnancy in Women with Diabetic Nephropathy Diabe c nephropathy (DN), is characterized by proteinuria, hypertension and decrease in crea nine clearance. Approximately 5% of pregnant women with type 1 diabetes have DN.83 A diagnosis of DN is made if there is proteinuria of >300 mg/day in first 20 weeks of pregnancy. Microalbuminuria refers to albumin excre on of 30–300 mg/day and is indica ve of incipient diabe c nephropathy.

Effect of Diabetic Nephropathy on Pregnancy Diabe c nephropathy is associated with pregnancy complica ons like pre-eclampsia, IUGR, preterm delivery and cesarean birth. 37

ECAB Clinical Update: Nephrology

A review of the world literature from 1981 to 1996 showed perinatal survival of pregnancy in DN was 95% compared to approximately 99% in the general obstetric popula on.84 Figure 3 represents the outcome of pregnancy in DN. Preterm delivery, intrauterine growth restric on and perinatal mortality were noted in 22%, 15% and 5% pregnancies, respec vely.84 The degree of renal impairment correlates with the risk of pregnancy complica ons. In a study of 45 women with diabe c nephropathy, women with proteinuria >3 g/day or serum crea nine >1.5 mg/dl had higher risk of preterm delivery, low birth weight and pre-eclampsia.85,86 In another study of 17 women with DN, preterm delivery and need of intensive care of the neonates was significantly higher in the group with serum crea nine >1.8 mg/dl.87 Pre-eclampsia is a common complica on of DN and may be related to proteinuria in early pregnancy. In one study, only 7% developed preeclampsia with proteinuria 140/90 mmHg) and proteinuria (≥1+ or 300 mg/d) in two samples at least 4 hours apart a er 20 weeks of gesta on.11 This is usually associated with pedal edema, which needs to be differen ated from the benign edema that develops in the la er half of pregnancy in 54

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a majority of women. The disease is classified as “severe” if the blood pressure is over 160/100 mmHg and proteinuria exceeds 3+. PE is in fact a mul system disorder, and may involve almost all organs in the body. Neurologic involvement leads to severe headache or visual changes. Pain in the right hypochondrium indicates stretching of liver capsule secondary to acute liver injury and subcapsular hematoma. Other manifesta ons include pulmonary edema and acute renal failure. Abnormali es in the clo ng system result in hemolysis and/or thrombocytopenia. A combina on of hemolysis, elevated liver enzymes and low platelets (HELLP syndrome) is a form of severe PE.12 Eclampsia, iden fied by onset of seizures, complicates 2% of all preeclamp c pregnancies. About one-fi h of all women with eclampsia, however, do not have prior PE. In contrast to the physiologically decreased peripheral vascular resistance, blood pressure and sensi vity to angiotensin II are seen during normal pregnancy.13 PE is associated with widespread The physiological decrease in peripheral vascular resistance, blood pressure and sensitivity to angiotensin II are abolished in pre-eclampsia.

vasoconstric on, high systemic vascular resistance, and exaggerated responsiveness to angiotensin II and norepinephrine.14 Subtle increase in blood pressure, pulse pressure and impaired flow-mediated vasodilata on (secondary to endothelial dysfunc on) antedate overt hypertension and proteinuria.15 Women with PE show elevated levels of circula ng von Willebrand an gen, cellular fibronec n, soluble ssue factor, soluble E-selec n, platelet-derived growth factor and endothelin, all markers of endothelial ac va on and dysfunc on.16 The clinical syndrome can be explained almost en rely by systemic endothelial dysfunc on and PE has been characterized as a “disease of the endothelium” (Fig. 1).17,18 Pathological evalua on of organs in women dying of eclampsia shows widespread involvement of vascular endothelium. The most obvious and characteris c lesions (glomerular endotheliosis) were noted in the kidneys: There was generalized swelling and vacuoliza on of the endothelial cells and subendothelial 55

ECAB Clinical Update: Nephrology

fibrin deposits, leading to the oblitera on of the capillary lumina. 19 Electron microscopy shows loss of glomerular endothelial fenestrae.20 Remarkably, the podocyte foot processes are rela vely well-preserved, unlike other proteinuric condi ons.21 Genetic factors

Environmental factors

Other

Placental dysfunction

Circulating factor(s)

n Vascular endothelial dysfunctio

Hypertension

Glomerular endotheliosis Proteinuria Edema Renal insufficiency

Headache Cerebral edema Seizures

↑ LFTs HELLP syndrome

Figure 1. Endothelial dysfunction is central to the manifestations of pre-eclampsia. 56

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Vascular involvement is also evident in the liver and adrenals (infarc on, necrosis and hemorrhage), heart (endocardial necrosis), brain (cerebral edema, hemorrhage and infarc on in the subcor cal white ma er and adjacent gray ma er, predominantly in the parietal and occipital lobes).22 It has been tradi onally believed that the clinical and laboratory abnormali es of PE resolve completely following delivery and do not leave any long-term sequelae. Recent data, however, indicate that these women carry an elevated cardiovascular risk profile.1,23–25 The risk of developing hypertension or microalbuminuria within 7 years of their pregnancy is 10-fold higher and that of developing cardiovascular and cerebrovascular disease double than those without PE. This associa on is stronger in those with early, severe or recurrent PE, and if the pre-eclamp c pregnancy was associated with IUGR. The increased risk persists despite correc on for other tradi onal The clinical and laboratory abnormalities of pre-eclampsia resolve completely following delivery.

cardiovascular disease risk factors. Pre-eclampsia also confers a small increase in the risk for subsequent end-stage renal disease. 26 Interes ngly, a few studies have shown reduced risk of solid tumors in these women. Taken together, these observa ons may be explained by the recently iden fied abnormali es in angiogenic state during PE (discussed below). Fetal and neonatal complica ons of PE include intrauterine growth restric on (secondary to placental ischemia), oligohydramnios and increased risk of perinatal death.

PLACENTAL VASCULAR DEVELOPMENT AND PRE-ECLAMPSIA Survival of the fetus depends on the provision and maintenance of adequate blood supply to the intervillous space. During placental development, the fetal extravillous cytotrophoblasts in floating villi detach from their basement membrane and fuse to form a syncytial 57

ECAB Clinical Update: Nephrology

layer in direct contact with maternal blood. At the distal tips of the anchoring villi, cytotrophoblasts aggregate and form columns of mononuclear cells that attach to and invade the decidualized maternal endometrium (interstitial invasion), migrating out through the decidua and proximal third of the myometrium. 27 These invasive trophoblast cells breach the uterine spiral arteries, replace the endothelial layers of maternal vessels and destroy the vascular medial and neural tissues. By the end of the second trimester, the spiral arteries are lined exclusively by cytotrophoblasts, and maternal endothelial cells are no longer present in the endometrial or superficial myometrial regions. These cells also exhibit a change in the phenotype to an endothelial one. 28 This process is called “pseudovasculogenesis” and is at least in part is secondary to a change in expression profile of the adhesion molecules. The “epithelial” adhesion molecules such as α6/β1 and α5/β1 integrins and E-cadherin are replaced by the “endothelial” ones, i.e., α 1/β1 and αv/β3 integrins and VE-cadherin. The mean diameter of the uterine spiral arteries in women with pre-eclampsia is less than one-half of similar vessels from uncomplicated pregnancies.

As a result, this small, high-resistance circulation gets transformed to low-flow high-caliber capacitance system that permits a dramatic increase in blood supply to meet the metabolic needs of the growing uteroplacental unit. PE is characterized by a failure of this mechanism.29 Invasion of the uterine spiral arteries is limited to the proximal decidua; as much as 30–50% of the spiral arteries of the placental bed escape remodeling. Myometrial segments of these arteries remain undilated, and adrenergic nerve supply to the spiral arteries is not affected. These cytotrophoblasts remain in the lumen of the spiral arteries in PE and fail to exhibit the crucial change in phenotype including the adhesion molecule profile.30,31 The mean diameter of the uterine spiral arteries in women with pre-eclampsia is less than one-half of similar vessels from uncomplicated pregnancies. This failure of vascular remodeling prevents an adequate response to increased demands for blood flow that 58

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occur as gesta on progresses and produces a state of “uteroplacental ischemia” (Fig. 2). Placentae obtained from pre-eclamptic pregnancies show evidence of hypoperfusion; they are relatively small and exhibit infarcts. Histologic abnormalities include the so-called “acute atherosis” in which the vessels are obstructed secondary to diffuse fibrin deposition, intimal thickening, necrosis, and atherosclerosis leading to placental infarcts.32 The pathology correlates with the severity of the clinical disease. Insights gained from recent research (discussed below) have drawn attention to the role of angiogenic factors, especially vascular endothelial growth factor (VEGF) and its receptors, in the regulation of early placental vascular development. 33 Mice with deletions in Flt-1 (VEGFR-1), KDR (VEGFR-2) and Tie-2 exhibit Placentae obtained from pre-eclamptic pregnancies show evidence of hypoperfusion; they are relatively small and exhibit infarcts.

defective placental vasculogenesis and early embryonic mortality. In humans, VEGF ligands and receptors are highly expressed by the placental tissue in the first trimester; this expression is altered in pre-eclampsia. 33

PATHOGENESIS Pre-eclampsia has been called a “disease of theories”, highligh ng the fact that an exact understanding about why it develops remains elusive. Efforts to unravel the pathogene c mechanisms have been hampered by the lack of a completely acceptable animal model of PE. A number of mechanisms have been postulated, but it is unclear whether the various theories are independent or influence/poten ate each other. The theories include abnormal placental development, uteroplacental ischemia, an altered angiogenic balance promo ng endothelial damage, abnormali es in endothelium derived vasoac ve factors, maladapta on of the immune system and maternal and/or paternal gene c factors (Fig. 3). 59

Placenta Anchoring villus cytotrophoblast column Cytotrophoblast stem cells

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Syncytiotrophoblast Maternal blood Bloo

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Inadequate trophoblast invasion into decidua and defective remodeling of spiral artery Placental ischemia & inflammation PRE-ECLAMPSIA Figure 2. The process of normal trophoblastic invasion and its failure in pre-eclampsia. 60

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That placenta is essen al to the development of PE, and its removal causes disease remission, has been conclusively demonstrated. The following observa ons support this: 1. PE can develop in molar pregnancies, where there is no fetus,9 2. PE persisted in cases with extrauterine pregnancies despite removal of the fetus,34 and 3. Postpartum eclampsia has been reported following deliveries that were associated with retained placental fragments.35,36 In all these examples, removal of the placenta resulted in rapid improvement of the clinical syndrome. Genetic factors NK cells Oxidative stress AT1-AAs

Placental dysfunction

Growth restriction

sFlt1 sEng

Hypertension

Other factors

Proteinuria

Other mediators

Other complications

Cerebral edema

Liver dysfunction

Figure 3. The possible pathways that lead to development of pre-eclampsia phenotype. 61

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In terms of its genesis, PE is considered a two-step process.16 The first stage is essen ally asymptoma c and is characterized by abnormal placental development during the first trimester resul ng in placental vascular insufficiency. The second or symptoma c stage appears a er 20 weeks of gesta on during which all the clinical features make their appearance and lead to end-organ involvement. It is likely that the development of second stage is dependent upon the intraplacental events that take place during the first stage.

