Cyclophosphamide or chlorambucil therapy is indicated in idiopathic membranous nephropathy with strong risk factors for progression

Abstract

The systematic review by Perna et al of idiopathic membranous nephropathy (IMN) therapy1Perna A. Schieppati A. Zamora J. Giuliano G.A. Braun N. Remuzzi G. Immunosuppressive treatment for idiopathic membranous nephropathy A systematic review.Am J Kidney Dis. 2004; 44: 385-401PubMed Scopus (112) Google Scholar is timely and rigorous but leaves the reader with a crucial unresolved paradox: alkylating agent therapy (chlorambucil or cyclophosphamide [CML/CTX]) significantly increased complete remission rate (CML/CTX versus placebo, P = 0.004; CML/CTX versus steroids, P = 0.0003) but did not decrease end-stage renal disease (ESRD) rate. The paradox is that IMN complete remission should prevent ESRD.2Troyanov S. Wall C.A. Miller J.A. Scholey J.W. Cattran D.C. Idiopathic membranous nephropathy Definition and relevance of a partial remission.Kidney Int. 2004; 66: 1199-1205Crossref PubMed Scopus (185) Google ScholarGlassock’s editorial3Glassock R.J. The treatment of idiopathic membranous nephropathy A dilemma or a conundrum?.Am J Kidney Dis. 2004; 44: 562-566PubMed Scopus (52) Google Scholar identifies Perna’s paradox and provides plausible explanations. However, its clinical significance is not discussed. We suggest the following: •CML/CTX therapy induces complete IMN remission better than other therapies.1Perna A. Schieppati A. Zamora J. Giuliano G.A. Braun N. Remuzzi G. Immunosuppressive treatment for idiopathic membranous nephropathy A systematic review.Am J Kidney Dis. 2004; 44: 385-401PubMed Scopus (112) Google Scholar•Complete IMN remission prevents progression to ESRD2Troyanov S. Wall C.A. Miller J.A. Scholey J.W. Cattran D.C. Idiopathic membranous nephropathy Definition and relevance of a partial remission.Kidney Int. 2004; 66: 1199-1205Crossref PubMed Scopus (185) Google Scholar and other risks of prolonged nephrotic syndrome, especially atherosclerosis and thrombosis.4Hebert L. Glomerular Diseases. American College of Physicians-American Society of Internal Medicine, Philadelphia, PA1998Google Scholar•Appropriate CML/CTX therapy (Ponticelli et al5Ponticelli C. Zucchelli P. Passerini P. et al.A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy.Kidney Int. 1995; 48: 1600-1604Crossref PubMed Scopus (339) Google Scholar or comparable protocol4Hebert L. Glomerular Diseases. American College of Physicians-American Society of Internal Medicine, Philadelphia, PA1998Google Scholar) is well tolerated.•Thus, CML/CTX therapy is justified in IMN if 1 or more strong progression risk factors are present (nephrotic-range proteinuria despite ≥6 months of aggressive antiproteinuria therapy,6Wilmer W.A. Rovin B.H. Hebert C.J. Rao S.V. Kumor K. Hebert L.A. Management of glomerular proteinuria A commentary.J Am Soc Nephrol. 2003; 14: 3217-3232Crossref PubMed Scopus (183) Google Scholar elevated serum creatinine, and kidney biopsy evidence of chronicity).4Hebert L. Glomerular Diseases. American College of Physicians-American Society of Internal Medicine, Philadelphia, PA1998Google Scholar, 7Cattran D.C. Pei Y. Greenwood C.M. Ponticelli C. Passerini P. Honkanen E. Validation of a predictive model of idiopathic membranous nephropathy Its clinical and research implications.Kidney Int. 1997; 51: 901-907Crossref PubMed Scopus (195) Google ScholarWith this strategy we have only rarely observed IMN progression to ESRD. Between 1983 and 1999 only 2 of our 134 IMN patients progressed to ESRD despite CML/CTX therapy.We suggest that CML/CTX is the gold standard to which other IMN therapies should be compared. Until better data become available, no