Diabetic Kidney Disease - ECAB 9788131226605, 9788131232026, 8131232026

Table of contents :
Font Cover
Title page
Copyright
ECAB Clinical Update:Nephrology
Diabetic Kidney Disease
About the Authors
Contents
ECAB Clinical Update InformationDiabetic Kidney Disease
Epidemiology and Demography of Diabetic Kidney Disease
ABSTRACT:
KEYWORDS
Prevalence of Diabetes
Diabetic Nephropathy- A Global Overview
Indian Scenario of Diabetic Nephropathy
Conclusion
Pathophysiology and Pathology of Diabetic Nephropathy
Abstract
Keywords
Pathophysiology of Diabetic Nephropathy
Role of Genetic Factors in the Development of Diabetic Nephropathy
Role of Animal Models in Understanding the Pathophysiology of Diabetic Nephropathy
Role of Hyperfiltration
Role of Hyperglycemia
Role of Advanced Glycosylation End Products
Role of Reactive Oxygen Species
Role of Polyol Pathway
Role of Hexosamine Pathway
Role of Protein Kinase C
Role of Transforming Growth Factor-
Role of Renin- Angiotensin System in the Pathogenesis of Diabetic Nephropathy
Final Common Pathway in the Pathogenesis of Diabetic Nephropathy
Pathology of Diabetic NePhroPathy
Gross Pathology
Microscopic Features
Light Microscopic Changes
Immunofluorescence
Electron Microscopy
Staging System for Glomerular Pathology
Conclusion
Acknowledgments
Clinical Presentation and Diagnosis of Diabetic Nephropathy
ABSTRACT
KEYWORDS
Introduction
Clinical Stages of Diabetic Nephropathy
Stage 1
Stage 2
Stage 3
Stage 4
Stage 5
Screening and Diagnosis
Timing of Screening
Methods of Screening
Prospective Future Markers
Retinol-Binding Protein 4
Adiponectin
Connective Tissue Growth Factor
Urinary 1-Microglobulin
Urinary Transforming Growth Factor-1
Liver-type Fatty acid Binding Protein
Conclusion
Non-Diabetic Glomerular Diseases in Diabetic Patients
ABSTRACT
KEYWORDS
Introduction
When to Suspect Non-Diabetic Glomerular Diseases in Diabetic Patients
Types of Non-Diabetic Glomerular Diseases
Differentiation of non-diabetic Glomerulonephritis from diabetic Nephropathy
Mesangial-Proliferative Glomerulonephritis
Minimal Change Nephropathy
Differences between biopsy findings of glomerular lesions In non-diabetic glomerular diseases and diabetic nephropathy
Occurrence and Pattern of glomerular lesions in Non-Diabetic glomerular diseases in diabetes mellitus
Global Published Literature
Indian published literature
Unpublished Data from the Nizam's Institute of Medical Sciences
Conclusion
Nephrologic Problems Other Than Diabetic Nephropathy in Diabetes Mellitus
ABSTRACT
KEYWORDS
Introduction
Pathogenesis21
Urinary Tract Infections in Diabetes-Clinical Importance
Urinary Tract Infections in Diabetes
Asymptomatic bacteriuria
Papillary Necrosis
Emphysematous Pyelonephritis
Xanthogranulomatous Pyelonephritis
Renal Abscess
Renal Cortical Abscess
Renal Corticomedullary Abscess
Perirenal Abscesses
Fungal Infections
Indian Experience
Published Data From Nizam's Institute of Medical Sciences (Nims), Hyderabad
Conclusion
Acknowledgments
Prevention of Diabetic Nephropathy
Abstract
Keywords
Introduction
Global Perspective
United States Native Indian Health Service Diabetes Care
Aboriginal Populations in Australia
Aboriginal Populations in Canada
Update in the Indian Context
Kidney Help Trust of Chennai-A Model to Emulate
Nipping in the Bud
Strategies for Prevention of Diabetic Nephropathy
DREAM Studies
Disease Management Strategies
Chronic Care Model
Care Delivery Models
Intervention strategies
Monitoring and Measurement
Prevention of Diabetic Nephropathy
Preventing the Onset of Diabetes
Preventing the Appearance of Diabetic Nephropathy
Primary Prevention
Secondary Prevention
Multifactorial Intervention
New Potential Therapeutic Strategies
Conclusion
Case Study
Discussion and Rationale of Preventive Treatment
Diabetic Nephropathy-Treatment Modalities
Abstract
Keywords
Introduction
The Indian Scenario of Diabetic Nephropathy
Overview of Treatment
Glycemic Control in Treatment of Diabetic Nephropathy
Benefits of Glycemic Control
Role of Pancreas Transplantation in Diabetic Nephropathy
Choice of Medication and Dose Modification in Diabetic Chronic Kidney Disease Patients
Blood Pressure Control in Diabetic Nephropathy
Role of Blood Pressure Control in Treatment of Diabetic Nephropathy
Choice of Antihypertensive Agents
Blockade of the Renin-Angiotensin-Aldosterone System
Management of Dyslipidemia in Diabetic Nephropathy
Animal Model Studies
Clinical Studies on Lipid Lowering Therapy
Role of Dietary Protein Restriction
Cardiovascular Risk Reduction
Other Innovative Strategies
InteGrated manaGement of dIabetIc nephropathy
Conclusion
Case Discussion
Case 1: Case Presentation
Management and Discussion
case 2: case presentation
Management and Discussion
Management of End Stage Renal Disease in Diabetic Nephropathy
Abstract
Keywords
Introduction
Special Issues in Management of CKD in Diabetics
Options of Renal Replacement
Bidirectional Influence of Diabetic Comorbidities and Renal Replacement Therapy
Influence of Comorbidities on Choice of Renal Replacement Therapy
Influence of Dialysis on Various Diabetic Comorbidities
Specific Problems in Diabetics who Undergo Renal Replacement Therapy
Problems in Hemodialysis
Vascular Access-Related Issues
Hypotension27
Hypertension and Interdialytic Weight Gain28
Problems in Peritoneal Dialysis
Peritonitis
Metabolic Bone Disease33,34
Malnutrition35
Hyperglycemia
Transplantation-Related Issues
Cardiovascular Disease
Evaluation for Cystopathy
Evaluation for Other Complications
Glycemic Control and Recurrence of Diabetic Nephropathy
Comparison of Outcome in Different Renal Replacement Modalities
Hemodialysis Versus Peritoneal Dialysis
Transplantation and Survival
Kidney-Pancreas Transplantation45
Surgical Issues47
Advantages of Pancreatic Transplantation48
Conclusion
Indian Perspective of Diabetic Kidney Disease
KEYWORDS
Historical Perspective and Early Studies
Chronic Renal Failure and Diabetes
Morbidity and Mortality Due to Diabetic Nephropathy
Need of Biomarkers for Nephropathy
Urinary Albumin/Creatinine Ratio
Genome-Wide analysis in diabetes with nephropathy
DiabetOmics-Glycoproteome and Nephropathy
Conclusion
Acknowledgments
Other Books in This Series

Citation preview

ECAB Clinical Update: Nephrology

Diabetic Kidney Disease

“This page intentionally left blank"

ECAB Clinical Update: Nephrology

Diabetic Kidney Disease K.V. Dakshinamurty Aruna Kumari Prayaga Bobby Chacko Lloyd Vincent Uttara Das Madhav Desai Sundaram Madhivanan

M. Jayakumar Chakko Korulla Jacob Paturi Vishnupriya Rao P. Soundararajan Rapur Ram Gudithi Swarnalata S.P.S. Subrahmanian

Editor

K.V. Dakshinamurty

ECAB Clinical Update: Nephrology

A division of Reed Elsevier India Private Limited

Copyright © 2011 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-todate. 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. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer.

ISBN 978-81-312-2660-5 Published by: Elsevier, a division of Reed Elsevier India Private Limited Registered Office: 622, Indraprakash Building, 21 Barakhamba Road, New Delhi-110001 CorporateOffice:14thFloor,Tower10B,DLFCyberCity,Phase-II,Gurgaon122002,Haryana Typeset at Digital Domain IT Services Pvt. Ltd., Kolkata Printed at Solar Print Process Pvt Ltd., New Delhi

ECAB Clinical Update: Nephrology 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 FISN FGSI FIMSA

Director of Nephrology & Transplant Medicine Fortis Institute of Renal Sciences Fortis Escort Heart Research Institute, 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. Vivekanand 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.

Diabetic Kidney Disease CONTRIBUTORS Dr K.V. Dakshinamurty Dr. Aruna Kumari Prayaga Dr. Bobby Chacko Dr. Lloyd Vincent Dr. Uttara Das Dr. Madhav Desai Dr. Sundaram Madhivanan

Dr. M. Jayakumar Dr. Chakko Korulla Jacob Dr. Paturi Vishnupriya Rao Dr. P. Soundararajan Dr. Rapur Ram Dr. Gudithi Swarnalata Dr. S.P.S. Subrahmanian

EDITOR Dr. K.V. Dakshinamurty

ELSEVIER INDIA Clinical Education and Reference Division DIRECTOR

CONTENT MANAGER

Vidhu Goel

Dr. Arundhati Kar

CONTENT DESIGNER AND EDITOR Ms. 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]

About the Authors 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. Dr. Dakshinamurty has been graced by many 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. Dr. Aruna K. Prayaga is the Professor of Pathology at Nizam’s Institute of Medical Sciences, Hyderabad. She has graduated from Gujarat Cancer and Research Institute, Ahmedabad in 1985 and has been practicing renal pathology for the past 12 years. She developed interest in renal pathology at KEM Hospital, Mumbai. Subsequently she established renal pathology as a subspecialty at Nizam’s Institute of Medical Sciences and has trained several students in that area. She has special interest in prognostic factors and semi-quantitative methods in renal biopsies and has participated in and organized several workshops, symposia and CME on renal pathology. Her other interests include cytology and breast pathology. She has authored publications in several international journals and has contributed chapters on various subjects in pathology. She is the associate editor of Indian Journal of Pathology and Microbiology and on the editorial board of the Journal of Cytology. She is a life member of Indian Association of Pathologists and Microbiologists as well as Indian Rheumatology Association and has held responsible positions in those organizations. Dr. P. Soundararajan is currently serving as Professor and Head of the Department of Nephrology at Sri Ramachandra University, Porur, Chennai. He has had a brilliant academic career beginning as the best outgoing student of the University during MBBS with gold medal in Medicine and then first rank in MD General Medicine from Madurai

ECAB Clinical Update: Nephrology    About the Authors

Kamaraj University. He has been the founder of Department of Nephrology in Government Thanjavur Medical College and thereafter he served the Tamilnadu medical service as Head of Nephrology in various other medical colleges in Tamilnadu. He organized the first kidney transplantation in Government Kilpauk Medical College, Chennai and the first cadaveric kidney transplantation in Sri Ramachandra Medical College. He was a commonwealth fellow to Guys Hospital London and International society fellow in CAPD program in Toronto Western Hospital, Canada. His area of special interest is Tropical Nephrology. He is a fellow of the Academy of Medical Sciences and the Indian Scientist Association. He has served various professional bodies of Nephrology and is a member of Association of Physicians of India. Dr Soundararjan has several national and international publications and has been invited as speaker in various nephrology conferences across the country. Dr. Lloyd Vincent is currently the Senior Consultant and Director of Dialysis Services at the Narayana Hrudayalaya Hospital and satellite centers. He was formerly the Associate Professor and Head of Nephrology at St. John’s Medical College, Bengaluru, where he established one of the largest single center dialysis units of the country in 1999. He is an undergraduate alumnus of St John’s Medical College, Bangaluru, and a DM in Nephrology from The Christian Medical College, Vellore (1995). He was an ISN Fellow at The University Maryland at Baltimore, under Prof Matthew Weir in 1999. He completed his Clinical Nephrology fellowship from the University of Toronto, Canada, where he trained with internationally known physician-scientists such as Prof Dimitrios Oreopoulos, Prof Daniel Cattran, Prof Sheldon Tobe and Prof Joanne Bargman. He was awarded the prestigious ‘Marc Goldstein Clinician of the Year award in Nephrology’ in 2005, from the University of Toronto. He completed his Renal Transplant fellowship from the Multiorgan Transplant Unit, University Health Network, Toronto, Canada and is a Fellow of the American Society of Transplantation. His passion for use of technology in medicine led him to a Masters Degree in Medical Informatics, from the Erasmus University Rotterdam, in 2001. His keen interest in quality healthcare and the use of evidencebased healthcare management led to a Masters Degree in Healthcare Administration from the University of Toronto in 2009. He is currently a

About the Authors   ECAB Clinical Update: Nephrology

credited Canadian Healthcare Executive and also actively involved with the NABH. He has extensive experience with the use of The Chronic Care Model and Disease Management Strategies in the prevention of Diabetic Nephropathy among the Canadian Aboriginals. His major research publications have focused on the various levels of prevention of diabetic renal disease and also the use of information technology such as point-of-care devices in remote rural settings. Dr. Bobby Chacko is an Associate Professor of Nephrology at St. John’s Medical College and Hospital, Bengaluru. He completed his MBBS from St. John’s, Bengaluru where he was recognized as the best outgoing student having secured the highest marks. He completed his DM (Nephrology) from Christian Medical College, Vellore following which he served there as a faculty. He received the gold medal for DNB Nephrology conducted at PGI, Chandigarh. The 2004 Rekha Memorial Tanker Young Investigator award was conferred on him for his exemplary work on IgA nephropathy in India. He is a reviewer for reputed journals like Kidney International and NDT and has numerous international publications to his credit. Dr. Chacko served as renal consultant at the prestigious Nephrology and Transplantation Services (The Queen Elizabeth Hospital, Adelaide) for 3 years during which he obtained the FRACP degree. As a transplant consultant, he has gained expertise in dealing with ABO incompatible, highly sensitized and islet cell transplants. Dr. M. Jayakumar is presently the Professor and HOD of the Department of Nephrology in Madras Medical College. After completing DM degree in Nephrology at Madras Medical College, he served in the same institution as Assistant Professor and Associate Professor in Nephrology and later became Professor and Head of the Department. So far, about 20 DM postgraduate students have been trained by him during his stay in this prestigious institution. He has rich academic experience in Nephrology and is a constant source of inspiration to all his juniors, colleagues and students. Thanks to his efforts, Cadaver Transplantation Program has been revived not only in this Institution but also at the State level. His areas of interest are Acute Renal Failure, Renal Transplantation and Preventive Nephrology. Dr. Jayakumar has authored many papers presented in the National and International journals. He was the winner of the First Prize for poster

ECAB Clinical Update: Nephrology    About the Authors

presentation at the Asia Pacific Congress of Nephrology in 1992. He has received Dr. B.C. Mehta JAPI award for the 2nd Best Original article twice, in the years 2003 and 2008, respectively. He served as a Member of the Board of Studies and Research in the Dr. MGR Medical University for 6 years. He was also a Member of the Board of Studies for Post Graduate Education in Sri Ramachandra Medical College. He is actively involved in CKD screening and prevention program as a Founder Trustee of Sanjeevani Medical Trust. He is currently the President of Indian Society of Nephrology—Southern Chapter. Dr. Chakko Korula Jacob Professor of Nephrology at the Christian Medical College, Vellore is also a Consultant Nephrologist at the Bangalore Baptist Hospital. He completed his undergraduate training and postgraduation in general medicine from Christian Medical College, Vellore. Subsequently he obtained DM as well as MNAMS in Nephrology from the same Institute. He was then part of the faculty of his alma mater until superannuation in 2006. Dr. Jacob has had advanced training in Nephrology at the University of Alberta Hospital in Edmonton, Canada and also at the Queen Elizabeth Hospital, Woodville, South Australia. He has also served as a specialist locum consultant in Nephrology at the RIPAS Hospital, Brunei for 2 years. His main area of interest in Nephrology is Renal Transplantation and its complications. He has over 100 peer reviewed publications to his credit. He has also been involved in the training of several nephrologists who are working in all parts of the globe. In addition Dr. Jacob has held several administrative posts in the Christian Medical College, Vellore. He has been the Medical Superintendent as well as Associate Director in his alma mater. When he superannuated he had been the Head of the Department of Nephrology at Vellore for 10 years. He is a member of several professional bodies, including the Indian Society of Nephrology, The Indian Society of Organ Transplantation, and the Transplant Society. Dr. Madhivanan Sundaram is currently working as an Assistant Professor in Christian Medical College, Vellore. He has secured several distinctions as an undergraduate student and was the recipient of API Gold Medal in Internal Medicine during his postgraduation. He graduated in Nephrology from CMC, Vellore in 2007 and secured DNB

About the Authors   ECAB Clinical Update: Nephrology

the following year. In his fledgling career, he has five publications so far. He was awarded the JCM Shastry prize for the Best Outgoing Postgraduate during his DM. His areas of interest include chronic kidney disease, hemodialysis and peritoneal dialysis as well as bone and mineral metabolism. Dr. Paturi Vishnupriya Rao graduated from Vizag, received MD from Stanley and became the first Clinician to receive PhD from the Department of Endocrinology in AIIMS. He worked full time for 7 years under Professor Ahuja at AIIMS and was closely associated with him for another 10 years. He has also been guided by the doyens of Medicine such as Professors Sam G.P. Moses, B.B. Tripathy and H.B. Chandalia for over 25 years. He has also worked for short periods with eminent physicians and teachers of Medicine in Himachal Pradesh, Delhi, Uttar Pradesh, West Bengal, Gujarat, Madhya Pradesh, Maharashtra, Orissa, Kerala, Karnataka and Tamil Nadu, and abroad (London) for 1 year, Zagreb in Yugoslavia and Phoenix in USA for 6 months each, and in Malaysia and Guyana for 3 months each while researching the diabetes epidemiology under the aegis of ICMR, CSIR, NHS (UK), NIH (USA) and WHO. He has served the Research Society for the Study of Diabetes in India (RSSDI) since 1983, and has been instrumental in increasing the membership of RSSDI from 90 to 4600 as RSSDI Secretary between 1993 and 2007. He has been a non-practicing teaching faculty of NIMS University Hospital in Hyderabad since 1990 and has been pursuing teaching and research careers simultaneously. He has published in British Medical Journal, Lancet, Diabetic Medicine, Diabetology, Diabetes Care, etc. He has authored the first publication on global gene expression in Asian Indians with diabetes and protein biomarkers of diabetes in human urine and saliva. His initiatives for postgraduate CME in diabetology include CME credits, PG Courses, Postgraduate Certificate programs, Accreditation in Diabetology and Web CME, which have benefitted hundreds of primary care clinicians across the country. Dr. Uttara Das is presently working as an Assistant Professor in Nizam’s Institute of Medical Sciences, Hyderabad, which is a premier medical institute in Andhra Pradesh. She completed her MBBS and MD from Assam

ECAB Clinical Update: Nephrology    About the Authors

Medical College, Dibrugarh and DNB in Nephrology from Nizam’s Institute of Medical Sciences. Since 1999 she has been working in NIMS initially as a Senior Resident and subsequently as an Assistant Professor. She has been a regular participant and has presented many papers on glomerular disease and chronic allograft nephropathy in various national and international conferences. She has many original articles on glomerular disease and lupus nephritis to her credit in several indexed journals and has been a speaker in several national and State level seminars. Dr. Rapur Ram is currently working as Assistant Professor in Nizam’s Institute of Medical Sciences. He completed his super-specialization in Nephrology from the same institute in February 2005 underwent advanced training in continuous peritoneal dialysis at Yonsei University, Seoul thereafter. He has more than 25 publications, both in national and international journals. He is a regular reviewer to many national and international journals and has authored a chapter in the ECAB clinical update book Polycystic Kidney Disease.