Altered Angiogenic Balance Data emerging in the last few years have made the theory of imbalance of innate angiogenic factors the preeminent one for explaining the maternal syndrome of PE. Most of the data has come from the lab of Ananth Karumanchi.37–58 Based on the belief that placenta generates the offending molecule, they performed microarray analysis on preeclamp c and normal placentae. This showed markedly increased expression of two an -angiogenic factors, soluble fms-like tyrosine It has been conclusively demonstrated that placenta is essential to the development of pre-eclampsia, and its removal causes disease remission.

kinase-1 (sFlt-1) and soluble endoglin (sEng). The former is a splice variant of the vascular endothelial growth factor (VEGF) receptor. It has an intact ligand-binding domain but lacks the transmembrane and intracytoplasmic domains, which permits it to be released in circula on.59 It antagonizes VEGF and PlGF (placental growth factor) by binding with them in circula on and limi ng availability to the target receptor on vascular endothelial cells.9 sEng is a novel truncated form of endoglin (CD105), a cell-surface co-receptor for transforming growth factor (TGF)-β. sEng also binds to and antagonizes this molecule in the same fashion. Both these molecules therefore act like sponges, soaking up their respec ve ligands required for normal endothelial physiology and making the milieu an -angiogenic (Fig. 4).42,60 These researchers subsequently confirmed high levels of these molecules in blood samples of women with PE. 47,48 Moreover, the 62

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Pre-eclampsia

TG

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Figure 4. sFlt-1 and sEng bind to their ligands in circulation and limit their availability to their natural cell surface receptors, creating an antiangiogenic milieu.

degree of elevation was directly correlated to the severity of disease. Whereas high sFlt-1 levels were found in all women with PE, sEng levels were more likely to be elevated in those with severe disease, including those with HELLP syndrome. As predicted, this elevation is accompanied by decreased free circulating PIGF and VEGF concentrations.61–63 PlGF (30 kDa) and VEGF (45 kDa) are small enough to cross the glomerular filtration barrier and appear in urine. Urinary Urinary concentrations of placental growth factor have been shown to be significantly lower in pregnant women with pre-clampsia compared to normotensive controls.

concentrations of PlGF have been shown to be significantly lower in pregnant women with pre-eclampsia compared to normotensive controls by several workers including us.64,65 Elevation in sFlt-1 levels precede the development of clinical syndrome by 8–12 weeks66–68 and correlate with disease severity, suggesting that serial monitoring in at-risk pregnancies could be a useful tool to predict the development of PE. 63

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The physiological function of VEGF is stabilization of endothelial cells in mature blood vessels, especially those in the kidney, liver and brain. VEGF is highly expressed by glomerular podocytes, and VEGF receptors are present on glomerular endothelial cells. 69 Clark et al.70 first demonstrated that placenta secreted sFlt-1, and postulated its role in regulation of circulating VEGF during pregnancy. In vitro effects of sFlt-1 include vasoconstriction and endothelial dysfunction. Infusion of adenoviruses transfected with sFlt-1 messenger ribonucleic acid in pregnant or nonpregnant rats was followed by increased circulating sFlt-1 levels and appearance of hypertension, glomerular endotheliosis and proteinuria, the hallmarks of PE.52 Other lines of evidence, both experimental and clinical, also suggest that antagonism of VEGF action could lead to PE. Administration of antibodies to VEGF can induce endothelial damage and proteinuria in mice.71 In a model of podocyte specific VEGF-A knockout, heterozygote mice (with a 50% reduced VEGF expression) developed glomerular Inhibition of both placental growth factors and vascular endothelial growth factor is necessary to produce a pre-eclampsia–like syndrome in pregnant rats.

endotheliosis and proteinuria. 72 The anti-angiogenic effect of PE plasma noticed in in-vitro endothelial tube formation assays could be reversed by addition of exogenous VEGF/PlGF or antibodies to sFlt-1.52,73 In clinical trials where VEGF antagonists were used for cancer, treated patients developed hypertension, proteinuria and endothelial activation accompanied by loss of fenestrae, all suggestive of PE. 74,75 In addition to glomerular circulation, fenestrated endothelium is present in choroids plexus and hepatic sinusoids, organs that are disproportionately affected in pre-eclampsia. Conditions where circulating maternal sFlt-1 levels are increased physiologically during pregnancy such as multiple pregnancies (because of increased placental mass), trisomy 13 in the fetus (because of higher “gene dose” as the gene for sFlt-1 is located on the same chromosome) confer an increased risk of PE.37,38,76 Conversely smokers, who have lower circulating sFlt-1 levels, have been shown to enjoy protection against 64

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PE.10,77,78 The balance of evidence therefore suggests that VEGF deficiency, as developed following production of excess sFlt-1, is likely responsible for proteinuria and glomerular endotheliosis. Inhibi on of both PIGF and VEGF is necessary to produce a preeclampsia–like syndrome in pregnant rats.52 The exact mechanism of how PIGF deficiency contributes to PE is unclear. PlGF is structurally homologous to VEGF-A and s mulates angiogenesis under condi ons of ischemia, inflamma on and wound healing. It may amplify VEGF signaling during pregnancy by preferen ally binding to the Flt-1 receptor thus making the circula ng VEGF available to bind to the more potent KDR receptor instead.59,79 sFlt-1 is primarily secreted by syncy otrophoblasts into the maternal circula on. Outside the placenta, sFlt-1 is made in monocytes.80. New sFlt-1 variants have been discovered recently. Of interest is sFlt1-14, a human-specific variant, which has been shown recently to be the sFlt1-14 is produced mainly in “syncytial knots”, structures that are induced by placental hypoxia and are found primarily in pre-eclampsia.

primary isoform produced in PE.81 It is produced mainly in “syncy al knots”, structures that are induced by placental hypoxia and are found primarily in PE. Venkatesha et al.58 showed that like sFlt-1, sEng was also upregulated in PE placentae and was an -angiogenic in in vitro assays of endothelial tube forma on. In experimental animals, administra on of exogenous sEng induced vascular permeability and hypertension but when given along with sFlt-1, induced features of severe PE including HELLP syndrome and cerebral edema. As with sFlt-1, the rise in circula ng sEng levels were shown to antedate the onset of PE by several weeks and peaked with disease manifesta on.47 Levels were higher in women with severe disease including those with “small for gesta onal age” infants. As opposed to sFlt-1, which is a naturally occurring splice variant, sEng is produced only in placenta. It is speculated that sEng is produced as a compensatory mechanism to limit the effects of cellsurface Eng.82 This process is exacerbated in pre-eclampsia, leading 65

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to release of sEng in the maternal circula on. As men oned above, Eng is a cell surface co-receptor for TGF-β and therefore the effect of sEng could be mediated by inhibi on of TGF-β mediated signaling. One important pathway downstream of TGF-β is NO produc on, and there is some evidence that sEng could contribute to PE phenotype by decreased NO produc on.83 The current belief is that sFlt-1 and sEng act by different mechanisms.

Placental Ischemia As described above, abnormali es in normal placental development that reduce the fetal blood flow precede the development of PE. In experimental animals, reduced uterine blood flow by mechanical constric on of the uterine arteries can induce hypertension and proteinuria, and development of growth retarded pups.84,85 Func onal imaging studies in pregnant women using Doppler ultrasound show decreased uteroplacental flow anteda ng the onset of PE.86 Recent experiments have provided support for a causal link between placental hypoxia and upregulation of soluble anti-angiogenic factors.

A role for the transcrip on factor hypoxia-inducible factor (HIF) and its targets has been postulated. The transcrip on of many angiogenic proteins, including VEGF, PlGF, Flt-1, VEGFR-2, TGFβ-3, Tie-1 and Tie-2 is under the influence of HIF.87,88 Many of these molecules are expressed by invasive cytotrophoblasts. The levels of HIF-1α and HIF-2α are elevated in pre-eclamp c placentae.89 Hypoxia can upregulate expression and secre on of sFlt-1 in primary trophoblast cultures from first trimester placentae.90 Interes ngly, the incidence of PE is increased in women residing at high al tudes, who show similar altera ons in HIF. Recent experiments have provided support for a causal link between placental hypoxia and upregula on of soluble an -angiogenic factors. In an ar ficial model of pre-eclampsia produced in nonhuman primates by decreasing the blood flow to the uteroplacental compartment, the appearance of hypertension and proteinuria was accompanied by 10-fold increase in circula ng concentra ons of sFlt-1. 66

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Primary cytotrophoblasts make excessive sFlt-1 in culture under hypoxic condi ons. Mice deficient in catechol-O-methyltransferase (COMT) fail to make 2-methoxyestradiol (2-ME), a natural metabolite of estradiol that is elevated during the third trimester. 2-ME suppresses placental hypoxia and HIF-1α and sFlt-1 expression.91 When pregnant, these mice develop a PE-like syndrome that can be reversed by administra on of exogenous 2-ME. The levels of COMT and 2-ME are significantly lower in severe PE.

Renin-Angiotensin System The normal pregnancy is a state of vascular hyporesponsiveness to angiotensin II (AII) in the face of elevated blood levels of AII.91 This physiology is altered PE: women with PE exhibit a heightened sensi vity to AII and other vasoconstric ve agents, and the levels of these hormones are suppressed in PE. Women with pre-eclampsia exhibit a heightened sensitivity to AII and other vasoconstrictive agents, and the levels of these hormones are suppressed in pre-eclampsia.

The mechanism of this altera on is not defined. Circula ng autoan bodies of the IgG class against the angiotensin type 1 receptor (AT1) were found in women with PE92 but did not receive sufficient a en on, as this finding was not specific to PE. Recent studies have resurrected the importance of these an bodies. Capable of s mula ng the AT1 receptor, they may play a key role upstream of the elabora on of an -angiogenic factors by pre-eclamp c placenta. IgG from the sera of PE pa ents increased produc on of sFlt-1 in placental villous culture. Infusion of IgG frac on isolated from PE pa ents induced the synthesis of sFlt-1 and development of key features of PE in pregnant but not in non-pregnant mice.93 In an in vitro assay, these an bodies decreased the invasiveness of immortalized human trophoblasts, an important ini al step in placental vasculogenesis. Losartan (an AT1 receptor blocker), or a neutralizing pep de has been shown to block many of these in vitro effects of the autoan bodies.94 These findings suggest that the AT1 an bodies may be one of the ini a ng events 67

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that contribute to the poor placental invasion by the cytotrophoblast leading to the produc on of an -angiogenic factors and the consequent manifesta ons secondary to endothelial damage.

Immunological Maladaptation Pregnancy is a state of immunological tolerance to the “semi-allogeneic” fetoplacental unit. Blun ng of the normal maternal immune reac ons allows the invasion and growth of the cytotrophoblasts in the maternal decidua. It has been hypothesized that failure of this adapta on may be responsible for preven ng adequate invasion of cytotrophoblasts. 95 The significance of an intact immune system in the genesis of PE is underscored by the observa on that the incidence of PE is lower in women with untreated HIV but not in those on an -retroviral therapy.96 The increased PE risk in gesta ons with a new partner, especially one who has previously fathered a pre-eclamp c pregnancy may also be mediated through immune maladapta on. Use of barrier contraception increases the incidence of pre-eclampsia, possibly by limiting exposure to sperm and hence, development of tolerance through continued exposure of the maternal immune system to paternal antigens.

