Polycystic Kidney Disease - ECAB 9788131224175, 9788131231999, 8131231992

Table of contents :
Front Cover
Title page
Copyright
ECAB Clinical Update:Nephrology
Polycystic Kidney Disease
About the autho rs
Contents
ECAB Clinical Update Information Polycystic Kidney Disease
Introduction
Genetics of Autosomal Dominant Polycystic Kidney Disease
ABSTRACT
KEYWORDS:
Introduction
Pkd1
Pkd2
Third Gene
Indian Experience
Two-Hit Suppressor Model Of Cystogenesis
Animal Studies
Diagnosis
Linkage Analysis
Prenatal Testing
Preimplantation Genetic Diagnosis (PGD)
DNA Banking
Conclusions
Pathology, Pathogenesis and Clinical Presentation of Autosomal Dominant Polycystic Kidney Disease
ABSTRACT
KEYWORDS
Introduction
Global Update
Pathology
Pathogenesis
Proliferation of Epithelial Cells
Role of Growth Factor Receptor Proteins
Role of cAMP in Cyst Epithelium Proliferation
Role of Cytokines in Cyst Proliferation
Role of PC-1 and PC-2 Proteins in Cyst Proliferation
Abnormal Secretory Process in Cyst Development and Expansion
Role of Cell Polarity in Abnormal Fluid Secretion and Cyst Expansion
Disturbed Organization of Extracellular Matrix
Cell Matrix Interaction
Cell-Cell Interaction
Other Factors Influencing Cystogenesis
Role of Genes and Their Proteins in ADPKD
Signaling
Role of Apoptosis in Cystogenesis
Role of Primary Cilia in Cystogenesis
Clinical Features
Renal Manifestations
Pain and Renal Size
Hematuria and Cyst Hemorrhage
Urinary Tract Infection and Cyst Infection
Nephrolithiasis
Hypertension
CKD Stage 5
Extrarenal Manifestations
Polycystic Liver Disease
Intracranial Aneurysm (ICA)
Vascular Abnormalities
Valvular Heart Disease
Other Associated Conditions
Acknowledgment
The Diagnosis of Autosomal Dominant Polycystic Kidney Disease
ABSTRACT
KEYWORDS
Genetic Analysis Of Autosomal Dominant Polycystic Kidney Disease
Imaging Studies In The Diagnosis Of Autosomal Dominant Polycystic Kidney Disease
Complications of Autosomal Dominant Polycystic Kidney Disease
ABSTRACT
KEYWORDS
Introduction
Renal Complications
Hematuria
Nephrolithiasis
Flank and abdominal pain
Cancer
Hypertension
Pathogenesis
Treatment
Recommendation
Infection
Diagnosis
Management
Non-response to antibiotic Therapy
Duration of Therapy
Other Interventions
Extrarenal Complications
Cerebral aneurysm
Clinical presentation
Diagnosis
Indications for Intervention
screening Recommendations
Cardiac Disease
Other Vascular abnormalities
Colonic Diverticula
Hernias
Hepatic Cysts
management
Medical Management of Autosomal Dominant Polycystic Kidney Disease
ABSTRACT
KEYWORDS
Molecular Pathogenesis And Targeted Therapeutic Options
Increased Apoptosis in Polycystic Kidney Disease
cAMP-Mediated Pathways
mTOR Activation
Cilia and Cell Cycle Disruption
Triptolide
TREATMENT
Water Intake and Diet
Treatment of Hypertension
Recommendations
HALT-PKD Trial
Vasopressin V2-Receptor Antagonists
Sirolimus
Somatostatin
Conclusions
Surgical Management of Autosomal Dominant Polycystic Kidney Disease Patients
ABSTRACT
KEYWORDS
Introduction
Nephrolithiasis in Autosomal Dominant Polycystic Kidney Disease Patients
Renal Cell Carcinoma in Autosomal Dominant Polycystic Kidney Disease Patients
Conclusions
Prognosis of Autosomal Dominant Polycystic Kidney Disease
ABSTRACT
KEYWORDS
Introduction
Prognosis Of Autosomal Dominant Polycystic Kidney Disease
Conclusion
Renal Replacement in Autosomal Dominant Polycystic Kidney Disease Patients
Renal Transplantation in Autosomal Dominant Polycystic Kidney Disease Patients
ABSTRACT
KEYWORDS
Introduction
In addition to routine pretransplant evaluation, do adpkd patients require specific evaluation?
Should potential renal complications require nephrectomy prior to transplantation?
When Transplantation From A Living Relative Is Considered, The Existence Of Adpkd In The Donor Should Be Formally Ruled Ou ...
Is There Any Immunosuppression Protocol That May Have A Favorable Course In Adpkd Patients?
Is there any increased incidence of post-transplant complication in adpkd patients?
As compared to nonadpkd patients, is there an increase in the rate of graft and patient survival in adpkd?
Conclusion
Other Books in This Series