IMN nephrotic patient with strong progression risk factors should be denied CML/CTX therapy, especially if cyclosporin,8Cattran D.C. Appel G.B. Hebert L.A. et al.Cyclosporine in patients with steroid-resistant membranous nephropathy A randomized trial.Kidney Int. 2001; 59: 1484-1490Crossref PubMed Scopus (301) Google Scholar mycophenolate,9Spetie D.N. Tang Y. Rovin B.H. et al.Mycophenolate therapy of SLE membranous nephropathy.Kidney Int. 2004; 66: 2411-2415Crossref PubMed Scopus (70) Google Scholar or rituximab10Remuzzi G. Chiurchiu C. Abbate M. Brusegan V. Bontempelli M. Ruggenenti P. Rituximab for idiopathic membranous nephropathy.Lancet. 2002; 360: 923-924Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar therapy was unsuccessful. ALL LETTERS TO THE EDITOR MUST BE SUBMITTED ONLINE VIA EDITORIAL MANAGER (http://ajkd.edmgr.com). Letters should be in response to an AJKD article, and that article should have appeared no more than 6 months previously. The title must be different from that of the original article. Letters must not exceed 250 words (excluding references, maximum number 10) and contain no more than 1 figure or table. Letters are subject to editing and abridgment without notice and there is no guarantee that your letter will be published. Submitting the letter constitutes your permission for its publication in any current or subsequent issue or edition of AJKD, in any form or media, now known or hereafter developed. The systematic review by Perna et al of idiopathic membranous nephropathy (IMN) therapy1Perna A. Schieppati A. Zamora J. Giuliano G.A. Braun N. Remuzzi G. Immunosuppressive treatment for idiopathic membranous nephropathy A systematic review.Am J Kidney Dis. 2004; 44: 385-401PubMed Scopus (112) Google Scholar is timely and rigorous but leaves the reader with a crucial unresolved paradox: alkylating agent therapy (chlorambucil or cyclophosphamide [CML/CTX]) significantly increased complete remission rate (CML/CTX versus placebo, P = 0.004; CML/CTX versus steroids, P = 0.0003) but did not decrease end-stage renal disease (ESRD) rate. The paradox is that IMN complete remission should prevent ESRD.2Troyanov S. Wall C.A. Miller J.A. Scholey J.W. Cattran D.C. Idiopathic membranous nephropathy Definition and relevance of a partial remission.Kidney Int. 2004; 66: 1199-1205Crossref PubMed Scopus (185) Google Scholar Glassock’s editorial3Glassock R.J. The treatment of idiopathic membranous nephropathy A dilemma or a conundrum?.Am J Kidney Dis. 2004; 44: 562-566PubMed Scopus (52) Google Scholar identifies Perna’s paradox and provides plausible explanations. However, its clinical significance is not discussed. We suggest the following: •CML/CTX therapy induces complete IMN remission better than other therapies.1Perna A. Schieppati A. Zamora J. Giuliano G.A. Braun N. Remuzzi G. Immunosuppressive treatment for idiopathic membranous nephropathy A systematic review.Am J Kidney Dis. 2004; 44: 385-401PubMed Scopus (112) Google Scholar•Complete IMN remission prevents progression to ESRD2Troyanov S. Wall C.A. Miller J.A. Scholey J.W. Cattran D.C. Idiopathic membranous nephropathy Definition and relevance of a partial remission.Kidney Int. 2004; 66: 1199-1205Crossref PubMed Scopus (185) Google Scholar and other risks of prolonged nephrotic syndrome, especially atherosclerosis and thrombosis.4Hebert L. Glomerular Diseases. American College of Physicians-American Society of Internal Medicine, Philadelphia, PA1998Google Scholar•Appropriate CML/CTX therapy (Ponticelli et al5Ponticelli C. Zucchelli P. Passerini P. et al.A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy.Kidney Int. 1995; 48: 1600-1604Crossref PubMed Scopus (339) Google Scholar or comparable protocol4Hebert L. Glomerular Diseases. American College of Physicians-American Society of Internal Medicine, Philadelphia, PA1998Google Scholar) is well tolerated.