Examina on of pre-eclamp c placentae has shown the presence of a significantly higher number of an gen presen ng cells (macrophages and dendri c cells) as well as higher levels of chemokines that facilitate recruitment of these cells.95 This inflammatory milieu may promote immune maladapta on and limit trophoblas c invasion of the spiral arteries. The observa on that PE is more frequent in primigravids and a er a long interpregnancy interval suggests that development of some sort of “tolerance” may protect against PE.97 This might wane with me or may not be opera ve in gesta ons fathered by a different partner, possibly secondary to encounter with a new set of an gens. Use of barrier contracep on also increases incidence of PE, possibly by limi ng exposure to sperm and hence, development of tolerance through con nued exposure of the maternal immune system to paternal an gens. 68

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Genetics Most cases of PE occur in nulliparous women without a family history of PE. However, the presence of PE in a first degree rela ve increases a woman’s risk of severe disease 2–4-fold even when controlling for body-mass index, smoking status and age, sugges ng the presence of a gene c component.11 Interes ngly, men who had fathered one pre-eclamp c pregnancy were significantly more likely to father a pregnancy affected by pre-eclampsia with a new partner, sugges ng a paternal component to the gene c predisposi on. A number of associa on studies have suggested linkage between PE and varia ons in genes that code for molecules that control blood pressure, coagula on or oxygen-free-radical metabolism, such as endothelin-1, nitric oxide synthase, angiotensin conver ng enzyme and angiotensinogen, factor V Leiden, methyltetrahydrofolate or lipoprotein lipase.98–102 We showed an associa on between PE and EDN1 gene, SNP that was associated with increased maternal ET-1 levels.103 These associa ons are however, weak and not confirmed in all studies. The possibility remains that they Endothelial-derived vasoactive factors have been investigated as candidate molecules in the pathogenesis of pre-eclampsia.

may have a minor effect on presenta on and determina on of disease severity. Gene microarray analysis will help pinpoint genes associated with PE. A meta-analysis failed to show a significant associa on of varia on in eNOS or ACE genes but found some role for a polymorphism in the angiotensinogen gene in PE.104

Endothelium-derived Vasoconstrictor and Vasodilators and Oxidative Stress Endothelial-derived vasoac ve factors have been inves gated as candidate molecules in the pathogenesis of PE. Important amongst these include vasoconstrictors such as endothelin-1 and vasodilators such as prostaglandins and NO. We and others have shown elevated circula ng ET-1 concentra ons in pre-eclamp c pregnancies. The degree of eleva on correlated with disease severity.63,103,105–107 At the same me, we found decreased 69

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placental ET-1 immunoreac vity in PE.103 This combina on of increased maternal and reduced fetal ET-1 expression could suggest an a empt to compensate for the reduced uteroplacental blood flow. Pregnant rats with reduced uteroplacental perfusion pressure developed hypertension and showed increased circula ng ET-1 levels. This hypertension was abolished by selec ve blockade of the endothelin type A receptor.108 ET-1 concentra on increased in the media of human umbilical vein endothelial cell cultures exposed to sera collected from these rats, sugges ng the s mulatory effect of a substance present in the PE sera on ET-1 synthesis. In another experiment, VEGF blockade induced ET-1 release from cultured endothelial cells, and the condi oned medium thus obtained triggered nephron loss from podocytes. A similar effect was seen when medium from endothelial cells incubated with PE sera was used. This nephron loss could be abrogated by ET-1 receptor antagonist.109 Nitric oxide and prostaglandins have been proposed as mediators of renal vasodilation and hyperfiltration during pregnancy, and suggestions have been made that reduced nitric oxide availability could contribute to pre-eclampsia.

NO and PG have been proposed as mediators of renal vasodilation and hyperfiltration during pregnancy, and suggestions have been made that reduced NO availability could contribute to PE. Generation of free radicals produces oxidative stress that disrupts normal endothelial function. Inhibition of nitric oxide synthase using N-nitro L-arginine methyl ester (L-NAME) induced a syndrome of hypertension, proteinuria, intrauterine growth restriction, and renal glomerular capillary endothelial lesions reminiscent of PE in pregnant rats.110 Rats treated with L-arginine, a precursor of NO, showed lower systolic blood pressure and proteinuria, higher birth weight, and better glomerular morphology.111 Patients with PE exhibit increased circulating levels of markers of oxidative stress in some but not all studies. A role for asymmetric dimethylarginine, an endogenous endothelial NO synthase inhibitor, in the development of pre-eclampsia has been suggested.112 One study showed a strong 70

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correlation between ADMA levels and flow-mediated vasodilation during PE. Small studies found some benefit of the antioxidant lycopene in reducing the risk of pre-eclampsia. 113 However, evidence for an important role for NO is weak. Most studies have failed to show any difference in NO concentration between normotensive and preeclamptic pregnancies. Large clinical trials have failed to establish the efficacy of antioxidants as treatment for pre-eclampsia and showed no reduction in the risk of intrauterine growth restriction, fetal deaths or maternal outcome.114,115 In conclusion, the role if any for these compounds is peripheral and likely to be a response to the primary abnormality i.e., the alteration in angiogenic factors.

HELLP Syndrome and Eclampsia Low grade coagulopathy (increased fibronec n and platelet aggrega on, and reduced platelet survival and an thrombin III) is noted frequently in PE and is thought to be secondary to endothelial ac va on. In about The only recognized and definitive treatment of pre-eclampsia is delivery of the placenta.

10% cases with severe PE, this progresses to a state of frank hemolysis along with evidence of liver injury. The trigger for this phenomenon is not known, albeit interference with TGFβ signaling secondary to increased sEng may have a role. Similarly why some of these women develop seizures and other neurological symptoms such as headache and visual disturbances, is unexplained. The proposed theories include cerebral vasospasm, deranged autoregula on and disrupted blood–brain barrier. MRI shows widespread cerebral edema, more so in the parietooccipital areas; these changes correlate with markers of endothelial dysfunc on.

MANAGEMENT Management of PE remains a challenge, especially in resourceconstrained environments. The only recognized and defini ve treatment of PE is delivery of the placenta. Women with PE require 71

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close medical supervision including regular monitoring of blood pressure and proteinuria to assess disease severity, serial blood counts to monitor for development of thrombocytopenia, hemolysis, elevated liver enzyme levels or renal impairment. Bed rest is the first measure advised by obstetricians. Blood pressure is controlled with medica on if necessary. The drugs that can be used safely in pregnancy include methyldopa, hydralazine, labetalol and dihydropyridine calcium channel blockers. Monitoring is also essen al to ensure fetal wellbeing and to determine development of any fetal distress. Mild disease can be managed expectantly un l fetal lungs are mature enough to allow delivery, usually at 38 weeks of gesta on. The situa on is more urgent in women who develop severe disease with uncontrollable hypertension, HELLP syndrome, frank eclampsia, or fetal distress. In such situa ons, when the risks of con nuing the pregnancy for the mother outweigh the risks of neonatal morbidity, prompt delivery is required.

FUTURE OUTLOOK The finding of the importance of an -angiogenic factors has opened up possibili es for developing new diagnos c tests and innova ve treatment approaches. The first step in reduc on of maternal and fetal morbidity and mortality is to iden fy at-risk pregnancies and detect the disease at an early stage. As there is no laboratory test currently that can confirm the diagnosis, the disease must be iden fied on clinical grounds alone. The signs and symptoms can mimic other clinical condi ons such as a primary or secondary glomerular disease or chronic hypertension with/without proteinuria that must be excluded, again mostly on the basis of clinical criteria. There is hope on the horizon, however. Recent data have shown that the altered level of sFlt-1 and sEng antedates the onset of PE by as much as 8 weeks. In fact some studies have shown abnormal levels as early as in the first trimester.66–68 It is likely that es ma on of the levels of one or more of these could act as reliable biomarker for disease predic on and diagnosis. The sFlt-1/PlGF ra o has been shown to have sensi vity and specificity approaching 100% for this purpose. Eleva ons in sFlt-1 72

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and sFlt-1:PlGF ra o in the late second or early third trimester confer a 30-fold increased risk of preterm PE. As a consequence of binding to the circula ng sFlt-1, the normal urinary excre on of PlGF is reduced in PE, and hence a urinary screening test for PIGF holds promise for domiciliary applica on. Cases that are suspected on the basis of this test should be selected for confirmatory blood test. Another approach is to combine Doppler ultrasound of uterine arteries and angiogenic factor assays.116 Early identification of those pregnant women who have not yet developed the disease but are highly likely to will allow timely referral for close maternal and fetal monitoring, institution of steroids to enhance fetal lung maturity, and prompt administration of antihypertensives or other medications; and expeditious delivery if necessary. Accurate diagnosis will allow studies to progress on a novel therapy or preventa ve strategies. Based on emerging data, a novel approach could entail manipula on of the altered angiogenic balance in favor of a proangiogenic milieu, which could conceivably postpone the onset of PE un l later gesta onal ages and allow fetal maturity, to reduce the clinical severity of the disease or to hasten the resolu on of the condi on a er delivery. Li et al51 could show ameliora on of clinical features and reversal of changes in gene expression by treatment with a VEGF isoform in a rat model of adenoviral sFlt-1 overexpression induced PE. Before these hopes are fulfilled, prospec ve longitudinal studies would be required to determine the relevance of these markers for the early iden fica on of PE and predic on of its severity. Further work to define the regula on of placental vascular development and expression of these factors would help understand of the heterogeneity of maternal response. Finally, as the long-term implica ons of PE become clearer, it may give us a be er insight into the rela onship between the “angiogenic profile” of an individual and the risk of developing cardiovascular disease and malignancies, and provide us with another point of interven on to modify the long-term risk of these condi ons. 73

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34. Shembrey MA, Noble AD. An instructive case of abdominal pregnancy. Aust N Z J Obstet Gynaecol 1995;35:220–1. 35. Matsuo K, Kooshesh S, Dinc M, et al. Late postpartum eclampsia: report of two cases managed by uterine curettage and review of the literature. Am J Perinatol 2007;24:257–66. 36. Hirshfeld-Cytron J, Lam C, Karumanchi SA, Lindheimer M. Late postpartum eclampsia: examples and review. Obstet Gynecol Surv 2006;61:471–80. 37. Bdolah Y, Lam C, Rajakumar A, et al. Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia? Am J Obstet Gynecol 2008;198:428e1–6. 38. Bdolah Y, Palomaki GE, Yaron Y, et al. Circulating angiogenic proteins in trisomy 13. Am J Obstet Gynecol 2006;194:239–45. 39. Cohen A, Lim KH, Lee Y, et al. Circulating levels of the antiangiogenic marker soluble FMS-like tyrosine kinase 1 are elevated in women with pregestational diabetes and preeclampsia: angiogenic markers in preeclampsia and preexisting diabetes. Diabetes Care 2007;30:375–7. 40. Dimitrakova ED, Dimitrakov JD, Karumanchi SA, et al. Placental soluble fmslike tyrosine-kinase-1 (sFlt-1) in pregnant women with preeclampsia. Folia Med (Plovdiv) 2004;46:19–21. 41. Germain AM, Romanik MC, Guerra I, et al. Endothelial dysfunction: a link among preeclampsia, recurrent pregnancy loss, and future cardiovascular events? Hypertension 2007;49:90–5. 42. Hladunewich M, Karumanchi SA, Lafayette R. Pathophysiology of the clinical manifestations of preeclampsia. Clin J Am Soc Nephrol 2007;2:543–9. 43. Holston AM, Qian C, Yu KF, et al. Circulating angiogenic factors in gestational proteinuria without hypertension. Am J Obstet Gynecol 2009;200:392e1– 10. 44. Karumanchi SA, Haig D. Flt1, pregnancy, and malaria: evolution of a complex interaction. Proc Natl Acad Sci U S A 2008;105:14243–4. 45. Karumanchi SA, Stillman IE. In vivo rat model of preeclampsia. Methods Mol Med 2006;122:393–9. 46. Levine RJ, Karumanchi SA. Circulating angiogenic factors in preeclampsia. Clin Obstet Gynecol 2005;48:372–86. 47. Levine RJ, Lam C, Qian C, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 2006;355:992–1005. 48. Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004;350:672–83. 49. Levine RJ, Qian C, Maynard SE, et al. Serum sFlt1 concentration during preeclampsia and mid trimester blood pressure in healthy nulliparous women. Am J Obstet Gynecol 2006;194:1034–41. 50. Levine RJ, Thadhani R, Qian C, et al. Urinary placental growth factor and risk of preeclampsia. JAMA 2005;293:77–85.