Citation preview

ECAB Clinical Update: Nephrology

Polycystic Kidney Disease

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ECAB Clinical Update: Nephrology

Polycystic Kidney Disease Kaligotla Venkata Dakshinamurty Gokulnath V Sivakumar Anuradha Uttara Das Madhav Desai Rapur Ram Sushma Rani R PVGK Sarma Guditi Swarnalatha

Editor

Kaligotla Venkata Dakshinamurty

ECAB Clinical Update: Nephrology

A division of Reed Elsevier India Private Limited

Copyright © 2010 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 978-81-312-2417-5 Published by: Elsevier, a division of Reed Elsevier India Private Limited Registered Office: Gate No. 3, Building No. A-1, 2 Industrial Area, Kalkaji, New Delhi - 110019 Corporate Office: 14th Floor, Tower 10B, DLF Cyber City, Phase-II, Gurgaon 122002, Haryana 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. Kaligotla Venkata Dakshinamurty Dr. Gokulnath Dr. Madhav Desai Dr. Sushma Rani R Dr. PVGK Sarma

Dr. Sivakumar Vishnubhotla Dr. Anuradha Dr. Rapur Ram Dr. Guditi Swarnalatha Dr. Uttara Das

EDITOR Dr. Kaligotla Venkata Dakshinamurty

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 DESIGNER AND EDITOR

Dr. Shveta Dhamija

Bobby Choudhury

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. Gokulnath is Professor and Head, Department of Nephrology since 2003 at St. Johns Hospital, Bangalore. He was also HOD of Nephrology at Command Hospital, Air Force, Bangalore and Senior Advisor of Medicine & Nephrology at CH (EC) at Kolkata. He has been awarded the Vishisht Seva Medal by President of India in 2000. He is an experienced Post Graduate teacher and examiner for M.D. Medicine & D.M. Nephrology. Dr. Kaligotla Venkata Dakshinamurty is Professor & Head, Department of Nephrology at Nizam’s Institute of Medical Sciences, Hyderabad. He has a teaching experience of about 30 years till date. Dr Dakshinamurthy has been graced by many of the prestigious Indian and international awards and has also been on the esteemed Governing Council member lists and administration of many national societies. He is also a well known speaker at many conferences and has almost 100 publications to his credit. Sivakumar Vishnubhotla is currently serving as Professor of Nephrology at Sri Venkateswara Institute of Medical Sciences, Tirupati. Through his academic career he has been a student with distinction and thereafter has been the recipient of many prestigious national and international awards. Dr. Sivakumar has vast administrative experience being the Dean at Sri Venkateswara Institute of Medical Sciences University for the year 2004–2005. He has seven publications in international journals and about 50 publications in national level journals. Dr. Madhav Desai is an Assistant Professor in the Department of Nephrology at Nizam’s Institute of Medical Sciences. He has been the receiver of Braun Medical Trust Foundation Award, year 2006 for outstanding achievement in postgraduate medical studies in the field of Nephrology. He has also been a regular participant and has presented many papers in the national conferences and also has quite a few publications to his credit.

