Main IgA Nephropathy Today
IgA Nephropathy TodayYasuhiko Tomino
A further step towards unraveling this mysterious disease Primary IgA nephropathy has first been described as a new disease entity almost 40 years ago. This disorder, considered to be an immune-complex-mediated glomerulonephritis, is characterized by granular deposition of IgA (mainly IgA1) and C3 in the glomerular mesangial areas and is defined as nephropathy showing proliferative changes in the glomerular mesangial cells and increases in the mesangial matrices. Apart from being one of the most common types of chronic glomerulonephritis, it is also the most frequent case of end-stage renal disease. But even though continuing efforts have gradually clarified various aspects of the pathogenesis of the disease, specific treatment is not yet available. In this publication, international nephrologists and basic scientists report the most recent data on IgA nephropathy. Starting with clinical reviews on topics such as the clinico-pathological classification, new treatment approaches, and the role of renal biopsies, the focus then shifts towards basic reviews on, for example, candidate genes, the pathogenic role of IgA receptors or immune complex formation. Updates on clinical and basic advances, discussing among other things the influence of obesity or various therapeutic approaches, make up the second part of the book. Presenting up-to-date information on this still mysterious disease, the publication at hand constitutes a valuable source of information for nephrologists, general practitioners, residents and interns.
IgA Nephropathy Today Contributions to Nephrology Vol. 157 Series Editor Claudio Ronco, Vicenza IgA Nephropathy Today Volume Editor Yasuhiko Tomino, Tokyo 24 figures, 5 in color, and 10 tables, 2007 Basel · Freiburg · Paris · London · New York · Bangalore · Bangkok · Singapore · Tokyo · Sydney Contributions to Nephrology (Founded 1975 by Geoffrey M. Berlyne) Yasuhiko Tomino Division of Nephrology Department of Internal Medicine Juntendo University School of Medicine 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan) Library of Congress Cataloging-in-Publication Data International Symposium on IgA Nephropathy (11th : 2006 : Tokyo, Japan) IgA nephropathy today / volume editor, Yasuhiko Tomino. p. ; cm. – (Contributions to nephrology, ISSN 0302-5144 ; v. 157) “11th International Symposium on IgA Nephropathy, October 5–7, 2006, Tokyo, Japan”–Foreword. Includes bibliographical references and index. ISBN-13: 978–3–8055–8286–5 (hard cover : alk. paper) 1. IgA glomerulonephritis–Congresses. I. Tomino, Yasuhiko, 1949– II. Title. III. Series. [DNLM: 1. Glomerulonephritis, IGA–etiology–Congresses. 2. Glomerulonephritis, IGA–therapy–Congresses. W1 CO778UN v.157 2007 / WJ 353 I6085i 2007] RC918.I35I585 2006 616.6⬘1–dc22 2007011107 Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and Index Medicus. Disclaimer. The statements, options and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage. 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Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISSN 0302–5144 ISBN 978–3–8055–8286–5 Contents IX Foreword Tomino, Y. (Tokyo) Chairman’s Reviews 1 Pathogenesis of IgA Nephropathy Tomino, Y. (Tokyo) 8 Treatment for IgA Nephropathy Tomino, Y. (Tokyo) Clinical Reviews of IgA Nephropathy 13 International IgA Nephropathy Network Clinico-Pathological Classification of IgA Nephropathy Feehally, J.; Barratt, J. (Leicester); Coppo, R. (Turin); Cook, T. (London); Roberts, I. (Oxford); on behalf of the International IgA Nephropathy Network 19 IgA Nephropathy: A Clinical Overview Julian, B.A. (Birmingham, Ala.); Wyatt, R.J. (Memphis, Tenn.); Matousovic, K. (Prague/Pilsen); Moldoveanu, Z.; Mestecky, J.; Novak, J. (Birmingham, Ala.) 27 Angiotensin Antagonists and Fish Oil for Treating IgA Nephropathy Coppo, R.; Amore, A.; Peruzzi, L.; Mancuso, D.; Camilla, R. (Turin) V 37 Treatment of IgA Nephropathy: Corticosteroids, Tonsillectomy, and Mycophenolate Mofetil Kawamura, T. (Tokyo) 44 Interpretation of Renal Biopsies in IgA Nephropathy Cook, H.T. (London) Basic Reviews of IgA Nephropathy 50 Altered Expression of Lymphocyte Homing Chemokines in the Pathogenesis of IgA Nephropathy Buren, M.; Yamashita, M. (Cleveland, Ohio); Suzuki, Y.; Tomino, Y. (Tokyo); Emancipator, S.N. (Cleveland, Ohio) 56 IgA Nephropathy: Current Views of Immune Complex Formation Mestecky, J. (Birmingham, Ala.); Suzuki, H.; Yanagihara, T. (Birmingham, Ala./Tokyo); Moldoveanu, Z.; Tomana, M. (Birmingham, Ala.); Matousovic, K. (Birmingham, Ala./ Prague/Pilsen); Julian, B.A.; Novak, J. (Birmingham, Ala.) 64 Pathogenic Role of IgA Receptors in IgA Nephropathy Monteiro, R.C. (Paris) 70 The Mucosa-Bone-Marrow Axis in IgA Nephropathy Suzuki, Y.; Tomino, Y. (Tokyo) 80 Searching for IgA Nephropathy Candidate Genes: Genetic Studies Combined with High Throughput Innovative Investigations Schena, F.P.; Cerullo, G.; Torres, D.D.; Zaza, G.; Cox, S. (Bari); Bisceglia, L. (San Giovanni Rotondo); Scolari, F. (Brescia); Frascà, G. (Ancona); Ghiggeri, G.M. (Genoa); Amoroso, A. (Turin); on behalf of the European IgA Nephropathy Consortium Clinical Advances (Update) 90 Clinicopathological Influence of Obesity in IgA Nephropathy: Comparative Study of 74 Patients Tanaka, M.; Tsujii, T.; Komiya, T.; Iwasaki, Y.; Sugishita, T.; Yonemoto, S.; Tsukamoto, T.; Fukui, S.; Takasu, A.; Muso, E. (Osaka) 94 A Multicenter Prospective Cohort Study of Tonsillectomy and Steroid Therapy in Japanese Patients with IgA Nephropathy: A 5-Year Report Miyazaki, M.; Hotta, O. (Sendai); Komatsuda, A. (Akita); Nakai, S. (Osaka); Shoji, T. (Nagoya); Yasunaga, C. (Kitakyusyu); Taguma, Y. (Sendai); Japanese Multicenter Study Group on the Treatment of IgA Nephropathy (JST-IgAN) 99 Tonsillectomy and Corticosteroid Therapy with Concomitant Methylprednisolone Pulse Therapy for IgA Nephropathy Suwabe, T.; Ubara, Y.; Sogawa, Y.; Higa, Y.; Nomura, K.; Nakanishi, S.; Hoshino, J.; Sawa, N.; Katori, H.; Takemoto, F.; Hara, S.; Ohashi, K.; Takaichi, K. (Tokyo) Contents VI 104 Impact of Annual Urine Health Check-Up System to Obtain Clinical Remission in Patients with IgA Nephropathy Ieiri, N.; Hotta, O.; Taguma, Y. (Miyagi) 109 Sequential Immunosuppressive Therapy in Progressive IgA Nephropathy Rasche, F.M.; Keller, F.; von Müller, L.; Czock, D. (Ulm); Lepper, P.M. (Berne) 114 Prospective Trial of Combined Therapy with Heparin/Warfarin and Renin-Angiotensin System Inhibitors in Progressive IgA Nephropathy Ishii, T.; Kawamura, T.; Tsuboi, N.; Ogura, M.; Utsunomiya, Y.; Hosoya, T. (Tokyo) Basic Advances (Update) 120 Downregulation of the ␤1,3-Galactosyltransferase Gene in Tonsillar B Lymphocytes and Aberrant Lectin Bindings to Tonsillar IgA as a Pathogenesis of IgA Nephropathy Inoue, T.; Sugiyama, H.; Kikumoto, Y.; Fukuoka, N.; Maeshima, Y.; Hattori, H.; Fukushima, K.; Nishizaki, K. (Okayama); Hiki, Y. (Toyoake); Makino, H. (Okayama) 125 Development of IgA Nephropathy-Like Disease with High Serum IgA Levels and Increased Proportion of Polymeric IgA in ␤-1,4-Galactosyltransferase-Deficient Mice Nishie, T. (Kanazawa); Miyaishi, O. (Aichi); Azuma, H. (Osaka); Kameyama, A. (Ibaraki); Naruse, C.; Hashimoto, N.; Yokoyama, H. (Kanazawa); Narimatsu, H. (Ibaraki); Wada, T.; Asano, M. (Kanazawa) 129 IgA Nephropathy: Characterization of IgG Antibodies Specific for Galactose-Deficient IgA1 Suzuki, H. (Birmingham, Ala./Tokyo); Moldoveanu, Z.; Hall, S.; Brown, R.; Julian, B.A. (Birmingham, Ala.); Wyatt, R.J. (Memphis, Tenn.); Tomana, M. (Birmingham, Ala.); Tomino, Y. (Tokyo); Novak, J.; Mestecky, J. (Birmingham, Ala.) 134 IgA Nephropathy and Henoch-Schoenlein Purpura Nephritis: Aberrant Glycosylation of IgA1, Formation of IgA1-Containing Immune Complexes, and Activation of Mesangial Cells Novak, J.; Moldoveanu, Z.; Renfrow, M.B.; Yanagihara, T.; Suzuki, H.; Raska, M.; Hall, S.; Brown, R.; Huang, W.-Q.; Goepfert, A. (Birmingham, Ala.); Kilian, M.; Poulsen, K. (Aarhus); Tomana, M. (Birmingham, Ala.); Wyatt, R.J. (Memphis, Tenn.); Julian, B.A.; Mestecky, J. (Birmingham, Ala.) 139 Patients with IgA Nephropathy Respond Strongly Through Production of IgA with Low Avidity Against Staphylococcus aureus Shimizu, Y.; Seki, M.; Kaneko, S.; Hagiwara, M.; Yoh, K.; Yamagata, K. (Tsukuba); Koyama, A. (Ami) Contents VII 144 Transferrin Receptor Engagement by Polymeric IgA1 Induces Receptor Expression and Mesangial Cell Proliferation: Role in IgA Nephropathy Tamouza, H.; Vende, F.; Tiwari, M.; Arcos-Fajardo, M.; Vrtovsnik, F.; Benhamou, M.; Monteiro, R.C.; Moura, I.C. (Paris) 148 IgA Fc Receptor I Is a Molecular Switch that Determines IgA Activating or Inhibitory Functions Kanamaru, Y.; Blank, U.; Monteiro, R.C. (Paris) 153 The Role of PDGF-D in Mesangioproliferative Glomerulonephritis Floege, J.; van Roeyen, C.; Boor, P.; Ostendorf, T. (Aachen) 159 Analysis of Innate Immune Responses in a Model of IgA Nephropathy Induced by Sendai Virus Yamashita, M.; Chintalacharuvu, S.R. (Cleveland, Ohio); Kobayashi, N. (Tokyo); Nedrud, J.G.; Lamm, M.E. (Cleveland, Ohio); Tomino, Y. (Tokyo); Emancipator, S.N. (Cleveland, Ohio) 164 Roles of Bone Marrow, Mucosa and Lymphoid Tissues in Pathogenesis of Murine IgA Nephropathy Aizawa, M.; Suzuki, Y.; Suzuki, H.; Pang, H.; Kihara, M.; Yamaji, K.; Horikoshi, S.; Tomino, Y. (Tokyo) 169 Concluding Remarks Glassock, R.J. (Los Angeles, Calif.) Abstracts 174 Clinical Reviews of IgA Nephropathy 180 Basic Reviews of IgA Nephropathy 185 Clinical Advances (Update) 215 Basic Advances (Update) 243 Closing Remarks 244 Author Index 249 Subject Index Contents VIII Foreword Almost 40 years have passed since Dr. Jean Berger first described primary IgA nephropathy as a new disease entity. This disease may lead to end-stage renal disease (ESRD) with its enormous economic impact on healthcare everywhere. Since the pathogenesis of IgA nephropathy is still obscure, specific treatment is not yet available. However, efforts by many investigators around the world have gradually clarified various aspects of the pathogenesis and treatment of this disease. The objectives of the 11th International Symposium on IgA nephropathy (October 5–7, 2006) are (1) to discuss the most up-to-date findings on pathogenesis and treatment of IgA nephropathy and (2) to build friendship among us. This symposium is truly a small specialized meeting with the participation of international nephrologists and basic scientists involved in the large topic of IgA nephropathy. This article is a summary of the topics presented in the 11th International Symposium on IgA nephropathy. This symposium was made possible by the generosity of our sponsors. Thanks go to the members of the Organizing and Scientific Committees, my colleagues in the Division of Nephrology at Juntendo University and the sponsors. Autumn 2006 Yasuhiko Tomino, MD, PhD President, 11th International Symposium on IgA Nephropathy Professor, Division of Nephrology, Department of Internal Medicine Dean, Juntendo University School of Medicine, Tokyo, Japan IX Acknowledgments We sincerely thank the people mentioned below for their collaboration with the 11th International Symposium of IgA Nephropathy in Tokyo, and with the editing of this book. In addition, we especially appreciate the excellent and dedicated assistance by Mr. Makishima and Dr. Hidaka. Medical Toyu Co. Ltd. Nobukazu Kai Syunta Aramaki Shigehiro Makishima Nana Harada Hiroyuki Miyazawa Michiko Kai Juntendo University School of Medicine Satoshi Horikoshi Isao Ohsawa Toshinao Tsuge Noriyoshi Kobayashi Hitoshi Suzuki Teruo Hidaka Masao Kihara Eri Izumida Hirofumi Ohba Rei Kuze Terumi Shibata Kazutaka Yoshida X Chairman’s Reviews Tomino Y (ed): IgA Nephropathy Today. Contrib Nephrol. Basel, Karger, 2007, vol 157, pp 1–7 Pathogenesis of IgA Nephropathy Yasuhiko Tomino Division of Nephrology, Department of Internal Medicine, Juntendo University, Tokyo, Japan Abstract IgA nephropathy is generally considered to be an immune-complex-mediated or aggregated (polymerized) IgA (IgA1)-mediated glomerulonephritis. Since the pathogenesis of IgA nephropathy is still obscure, it is important to determine the initiation and progression of this disease using the spontaneous animal model. The ddY mouse strain can serve as a spontaneous animal model for IgA nephropathy. 