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51. Li Z, Zhang Y, Ying Ma J, et al. Recombinant vascular endothelial growth factor 121 attenuates hypertension and improves kidney damage in a rat model of preeclampsia. Hypertension 2007;50:686–92. 52. Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003;111: 649–58. 53. Maynard SE, Venkatesha S, Thadhani R, Karumanchi SA. Soluble Fmslike tyrosine kinase 1 and endothelial dysfunction in the pathogenesis of preeclampsia. Pediatr Res 2005;57:1R–7R. 54. Rana S, Karumanchi SA, Levine RJ, et al. Sequential changes in antiangiogenic factors in early pregnancy and risk of developing preeclampsia. Hypertension 2007;50:137–42. 55. Salahuddin S, Lee Y, Vadnais M, et al. Diagnostic utility of soluble fmslike tyrosine kinase 1 and soluble endoglin in hypertensive diseases of pregnancy. Am J Obstet Gynecol 2007;197:28e1–6. 56. Shan HY, Rana S, Epstein FH, et al. Use of circulating antiangiogenic factors to differentiate other hypertensive disorders from preeclampsia in a pregnant woman on dialysis. Am J Kidney Dis 2008;51:1029–32. 57. Thadhani R, Mutter WP, Wolf M, et al. First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. J Clin Endocrinol Metab 2004;89:770–5. 58. Venkatesha S, Toporsian M, Lam C, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 2006;12:642–9. 59. Kendall RL, Wang G, Thomas KA. Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR. Biochem Biophys Res Commun 1996;226: 324–8. 60. Steinberg G, Khankin EV, Karumanchi SA. Angiogenic factors and preeclampsia. Thromb Res 2009;123(Suppl 2):S93–9. 61. Livingston JC, Chin R, Haddad B, et al. Reductions of vascular endothelial growth factor and placental growth factor concentrations in severe preeclampsia. Am J Obstet Gynecol 2000;183:1554–7. 62. Polliotti BM, Fry AG, Saller DN, et al. Second-trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early-onset preeclampsia. Obstet Gynecol 2003;101:1266–74. 63. Taylor RN, Varma M, Teng NN, Roberts JM. Women with preeclampsia have higher plasma endothelin levels than women with normal pregnancies. J Clin Endocrinol Metab 1990;71:1675–7. 64. Aggarwal PK, Jain V, Sakhuja V, et al. Low urinary placental growth factor is a marker of pre-eclampsia. Kidney Int 2006;69:621–4. 65. Buhimschi CS, Norwitz ER, Funai E, et al. Urinary angiogenic factors cluster hypertensive disorders and identify women with severe preeclampsia. Am J Obstet Gynecol 2005;192:734–41.

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66. Hertig A, Berkane N, Lefevre G, et al. Maternal serum sFlt1 concentration is an early and reliable predictive marker of preeclampsia. Clin Chem 2004;50:1702–3. 67. McKeeman GC, Ardill JE, Caldwell CM, et al. Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is increased throughout gestation in patients who have preeclampsia develop. Am J Obstet Gynecol 2004;191:1240–6. 68. Wathen KA, Tuutti E, Stenman UH, et al. Maternal serum-soluble vascular endothelial growth factor receptor-1 in early pregnancy ending in preeclampsia or intrauterine growth retardation. J Clin Endocrinol Metab 2006;91:180–4. 69. Maharaj AS, Saint-Geniez M, Maldonado AE, D’Amore PA. Vascular endothelial growth factor localization in the adult. Am J Pathol 2006;168: 639–48. 70. Clark DE, Smith SK, He Y, et al. A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation. Biol Reprod 1998;59:1540–8. 71. Sugimoto H, Hamano Y, Charytan D, et al. Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J Biol Chem 2003;278:12605–8. 72. Eremina V, Sood M, Haigh J, et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 2003;111:707–16. 73. Ahmad S, Ahmed A. Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ Res 2004;95: 884–91. 74. Izzedine H, Rixe O, Billemont B, et al. Angiogenesis inhibitor therapies: focus on kidney toxicity and hypertension. Am J Kidney Dis 2007;50:203–18. 75. Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis 2007;49:186–93. 76. Maynard SE, Moore Simas TA, Solitro MJ, et al. Circulating angiogenic factors in singleton vs multiple-gestation pregnancies. Am J Obstet Gynecol 2008;198:200e1–7. 77. Beste LA, England LJ, Schisterman EF, et al. Pregnancy outcomes in smokers who develop pre-eclampsia. Paediatr Perinat Epidemiol 2005;19:12–8. 78. Jeyabalan A, Powers RW, Durica AR, et al. Cigarette smoke exposure and angiogenic factors in pregnancy and preeclampsia. Am J Hypertens 2008;21:943–7. 79. Autiero M, Luttun A, Tjwa M, Carmeliet P. Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders. J Thromb Haemost 2003;1:1356–70. 80. Rajakumar A, Michael HM, Rajakumar PA, et al. Extra-placental expression of vascular endothelial growth factor receptor-1, (Flt-1) and soluble Flt-1

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82.

83.

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85. 86.

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(sFlt-1), by peripheral blood mononuclear cells (PBMCs) in normotensive and pre-eclamptic pregnant women. Placenta 2005;26:563–73. Sela S, Itin A, Natanson-Yaron S, et al. A novel human-specific soluble vascular endothelial growth factor receptor 1: cell-type-specific splicing and implications to vascular endothelial growth factor homeostasis and preeclampsia. Circ Res 2008;102:1566–74. Caniggia I, Taylor CV, Ritchie JW, et al. Endoglin regulates trophoblast differentiation along the invasive pathway in human placental villous explants. Endocrinology 1997;138:4977–88. Sandrim VC, Palei AC, Metzger IF, et al. Nitric oxide formation is inversely related to serum levels of antiangiogenic factors soluble fms-like tyrosine kinase-1 and soluble endogline in preeclampsia. Hypertension 2008;52:402–7. Granger JP, LaMarca BB, Cockrell K, et al. Reduced uterine perfusion pressure (RUPP) model for studying cardiovascular-renal dysfunction in response to placental ischemia. Methods Mol Med 2006;122:383–92. Makris A, Thornton C, Thompson J, et al. Uteroplacental ischemia results in proteinuric hypertension and elevated sFLT-1. Kidney Int 2007;71:977–84. North RA, Ferrier C, Long D, et al. Uterine artery Doppler flow velocity waveforms in the second trimester for the prediction of preeclampsia and fetal growth retardation. Obstet Gynecol 1994;83:378–86. Forsythe JA, Jiang BH, Iyer NV, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 1996;16:4604–13. Gerber HP, Condorelli F, Park J, Ferrara N. Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J Biol Chem 1997;272: 23659–67. Karumanchi SA, Bdolah Y. Hypoxia and sFlt-1 in preeclampsia: the “chickenand-egg” question. Endocrinology 2004;145:4835–7. Rajakumar A, Doty K, Daftary A, et al. Impaired oxygen-dependent reduction of HIF-1alpha and -2alpha proteins in pre-eclamptic placentae. Placenta 2003;24:199–208. Kanasaki K, Palmsten K, Sugimoto H, et al. Deficiency in catechol-Omethyltransferase and 2-methoxyoestradiol is associated with preeclampsia. Nature 2008;453:1117–21. Wallukat G, Homuth V, Fischer T, et al. Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J Clin Invest 1999;103:945–52. Zhou CC, Ahmad S, Mi T, et al. Autoantibody from women with preeclampsia induces soluble Fms-like tyrosine kinase-1 production via angiotensin type 1 receptor and calcineurin/nuclear factor of activated T-cells signaling. Hypertension 2008;51:1010–9. Xia Y, Wen H, Bobst S, et al. Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human trophoblast cells. J Soc Gynecol Investig 2003;10:82–93.

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95. Huang SJ, Chen CP, Schatz F, et al. Pre-eclampsia is associated with dendritic cell recruitment into the uterine decidua. J Pathol 2008;214:328–36. 95. Mattar R, Amed AM, Lindsey PC, et al. Preeclampsia and HIV infection. Eur J Obstet Gynecol Reprod Biol 2004;117:240–1. 96. Skjaerven R, Wilcox AJ, Lie RT. The interval between pregnancies and the risk of preeclampsia. N Engl J Med 2002;346:33–8. 97. O’Shaughnessy KM, Fu B, Ferraro F, et al. Factor V Leiden and thermolabile methylenetetrahydrofolate reductase gene variants in an East Anglian preeclampsia cohort. Hypertension 1999;33:1338–41. 98. Arngrimsson R, Hayward C, Nadaud S, et al. Evidence for a familial pregnancy-induced hypertension locus in the eNOS-gene region. Am J Hum Genet 1997;61:354–62. 99. Dizon-Townson DS, Nelson LM, Easton K, Ward K. The factor V Leiden mutation may predispose women to severe preeclampsia. Am J Obstet Gynecol 1996;175:902–5. 100. Ward K, Hata A, Jeunemaitre X, et al. A molecular variant of angiotensinogen associated with preeclampsia. Nat Genet 1993;4:59–61. 101. Sohda S, Arinami T, Hamada H, et al. Methylenetetrahydrofolate reductase polymorphism and pre-eclampsia. J Med Genet 1997;34:525–6. 102. Aggarwal PK, Jain V, Srinivasan R, Jha V. Endothelin-1 levels and plays a role in determination of preeclampsia phenotype. J Hypertens 2009 (in press). 103. Medica I, Kastrin A, Peterlin B. Genetic polymorphisms in vasoactive genes and preeclampsia: a meta-analysis. Eur J Obstet Gynecol Reprod Biol 2007;131:115–26. 104. Barden AE, Herbison CE, Beilin LJ, et al. Association between the endothelin-1 gene Lys198Asn polymorphism blood pressure and plasma endothelin-1 levels in normal and pre-eclamptic pregnancy. J Hypertens 2001;19: 1775–82. 105. Clark BA, Halvorson L, Sachs B, Epstein FH. Plasma endothelin levels in preeclampsia: elevation and correlation with uric acid levels and renal impairment. Am J Obstet Gynecol 1992;166:962–8. 106 Greer IA, Leask R, Hodson BA, et al. Endothelin, elastase, and endothelial dysfunction in pre-eclampsia. Lancet 1991;337:558. 107. Alexander BT, Rinewalt AN, Cockrell KL, et al. Endothelin type a receptor blockade attenuates the hypertension in response to chronic reductions in uterine perfusion pressure. Hypertension 2001;37:485–9. 108. Collino F, Bussolati B, Gerbaudo E, et al. Preeclamptic sera induce nephrin shedding from podocytes through endothelin-1 release by endothelial glomerular cells. Am J Physiol Renal Physiol 2008;294:F1185–94. 109. Yallampalli C, Garfield RE. Inhibition of nitric oxide synthesis in rats during pregnancy produces signs similar to those of preeclampsia. Am J Obstet Gynecol 1993;169:1316–20. 110. Helmbrecht GD, Farhat MY, Lochbaum L, et al. L-arginine reverses the adverse pregnancy changes induced by nitric oxide synthase inhibition in the rat. Am J Obstet Gynecol 1996;175:800–5.

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111. Holden DP, Fickling SA, Whitley GS, Nussey SS. Plasma concentrations of asymmetric dimethylarginine, a natural inhibitor of nitric oxide synthase, in normal pregnancy and preeclampsia. Am J Obstet Gynecol 1998;178:551–6. 112. Sharma JB, Kumar A, Malhotra M, et al. Effect of lycopene on pre-eclampsia and intra-uterine growth retardation in primigravidas. Int J Gynaecol Obstet 2003;81:257–62. 113. Poston L, Briley AL, Seed PT, et al. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 2006;367:1145–54. 114. Rumbold AR, Crowther CA, Haslam RR, et al. Vitamins C and E and the risks of preeclampsia and perinatal complications. N Engl J Med 2006;354: 1796–806. 115. Espinoza J, Romero R, Nien JK, et al. Identification of patients at risk for early onset and/or severe preeclampsia with the use of uterine artery Doppler velocimetry and placental growth factor. Am J Obstet Gynecol 2007;196:326 e1–13.