ECAB Clinical Update: Nephrology    n   About the Authors

Dr. P. Venkat Gurnadha Krishna Sarma is a biochemist of great repute. She was awarded IVRI/DBT Junior Fellowship during M.Sc. program and has also graced the National Institute of Standards and Technology, Gaithersburg, Maryland, U.S.A. as a Guest Researcher Fellow “to clone calmodulin-like protein and cardiolipin synthetase gene from Mycobacterium phlei.” She is presently working as Associate Professor in Department of Biotechnology, Sri Venkateswara Institute of Medical Sciences, Tirupati. She is also a PhD guide and was awarded by the International Publishing House the ‘Best Citizens of India’ award for the year 2007.

ECAB Clinical Update Information.......................................... i Introduction...............................................................................1 Dr. KV Dakshinamurty and Dr. Rapur Ram

Genetics of Autosomal Dominant Polycystic Kidney Disease������������������������������������������6 Dr. KV Dakshinamurty and Dr. Madhav Desai

Pathology, Pathogenesis and Clinical Presentation of Autosomal Dominant Polycystic Kidney Disease�����������������32 Dr. Gokulnath and Dr. Sushma Rani R

The Diagnosis of Autosomal Dominant Polycystic Kidney Disease����������������������������������������59 Dr. PVGK Sarma and Dr. V Sivakumar

Complications of Autosomal Dominant Polycystic Kidney Disease����������������������������������������70 Dr. Anuradha

Medical Management of Autosomal Dominant Polycystic Kidney Disease����������������������������������������91 Dr. KV Dakshinamurty and Dr. Rapur Ram

Surgical Management of Autosomal Dominant Polycystic Kidney Disease Patients������������������������118 Dr. KV Dakshinamurty and Dr. Guditi Swarnalatha

ECAB Clinical Update: Nephrology    n   Contents

Prognosis of Autosomal Dominant Polycystic Kidney Disease......................................126 Dr. Uttara Das

Renal Replacement in Autosomal Dominant Polycystic Kidney Disease Patients������������������������131 Dr. KV Dakshinamurty and Dr. Rapur Ram

Renal Transplantation in Autosomal Dominant Polycystic Kidney Disease Patients������������������������135 Dr. KV Dakshinamurty and Dr. Guditi Swarnalatha

Other Books in This Series�����������������������������������������������������156

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 superspeciality 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 practicing clinician to have an authoritative source of quality advice and genuine practice wisdom. Keeping in mind the requirements of the society, the practitioners need to update themselves on the current approach and the wide variety of choices now available. India has a distinct need for comprehensive programs i

ECAB Clinical Update: Nephrology    n   Information

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 from which 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 work.

Polycystic Kidney Disease Renal cystic diseases include a large number of sporadic and genetically determined congenital, developmental, or acquired conditions. A cyst is a cavity lined by epithelium and filled with fluid. Cysts derive primarily from tubules (from Bowman’s capsule to the collecting duct). Cystic kidneys of different etiologies may appear morphologically similar, whereas the same etiologic entity may cause a wide spectrum of renal abnormalities. Simple renal cysts are acquired and are not associated with any disease. In contrast, polycystic kidney diseases can be complicated by renal failure or tumor development. Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially lethal single-gene disorder. Its prevalence at birth is between 1:400 and 1:1,000. It may progress to end stage renal disease by age 60 with 4.4% of patients requiring renal replacement therapy (dialysis or transplant) have ADPKD. The book is a comprehensive guide to diagnosis and management of the condition with special reference and experience around the same in India. The authors have put together the most relevant facts about the disease for an easy comprehension and understanding of the same by practitioners and students across the specialty.

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 The reader of the books shall find the content useful to •

Understand the etiology and pathogenesis of the condition

•

Determine approach to the patient and prognosis

•

The medical and surgical management options currently available

•

The status of renal transplantation in a patient with ADPKD

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 interest, excluding diversified mutual funds), or other financial benefit. iii

ECAB Clinical Update: Nephrology    n   Information

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. KV Dakshinamurty MBBS MD DM DNB Dr. Madhav Desai MBBS MD DM Dr. Gokulnath BSc MD DM DNB Dr. Sushma Rani R MD DM Dr. PVGK Sarma PhD Dr. V Sivakumar MD, DM, DNB, FISN Dr. Anuradha MD MNAMS Dr. Rapur Ram MD DM Dr. Guditi Swarnalatha MD DM Dr. Shveta Dhamija MBBS Ms. Bobby Choudhury