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 this model. The peak marker D10MIT 86 on chromosome 10 is located on the region syntenic to human 6q22–23 with IGAN1, which is responsible for familiar IgA nephropathy. There are several developmental and/or exacerbating factors in this disease. Among them, the loss of glomerular epithelial cells (podocytes) and interstitial mast cell infiltration are important factors for progression of glomerulosclerosis and tubulointerstitial injury in patients with IgA nephropathy. Copyright © 2007 S. Karger AG, Basel Determination of Pathogenesis of IgA Nephropathy using ddY Mice, a Spontaneous Animal Model for IgA Nephropathy Although the etiology and pathogenesis of IgA nephropathy are still obscure, much is known about serum IgA and mesangially deposited IgA (fig. 1). IgA is the most common immunoglobulin produced by lymphocytes and plasma cells lining the mucosal membranes, and is the main immunoglobulin directed against bacterial or viral antigens in exogenous secretions. Imai et al.  reported that the ddY mouse strain can serve as a spontaneous animal model for IgA nephropathy, since these mice show mesangioproliferative glomerulonephritis with severe glomerular IgA deposition. In these mice, at over 40 weeks of age Antibody Antigen Trigger ? Genetic ? Alteration of molecules in the hinge region of IgA (IgA1) Virus, fungus, bacteria, food, IgG, IgM, IgA1, fibronectin, laminin Genetic factors Antigen antibody-dependent Antigen antibody-independent Aggregated IgA1 (nephritogenic IgA1) IgA (IgA1)-IC • Pinocytosis • Charge • Cytokine • Complement Receptors • Fc␣R, novel Fc␣R • Fc␣R • ASGPR • plgR • Transferrin R IgA deposition in mesangial areas/cells Fig. 1. Initiation of IgA nephropathy. marked deposition of IgA and C3 occurs in the glomerular mesangial areas, in association with an increase in the levels of IgA and macromolecular IgAimmune complex in the serum [1, 2]. IgA nephropathy is generally considered to be an immune-complex-mediated or aggregated (polymerized) IgA (IgA1)mediated glomerulonephritis. However, the antigens or stimulators that produce the aggregated (polymerized) IgA involved in this disease are still obscure. Several antigens originating in the respiratory, intestinal and/or biliary tracts and some dietary antigens have been implicated. Previous studies revealed that murine retroviral gp70 is involved in the pathogenesis of lupus nephritis in systemic lupus erythematosus (SLE)-prone NZB, NZB ⫻ NZWF1, BXSB and MRL/Mp-lpr/lpr mice [3, 4]. Takeuchi et al.  reported that the murine retroviral envelope glycoprotein, gp70, is deposited in the glomerular mesangial areas in ddY mice over 24 weeks, in the same way as IgG and IgA. Gp70 is also present in various lymphoid tissues. Thus, they suggested that gp70 derived from lymphoid tissues circulates as immune complexes and is deposited in the glomerular mesangial areas. It may be one of the pathogenic antigens involved in renal disease of ddY mice. We examined the deposition of the major retroviral envelop glycoprotein, gp70, in glomeruli of ddY mice by immunofluorescence . Positive staining of gp70 was not observed in glomeruli of our strain of ddY mice at any age examined using two different anti-gp70 antisera and three Tomino 2 different staining conditions, whereas deposition of IgA, IgG and IgM was manifest in mice aged over 40 weeks. It appears that gp70 deposition may not be sine qua non for the pathogenesis of IgA nephropathy, and that ddY mice may have a heterogenous genetic background, resembling the situation in humans. Genetic factors are considered to be involved in the initiation and progression of IgA nephropathy on the basis of racial differences in prevalence and familial aggregation. It has been hypothesized that susceptibility genes for IgA nephropathy can be detected by a genome-wide scan using this model . First, serial renal biopsies were performed at 20, 40 and 60 weeks of age in 361 ddY mice. The ddY mice were classified into three groups on the basis of onset of glomerular injury as follows: early onset at 20 weeks (31.9%), late onset at 40 weeks (37.9%) and quiescence at 60 weeks (30.2%). The severity of glomerular lesions in both onset groups correlated with the intensity of glomerular IgA deposition but not with serum IgA levels. A genome-wide scan using 270 microsatellite markers identified three chromosomal regions on chromosomes 1, 9 and 10, which were significantly associated with the glomerular injuries. Surprisingly, the peak marker D10MIT86 on chromosome 10 is located on the region syntenic to human 6q22–23 with IGAN1, which might be responsible for familial IgA nephropathy . In addition, D1MIT16 on chromosome 1 was located very close to the locus of the selectin gene, which is a known candidate for human IgA nephropathy. It appears that the three-group ddY mouse model can be a useful tool for identifying susceptibility genes and also for examining their roles in the pathogenesis of IgA nephropathy. Mechanisms of Progression in IgA Nephropathy Factors previously reported to be associated with disease progression include male sex, age, prolonged duration, nephrotic range proteinuria, hypertension and glomerular sclerosis 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) activity of cytokines/growth factors; (4) activity of reactive oxygen species (ROS); (5) activation of adhesion molecules; (6) apoptosis; (7) podocyte injury (loss) and (8) interstitial mast cell infiltration (fig. 2). Among them, podocyte injury and interstitial mast cell infiltration from our data are reviewed in this chapter. Loss of Glomerular Epithelial Cells (Podocytes) It is widely assumed that glomerular mesangial cell proliferation and mesangial expansion represent major pathological mechanisms underlying Pathogenesis of IgA Nephropathy 3 IgA deposition in mesangial areas/cells (activation) Cell infiltration Genetic factors Cytokine, chemokine and growth factor ROS (reactive oxygen species) Complement (local production) Platelet aggregation/blood coagulation Adhesion molecule Repair ? Mesangial expansion Podocyte damage Chemokine Cytokine Transferrin Complement FcRn (IgG) ? Cell proliferation Result Glomerulo-tubular cross-talk Cause Apoptosis Proteinuria Interstitial damage Tubulo-interstitial cross-talk Tubular damage Macrophage, lymphocyte, mast cell, fibroblast ESRF Fig. 2. Progression of IgA nephropathy. progression to glomerular sclerosis. Marked glomerular mesangial expansion is accompanied by a further increase in total glomerular volume. Broadening of the podocyte foot processes is associated with a reduction in the number of podocytes per glomerulus and an increase in the surface area covered by the remaining podocytes. Podocyte loss appears to contribute to progression of IgA nephropathy. Hypotheses concerning the cause of podocyte loss are: (a) glomerular hypertrophy and hypertension may cause podocyte injury, and (b) mesangial expansion beyond some critical point can presumably cause closure of capillary loops and obliteration of the podocytes . Morphological studies on experimental models of progressive glomerular disease have identified the detachment of podocytes from the glomerular basement membrane (GBM) as a critical step in the development and progression of glomerulosclerosis. Several molecular mechanisms for the detachment have been proposed, including reorganization of the actin cytoskeleton in podocytes, apoptosis of podocytes and oxidation of the GBM . To predict progression in patients with IgA nephropathy, we analyzed glomerular lesions except for sclerosis, adhesion and/or crescents in 34 patients with this disease by morphometric analysis. Levels of urinary protein excretion, creatinine clearance (Ccr), serum creatinine (sCr) and mean blood pressure at the time of renal biopsy were used as clinical parameters. The slope of 1/sCr was also used as a prognostic parameter. Renal Tomino 4 specimens were obtained by echo-guided biopsy. In PAS-stained light microscopic renal sections, three mid sections of open glomeruli were selected and photographed. Stereologic estimation was performed as follows: absolute values of glomerular volume (V(G)), glomerular surface area (S(G)), podocyte and nonpodocyte cell number per glomerulus [N(G(pod)) and N(G(Non-pod))], glomerular surface area covered by one podocyte [S(G)/N(G(pod))] and glomerular volume occupied by one nonpodocyte cell [V(G)/N(G(Non-pod))]. There was a significant correlation between the levels of urinary protein excretion and the change of podocyte injury parameters [N(G(pod)) and S(G)/N(G(pod))] or N(G(Non-pod)). N(G(pod)) was negatively correlated but S(G)/N(G(pod)) and N(G(Non-pod)) were positively correlated with urinary protein excretion. S(G)/N(G(pod)) and N(G(Non-pod)) were correlated with mean blood pressure. N(G(pod)), S(G)/N(G(pod)), N(G(Non-pod)), urinary protein excretion and mean blood pressure were significantly correlated with the slope of 1/sCr. High specificity was observed for N(G(pod)), S(G)/N(G(pod)) and mean blood pressure. High sensitivity was also observed for N(G(Non-pod)) and urinary protein excretion. It appears that podocyte injury might provide additional prognostic information in patients with IgA nephropathy . Further examinations are warranted to calculate the number of podocytes by electron microscopy to detect the outcome in patients with IgA nephropathy. Interstitial Mast Cell Infiltration Mast cells (MC) are derived from hematopoietic progenitors and migrate into inflammatory lesions. Human MC can be classified into two types according to their protease composition: those containing only tryptase (MC(T)) and those containing both tryptase and chymase (MC(TC)) . MC(T) may play a role in immunological responses, whereas MC(TC) seem to play roles in angiogenesis and tissue remodeling. The role of MC in renal inflammatory and fibrotic processes has recently attracted considerable attention. Although the mechanism of the protection provided by MC is poorly understood, hormonal mediators released from MC are thought to protect against interstitial fibrosis. Heparin, e.g., is one of the molecules released by the secretory granules of MC and is well known for its anticoagulant activity and inhibition of the production of TGF-␤. MC have been observed in the renal interstitium of patients with primary glomerular diseases. Their levels increase with progression of tubulointerstitial fibrosis in patients with IgA nephropathy. Kurusu et al.  reported that the number of MC in non-fibrotic tubulointerstitial fields can be a predictor of the renal prognosis of patients with IgA nephropathy. In vitro studies have revealed that MC also produce inflammatory mediators other than histamine, such as Pathogenesis of IgA Nephropathy 5 fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF). Accordingly, MC are assumed to contribute to the development of renal interstitial fibrosis in humans. Angiotensin II (Ang II) is closely involved in the pathogenesis of renal fibrosis and is generated by chymases as well as by angiotensin converting enzyme (ACE). It has been suggested that ACE works mainly in intravascular areas, while chymases work mainly in extravascular areas. Human MC have one ␣-chymase, which generates Ang II by cleaving the terminal His and Leu residues from Ang I, whereas rodents express various kinds of ␤-chymase . Rat ␤-chymase destroys Ang II by cleaving it between Tyr4 and Ile5, but the mouse ␤-chymase MC protease 4 (mMCP-4) generates Ang II in the same way as human ␣-chymase . Sakamoto-Ihara et al. investigated whether human MC contribute to renal fibrosis through local activation of the renin-angiotensin system by assessing their numbers in renal biopsy specimens from patients with IgA nephropathy or minimal change nephrotic syndrome (MCNS). In patients with IgA nephropathy and MCNS, the numbers of tryptase-positive MC (MC(T)) and MC positive for both tryptase and chymase (MC(TC)) were examined histopathologically. sCr, mean blood pressure and the severity of glomerular and tubulointerstitial lesions were also determined. MC(TC) numbers differed between IgA nephropathy patients and MCNS patients. IgA nephropathy patients had more MC(TC) than MC(T). MC were found around but not in the conglomerate of Ang II-positive infiltrating cells. In IgA nephropathy patients with the most severe pathology, the number of Ang II-positive cells was correlated with that of MC(TC) and MC(T). It appears that chymase-dependent Ang II synthesis due to human MC may be involved in the inflammatory and fibrotic processes of IgA nephropathy (submitted). References 1 2 3 4 5 6 Imai H, Nakamoto Y, Asakura K, et al: Spontaneous glomerular IgA deposition in ddY mice: An animal model of IgA nephritis. Kidney