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Case Studies

Pre-eclampsia: Recent Advances CASE 1 A 34-year-old woman presented to an obstetrician with history of amenorrhea of 6 weeks’ dura on. She was a third gravid who had got married at the age of 18; and had two uneven ul pregnancies at the age of 20 and 22 years. The marriage ended in a divorce at the age of 26. She remarried at the age of 31 years. At the age of 32, she was found to have hypertension on rou ne evalua on and started on diure cs and angiotension conver ng enzyme inhibitors. Inves ga ons did not reveal a secondary cause. The blood pressure was well controlled. Her elder sister had pre-eclampsia in her first pregnancy. On examina on, she was found to have a blood pressure of 106/70 mmHg, there was no edema and the systemic examina on was normal. Pregnancy was confirmed. Urinanalysis showed no proteinuria, the serum crea nine was 0.5 mg/dl and uric acid 2.6 mg/dl. The an hypertensive was changed to methyldopa. On follow-up, the BP con nued to remain low, and the an hypertensives were withdrawn by 8 weeks of gesta on. The pregnancy proceeded uneven ully ll week 31 when the blood pressure was noted to be 140/96 mmHg and urinalysis revealed proteinuria 2+. The fetal growth was corresponding to the period of gesta on. Inves ga on revealed serum crea nine of 0.9 and uric acid of 6.4 mg/dl. A diagnosis of pre-eclampsia was made and she was advised bed rest. The blood pressure kept increasing and she needed increasing dosage of methyldopa and later hydralazine to keep it below 140/90 mmHg. The 24-hour urine protein excre on was 2.4 g. She was being closely monitored. At 35 weeks, she complained of headache and 82

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upper abdominal pain. The blood pressure was 160/104 mmHg. The hemoglobin was found to be 9 g/dl, uric acid 8.9 mg/dl, indirect bilirubin 2.1 mg/dl, LDH 2600 U/l, AST 396 IU/l, ALT 988 IU/l and platelet count was 96,000/cumm. At this me with a diagnosis of HELLP syndrome and impending eclampsia, i.v. labetalol and magnesium sulfate were started. Dexamethasone was administered to promote fetal lung maturity, labor was induced and a live female child was delivered. The BP began to come down 12 hours following the delivery and other symptoms resolved. A er 2 weeks, the blood pressure was well-controlled with 500 mg/day of methyldopa, serum crea nine was 0.8 mg/dl, platelets had increased to 210,000/cumm and AST and ALT had come down to 65 and 88 IU/l, respec vely, and uric acid had come down to 3.2 mg/dl. This case exemplifies the behavior of hypertension during pregnancy. This lady had essen al hypertension which followed the normal physiological behavior. The hypertension disappeared in the early part of pregnancy. The new onset rise in blood pressure, proteinuria and hyperuricemia a er 20 weeks of gesta on suggested the development of pre-eclampsia. She had several risk factors for developing pre-eclampsia, viz. pre-exis ng hypertension, advanced maternal age, history of preeclampsia in a first-degree rela ve and pregnancy with a new partner. Although prompt delivery would have led to remission, it had to be delayed to allow fetal maturity. The hand was forced when she developed features of HELLP syndrome and impending eclampsia. As expected, all features resolved following the delivery.

CASE 2 A 26-year-old second gravid lady was enrolled in the high-risk pregnancy clinic at 10 weeks of gesta on. She lived in a rural area over 100 km away from a hospital. During the first pregnancy, she came to our ins tute at 32 weeks of gesta on with history of edema of 4 weeks’ dura on and seizures for 2 days. Her pregnancy had been supervised only by a village dai and her blood pressure was never checked. At arrival, she had a blood pressure of 210/126 mmHg and fetal heart sounds were not audible. A s llborn fetus was delivered by LSCS 83

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following which there were no further seizures and the blood pressure became normal. She was counseled about the possibility of recurrence in future pregnancies and need for medical supervision. Initial evaluation revealed normal blood pressure, urinalysis and glomerular filtration rate. She explained difficulty in regular follow up because of the distance. At this time, she was enrolled in a study that was aimed to evaluate the utility of anti-angiogenic molecules in early diagnosis of pre-eclampsia. Blood and urine samples were collected at 4-week intervals starting at 12 weeks. Compared to control subjects, her sFIt-1 levels were elevated approximately 2-fold at 16 weeks and rose further to 5-fold at 24 weeks. This was accompanied by a decline in urinary and serum PlGF levels. The sEng levels showed only a 2-fold increase from baseline at 24 weeks. The plasma VEGF levels were undetectable. At this time, domiciliary follow-up was arranged through village health workers. She was noted to have a rise in blood pressure at 31 weeks of gestation and urinalysis showed appearance of proteinuria. At this me she was admi ed at our ins tute and put on bed rest. An hypertensives were started when the blood pressure rose above 140/90 mmHg. Blood pressure control and fetal well-being were monitored con nuously. The labor was elec vely induced at 36 weeks of gesta on culmina ng in the delivery of a healthy baby. The blood pressure normalized in a week and proteinuria disappeared. The sFIt-1 levels came back to baseline and PlGF levels went back up a er 2 weeks. This case illustrates the morbidity and mortality associated with undiagnosed PIH and how availability of a predic ve test can help in management. Lack of medical care in the first pregnancy led to development of severe disease which resulted in neonatal morbidity. Delivery of appropriate care was made difficult due to the remote loca on. The experience during the second pregnancy shows that emerging biomarkers make it possible to predict the development of pre-eclampsia before the appearance of clinical signs. Increasing sFlt-1 and reduced PlGF levels alerted the trea ng team of the need of intensified clinical surveillance. Delivery of mely medical care allowed this pregnancy to end successfully.

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Pregnancy in Kidney Transplant Recipients Dr. Suman Kher

MD

Senior Consultant and Head Department of Obstetrics & Gynecology Apollo Hospital, NOIDA

Dr. Vijay Kher

MD, DM, FAMS, FRCPE

Director Department of Nephrology & Transplant Medicine Fortis Hospital, New Delhi

ABSTRACT:  Kidney  transplant  is  the  best  modality  of  treatment for end‐stage renal disease (ESRD) patients, especially  for the quality of life it provides to these patients in comparison  to  that  provided  by  various  dialysis  modalities.  A  successful  pregnancy  outcome  is  a  good  test  of  a  successful  transplant.  Resumption of cyclic menses and return of fertility occurs within  an  average  of  6  months  after  transplant  in  women  with  kidney  failure  and  pregnancy  is  common  among  young  female  transplant recipients. Pregnancy success rates exceed 90% after  the  first  trimester.  Approximately  14,000  births  have  been  reported  worldwide  among  women  with  transplanted  organs.  There  is  however,  a  slight  increase  in  spontaneous  intrauterine  growth restriction  (IUGR) and/or  premature  delivery. Data from  the  National  Transplantation  Pregnancy  Registry  (NTPR)  in  the    

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United  States,  the  European  Dialysis and Transplant  Association  Registry,  and  the  UK  (United  Kingdom)  Transplant  Pregnancy  Registry  show  similar  trends  in  miscarriages,  therapeutic  terminations, stillbirths, ectopic pregnancies, preterm birth, low‐ birth weight  babies,  and neonatal  deaths. This chapter explores  the  effect  of  pregnancy  on  allograft  function.  Other  aspects  covered include pre‐pregnancy counseling, timing of pregnancy,  and  gestational  therapeutic  management  issues  such  as  immunosuppressive  drug  therapy  and  administration  of  antihypertensive  medications,  diuretics,  antibiotics,  and  analgesics.  Management  of  antenatal  and  intrapartum  complications  as  well  as  advice  on  breast  feeding  and  contraception has also been addressed.   

KEYWORDS:  Post‐transplantation  pregnancy,  pre‐pregnancy  counseling,  timing  of  pregnancy,  immunosuppressive  drug  therapy,  antenatal  management,  intrapartum  complications,  post‐transplant  contraception,  pre‐eclampsia,  pregnancy‐ induced hypertension.   

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Pregnancy in Kidney Transplant Recipients Dr. Suman Kher

MD

Senior Consultant and Head Department of Obstetrics & Gynecology Apollo Hospital, NOIDA

Dr. Vijay Kher

MD, DM, FAMS, FRCPE

Director Department of Nephrology & Transplant Medicine Fortis Hospital, New Delhi

INTRODUCTION Kidney transplant is the best modality of treatment for ESRD pa ents especially for the quality of life it provides to these pa ents in comparison to that provided by various dialysis modali es. A successful kidney transplant o en allows recipients to resume and maintain rela vely normal lives. A successful pregnancy outcome is a good test of a successful transplant. Resump on of cyclic menses and return of fer lity occurs within an average of 6 months a er transplant in women with kidney failure. Thus pregnancy is common among young female transplant recipients.1 Pregnancy success rates exceed 90% a er the first trimester. There is however, a slight increase in spontaneous intrauterine growth restric on (IUGR) and/or premature delivery which can occur in onehalf to two-third of the cases.2 First documented pregnancy in renal transplant recipient occurred in 1958 and the first child born to a transplant recipient turned 48 years old on March 10, 2008.3,4 The data regarding pregnancy outcomes is offered mainly by voluntary registries, case reports and retrospec ve center studies in recipients of solid organ transplants. Approximately 14,000 births have been 85

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reported worldwide among women with transplanted organs.5 The three main registries which offer data are: the Na onal Transplanta on Pregnancy Registry in the United States (NTPR), the European Dialysis and Transplant Associa on Registry, and the UK (United Kingdom) Transplant Pregnancy Registry. All three registries show similar trends in miscarriages, therapeu c termina ons, s ll births, ectopic pregnancies, preterm birth, low birth weight babies and neonatal deaths.6,7

PHYSIOLOGY OF PREGNANCY IN KIDNEY TRANSPLANTATION Kidney Function In normal pregnancy in non-transplant pa ents, renal plasma flow and glomerular filtra on rate (GFR) increase as early as 3–4 weeks a er concep on and con nue to rise throughout most of pregnancy, decreasing to normal as term approaches. Therefore blood urea nitrogen (BUN) and s. crea nine values decrease to 1/2 to 1/3rd of Most studies indicate that pregnancy does not have adverse effect on renal allograft if renal function is well preserved before pregnancy.

non-pregnant values. In renal transplant pa ents also this renal vasodilata on and increased GFR occurs.8 In general, slight reduc on in GFR occurs in late third trimester and 15% transplant recipients display significantly decreased renal func on a er pregnancy. Proteinuria occurs near term in 40% of renal transplant recipients but disappears post partum.9 If there is no associated uncontrolled hypertension and significant proteinuria, most studies indicate that pregnancy does not have adverse effect on renal allogra if renal func on is well preserved before pregnancy.10 When moderate to severely impaired renal func on exists, then pregnancy accelerates decline in renal func on.10 According to UK registry, pregnancy success is related to s. crea nine level within 3 months before concep on. Gra loss is 3 mes more if s. crea nine is ≥2.5 mg/dl as compared to a level of 1.5 mg/dl.7 86

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The long term effect of pregnancy on allogra func on is less clear. In one of the largest be er designed studies, the long term outcomes of 39 women who became pregnant with a func oning allogra were each compared with three matched control pa ents. At the end of 15 years of follow-up, allogra and pa ent survival were similar in both groups (72% and 85% in women who had pregnancy vs 69% and 79% in the control group), respec vely. Also the kidney func on was similar at 1, 5 and 10 years post-transplant.11 Though a single center study, this study does suggest that pregnancy does not have any long term adverse effects on survival of either allogra or the pa ent.

Renal Morphology Renal morphology in transplanted pregnant female shows similar changes as in non-transplanted pregnant female including 30% increase in renal volume. Post partum transplanted kidney shows 1.5 cm greater mean kidney length on intravenous pyelography (IVP) as Increased urinary stasis in pregnant transplant patients would be expected to predispose them to an increased risk of urinary tract infection.

compared to non-pregnant non-transplanted pa ents. The dilata on of renal pelvis, calyces and ureters especially on right side may persist for several months a er delivery due to mechanical issues. Bladder undergoes func onal and structural changes during normal pregnancy leading to incomplete emptying in 20% of pa ents for about 3 months post partum. This increased urinary stasis in pregnant transplant pa ents would be expected to predispose them to an increased risk of urinary tract infec on.

