Pathogenesis and Treatment in IgA Nephropathy

Transcription

1 Pathogenesis and Treatment in IgA Nephropathy

2 ThiS is a FM Blank Page

3 Yasuhiko Tomino Editor Pathogenesis and Treatment in IgA Nephropathy An International Comparison

4 Editor Yasuhiko Tomino Medical Corporation SHOWAKAI Tokyo Japan ISBN ISBN (ebook) DOI / Library of Congress Control Number: Springer Japan 2016 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer Japan KK

5 Preface I have studied IgA nephropathy for more than 40 years and have obtained several findings in the fields of pathology, immunology, molecular biology, and experimental pathology all of which have shed much light on the mechanisms of initiation, development, and progression of this disease. I have also undertaken new treatments for patients and developed animal models for IgA nephropathy. This book discusses the latest findings on the pathogeneses and treatment of IgA nephropathy. It particularly focuses on recently recognized initiation and progression factors and varying treatment strategies in different regions such as Asia, the EU, and the U.S. Nearly 50 years have passed since Dr. Jean Berger first described primary IgA nephropathy ( Nephropathy with mesangial IgA-IgG deposits ) as a new disease entity. Immunohistopathologically, IgA nephropathy is characterized by the granular deposition of IgA (polymeric IgA1) and C3 in glomerular mesangial areas with mesangial cell proliferation and the expansion of mesangial matrices. It is clear that IgA nephropathy is one of the most common types of chronic glomerulonephritis in the world. This disease may lead to end-stage kidney disease (ESKD), with its enormous economic impact on healthcare everywhere. Efforts by many investigators around the world have gradually clarified various aspects of the pathogenesis and treatment of IgA nephropathy. It should be noted however, that there are many controversial strategies for the treatment of patients with IgA nephropathy throughout the world, and there are several limitations for treatment in each country. At present, the most important therapeutics goal for patients with IgA nephropathy is the decrease of urinary protein excretion. For example, it has been assumed that the removal of palatine tonsillar tissues might reduce the production of polymeric IgA1 and decrease the frequency of renal parenchymal injury resulting from episodes of macroscopic hematuria and proteinuria. This volume provides nephrologists everywhere with an overview and comparison of both global and regional findings in basic and clinical fields in IgA nephropathy. It covers genetic variation, aberrant IgA1 v

6 vi Preface production, and classification, etiology, guidelines, and treatment goals, with each chapter written by top international researchers. Many thanks go to Professor Emeritus Toshikazu Shirai, Juntendo University, Tokyo, Japan, who introduced me to the field of IgA nephropathy and first suggested ways in which it could be studied in the laboratory; to many other physicians who have continuously sustained me in my efforts over the years; to the technicians, dieticians, and nurses who have performed so many of the experiments or clinical tests; and to my many patients whose diseases have always provided the most important of insights. Finally, I wish to thank all of the authors for their contributions to this volume and my family for the many hours of relaxation they provided when I was away from my work. Overlooking the Tokyo Metropolitan Building Tokyo, Japan August 2015 Yasuhiko Tomino

7 Overview Yasuhiko Tomino Division of Nephropathy, Department of Internal Medicine, Faculty of Medicine, Juntendo University, Tokyo, Japan, (Present Address: Medical Corporation SHOWAKAI, Tokyo, Japan) Pathogenesis of IgA Nephropathy IgA nephropathy is generally considered to be an immune-complex-mediated or galactose-deficient polymerized IgA (Gd IgA1)-mediated glomerulonephritis. Genetic factors are considered to be involved in the initiation and progression of IgA nephropathy. It has been hypothesized that susceptibility genes for IgA nephropathy can be detected by a genome-wide scan using a spontaneous animal model, i.e., the ddy mouse strain. The peak marker D10MIT 86 on chromosome 10 is located on a region syntenic to human 6q22-23 with IGAN1, which is responsible for familiar IgA nephropathy. Thus, it is important to determine the pathogenesis of Gd IgA1 production and the occurrence of sporadic IgA nephropathy. There are several developmental and/or exacerbating factors in this disease. Factors previously reported to be associated with disease progression include the male sex, age, prolonged duration, nephrotic range proteinuria, hypertension, glomerular sclerosis, and tubulointerstitial injury in patients with IgA nephropathy. Other developmental and/or exacerbating factors for patients with IgA nephropathy are: (1) complement activation, (2) blood coagulation activity and/or its inhibition in plasma, (3) the activity of cytokines/growth factors, (4) the activity of reactive oxygen species (ROS), (5) the activation of adhesion molecules, (6) apoptosis, (7) podocyte loss (podocytopenia), and (8) the role of megalin. It is widely assumed that glomerular mesangial cell proliferation and mesangial expansion represent major pathological mechanisms in this disease using the animal models. Treatment for IgA Nephropathy Previous global approaches to drug therapy of IgA nephropathy have included antiplatelet drugs, anticoagulants, prednisolone (PSL), immunosuppressants, fish oil, renin angiotensin system (RAS) inhibitors (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers), and/or tonsillectomy. At present, the most vii