Int 1985;27:756–761. Tomino Y, Nakamura T, Ebihara I, et al: Altered steady-state of mRNA coding for extracellular matrices in renal tissues of ddY mice, an animal model for IgA nephropathy. J Clin Lab Anal 1991;5:106–113. Yoshiki T, Mellors RC, Strand M, et al: The viral envelope glycoprotein of murine leukemia virus and the pathogenesis of immune complex glomerulonephritis of New Zealand mice. J Exp Med 1974;140:1011–1027. Izui S, MaConahey PJ, Theofilopoulos AN, et al: Association of circulating retroviral gp70-anti-gp70 immune complexes with murine systemic lupus erythematosus. J Exp Med 1979;149:1099–1116. Takeuchi E, Doi T, Shimada T, et al: Retroviral gp70 antigen in spontaneous mesangial glomerulonephritis of ddY mice. Kidney Int 1989;35:638–646. Shimizu M, Tomino Y, Abe M, et al: Retroviral envelope glycoprotein(gp 70) is not a prerequisite for pathogenesis of primary immunoglobulin A nephropathy in ddY mice. Nephron 1992;62: 328–331. Tomino 6 7 8 9 10 11 12 13 14 Suzuki H, Suzuki Y, Yamanaka T, et al: Genome-wide scan in a novel IgA nephropathy model identifies a susceptibility locus on murine chromosome 10, in a region syntenic to human IGAN1 on chromosome 6q22–23. J Am Soc Nephrol 2005;16:1289–1299. Pagtaluman ME, Miller PL, Jumping-Eagle S, et al: Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest 1997;99:342–348. Asanuma K, Shirato I, Ishido K, et al: Selective modulation of the secretion of proteinases and their inhibitors by growth factors in cultured differentiated podocytes. Kidney Int 2002;62: 822–831. Hishiki T, Shirato I, Takahashi Y, et al: Podocyte injury predicts prognosis in patients with IgA nephropathy using a small amount of renal biopsy tissue. Kidney Blood Press Res 2001:24: 99–104. Irani AA, Schechter NM, Craig SS, et al: Two types of human mast cells that have distinct neutral protease compositions. Proc Natl Acad Sci USA 1986;83:4464–4468. Kurusu A, Suzuki Y, Horikoshi S, et al: Relationship between mast cells in the tubulointerstitium and prognosis of patients with IgA nephropathy. Nephron 2001;89:391–397. Chandrasekharan UM, Sanker S, Glynias MJ, et al: Angiotensin II-forming activity in a reconstructed ancestral chymase. Science 1996;271:502–505. Caughey GH, Raymond WW, Wolters PJ, et al: Angiotensin II generation by mast cell alpha- and beta-chymases. Biochim Biophys Acta 2000;1480:245–257. Yasuhiko Tomino Division of Nephrology, Department of Internal Medicine Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku 113–8421 Tokyo (Japan) Tel. ⫹81 3 5802 1065, Fax ⫹81 3 3813 1183, E-Mail firstname.lastname@example.org Pathogenesis of IgA Nephropathy 7 Tomino Y (ed): IgA Nephropathy Today. Contrib Nephrol. Basel, Karger, 2007, vol 157, pp 8–12 Treatment for IgA Nephropathy Yasuhiko Tomino Division of Nephrology, Department of Internal Medicine, Juntendo University, Tokyo, Japan Abstract The Committee on IgA nephropathy in Japan has published new clinical guidelines (2nd edition) for the diagnosis and treatment of patients with this disease. The nonspecific therapeutic approach involves a reduction of dietary intake of protein in patients with IgA nephropathy who have developed renal failure. At present, the most important therapeutic goal in patients with IgA nephropathy is the control of hypertension. It has been assumed that removal of tonsillar tissues might reduce the production of polymeric IgA and decrease the frequency of renal parenchymal damage resulting from episodes of macroscopic hematuria and proteinuria. Although there have been no randomized controlled trials (RCT) of tonsillectomy, these are necessary to determine the efficacy of tonsillectomy in patients with IgA nephropathy. Copyright © 2007 S. Karger AG, Basel Current Strategy of Treatment in Patients with IgA Nephropathy in Japan Nonspecific therapeutic approach involves reduction of 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. Previous approaches to drug therapy of IgA nephropathy in Japan have included anti-platelet drugs, anticoagulants, prednisolone (PSL), immunosuppressants, fish oil, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB) and/or tonsillectomy. At present, the most important therapeutic goal in patients with IgA nephropathy is the control of hypertension. Blood pressure of less than 130/80 mm Hg 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 ACE inhibitors. Several investigators reported that ACE inhibitors reduce the levels of urinary protein excretion and preserve renal function on patients with IgA nephropathy. Furthermore, ACE 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. ACE inhibitors are generally considered to have cardiac and renal protective actions, and they may improve glomerular hypertension due to dilatation of efferent arterioles in the kidneys and suppress glomerular sclerosis. Pulse therapy with high-dose corticosteroids has not been accepted in patients with IgA nephropathy, except in cases presenting as rapidly progressive glomerulonephritis characterized histologically by necrotizing and/or crescent formation, because the majority of patients with IgA nephropathy have an indolent course. Tonsillectomy has been applied in patients with IgA nephropathy for two reasons . First, tonsillar lymphocytes from patients with IgA nephropathy have been found to produce more polymeric IgA than healthy controls. Second, tonsillitis is a frequent precipitating event leading to macroscopic hematuria and, frequently, glomerular crescent formation, acute tubular injury, and/or a reduction in glomerular filtration rate (GFR). As a result of these observations, it has been assumed that removal of tonsillar tissues might reduce the production of polymeric IgA and decrease the frequency of renal parenchymal damage resulting from episodes of macroscopic hematuria . The macroscopic hematuria seen in IgA nephropathy is commonly precipitated by mucosal stimulation (e.g. pharyngitis) suggesting the possibility of aberrant mucosal immunity in the pathogenesis of IgA nephropathy. The tonsils are also a significant source of under-glycosylated IgA1, implicated in the pathogenesis of IgA deposition. Tonsillectomy also decreases the levels of serum IgA. However, there have been no randomized controlled trials (RCT). No recommendations can be made regarding tonsillectomy for disease progression in patients with IgA nephropathy on the basis of currently available retrospective studies and case reports in Kidney Disease Outcomes Quality Initiatives, UK Renal Association, European Best Practice Guidelines, International Guidelines and CARI (Caring for Australasians with Renal Impairment) Guidelines . The Canadian Society of Nephrology guidelines state that tonsillectomy could reduce proteinuria and hematuria in IgA nephropathy patients with recurrent tonsillitis. Tonsillectomy should be performed in patients with appropriate ENT (ear, nose, and throat) indications. Controlled trials are needed before tonsillectomy should be considered for any other group. Kano et al. in my division investigated toll-like receptor (TLR) expression in tonsils from IgA nephropathy and determined their cell types. It is suggested Treatment for IgA Nephropathy 9 that tonsillectomy with steroid pulse therapy may provide rapid and good therapeutic outcomes in IgA nephropathy patients who show high expression of TLR9 in tonsillar plasmacytoid dendric cells. It appears that TLR9 activation in the mucosa may be involved in the pathogenesis of this disease (submitted). Guidelines for the Treatment of IgA Nephropathy in Japan, 2nd Version (Joint Committee of the Japanese Ministry of Health, Labor and Welfare) The committee on IgA nephropathy of the Special Study Group on Progressive Glomerular Diseases of the Japanese Ministry of Health, Labor and Welfare published new clinical guidelines (2nd version) for the diagnosis and treatment of patients with IgA nephropathy in Japan . Patients with IgA nephropathy are divided into the following four groups at the time of renal biopsy: (a) good prognosis group: almost no necessity of dialysis; (b) relatively good prognosis group: probability of dialysis requirement is relatively low; (c) relatively poor prognosis group: dialysis is likely to be required within 5–20 years, and (d) poor prognosis group: high probability of dialysis requirement within 5 years. Selection of treatment should be based on renal biopsy and clinical findings (renal function) in each patient . Procedures Good Prognosis Group Regimen. No particular regimen. There are no special restrictions related to status except that extremely vigorous exercise should be avoided. Visits to an outpatient clinic once or twice a year for urinalysis and blood pressure determination are recommended. Diet Therapy. No particular therapy except for the avoidance of excessive salt intake. Drug Therapy. Drug therapy is not required in principle, but antiplatelet drugs are administered as required. Relatively Good Prognosis Group Regimen. No particular regimen is required, but the same recommendations apply as for the good prognosis group mentioned above. Visits to an outpatient clinic should be made at least three or four times a year. Diet Therapy. There is no particular diet therapy, but the same recommendations apply as for the good prognosis group mentioned above. Drug Therapy. Drug therapy is not required in principle, but antiplatelet drugs or adrenocorticosteroids are administered as required. Tomino 10 Relatively Poor Prognosis Group Regimen. Patients are instructed to avoid overworking. Regular office work or school activities are allowed. Working (especially night work) and sports are restricted based on urinalysis and renal function data. Care is necessary during childbearing and parturition. Visits to an outpatient clinic should be made once a month in principle, and blood chemistry and urinary protein should be tested, in addition to urinalysis and determination of blood pressure. Diet Therapy. Diet therapy includes a low-salt diet of 7–8 g/day, a low protein diet of 0.8–0.9 g/kg ideal body weight (IBW)/day and a calorie intake of 35 kcal/kg IBW/day. Water intake is not restricted unless edema is present. Diet therapy in children is adjusted according to age. Drug Therapy. The drug therapy regimen is summarized below: (a) Antiplatelet agents: Prolonged administration of an antiplatelet agent is common, but each drug must be checked for indications covered by health insurance. (b) Antihypertensive agents: Angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB) and/or diuretics should be used in patients without renal failure. For those with insufficient hypotensive effects or with renal failure, calcium antagonists (CCB) or ␣-blockers should be administered. If the decrease in blood pressure is still insufficient, ␣-methyldopa may be used concomitantly. (c) Adrenocorticosteroids: Adrenocorticosteroids should be administered to patients who show slight increases in mesangial matrix and interstitial fibrosis associated with acute inflammatory changes in renal biopsy specimens. In addition to these histological changes, if the patients show more than a moderate degree of proteinuria (⬎0.5 g/day) and their creatinine clearance (Ccr) exceeds 70 ml/min, adrenocorticosteroids should be used. (d) Anticoagulants: When crescent formation, glomerulosclerosis and adhesion to Bowman’s capsule are evident in renal biopsy, warfarin should be used, although heparin may be used for inpatients. (e) Immunosuppressants: Immunosuppressants are not usually used. Poor Prognosis Group Regimen. The regimen is based on that for chronic renal failure (CRF). Pregnancy and parturition should be avoided. Visits to an outpatient clinic must be made at least once a month, and laboratory examinations are basically the same as those for CRF. Diet Therapy. Diet therapy includes a low-salt diet of 7 g/day, a low-protein diet of 0.6 g/kg IBW/day and a calorie intake of 35 kcal/kg IBW/day. Water Treatment for IgA Nephropathy 11 intake is not restricted unless edema is present. Diet therapy in children is adjusted according to age. Drug Therapy. Drug therapy is similar to that for the relatively poor prognosis group. CRF is treated according to the disease state. References 1 2 3 Silva G, Hogg RJ: IgA nephropathy; in Tisher CC, Brenner BM (eds): Renal Pathology. Philadelphia. Lippincott, 1989, pp 434–491. Thomas M: Specific management of IgA nephropathy: role of tonsillectomy. The CARI Guidelines. Nephrology 2006;11(suppl 1):S146–S148. Tomino Y, Sakai H, Special Study Group (IgA