Contents ECAB Clinical Update Information...............................................i Epidemiology and Demography of Diabetic Kidney Disease.........................................................................1 Dr. K.V. Dakshinamurty and Dr. Gudithi Swarnalata

Pathophysiology and Pathology of Diabetic Nephropathy..............................................................................8 Dr. K.V. Dakshinamurty, Dr. Rapur Ram and Dr. Aruna Kumari Prayaga

Clinical Presentation and Diagnosis of Diabetic Nephropathy..............................................................................41 Dr. P. Soundararajan

Non-Diabetic Glomerular Diseases in Diabetic Patients..........54 Dr. K.V. Dakshinamurty and Dr. Uttara Das

Nephrologic Problems Other Than Diabetic Nephropathy in Diabetes Mellitus...................................................................64 Dr. K.V. Dakshinamurty and Dr. Madhav Desai

Prevention of Diabetic Nephropathy....................................85 Dr. Bobby Chacko and Dr. Lloyd Vincent

Diabetic Nephropathy—Treatment Modalities......................119 Dr. M. Jayakumar, Dr. S.P.S. Subrahmanian

Management of End Stage Renal Disease in Diabetic Nephropathy........................................................................151 Dr. Chakko Korulla Jacob and Dr. Sundaram Madhivanan

Indian Perspective of Diabetic Kidney Disease....................171 Dr. Paturi Vishnupriya Rao

Other Books in This Series......................................................180

“This page intentionally left blank"

Information   ECAB Clinical Update: Nephrology

ECAB Clinical Update Information

Diabetic Kidney Disease 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    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 series 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 work.

Diabetic Kidney Disease The prevalence of Diabetes Mellitus is increasing rapidly all over the world and more so in the developing countries. The global burden of diabetes is expected to double between 2000 and 2030, with the greatest increases in prevalence occurring in the Middle East, sub-Saharan Africa and India. Moreover, the development of type 2 diabetes during the childbearing years is also likely to increase, primarily in the developing countries. It has already been established that Diabetes is the most common primary cause leading to end stage renal disease (ESRD) and Diabetic Nephropathy is the leading cause of chronic kidney disease (CKD) in India. The cornerstones of management of Diabetic Kidney Diseases include early diagnosis of diabetic nephropathy, prevention of its progression and treatment of the co-morbid conditions. Substantial under-diagnosis of both diabetes and chronic kidney disease leads to lost opportunities for prevention. An inadequate or inappropriate care of patients with diabetic kidney disease contributes to disease progression eventually up to a stage that requires renal replacement therapy, which is not a feasible option for many on a long-term basis, especially in a developing country like ours. This book covers various aspects of diabetic kidney disease in detail and attempts to familiarize the reader with the existing aspects of the conditions as well as touch upon the new advances in the field. The first chapter outlines the extent to which the condition affects the population globally as well as in our country. The second chapter explores the ii

Information   ECAB Clinical Update: Nephrology

underlying mechanism by which the disease starts and progresses and the pathological markers of the same. The third chapter delineates the clinical and diagnostic markers of the condition. The fourth and fifth chapters speak of the non-diabetic glomerular and non-glomerular diseases in diabetics. The sixth chapter addresses the most important and desirable goal of preventing the progression and ideally the onset of the disease. The seventh chapter puts together the various treatment modalities available and the subsequent chapter explores the management options for cases requiring renal replacement. In addition to the emphasis to Indian literature at the end of each chapter, the ninth chapter is specially included to highlight the salient aspects of this condition from the Indian perspective. This book will be beneficial not only for the nephrologists, but also for the epidemiologists, medical students, diabetologists and every doctor who deals with diabetes mellitus.

TARgET AUDIENCE This book is intended for the Indian Nephrologists, advanced practitioners, and other healthcare professionals interested in the treatment of kidney disorders, especially Diabetic Kidney Disease.

EDUCATIONAL OBjECTIVES Readers will find the contents of this book helpful to gain knowledge and update themselves about: • the extent of disease burden due to Diabetes and Diabetic kidney diseases • the mechanisms underlying the development and progression of diabetic kidney disease and pathological markers of this condition • the clinical and diagnostic features of the condition including novel markers being researched • the other associated kidney diseases that can co-exist of mimic diabetic nephropathy such as non-diabetic glomerular diseases and non-glomerular kidney diseases in diabetics • the prevention of onset and progression of diabetic kidney disease at primordial, primary, secondary, and tertiary levels

iii

ECAB Clinical Update: Nephrology    Information

• the treatment modalities available for manifestations of diabetic kidney diseases and associated conditions • the management of end stage renal disease as a result of diabetic nephropathy, including renal as well as pancreatic transplantation and special aspects of dialysis in the presence of diabetes • the salient aspects of diabetic kidney disease from the Indian perspective.

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. Financial benefits are usually associated iv

Information   ECAB Clinical Update: Nephrology

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. K.V. Dakshinamurty MD DM (Nephro) DNB (Nephro) Dr. M. Jayakumar MD DM (Nephro) Dr. Aruna Kumari Prayaga MD (Pathology) BCT Dr. Chakko Korulla Jacob MD DM (Nephro) MNAMS Dr. Bobby Chacko MD Dnb (Med) DM DNB (Nephro) FRACP Dr. Paturi Vishnupriya Rao MD Dip. Diab PhD FACE FRCP Dr. Lloyd Vincent MD DM (Nephro) MSc (Med Info) MHSc (Health Adm) CHE Dr. P. Soundararajan MD DM (Nephro) PhD Dr. Uttara Das MD DNB (Nephro) Dr. Rapur Ram MD DM (Nephro) Dr. Madhav Desai MD DM (Nephro) Dr. Gudithi Swarnalata MD DM (Nephro) Dr. Sundaram Madhivanan MD DM (Nephro) DNB (Nephro) Dr. S.P.S. Subrahmanian md Dr. Arundhati Kar DNB Ms. Bobby Choudhury

v

“This page intentionally left blank"

Epidemiology and Demography of Diabetic Kidney Disease Prof. Dr. Kaligotla Venkata Dakshinamurty

MD DM (Nephro)

DNB (Nephro)

Professor and Head

Dr. Gudithi Swarnalata

MD DM (Nephro)

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

ABSTRACT: The present era has the most diabetogenic environment seen so far in the human history. Over the past 25 years or so, the prevalence of type 2 diabetes mellitus (DM) in the United States has almost doubled. Same is the situation closer home with a 3–5 times increase in the number of diabetics over the same period in India, Indonesia, China, Korea, and Thailand. Unless this trend is obtunded, the future projection also looks quite alarming. In 2007, globally, there were 246,000,000 people with DM, but by 2025, the number is estimated to reach 380,000,000. It is expected that with urbanization of lifestyle, the increase in the prevalence of DM will be greater in the developing countries with >60% of the total number of diabetics hailing from

1a

Asia. According to the World Health Organization (WHO) estimates, by 2025, the number of diabetics in China and India will be about 130 million. From the Indian point of view, there has been an alarming rise in the prevalence of diabetes, which has gone beyond epidemic form to a pandemic one. It was estimated to be 40.9 million in the year 2007 and is expected to increase to 69.9 million by the year 2025. Diabetic nephropathy is one of the leading causes of chronic kidney diseases (CKDs) in India. According to India’s national CKD registry, southern India has the highest number of diabetics suffering from CKDs, followed by the eastern, northern, and western regions in that order. It is important to understand the epidemiological aspects of the condition and demographic pattern of the population along with the pathophysiology and comprehensive management steps that need to be taken to prevent the progression of diabetic kidney disease. KEYWORDS: Diabetic kidney disease, epidemiology, demography, diabetic nephropathy, chronic kidney disease, incidence, prevalence, chronic kidney disease (CKD).

1b

Epidemiology and Demography of Diabetic Kidney Disease Prof. Dr. Kaligotla Venkata Dakshinamurty

MD DM (Nephro)

DNB (Nephro)

Professor and Head

Dr. Gudithi Swarnalata

MD DM (Nephro)

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

PREVALENCE OF DIABETES The present era has the most diabetogenic environment seen so far in the human history.1 Over the past 25 years or so, the prevalence of type 2 diabetes mellitus (DM) in the United States has almost doubled. Same is the situation closer home with a 3–5 times increase in the number of diabetics over the same period in India, Indonesia, China, Korea, and Thailand.2 Unless this trend is obtunded, the future projection also looks quite alarming. In 2007, globally, there were 246,000,000 people with DM, but by 2025, the number is estimated to reach 380,000,000.3 It is expected that with urbanization of lifestyle, the increase in the prevalence of DM will be greater in the developing countries with more than 60% of the total number of diabetics hailing from Asia. According to the WHO estimates, by 2025, the number of diabetics in China and India will be about 130 millions. From the Indian point of view, there has been an alarming rise in the prevalence of diabetes, which has gone beyond epidemic form to a pandemic one. It was estimated to be 40.9 million in the year 2007 and is expected to increase to 69.9 million by the year 2025.3 India presently 1

ECAB Clinical Update: Nephrology

has the largest number of diabetics and is being called the `diabetic capital of the world’. It is estimated that very soon every fifth person with diabetes will be an Indian.

DIABETIC NEPHROPATHY—A GLOBAL OVERVIEW Diabetes mellitus is now the major cause of end-stage kidney failure throughout the world in both developed and developing nations. 4 It is the primary cause of kidney disease in 20–40% of people who require treatment for the end-stage renal disease (ESRD) worldwide.5 This can be attributed to the increased prevalence of diabetes, particularly type 2 DM, increased longevity of diabetic patients, and increased acceptance of diabetic nephropathy patients as candidates for treatment in ESRD programmes, which formerly excluded this group of patients. Overall about 20–30% of patients with type 1 or type 2 diabetes eventually develop nephropathy. The incidence of nephropathy with progression to ESRD is greater in those with type 1 diabetes as compared to those with type 2 diabetes. However, because of the much greater prevalence of type 2 diabetes, such patients constitute over half of the diabetic patients requiring dialysis.6 The propensity of development of nephropathy in diabetic patients also depends on other demographic factors. For instance, racial differences have been seen to influence the prevalence of diabetic nephropathy. In the United States, the risk of ESRD is reported to be higher among Hispanics and Afro-Americans than among Caucasian subjects,7,8 even after adjusting for confounding factors. Asian subjects have significantly (p < 0.01) higher prevalence (52.6%) of diabetic ESRD when compared with the Caucasians (36.2%).9 Two studies from the UK10,11 have also reported higher rates of ESRD among Asians. Type 2 diabetes in AsianIndians differs from that in Europeans in several aspects, namely earlier onset of the disease, less common association with obesity, and greater influence of genetic factors.12 Even in migrant Asian-Indians in the UK and Europe, an increased prevalence of diabetic nephropathy as compared to Caucasians has been observed.13–15 Migrant Asian-Indians have been 2

Epidemiology and Demography „ Dakshinamurty and Swarnalata

seen to be at a 40 times greater risk of developing ESRD when compared with Caucasians.16 However, one study17 found no difference in the incidence of proteinuria between Afro-Americans and Caucasians.

INDIAN SCENARIO OF DIABETIC NEPHROPATHY The prevalence of diabetic nephropathy in type 2 diabetic subjects is reported to be 5–9% in data analyzed from various Indian studies.18–21 This value is much less when compared with the prevalence of the same in Asian-Indians in the UK (22.3%) in a study conducted by Samanta et al.10 The first population-based study from India on the prevalence of, and risk factors for, diabetic nephropathy showed that in urban Asian-Indians, the prevalence of overt diabetic nephropathy was 2.2% and that of microalbuminuria 26.9%.22 The lower prevalence of microvascular complications noted in these studies can be explained by the following factors. First, due to wide publicity of the Diabetes Control and Complications Trial and the U.K. Prospective Diabetes Study results, control of diabetes is improving globally as well as in India. Secondly, the prevalence of hypertension is known to be lower in native south Asians, which confers a relative protection against diabetic kidney diseases23; and finally, there is a greater awareness about the nephroprotective action of angiotensin-converting enzyme inhibitors and angiotensin receptor blocking agents and increased usage of these drugs for preventing nephropathy. In a study based on diabetic population from south India, the incidence of renal failure among these subjects was estimated to be 0.69% per annum (CI 0.28–1%).24 Diabetic nephropathy is one of the leading causes of chronic renal failure in India. Among 4837 patients with chronic renal failure seen over a period of 10 years, the prevalence of diabetic nephropathy was 30.3% followed by chronic interstitial nephritis (23%) and chronic glomerulonephritis (17.7%).25 A separate study conducted by Modi et al26 also showed that 44% of ESRD cases in India were due to diabetic nephropathy. A total of 346 new ESRD patients were diagnosed during the study period (2002–2005) and the incidence was found to be 232 per one million people annually. This 3

ECAB Clinical Update: Nephrology

study found the prevalence of ESRD to be much higher than estimated and also confirmed that diabetic nephropathy is the leading cause of ESRD.26 In another study on ‘Incidence of Chronic Kidney Disease in India’,27 29% of chronic kidney disease patients had diabetic nephropathy. Diabetes was the most common cause (31.22%) of ESRD even in an unpublished survey of data done by us at the Nizam’s Institute of Medical Sciences. In the Indian type 2 diabetic subjects with diabetic nephropathy, a strong familial clustering has also been noted.28 The fact that nearly 75% of the type 2 diabetic patients have first-degree family history of diabetes indicates a strong familial aggregation in the Indian diabetic patients.29 A study30 conducted to determine familial aggregation of diabetic nephropathy in south Indian type 2 diabetic subjects found that proteinuria was present in 50% and microalbuminuria in 26.7% of the diabetic siblings of probands with diabetic nephropathy. In contrast, the prevalence of proteinuria and microalbuminuria among diabetic siblings of probands with normal levels of albumin in urine was 0 and 3.3%, respectively (p = 0.057 for microalbuminuria). Some evidence has suggested that polymorphism in the gene for the angiotensinconverting enzyme contributes in either predisposing to nephropathy or accelerating its course. In a study from south India,31 it was shown that a positive association exists between the D’allele (ID and DD genotype) of the angiotensin-converting enzyme polymorphism and proteinuria in type 2 diabetic patients from south India. However, definitive genetic markers have yet to be identified. The data accumulated from 45,885 subjects admitted to 166 kidney centres in India up to January 2010 by the India’s National Chronic Kidney Disease registry organized under the auspices of the Indian Society of Nephrology and housed in the Kidney Institute at Nadiad reflect that diabetes is the most common cause leading to a chronic kidney disease (CKD). In fact, CKDs secondary to diabetes top the list of various types of CKDs at 31.2%. According to the registry’s data, eastern and southern regions of the country have the highest prevalence of CKDs in diabetics, while the western regions, which include Mumbai, have the lowest incidence of CKDs in diabetics. Of the total figures, south India has the highest number of diabetics (33.9%), who suffer from CKDs, while the eastern region is in the second position with 33.7%, followed by the 4

Epidemiology and Demography „ Dakshinamurty and Swarnalata

north with 30.5%. The western region has the lowest number of diabetics (27.8%) having CKDs.32

CONCLUSION Currently, there is an alarming rise in the prevalence of diabetes, which has gone beyond an epidemic form to a pandemic one. India has the largest diabetic population and is being called the `diabetic capital of the world’. Diabetic nephropathy is one of the leading causes of CKDs in India. According to India’s national CKD registry, southern India has the highest number of diabetics suffering from CKDs, followed by the eastern, northern, and western regions in that order. It is important to understand the epidemiological aspects of the condition and demographic pattern of the population along with the pathophysiology and comprehensive management steps that need to be taken to prevent the progression of diabetic kidney diseases.

REFERENCES 1. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001;414:782–7. 2. Yoon KH, Lee JH, Kim JW, et al. Epidemic obesity and type 2 diabetes in Asia. Lancet 2006;368:1681–8. 3. Sicree R, Shaw J, Zimmet P. Diabetes and impaired glucose tolerance. In: Gan D, ed. Diabetes Atlas 3rd ed. Brussels: International Diabetes Federation; 2006: 15–109. 4. Reutens AT, Prentice L, Atkins R. The epidemiology of diabetic kidney disease. In: Ekoe J, ed. The Epidemiology of Diabetes Mellitus 2nd ed. Chichester: John Wiley & Sons Ltd; 2008:499–518. 5. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. International comparisons, in 2007 Annual Data Report: atlas of chronic kidney disease and end-stage renal disease in the United States. Bethesda: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2007:239–54. 6. Ayodele OE, Alebiosu CO, Salako BL. Diabetic nephropathy: a review of the natural history, burden, risk factors and treatment. J Natl Med Assoc 2004;96: 1445–54. 7. Cowie CC, Port FK, Wolfe RA, et al. Disparities in incidence of diabetic end-stage renal disease according to race and type of diabetes. N Engl J Med 1989;321:1074–9. 8. Pugh JA, Stern MP, Haffner SM, et al. Excess incidence of treatment of end-stage renal disease in Mexican Americans. Am J Epidemiol 1988;127:135–44.