8 viii Overview important therapeutic goal in patients with IgA nephropathy is the control of hypertension and the decrease of urinary protein excretion. Blood pressure of less than 130/80 mmhg is the therapeutic target in patients with IgA nephropathy. Patients with more or less normal renal function, with or without proteinuria or hypertension, have been preferably treated with RAS inhibitors. Several investigators reported that RAS inhibitors reduce the levels of urinary protein excretion and preserve renal function in patients with IgA nephropathy. Furthermore, RAS inhibitors are recommended on the basis of their beneficial effects on the production of cytokines and extracellular matrix (ECM) components, even when hypertension is not present. RAS inhibitors are generally considered to have cardiac and renal protective actions, and they may improve glomerular hypertension due to the dilatation of efferent arterioles in the kidneys and also suppress glomerular sclerosis. The nonspecific therapeutic approach involves a reduction in the dietary intake of protein in patients with IgA nephropathy who have developed renal failure. Long-term dietary restriction is generally considered to reduce the levels of urinary protein and ameliorate glomerular injuries in patients with IgA nephropathy. The committees on IgA nephropathy locally and internationally have published several clinical guidelines, including the KDIGO and Japanese guidelines, for the diagnosis and treatment of patients with this disease. However, there are controversies surrounding the treatment of this disease in many societies of nephrology. One such controversy is the use of tonsillectomy, which has been applied in patients with IgA nephropathy for two reasons, especially in Japan. First, tonsillar lymphocytes from patients with IgA nephropathy have been found to produce more polymeric IgA than healthy controls. It has been assumed that the removal of tonsillar tissues might reduce the production of polymeric Gd IgA1. Second, tonsillitis is a frequent precipitating event leading to macroscopic hematuria and proteinuria, frequent glomerular crescent formation, acute tubular injury, and/or a reduction in glomerular filtration rate (GFR). Therefore, tonsillectomy may reduce the frequency of renal parenchymal damage resulting from episodes of macroscopic hematuria and proteinuria. In Japan, it is suggested that tonsillectomy with steroid pulse therapy may provide a rapid and good therapeutic outcome in IgA nephropathy patients who show high expression of TLR9 in tonsillar plasmacytoid dendritic cells. Because controversies continue to exist for the treatment of this disease, it is important to develop new treatment strategies for this disease, such as bone marrow transplantation (BMT), using spontaneous animal models and then applying it to patients. Because the treatment of IgA nephropathy is still controversial internationally, several current topics of etiology and treatment amongst the various societies of nephrology will be discussed in this book.

9 Contents Part I Pathogenesis 1 Is IgA Nephropathy a Single Disease?... 3 Chee Kay Cheung and Jonathan Barratt 2 Advances in Genetics of Immunoglobulin A Nephropathy Hong Zhang, Riccardo Magistroni, and Ali Gharavi 3 Is IgA Nephropathy (IgAN) a Familial or Sporadic Disease? Ichiei Narita, Yoshikatsu Kaneko, Yumi Itoh, Yuichi Sakamaki, Seitaro Iguchi, Suguru Yamamoto, Minako Wakasugi, Junichiro J. Kazama, and Shin Goto 4 Heterogeneity of Aberrant O-Glycosylation of IgA1 in IgA Nephropathy Jan Novak, Kazuo Takahashi, Hitoshi Suzuki, Colin Reily, Tyler Stewart, Hiroyuki Ueda, Koshi Yamada, Zina Moldoveanu, M. Colleen Hastings, Robert J. Wyatt, Jiri Mestecky, Milan Raska, Bruce A. Julian, and Matthew B. Renfrow 5 Differences of Histological Classification Between the Japanese Histological Grade Classification and the Oxford Classification Kensuke Joh and Keely May McNamara 6 Podocyte Injury and Significance of Urinary Podocalyxin and Megalin Katsuhiko Asanuma 7 Complement Activation Isao Ohsawa ix

10 x Contents Part II Treatment 8 How Different Are the Current Understandings of Treatments for IgA Nephropathy? Hitoshi Suzuki 9 Prognostic Indicators and Treatment of IgA Nephropathy in China Wei-Bo Le and Zhi-Hong Liu 10 The Differences in Etiology and Treatment of IgA Nephropathy in Korea Dong-Wan Chae 11 Differences in Etiology and Treatment in Japan Ritsuko Katafuchi 12 IgA Nephropathy from the VALIGA European Study: Differences in Treatment Approaches Within Europe Rosanna Coppo 13 Differences in Etiology and Treatment in Scandinavian Countries Jukka Mustonen, Kati Kaartinen, Jaana Syrjänen, and Ilkka P orsti 14 The Implication of the KDIGO Clinical Practice Guidelines on Management of IgA Nephropathy Philip Kam-tao Li and Kai Ming Chow 15 Japanese Clinical Practice Guidelines for IgA Nephropathy: Difference from KDIGO Guidelines Kazuo Takahashi, Ryohei Yamamoto, and Yukio Yuzawa 16 Limitations of RAS Blockade in IgA Nephropathy Ryohei Yamamoto 17 What Is the Goal for Proteinuria in IgA Nephropathy? Kyoko Watanabe and Keita Hirano 18 Beyond the Differences in Tonsillectomy in IgA Nephropathy: From Rationale To Indications in Patients Yusuke Suzuki, Rosanna Coppo, and Yasuhiko Tomino 19 Is Tonsillectomy a Possible Treatment for IgA Nephropathy from Randomized Controlled Trial (RCT)? Tetsuya Kawamura 20 Validity of the Japanese Clinical Grade Criteria: Results from the Nationwide Retrospective Cohort Study in IgA Nephropathy Takashi Yasuda, Yoshinari Yasuda, Sachiko Ohde, Osamu Takahashi, Tetsuya Kawamura, and Seiichi Matsuo

11 Contents xi Column 1: Spontaneous Animal Model Hitoshi Suzuki Column 2: Bone Marrow Transplantation (BMT) Using an Animal Model Hitoshi Suzuki