PRE-PREGNANCY COUNSELING Pregnancy should be deferred for some me a er transplant of any organ to allow the pa ent to recover from surgery, to allow gra func on to stabilize and to decrease the dose of immunosuppressive agents to maintenance levels. The preconcep on counseling should be introduced at least at the pretransplant evalua on and followed 87

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up throughout the post-transplant period. It should be offered to both the pa ent and the partner. Ideally pa ents should be vaccinated pretransplant but if not, then prepregnancy vaccina on for influenza, pneumococcus, hepa s B, tetanus, Rubella and varicella should be given.12

Timing of Pregnancy A consensus conference held by women health commi ee of the American Society of Transplanta on in March 2003 concluded that pregnancy is usually safe a er the first year provided the following criteria are met.12 z Adequate and stable gra func on z Serum crea nine level of 1.5 mg/dl or less z No or minimal proteinuria z No rejec on in past year z No acute infec ons which might impact fetus z Maintenance immunosuppression at stable dosing The preconception counseling should be introduced at least at the pretransplant evaluation and followed up throughout the post-transplant period.

Special circumstances that may impact the recommendations z Maternal age z Rejec on within the first year (consider further gra assessment―biopsy and GFR) z Comorbid factors that may impact pregnancy and gra func on (Table 1) z Established medical non-compliance.

MANAGEMENT ISSUES DURING PREGNANCY Pregnancy in renal allogra recipients should be considered high risk and preferably managed by both the transplant physician and a specialist in high-risk pregnancies. The expectant mother needs to be monitored 88

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Table 1. Comorbid Factors That May Influence Pregnancy Outcome Etiology of native kidney disease (risk of recurrent disease) Chronic allograft dysfunction Proteinuria and renal function Cardiovascular and pulmonary status Diabetes mellitus (DM) (or history of DM) Hypertension Inherited diseases in mother and/or father (genetic/chromosomal) HBV, HCV, CMV Obesity

closely. All Rh nega ve females of child bearing age undergoing transplanta on should receive 500 IU of an -D as prophylaxis. During pregnancy, Rh an bodies should be monitored rou nely.13

Immunosuppressive Drug Therapy For good gra func on, it is essen al to con nue immunosuppression. Animal studies in mice have shown them to be teratogenic as they cross placenta and affect the fetus.14,15 However in humans, observa onal studies have not documented increase in the rate of congenital malforma ons.14 A transient immunosuppression at birth and at 10 months of age which returns to normal at 24 months, has been no ced in neonates when exposed to cyclosporine in utero.16 Normal or increased levels of immunoglobulins have been detected in infants exposed to azathioprine. However, no immunosuppressive effect has been seen in infants exposed to cor costeroids, tacrolimus or cyclosporine in another study.15 Most immunosuppressive drugs are classified as FDA category ‘C’ (risk unknown―but to be given if essen al) agents due to lack of adequate data except for prednisolone, which is category ‘B’. (No adverse known risk in human and animal studies.) Prednisolone Most transplant recipients are on long-term steroids. Though a daily 89

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prednisolone dose of ≤15 mg prior to pregnancy is recommended; it has been reported that a dosage of no more than 7.5 mg daily was the most significant predictor of posi ve pregnancy outcome.17 These drugs are considered category ‘B’―being compa ble with pregnancy and breast feeding though Cote et al reported one case of temporary immunosuppression in a newborn.17 Stress dose steroids in the form of 50–100 mg i.v. hydrocor sone every 8 hours should be given if lower segment cesarean sec on (LSCS) is required and con nued for 2–3 days or un l she can tolerate oral cor costeroids. Calcium supplementa on 1000 mg/day should be given to improve bone mineral density.18 There is no definite increase in congenital malforma on rate noted in pa ents on prednisolone (3.5%). There is increased risk of preterm labor, preterm premature rupture of membranes and intrauterine growth reduc on. Steroids aggravate hypertension and hyperglycemia, thus close monitoring is required.18 There is also an increased risk of osteoporosis and infec on in the mother. RecommendaƟons: Use the lowest effec ve dose. There is no definite increase in congenital malformation rate noted in patients on prednisolone (3.5%).

Azathioprine (AZA) Azathioprine inhibits the purine metabolism. During organogenesis, fetus may be protected from any adverse effect of AZA because it lacks the enzyme inosinate pyrophosphorylase to convert the drug to active metabolite. Though no specific anomalies have been associated with its use in humans, few animal studies have shown a dose related increase in congenital malformations when dose increased from 2.02 mg/kg/day to 2.64 mg/kg/day.18 Clinically most patients after 1 year of transplant are at 1.5–2.0 mg/kg/day of AZA. Neonatal leukopenia, thrombocytopenia and anemia have been reported.18 Maternal leukocyte count at 32 weeks correlates with cord blood leukocyte count. DeWitte et al found that at 32 weeks if leukocyte count was ≤1 SD for normal pregnancy; a 50%

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dose reduction of AZA was not associated with neonatal leukopenia or thrombocytopenia.19 IUGR has been associated with the use of AZA but it is not clear that it is caused by the drug or by underlying medical condition of patients. 20 Cyclosporine (CSA) It is a calcineurin inhibitor, which inhibits interleukin 1, and 2 mediated lymphocyte prolifera on without depressing bone marrow func on. It is classified as category ‘C’ for pregnancy. Animal studies do not demonstrate a teratogenic effect and no specific pa ern of anomalies has been seen in human infants exposed to CSA. Only one study has noted an increased rate of spontaneous abor ons. IUGR has been noted in pregnancies exposed to CSA.20 Monthly trough levels of CSA should be checked and dose adjusted frequently in pregnancy. Liver During pregnancy, the hepatic, cytochrome enzymes may be inhibited, which can lead to increased serum levels of tacrolimus and cyclosporine. Monthly trough levels of cyclosporine should be checked and dose adjusted frequently in pregnancy.

toxicity, nephrotoxicity and hypertension can occur. There can be confusion created due to presence of pregnancy-induced hypertension (PIH) and or nephrotoxicity induced by CSA. This drug is metabolized by cytochrome P450 system and is thus influenced by other drugs. Increased cyclosporine levels can be caused by ketoconazole, dil azem, erythromycin, verapamil and grapefruit products. Decreased cyclosporine levels can be due to associated use of phenytoin, rifampicin, phenobarbitone, and carbamazepine. Increased nephrotoxicity of CSA can be induced by use of gentamycin, ketoconazole, amphotericin B, cime dine, trimethoprim + sulfamethoxazole (cotrimoxazole). Tacrolimus It is a calcineurin inhibitor which acts like cyclosporine. It is category ‘C’ drug in terms of risk for pregnancy. Its adverse effects are: neurotoxicity, diabetes mellitus, hypertension and thrombo c thrombocytopenia (TTP). Its nephrotoxicity is less than that of CSA. The maternal fetal toxici es are dose dependent. Among 100 pregnancies in 84 women 91

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treated with tacrolimus of which 27% were renal transplant recipients, 68 progressed to live birth, 60% being premature.21 As with cyclosporine, pa ents taking tacrolimus require frequent monitoring of renal func on and drug levels. During pregnancy, the hepa c, cytochrome enzymes may be inhibited, which can lead to increased serum levels of tacrolimus. The dose may have to be significantly reduced to prevent toxicity (some mes by as much as 60%).20 Mycophenolate Mofetil It is reversible inhibitor of de novo purine synthesis. There are no studies on safety of this drug in pregnancy. It is listed as category ‘D’ drug (posi ve evidence of risk) due to increase in both first trimester pregnancy loss and congenital malforma ons e.g. cle lip, cle palate, Calcineurin inhibitors (cyclosporine and tacrolimus), steroids and azathioprine are the mainstays of safe immunosuppressive therapy in pregnant transplant recipients.

anomalies of distal limbs, heart, esophagus and kidneys. It should be discon nued 6 weeks before contempla ng pregnancy.22 M-TOR Inhibitors (Sirolimus and Everolimus) Inadequate human data is available on safety in pregnancy. Animal studies suggest teratogenicity. Thus, should be avoided in pregnancy and discon nued 12 weeks before concep on.22

Antihypertensive Medications Drugs to control hypertension are typically used to target BP below 140/90 mmHg; however, it has not been proven that this strategy in pregnancy benefits either maternal or fetal outcome. There is 30% incidence of PIH in pregnant transplant recipients.2 First-line therapeu c agent is α-methyldopa. If α-methyldopa is not able to control BP adequately, then labetalol and calcium channel blockers are preferred for long-term use. Atenolol is a category ‘D’ drug due to risk of IUGR. β blockade has been reported in some newborns.23 Hydralazine is a category ‘C’ drug. It is used for acute hypertensive control during hospitaliza on. ACE inhibitors are contraindicated in pregnancy due to associa on with fetal hypocalvarium, renal failure, oligohydramnios, 92

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fetal or neonatal death. If concep on occurs, drug should be discon nued.

Diuretics Diure cs should not be ins tuted during pregnancy as reduced plasma volume can decrease placental perfusion. Thiazide diure cs have been reported to produce neonatal thrombocytopenia.24

Antibiotics Most an bio cs of penicillin and cephalosporin group can be prescribed during pregnancy. Fluoroquinolones may cause fetal car lage damage and arthropathies, so should be avoided during pregnancy.

Analgesics Pain in pregnancy is best controlled with acetaminophen. If required, codeine can be given with acetaminophen. Aspirin and ibuprofen are Diuretics should not be instituted during pregnancy as reduced plasma volume can decrease placental perfusion.

contraindicated especially for long-term use and in third trimester of pregnancy. Demerol and morphine can be used for short periods as needed during pregnancy or a er delivery to control surgical pain.

ANTE PARTUM MANAGEMENT Best pregnancy outcome is assured with mul disciplinary team approach. Ini al obstetrical visit should include complete history, physical examina on and antenatal evalua on with CBC, urinalysis, urine culture, 24-hour urine protein and crea nine clearance, biochemical tests like BUN, s. crea nine, uric acid, blood group with Rh and screening for HBsAg, HIV, syphilis, rubella, gonorrhea, Chlamydia and TORCH panel. For women 1.5 mg/dl). Long term developmental outcome of surviving infants seems to be good.25 There is increased incidence of pregnancy complica ons e.g. hypertension, PIH, infec ons, preterm birth and intrauterine growth retarda on in 20% of pregnancies in transplant recipients.19 94

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Evaluation of Renal Function The differen al diagnosis of renal dysfunc on and the evalua on of the pregnant allogra recipient is similar to that in the non-pregnant transplant pa ent. Addi onal concerns include the causes of renal dysfunc on unique to pregnancy as well as the interplay between pregnancy and the presence of a renal allogra . z

z

z

Although women are advised to wait for a sufficient period of me a er transplanta on to become pregnant, episodes of acute rejec on are not uncommon in this se ng. Obstruc on of the transplant ureter by the uterus, although unusual, has been reported. Severe pre-eclampsia and thrombo c thrombocytopenic purpurahemoly c uremic syndrome (TTP-HUS) (due to pregnancy) may be difficult to dis nguish in the pregnant transplant pa ent, The differential diagnosis of renal dysfunction and the evaluation of the pregnant allograft recipient is similar to that in the non-pregnant transplant patient.

par cularly since they both present with hemolysis and thrombocytopenia. Although a TTP-HUS-like picture may also be observed in transplant pa ents with hyperacute rejec on or in those administered OKT3 or cyclosporine, these clinical se ngs occur immediately or soon a er transplanta on and are therefore unlikely to be observed in a pregnant pa ent.