5

ECAB Clinical Update: Nephrology 9. Young BA, Maynard C, Boyko EJ. Racial differences in diabetic nephropathy, cardiovascular disease, and mortality in a national population of veterans. Diabetes Care 2003;26:2392–9. 10. Samanta A, Burden AC, Jagger CA. Comparison of the clinical features and vascular complications of diabetes between migrant Asians and Caucasians in Leicester. UK Diabetes Res Clin Pract 1991;14:205–13. 11. Burden AC, McNally PG, Feehally J, Walls J. Increased incidence of end-stage renal failure secondary to diabetes mellitus in Asian ethnic groups in the United Kingdom. Diabet Med 1992;9:641–5. 12. Mohan V, Alberti KGMM. Diabetes in the tropics. In: Alberti KGMM, Zimmet P, Defronzo RA, Keen H, eds. International Text Book of Diabetes Mellitus 2nd ed. Chichester, UK: John Wiley and Sons; 1997:171–87. 13. Samanta A, Burden AC, Feehally J, Walls J. Diabetic renal disease: differences between Asian and white patients. Br Med J (Clin Res Ed) 1986;293:366–7. 14. Mather HM, Chaturvedi N, Fuller JH. Mortality and morbidity from diabetes in South Asians and Europeans: 11-year follow- up of the Southall Diabetes Survey, London, UK. Diabet Med 1998;15:53–9. 15. Chandie Shaw PK, Baboe F, et al. South-Asian type 2 diabetic patients have higher incidence and faster progression of renal disease compared with Dutch-European diabetic patients. Diabetes Care 2006;29:1383–5. 16. Chandie Shaw PK, Vandenbrouke JP, Tjandra YI, et al. Increased end-stage diabetic nephropathy in Indo-Asian immigrants living in the Netherlands. Diabetologia 2002;45:337–41. 17. Chaturvedi N, Jarrett J, Morrish N, et al. Differences in mortality and morbidity in African Caribbean and European people with non-insulin dependent diabetes mellitus: results of 20 year follow up of a London cohort of a multinational study. BMJ 1996;313:848–52. 18. John L, Sundar Rao PSS, Kanagasabapathy AS. Prevalence of diabetic nephropathy in non-insulin dependent diabetics. Indian J Med Res 1991;94:24–9. 19. Chugh KS, Kumar R, Sakhuja V, et al. Nephropathy in type 2 diabetes mellitus in Third World Countries. Chandigarh Study. Int J Artif Organs 1989;12:299. 20. Acharya VN, Chawla KP. Diabetic Nephropathy. Rev J Post-graduate Med 1978;243:138–46. 21. Ramachandran A, Snehalatha C, Satyavani K, et al. Prevalence of vascular complications and their risk factor in type 2 diabetes. J Assoc Phys India 1999;47:1152–6. 22. Unnikrishnan RI, Rema M, Pradeepa R, et al. Prevalence and risk factors of diabetic nephropathy in an urban South Indian population: the Chennai Urban Rural Epidemiology Study (CURES 45). Diabetes Care 2007;30:2019–24. E-pub 2007 May 8. 23. Bhopal R, Unwin N, White M, et al. Heterogeneity of coronary heart disease risk factors in Indian, Pakistani, Bangladeshi, and European origin populations: cross-sectional study. Br Med J 1999;319:215–20. 24. Viswanathan V. Type 2 diabetes and diabetic nephropathy in India—magnitude of the problem. Nephrol Dial Trans 1999;14:2805–7. 25. Mani MK. Patterns of kidney disease in indigenous populations in India. Nephrology 1998;4:S4–S7.

6

Epidemiology and Demography „ Dakshinamurty and Swarnalata 26. Modi GK, Jha V. The incidence of end-stage renal disease in India: a population-based study. Kidney Int 2006;7:2131–3. 27. Dash SC, Agarwal SK. Incidence of chronic kidney disease in India. Nephrol Dial Transplant 2006;21:232–3. 28. Viswanathan V, Snehalatha C, Shina K, et al. Familial aggregation of diabectic kidney disease in type 2 diabetes in South India. Diab Res Clin Prac 1999; 43:167–71. 29. Viswanathan M, McCarthy MI, Snehalatha C, et al. Familial aggregation of type 2 (non-insulin-dependent) diabetes mellitus in South India; Absence of excess maternal transmission. Diabetic Medicine 1996;13:232–7. 30. Vijay V, Snehalatha C, Shina K, et al. Familial aggregation of diabetic kidney disease in type 2 diabetes in South India. Diab Res Clin Prac 1999;43:167–71. 31. Viswanathan V, Zhu Y, Bala K, et al. Association between ACE gene Polymorphism and diabetic nephropathy in South Indian patients. J Pancreas 2001;2:83–7. 32. First annual report of Indian CKD registry accessed at http://www.ckdri .org/1st;annualreport/ppf on March 15, 2007.

7

Pathophysiology and Pathology of Diabetic Nephropathy Prof. Dr. Kaligotla Venkata Dakshinamurty

MD DM

(Nephro) DNB (Nephro)

Professor and Head, Department of Nephrology

Dr. Rapur Ram

MD DM (Nephro)

Assistant Professor, Department of Nephrology

Prof. Dr. Aruna Kumari Prayaga

MD (Pathology) BCT

Professor, Department of Pathology Nizam’s Institute of Medical Sciences, Hyderabad

ABSTRACT: Persistent hyperglycemia has long been accepted as the implicated factor that leads to diabetic nephropathy (DN). The relationship between hyperglycemia and renal disease in diabetes was proposed in the 1970s. By the mid-1980s, it was evident that numerous intermediate steps were involved in translating the increased ambient glucose levels to renal tissue injury. Presently, the aim of pathophysiological analysis is to have a better understanding of the exact mechanisms that cause the microvasculopathy and macrovasculopathy of diabetes. An indepth understanding of the pathophysiology of the disease can

8a

help in the formulation of the appropriate management strategies to combat it. The pathological pictures of the condition are equally important to help confirm the diagnosis and distinguish it from other similar conditions. KEYWORDS: Diabetic nephropathy, pathophysiology, insulindependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM), end-stage renal disease (ESRD), hyperfiltration, hyperglycemia, atrial natriuretic peptide (ANP), renin-angiotensin aldosterone system (RAAS), GLUT-1, advanced glycation end products (AGEs), reactive oxygen species (ROS), hexosamine, polyol pathway, protein kinase C (PKC), KW nodule, fibrin cap, capsular drop.

8b

Pathophysiology and Pathology of Diabetic Nephropathy Prof. Dr. Kaligotla Venkata Dakshinamurty

MD DM

(Nephro) DNB (Nephro)

Professor and Head, Department of Nephrology

Dr. Rapur Ram

MD DM (Nephro)

Assistant Professor, Department of Nephrology

Prof. Dr. Aruna Kumari Prayaga

MD (Pathology) BCT

Professor, Department of Pathology Nizam’s Institute of Medical Sciences, Hyderabad

PATHOPHYSIOLOGY OF DIABETIC NEPHROPATHY Diabetic nephropathy (DN) is a major contributor to chronic kidney diseases globally as well as in India. However, not all individuals with diabetes develop DN to a similar extent and within a similar duration of time. As was summarized by Ritz and Orth,1 the risk factors associated with the development of DN in the diabetic population include advanced age; nonCaucasian race; male gender; and poor glycemic, lipid and blood pressure control in the diabetic individuals. Though the risk factors and possible associations have been extensively studied, the exact pathophysiology of DN is yet to be understood completely. In the pathogenesis of DN, there appears to be an interaction of genetic, metabolic, and hemodynamic factors, and it appears to be similar in both type 1 and type 2 diabetes.

Role of Genetic Factors in the Development of Diabetic Nephropathy The presence of DN and associated conditions such as hypertension and cardiovascular diseases in the family members of patients with diagnosed 8

Pathophysiology and Pathology

„ Dakshinamurty, Ram and Prayaga

DN may be indicative of a genetic basis. Some studies have also established genetic patterns regarding the same.2 The clustering of DN in some families with insulin-dependent diabetes mellitus (IDDM) and non–insulin-dependent diabetes mellitus (NIDDM) has led to the belief that a genetic susceptibility predisposes to the development of DN and ultimately end-stage renal disease (ESRD). An increase of 25–72% in the cumulative risk of DN has been observed if the index case in a diabetic family had persistent proteinuria. In a defined population of patients with type 2 diabetes, the Pima Indians, it was found that proteinuria developed in 46% of diabetic offsprings with a family history of diabetes in both parents as opposed to only 14% diabetic offsprings of non-proteinuric parents. This finding points to the role of genetic factors in the pathogenesis of DN.3 Similar findings have also been reported in other defined populations of type 2 diabetics.4–6 Linkage to at least one major gene on chromosome 3q, in vicinity of the AT1 locus, has been observed, and polymorphisms in the angiotensinogen- and angiotensin-1-converting enzyme (ACE) genes appear to make similar contributions, though reports are conflicting.7 The insertion–deletion polymorphism is responsible for the individualized differences in plasma levels of ACE between people. In patients with type 2 diabetes, the DD polymorphism of the ACE gene has been associated with an increased risk of developing DN, severe proteinuria, progressive renal failure, and mortality during dialysis.8,9 In addition, an analysis of more than 1,000 Caucasian patients with type 1 diabetes showed a strong correlation between genetic variation in the ACE gene and the development of nephropathy.10 But a critical review of 19 studies that examined a possible link between this gene and DN failed to confirm an association among Caucasians with either type 1 or type 2 diabetes, although a possible association in Asians could not be excluded.11 A genetic defect in the regulation of glycosaminoglycan production by endothelial and mesangial cells has also been correlated with susceptibility of diabetics to progress to DN.12 In the search for susceptibility genes for microvascular complications of diabetes in Pima Indians, three more loci on chromosomes 7, 9, and 20 were identified in addition to chromosome 3.13 Some other additional loci have also been identified as DN-susceptibility gene areas on chromosomes 7q21.3, 10p15.3, 14q23.1, and 18q22.3.14,15 9

ECAB Clinical Update: Nephrology

Role of Animal Models in Understanding the Pathophysiology of Diabetic Nephropathy One of the commonly used methods to understand the pathophysiology of a disease condition without exposing the affected population to undue risk is experiments on animal models. The animal model most frequently used for the study of DN is rat. However, rats do not develop advanced renal failure or the severe histological lesions, like nodular glomerular sclerosis and hyaline arteriosclerosis that are seen in the human diabetic individuals. There are also considerable species differences in the glomerular hemodynamic responses to glycemia, which renders extrapolation of animal data to human difficult.16,17 In addition, highly inbred strains of rat are used as models of chemically induced or genetic diabetes, and this is not representative of the genetic heterogeneity of human diabetics. To overcome these difficulties, certain specially bred animal models are used to study DN. The classic animal models for type 1 and type 2 diabetic nephropathies are streptozotocin-induced diabetic rat and Zucker diabetic fat rat respectively. An interesting spontaneous model of IDDM is the Bio-Breeding (BB) rat. These animals develop typical diabetic complications including nephropathy, but again, the glomerular manifestations are primarily shown by increased thickness of the glomerular basement membrane (GBM).18

Role of Hyperfiltration Stadler and Schmidt had recognized that the glomerular filtration rate (GFR) increases early in the course of diabetes mellitus way back in 1959.19 A very common pathologic feature of early DN is the presence of glomerular hypertrophy, with mesangial expansion and GBM thickening. Likewise, the early hemodynamic alterations include low afferent and efferent arteriolar resistance, a markedly increased plasma flow, and a moderately increased glomerular capillary pressure leading to an increased GFR. This early stage of hyperfiltration precedes the eventual deterioration of renal function. Some of the important factors that influence hyperfiltration are summarized in Table 1.

10

Pathophysiology and Pathology

„ Dakshinamurty, Ram and Prayaga

Table 1. Effect of Various Factors on Early Hyperfiltration Factors that influence hyperfiltration

Factors with no influence on hyperfiltration

1. Hyperglycemia: Hyperfiltration occurs following vasodilatation due to osmotic effect of hyperglycemia and/or sorbitol-induced activation of the polyol pathway 2. Elevated atrial natriuretic peptide (ANP) Fluid and sodium retention due to sodium-coupled reabsorption by the brush-border co-transporters in the proximal tubule20 3. Reduced renin-angiotensinaldosterone system (RAAS) activity20,21 4. Nitric oxide and endothelin: Altered production under diabetic conditions causing an imbalance that may be at least partially responsible for the development of hyperfiltration22,23

1. Prostaglandins

2. Thromboxane

3. Kalikrein

4. Norepinephrine21

Hyperfiltration is commonly associated with enlargement of kidneys (nephromegaly). Nephromegaly can be found in the early stages and is a poor prognostic factor for the development of DN.24 Studies have shown that a strict glycemic control can ameliorate hyperfiltration but not the nephromegaly.25,26 This is because the increase in reabsorption of sodium in the proximal tubules that causes GFR to increase by the physiologic action of the tubule-glomerular-feedback (TGF)27 spurs filtration and results in initial kidney growth. Growth factors such as growth hormone (GH), insulin growth factor (IGF), transforming growth factor β (TGF-β), and platelet-derived growth factor (PDGF) have also been found to be involved in this process.28,29 An overview of the pathophysiological process resulting in hyperfiltraton is depicted in Figure 1.

11

ECAB Clinical Update: Nephrology

Glucose Insulin

Myoinositol

Volume expansion

RAAS

ANP

Proteinuria

Proximal Na reabsorpon

TGF-β

Afferent arteriolar resistance Efferent arteriolar resistance Plasma flow

NO

Acvaon of TG feedback

Glomerular filtraon

Hyperfiltraon

Figure 1. Pathophysiology of hyperfiltration.30

Role of Hyperglycemia Renal cells do not require insulin for glucose uptake. They rely on a family of transmembrane proteins to facilitate glucose transport across the cell membrane. The prominent among these is GLUT-1, which is implicated in the pathogenesis of nephropathy in the presence of hyperglycemia. GLUT-1 is normally found in the glomerulus and the tubules, but diabetes changes its distribution and cellular expression. While most tissues downregulate GLUT-1 expression in the face of hyperglycemia to protect cells from excessive glucose transport and metabolism, some renal cells such as mesangial cells upregulate GLUT-1 gene transcription and protein translation when cultured in high-glucose media. This positive feedback is an apparent maladaptive response in mesangial cells because the cells can readily take up more glucose from a diabetic environment. The other factors in a diabetic milieu, which can upregulate GLUT expression include TGF-β, angiotensin-II, and shear stress. All these factors stimulate net glucose uptake and intracellular metabolism and therefore promote glucotoxicity.31 Figure 2 depicts the pathophysiological mechanism 12

Pathophysiology and Pathology „ Dakshinamurty, Ram and Prayaga

↑ Glucose

TGF β

Glucose

Sorbitol

Fructose

GLUT 1 DAG

↑ NAD/NADH

PKC

↑ Fibronecn α 1, 3, 5 IV collagen

Figure 2. Effects of GLUT-1 signaling in mesangial cells.

involving GLUT-1, which leads to increased glucose uptake in the presence of hyperglycemia. Increased GLUT-1 expression leads to enhanced polyol pathway and production of protein kinase C (PKC). This, in turn, enhances the synthesis of fibronectin and other ECM proteins. Increased extracellular glucose and TGF-β further augment GLUT-1 expression and enhance this signaling cascade.31

Role of Advanced Glycosylation End Products Advanced glycation end products (AGEs) are the by-products of non-enzymatic glycation and oxidation of proteins and lipids found in diabetes. The non-enzymatic reactions between glucose and the lysine amino terminus of circulating and structural proteins give rise to two major classes of glycation products.32 Relatively short-lived proteins form a Schiff base which undergoes an Amadori rearrangement, with the formation of a stable, but still chemically reversible, sugar–protein adduct. Structural proteins that turn over at a much slower rate, such as collagen, accumulate different products derived from slow reactions of dehydration, degradation, and rearrangement of the Amadori adducts to form chemically irreversible AGEs.32,33 This occurs by Maillard reaction (Figure 3). 13

ECAB Clinical Update: Nephrology

  $

  %

$ 



 
 

 

% $

 
  

& $ !#!'& $

%  !    

#! $ ! " #

!#

$$!

CML

$ !$ !'

#

'


!

#

 !

  % 

&( $( !(#!(& %

!#

Figure 3. Maillard reaction pathway for the formation of N-(epsilon)(carboxymethyl) lysine (CML), pentosidine, and pyrraline. Fructoselysine is the Amadori compound, the first intermediate in the Maillard reaction occurring between glucose and protein. Pentosidine, pyrraline, and CML are the other advanced glycosylation products.34

One of the well-known Amadori products, hemoglobin A1C (Hb1C), is widely accepted as an indicator of glycemic control. AGEs have been suggested to represent a general marker of oxidative stress and longterm damage to proteins in aging, atherosclerosis, and diabetes.35,36 Another prominent AGE, renal CML-AGE, has been found to be increased in diabetes.37,38 Immunolocalization of CML in skin, lung, heart, kidney, intestine, intervertebral discs, and particularly in arteries provide evidence for age-dependent increases in CML accumulation in distinct locations, and acceleration of this process in diabetes.39 Immunostaining and immune blots of diabetic human kidneys show increased CML in diabetic glomeruli, especially in the mesangial matrix and capillary walls. AGEs interact with specific receptors like CD36, macrophage scavenger receptor (MSR) type II, OST-48, 80K-H40–42, and a signaltransducing receptor designated as receptor for advanced glycation 14

Pathophysiology and Pathology „ Dakshinamurty, Ram and Prayaga

$'+!
 %

  !&$+"!

)+( %&$%%

$"&!
",+"! /
&$
&"%

   
  
  !. +"!   $!
$#&"$% $#&"$% (!$
 #""*+ %

&$'&'$ !% /
$"%%!!
"


#$"&!% /
+-!!
" %+
%&$'&'$%

!. +"! &"
&% &$'&'$ !"$ +%

    

!
$!