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

iv

Introduction

Dr. Kaligotla Venkata Dakshinamurty Senior Professor Department of Nephrology Nizam’s Institute of Medical Sciences Hyderabad

MBBS MD DM DNB

Renal cystic disease includes a large number of sporadic and genetically determined congenital, developmental, or acquired conditions. A cyst is a cavity lined by epithelium and filled with fluid. Cysts derive primarily from tubules (from Bowman’s capsule to the collecting duct). Cystic kidneys of different etiologies may appear morphologically similar, whereas the same etiologic entity may cause a wide spectrum of renal abnormalities. Simple renal cysts are acquired and are not associated with any disease. In contrast, polycystic kidney diseases can be complicated by renal failure or tumor development. Autosomal dominant polycystic kidney disease (ADPKD) is generally a late-onset multisystem disorder characterized by bilateral renal cysts. Cysts in other organs include the liver, seminal vesicles, pancreas, and arachnoid membrane; vascular abnormalities include intracranial aneurysms, dilatation of the aortic root, and dissection of the thoracic aorta; mitral valve prolapse; and abdominal wall hernias. Renal manifestations include hypertension, renal pain, and renal insufficiency. ADPKD is the most common potentially lethal single-gene disorder. Its prevalence at birth is between 1:400 and 1:1,000.1,2 ADPKD is the 1

2

1:400 to 1:1000

50% by age 60 years, 75% by age 70 years

Prevalence

End stage renal disease

ADPKD

Invariable, unless child dies from other cause

1:20,000 to 1:40,000

ARPKD

Occurs particularly in patients with the contiguous gene deletion syndrome

1:6,000 to 1:10,000

Tuberous sclerosis

Occurs in some patients with polycystic kidneys

1:36,000

Von HippelLindau disease

Invariable by definition

Up to 90% of patients on long-term (>10 years) dialysis

Acquired cystic kidney disease

Table 1. Differential Diagnosis of Common Cystic Disorders

Never

30–49 years: 1%, 50–69 years: 4%, Age ≥70 years: 9%

The prevalence of bilateral renal cysts (≥1 in each kidney) by ultrasound

Simple renal cysts

ECAB Clinical Update: Nephrology

Introduction      Dakshinamurty and Ram

most common of all inherited renal diseases, with 600,000–700,000 cases in the United States and about 12.5 million cases worldwide. About 5,000–6,000 new cases are diagnosed yearly in the United States, about 40% of them by age 45. In about 50% of cases, ADPKD progresses to end stage renal disease by age 60.3 4.4% of patients requiring renal replacement therapy (dialysis or transplant) have ADPKD.4 ADPKD is the cause of end stage renal disease in various series with a prevalence of 1.6% (Nizam’s Institute of Medical Sciences, Hyderabad), 2%,5 3.53%,6 2.07%,7 2.3% (OKIDS registry),8 and 6% (UK Renal Registry).9 The other common cystic disorders that are considered as differential diagnosis to ADPKD includes autosomal recessive polycystic kidney disease, tuberous sclerosis complex (TSC), von Hippel-Lindau (VHL) syndrome, and acquired renal cystic disease (Table 1). These cystic diseases are differentiated based on the presence of family history, mode of inheritance, extrarenal manifestations, age of clinical presentation and genetic analysis.

INDIAN SCENARIO Dr. Kaligotla Venkata Dakshinamurty Dr. Rapur Ram

Number of ADPKD patients attended to NIMS nephrology outpatient department in 1 year (2008) were 63 out of 2400 all nephrology patients (2.62%). Out of these, 48 (76.19%) were male (refer Tables 2–4).

Acknowledgment I am thankful to Mr. V. R. Kalyan for the secretarial assistance.