Pre-eclampsia/Pregnancy-induced Hypertension NTPR database indicates 28% pre-eclampsia in pa ents treated with Sandimmune based therapy while 15% and 17% in pa ents treated with neoral or tacrolimus, respec vely,6 In 40% transplant pa ents increasing proteinuria is seen near term but in absence of hypertension, it regresses postpartum and does not need evalua on. Proteinuria needs evalua on if associated with hypertension or decreased renal func on or if it persists postpartum. Delivery should be considered in pa ents with severe PIH. 95

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Infections There is increased risk of infec ons in transplant pa ents in pregnancy. Prophylac c an bio cs should be used for all invasive procedures for instance Foley’s catheteriza on, fetal scalp electrode placement, ar ficial rupture of membranes and episiotomy. During labor, broad spectrum intravenous an bio cs should be used. Cytomegalovirus (CMV) There is increased risk of CMV infec on both primary as well as reac va on. 0.2–2% newborns of transplant pa ents have CMV infec on but only 10% of these are symptoma c for primary CMV. There is 40% risk of transplacental passage of virus. Theore cally i.v. ganciclovir may be used to prevent or ameliorate effects of fetal CMV exposure and medical termina on of pregnancy (MTP) is not recommended.26 Herpes Simplex Virus (HSV) Presence of ac ve genital HSV especially primary lesions on perineum and cervix demand a cesarean delivery. Pa ents with a history of genital HSV can be offered acyclovir 400 mg thrice daily beginning at 36 weeks to prevent outbreak of fresh lesions and thus decrease the rate of cesarean deliveries.

INTRAPARTUM MANAGEMENT 1. 2.

3.

4.

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During labor con nuous fetal monitoring is advisable. Cesarean sec on is indicated primarily for obstetric indica ons. Reported incidence is however 50% in transplant pa ents due to IUGR, prematurity and other associated condi ons. Occasionally pelvic renal osteodystrophy due to steroid use for long may lead to obstructed labor. Stress dose steroid therapy is indicated during labor, delivery and first 24–48 hours post partum. An bio c prophylaxis for group B streptococcus (GBS) should be given during labor for all infants under 37 weeks, for a posi ve GBS culture, for history of GBS urinary infec on during pregnancy or for risk factors such as rupture of membranes more than 18 hours or fever >38°C.

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For cesarean sec on, cephalosporin coverage (1 g cefazolin or 2 g cefoxi n) along with anaerobic coverage should be given a er cord clamping. To avoid injury to transplanted kidney, a mid-ver cal incision should be used instead of a Pfannens el incision. A SmeadJones closure of abdominal incision (farnear–nearfar) should be employed. Delayed removal of staples/sutures is recommended. Post partum fever of 38°C is due to endomyometri s and should be treated with broad spectrum an bio cs e.g. Sulbacin, Timen n, etc.

BREAST FEEDING There is no or li le informa on available regarding risk associated with immunosuppressive drugs in human milk. Though small amount of prednisolone is secreted, it is not a contraindica on to lacta on. Breast feeding should be delayed for 4 hours a er dosing. American Academy of Pediatrics (AAP) considers cyclosporine and azathioprine as contraindica ons to lacta on.

CONTRACEPTION There is limited data available regarding efficacy and safety of various contraceptive methods in transplanted patients. Barrier methods are preferred by some in these patients as these have least problems.

Intrauterine Devices Theoretically there is a risk of infection in immune compromised patients. It is recommended to use doxycycline to prevent infection at the time of insertion. IUD may not be effective in transplant patients, as there may not be adequate inflammatory response for efficacy. 27

Oral Contraceptive Pills (OCPs) These pills are safe and effec ve in normotensive pa ents. These should be avoided in hepa c transplant pa ents. Since OCPs poten ally affect metabolism of certain drugs, surveillance is necessary e.g. cyclosporine hepatotoxicity may increase with OCPs.27 97

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SUMMARY Close monitoring of a pregnant transplant pa ent by a combined team of nephrologist and high risk specialist obstetrician should lead to a successful outcome in large majority of such pregnancies.28

REFERENCES 1. 2.

Framarino dei Malatesta M, Rossi M, Rocca B, et al. Fertility following solid organ transplantation. Transplantation Proceedings 2007;39:2001–4. Davison JM. Dialysis, transplantation, and pregnancy. Am J Kidney Dis 1991;17:127.

3.

Murray JE, Reid DE, Harrison JH, Merrill JP. Successful pregnancies after human renal transplantation. N Engl J Med 1963;269:341–3.

4.

Mckay DB, Josephson MA. Pregnancy in recipients of solid organs -effects on Mother and Child. N Engl J Med 2006;354:1281–93.

5.

Davison JM, Baylis C. Renal disease. In: de Sweit M, ed. Medical Disorders in Obstetric Practice 4th ed. Malden, Mass: Blackwell Science, 2002:198–266.

6.

Armenti VT, Radomski JS, Moritz MJ, et al. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. In: Cecka JM, Terasaki PI, eds. Clinical Transplants 2004 Los Angeles: UCLA Immunogenetics Center, 2004:103–19.

7.

Sibanda N, Briggs JD, Davison JM, et al. Outcomes of pregnancy after renal transplantation: a report of UK transplant pregnancy registry. Hypertens Pregnancy 2004;23(Suppl 23):136.

8.

Baylis C. Glomerular filtration rate in normal and abnormal pregnancies. Semin Nephrol 1999;19:133–9.

9.

Davison JM. Towards long-term graft survival in renal transplantation: pregnancy. Nephrol Dial Transplant 1995;10:85–9.

10. Hou S. Pregnancy in transplant recipients. Med Clin North Am 1989;73: 667–83. 11. Rahaminov R, Haroush AB, Wittenberg C, et al. Pregnancy in renal transplant recipients: long term effect on patient and graft survival. A single center experience. Transplantation 2006;81:5:660–4. 12. Mckay DB, Josephson MA. Reproduction and transplantation: report on the AST consensus conference on reproductive issues and transplantation. Am J Transp 2005;5:1592–9. 13. Quan VA, Kemp LJ, Payne A, et al. Rhesus immunization after renal transplantation. Transplantation 1996;61:149–50. 14. Albengres E, Louet HL, Tillement JP. Immunosuppressive drugs and pregnancy: experimental and clinical data. Transplant Proc 1997;29:2461–6. 15. Little BB. Immunosuppressant therapy during gestation. Semin Perinat 1997;21:143–8.

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Case Studies

Pregnancy in Renal Transplant Recipients CASE 1 A 25-year-old lady who had received a living donor kidney transplant 10 years ago from her mother has been on regular followup in the transplant clinic. She was ini ally put on cyclosporine, azathioprine and prednisolone, and was maintained on the triple immunosuppression with cyclosporine A 150 mg/day in two divided doses (trough cyclosporine A maintained ini ally between 250–350 ng/ml and later between 150–250 ng/ml), 50 mg azathioprine and 7.5 mg prednisolone/day. A er 5 years, she developed gum hyperplasia with bleeding gums, difficulty in ea ng and hirsu sm; she was then switched to tacrolimus (1 mg twice daily) instead of cyclosporine and mycophenolate 500 mg twice daily instead of azathioprine. The tacrolimus levels were trated between 4–6 ng/ml. She maintained normal renal func on with serum crea nine of 0.7–0.9 mg/dl, urea nitrogen of 6–10 mg/dl, fas ng blood sugar of 80–100 mg/dl (HbA1c 5.6%). She had no acute rejec ons during her post-transplant period, was normotensive, given prophylaxis for steroid-induced osteoporosis for last 4 years in form of alendronate 70 mg once a week as well as calcium carbonate supplementa on. She and her fiancé came for a premarital detailed discussion about the impact of marriage and pregnancy on the gra and the pa ent, as well as on the fetus. Both of them were counseled and educated about the worldwide experience of pregnancy in kidney transplant recipients and the effects of pregnancy on gra func on and of immunosuppressive drugs on fetus. They were married on 12.2.07. Both decided to plan for pregnancy in October 2007 and were counseled again. Her renal func ons were normal and mycophenolate mofe l was stopped on 13.10.07 and switched to azathioprine 100

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50 mg/day. She con nued on 2 mg/day tacrolimus and 5 mg prednisolone. She became pregnant in May 2008, however had a missed abor on at 9 weeks. She became depressed but further counseling allayed fears of second pregnancy which happened in October 2008. She was monitored very closely by obstetrician and nephrologist during the whole of pregnancy and she delivered a full term normal baby weighing 2.8 kg by a caesarean sec on, which she opted for. She was switched to i.v. steroids started just before caesarean sec on for 24 hrs and then given 15 mg prednisolone for next 2 days and then brought back to her maintenance doses of 5 mg prednisolone in 4–5 days. All other immunosuppressives were con nued as such. Baby was not allowed to breas eed and milk suppression was done with high dose pyridoxine.

Comments This case highlights that successful outcome of pregnancy with normal full term baby can be achieved with combined careful monitoring of the pregnant transplant recipient by high risk pregnancy specialist obstetrician and transplant nephrologist. In well selected young transplant recipients, successful outcome of pregnancy can be an extremely fulfilling and joyful experience.

CASE 2 A young lady received a live donor kidney transplant in August 1999 at the age of 24, father being the donor. She was on maintenance hemodialysis for 4 months prior to the transplant. The course on dialysis was complicated by recurrent urinary tract infec ons, hematuria, anemia and large number of blood transfusions. Post-transplant period was complicated by repeated urinary infec on which responded to i.v. an bio cs, received long term prophylaxis with cotrimoxazole and nitrofurantoin. She developed pulmonary tuberculosis post-transplant for which she received isoniazid, ethambutol and pyrazinamide for 18 months. She responded well clinically and radiologically. She was on cyclosporine, azathioprine and prednisolone. Her renal func ons were normal and well maintained and so were the hematological and urinary parameters with no proteinuria. She required amlodipine 10 mg/day and prazosin 10 mg/day for blood pressure control. Her maintenance 101

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16. Ersay A, Oygur N, Coskun M, et al. Immunologic evaluation of a neonate born to an immunosuppressed kidney transplant recipient. Am J Perinat 1995;12:413–5. 17. Bar J, Fisch B, Wittenberg C, et al. Prednisone dosage and pregnancy outcome in renal allograft recipients. Nephrol Dial Transplant 1997;12:760–3. 18. Armenti VT, Moritz MJ, Davison JM. Drug safety issues in pregnancy following transplantation and immunosuppression: effects and outcomes. Drug Safety 1998;19:219–32. 19. DeWitte DB, Buick MK, Cyran SE, Maisels MJ. Neonatal pancytopenia and severe combined immunodeficiency associated with antenatal administration of azathioprine and prednisone. In: Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in Pregnancy and Lactation 5th ed. Baltimore: Williams & Wilkins 1984:625–8. 20. Bar Oz B, Hackman R, Einarson T, Koren G. Pregnancy outcome after cyclosporine therapy during pregnancy: a meta-analysis. Transplantation 2001;71:1051. 21. Kainz A, Harabacz I, Cowlrick IS, et al. Review of the course and outcome of 100 pregnancies in 84 women treated with tacrolimus. Transplantation 2000;70:1718. 22. European Best Practices Guidelines (Part 2). Nephrol Dial Transplant 2002;17(Suppl 4):50. 23. Framarino di Malatesta ML, Poli L, Pierucci F, et al. Pregnancy and kidney transplantation: clinical problems and experience. Transplant Proc 1993; 25:2188–9. 24. Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in Pregnancy and Lactation Baltimore: Williams & Wilkins, 1998. 25. Blowey DL, Warady BA. Outcome of infants born to women with chronic kidney disease. Adv Chronic Kidney Dis 2007;14:199–205. 26. Kher S, Kher V. Pregnancy in transplant recipients: a review. J Trans Devlop Nations 2003:24–31. 27. Alston PK, Kuller JA, McMohon MJ. Pregnancy in transplant recipients. Obstetrical & Gynecological Survey 2001;56:289–95. 28. Maynand SE, Thadani R. Pregnancy & the kidney. JASN 2009;20:1–22.