Figure 4. AGEs and their receptor-independent or dependent effects leading to renal clearance or inflammation, metabolic defects, and structural abnormalities. TCA, tricarboxylic acid cycle; MSR A,B, macrophage scavenger receptor types A, B.40

end-products (RAGE).38 RAGE is upregulated in kidneys of diabetic animals, and nephropathy is ameliorated by blocking RAGE activation.38 Binding of AGEs to RAGE activates cell-signaling mechanisms coupled to increased TGF-β and vascular endothelial growth factor (VEGF) expression that are thought to contribute to the pathogenesis of diabetic complications.37,38 The mechanism by which circulating AGEs cause the detrimental changes in DN are shown in Figure 4 and summarized in Tables 2 and 3. Other pathological consequences of AGEs include 1. Reduced ability of basement membrane proteins to bind to anionic proteins. 2. Enhanced hypertrophy and hyperplasia of vessel wall cells. 3. Increased vascular permeability, resulting in albumin leakage. 4. Enhanced DNA breakage, resulting in mutations. 5. Enhanced release of matrix promoting cytokines and growth factors. 6. Increased free radical generation. 7. Promotion of insulin resistance and hypertension. 15

ECAB Clinical Update: Nephrology

Table 2. AGEs and Mechanism of Injury Property of AGE

Mechanism of injury

Resistance to proteolytic digestion

Accumulation of AGEs

High reactivity

Disruption of basement membrane of self-assembly Increased cross-link formation in collagens leading to reduced degradation Increased immunogenicity of collagen Trapping of substances such as lipoproteins leading to accelerated atherosclerosis AGE-modified LDL Sare not cleared by LDL receptors

Lipid oxidation

Tissue injury

Inactivation of nitric oxide

Defective vascular relaxation

Table 3. Effects of Interaction of AGE with Its Receptors at a Cellular Level41 Cell type

Function

Monocyte/macrophage

Growth factor production Chemotaxis Degradation Cytokine release

T-lymphocyte

Ligand binding Interferon-c production

Endothelial cell

Increased tissue factor Reduced thrombomodulin Degradation Increased permeability

Mesangial cell

Degradation Increased matrix substance synthesis Platelet-derived growth factor induction

Fibroblast

Increased growth factor Increased proliferation

Smooth muscle cell

Increased proliferation

16

Pathophysiology and Pathology

„ Dakshinamurty, Ram and Prayaga

Role of Reactive Oxygen Species A high flux of glucose through the glucose transporters on endothelial cells soon overwhelms the mitochondrial electron transport system. Excess mitochondrial substrate flux results in the generation of reactive oxygen (ROS) species that cause DNA strand breakage and activation of poly ADP-ribose polymerase (PARP). PARP ribosylates and inactivates glyceraldehyde 3-phosphate dehydrogenase (GAPDH), thereby disrupting normal glucose metabolism. Inactivation of GAPDH effectively shunts glucose into the polyol pathway and leads to the activation of PKC and accumulation of AGEs and glucosamines.42 This mechanism is picturized in Figure 5. Increased production of ROS has the following effects: 1. It damages DNA. 2. It activates aldose reductase and hence polyol pathway. 3. There is activation of hexosamine pathway. Glucose

Cytoplasm Glucose

Polyol

Glucose-6-phosphate Glucosamine Mitochondria

Energy substrates O2-

DNA

Fructose-6-phosphate Glyceraldehyde-3-phosphate GAPDH 1, 3 Diphosphoglycerate

DAG
PKC Methylglyoxal
AGE PARP acvaon

DNA strands

Figure 5. Role of reactive oxygen species in the pathogenesis of Diabetic Nephropathy. 17

ECAB Clinical Update: Nephrology

4. It activates the PKC particularly the β isoenzyme. 5. It induces the formation of AGE. 6. It activates the pleiotropic transcription factor nuclear factor-κB (NF-κB).43,44 7. It leads to the breakage of single-strand DNA48–50 providing an obligatory stimulus for the activation of the nuclear enzyme PARP (Figure 5). PPA transfers ADP-ribose from NAD to nuclear proteins through an energy-consuming process.45

Role of Polyol Pathway The increased intracellular glucose provides substrate for increased flux through the polyol pathway, metabolizing glucose to sorbitol via aldose reductase and then to fructose via sorbitol dehydrogenase.30 The conversion of glucose to sorbitol competes with reduced glutathione disulfide (GSSH) for the availability of reduced nicotinamide adenine dinucleotide phosphate (NADPH), blunting the formation of reduced glutathione sulfide (GSH) from GSSH and thereby reducing the antioxidant capacity of the cell. The consequent increased NADH:NAD ratio (increase in redox state), resulting from the conversion of sorbitol to fructose can lead to de novo synthesis of PKC-activating diacyl glycerols (DAGs).46,47 An increased level of fructose contributes to increased AGE and ROS formation. The potential link between the polyol pathway and the development of diabetic complications was first described over 25 years ago.48 In the kidney, aldose reductase is present in the papilla, glomerular epithelial cells, distal tubular cells, and mesangial cells.53–55 In the renal medullary cells of the kidney, this enzyme seems to be involved in the generation of sorbitol, an organic osmolyte, from glucose in response to the high salinity in the medullary interstitium. Sorbitol is helpful in preventing osmotic stress.49 Under normal physiologic conditions, only a small amount of glucose is handled through this pathway. However, significant increases from 3 to 30% can be seen in the diabetic state, particularly, in tissues where glucose uptake is independent of insulin, such as in lens, retina, and kidney. The role of polyol pathway in the development of ROS and the reduction of antioxidants is shown in Figure 6. 18

Pathophysiology and Pathology „ Dakshinamurty, Ram and Prayaga

Aldose reductase

Glucose

NADPH

GSSG

Sorbitol dehydrogenase

Sorbitol

NAD+

NADP+

GSH

Anoxidant

Fructose

NADH

NADH Oxidase

AGEs

ROS

Figure 6. Effects of polyol pathway on the development of Diabetic Nephropathy.

Role of Hexosamine Pathway The hexosamine biosynthetic pathway has been hypothesized to be involved in the development of insulin resistance and diabetic vascular complications. Hyperglycemia induces the production of TGF-β, a prosclerotic cytokine that has been demonstrated to be causally involved in the development of DN. Several lines of evidence indicate that TGF-β induction is mediated by the hexosamine pathway. In cultured mesangial cells, high glucose levels have been seen to induce TGF-β production. This effect is eliminated by the inhibition of glutamine-fructose-6-phosphate aminotransferase (GFAT), the ratelimiting enzyme of this pathway. Furthermore, a stable over-expression of GFAT has been shown to increase the levels of TGF-β protein and mRNA. Both the stimulation and inhibition of GFAT have been noted to be transduced by PKC. Figure 7 depicts the fate of glucose (Gluc) as it enters the cell through the glucose transporter and is metabolized by the 19

ECAB Clinical Update: Nephrology

ADP

ATP Gluc

Gluc

Hexokinase GlucN

Glycolysis

Gluc-6-P

Fruct-6-P GlucN

Glu

GlucN

Pyruvate

GFAT

Gluc-N-6-P ADP ATP

GlucNAc-6-P

UDP

GlucNAc-1-P

Pi UDP-GlucNAc

Proteoglycans

Glycolipids

Glycoproteins

Figure 7. The hexosamine biosynthetic pathway.50

hexosamine pathway. The hexosamine biosynthetic pathway emerges from glycolysis using fructose-6-phosphate (Fruc-6-P) to form glucosamine-6-phosphate (GlucN-6-P). Glutamine (GluN) serves as the donor of the amino group. This action is catalyzed by the rate-limiting enzyme GFAT. GlucN-6-P is acetylated, isomerized to N-acetylglucosamine-6-phosphate (GlucNAc-1-P), and activated to UDP-N-acetylglucosamine (UDP-GlucNAc) that serves as common precursor for all amino sugars used for the synthesis of glycoproteins, lipids, and proteoglycans. Glucosamine (GlucN) can also enter the cell through the glucose transporter and is rapidly phosphorylated by hexokinase yielding GlucN-6-P, thereby bypassing the rate-limiting first step of the hexosamine biosynthetic pathway. An increased flux through the hexosamine pathway results in the activation of protein kinase C (PKC). Activated and translocated PKC in turn activates transcription factors(s) to form a complex that induces transcription of TGF-β. Finally, TGF-β protein is secreted and acts autocrine/paracrine as prosclerotic cytokine (Figure 8). 20

Pathophysiology and Pathology „ Dakshinamurty, Ram and Prayaga

Glycolysis Nucl

Gluc

Gluc

Gluc-6-P

eus

Fruc-6-P TGF β1 gene GlucN-6–P

PKC

TGF β1 mRNA TGF β1 protein

TGF β1

Figure 8. The hexosamine pathway as the possible pathobiochemical link between hyperglycemia and mesangial TGF-β1 production.50

Role of Protein Kinase C The protein kinase C (PKC) family is a group of structurally related serine and threonine kinases that are typically activated by certain lipids, particularly DAG, together with phosphatidylserine.51 Activation of the conventional PKC (cPKC) subfamily including PKCα, PKCβ1, PKC β2, and PKCγ also requires the presence of increased cell calcium, typically initiated by the accompanying generation of inositol trisphosphate (IP3) as a result of phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositol trisphosphate (PIP3) to IP3 and DAG (Figure 9).52,53 PKC activation has been implicated in the pathogenesis of microvascular diabetic complications in both the eye and kidney.54 PKC activation results in a wide range of cellular consequences and the specific effects proposed to contribute to diabetic complications are manifold. PKC has been proposed to increase ROS formation, impair insulin receptor signaling,56 and enhance vascular damage.51 The activation of PKC induces the mitogen-activated protein kinases (MAPKs) 21

ECAB Clinical Update: Nephrology

PKC

Hormone

Seven spanning receptor

DAG G protein PLA2

PIP2

Cellular response IP3

Protein inacve Protein acve

ER Ca 2+

Cellular response

Figure 9. Activation of protein kinase C.55

in response to extracellular stimuli through dual phosphorylation at conserved threonine and tyrosine residues. The co-activation of PKC and MAPK in the presence of high glucose concentrations indicates that these two families of enzymes are linked.57 The regulation of vascular functions such as vasodilation, permeability, endothelial activation, and growth factor signaling occurs through intracellular signaling molecules such as MAPK, PKC, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The MAPK cascade plays a central role in a range of biological processes relevant to DN, including cell growth, differentiation, and apoptosis. Three main groups of MAPK, extracellular signal-regulated kinases (ERK), c-JunNterminal kinases (JNK), and p38 kinases vary in their involvement in diabetic induced nephropathy. Classically, p38 MAPK is linked to osmotic stress, JNK responds to forms of cellular stress, whereas ERKs primarily are regarded as growth-signaling kinases. In concert, all MAPKs produce the full range of cellular adaptation found as the basis of diabetic complications. Vascular damage due to increased vascular permeability, alterations in blood flow, nitric oxide (NO) dysregulation, and leukocyte 22

„ Dakshinamurty, Ram and Prayaga

Pathophysiology and Pathology

Growth factor ligand

Receptor ligand complex

Other substrates PL3 kinase PI3 -
Src

P

Bridging protein complex (GRB2, SOS)

Cytoplasm

ras ras GDP GDP

P

ras GTP

GAP GAP

Raf

MEK Transcripon factors Transcripon factors

P

ERK

Nucleus

Gene acvaon

Figure 10. Pathophysiology of tyrosine kinase receptor signaling.

adhesion is the result of increased signaling molecules, hyperosmolar stress, and dysregulation of oxidants and antioxidants. Associated induction of growth factors (TGF-β, VEGF) and cytokines (TNF-α, IL-1, IGF-1) have also been shown to stimulate the proliferation of mesangial cells, contributing to nephromegaly and fibrosis. Tyrosine kinase receptor, intended to bind a specific subgroup of protein kinases (tyrosine kinase), influences the pathophysiology to a large extent (Figure 10). Binding of a growth factor to this receptor induces it to dimerize and autophosphorylate tyrosine residues. This results in the binding of adapter or bridging proteins such as GRB2 and SOS with the receptor and coupling of inactive ras. Cycling of ras between its inactive and active forms is regulated by GTPase-activating protein (GAP). Activated ras interacts with and activates Raf. This kinase then phosphorylates a component of the MAPK signaling pathway MEK, which then phosphorylates ERK (MAPK). Activated MAPK phosphorylates other cytoplasmic proteins and nuclear transcription factors generating cellular responses. The phosphorylated tyrosine kinase receptor 23

ECAB Clinical Update: Nephrology

Hyperglycemia

Polyol

AGE/RAGE

Hyperosmolality

Oxidave stress

GSH depleon

PPP

Acvaon of transcripon factors PKC, MAPKs, DAG, NF-kB,TGFβ

VEGF

TNFa

IL-1

IGF

NF-kB

Mesangial proliferaon, intersal fibrosis, glomerulosclerosis

Figure 11. Effects of hyperglycemia.30

can also bind other components, such as PI3 kinase which activates distant signaling system.58 Figure 11 gives a broad overview of how hyperglycemia induces nephrotoxicity via the protein kinases and their by-products.

Role of Transforming Growth Factor-β Transforming Growth Factor-β (TGF-β) plays an important role in the pathogenesis of DN. TGF-β types I, II, and III belong to a superfamily also consisting of activins, bone morphogenetic proteins (BMPs), and inhibins. TGF-β is secreted as a homodimer of mature TGF-β, a TGF-β latency-associated peptide, and a latent TGF-β-binding protein. Cleavage of the latency-associated peptide from its binding protein is necessary for TGF-β activation. One of the important mediators that bring about this cleavage is thrombospondin. TGF-β initially binds to the type II receptor and the TGF-β-type II receptor complex then binds to and initiates phosphorylation of the type I receptor, initiating intracellular signaling. Ligand binding leads to recruitment and serine phosphorylation of the type I TGF-β receptor and activation of intracellular signaling cascades. In 24

Pathophysiology and Pathology

„ Dakshinamurty, Ram and Prayaga

normal kidney glomerulus and proximal tubule, TGF-p mRNA and protein are weakly expressed, with an isoform distribution of types 1 > 3 > 2.59 Induction of TGF-β by glucose and glycated proteins seems to be a PKCdependent phenomenon. TGF-β, in general, stimulates the proliferation of fibroblasts and smooth muscle cells, though its effects on mesenchymal cells depend on concentration. It acts as a growth inhibitor for most of the epithelial cell types and leucocytes. TGF-β is considered to be the pivotal cytokine in mediating collagen formation of the kidney. Its uniquely powerful fibrogenic potential results from its ability to upregulate matrix synthesis, inhibit matrix degradation, and modulate matrix receptor expression to facilitate cell–matrix interactions. Knockout mice lacking the TGF-β1 gene have a widespread inflammation and abundant lymphocyte proliferation, presumably because of upregulated T-cell proliferation and macrophage activation. Some evidences supporting the role of TGF-β in the pathogenesis of DN are enumerated in Table 4.

Table 4. Evidences Supporting the Role TGF-β in the Pathogenesis of DN 1. Hyperglycemia increases the expression of TGF-β1 and of matrix proteins specifically stimulated by this cytokine in the glomeruli. 60 2. TGF-β levels are increased in the glomeruli of rats with streptozotocin-induced diabetes, and the use of an antibody to neutralize TGF-β prevents the renal changes of diabetic nephropathy in these animals.The connective tissue growth factor and heat-shock proteins, which are encoded by TGF-β-inducible genes, have fibrogenic effects on the kidneys of patients with diabetes. The protective mechanism against this is a decreased expression of renal BMP 7, which counters the profibrogenic actions of TGF-β1.61 3. TGF-β1 contributes to the cellular hypertrophy and increased synthesis of collagen, both of which occur in diabetic nephropathy.60,61 4. A combination therapy of TGF-β1 antibody and ACE inhibitor normalized proteinuria and improved the glomerulosclerosis and tubulointerstitial injury in rats with diabetic nephropathy as opposed to the partial resolution of proteinuria only achieved by the use of ACE inhibitor alone.62 5. The administration of hepatocyte growth factor, which specifically blocks the profibrotic actions of TGF-β1, ameliorates DN in mice.63

25

ECAB Clinical Update: Nephrology

Role of Renin–Angiotensin System in the Pathogenesis of Diabetic Nephropathy Actions of the renin–angiotensin system (RAS) to promote the pathogenesis of DN were identified more than 2 decades ago. Angiotensinogen (Figure 12) is cleaved by renin to form angiotensin-I, which is then cleaved further by ACE to form angiotensin-II. The effects of angiotensin-II are mediated by specific cell-surface receptors, AT1 and AT2, which exist in the kidney, adrenal glands, heart, and vascular smooth muscles. ACE also degrades bradykininin to inactive peptide fragments. ACE2 is a recently identified homolog of ACE that cleaves both angiotensin-I and angiotensin-II to form angiotensin 1–9 and angiotensin1–7, respectively.73 The hemodynamic and nonhemodynamic actions of angiotensin-II are listed in Table 5. The role of renin–angiotensin system in the pathogenesis of diabetic nephropathy has been explored thoroughly. Nonetheless, a number of questions still remain unanswered. Some such controversial aspects are discussed here. To begin with, the patient groups or animal models in which the beneficial effects of RAS inhibition has been demonstrated do not reveal Angiotensinogen

Renin Angiotensin I

Bradykinin

ACE2 Angiotensin 1–9

ACE Angiotensin II

ACE2

Inacve Pepdes

Angiotensin 1–7

AT1 Receptor

Figure 12. The renin–angiotensin system. 26

AT2 Receptor

Pathophysiology and Pathology

„ Dakshinamurty, Ram and Prayaga

Table 5. Actions of Angiotensin-II in Diabetic Nephropathy Hemodynamic effects ● Systemic hypertension ● Systemic and renal vasoconstriction ● Stimulation of other vasoconstrictors like endothelin ● Inhibition of vasodilators like nitric oxide and atrial natriuretic peptide ● Increased glomerular capillary pressure and permeability ● Mesangial cell contraction resulting in the reduction of filtration surface area

Non-hemodynamic effects ● Induction of renal hypertrophy and cell proliferation ● Stimulation of extracellular matrix synthesis ● Inhibition of extracellular matrix degradation ● Increased tubular uptake of proteins ● Stimulation of cytokines like TGF-β1, vascular endothelial growth factor, endothelin ● Stimulation of superoxide production ● Activation of nuclear factor-κB ● Reduction of podocyte nephrin expression

any clear-cut evidence of systemic activation of RAS. For example, in patients with diabetes, plasma renin activity is typically normal or suppressed.74–77 This has led to the speculation that in diabetes, and perhaps other renal diseases, there may be local activation of RAS. However, there is a lack of direct evidence to support local activation of the RAS in kidney diseases. The constituents of the diabetic milieu responsible for activating the local RAS are yet to be defined conclusively. Second, the precise mechanism by which reduction in glomerular pressure by RAS antagonism and its renoprotective role has not been demonstrated in human studies, though it has been proven in diabetic rats. The reduction of proteinuria associated with ACE inhibitors and angiotensin receptor blocker (ARBs) may be a possible renoprotective mechanism but direct evidence for this hypothesis is lacking. Furthermore, the precise mechanism by which RAS antagonism reduces proteinuria is very clear. The suggested mechanisms inferred by the use of experimental inhibitors are given in the Table 6. 27