nephropathy) on Progressive Glomerular Disease: Clinical guidelines for immunoglobulin A (IgA) nephropathy in Japan, ed 2. Clin Exp Nephrol 2003;7:93–97. Yasuhiko Tomino Division of Nephrology, Department of Internal Medicine Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku 113–8421, Tokyo (Japan) Tel. ⫹81 3 5802 1065, Fax ⫹81 3 3813 1183, E-Mail email@example.com Tomino 12 Clinical Reviews of IgA Nephropathy Tomino Y (ed): IgA Nephropathy Today. Contrib Nephrol. Basel, Karger, 2007, vol 157, pp 13–18 International IgA Nephropathy Network Clinico-Pathological Classification of IgA Nephropathy John Feehallya, Jonathan Barratta, Rosanna Coppob, Terry Cookc, Ian Robertsd, on behalf of the International IgA Nephropathy Network a The John Walls Renal Unit, Leicester General Hospital, Leicester, UK; bNephrology and Dialysis Unit, ‘Regina Margherita’ Children’s Hospital, Turin, Italy; cDepartment of Histopathology, Imperial College London, Hammersmith Hospital, London, and d Oxford Radcliffe Hospitals and University of Oxford, Oxford, UK Abstract There is no international consensus for the pathological or clinical classification of IgA nephropathy (IgAN). This has limited international comparisons between outcome studies which use different histological classifications, and made it more difficult to identify appropriate patients to enter into clinical intervention trials, as well as making it harder to choose appropriate therapy in individual patients. The International IgA Nephropathy Network [www.igan-world.org], working with members of the Renal Pathology Society, has established an international working group which is developing a consensus classification. Agreement has been reached on definitions of pathological features, and the consistency of scoring these features has been tested by pathologists around the world. Pathological features are now being scored in biopsies from large cohorts of patients from many parts of the world in whom sequential clinical information is available. From the integrated analysis of these clinical and pathological features, a clinico-pathological classification will be proposed which will be further refined and tested in additional cohorts of patients. The goal is to establish a reproducible and clinically effective classification which will gain worldwide acceptance for use in clinical practice and research. Copyright © 2007 S. Karger AG, Basel Introduction There is no international consensus for the pathological or clinical classification of IgA nephropathy (IgAN). Nephrologists use clinical information to identify the risk of developing progressive chronic kidney disease (CKD) in individual patients with IgAN. Pathologists have developed a number of classifications over the last 25 years, some semiquantitative [1–3], some single-grade [4, 5]; each has strengths and limitations in predicting prognosis, and none has gained pre-eminence. This lack of consensus has a number of disadvantages. It has contributed to the slow progress in developing prognostic systems with the sensitivity and specificity to predict outcome for individual patients. It limits opportunities to make international comparisons between different outcome studies which use different histological classifications. It has also limited opportunities to refine the stratification of risk for the design of clinical intervention trials. In 2004, a proposal to develop a consensus classification was developed by the International IgA Nephropathy Network – an informal network of nephrologists and scientists with representation from the majority of nephrology research groups around the world active in the field of IgAN [www.igan-world.org] – working with members of the Renal Pathology Society interested in IgAN. A questionnaire among renal pathologists showed support for the development of a consensus classification of IgAN provided it could be demonstrated to have real clinical benefit. Therefore, representatives of IIgANN and RPS together developed a programme of work leading to a consensus classification. From the beginning this was designed as an international consensus aiming to involve nephrologists and pathologists from as many parts of the world as possible, including all areas where IgAN is known to be of high prevalence. Goals and Strategy Our goal is to develop a new clinico-pathological classification for IgAN. The purpose of this new consensus classification would be to identify the risk of progression of renal disease in IgAN, thus enabling clinicians and researchers to improve individual patient prognostication, identify potential for response to immunosuppression or other specific treatments, and refine recruitment to clinical trials. It is necessary to approach this work without preconceptions, in order to test the predictive power of a wide range of pathological and clinical features. The consensus work has also required unity of purpose and a collaborative approach. Organisational challenges have included the need to develop tools allowing consistent data collection, and the need to meet the varying requirements of institutional review boards and ethics committees so that anonymised pathological material and clinical data can be circulated within and beyond its country of origin. In more detail the goals are: (1) to agree a consensus classification of histopathology of IgA nephropathy; (2) to test reproducibility of this classification Feehally/Barratt/Coppo/Cook/Roberts 14 Agree pathological definitions Data collection Agree pathological scoring process Data analysis to identify elements with prognostic predictive power Agree clinical dataset Select patient cohorts Agree data collection process and data verification Refine and agree a clinico-pathological classification Publish Achieve international usage Test on further patient cohorts Fig. 1. Overall strategy for development of the IgA nephropathy consensus classification. among pathologists; (3) to agree a clinical dataset useful for outcome studies in IgA nephropathy; (4) to evaluate the value of pathology parameters combined with clinical parameters in outcome studies in large cohorts of patients with IgA nephropathy, including cohorts varying in age, and in geographical and racial origin; (5) to develop from this work a validated clinico-pathological classification that discriminates patients with IgA nephropathy into groups identifiable from their presenting clinical and laboratory data; and which predicts different outcome out to at least 5 years as estimated by renal survival or by rate of deterioration in renal function, and (6) to promote the use of the new classification once published as the convention to be used in future clinico-pathological outcome reports of IgA nephropathy, as well as in routine clinical practice. The overall strategy for the project is shown in figure 1. Summary of Achievements up to October 2006 A group of nephrologists and pathologists have committed themselves to achieving these goals, and have met on several occasions: A first meeting of interested nephrologists and pathologists was held in St Louis USA in October 2004; a draft plan was published for web-based consultation in July 2005; a consensus meeting was held in Oxford, UK in September 2005, and pathologists involved in the project met in San Antonio, USA in February 2006. These meetings were attended by 15 nephrologists and 18 pathologists, from 10 countries on 4 continents. Clinico-Pathological Classification of IgAN 15 Progress so far includes the following areas listed below. Pathological Definitions and Scoring The consensus group agreed on the pathological features on light microscopy which need to be evaluated, and definitions for each of those features. The inter-observer reproducibility in identifying those features was then tested by circulating biopsies of 40 patients with IgAN among a worldwide group of 16 pathologists. Inconsistencies were debated at a further meeting, leading to agreement on a scoring system to be applied in subsequent analyses. Clinical Dataset The consensus group agreed on a clinical dataset sufficient to make useful correlations with pathological parameters. This included demographic data, and clinical and laboratory features at the time of diagnostic renal biopsy and annually thereafter. It was recognised that an ideal dataset was not always available from clinical records (e.g., smoking history is inconsistently recorded), but a minimum dataset was defined, including measurements of blood pressure, proteinuria and excretory renal function. Selection of Patient Cohorts for Testing 300 patients with available clinical datasets, available biopsies for review and a minimum of 5 years follow-up from time of biopsy are being selected for the next analysis which will lead to an initial proposal for a classification. The 300 cases comprise 250 adults and 50 children, and are being identified from centres across the world whose staff are involved in the consensus group and from others who have indicated their support. Centres are asked to contribute between 10 and 50 cases. It is necessary to ensure that selected cases include some in whom there is significant deterioration in GFR over 5 years to maximise the opportunity to identify discriminatory clinical or pathological features. Patients who have received a range of treatments are included. So far 15 centres (3 paediatric centres and 12 adult centres) from 9 countries in 4 continents have contributed cases (table 1). Biopsies from these cases are being circulated among pathologists for scoring, after ensuring that the various requirements of institutional review boards and ethics committees have been met, to allow circulation of pathological material and clinical data within and beyond the country of origin. Data Analysis, Definition and Testing of a Proposed Classification The anonymised clinical and laboratory data are being collected centrally with the biopsy scores. From the analysis of these data will emerge a proposed Feehally/Barratt/Coppo/Cook/Roberts 16 Table 1. Centres providing cases for the first phase of IgAN consensus classification 2006/07 Asia PR China Japan Europe France Italy United Kingdom North America Canada United States South America Chile Beijing Hong Kong Nanjing Tokyo St Etienne Bari Milano Roma Torino Glasgow Toronto Birmingham Mayo Clinic South West Study Group Santiago classification of IgAN which will then be tested and re-tested in further cohorts of patients until its consistency and clinical utility have been determined as far as is possible with retrospective analysis. If necessary, additional centres will be involved in the study, and it is hoped that the truly international dimension and careful design of this project will encourage other centres to be involved. It will be important to avoid premature publication of the proposed new classification, which will be tested and validated thoroughly before dissemination of the proposal. Conclusion The eventual success of this project will depend on the validity and clinical utility of the classification, and also the confidence with which it is received within the worldwide IgAN community. By our inclusive approach and systematic planning, we hope that we have given it the best chance of success. Clinico-Pathological Classification of IgAN 17 References 1 2 3 4 5 Alamartine E, Sabatier JC, Berthoux FC, et al: Comparison of pathological lesions on repeated renal biopsies in 73 patients with primary IgA glomerulonephritis: value of quantitative scoring and approach to final prognosis. Clin Nephrol 1990;34:45–51. Radford MG, Donadio JV, Bergstralh EJ, Grande JP: Predicting renal outcome in IgA nephropathy. J Am Soc Nephrol 1997;8:199–207. Katafuchi R, Kiyposhi Y, Oh Y, et al: Glomerular score as a prognosticator in IgA nephropathy: its usefulness and limitation. Clin Nephrol 1998;49:1–8. Lee SM, Rao VM, Franklin WA, et al: IgA nephropathy: morphologic predictors of progressive renal disease. Hum Pathol 1982;13:314–332. Haas M: Histologic subclassification of IgA nephropathy: a clinicopathologic study of 244 cases. Am J Kidney Dis 1997;29:829–842. Prof. John Feehally The John Walls Renal Unit, Leicester General Hospital Gwendolen Road Leicester LE5 4PW (UK) Tel. ⫹44 1162 58 4132, Fax ⫹44 1162 58 4764, E-Mail firstname.lastname@example.org Feehally/Barratt/Coppo/Cook/Roberts 18 Tomino Y (ed): IgA Nephropathy Today. Contrib Nephrol. Basel, Karger, 2007, vol 157, pp 19–26 IgA Nephropathy: A Clinical Overview Bruce A. Juliana, Robert J. Wyattb, Karel