3

ECAB Clinical Update: Nephrology

Table 2. Age at Presentation Age (years)

Number of patients (%)

30–40

18 (28.57)

40–50

22 (34.92)

50–60

12 (19.04)

60–70

11 (17.46)

Table 3. Renal Function at Presentation Renal function

Number of patients (%)

Normal

21 (33.33)

Renal failure

42 (66.66)

REFERENCES 1. Dalgaard OZ. Bilateral polycystic disease of the kidneys: a follow-up of two hundred and eighty-four patients and their families. Acta Med Scand 1957;328:332. 2. Iglesias CG, Torres VE, Offord KP, et al. Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935–1980. Am J Kidney Dis 1983;2:630. 3. USRDS. Annual Data Report 2008;3:7. 4. Harris PC. Annu Rev Med 2009;60:321–37. 5. Mittal, Kher, Gulati S. Chronic renal failure in India. Renal Fail 1997;19: 763–70. 6. Sakhuja V, Jha V, Ghosh AK. Chronic renal failure in India. Nephrol Dial Transplant 1994;9:871–2. 7. Mani MK. Chronic renal failure in India. Nephrol Dial Transplant 1993;8:684–9. 8. Iseki K, Tozawa M, Iseki C, et al. Demographic Trends in the Okinawa Dialysis Study (OKIDS) Registry (1971–2000). 9. Ansell D, Feest T. 2nd Annual Report of the UK Renal Registry 1999.

4

2004–2007

1998–2007

1998–2004

Hemodialysis

CAPD

Renal transplantation

Period of study

7 out of 304 (2.30%)

8 out of 238 (3.36%)

4 out of 237 (1.68%)

Number of ADPKD patients in total patients

44.2%

51.9

45.6

Mean age at presentation (years)

100%

25%

75%

3 year patient technique survival rate

Bilateral nephrectomy—1 Recurrent cyst infection—1

No issue of dialysis inadequacy

Abdominal hernias—2

4 episodes of hemoperitoneum in 3 patients

Intracerebral hemorrhage—1

Complications attributable to ADPKD

Table 4. ADPKD Patients on Renal Replacement Therapy: NIMS Data

Introduction      Dakshinamurty and Ram

5

Genetics of Autosomal Dominant Polycystic Kidney Disease Dr. Kaligotla Venkata Dakshinamurty

MBBS MD DM DNB

Senior Professor Department of Nephrology Nizam’s Institute of Medical Sciences, Hyderabad

Dr. Madhav Desai

MBBS MD DM

Assistant Professor Department of Nephrology Nizam’s Institute of Medical Sciences, Hyderabad

ABSTRACT : ADPKD is an autosomal dominant disorder with intra- and interfamilial variability due to genetic heterogeneity, genetic, and environmental modifying factors. Knowledge about the gene mutation helps in predicting the age of onset of the disease, severity of symptoms, and disease progression. Absence of family history may occur due to de novo mutations. Cystogenesis may not always follow a simple ‘two-hit rule’; an alternative proposal is that haploinsufficiency itself may be sufficient to elicit a cystic or extrarenal noncystic phenotype. The reduced PKD1 expression of normal allele below a critical level may lead to cyst formation in the kidney. Though ADPKD commonly manifests in adults, it still can occur in fetus, where molecular diagnosis is important to diagnose. Further analysis of and additional large-scale mutation screens in ADPKD supported by detailed phenotypic analysis and family studies are now required to determine whether the total burden of all sequence variants and missense changes, either in cis or trans, is correlated with disease severity.

KEYWORDS: Autosomal dominant polycystic kidney disease, ADPKD, cystogenesis, two-hit rule, haploinsufficiency, PKD1, missense, cis, trans, PKD2, mutation.