ECAB Clinical Update: Nephrology

Table 6. Experimental Inhibitors of RAS with Their Possible Mechanisms of Action Inhibitor Ruboxistaurin mesylate

Mechanism of action Selective inhibition of PKC-β

Aminoguanidine

Inhibition of AGE formation

Phenacylthiazolium bromide

Cleavage of AGE-derived protein cross-links and reversal of AGE-mediated damage

Sorbinil, Tolrestat, Pornalrestat

Inhibition of aldose reductase

GC1008

Anti-TGF-β antibody

Decorin

Antagonism of prosclerotic actions of TGF-β

Denosumab

Inhibition of NF-κB

Disulfiram, olmesartan dithiocarbamates

Inhibition of nuclear factor-κB (NF-κB)-signaling cascade

N-acetyl cysteine, vitamin E, diphenyliodonium

Inhibition of MAPK pathway

Azaserine

Inhibition of hexosamine pathway

Alzforum

RAGE inhibitor

Final Common Pathway in the Pathogenesis of Diabetic Nephropathy The interaction of hemodynamic factors and metabolic changes compound the deleterious effects of the diabetic milieu on a backdrop of genetic susceptibility.64 The hemodynamic factors include increased systemic and intraglomerular pressures, activation of the RAS with subsequent hemodymanic changes, and increased levels of endothelin and other vasoactive hormones. The metabolic changes involve factors like ROS, AGE, polyols, angiotensin, reduction of nephrin, cell-growth stimulants, and increase in cellular matrix, cytokines and intracellular mediators (Figure 13). Nephrin, a protein found in podocytes, is crucial for maintaining the integrity of the intact filtration barrier. Patients with DN have markedly reduced the expression of renal nephrin and fewer electron-dense slit diaphragms as compared to patients without diabetes and with minimal nephropathic changes.65 28

Pathophysiology and Pathology „ Dakshinamurty, Ram and Prayaga

Haemodynamic factors

Metabolic factors

Vasoacve hormones () Ang II, ET)

Glucose

TGF

Hypertension

-β

Systemic AGEs

Polyol

Intraglomerular

ROS

Intracelluar signalling molecules (PKC, MAPK, NF-kB) Growth factors & cytokines (TGF-β. IL-1, PGDF)

Glomerular & tubulointersal pathology

Figure 13. Final common pathway.30

This constellation of factors may seem huge, but the ultimate threshold for renal injury is breached via a final common pathway involving increased intracellular messengers (PKC, MAPK) and nuclear transcription factors (NF-κB). NF-κB is the central switch for the inflammatory processes into the nucleus. The important secondary mediators for the development of renal damage are TGF-β and locally generated angiotensin-II, VEGF, and several other cytokines. All these changes subsequently result in the development of proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis. It should be noted that the interaction of hemodynamic and nonhemodynamic pathways seems to involve TGF-β, making it a prime candidate for the development of antagonists to treat DN.

PATHOLOGY OF DIABETIC NEPHROPATHY The diagnosis of DN should be based on supportive clinical and information.66 However, the typical pathological picture can aid in differentiating the DN cases from those with similar presentation. Historically, Kimmelsteil and Wilson studied autopsy cases and found mesangial nodules, now known as Kimmelsteil–Wilson’s (KW’s) nodules, which are the hallmark findings in diabetes mellitus.67 The initial 29

ECAB Clinical Update: Nephrology

pathology findings were reported from cases of IDDM. The lesions in NIDDM are similar to those found in IDDM, but the clinical progression is variable. Morgensen et al described the clinical stages in the evolution of glomerulosclerosis with special emphasis on the stage of incipient DN.68

Gross Pathology In the gross appearance, the kidneys are enlarged in the initial stages. Later on, once the glomerular sclerosis sets in, the kidney size reduces. At the end stage, the size of a DN kidney is usually more that of ESRD kidneys due to other causes. The cut surface shows preservation of corticomedullary distinction with prominence of vessels. The pelvicalyceal system may be dilated. Intrarenal abscesses and renal papillary necrosis may be seen as complications of severe infections. The renal artery and its branches may show signs of atherosclerosis. Emphysematous pyelonepritis is a form of fulminant infection seen only in DM. This lesion is characterized by pockets of air, parenchymal necrosis, and intrarenal abscesses.

Microscopic Features The research committee of renal pathology society of American society of nephrologists recommends the evaluation of renal tissue using appropriate standards for renal biopsy, and a clinical diagnosis of diabetes mellitus is mandatory to apply the classification. An adequate biopsy has been defined as one containing at least 10 glomeruli, excluding incomplete glomeruli along the biopsy edge. The committee recommended hematoxylin and eosin, periodic acid–Schiff (PAS), Masson trichrome, and periodic acid methanamine silver stains for light microscopy. Immunofluorescence examination requires using antibodies against IgA, IgG, IgM, C3, C1q, and kappa and lambda light chains to rule out other renal diseases. Electron microscopy (EM) has been made mandatory.66 Light Microscopic Changes The light microscopic changes in DN are discussed below based on the compartments involved: 30

Pathophysiology and Pathology

„ Dakshinamurty, Ram and Prayaga

Glomerular Changes: Increased thickness of the GBM is considered one of the earliest changes in the kidney. Østerby measured the thickness of GBM in IDDM and compared with controls. 69 A recent pathologic classification of DN has made EM mandatory to detect and measure the thickness of GBM. Mesangial expansion is another early change in DN. The histological specimens from DN kidney are seen to have increased glomerular volume and mesangial matrix as well as increased capillary length and surface area. Morphometric analysis of glomerular size and volume has been used by several workers for the confirmation of the disease. The glomerular hypertrophy is postulated to be a physiologic change in response to hyperfiltration. Morgensen et al observed the reversal of hypertrophy with appropriate insulin therapy in IDDM.68 Diffuse Lesions: Widespread increase in GBM thickening with increase in the mesangial matrix results in diffuse glomerular sclerosis. The material is PAS positive, indicating the presence of AGEs. The shrinkage in the size of the glomerulus is less compared to the other causes of sclerosis. Ischemic change seen as collagen deposition in the Bowman’s space is a typical feature of DN. The lesions resemble fibrous crescents and are PAS negative. Nodular Lesions: Nodular lesions are by far the most striking finding, and the typical lesion is the KW nodule (Figure 14). The lesions measure >40 μ and ≤100 μ, are PAS positive, often multiple, and are acellular. They stain black with silver stain and green with Masson trichrome. A variant of this lesion can occur as a larger, single lesion that has a laminated appearance with silver stain. These lesions are associated with micro aneurysms of the glomerular capillaries and mesangiolysis. “Fibrin Cap” Lesions: These are hyalinosis or exudative lesion and are brightly eosinophilic, intensely PAS positive, and seen intra luminally within the glomerular capillaries. Though these lesions are frequently seen with DM, they are not specific as they can be seen in focal segmental glomerulosclerosis (FSGS) and several other glomerular diseases. 31

ECAB Clinical Update: Nephrology

Figure 14. Renal biopsy shows diffuse mesangial expansion with Kimmelsteil–Wilson (KW) nodules. Tubular basement membrane is thickened. H&E ×200.

“Capsular Drop” Lesions: A capsular drop lesion (Figure 15) is the least frequently encountered one but is the most specific for DN. It has the same staining properties as hyalinosis lesion and is located in the Bowman’s membrane between the basement membrane and the parietal epithelial cells. Tubules: Proximal tubular epithelium may show fine vacuolations in patients with nephrotic syndrome. Atrophic tubules show marked thickening and splitting of tubular basement membrane. Armanni Ebstein lesions are due to glycogen deposition but are not generally seen in the recent times.70 Interstitium: Interstitial fibrosis is frequent in DN and is usually associated with interstitial infiltration by lymphocytes. Fibrosis and inflammatory cells correlate with serum creatinine and renal survival. The fibrosis may be due to ischemia or infections. Acute 32

Pathophysiology and Pathology

„ Dakshinamurty, Ram and Prayaga

Figure 15. Renal biopsy shows “capsular drop” lesion in the Bowman’s capsule, GBM thickening. SMPAS ×600.

inflammation with neutrophils in interstitium and tubular lumina are common autopsy findings. Necrotic areas with a zone of neutrophils are the microscopic findings for abscesses and renal papillary necrosis. Vessels: Hyaline arteriolosclerosis (Figure 16) of afferent and efferent arterioles is a useful finding for the diagnosis of DN. Arteries show intimal thickening and reduplication of internal elastic lamina. The main renal artery and its branches may show evidence of atherosclerosis. Immunofluorescence Linear staining of glomerular and tubular basement membrane is seen with IgG in DN. This finding should not be misinterpreted as evidence for anti-GBM antibody disease. Hyalinosis lesions in glomeruli and arterioles with hyalinosis show positivity with IgM and C3. 33

ECAB Clinical Update: Nephrology

Figure 16. Iscemic lesion seen between the Bowman’s capsule and the glomerular capillary tuft, vessel at the hilum shows arteriolosclerosis. H&E ×200.

Electron Microscopy GBM thickening is a consistent feature and is seen in most of the loops. As the disease advances, the thickening becomes variable with areas of thinning resulting in microaneurysm formation. The current international classification recommends a thickness more than 395 nm in females and more than 430 nm in males older than 9 years of age. In the early stages, effacement of podocyte foot processes is seen. Later stages result in the detachment of podocytes from GBM, synechiae formation, and atubular glomeruli.71 34

Pathophysiology and Pathology

„ Dakshinamurty, Ram and Prayaga

Staging System for Glomerular Pathology A new staging system for glomerular pathology has been proposed by the research committee of renal pathology society of American society of nephrologists.66 The staging aspires to create a better communication amongst the pathologists and between pathologists and the clinicians. Class I: EM-proven GBM thickening with mild or non-specific LM changes and does not qualify for any other class. Class IIa: Mild mesangial expansion in >25% of the observed mesangium. Class IIb: Severe mesangial expansion in >25% of the observed mesangium. Class III: Nodular sclerosis (KW lesion). Class IV: Advanced diabetic glomerulosclerosis: global glomerular sclerosis in >50% of glomeruli.

CONCLUSION Persistent hyperglycemia has long been accepted as the implicated factor that leads to DN. The relationship between hyperglycemia and renal disease in diabetes was proposed in the 1970s. By the mid-1980s, it was evident that numerous intermediate steps were involved in translating the increased ambient glucose levels to renal tissue injury. Presently, the aim of pathophysiological analysis is to have a better understanding of the exact mechanisms that cause the microvasculopathy and macrovasculopathy of diabetes. An in-depth understanding of the pathophysiology of the disease can help in the formulation of the appropriate management strategies to combat it. The pathological pictures of the condition are equally important to help confirm the diagnosis and distinguish it from other similar conditions.

ACKNOWLEDGMENTS The authors thank Dr. Megha S Uppin, Assistant Professor, Nizam’s Institute of Medical Sciences, Hyderabad, for helping with the manuscript and photomicrographs. 35

ECAB Clinical Update: Nephrology

REFERENCES 1. Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med 1999;341:1127–33. 2. Bowden DW, Sale M, Howard TD, et al. Linkage of genetic markers on human chromosomes 20 and 12 to NIDDM in Caucasian sib pairs with a history of diabetic nephropathy. Diabetes 1997;46:882–6. 3. Pettitt DJ, Saad MF, Bennett PH, et al. Familial predisposition to renal disease in two generations of Pima Indians with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1990;33:438–43. 4. Fava S, Azzopardi J, Hattersley AT, Watkins PJ. Increased prevalence of proteinuria in diabetic sibs of proteinuric type 2 diabetic subjects. Am J Kidney Dis 2000;35:708–12. 5. Faronato PP, Maioli M, Tonolo G, et al. Clustering of albumin excretion rate abnormalities in Caucasian patients with NIDDM. The Italian NIDDM Nephropathy Study Group. Diabetologia 1997;40:816–23. 6. Canani LH, Gerchman F, Gross JL. Familial clustering of diabetic nephropathy in Brazilian type 2 diabetic patients. Diabetes 1999;48:909–13. 7. Krolewski AS. Genetics of diabetic nephropathy: evidence for major and minor gene effects. Kidney Int 1999;55:1582–96. 8. Movva S, Ravindra V, Alluri RV, et al. Relationship of angiotensin-converting enzyme gene polymorphism with nephropathy associated with type 2 diabetes mellitus in Asian Indians. J Diabetes Complications 2007;21:237–41. 9. Jeffers BW, Estacio RO, Raynolds MV, Schrier RW. Angiotensin-converting enzyme gene polymorphism in non-insulin dependent diabetes mellitus and its relationship with diabetic nephropathy. Kidney Int 1997;52:473–7. 10. Kunz R, Bork JP, Fritsche L, et al. Association between the angiotensinconverting enzyme-insertion/deletion polymorphism and diabetic nephropathy: a methodologic appraisal and systematic review. J Am Soc Nephrol 1998;9: 1653–63. 11. Boright AP, Paterson AD, Mirea L, et al. Genetic variation at the ACE gene is associated with persistent microalbuminuria and severe nephropathy in type 1 diabetes: the DCCT/EDIC Genetics Study. Diabetes 2005;54:1238–44. 12. Deckert T, HorowitzI M, Kofoed-Enevoldsen A, et al. Possible genetic defects in regulation of glycosaminoglycans in patients with diabetic nephropathy. Diabetes 1991;40:764–70. 13. Imperatore G, Hanson RL, Pettitt DJ, et al. Sib-pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes. Pima Diabetes Genes Group. Diabetes 1998;47:821–30. 14. Vardarli I, Baier L J, Hanson RL, et al. Gene for susceptibility to diabetic nephropathy in type 2 diabetes maps to 18q223-23. Kidney Int 2002;62:2176–83. 15. Iyengar SK, Abboud HE, Goddard KAB, et al. Genome-wide scans for diabetic nephropathy and albuminuria in multiethnic populations: the family investigation of nephropathy and diabetes (FIND). Diabetes 2007;56:1577–85. 16. Brown DM, Andres GA, Hostetter TH, et al. Proceedings of a task force on animals appropriate for studying diabetes mellitus and its complications. Kidney complications. Diabetes 1982;31(Suppl 1):71–81. 17. O’Donnell MP, Kasiske BL, Keane WF. Glomerular haemodynamics and structural alterations in experimental diabetes mellitus. FASEB J 1988;2:2339–47.

36

Pathophysiology and Pathology

„ Dakshinamurty, Ram and Prayaga

18. Like AA, Butler L, Williams RM, et al. Spontaneous autoimmune diabetes mellitus in BB rat. Diabetes 1982;31:7. 19. Stadler G, Schimdt R. Severe functional disorders of glomerular capillaries and renal haemodynamics in treated diabetes mellitus during childhood. Ann Pediatr (Paris) 1959;193:129. 20. Bank N, Aynedjian HS. Progressive increases in luminal glucose stimulate proximal sodium absorption in normal and diabetic rats. J Clin Invest 1990; 86:309–16. 21. Bank N. Mechanisms of diabetic hyperfiltration. Kidney Int 1991;40:792–807. 22. Wakabayashi I, Hatake K, Kimura N, et al. Modulation of vascular tonus by the endothelium in experimental diabetes. Life Sci 1987;40:643–8. 23. Veelken R, Hilgers KF, Hartner A, et al. Nitric oxide synthase isoforms and glomerular hyperfiltration in early diabetic nephropathy. J Am Soc Nephrol 2000;11:71–9. 24. Baumgart lHJ, Sigl G, Banholzer P, et al. On the prognosis of IDDM patients with large kidneys. Nephrol Dial Transplant 1998;13:630–4. 25. Wiseman MJ, Saunders AJ, Keen H, Viberti G. Effect of blood glucose control on increased glomerular filtration rate and kidney size in insulin-dependent diabetes. N Engl J Med 1985;312:617–21. 26. Tuttle KR, Bruton JL, Perusek MC, et al. Effect of strict glycemic control on renal hemodynamic response to aminoacids and renal enlargement insulindependent. Diabetes mellitus. N Engl J Med 1991;324:1626–32. 27. Thomson SC, Deng A, Bao D, et al. Ornithine decarboxylase, kidney size, and the tubular hypothesis of glomerular hyperfiltration in experimental diabetes. J Clin Invest 2001;107:217–24. 28. Flyvbjerg A. Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease. Diabetologia 2000;43:1205–23. 29. Cooper ME. Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. Diabetologia 2001;44:1957–72. 30. Dijk C, Berl T. Pathogenesis of diabetic nephropathy. Rev Endocr Metab Dis 2004;5:237–48. 31. Brosius FC, Heilig CW. Glucose transporters in diabetic nephropathy. Pediatr Nephrol 2005;20:447–51. 32. Brownlee M, Vlassara H, Cerami A. Non-enzymatic glycosylation and the pathogenesis of diabetic complications. Ann Int Med 1984;101:527–37. 33. Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end-products in tissue and the biochemical basis of diabetic complications. N Engl J Med 1988;318:1315–21. 34. Horie K, Miyata T, Maeda K, et al. Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions implication for glycoxidative stress in the pathogenesis of diabetic nephropathy. J Clin Invest 1997;100:2995–3004. 35. Degenhardt TP, Thorpe SR, Baynes JW. Chemical modification of proteins by methylglyoxal. Cell Mol Biol (Noisy-Ie-grand) 1998;44:1139–45. 36. Frye EB, Degenhardt TP, Thorpe SR, Baynes JW. Role of the Maillard reaction in aging of tissue proteins. Advanced glycation end product-dependent increase in imidazolium cross-links in human lens proteins. J Biol Chem 1998;273:18714–9. 37. Wendt T, Tanji N, Guo J, et al. Glucose glycation and RAGE: Implications for amplification of cellular dysfunction in diabetic nephropathy. J Am Soc Nephrol 2003;14:1383–95.