Matousovicc, Zina Moldoveanua, Jiri Mesteckya, Jan Novaka a University of Alabama at Birmingham, Birmingham, Ala., bUniversity of Tennessee Health Sciences Center, Memphis, Tenn., USA; cCharles University School of Medicine and Faculty Hospital, Prague and Pilsen, Czech Republic Abstract Our understanding of the clinical aspects of IgA nephropathy (IgAN) has advanced since the 10th International Symposium on IgA Nephropathy in 2004. In this review we discuss new developments in areas of familial IgAN, the emerging field of biomarkers, and prognostic features. Familial disease continues to account for a significant number of newly diagnosed patients with IgAN. These patients have clinical manifestations and long-term outcomes similar to those of patients with sporadic disease. Characterization of the IgAN1 gene linked to IgAN in some Italian and American multiplex families has remained elusive. Other multiplex IgAN pedigrees have shown no linkage to any locus. With advances in technology to better measure and characterize polypeptides in small concentrations, the area of biomarkers has generated substantial interest since 2004. New potential disease-specific biomarkers of IgAN include the IgA1 neoepitope at the threonine228 and/or serine230 IgA1 hinge-region residues, serum levels of galactose-deficient IgA, and urinary IgA-IgG immune complexes. Other investigators have used proteomic approaches to find panels of urinary polypeptides (many of which have not been sequenced) that discriminate patients with IgAN from normal healthy controls as well as patients with various other proteinuric renal diseases. These or other related findings may provide the necessary tools to better classify phenotypes in multiplex pedigrees and to improve monitoring of disease progression or response to therapy. Copyright © 2007 S. Karger AG, Basel Since the 10th International Symposium on IgA Nephropathy in March 2004 in St. Etienne, France, investigators continue to unravel the clinical complexities of IgAN. Here, we review recent advances in the areas of genetics and familial IgAN, the emerging field of proteomic biomarkers, and prognostic markers. Papers elsewhere in this volume address treatment of patients with IgAN. The proportion of native-kidney biopsies with IgAN in the USA has recently been shown to be higher than that published 10–20 years ago. In an Arkansas referral center, IgAN was diagnosed in 6.9% of the 4,504 biopsy specimens processed from March 2001 to February 2005 from patients older than 20 years . In young adults aged 20–39 years, IgAN was the most common glomerulonephritis, accounting for 14.2% of the 1,082 biopsy specimens. Genetics and Familial IgAN As many as 10–15% of newly diagnosed patients with IgAN have a family history of renal disease. Families with multiple members with IgAN have been discovered worldwide, but the precise location and function of a gene linked to IgAN remain elusive. The IgAN1 gene at chromosome 6q22–23 linked to IgAN in Italian and American pedigrees has not been characterized. Other multiplex families have failed to show linkage to any locus. Individuals in some multiplex families have non-IgAN renal disease, including immune-complex glomerulonephritis  or thin glomerular basement membrane glomerulopathy , whereas renal disease in other families is restricted to IgAN and HenochSchoenlein purpura nephritis . A recent study from Italy found that the longterm outcome is similar in patients with familial and sporadic IgAN . Pursuit of a gene that accounts for familial IgAN has been hampered by the lack of a non-invasive diagnostic marker of disease. Thus, individuals with subclinical renal disease may be misclassified as unaffected, confounding the analysis of the segregation of renal disease with genetic markers. Biomarkers for IgAN Advances in the last few years in the methodology for precise analysis of the composition of polypeptides have renewed interest in the field of biomarkers. Biomarkers may be any of several biological characteristics that can be objectively measured and evaluated as indicators of normal biological processes, pathogenic processes or pharmacologic response to therapy . Candidates for biomarkers include metabolites, mRNA profiles, lipids, proteins, and polypeptide fragments. The best candidates would be measured with accurate and easy-to-perform assays that can be performed quickly and serially. Biomarkers should be in an easily sampled medium; urine would likely provide the best source for patients with renal disease. For patients with IgAN, ideal biomarkers would obviate the need for a requisite invasive kidney biopsy for Julian/Wyatt/Matousovic/Moldoveanu/Mestecky/Novak 20 diagnosis, elucidate pathogenetic mechanisms, forecast clinical course, and monitor response to treatment. A fundamental biochemical abnormality with immunological consequences in patients with IgAN is the increased amount of circulating IgA1 with galactose-deficient hinge-region O-linked glycans . The serum level of this aberrantly glycosylated IgA1 can be measured by its selective binding to Helix aspersa (HAA) lectin that is specific for N-acetylgalactosamine. In a group of 153 Caucasian patients with IgAN, we found that 76% had a serum HAAbinding IgA level above the 90th percentile value for the 150 Caucasian controls (Moldoveanu Z et al., Kidney Int, in press). High levels were detected in patients with familial and sporadic IgAN. About 30% of 133 firstdegree relatives had high levels, possibly indicating a genetically determined predisposition. Another potential serum biomarker for IgAN derives from the galactosedeficient IgA1 hinge-region glycans. Using mass spectrometry and Western blots, we have narrowed the span in the hinge-region that apparently serves as the antigenic epitope in the nephritogenic circulating immune complexes. After digestion of the IgA1 heavy chain from an IgAN patient by site-specific IgA proteases, a Western blot developed with HAA showed that the threonine228 and/or the serine230 were the amino acid residues with attached galactosedeficient glycans [8; also Novak J et al., this volume]. Urine also contains biomarkers for IgAN. Much of the growing interest in this field has centered on proteomics. Proteomics is the assessment of proteins and peptides within a particular compartment, a proteome, using a wide range of analytical methods. The technology has evolved to include two-dimensional gel electrophoresis and other electrophoretic methods, protein arrays, chromatography, and mass spectrometry (fig. 1). Urine is a better fluid than serum for proteomic analysis because it is less complex. In serum, concentrations of various proteins span 10 orders of magnitude, the predominance of a few proteins obscures less abundant peptides, and some potential biomarkers escape detection due to their binding to albumin. Furthermore, the urinary proteome is more stable. Polypeptides do not degrade in urinary samples stored up to six hours at room temperature or for several months at –20⬚C. Proteomics has uncovered urinary biomarkers for several renal diseases, including IgAN. Using a cross-capture ELISA and factoring for creatinine concentration, we found that patients with IgAN excreted more IgA-IgG-containing immune complexes than did disease controls with non-IgA nephropathies with comparable or greater proteinuria . Using capture ELISA and immune complex-specific ELISA, the amounts of urinary IgA and IgA-containing immune complexes were significantly higher in patients with IgAN than in patients with primary non-IgAN glomerulonephritis or healthy controls (Novak J. et al., IgA Nephropathy: A Clinical Overview 21 Sample collection and preparation Sample separation (electrophoresis, liquid chromatography, chips and microfluidics) Verification in an independent cohort of patients and controls Sample analysis (mass spectrometry, image analysis) Identification of biomarkers for diagnosis of IgAN Data processing and database searches Fig. 1. Scheme of proteomic approaches to identification of polypeptide biomarkers for diagnosis of IgAN. Samples (blood, urine, or tissue) from patients with IgAN, healthy controls, and disease controls are collected and processed. Separation by electrophoretic methods (1- or 2-dimensional gel electrophoresis, capillary electrophoresis), liquid chromatography, or chip-based techniques is followed by analytical techniques (image analysis or mass spectrometry) to characterize and quantify differentially present polypeptides. Additional characterization of these polypeptides may include peptide mass fingerprinting and/or sequencing by tandem mass spectrometry and characterization of post-translational modifications. Data analysis by bioinformatic approaches and database searches will assist in the identification of potential biomarkers. Candidate biomarkers must be validated in an independent cohort of patients. poster at this conference). Furthermore, these urine samples were analyzed by SDS-PAGE and Western blot with IgA- and IgG-specific antibodies. Sample loading was normalized to urinary creatinine concentration. Protein profiles of IgAN samples showed high concentrations of the IgA heavy chain and its proteolytic fragments. In contrast, samples from controls without nephritis had profiles similar to those of healthy controls showing modest IgA and no proteolytic fragments. Julian/Wyatt/Matousovic/Moldoveanu/Mestecky/Novak 22 In a study using the classic method of two-dimensional electrophoresis with subsequent isolation of proteins from the gel for analysis by mass spectrometry, Park et al.  found 84 protein spots that were differentially expressed in the pooled urine sample from 13 patients with IgAN compared to that from 12 normal controls. Of these protein spots, 42 were over-expressed in the IgAN patients and 42 were under-expressed. By mass spectrometry sequencing, the over-expressed protein spots were found to be derivatives of 27 different proteins. The over-expressed proteins included intracellular or cytoplasmic proteins, nuclear-associated proteins, membrane-associated proteins, and secreted or plasma proteins. Unfortunately, this technology is time-consuming and small proteins (below 10 kDa) may escape detection. Another method, surface-enhanced laser desorption and ionization (SELDI) mass spectrometry, is fast but has low resolution, and many proteins are lost in the process due to the matrices selecting particular polypeptides. Some investigators have turned to capillary electrophoresis coupled on-line to mass spectrometry because it is faster, has high resolution, and can identify up to 600 polypeptides in a urine sample. Haubitz et al.  evaluated 45 patients with IgAN, 13 patients with membranous glomerulopathy, and 57 healthy controls. They described 22 urinary polypeptides that discriminated patients with IgAN from normal controls, 12 of which were over-expressed in the patients. Frequencies of the discriminating polypeptides did not differ by magnitude of proteinuria, gender, age, or serum creatinine concentration. Even patients with IgAN in clinical remission without pathological proteinuria were distinguished from healthy controls. After grouping patients by the number of antihypertensive medications, the polypeptide pattern trended toward normal with more intensive therapy, independent of age or magnitude of proteinuria. Comparison of the marker peptides of patients with IgAN to those of patients with membranous glomerulopathy showed a sensitivity of 77% and specificity of 100%. The authors also compared their biomarkers to previously identified markers for other renal diseases compiled in a database. Patients with IgAN were discriminated from patients with focal segmental glomerulosclerosis, minimal-change disease or diabetic nephropathy with a sensitivity of 100% and a specificity of 100%. Sequencing of three of the polypeptides that discriminated between patients IgAN from healthy controls by mass spectrometry identified three different fragments of serum albumin. The basis by which these fragments were restricted to IgAN remains unknown. Perhaps the polypeptides were generated by unique protease activity in inflamed glomeruli. In view of these preliminary studies, disease-specific biomarkers are more likely to be comprised of a panel of several distinct and well-defined peptides than a single molecule. In any event, with proteomics the search for disease-specific biomarkers is not hindered by antecedent bias arising from hypothesized mechanisms of disease. IgA