6a

Genetics of Autosomal Dominant Polycystic Kidney Disease Dr. Kaligotla Venkata Dakshinamurty

MBBS MD DM DNB

Senior Professor Department of Nephrology Nizam’s Institute of Medical Sciences, Hyderabad

Dr. Madhav Desai

MBBS MD DM

Assistant Professor Department of Nephrology Nizam’s Institute of Medical Sciences, Hyderabad

INTRODUCTION Autosomal dominant polycys c kidney disease (ADPKD) is the most frequent life-threatening inherited disorder affec ng between 1 in 400, and 1 in 1000 individuals.1,2 It usually manifests in adulthood and is characterized by the development of mul ple renal cysts that increases in number and size over me, ul mately destroying normal renal ssue leading to end stage renal disease (ESRD) in the sixth decade. Ul mately, the pa ent will need renal replacement therapy, i.e. dialysis or renal transplanta on.3 Renal func on remains stable over many years un l the kidneys have approximately quadrupled in volume to 1500 cm3 (normal combined kidney volume is about 250–400 cm3), later renal func on can rapidly decline.4,5 Cys c dilata on involves all parts of nephron. ADPKD is inherited as an autosomal dominant trait with 100% penetrance but variable expression. Therefore, each child of an affected parent has a 50% chance of inheri ng the abnormal gene. 6

Genetics of ADPKD

„

Dakshinamurty and Desai

Spontaneous muta on (de novo) occurs in about 5% of pa ents, these pa ents have absent family history for renal cysts. ADPKD is a gene cally heterogeneous disease. Renal cysts occur in 100% of gene carriers. ADPKD is caused by muta ons in at least two different genes, PKD1 and PKD2 genes (Table 1).6–9 In 1520, Bartolomeo Eustachi, from Rome first described enlarged kidneys with bilateral cysts. In 1700, Alexis Li re, from Paris made early thoughts on the pathophysiology mechanisms of cystogenesis. Dalgaard published first large-scale epidemiological study of ADPKD in 1957. In 1996, Two-hit model for cystogenesis was proposed. Complete muta on screen of PKD1 and PKD2 was done by denaturing highperformance liquid chromatography (DHPLC) method in 2002. The muta ons are sca ered throughout the genes and are unique for most families in both ADPKD1 and ADPKD2, only a very few muta ons Autosomal dominant polycystic kidney disease is caused by mutations in at least two different genes, PKD1 and PKD2 genes.

have been found in more than one family (Fig. 1). Most muta ons in either gene are single base changes or inser ons or dele ons of a small number of base pairs, resul ng in truncated proteins and loss of func on.10 Homozygous or ‘compound’ heterozygous genotypes are lethal in utero.11 Individuals heterozygous for a PKD1 and a PKD2 muta on are viable to adulthood but have more severe renal disease.12 ADPKD has large inter- and intrafamilial variability. Significant intrafamilial variability in the severity of renal and extrarenal manifesta ons suggests the role of gene c and environmental modifying factors. Analysis of the variability in renal func on between monozygo c twins and siblings supports a role for gene c modifiers.13 Heritable modifying factors influences the age of onset of ESRD in 43–50% of the pa ents.14 Risk for hypertension and ESRD is more, if the non-affected parent has hypertension.15 Parents are as likely to show more severe disease as children.16 7

8

1985

1994

16p 13.3–p13.1

85–90%

Polycystin 1

46

53 kb of genomic DNA

14 kb of mRNA transcripts

Identified (year)

Isolated (year)

Localized on chromosome region

Frequency of manifestation

Encodes

No. of exons

Spans/stretches

Encodes

PKD1 Gene

5.4 kb of mRNA transcripts

68 kb of genomic DNA

15

Polycystin 2

10–15%

4q21–q23

1996

1988

PKD2 Gene

PKD1: Hughes et al.,69 Consortium TIPKD,70 and Consortium TAP71

PKD2: Kimberling et al.67; Peters et al.68

PKD2: Mochizuki et al.9

PKD1: EPKDC8

PKD2: Kimberling et al.7

PKD1: Reeders et al.6

References

Table 1. Summary of The PKD1 and PKD2 Gene Mutations and Its Clinical Presentation

ECAB Clinical Update: Nephrology

Complex and unusual

873

Less than 60%

Mutation deletions

Total mutations—both germline and somatic (till date)

Mutation detection rate

Mutation detection rate by “Deletion/Duplication” analysis

Mutation detection rate by “Linkage” analysis

~4%

Probably suitable in fewer than 50% of families

~88%

4303 amino acids

Translates into

Mutation detection rate by “Sequence” analysis

12,909 bp

Open reading frame (ORF)