37

ECAB Clinical Update: Nephrology 38. Wendt TM, Tanji N, Guo J, et al. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol 2003;162:1123–37. 39. Schleicher ED, Wagner E, Nerlich AG. Increased accumulation of the glycoxidation product N(epsilon)-(carboxymethyl)lysine in human tissues in diabetes and aging. J Clin Invest 1999;99:457–68. 40. Tan ALY, Forbes JM, Cooper ME. AGE, RAGE, and ROS in diabetic nephropathy. Semin Nephrol 2007;27:130–43. 41. Vlassara H. Recent progress on the biologic and clinical significance of advanced glycosylation end products. J Lab Clin Med 1994;124:19–30. 42. Reusch, JEB. Diabetes, microvascular complications, and cardiovascular complications: What is it about glucose? J Clin Invest 2003;112:986–8. 43. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414:813–20. 44. Ceriello A. New insights on oxidative stress and diabetic complications may lead to a “causal” antioxidant therapy. Diabetes Care 2003;26:1589–96. 45. Pieper AA, Verma A, Zhang J, Snyder SH. Poly (ADP-ribose) polymerase nitric oxide and cell death. Trends Pharmacol Sci 1999;20:171–81. 46. Ayo SH, Radnik R, Garoni JA, et al. High glucose increases diacylglycerol mass and activates protein kinase C in mesangial cell cultures. Am J Physiol 1991;261:F571–7. 47. Itagaki I, Shimizu K, Kamanaka Y, et al. The effect of an aldose reductase inhibitor (Epalrestat) on diabetic nephropathy in rats. Diabetes Res Clin Pract 1994;25:147–54. 48. Gabbay KH, Merola LO, Field RA. Sorbitol pathway: presence in nerve and cord with substrate accumulation in diabetes. Science 1966;151:209–10. 49. Burg, MB. Role of aldose reductase and sorbitol in maintaining the medullary intracellular milieu. Kidney Int 1988;33:635–41. 50. Schleicher ED, Weigert C. Role of the hexosamine biosynthetic pathway in diabetic nephropathy. Kidney Int 2000;58:S.77:S13–S18. 51. Parker PJ, Murray-Rust J. PKC at a glance. J Cell Sci 2004;117:131–2. 52. Porte D Jr, Schwartz MW. Diabetes complications: Why is glucose potentially toxic? Science 1996;272:699–700. 53. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 1992;258:607–14. 54. Retnakaran R, Cull CA, Thorne KI, et al. UKPDS Study Group. Risk factors for renal dysfunction in type 2 diabetes. UK Prospective Diabetes Study 74. Diabetes 2006;55:1832–9. 55. Tissue repair: Cellular growth, fibrosis and wound healing. In: Cotran RS, Kumar V, Collins T, eds. Robbins Pathologic Basis of Disease 6th ed, Philadelphia: WB Saunders Company, 1999;89–112. 56. Leitges M, Plomann M, Standaert ML, et al. Knockout of PKC α enhances insulin signaling through P13K. Mol Endocrinol 2002;16:847–58. 57. Haneda M, Kikkawa R, Sugimoto T, et al. Abnormalities in protein kinase C and MAP kinase cascade in mesangial cells cultured under high glucose conditions. J Diabetes Complications 1995;9:246–8. 58. Tissue repair: Cellular growth, fibrosis and wound healing. In: Kumar V, Abbas AK, Fausto N, Aster JC, eds. Robbins Pathologic Basis of Disease 8th ed, Philadelphia: WB Saunders Company, 2010;79–110.

38

Pathophysiology and Pathology

„ Dakshinamurty, Ram and Prayaga

59. Shi Y. Structural insights on Smad function in TGF beta signaling. Bioessays 2001;23:223–32. 60. Sharma K, Ziyadeh FN. Hyperglycemia and diabetic kidney disease. The case for transforming growth factor-beta as a key mediator. Diabetes 1995;44:1139–46. 61. Sharma K, Eltayeb BO, McGowan TA, et al. Captopril-induced reduction of serum levels of transforming growth factor-β1 correlates with long-term renoprotection in insulin-dependent diabetic patients. Am J Kidney Dis 1999;34:818–23. 62. Benigni A, Zoja C, Corna D, et al. Add-on anti-TGF-beta antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat. J Am Soc Nephrol 2003;14:1816–24. 63. Dai C, Yang J, Bastacky S, et al. Intravenous administration of hepatocyte growth factor gene ameliorates diabetic nephropathy in mice. J Am Soc Nephrol 2004;15:2637–47. 64. Friedman EA, Friedman AL, Sommer BG. Renal and pancreatic transplantation for diabetic nephropathy. In: Morris PJ, ed. Principles and Practice of Kidney Transplantation 5th ed, Philadelphia: WB Saunders Company, 2001;571–603. 65. Benigni A, Gagliardini E, Tomasoni S, et al. Selective impairment of gene expression and assembly of nephrin in human diabetic nephropathy. Kidney Int 2004;65:2193–200. 66. Tervaert TWC, Mooyaart AL, Amann K, et al. Pathologic classification of diabetic nephropathy. J Am Soc Nephrol 2010;21:556–63. 67. Kimmelstiel P, Wilson C. Intercapillary lesions of the glomeruli of the kidney. Am J Pathol 1936;12:83–96. 68. Morgensen CE, Christensen CK, Vittinghus E. The stages in diabetic renal disease: with emphasis on the stage of incipient diabetic nephropathy. Diabetes 1983;32(Suppl 2):64–78. 69. Østerby R, Gall MA, Schmitz A, et al. Glomerular structure and function in proteinuric type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1993;36:1064–70. 70. Olson JL, Laszik ZG. Diabetic nephropathy. In: Jennette JC, Oslon JL, Schwartz MM, Silva FG, eds. Heptinstall’s Pathology of Kidney Diseases Lippincott: Williams & Wilkins, 2006;840–51. 71. Maur M, Najafian B. The structure of human diabetic nephropathy. In Cortes P, Morgensen CE, eds. Contemporary Diabetes: The Diabetic Kidney Humana Press: Totowa, 2006:361–74. 72. Yan SF, Ramasamy R, Naka Y, Schmidt AM. Glycation inflammation and RAGE: A scaffold for the macrovascular complications of diabetes and beyond. Circ Res 2003;93:1159–69. 73. Li YM, Mitsuhashi T, Wojciechowicz D, et al. Molecular identity and cellular distribution of advanced glycation endproduct receptors: Relationship of p60 to OST-48 and p90 to 80K-H membrane proteins. Proc Natl Acad Sci U S A 1996;93:11047–52. 74. el Khoury J, Thomas CA, Loike JD, et al. Macrophages adhere to glucosemodified basement membrane collagen IV via their scavenger receptors. J Biol Chem 1994;269:10197–200.

39

ECAB Clinical Update: Nephrology 75. Pitozzi V, Giovannelli L, Bardini G, et al. Oxidative DNA damage in peripheral blood cells in type 2 diabetes mellitus: Higher vulnerability of polymorphonuclear leukocytes. Mutat Res 2003;529:129–33. 76. Panayiotidis M, Tsolas O, Galaris D. Glucose oxidase-produced H202 induces Ca2+ dependent DNA damage in human peripheral blood lymphocytes. Free Radic Biol Med 1999;26:548–56. 77. Coleman JB, Gilfor D, Farber JL. Dissociation of the accumulation of single-strand breaks in DNA from the killing of cultured hepatocytes by an oxidative stress. Mol Pharmacol 1989;36:193–200. 78. Ludvigson MA, Sorenson RL. Immunohistochemical localization of aldose reductase. II. Rat eye and kidney. Diabetes 1980;29:450–9. 79. Kikkawa R, Umemura K, Haneda M, et al. Evidence for existence of polyol pathway in cultured rat mesangial cells. Diabetes 1987;36:240–3. 80. Larkins RG, Dunlop ME. Prostaglandins, polyols and mesangial cell function in experimental diabetes. In: Rifkin H, Colwell JA, Taylor SI, eds. Diabetes Amsterdam: Excerpta Medica, 1991:180–3. 81. Gurley SB, Coffman TM. The renin-angiotensin system and diabetic nephropathy. Semin Nephrol 2007;27:144–52. 82. Trujillo A, Eggena P, Barrett J, et al. Renin regulation in type II diabetes mellitus: influence of dietary sodium. Hypertension 1989;13:200–5. 83. Tuck ML, Sambhi MP, Levin L. Hyporeninemic hypoaldosteronism in diabetes mellitus. Studies of the autonomic nervous system’s control of renin release. Diabetes 1979;28:237–41. 84. Burden AC, Thurston H. Plasma renin activity in diabetes mellitus. Clin Sci (Lond) 1979;56:255–9. 85. Rudberg S, Persson B, Dahlquist G. Increased glomerular filtration rate as a predictor of diabetic nephropathy: an 8-year prospective study. Kidney Int 1992;41:822.

40

Clinical Presentation and Diagnosis of Diabetic Nephropathy Dr. P. Soundararajan

MD DM (Nephro) PhD

Professor and HOD of Nephrology Sri Ramachandra University, Porur, Chennai

ABSTRACT: Diabetic nephropathy (DN) is typically defined by macroalbuminuria (urinary albumin excretion of >300 mg in a 24hour collection) or a combination of macroalbuminuria and abnormal renal function represented by an abnormality in serum creatinine, calculated creatinine clearance, or glomerular filtration rate (GFR). Clinically, DN is characterized by a progressive increase in proteinuria and decline in GFR, presence of hypertension, and a high risk of cardiovascular morbidity and mortality. In a person with long-standing diabetes, DN should be suspected in the presence of a recently developed edema, hypertension, anemia, azotemia or unexpected hypoglycemia with the usual diet and antidiabetic medication being used so far. In a

41a

recently diagnosed type 2 diabetic person, DN may be indicated by other end organ complications, such as retinopathy. Although the presence of retinopathy supports the diagnosis of DN, the lack of diabetic retinopathy does not rule out DN, particularly in type 2 diabetics. The earliest evidence of DN is the appearance of low but abnormal levels (≥30 mg/d or 20 μg/min)  of  albumin  in  the  urine,  referred  to  as microalbuminuria. Microalbuminuria progresses to overt proteinuria or macroalbuminuria as the nephropathy worsens. Patients with overt proteinuria subsequently develop chronic kidney diseases requiring dialysis and transplantation. This progression can be prevented by optimal control of blood pressure, glucose levels, lipid levels, and use of anti proteinuric agents, like angiotensin-converting enzymes (ACEs)/ angiotensin receptor blockers (ARBs). KEYWORDS: Clinical presentation, diagnosis, diabetic nephropathy, proteinuria, glomerular filtration rate (GFR), edema, hypertension, anemia, azotemia, retinopathy, microalbuminuria, albumin to creatinine ratio, urinary albumin excretion (UAE), dipstick, National Kidney Foundation, MDRD, retinol-binding protein 4, RBP 4, adiponectin, connective tissue growth factor (CTGF), microglobulin.

41b

Clinical Presentation and Diagnosis of Diabetic Nephropathy Dr. P. Soundararajan

MD DM (Nephro) PhD

Professor and HOD of Nephrology Sri Ramachandra University, Porur, Chennai

INTRODUCTION Diabetic nephropathy (DN) is typically defined by macroalbuminuria (urinary albumin excretion of more than 300 mg in a 24-hour collection) or a combination of macroalbuminuria and abnormal renal function represented by an abnormality in serum creatinine, calculated creatinine clearance, or glomerular filtration rate (GFR).1–3 Clinically, DN is characterized by a progressive increase in proteinuria and decline in GFR, presence of hypertension, and a high risk of cardiovascular morbidity and mortality.4,5 In a person with long-standing diabetes, DN should be suspected in the presence of a recently developed edema, hypertension, anemia, azotemia or unexpected hypoglycemia with the usual diet and antidiabetic medication being used so far. In a recently diagnosed type 2 diabetic person, DN may be indicated by other end organ complications, such as retinopathy.4 Although the presence of retinopathy supports the diagnosis of DN, the lack of diabetic retinopathy does not rule out DN, particularly in type 2 diabetics. The earliest evidence of DN is the appearance of low but abnormal levels (≥30 mg/d or 20 μg/min) of albumin in the urine, referred to as microalbuminuria, and patients with microalbuminuria are referred to

41

ECAB Clinical Update: Nephrology

as having incipient nephropathy.13 Microalbuminuria is defined as the presence of albumin ranging from 30 mg to 300 mg in a 24-hour urine collection.14 Without specific interventions, 80% of subjects with type 1 diabetes, who develop sustained microalbuminuria, have worsening of their urinary albumin excretion at a rate of 10–20% every year to reach the stage of overt nephropathy or clinical albuminuria (≥300 mg/24 hour or ≥200 μg/min) over a period of 10–15 years. These patients, somewhere along the course of worsening of renal functions, also end up developing hypertension.14 Once overt nephropathy occurs, without specific interventions, the GFR gradually falls over a period of several years at a rate that is highly variable from individual to individual. Amongst all the patients with type 1 diabetes and overt nephropathy, about 50% develop an end-stage renal disease (ESRD) within 10 years and more than 75% develop the same by the end of 20 years.6 In addition to its being the earliest manifestation of nephropathy, albuminuria is also a marker of increased risk of cardiovascular morbidity and mortality in patients with both type 1 and type 2 diabetes.5 Thus, the finding of microalbuminuria is an indication for screening for possible vascular diseases and aggressive intervention to reduce all cardiovascular risk factors. Interventions recommended to reduce the cardiovascular risk in these patients include lowering of low-density lipoprotein cholesterol, antihypertensive therapy, cessation of smoking, institution of exercise, etc.20

CLINICAL STAGES OF DIABETIC NEPHROPATHY Diabetes nephropathy in its early phase is characterized by renal enlargement and hyperfiltration. Microalbuminuria, indicative of incipient nephropathy, develops over the next 10–15 years. Overt nephropathy, evidenced by macroalbuminuria, ensues over the next few years, which is followed by progressive renal failure evident as severe proteinuria by the end of 25 years. The manifestations of DN in various stages are described below.9

42

Clinical Presentation and Diagnosis „ Soundararajan

Stage 1 This is seen in patients with very early DN and is characterized by an increased demand on the kidneys, which is indicated by a GFR above the normal range. This hyperfiltration is caused by the osmotic load of hyperglycemia and the toxic effects of high sugar levels on kidney cells. The increased GFR is evident clinically as enlarged kidneys.

Stage 2 This is the stage of developing DN. It is a clinically silent phase with continued hyperfiltration and hypertrophy. The GFR may remain elevated or return to normal in this stage, but the progressive glomerular damage, if significant enough, results in microalbuminuria (small but abovenormal level of the protein albumin in the urine). Once microalbuminuria has started, it is only a matter of time before it progresses to overt nephropathy and eventually an ESRD. Therefore, all diabetic patients should be screened for microalbuminuria on a routine basis.

Stage 3 This is the stage of overt DN, otherwise called dipstick-positive DN stage. By the time the patient reaches this stage, the glomerular damage has progressed enough, manifested as clinical albuminuria. The urine is ‘dipstick positive,’ containing more than 300 mg of albumin in a 24-hour period. There is thickening of the basement membrane due to deposition of advanced glycation end products. This stage is typically associated with development of hypertension.

Stage 4 This is the stage of advanced or late changes in DN. In this stage, the glomerular damage continues with increasing amounts of protein albumin in the urine. There is a steady decline in the filtering ability of the kidneys, and blood urea nitrogen and creatinine levels begin to increase. Once this stage has begun, there is a steady decrease in the GFR by about 10% annually. Almost all patients in stage 4 have hypertension.

43

ECAB Clinical Update: Nephrology

Stage 5 This is the extreme end of the spectrum of DN and is characterized by features of an ESRD. By this time, the GFR is usually less than 10 mL/ min and renal replacement therapy, such as haemodialysis, peritoneal dialysis, or kidney transplantation, is needed.

SCREENING AND DIAGNOSIS Timing of Screening Screening for DN must be initiated at the time when diabetes is first diagnosed in patients with type 2 diabetes,11 since about 7% of them already have microalbuminuria at that time.12 For patients with type 1 diabetes, the first screening has been recommended at 5 years after diagnosis.11 However, the prevalence of microalbuminuria before 5 years in this group has been seen to be up to 18%, especially in patients with poor glycemic and lipid control and high normal blood pressure levels.13 Furthermore, puberty is an independent risk factor for microalbuminuria.14 Therefore, in type 1 diabetes, screening for microalbuminuria could be started 1 year after the diagnosis of diabetes, especially in patients with poor metabolic control and after the onset of puberty. If microalbuminuria is absent, the screening must be repeated annually for both type 1 and 2 diabetic patients.11

Methods of Screening The first step in the screening and diagnosis of DN is to measure albumin in a spot urine sample, collected either as the first urine in the morning or at random, for instance, during the medical visit. This method is accurate, easy to perform and recommended by American Diabetes Association guidelines.11 Both 24-hour urine collection and timed-urine collection are cumbersome and prone to errors related to collection of samples or recording of time. The results of albumin measurements in spot collections may be expressed as urinary albumin concentration (mg/L)15,16 or as a urinary albumin-to-creatinine ratio (mg/g or mg/mmol).11,16,17 Although expressing the results as albumin concentration might be

44

Clinical Presentation and Diagnosis „ Soundararajan

influenced by dilution/concentration of the urine sample, this option is still accurate and cheaper than the expression as the albumin-tocreatinine ratio.15 The cut-off value of 17 mg/L in a random urine specimen had a sensitivity of 100% and a specificity of 80% for the diagnosis of microalbuminuria, as was evident from a study that evaluated this method with 24-hour timed urine collection as a reference standard.18 This value is similar to the cut-off value of 20 mg/L recommended by the European Diabetes Policy Group.16 All abnormal tests must be confirmed in two out of three samples collected over a 3–6 month period,11,17 to account for the day-to-day variability in urinary albumin excretion (UAE). Screening should not be performed in the presence of conditions that increase UAE, such as urinary tract infection, hematuria, acute febrile illness, vigorous exercise, short-term pronounced hyperglycemia, uncontrolled hypertension, and heart failure.19 Samples must be refrigerated, if they are to be used the same day or the next day, and one freeze is acceptable before measurements.17 Figure 1 depicts an algorithmic summary of the screening protocol to be followed to arrive at the diagnosis of treatable microalbuminuria after it is initially detected. Immunoassays routinely used for albumin measurements present adequate diagnostic sensitivity for detection of DN. However, it was recently demonstrated that conventional immunochemical-based assays do not detect an unreactive fraction of albuminuria, thus underestimating the UAE.20 High-performance liquid chromatography measures total albumin, including immunoreactive and immunounreactive forms, and may allow early detection of incipient DN. In situations where specific UAE measurements are not available, semiquantitative dipstick measurements of albuminuria, such as Micral Test II, can be used.11,21 Another alternative is to use a qualitative test for proteinuria (dipstick)22 or a quantitative measurement of protein in a spot urine sample.15,17,23 The presence of a positive dipstick test has a sensitivity of 100% and specificity of 82% for detection of proteinuria, and a quantitative measurement of urinary protein >430 mg/L has a sensitivity of 100% and a specificity of 93% for the diagnosis of proteinuria.23 An abnormal result should be confirmed by measurement of total protein in a 24-hour urine sample. Values of >500 mg/24 hour

45

ECAB Clinical Update: Nephrology

!"