Nephropathy: A Clinical Overview 23 Table 1. Recently reported genetic polymorphisms that have been associated with development or progression of IgA nephropathy Polymorphism Ethnicity Development of IgAN Megsin A23167G Interleukin-10 promoter Chinese (14) Korean (15) Progression of IgAN Megsin A23167G MUC20, a novel mucin protein CC-chemokine receptor 5 Monocyte chemoattractant protein-1 Fc␥RIIa Fc␥RIIIa Chinese (14) Chinese (16) French (17) Japanese (18) Japanese (19) Japanese (19) Loss of renal allograft HLA-B8DR3 haplotype European (20) Prognosis and Monitoring Progressive Disease in IgAN In the absence of a validated biomarker to predict prognosis and monitor response to treatment, investigators continue to use the well-known clinical measures to assess the activity of IgAN. There has been a general consensus that hypertension and increasing magnitude of proteinuria, and the pathological findings of glomerular crescents or sclerosis, tubular atrophy and interstitial fibrosis portend a less favorable long-term outcome. Proteinuria is the focus of great attention because it is amenable to therapy. Whether the benefits of twodrug suppression of the effects of angiotensin (with angiotensin-convertingenzyme inhibitors and angiotensin-receptor-type-1 blockers) for preservation of renal function can be monitored by serially measuring proteinuria has not yet been clarified. In the last few years, other features have been proposed as prognostic markers. An increased serum uric acid level appears to be an independent risk factor for progressive disease . Other investigators have found that patients with IgAN and thin glomerular basement membranes have a better outcome than patients with membranes of normal thickness . In addition, the prognosis of IgAN is undoubtedly impacted by genetically determined variations of factors that likely influence the inflammatory and scarring consequences of an immune-complex-mediated glomerular injury. Since 2004, polymorphisms of Julian/Wyatt/Matousovic/Moldoveanu/Mestecky/Novak 24 several such factors have been associated with development of IgAN or progressive renal injury (table 1; [14–20]). Acknowledgments Supported in part by a grant from the National Institutes of Health, PO1 DK61525, by the General Clinical Research Centers of the University of Alabama at Birmingham M01 RR00032 and the University of Tennessee Health Sciences Center, M01 RR00211 (USA), and by a grant from the Research Project MSM 0021620819 (Czech Republic). References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Nair R, Walker PD: Is IgA nephropathy the commonest primary glomerulopathy among young adults in the USA? Kidney Int 2006;69:1455–1458. Izzi C, Sanna-Cherchi S, Prati E, et al: Familial aggregation of primary glomerulonephritis in an Italian population isolate: Valtrompia study. Kidney Int 2006;69:1033–1040. Frasca GM, Soverini L, Gharavi AG, et al: Thin basement membrane disease in patients with familial IgA nephropathy. J Nephrol 2004;17:778–785. Julian BA, Quiggins PA, Thompson JS, et al: Familial IgA nephropathy: evidence for an inherited mechanism of disease. N Engl J Med 1985;312:202–208. Izzi C, Ravani P, Torres D, et al: IgA nephropathy: the presence of familial disease does not confer an increased risk for progression. Am J Kidney Dis 2006;47:761–769. Hewitt SM, Dear J, Star RA: Discovery of protein biomarkers for renal diseases. J Am Soc Nephrol 2004;15:1677–1689. Tomana M, Matousovic K, Julian BA, et al: Galactose-deficient IgAl in sera of IgA nephropathy patients is present in complexes with IgG. Kidney Int 1997;52:509–516. Novak J, Moldoveanu Z, Renfrow MB, et al: Analysis of aberrant O-glycosylation of IgA1 in patients with IgA nephropathy (IgAN). American Society of Nephrology, 39th Renal Week Annual Meeting, San Diego, CA, November 14–19, 2006. Matousovic K, Novak J, Yanagihara T, et al: IgA1-containing immune complexes in the urine of IgA nephropathy patients. Nephrol Dial Transplant 2006;21:2478–2484. Park M-R, Wang E-H, Jin D-C, et al: Establishment of a 2-D human urinary proteomic map in IgA nephropathy. Proteomics 2006;6:1066–1076. Haubitz M, Wittke S, Weissinger EM, et al: Urine protein patterns can serve as diagnostic tools in patients with IgA nephropathy. Kidney Int 2005;67:2313–2320. Myllymaki J, Honkanen T, Syrjanen J, et al: Uric acid correlates with the severity of histopathological parameters in IgA nephropathy. Nephrol Dial Transplant 2005;20:89–95. Linossier M-T, Palle S, Berthoux F: Different glycosylation profile of serum IgA1 in IgA nephropathy according to the glomerular basement membrane thickness: normal versus thin. Am J Kidney Dis 2003;41:558. Xia YF, Huang S, Li X, et al: A family-based association study of megsin A23167G polymorphism with susceptibility and progression of IgA nephropathy in a Chinese population. Clin Nephrol 2006;65:153–159. Chin HJ, Na KY, Kim SJ, et al: Interleukin-10 promoter polymorphism is associated with the predisposition to the development of IgA nephropathy and focal segmental glomerulosclerosis in Korea. J Korean Med Sci 2005;20:989–993. Li G, Zhang H, Lv J, et al: Tandem repeats polymorphism of MUC20 is an independent factor for the progression of immunoglobulin A nephropathy. Am J Nephrol 2006;26:43–49. IgA Nephropathy: A Clinical Overview 25 17 18 19 20 Berthoux FC, Berthoux P, Mariat C, et al: CC-chemokine receptor five gene polymorphism in primary IgA nephropathy: the 32 bp deletion allele is associated with late progression to end-stage renal failure with dialysis. Kidney Int 2006;69:565–572. Mori H, Kaneko Y, Narita I, et al: Monocyte chemoattractant protein-1 A-2518G gene polymorphism and renal survival of Japanese patients with immunoglobulin A nephropathy. Clin Exp Nephrol 2005;9:297–303. Tanaka Y, Suzuki Y, Tsuge T, et al: Fc␥RIIa-131R allele and Fc␥RIIIa-176V/V genotype are risk factors for progression of IgA nephropathy. Nephrol Dial Transplant 2005;20:2439–2445. Andresdottir MB, Haasnoot G, Persijn GG, et al: HLA-B8DR3: a novel risk factor for graft failure after renal transplantation in patients with underlying IgA nephropathy. Transplantation 2006; 82(suppl 2):646–647. Bruce A. Julian, MD University of Alabama at Birmingham, Division of Nephrology Department of Medicine, 1530 Third Avenue South, THT 643 Birmingham, AL 35294 (USA) Tel. ⫹1 205 934 9045, Fax ⫹1 205 934 7742, E-Mail email@example.com Julian/Wyatt/Matousovic/Moldoveanu/Mestecky/Novak 26 Tomino Y (ed): IgA Nephropathy Today. Contrib Nephrol. Basel, Karger, 2007, vol 157, pp 27–36 Angiotensin Antagonists and Fish Oil for Treating IgA Nephropathy R. Coppo, A. Amore, L. Peruzzi, D. Mancuso, R. Camilla Pediatric Nephrology School, Nephrology, Dialysis and Transplantation Department, Regina Margherita University Hospital, Turin, Italy Abstract In IgA nephropathy (IgAN), ACE inhibitors (ACE-I) and angiotensin receptor blockers (ARB) are beneficial against hypertension, and their anti-proteinuric effect has been clearly demonstrated. However, sub-analyses of IgAN patients enrolled in large studies failed to prove a benefit against progression to renal failure. The European Community Biomed Concerted Action – a placebo-controlled randomized controlled trial begun in 1995 – in children and adults (9–35 years old) with proteinuria ⬎ 1 ⬍ 3.5 g/day/1.73 m2 and normal or moderately reduced renal function proved the significant benefit of ACE-I on progression of kidney disease. The combination of ACE-I and ARB in proteinuric normotensive IgAN patients showed greater antiproteinuric effect and the COOPERATE trial also reported a superior effect of combination therapy in protecting against renal function deterioration. Treating IgAN with fish oil has a good rationale for renal inflammation as well as for prevention of cardiovascular morbidity. However, the published reports gave conflicting conclusions and also very recent data did not show significant benefits. In conclusion, ACE-I and ARB have a definite role in treating IgAN, particularly the hypertensive and proteinuric forms. These patients should be treated to target BP to ⬍130/70 mm Hg and proteinuria ⬍0.5 g/day. Copyright © 2007 S. Karger AG, Basel It is well known that the effects of angiotensin II go beyond the regulation of renal hemodynamics and glomerular permselectivity . Angiotensin II can modulate the immune system, triggering pro-fibrogenic cytokines (TGF-␤), stimulating fibroblast proliferation, acting as a growth factor and leading to cell hypertrophy and proliferation, inducing cytokines (IL-6, IL-8, RANTES, MCP-1), generating ROS, activating the transcription factor NF-B, upregulating TLR-4 on mesangial cells, and downregulating nephrin and podocin on podocytes . All these activities, summarized in figure 1, lead to inflammation, MCP1 RANTES IL-8 Angiotensin II Proteinuria LM infiltration and activation ↑ Cytokine production ↑ TGF-β and ECM ↑ Glomerular hyperfiltration Endothelial and mesangial cell exposure to shear stress/stretch ↑ PAI-1 ↑ Aldosterone ROS ↓ ECM degradation ECM accumulation Inflammation Injury to glomerular cells Glomerular and tubulointerstitial fibrosis Fig. 1. Activities of angiotensin II. injury of glomerular cells and matrix accumulation. To sum up, the reninangiotensin system (RAS) plays a pivotal role in the progression of renal diseases, promoting both intraglomerular and systemic hypertension, and acting on angiotensin receptors of mesangial and tubular cells triggering progression of interstitial fibrosis. On the other hand, IgA deposits may activate mesangial cells, leading to production of biological effects which contribute to amplification of the angiotensin II-induced damage, suggesting a unique role for RAS in IgA nephropathy (IgAN). Among the intracellular signaling activated by both angiotensin II and deposited IgA, NF-B has been supposed to play a major role in IgAN, as it was detected in renal biopsies from these patients, particularly in those with active lesions . NF-B was demonstrated to be activated and translocated into the nucleus of mesangial cells upon incubation with aggregated IgA or IgA immune complexes. We previously demonstrated that aberrantly glycosylated IgA, which are thought to play a pathogenetic role in IgAN, when incubated with cultured mesangial cells, trigger the nuclear translocation of the two NF-B active subunits p65 and p50  and the coincubation of angiotensin-converting-enzyme inhibitors (ACE-I) or angiotensinreceptor-1 blockers (ARB) significantly blunts the activation of this transcription factor in a dose-dependent manner. Coppo/Amore/Peruzzi/Mancuso/Camilla 28 Hence there is a theoretical disease-specific benefit in IgAN for angiotensin II antagonism, since it is aimed to normalize altered mesangial cell responses enhanced by aberrantly glycosylated IgA. We previously demonstrated that in IgAN, particularly in proteinuric cases, there is a local RAS hyperreactivity , and precocious activation of the RAS was also reported. There is a general consensus that high urinary protein excretion is one of the most relevant risk factors for progression of IgAN . Proteinuria mostly precedes the development of other clinical risk factors such as hypertension and reduced renal function, which tend to be more related to irreversible sclerotic changes. Persistent nephrotic-range proteinuria in IgAN – as well as in other nephropathies – has been found to be associated with very poor outcome , but also moderate proteinuria has been recognized as a risk factor for progression of IgAN . Proteinuria may activate tubular cells and trigger a local activation of the RAS system and the NF-B nuclear translocation with consequent release of a large series of mediators inducing lymphomonocyte interstitial infiltration, and release of mediators which lead to interstitial fibrosis [reviewed in 1]. Finally, hypertension is one of the major risk factors for progression of IgAN , as recognized by several investigators, who recently stressed that even border-line high values of BP may be harmful, particularly when proteinuria is associated. For all the above reviewed mechanisms of renal damage related to angiotensin activation and concomitant IgA mesangial deposition, angiotensin II antagonists have a specific strong theoretical indication for IgAN, particularly the hypertensive and proteinuric forms. Table 1 reports a synopsis of the most relevant clinical studies which used angiotensin antagonism (mostly ACE-I) in hypertensive IgAN and the different blood pressure (BP) targets. Most of the retrospective study