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immunosuppressive drugs were cyclosporine 50 mg twice daily (target cyclosporine levels 150–250 ng/ml), and azathioprine 50 mg daily and prednisolone 2.5 mg daily. Three years a er the transplant, she had a planned concep on and pregnancy, and delivered a baby girl in 2002 via a caesarean sec on at 35 weeks. Pregnancy was uneven ul except for anemia which responded to i.v. iron sucrose. The baby’s weight was 2.4 kg and there were no complica ons. The baby has grown into a schoolgoing child now. In 2004, she had liver enzyme eleva on and was diagnosed to have hepa s C (an -HCV +ve and HCV RNA +ve). She was not given interferon in considera on of chances of acute rejec on with interferon. Azathioprine was discon nued and she was maintained on cyclosporine and prednisolone only. Her liver func on tests were stable over next 3 years. In 2007 she planned for a second pregnancy a er consulta on with a gastroenterologist and pediatrician about the impact of HCV on the fetus as well as on pregnancy. They were keen for a second child and decided to go ahead with pregnancy which was monitored very closely for any fetal abnormali es and growth, liver and renal func ons. She delivered a full term baby boy (weight - 2.3 kg) via a cesarean sec on. The baby was monitored for an -HCV an body. The baby was HCV +ve (maternal to fetal transmission) and treated with interferon and has become HCV –ve (HCV RNA –ve). Both the mother and baby are doing well. The first baby and husband have been nega ve for HCV. She is on immunosuppression with cyclosporine 50 mg twice daily and 2.5 mg/day of prednisolone for last 5 years and her renal func ons and liver func ons are normal.

Comments This case study highlights the infec ous complica ons of chronic kidney disease pa ents on dialysis and transplanta on, and the impact it can have on the outcome of renal transplanta on and pregnancy and the children. However, appropriate management leads to good outcome. Pa ents with HCV should have reduc on in immunosuppression to decrease viral replica on. Despite this, her baby had maternal to fetal transmission of HCV infec on and had to be treated with interferon. She has achieved a sustained viral response. 102

Nutrition in Pregnancy and Kidney Disease, Counseling, and Contraception Dr. Vijay Kher

MD, DM, FAMS, FRCPE

Director Department of Nephrology & Transplant Medicine Fortis Hospital, New Delhi

ABSTRACT: The dietician’s role in the nutritional management  of  pregnant  women  with  chronic  kidney  disease  (CKD)  is  very  important  in  guiding  the  patient  to  the  increased  protein,  energy, vitamin, and mineral needs of pregnancy, while allowing  for  decreased  kidney  function  that  affects  serum  levels  of  electrolytes,  calcium,  and  phosphorus,  as  well  as  volume  status  and  specific  vitamin  needs.  It  presents  the  challenge  of  combining  necessary  modifications  in  nutrient  requirements  for  both pregnancy and kidney impairment. Furthermore, the weight  gain  during  pregnancy  must  also  be  evaluated  carefully  considering  the  greater  potential  for  fluid  retention  in  these  patients  with  CKD.  Those  undergoing  dialysis  should  also  be  assessed and educated as soon as possible after the pregnancy is  confirmed.  The  key  to  success  in  the  care  and  counseling  of  women  with  CKD  who  are  contemplating  or  choosing  to  avoid  pregnancy  is  a  multidisciplinary  approach  consisting  a  nephrologist, obstetrician, and, eventually, a pediatrician familiar  with  high‐risk  patients.  This  team  approach  allows  for  optimal  counseling  and,  hopefully,  optimal  outcomes  in  both  maternal  and fetal care.  KEYWORDS: Nutritional management, energy needs, protein  needs,  supplemental  calcium,  iron  supplementation,  sodium  allowances,  maternal  kidney  disease,  injectable  medroxyprogesterone, tubal ligation.      103a    

Nutrition in Pregnancy and Kidney Disease, Counseling, and Contraception Dr. Vijay Kher

MD, DM, FAMS, FRCPE

Director Department of Nephrology & Transplant Medicine Fortis Hospital, New Delhi

NUTRITION IN PREGNANCY WITH CHRONIC KIDNEY DISEASE The die cian’s role in the nutri onal management of pregnant women with chronic kidney disease (CKD) is very important in guiding the pa ent to the increased protein, energy, vitamin, and mineral needs of pregnancy, while allowing for decreased kidney func on that affects serum levels of electrolytes, calcium, and phosphorus, as well as volume status and specific vitamin needs. It presents the challenge of combining necessary modifica ons in nutrient requirements for both pregnancy and kidney impairment. Furthermore, the weight gain during pregnancy must also be evaluated carefully considering the greater poten al for fluid reten on in these pa ents with CKD. The die an needs to counsel, monitor, and meet women in the early stages of CKD or a er kidney transplanta on within the first month of confirmed pregnancy, and then have a stringent follow-up with them during the en re course of pregnancy. Those undergoing dialysis should also be assessed and educated as soon as possible a er the pregnancy is confirmed and followed weekly for assessment of nutrient intakes, laboratory values, and counseling.1

Energy and Protein Needs There are no defini ve recommenda ons for the es mate of energy 103

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and protein requirements for pregnant women with CKD. Thus, the recommenda ons are based on the combined guidelines of the Na onal Kidney Founda on Kidney Disease Quality Outcomes Ini a ves (KDOQI) with the recommended daily allowances (RDAs) and more recently published dietary reference intakes (DRIs) for the general popula on. Generally, 35 kilocalories (kcal) per kilogram of pregravida ideal body weight (IBW) or adjusted IBW per day are prescribed in the first trimester, and an average of at least 300 kcal/d are added to this value for the second and third trimesters during all stages of CKD and a er kidney transplanta on.2–4 Protein needs of approximately 0.8 g/kg/d for CKD stages 1 to 3 are thought to be reasonable (although data are inconclusive),5 and this value plus 10 g/d added for pregnancy seems feasible. For CKD stage 4 and CKD stage 5 without dialysis, a lower protein intake of 0.6 g/kg IBW plus 10 g/d may be advised1 but caloric The recommendations are based on the combined guidelines of the National Kidney Foundation Kidney Disease Quality Outcomes Initiatives with the recommended daily allowances and more recently published dietary reference intakes for the general population.

needs would be difficult to meet with this restric on. Most likely, a woman who becomes pregnant during these stages of CKD would need dialysis at some point during the pregnancy. Protein needs for pregnant women undergoing hemodialysis and peritoneal dialysis (PD) are generally 1.2–1.3 g/kg IBW plus at least 10 g/d.2,3 These needs for the pregnant dialysis pa ent may be easier to meet, as the diet can frequently be liberalized for sodium, potassium, and phosphorus content because of increased solute removal with more intensive dialysis. However, at mes, the mother may require protein or calorie/protein supplements to a ain her es mated energy and protein requirements.

Vitamins and Minerals Vitamin and mineral needs for pregnant adults in the earlier stages of CKD or a er kidney transplanta on are generally the same as for the general healthy popula on during pregnancy.1 Prenatal vitamins 104

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are usually prescribed to meet these needs, including at least 11 mg of zinc, 27 mg of iron, 600 μg of folate, and 1.4 mg of thiamine per day. Approximately 800 μg of vitamin A per day are required, and excess should be avoided.1,4 Pregnant women undergoing dialysis treatment are frequently prescribed about 2 mg folic acid, because folate deficiency has been associated with neural tube defects for infants born to women who do not have CKD, and thus an addi onal dosage is recommended in these pa ents considering the an cipated vitamin losses with more intense dialysis.6 Supplemental vitamin A is not rou nely given to pregnant dialysis pa ents because of the poten al for toxicity with decreased kidney func on, as well as spontaneous abor on and birth defects with its excess intake.1 Vitamin D analogs have been given intravenously during hemodialysis to pregnant women for suppression of parathyroid hormone and to Supplemental vitamin A is not routinely given to pregnant dialysis patients because of the potential for toxicity with decreased kidney function, as well as spontaneous abortion and birth defects with its excess intake.

maintain normal serum levels of calcium. Defini ve informa on about the safety of these forms of vitamin D rela ve to fetal development is not known.7,8 On the other hand, the poten al impact of vitamin D deficiency during pregnancy,9 combined with the inability of the diseased kidney to ac vate vitamin D, may be reason to use small doses of these vitamin D analogs for pregnant dialysis pa ents. Supplemental calcium may also be needed to be given during the early stages of CKD and after kidney transplantation. At least 1000 mg/d is recommended from diet and supplements to meet the increased needs for skeletal development in the fetus.4,10 With more intense dialysis, calcium carbonate may be used apart from dietary supplementation if necessary. The increased absorption of calcium from the dialysate for women undergoing more intensive hemodialysis, as well as probable increased calcium absorption resulting from calcitriol production by the placenta must be 105

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considered and thus calcium/phosphorus levels should be monitored frequently in these patients.10 Because anemia usually occurs during pregnancy, iron supplementation is done for women with CKD stages 1 to 3 and after kidney transplantation. For those undergoing hemodialysis, intravenous iron can also be safely given during the treatment.8 Iron dextran has been used, but iron gluconate or iron sucrose preparations are generally given.8,10 Women who are receiving peritoneal dialysis may be prescribed oral forms of iron, but intravenous iron could be given safely as well. The doses provided should be based on achieving the goals for hemoglobin, transferrin saturation, and ferritin utilized in the general dialysis population. Worsening anemia during pregnancy usually results in increased requirements for iron and erythropoetin, especially for women undergoing hemodialysis. 11 Because anemia usually occurs during pregnancy, iron supplementation is done for women with chronic kidney disease stages 1 to 3 and after kidney transplantation.

Zinc requirements for pregnant dialysis pa ents are at least 15 mg/d. Zinc is supplemented during pregnancy to prevent increased risks of fetal malforma on, preterm delivery, low birth weight, and pregnancy induced hypertension.1,7

Other Considerations Sodium allowances for pregnant pa ents with early stages of CKD while undergoing dialysis or a er kidney transplanta on are dependent upon fluid reten on and hypertension. For the general popula on, 2–4 g of sodium per day is recommended during pregnancy.1 Potassium allowances during all stages of CKD and a er kidney transplanta on are dependent upon serum potassium levels. In general, most pregnant pa ents with CKD do not require potassium-restricted diets. The nutri onal management of the adult pregnant pa ent with CKD is a challenge requiring ini al interven on and close monitoring by the die an. Although diets may need to be restricted because of CKD, goals are to have good communica on among members of the 106

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Kher

healthcare team to allow the pa ent op mal nutri on combined with medical treatment.

COUNSELING OF WOMEN WITH CKD Fer lity in women with chronic kidney disease is generally reduced, in part because of gonadal dysfunc on and secondary amenorrhea.12–14 For counseling women with chronic kidney disease about pregnancy, one needs to accept that informa on on outcomes is limited, both due to lack of systemic data, inability to randomize pa ents, and difficulty to find appropriate controls.15,16 For most pa ents with serum crea nine (SCr) 2.0 mg/dL at the me of concep on, one-third progress to end-stage renal disease (ESRD) over the postpartum year of follow-up.21 This Fertility in women with chronic kidney disease is generally reduced, in part because of gonadal dysfunction and secondary amenorrhea.

needs to be conveyed to women with chronic kidney disease who are contempla ng pregnancy as well as those who become pregnant. Women with chronic kidney disease must also receive counseling and informa on about fetal outcome. Fetal outcomes are more op mis c and less variable with the improvements in prenatal care that have developed over the past several decades, such as cor costeroids for lung maturity, screening for beta Streptococcus, and easier access to neonatal specialty care. However, significant intrauterine growth restric on and preterm labor commonly occur with prematurity and range from 40% to 70% of all pregnancies. Though fetal survival is at par with the general popula on when mother’s SCr is 70% in those not requiring dialysis;19,22 it is definitely lower with uncontrolled hypertension, and thus women should be ac vely counseled about the need for hypertension control.17,22,23 Controlling proteinuria to