 ## 





!($

#
!


(
""
'
$"
# 
#
& (
!








 "

%"
#(
!$
"
"!"


!($

 "
!
"
 ## 
"!"
"%
%"
*
"
 


"   

'







"!"!
!($
!
 ## 
) 

+
" ""


Figure 1. Algorithm for confirming the diagnosis of microalbuminuria.

confirm the diagnosis of proteinuria. Patients with lower values may still have microalbuminuria, since this method is not sensitive enough to detect small increments in UAE. Some commonly used methods of measuring urinary protein excretion are summarized in Table 1. Although the measurement of UAE is the cornerstone for the diagnosis of DN, there are some patients with either type 1 or type 2 diabetes, who have decreased GFR in the presence of normal UAE.24,25 In patients with type 1 diabetes, this phenomenon seems to be more common among female patients with long-standing 46

Clinical Presentation and Diagnosis „ Soundararajan

Table 1. Methods of Measuring Urinary Protein with Normal and Abnormal Ranges Abnormal value Method

Normal value

Microalbuminuria

Macroalbuminuria

24-h urine collection

300 mg/d

Spot protein-tocreatinine ratio (mg/ mg)

● Estimate 1 g creatinine excretion/ 1.73 m2 (ratio of 0.15 = 150 mg protein/ 24 h/1.73 m2) ● Or estimate per 20 mg/ kg creatinine excretion for men, 15 mg/ kg for women

Ratio: 0.18–0.36 for 60-kg male, 0.135–0.27 for 60-kg female

Ratio: >0.36 for 60-kg male, >0.27 for 60-kg female

Albumin-tocreatinine ratio (μg/mg)

300 μg/mg

diabetes, hypertension and/or retinopathy.24 For patients with type 2 diabetes in the Third National Health and Nutrition Examination Survey (NHANES III; n = 1,197), low GFR (10 years

55

ECAB Clinical Update: Nephrology

hematuria and granular cast to predict the presence of NDGDs and they found that absence of DR had highest sensitivity (87%) and specificity (93%). They also recommended that the absence of DR could be used as a marker of NDRD in patients with type 2 DM.8

TYPES OF NON-DIABETIC GLOMERULAR DISEASES Non-diabetic glomerular diseases may be caused by various renal conditions. Among all types of NDGDs in patients with type 2 DM, primary glomerulonephritis is the most common renal pathology. Other types of glomerulonephritis reported include IgA nephropathy, membranous nephropathy, mesangiocapillary glomerulonephritis, rapidly progressive glomerulonephritis, focal proliferative glomerulonephritis, lupus nephritis, minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). In fact, coexistence of more than one type of glomerulonephritis, superimposed on DN, although not common, has also been reported in diabetic subjects.3,6 From the morphological point of view, Olsen7 has described a classification of the renal lesions into the following categories: 1. Class 1: Diffuse or nodular glomerulosclerosis 2. Class 2: Vascular change without any evidence of glomerulosclerosis 3. Class 3: NDRDs ƒ Class 3a: NDRDs superimposed on diabetic glomerulosclerosis ƒ Class 3b: NDRDs not superimposed on diabetic glomerulosclerosis

DIFFERENTIATION OF NON-DIABETIC GLOMERULONEPHRITIS FROM DIABETIC NEPHROPATHY As most types of glomerulonephritis are due to deposition of antibodies in the walls of the glomerular capillaries or the mesangium, immunohistochemical and light microscopic (LM) examination along with the characteristic appearance of the glomerular lesions are usually enough to lead to an unambiguous diagnosis. This stands true for most of the 56

Non-Diabetic Glomerular Diseases „ Dakshinamurty and Das

commonly seen forms of GN, including IgA nephropathy, membranous GN, membranoproliferative GN, post-infectious GN, immune-complex mediated GN and GN associated with systemic lupus erythematosus. Thus, identification of these types of GN lesions in NIDDM is not too difficult. However, two specific forms of GN, namely mesangial-proliferative GN and NCDs, are sometimes difficult to differentiate from DN.9

Mesangial-Proliferative Glomerulonephritis As defined by the WHO committee,10 this condition is characterized by increased mesangial cell number (more than three mesangial cells per mesangial region in at least 80% of all glomeruli) on LM evaluation. Similar findings can be seen in several types of GN, such as IgA nephropathy, the resolution phase of postinfectious GN, systemic lupus erythematosus associated GN, etc. However, all these types of GN have heavy immune deposits and their composition (class of immunoglobulins) pattern and location makes it easy to distinguish them from diabetic glomerulopathy. There is, however, a comparatively rare mesangioproliferative GN without immune deposits, which is difficult to distinguish from DN as mesangial hypercellularity may also be a feature of diabetic glomerulopathy. A biopsy diagnosis in a diabetic patient of slight or moderate mesangioproliferative GN without immune deposits must therefore be regarded as questionable.

Minimal Change Nephropathy According to the WHO classification of glomerular diseases,9 this term indicates a normal glomerular structure or minor glomerular abnormalities, such as slight hypercellularity of the mesangium. Clinically, it comprises minimal change nephrotic syndrome as well as mild or moderate persistent isolated proteinuria. There is an absence of a significant amount of immune deposits detectable by immunohistochemistry or electron microscopy (EM). The podocyte foot processes are more or less effaced, but this change is non-specific and can be seen in all renal diseases with protienuria.10 Hence, it is difficult to apply this diagnosis in a patient with DM. Light microscopic findings of normal glomeruli with no deposits on immunofluorescence (IF) or EM are completely compatible with early diabetic glomerulopathy with slight 57

ECAB Clinical Update: Nephrology

or even moderate albuminuria. On the other hand, patients suffering from DM may also be affected by other glomerular diseases, and biopsy findings of normal glomeruli may not rule out the presence of a more serious renal diseases. Misdiagnosis may also occur in FSGS and hyalinosis, due to missing representation of the abnormal glomeruli in a biopsy with a restricted number of glomeruli. The correct diagnosis in such cases may be made by a subsequent biopsy from the same patient.6 Thus, it is hazardous to make the diagnosis of glomerulonephritis based upon light microscopy alone, especially in situations similar to those stated above. This approach may underestimate the prevalence of GN in DM,11 but the use of slight or moderate mesangial hypercellularity alone as a criterion could probably overestimate the condition. Immunofluorescence microscopy as well as EM should always be done in such cases. It is also important to keep the clinical context in perspective while making a diagnosis in these situations. Clinicians should note that a hyalinosis lesion is not specific for identification of DN. This lesion may also be seen in other conditions, such as FSGS.

DIFFERENCES BETWEEN BIOPSY FINDINGS OF GLOMERULAR LESIONS IN NON-DIABETIC GLOMERULAR DISEASES AND DIABETIC NEPHROPATHY Although kidney biopsy is considered the most unbiased diagnostic modality in proteinuric patients, as it is invasive, it is not used as a routine diagnostic test in all diabetic patients with protienuria.1 It is indicated when the patient has features atypical of DN. In such cases, the primary aim of kidney biopsy is to confirm/exclude NDRDs and avoid missing a more treatable disease. The characteristic glomerular lesions of DN are: 1. Diffuse lesions with mesangial sclerosis manifested as an increase in mesangial matrix and uniform thickening of capillary walls. Hypercellularity is uncommon in this form. 2. Nodular lesions characterized by the accumulation of homogeneous eosinophilic material within the mesangium. These often appear as a 58

Non-Diabetic Glomerular Diseases „ Dakshinamurty and Das

rounded accentuation of the mesangial expansion. When expansion of the mesangium attains a size at least one and one-half times that of the normal mesangial stalk, it is termed a Kimmelstiel–Wilson nodule. These nodules measure at least 40 μm in size and are PAS positive. Nodular lesions are almost always associated marked diffuse lesions. 3. Hyalinosis lesion or exudative lesions sometimes occur in the form of capsular drops and hyaline caps. The differentiating points in a renal biopsy against DN are as follows: 1. Mesangial proliferative GN is hypercellular in appearance as compared to DN, so a hypercellular lesion on biopsy goes against the presence of DN. 2. Presence of linear staining of capillary walls for IgG by IF in addition to non-uniform thickening of glomerular basement membrane (GBM) and presence of immune deposits by EM eliminate the possibility of DN. 3. Differential diagnoses of the nodular form of diabetic glomerulosclerosis are amyloidosis, light chain deposition diseases, immunotactoid glomerulonephritis and membranoproliferative glomerulonephritis, which can be differentiated easily by the difference in staining pattern, IF and EM characteristics. 4. MPGN can additionally be differentiated from DN by the fact that MPGN affects all glomeruli to a similar degree, whereas a nodular change of DN affects only some glomeruli and that it is associated with increased cellularity of the mesangium.

OCCURRENCE AND PATTERN OF GLOMERULAR LESIONS IN NON-DIABETIC GLOMERULAR DISEASES IN DIABETES MELLITUS Global Published Literature In a Korean study of 46 patients with DN, NDGDs superimposed on diabetic glomerulosclerosis was observed in 21% cases, of which IgA nephropathy was reported as the commonest NDGD.12 Similarly, in 59

ECAB Clinical Update: Nephrology

another study published from Hong Kong, out of 51 renal biopsies of NIDDM patients, 17 had NDRD (33.3%) of which IgA nephropathy accounted for 59%. In this study, microscopic hematuria and nonnephrotic proteinuria predicted the presence of NDRDs among NIDDM patients. Four (24%) had hypertensive nephrosclerosis and one had MPGN.13 In a separate retrospective study, Chike et al14 went over the renal biopsies of 33 patients with type 2 DM and observed three patterns of glomerular diseases. Diabetic nephropathy alone was seen in 13 patients (41.9%), DN with glomerulonephritis was seen in 12 patients (38.7%), while NDRD alone was seen in 6 patients (19.4%). Another retrospective analysis15 from the USA by Pham and coworkers reported a high prevalence of NDRDs among diabetic patients undergoing renal biopsy. In this study, the biopsy reports of 233 adults (mean age 58.1 ± 13.7 years), who underwent renal biopsy at a single centre during the period 1995–2005, were reviewed. It was found that 53.2% of the patients had been diagnosed with NDRD, 27.5% with pure diabetic glomerulosclerosis and 19.3% with concurrent NDRDs and diabetic glomerulosclerosis. In patients with NDRDs, the commonest lesion was FSGS (21%) followed by minimal-change diseases (15.3%). In patients with concurrent NDRDs and diabetic glomerulosclerosis, the common lesions were IgA nephropathy (15.6%), membranous glomerulonephritis (13.3%) and arterial/arteriolar nephrosclerosis (13.3%). This study also found that the absence of DR was predictive of NDRDs.

Indian Published Literature A study by Prakash et al2 based on a total number of 260 patients with NIDDM reported the prevalence of NDRDs to be 12.3% (32 out of 260 cases). The presenting clinical syndromes were chronic renal failure (15 cases, 47%), acute nephritic syndrome (6 cases, 18.7%), nephrotic syndrome (5 cases, 15.6%), acute renal failure (4 cases, 12.5%) and rapidly progressive glomerulonephritis (2 cases, 6.2%). Overall, incidence of glomerular (46.8%) and tubulointerstitial lesions (53.2%) was almost equal in type 2 DM patients. The spectrum of NDRDs included primary isolated glomerulopathy in 12 cases (37.5%), mesangioproliferative GN superimposed on 60

Non-Diabetic Glomerular Diseases „ Dakshinamurty and Das

diabetic glomerulosclerosis in 3 cases (9.3%), acute tubulointerstitial nephropathy in 4 cases (12.5%), chronic tubulointerstitial nephropathy in 10 cases (31.25%) and chronic pyelonephritis in 3 cases. Diabetic retinopathy was absent in 22 cases (69%), whereas 10 patients (31%) had background DR. None of the patients with NDGDs had DR, except two who had diabetic glomerulosclerosis in addition to mesangioproliferative GN on renal biopsy. Background DR was seen in 47% of patients with tubulointerstitial nephropathy without clinical evidence of DN. The recovery of renal function or clinical improvement was observed in 47% of patients with NDRDs with institution of appropriate treatment. Another study from South India16 reported 16 cases of renal biopsy done in patients with type 2 DM. Eight cases (50%) had pathological changes suggestive of diabetic etiology, 5 (33.3%) had classical membranous nephropathy, 1 (6.2%) had tubulointerstitial disease and 2 (12.5%) were found to have only minimal changes. The subjects with NDRDs had significantly higher creatinine clearance (p = 0.024), serum cholesterol levels (p = 0.036), triglyceride levels (p = 0.045) and LDL cholesterol levels (p = 0.048) when compared to subjects with DN.

Unpublished Data from the Nizam’s Institute of Medical Sciences We have retrospectively analyzed 1708 cases in which renal biopsy was done during the period 1990–2008 to observe the pattern and occurrence of NDRDs. Out of the 1708 cases, 148 were excluded either due to lack of clinical data or due to inadequate biopsy sample. Out of the total number of renal biopsies, 105 cases were found to be type 2 diabetic. Out of these cases, 75 cases with adequate renal biopsy were considered for the final analysis. The mean age was found to be 44.84 ± 10.23 years, male to female ratio was found to be 57:18 and hypertension was observed in 65 (86.66%) cases. The renal syndromes of NDGDs at presentation included acute renal failure (ARF) in 14 cases, acute nephritic syndrome in 6, rapidly progressive glomerulonephritis (RPGN) in 14, nephrotic syndrome in 21, chronic renal insufficiency in 9, nephritic/nephrotic syndrome in 2, nephritic syndrome with renal insufficiency in 6 and lupus nephritis 61

ECAB Clinical Update: Nephrology

in 3 cases. Urinalysis revealed microscopic hematuria in 24 cases. Proteinuria was 3 μg/dL in 29 cases. The spectrum of renal changes observed included acute tubular necrosis (ATN) in 2 cases, cast nephropathy due to multiple myeloma in 3 cases, chronic GN in 3 cases, chronic interstitial nephritis in 1 case, hypertensive changes in 3 cases, crescentic GN in 2 cases, diabetic glomerulosclerosis in 25 cases, membranous nephropathy in 5 cases, MCD in 6 cases, postinfectious glomerulonephritis (PIGN) in 11 cases, FPGN in 1 case, FSGS in 4 cases, IgA nephropathy in 2 cases, Lupus nephritis in 3 cases and sclerosed glomeruli in 4 cases.

CONCLUSION If a patient suffering from DM develops clinical nephropathy as evidenced by proteinuria, it could logically be due to three reasons. First, it could be a progression of diabetic glomerulopathy; secondly, it could be a NDRD in a diabetic subject; and last but not the least, a combination of both these conditions. Non-DN most often affects the glomeruli leading to glomerulonephritis, but rarely other renal conditions not related to the diabetic diseases (such as amyloidosis) may also be present. A renal biopsy studied by light microscopy and immunofluorescence techniques may provide the key to correct diagnosis, by presenting the characteristic findings of diabetic glomerulopathy or unequivocal features of GN, such as glomerular immune deposits. There are, however, situations where a biopsy cannot lead to a reliable diagnosis. Renal diseases associated with the normal glomerular structure (MCDs) or with slight or moderate alterations (mesangial proliferative GN without immune deposits), which cannot be differentiated with certainty from diabetic renal diseases, especially in early stages, may present situations of diagnostic dilemma. The patient may also belong to the category, which never develops diabetic renal diseases or the patient may have diabetic glomerulopathy at an early stage, where there is proteinuria, but no structural changes on LM. Even if the biopsy is investigated with EM, the situation is not necessarily unambiguous; for instance, slight or moderate thickening of the GBM or mesangial matrix may be present in patients with long-standing diabetes without proteinuria. In cases with 62

Non-Diabetic Glomerular Diseases „ Dakshinamurty and Das

ambiguous findings, clinical correlation and differential findings can help in arriving at the correct diagnosis. An early diagnosis of NDGDs is crucial, as appropriate therapy could prolong renal survival in this patient population.

REFERENCES 1. Olsen S, Mogensen CE. How often is NIDDM complicated with non-diabetic renal disease? An analysis of renal biopsies and the literature. Diabetologia 1996;39:1638–45. 2. Prakash J, Sen D, Usha, Kumar NS. Non-diabetic renal disease in patients with type 2 diabetes mellitus. J Assoc Physicians India 2001;49:415–20. 3. Jean LO, Zoltan GL. Diabetic Nephropathy: Heptinstall’s Pathology of the Kidney 801–52. 4. Steen O. Identification of non-diabetic glomerular disease in renal biopsies from diabetics—a dilemma. Nephrol Dial Trans 1999;14:1846–9. 5. Geraldine AS, Byron PC. Renal biopsy as a guide to the treatment of glomerulonephritis. The Therapy in Nephrology and Hypertension. A Companion to Brenner and Rector’s The Kidney 5th ed., p. 85. 6. Tone A, et al. Clinical features of nondiabetic renal disease in patients with type 2 diabetes. Diabetes Res Clin Pract 2005;69:237. 7. Mazzucco G, Bertani T, Fortunato M, et al. Different patterns of renal damage in type 2 diabetes mellitus: a multicentric study on 393 biopsies. Am J Kidney Dis 2002;39:713–20. 8. Zukowska-Szczechowska E, Tomaszewski M. Renal affection in patients with diabetes mellitus is not always caused by diabetic nephropathy. Rocz Akad Med Bialymst 2004;49:185–9. 9. Steen O. Identification of non-diabetic glomelrular disease in renal biopsies from diabetics—a dilemma. Nephrol Dial Transpl 1999;14:1846–9. 10. Churg J, Bernstein J, Glassock R. Renal Disease: Classification and Atlas of Glomerular Diseases New York, Tokyo: Igaku-Shoin, 1995. 11. Seefeldt T, Bohman S-O, Gundersen H, et al. Quantitative relationship between glomerular foot process width and proteinuria in glomerulonephritis. Lab Invest 1981;44:541–6. 12. Ditscherlein G. Pathomorphology of the diabetic kidney. Clin Nephrol 1996; 46:256–8. 13. Jang S, Park MH. The morphologic patterns of diabetic nephropathy in Koreans. The Korean J Pathol 2009;43:36–42. 14. Mak SK, Gwi E, Chan KW, et al. Clinical predictors of non-diabetic renal disease in patients with non-insulin dependent diabetes mellitus. Nephrol Dial Transplant 1997;12:2588–91. 15. Chike MN, Karlene H, Lowe PH. Prevalence of non-diabetic renal disease among African-American patients with type II diabetes mellitus. Scand J Urol Nephrol 2000;34:331–5. 16. Pham TT, et al. Prevalence of nondiabetic renal disease in diabetic patients. Am J Nephrol 2007;27:322–8.