reported ACE-I superior effects in comparison to other antihypertensive drugs in limiting the glomerular filtration rate (GFR) loss and the amount of proteinuria . Most recent prospective studies detected a stabilization of GFR only in intensive treatment groups, when BP was reduced to ⬍130/70 mm Hg often with a multidrug combination, while patients who had BP ⬎135/75 mm Hg failed to be protected against functional decline . The antiproteinuric effect was reported in early short-term investigations and confirmed in long-term studies (table 2); however, the effect was not reproduced in each patient and did not lead to complete remission of proteinuria, as only 40% of the cases showed a reduction of urinary protein excretion by more than 50%. It was therefore logical to wonder whether this partial effect was enough for a relevant reno-protection. Ruggenenti  made a sub-analysis of Angiotensin Antagonists and Fish Oil for Treating IgAN 29 Table 1. Angiotensin antagonism in patients with hypertensive IgAN Author (year) Target BP Regimen-FU Efficacy of ACE-I Cattran (1994) retrospective ⬍140/90 ACE-I vs. other treatments 30 months FU Significant reduction of GFR loss and proteinuria Rekola (1991) retrospective ⬍140/90 ACE-I or ␤-blockers 3 years FU Significant reduction of GFR loss ACE-I or CCB 1 year FU No effect on GFR loss, some reduction in proteinuria ACE-I plus CCB 3 years FU Stabilization of GFR only in intensive treatment group (BP ⬍ 130/70), while BP ⬎ 135/75 had GFR decline Bannister (1995) prospective Kanno (2000) Non randomized Different BP targets ACE-I ⫽ Angiotensin converting enzyme inhibitors; CCB ⫽ calcium channel blockers; BP ⫽ blood pressure; FU ⫽ follow-up. Table 2. Angiotensin antagonism in patients with proteinuric IgAN Author (year) uP Regimen-FU Efficacy of ACE-I Maschio (1994) 1–2.5 g Fosinopril vs. Placebo 12 months FU Mild significant reduction in proteinuria Perico (1998) 0.5–4 g ACE-I or ARB 1 month FU Significant reduction of proteinuria in both arms Russo (1994) 1–3 g ACE-I 1 or x2 ARB 1 or x2 or ACE-I plus ARB Significant reduction in proteinuria, even more in combination group Song (2003) ⬎1 g/day ACE-I plus ARB 33 weeks FU Significant mild reduction in proteinuria no BP effect Park (2003) 2–2.3 g ARB or CCB 12 weeks ARB reduced proteinuria ACE-I ⫽ Angiotensin converting enzyme inhibitors; ARB ⫽ angiotensin I receptor blockers; uP ⫽ urinary protein (g/day); FU ⫽ follow-up. Coppo/Amore/Peruzzi/Mancuso/Camilla 30 the response to ACE-I in 352 proteinuric nephropathies enrolled in the REIN prospective, double-blind, placebo-controlled trial. In a subgroup of 75 IgAN patients with 3 ⫾ 2 g/day proteinuria (always ⬎1 g/day), ACE-I had some protective effect, as it saved a loss of 2.3 ml/min/year in comparison to the untreated patients. The effect was not statistically significant, possibly due to the small sample size. In 2001, Dillon  performed a meta-analysis of 237 IgAN patients enrolled in 3 short-term crossover trials (3 months), 1 randomized and controlled trial (1 year) and 3 retrospective controlled trials (2 years), and reported that the effect on proteinuria was clearly seen, while, due to defects in the original design, no definitive conclusion could be drawn about the nephro-protective effect. His conclusions were that ‘we do not know which treatment is the most effective’. In 2003, the first randomized controlled trial (RCT) of ACE-I in IgAN was published by Praga et al. , but it was not placebo-controlled, and enrolled a limited number of patients (44 subjects) from only one center with a wide range of proteinuria (from 0.5 to 5 g/day) and various degrees of renal function impairment, hence with likely variable prognosis. After a mean follow-up of 75 months, the proportion of patients developing the primary endpoint (50% increase of baseline plasma creatinine) was significantly lower in the treated group than in the control group (12 vs. 57%, respectively). In 1995 we designed a double-blind placebo RCT, supported by the European Community Concerted Action of Biomedicine and Health (Biomed) . At that time there was a definite expectation for a trial on ACE-I in IgAN, since the effect of ACE-I on progression of chronic nephropathies had just been proved, but not yet for IgAN. This was the first multicenter, double-blind, placebo-controlled RCT, investigating, in a selected cohort of IgAN, the effects of ACE-I on renal function decline and proteinuria. The trial strictly selected young patients (3–35 years old) of a very constant level of moderate proteinuria (between 1 and 3.5 g/day/1.73 m2 over the 3 months before enrolment) and normal or moderately reduced renal function (creatinine clearance (CrCl) ⬎ 50 ml/min/1.73 m2). Fifty-seven patients, average age 19.9 years (range 9–35 years), randomized to receive Benazepril 0.2 mg/kg/day (ACE-I) or placebo (PL), completed the trial (median follow-up 42 months). The primary outcome was progression of kidney disease, defined as ⬎30% decrease of baseline CrCl and/or worsening of proteinuria until ⱖ3.5 g/day/1.73 m2. Secondary outcome was proteinuria partial (⬍0.5 g/day/1.73 m2) or total remission (⬍160 mg/day/1.73 m2) for ⬎6 months. The survival to the events was evaluated by univariate (KaplanMeier, log-rank test) and Cox multivariate analysis. Of the 57 subjects who had a follow-up, one single patient (4.3%) in the ACE-I group and 5 (14.7%) in the PL group showed a worsening of CrCl ⬎30%. Angiotensin Antagonists and Fish Oil for Treating IgAN 31 No patient on ACE-I developed nephrotic syndrome, versus 7 (20.6%) on PL. The primary outcome of renal disease progression resulted significantly different between the two groups (log-rank P ⫽ 0.035). Mean levels of proteinuria were significantly reduced, as expected, and a stable partial remission of proteinuria was observed in 13/23 (56.5%) ACE-I patients versus 3/34 (8.8%) PL patients (log-rank P ⫽ 0.033), with total remission in 17.4% of ACE-I treated patients and in none of PL (log-rank P ⫽ 0.029). The multivariate Cox analysis showed that treatment with ACE-I was the independent predictor of prognosis, while no influence on the progression of renal damage was found for gender, age, baseline CrCl, systolic or diastolic blood pressure, mean arterial pressure, or proteinuria . In conclusion, angiotensin antagonism is successful in limiting progression of renal damage in young IgAN patients with proteinuria between 1 and 3.5 g/day. A new trial is ongoing in collaboration with Pozzi et al. , to test whether the angiotensin inhibition by both ACE-I and ARB may decrease the risk of progression in patients with IgAN so far considered benign (proteinuria ⬍ 0.5 g/day). Such inhibition will be at first achieved with a unique pharmacological class (ACEI or ARB), then shifting to the association of the two classes as soon as the inhibition with one drug becomes ineffective. Is it possible to increase the angiotensin antagonist effect? We could consider using higher doses, or switching from ACE-I to ARB, or combining ACE-I and ARB. High doses of ACE-I or ARB (up to four-fold increase) have been proved to be of benefit by experimental evidence in a model of remnant kidneys  limiting the development of renal sclerosis. The superior effect of higher doses versus conventional ones was, however, not confirmed in other models. In some clinical investigations, doubling ACE-I or ARB doses in 12 adults with IgAN did not improve the anti-proteinuric effect, while the side effects were increased . Inhibition of the RAS can be achieved by means of ACE-I or ARB. Both drugs have positive effects and drawbacks. ACE-I drugs depress aldosterone synthesis, which has independent deleterious effects, and limit the degradation of bradykinin, with some additional favourable effects on reduction of proteinuria and of glomerular hypertension. On the other hand, ACE-I also reduces the effects related to AT2-R stimulation, which are thought to lead to vasodilation and inhibition of fibrosis. This treatment leaves uncontrolled non-ACE produced angiotensin II by chymase and CAGE. ARB have the advantage of being placebo-like, without any relevant side effect, but their main supposed advantage, the lack of inhibition and even stimulation of AT2-R, seems indeed more harmful than benign, after the last reports indicating that AT2-R may trigger NF-B. No reduction of aldosterone is induced by ARB, while angiotensin II and angiotensin IV are left active with consequent increase in PAI-1 and Coppo/Amore/Peruzzi/Mancuso/Camilla 32 proteolysis. The combination of these two drugs has the advantage of overcoming the limitations of either individual drug, and an effective blocking of TGF␤ has been observed. The combination of ACE-I and ARB in proteinuric normotensive IgAN patients has obtained much greater effect than each individual drug. The effect of the combination therapy was not further increased by doubling the doses . Information on the effects of combination treatment of ARB and ACE-I in IgAN can be derived by the COOPERATE trial , which involved 263 patients of whom 131 (50%) were IgAN. Patients were randomized to maximal antiproteinuric effect ACE-I Trandolapril 3 mg/day or Losartan 100 mg/day, or a combination of both. BP was targeted at 130/80 mm Hg. The end points were doubling of serum creatinine or ESRF. Nakao  reported a superior effect of combination therapy over individual drug use in reducing proteinuria as well as in protecting against renal function deterioration. The 3-year renal survival in the combination group was mainly due to reduction of proteinuria and irrespective of patients’ baseline proteinuria levels. The effect was not increased by doses of ARB increased up to threefold. Angiotensin antagonism therapy has still debated points. The relative contribution of BP reduction and other additional in vivo effects has been questioned . It is not clear whether ACE-I remains effective over time or whether there is an escape mechanism . An additional effect has been envisaged for anti-aldosterone drugs. Aldosterone increases after long-term ACE-I, showing an ‘aldosterone escape’ ; in is still unclear whether this is relevant to longterm prognosis. Cardiovascular complications are major causes of morbidity and mortality in patients with chronic kidney diseases (CKD). IgAN patients with CKD are more likely to die of cardiovascular events than reach the need of dialysis. We must prevent not only end stage renal failure but, perhaps even more, the risk factors for cardiovascular events: hypertension, proteinuria, smoking, and dyslipemia. Considering these points, treating IgAN with fish oil has a good rationale, since eicosapentanoic (EPA) and docosahexaenoic (DHA) acids shift the cyclooxygenase effects from the synthesis of pro-inflammatory mediators, like thromboxane TxA2 and prostaglandin PGI2, towards the less harmful products TxA3 and PGI3; similarly, the lipoxygenase activity is shifted from the synthesis of TB4 to the less phlogogenic leucotriene LTB5. Fish-oil and omega-3 polyunsaturated fatty acids (PUFA) have been shown to be useful in prevention of cardiovascular events and reduction of proteinuria in several experimental glomerular diseases. In anti-Thy1–1 experimental glomerulonephritis, omega-3 PUFA had suppressive effects on mesangial cell proliferation, effect on reduction of proteinuria, and inhibition of renal inflammation. Preliminary pilot studies gave conflicting results: stabilization of GFR for some Angiotensin Antagonists and Fish Oil for Treating IgAN 33 patients, but no benefit for others. In a controlled trial of fish oil in IgAN , 106 IgAN patients with proteinuria ⬎1 g/day, hypertension (60%), and impaired GFR were treated with EPA 1.8 g/day and DHA 1.2 g/day for 2 years and followed up for 5 years. A significant benefit was observed on renal function decline, even though proteinuria levels remained unchanged. The outcome of studies treating IgAN with fish oil evaluated in a meta-analysis by Dillon  failed to prove an overall benefit of this therapy. A controlled trial of fish oil and prednisone in IgAN (Hogg R et al., personal communication), on 100 IgAN patients, aged under than 40 years, with a urinary protein/creatinine ratio ⬎0.5 and GFR ⬎50 ml/min, randomized the patients to 4 g/day omega-3 PUFA or alternate day prednisone or placebo for 2 years. No significant difference was found between treatment groups and placebo, as the end-points were reached in 2 patients on prednisone, 8 on fish oil and 4 on placebo. Ron Hogg has recently reported