63

Nephrologic Problems Other Than Diabetic Nephropathy in Diabetes Mellitus Prof. Dr. Kaligotla Venkata Dakshinamurty

MD DM (Nephro)

DNB (Nephro)

Professor and Head

Dr. Madhav Desai

MD DM (Nephro)

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

ABSTRACT: In diabetic patients the early detection and prevention of progression of diabetic nephropathy is a very important aspect of management. However, the existence of nephrological manifestations other than diabetic nephropathy cannot be ignored as these too contribute to the morbidity and mortality in this group of patients. The diabetic patients with symptomatic urinary tract infections (UTIs), especially those who present with septicemia or those with delayed response and/or resistance to antibiotics require an aggressive approach of management. An early evaluation with investigations such as urine culture and sensitivity, ultrasound or computed tomography (CT) scan should be done where indicated. An early assessment

64a

can detect the treatable, though less common, conditions like emphysematous pyelonephritis, papillary necrosis, and renal abscess and help avoid prolonged antibiotic treatment, hospitalization, and increased interventions. KEYWORDS: Nephrologic, nephropathy, diabetes, urinary tract infection (UTI), acidosis, leukocyte adherence, chemotaxis, phagocytosis, emphysematous pyelonephritis (EPN), renal abscess, antibiotic, bacteremia, urosepsis, indwelling, catheters, glycemic, papillary necrosis, renal calculi, obstruction, urethral, hospital-acquired infection, bacteriuria, asymptomatic bacteriuria, intravenous pyelogram (IVP), xanthogranulomatous, renal carbuncle, corticomedullary, perirenal, septicemia.

64b

Nephrologic Problems Other Than Diabetic Nephropathy in Diabetes Mellitus Prof. Dr. Kaligotla Venkata Dakshinamurty

MD DM (Nephro)

DNB (Nephro)

Professor and Head

Dr. Madhav Desai

MD DM (Nephro)

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

INTRODUCTION Diabetes mellitus is the commonest endocrine disease and associated with organ complications due to microvascular and macrovascular diseases. Though diabetic nephropathy is the commonest renal manifestation, other nephrological problems, especially urinary tract infection (UTI), are equally important because their presence is associated with increased morbidity and mortality. People with diabetes mellitus suffer from infections, although the association between diabetes and increased susceptibility to infection has been questioned.1 UTIs are common in diabetics and may occur with increased severity and may be associated with greater risk of complications.2 An association between UTI and diabetes mellitus was noted in an autopsy series reported as early as the 1940s.3 The urinary tract is the principal site of infection in diabetes. UTIs are the most commonly found bacterial infections, accounting for nearly 7 million office visits and 1 million emergency department visits, resulting in 100,000 hospitalizations of women, the elderly, and patients with spinal cord injuries and/or catheters and diabetes.4 Severe less commonly encountered UTIs as well as those caused by resistant bacteria have also been seen to occur more frequently in diabetic patients.5,6 64

Nephrologic Problems Other Than Diabetic „ Dakshinamurty and Desai

PATHOGENESIS21 The reasons for UTIs in diabetics are multifactorial, which include both host (immunologic, metabolic, anatomic changes, etc.) and microbiological factors. In the host factors, there is depression of Polymorphonuclear leukocyte functions particularly in the presence of acidosis. Leukocyte adherence, chemotaxis, and phagocytosis are also affected.22–24 Additionally an impairment of the antioxidant systems involved in bactericidal activity is also seen.25 A lower urinary concentration of cytokines (IL6 and IL8) has been shown to correlate with a lower urinary leukocyte cell count in diabetic patients, which may contribute to the increased incidence of UTIs in this patient group.26,27 However, poor glycemic control by itself does not predict increased rates of multiplication of bacteria and has not always been shown to be a major determinant of the incidence of bacteriuria or its subsequent complications.23,28,29 Microbial factors such as increased adherence of Escherichia coli expressing type 1 fimbriae (a virulence factor) to uroepithelial cells of diabetic women may play an important role in the pathogenesis of UTI, especially if diabetes is poorly controlled.30 Tamm-Horsfall protein, which traps type 1 fimbriated E. coli in uromucoid present on epithelial cells, acts as an important defence mechanism as it prevents adherence and cell entry of pathogens. This protein is significantly reduced in some patients with diabetes.31,32 Biofilm formation by E. coli, Staphylococcus aureus, and E. fecalis contributes to increased antibiotic resistance and prolonged infection in diabetics.33 A biofilm is a collection of micro-organisms surrounded by the slime they secrete attached to an inert surface or a living surface. Bacteria in the biofilm are less sensitive to antibiotics, which contributes to the increased antimicrobial resistance. The fact that diabetic neuropathy is associated with neurologic dysfunction may result in a neurogenic bladder with incomplete bladder emptying (impaired bladder evacuation due to detrusor paresis), urinary stasis, and retention also contributes to the increased susceptibility to UTI. The increased likelihood of urethral instrumentation in these patients too predisposes them to infection as may diabetic microangiopathy, which can contribute to local ischemia and impaired host defenses.1,34

65

ECAB Clinical Update: Nephrology

URINARY TRACT INFECTIONS IN DIABETES–CLINICAL IMPORTANCE For a long time it had been controversial whether the frequency of bacteriuria is higher in diabetic patients, but there has never been any doubt that symptomatic UTIs are more severe and more aggressive in diabetic individuals. The hypothesis of a higher prevalence of UTI in diabetes with a gender based bias was suggested in a study by Vejlsgaard35 which noted a higher frequency of bacteriuria of >105 colony forming units per milliliter urine in females (18.8% vs 7.9% in control) but not in male diabetics. Such UTI was mostly asymptomatic (33%). The results of prospective studies remained controversial. A higher prevalence in diabetic women was noted by Balasoiu et al29 but not by Brauner et al.36 The risk was higher in women on insulin and with longer duration of diabetes.37 While doing a clinical evaluation of diabetic patients with suspected nephrologic involvement certain aspects have to be especially considered. Patients with diabetes mellitus may have renal infection with minimal localizing symptoms or signs. Conditions such as Emphysematous Pyelonephritis (EPN) and renal abscess should be considered in the event of non-response to appropriate antibiotic therapy for urinary infection in diabetic patients. Diabetic patients with urinary infections are more likely to be bacteremic or uroseptic than nondiabetic patients.8,38 These patients are also five times more likely to develop acute pyelonephritis than non-diabetic patients.20 Diabetic patients with systemic signs of urinary infection should be studied with abdominal radiography to detect renal EPN. Ultrasound or computerized tomography should be performed if an obstruction or abscess is suspected. The urinary tract is implicated as the source of bacteremia more frequently in diabetic than non-diabetic patients.38 Women with type 2 diabetes and history of UTI (especially upper UTI) are at increased risk for renal scarring and damage as demonstrated by renal cortex scans.39 Most of the bacteria responsible for urosepsis in diabetics are gram negative rods, with E. coli and Klebsiella sp. accounting for about 70%. Klebsiella sp. is isolated twice as frequently in diabetic patients with bacteremic urinary infections, especially in those with indwelling urinary bladder catheters.

66

Nephrologic Problems Other Than Diabetic „ Dakshinamurty and Desai

Symptomatic UTIs definitely run a more aggressive course in diabetic patients. Recent studies show that in multivariate analysis diabetes and poor glycemic control are independent factors associated with upper urinary tract involvement. At times the involvement of other organ systems can also complicate the presentation of UTI in diabetics. However as suggested in a study by Lukman M Hakeem et al,21 the diagnosis of ‘Complicated UTI’ should be reserved for diabetic patients with ketoacidosis, hyperosmolar state, renal impairment or structural abnormalities such as neurogenic bladder, renal perinephric abscess, papillary necrosis, renal/bladder emphysema, renal calculi, obstruction, and urethral catheterization. While treating UTI in diabetic patients, the clinician should consider the potential interaction between the drugs administered and the pre-existing anti-diabetic medication. In diabetic patients taking oral hypoglycemic agents, trimethoprim-sulfamethoxazole could lead to further hypoglycemia. No such potentiation is seen with most fluoroquinolone antibiotics but hypoglycemia is reported with gatifloxacin.41 The clinician should also consider the increasing concerns about emergence of resistant organisms while prescribing empirical antibiotics, especially during treatment of recurrent UTIs. The most common amongst such organisms are those producing Extended Spectrum β-Lactamases (ESBLs) which can hydrolyse oxyimino-cephalosporins and monobactams. Enterobacteriaceae such as Klebsiella species with ability to produce ESBLs such as SHV- and TEM-type enzymes, cause hospital-acquired infection and those producing CTX-M enzymes cause community-acquired UTIs.42 Resistance to other classes of antibiotics, especially the fluoroquinolones and aminoglycosides, are often associated with ESBL-producing organisms, which lead to increased prescription of more broad-spectrum and expensive drugs such as the carbapenems.43 An increased awareness of these organisms by clinicians and enhanced testing by laboratories, including molecular surveillance studies, is required to reduce treatment failures to limit the introduction of resistant infections into hospitals and prevent the spread of these emerging antibiotic resistant pathogens within the community.

67

ECAB Clinical Update: Nephrology

Recurrent bacteriuria can be prevented by complete emptying of the bladder during voiding, antimicrobial prophylaxis, less use of spermicides, and optimal catheter care.44 Advice about these should be provided to all patients during diabetic education programmes and particularly after an initial episode of UTI. The clinician should also look out for extrarenal involvement in these patients. Extrarenal bacterial metastases are common in patients with UTI and septicemia, particularly with methicillin-resistant staphylococci. These patients may have extrarenal involvement such as endophthalmitis,40 spondylitis, and iliopsoas abscess formation.

Urinary Tract Infections in Diabetes The spectrum of urinary infections in patients with diabetes mellitus includes asymptomatic bacteriuria,7–10 acute papillary necrosis,1,11 emphysematous cystitis,12,13 EPN,14,15 fungal infections,16 renal abscess, perinephric abscess,17 and xanthogranulomatous pyelonephritis.18–20

Asymptomatic Bacteriuria Asymptomatic bacteriuria is a common and by itself a generally benign infection.10,45 However, if left untreated, it may lead to renal function impairment.49 It is associated more commonly (2–4 times) with women as compared to men with diabetes.1,7 It is also seen to be more prevalent in female diabetics as compared to their male counterparts.46 The prevalence of asymptomatic bacteriuria in diabetic women is 9–27% and men is 0.7–11%.47 Bacteriuria in diabetic patients may be associated with a disproportionate risk of infection in the upper urinary tract and kidneys. A study has reported that upper UTI could be documented in 79% of diabetic women with asymptomatic bacteriuria.7 Pyuria is often present, especially in elderly people, and a predictor for subsequent symptomatic UTI in some groups.45 A recent study found, however, that asymptomatic bacteriuria was predictive of subsequent hospitalization due to symptomatic UTI.48 It has always been recognized that diabetic patients are particularly susceptible to rapid progression of renal parenchymal infection and ensuing complications.

68

Nephrologic Problems Other Than Diabetic „ Dakshinamurty and Desai

The causative uropathogens of asymptomatic bacteriuria are the same as those causing UTIs in the same population. E. coli remains the single most common organism causing asymptomatic bacteriuria. Other Enterobacteriaceae such as Klebsiella pneumonia and other organisms like Enterococcus species, group B streptococci, and Gardnerella vaginalis can also cause asymptomatic bacteriuria.50 Virulence factors in E. coli isolated from diabetic women with asymptomatic bacteriuria did not differ from those in non-diabetic women51 and the spectrum of bacterial isolates as well as the resistance rates to antibiotics did not differ between diabetic and non-diabetic individuals.52,53 Treatment of asymptomatic bacteriuria is generally not warranted.45 However, patients at high risk for serious complications may require a more aggressive approach in diagnosis and treatment. These include pregnant women and patients undergoing urologic surgery.45 Some authorities advise treatment of asymptomatic bacteriuria found in patients with anatomic or functional abnormalities of the urinary tract, diabetic patients, and patients with urea-splitting bacteria, such as P. mirabilis, and Klebsiella species.47 Until recently, there was no consensus on the pre-emptive screening, treatment, and prophylaxis of asymptomatic bacteriuria. However, these issues have been addressed in a placebo-controlled double-blind randomized trial,54 which concluded that treatment did not reduce complications and diabetes should not therefore be regarded as an indication for screening or treatment of asymptomatic bacteriuria. The findings from this trial were subsequently recognized in the guidelines published by the Infectious Diseases Society of America (IDSA)55 on the diagnosis and treatment of asymptomatic bacteriuria in general. The IDSA, 200555 criteria for the diagnosis of asymptomatic bacteriuria make the following recommendations: 1) Asymptomatic bacteriuria in women is defined as two consecutive voided urine specimens with isolation of the same bacterial strain in quantitative counts ≥ 105 cfu/mL. 2) In men, a single, clean-catch voided urine specimen with 1 bacterial species isolated in a quantitative count ≥ 105 identifies bacteriuria.

69

ECAB Clinical Update: Nephrology

3) For catheterized patients, a single catheterized urine specimen with 1 bacterial species isolated in a quantitative count ≥102 cfu/mL in women or men indicates bacteriuria. 4) Pyuria accompanying asymptomatic bacteriuria is not an indication for antimicrobial treatment. 5) Screening for or treatment of asymptomatic bacteriuria is not recommended for diabetic women. Women with type 1 diabetes are particularly at risk if they have had diabetes for a long time or complications such as peripheral neuropathy and proteinuria have developed. Risk factors in patients with type 2 diabetes include advanced age, proteinuria, low body mass index and a past history of recurrent UTIs.27

Papillary Necrosis The existence of papillary necrosis has been known since the 19th century and was rediscovered in the 1930s.56 In 1969, a large autopsy series57 documented papillary necrosis in approximately 10% of 400 diabetic patients. However, this finding has not been confirmed in recent autopsy series.58 In that study among hundreds of diabetic patients, clinical evidence of this complication was found only once. Papillary necrosis should be suspected in diabetic patients with UTI along with septicemia, renal colic, hematuria or obstructive uropathy. More than half of those who develop papillary necrosis have diabetes, almost always in conjunction with an UTI. Renal papillae are vulnerable to ischemia especially in diabetics possibly due to the microvascular insufficiency.11 This occurs because of the sluggish blood flow in the vasa recta, and relatively modest ischemic insults culminating in papillary necrosis. These patients may present with flank pain, chills, and fever and 15% may also have renal insufficiency.1 The passage of sloughed papillae into the ureter may cause renal colic, renal insufficiency or failure, or obstruction with severe urosepsis. Papillary necrosis in the setting of pyelonephritis is associated with pyuria and a positive urine culture. Causative uropathogens are those typical of complicated UTI. 70

Nephrologic Problems Other Than Diabetic „ Dakshinamurty and Desai

Figure 1. Papillary necrosis—intravenous pyelography shows calyces in upper pole of right kidney that are irregular with clefting of fornices suggestive of sloughed papillae (→).

Retrograde pyelogram is the preferred diagnostic procedure. Radiologic findings include an irregular papillary tip, dilated calyceal fornix, extension of contrast material into the parenchyma, and a separated crescent-shaped papilla surrounded by contrast called the ring sign. Figure 1 demonstrates the findings on intravenous pyelography (IVP) in a case with papillary necrosis. 71

ECAB Clinical Update: Nephrology

The treatment includes administration of broad-spectrum antibiotics cystoscopic removal of papillae obstructing the ureter by a ureteral basket or removal of the obstruction by insertion of a ureteral stent.

Emphysematous Pyelonephritis EPN is a fulminant, necrotizing, life-threatening variant of acute pyelonephritis caused by gas-forming organisms. E. coli is the most frequently isolated bacteria, followed by Proteus, Pseudomonas, and Klebsiella sp., but Clostridium sp. is not typically involved.15 Up to 90% of cases occur in diabetic patients, and obstruction may be present in many. In diabetic patients, EPN presents with fever, flank pain, and often the finding of a mass in the flank or a renal mass on pyelography.14 The diseases like dehydration and ketoacidosis are common. Pyuria and a positive urine culture are usually present. Bacteremia is usually present and blood cultures also may be positive. Gas is usually detectable on a plain abdominal radiograph or by ultrasound. However, CT (Fig. 2) is the diagnostic modality of choice as it can better localize the gas than ultrasonography or skiagraph. Accurate localization of gas is important because gas may also be found in an infected obstructed collecting system or renal abscess. It is important to differentiate the conditions because although serious, an infected obstructed collecting system or renal abscess do not carry the same grave prognosis and are managed differently. The treatment of EPN includes intravenous fluid support, appropriate antibiotics, and percutaneous catheter drainage. Hyperbaric oxygen may be an additional treatment option along with antibiotics.59 Surgical intervention may be required if the response to medical therapy is delayed. Obstructing lesions must be removed and collections drained; nephrectomy may be required,60 especially in patients with extensive renal involvement and/or multiorgan system dysfunction.61 In the past, treatment of EPN usually involved nephrectomy or open drainage along with systemic antibiotics. However, in the present scenario, selected patients can be managed successfully with systemic antibiotics, catheter drainage of gas and purulent material, and, if present, relief of urinary tract obstruction. Huang et al61 explained the management of EPN. According to the clinicoradiological classification the details of which are beyond 72

Nephrologic Problems Other Than Diabetic „ Dakshinamurty and Desai

Figure 2. Emphysematous pyelonephritis—CECT abdomen reveals enlarged, disorganized right kidney with few pockets of air (↓) within and perinephric stranding noted suggestive of emphysematous pyelonephritis.

the scope of this chapter. EPN of Classes 1, 2 and 3A can be managed conservatively with antibiotics and percutaneous catheter drainage and prognosis is better in this group. For Class 3B and Class 4, intensive care followed by nephrectomy is usually required. 73

ECAB Clinical Update: Nephrology

The prognosis of EPN depends on several clinicopathological factors. The study by Huang et al61 showed that poor prognostic factors in EPN included shock, severe proteinuria, thrombocytopenia, acute renal function impairment, and disturbance of consciousness. It was found that these prognostic factors are not unique to EPN and may be applied to other patients with DM and sepsis. In a separate study Wan et al62 implicated serum creatinine >1.4 mg/dL, platelet count