that the effect of Omacor (omega-3 PUFA) in patients with IgAN is dependent upon the serum levels of EPA and DHA, and the antiproteinuric effect is significantly correlated to the dose (mg per kg body weight). However, fish oil in IgAN remains of controversial benefit; it is expensive and carries some side effects; however, it can be of benefit for patients with IgAN since it is of benefit against the cardiovascular deterioration. Hence, it is mostly left to individual choice. In conclusion, ACE-I and ARB have a definite role in treating IgAN, particularly the hypertensive and proteinuric forms. The best strategy for proteinuric and hypertensive IgAN patients includes the following therapies : control BP aggressively by means of ACE-I and/or ARB; give the maximum tolerated doses or target BP to proteinuria ⬍0.5 g/day; control blood lipids with statins; reduce salt intake; reduce excessive body weight, and increase physical activity. BP should be targeted according to concomitant proteinuria levels: in cases with proteinuria ⬍1 g/day, BP should not exceed 135/85 mm Hg (MAP 99 mm Hg); when proteinuria is ⬎1 g/day, BP should not exceed ⬎125/75 mm Hg (MAP 92 mm Hg); target BP is ⬍130/70 mm Hg (MAP 92 mm Hg) when proteinuria is ⬎1 g/day. The target for proteinuria is ⬍0.5 g/day and it should be attained by combination therapy ACE-I and ARB, wait for the effect 12 months. Consider other therapeutic options (steroids) in case of failure. References 1 Wolf G, Ritz E: Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications. Kidney Int 2005;67: 799–812. Coppo/Amore/Peruzzi/Mancuso/Camilla 34 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Ashizawa M, Miyazaki M, Abe K, Furusu A, Isomoto H, Harada T, Ozono Y, Sakai H, Koji T, Kohno S: Detection of nuclear factor-kappa B in IgA nephropathy using Southwestern histochemistry. Am J Kidney Dis 2003;42:76–86. Coppo R, Amore A: Aberrant glycosylation in IgA nephropathy (IgAN). Kidney Int 2004;65: 1544–1547. Coppo R, Amore A, Gianoglio B, Cacace G, Picciotto G, Roccatello D, Peruzzi L, Piccoli G, De Filippi PG: Angiotensin II local hyperreactivity in the progression of IgA nephropathy. Am J Kidney Dis 1993;21:593–602. Coppo R, D’Amico G: Factors predicting progression of IgA nephropathies. J Nephrol 2005;18:503–512. Radford MG Jr, Donadio JV Jr, Bergstralh EJ, Grande JP: Predicting renal outcome in IgA nephropathy. J Am Soc Nephrol 1997;8:199–207. Usui J, Yamagata K, Kai H, Outeki T, Yamamoto S, Muro K, Hirayama A, Yoh K, Tomida C, Hirayama K, Suzuki S, Kobayashi M, Nagata M, Koyama A: Heterogeneity of prognosis in adult IgA nephropathy, especially with mild proteinuria or mild histological features. Intern Med 2001;40:697–702. Cattran DC, Greenwood C, Ritchie S: Long-term benefits of angiotensin-converting enzyme inhibitor therapy in patients with severe immunoglobulin A nephropathy: a comparison to patients receiving treatment with other antihypertensive agents and to patients receiving no therapy. Am J Kidney Dis 1994;23:247–254. Kanno Y, Okada H, Saruta T, Suzuki H: Blood pressure reduction associated with preservation of renal function in hypertensive patients with IgA nephropathy: a 3-year follow-up. Clin Nephrol 2000;54:360–365. Ruggenenti P, Gherardi G, Benini R, Remuzzi G: Chronic proteinuric nephropathies: outcomes and response to treatment in a prospective cohort of 352 patients with different patterns of renal injury. Am J Kidney Dis 2000;35:1155–1165. Dillon JJ: Treating IgA nephropathy. J Am Soc Nephrol 2001;12:846–847. Praga M, Gutierrez E, Gonzalez E, Morales E, Hernandez E: Treatment of IgA nephropathy with ACE inhibitors: a randomized and controlled trial. J Am Soc Nephrol 2003;14:1578–1583. Coppo R, Peruzzi L, Amore A, Piccoli A, Cochat P, Stone R, Kirschstein M, Linnè T: First prospective double-blind randomized placebo-controlled multicenter trial of ACE-inhibitors (ACE-I) in moderately proteinuric IgA nephropathy in the young (in press). Pozzi C, Del Vecchio L, Casartelli D, Pozzoni P, Andrulli S, Amore A, Peruzzi L, Coppo R, Locatelli F; Adulto e Bambino Study Group; Immunopatologia Renale Study Group of the Italian Society of Nephrology: ACE inhibitors and angiotensin II receptor blockers in IgA nephropathy with mild proteinuria: the ACEARB study. J Nephrol 2006;19:508–514. Ma LJ, Nakamura S, Aldigier JC, Rossini M, Yang H, Liang X, Nakamura I, Marcantoni C, Fogo AB: Regression of glomerulosclerosis with high-dose angiotensin inhibition is linked to decreased plasminogen activator inhibitor-1. J Am Soc Nephrol 2005;16:966–976. Russo D, Pisani A, Balletta MM, De Nicola L, Savino FA, Andreucci M, Minutolo R: Additive antiproteinuric effect of converting enzyme inhibitor and losartan in normotensive patients with IgA nephropathy. Am J Kidney Dis 1999;33:851–856. Nakao N, Seno H, Kasuga H, Toriyama T, Kawahara H, Fukagawa M: Effects of combination treatment with losartan and trandolapril on office and ambulatory blood pressures in non-diabetic renal disease: a COOPERATE-ABP substudy. Am J Nephrol 2004;24:543–548. Casas JP, Chua W, Loukogeorgakis S, Vallance P, Smeeth L, Hingorani AD, MacAllister RJ: Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet 2005;366:2026–2033. Suissa S, Hutchinson T, Brophy JM, Kezouh A: ACE-inhibitor use and the long-term risk of renal failure in diabetes. Kidney Int 2006;69:913–919. Aldigier JC, Kanjanbuch T, Ma LJ, Brown NJ, Fogo AB: Regression of existing glomerulosclerosis by inhibition of aldosterone. J Am Soc Nephrol 2005;16:3306–3314. Donadio JV Jr, Bergstralh EJ, Offord KP, Spencer DC, Holley KE: A controlled trial of fish oil in IgA nephropathy. Mayo Nephrology Collaborative Group. N Engl J Med 1994;331: 1194–1199. Angiotensin Antagonists and Fish Oil for Treating IgAN 35 22 23 Dillon JJ: Fish oil therapy for IgA nephropathy: efficacy and interstudy variability. J Am Soc Nephrol 1997;8:1739–1744. Nagy J, Kovacs T, Wittmann I: Renal protection in IgA nephropathy requires strict blood pressure control. Nephrol Dial Transplant 2005;20:1533–1539. Prof. Rosanna Coppo Nephrology Dialysis Transplantation Regina Margherita University Hospital Piazza Polonia 94 IT–10126 Torino (Italy) Tel. ⫹39 011 3135362, Fax ⫹39 011 6635543 E-Mail firstname.lastname@example.org Coppo/Amore/Peruzzi/Mancuso/Camilla 36 Tomino Y (ed): IgA Nephropathy Today. Contrib Nephrol. Basel, Karger, 2007, vol 157, pp 37–43 Treatment of IgA Nephropathy: Corticosteroids, Tonsillectomy, and Mycophenolate Mofetil Tetsuya Kawamura Department of Medicine, Division of Kidney and Hypertension, Jikei University School of Medicine, Tokyo, Japan Abstract Previous studies exploring the potential of glucocorticoid therapy on proteinuria and renal survival of patients with IgA nephropathy (IgAN) indicate that corticosteroid therapy is recommended if the patients show a moderate degree of proteinuria and their creatinine clearance exceeds 70 ml/min, although these studies, most of which are not prospective or randomized, have not provided conclusive results. Recently, Pozzi et al. demonstrated that treatment with glucocorticoids for 6 months significantly improved renal survival and proteinuria for 10 years of follow-up. A recent meta-analysis by Samuels et al. supports the use of corticosteroids in reducing proteinuria and preventing progression to end-stage renal disease. Increasing attention has been drawn to the role of tonsillectomy in the longterm prognosis of IgAN. The notion that tonsillectomy not only helps to prevent episodic macroscopic hematuria in the short-term but also gives long-term renal protection in IgAN is supported by two large retrospective studies from Japan. A study of 329 patients with IgAN by Hotta et al. found that tonsillectomy plus high-dose methylprednisolone was identified as one of the independent variables in predicting remission of clinical findings and lack of renal progression. Moreover, Xie et al. have reported that, for 20 years of follow-up, renal survival was significantly better in IgAN patients who underwent tonsillectomy than those who did not undergo the procedure. However, the role of tonsillectomy in the long-term prognosis of IgAN remains unclear, since it has not yet been tested in a controlled randomized trial. The role of mycophenolate mofetil (MMF) in IgAN has been examined in four major trials. Two prospective randomized studies report no benefit from MMF. The remaining two studies showed a greater reduction of proteinuria in patients treated with MMF compared to prednisone or placebo. In both studies, however, MMF did not effectively modify the progressive course of the disease. Thus, despite promising results in large randomized controlled trials in lupus nephritis, the evidence for the use of MMF in IgAN is inconclusive. Copyright © 2007 S. Karger AG, Basel Corticosteroids Many previous studies have examined the renoprotective effects of corticosteroids in patients with IgA nephropathy (IgAN). An early retrospective study by Kobayashi et al. demonstrated the potential of glucocorticoid therapy on proteinuria and renal survival of IgAN patients, especially of those with initial creatinine clearance (Ccr) values of 70 ml/min or more, but not of those with values below than 70 ml/min . The same authors also reported that steroid therapy for an average period of 18 months in IgAN patients with a Ccr of 70 ml/min or more and proteinuria between 1 and 2 g/day resulted in a better renal survival rate 10 years after therapy compared with an untreated group (80 vs. 34%) . On the other hand, most randomized prospective studies clearly demonstrated that corticosteroids have an antiproteinuric effect, but do not preserve the glomerular filtration rate (GFR). This is probably because of small sample sizes and short duration of follow-up. Among those previous prospective studies, an exception to the mixed results comes from the well-designed, randomized, controlled trial by Pozzi et al. [3, 4]. In this study, 86 IgAN patients with serum creatinine of 1.5 mg/dl or less and proteinuria of 1.0–3.5 g/day were randomized to receive ‘pulse’ methylprednisolone (1 g/day for 3 days at the beginning of months 1, 3, and 5) followed by alternate day oral prednisolone (0.5 mg/kg) or placebo for 6 months. After 12 months, proteinuria in 31 patients (72%) of steroid group had dropped below 1 g/day, whereas only 13 patients (30%) of the placebo group experienced a similar improvement in proteinuria. After 10 years of follow-up, the renal survival was significantly better in the steroid group than in the placebo group (97 vs. 53%)  (fig. 1). Thus, this well-designed trial strongly suggests a role for a 6-month trial of corticosteroids in IgAN patients with urinary protein excretion more than 1.0 g/day yet with preserved renal function. A recent metaanalysis by Samuels et al. supports the use of corticosteroids in reducing proteinuria and preventing progression to end-stage renal disease . A prospective multicenter trial of corticosteroids in Japanese patients with IgAN was performed in 1996–2001 by the Special Study Group on Progressive Glomerular Disease of the Japanese Ministry of Health, Labor and Welfare . Sixty-nine IgAN patients with proteinuria of 0.5–3.4 g/day and Ccr of 70 ml/min or more were divided into two groups: an anti-platelet drug (Dilazep) group and a corticosteroid (PSL) group. The PSL group received prednisolone for 2 years as well as the anti-platelet drug dilazep hydrochloride. There were no differences between the two groups in terms of blood pressure, proteinuria, Ccr, total protein or albumin at baseline. Proteinuria in the PSL group was significantly attenuated at one year and three years compared to baseline, whereas it was not significantly changed in the Dilazep group. Of note, Ccr significantly decreased in the Dilazep group at four years compared to baseline, while it was Kawamura 38 1.0 Log rank p = 0.0003 0.8 0.6 0.4 0.2 Treatment Events Yes No 1/43 13/43 0 0 2 4 6 Follow-up (years) Treatment Yes No 43 43 42 40 39 33 33 23 20 14 8 10 12 7 Fig. 1. Renal survival estimated on the basis of an increase in plasma creatinine concentrations to ⬎100% above baseline values. well preserved throughout the course in the PSL group, suggesting that corticosteroids can confer antiproteinuric and GFR-preserving effects in IgAN patients with normal renal function. In contrast to the efficacy of corticosteroids in IgAN patients with normal renal function, it is not well elucidated whether corticosteroids might be effective for patients with advanced IgAN and impaired re