•Thus, CML/CTX therapy is justified in IMN if 1 or more strong progression risk factors are present (nephrotic-range proteinuria despite ≥6 months of aggressive antiproteinuria therapy,6Wilmer W.A. Rovin B.H. Hebert C.J. Rao S.V. Kumor K. Hebert L.A. Management of glomerular proteinuria A commentary.J Am Soc Nephrol. 2003; 14: 3217-3232Crossref PubMed Scopus (183) Google Scholar elevated serum creatinine, and kidney biopsy evidence of chronicity).4Hebert L. Glomerular Diseases. American College of Physicians-American Society of Internal Medicine, Philadelphia, PA1998Google Scholar, 7Cattran D.C. Pei Y. Greenwood C.M. Ponticelli C. Passerini P. Honkanen E. Validation of a predictive model of idiopathic membranous nephropathy Its clinical and research implications.Kidney Int. 1997; 51: 901-907Crossref PubMed Scopus (195) Google Scholar With this strategy we have only rarely observed IMN progression to ESRD. Between 1983 and 1999 only 2 of our 134 IMN patients progressed to ESRD despite CML/CTX therapy. We suggest that CML/CTX is the gold standard to which other IMN therapies should be compared. Until better data become available, no IMN nephrotic patient with strong progression risk factors should be denied CML/CTX therapy, especially if cyclosporin,8Cattran D.C. Appel G.B. Hebert L.A. et al.Cyclosporine in patients with steroid-resistant membranous nephropathy A randomized trial.Kidney Int. 2001; 59: 1484-1490Crossref PubMed Scopus (301) Google Scholar mycophenolate,9Spetie D.N. Tang Y. Rovin B.H. et al.Mycophenolate therapy of SLE membranous nephropathy.Kidney Int. 2004; 66: 2411-2415Crossref PubMed Scopus (70) Google Scholar or rituximab10Remuzzi G. Chiurchiu C. Abbate M. Brusegan V. Bontempelli M. Ruggenenti P. Rituximab for idiopathic membranous nephropathy.Lancet. 2002; 360: 923-924Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar therapy was unsuccessful. ALL LETTERS TO THE EDITOR MUST BE SUBMITTED ONLINE VIA EDITORIAL MANAGER (http://ajkd.edmgr.com). Letters should be in response to an AJKD article, and that article should have appeared no more than 6 months previously. The title must be different from that of the original article. Letters must not exceed 250 words (excluding references, maximum number 10) and contain no more than 1 figure or table. Letters are subject to editing and abridgment without notice and there is no guarantee that your letter will be published. Submitting the letter constitutes your permission for its publication in any current or subsequent issue or edition of AJKD, in any form or media, now known or hereafter developed. ALL LETTERS TO THE EDITOR MUST BE SUBMITTED ONLINE VIA EDITORIAL MANAGER (http://ajkd.edmgr.com). Letters should be in response to an AJKD article, and that article should have appeared no more than 6 months previously. The title must be different from that of the original article. Letters must not exceed 250 words (excluding references, maximum number 10) and contain no more than 1 figure or table. Letters are subject to editing and abridgment without notice and there is no guarantee that your letter will be published. Submitting the letter constitutes your permission for its publication in any current or subsequent issue or edition of AJKD, in any form or media, now known or hereafter developed. ALL LETTERS TO THE EDITOR MUST BE SUBMITTED ONLINE VIA EDITORIAL MANAGER (http://ajkd.edmgr.com). Letters should be in response to an AJKD article, and that article should have appeared no more than 6 months previously. The title must be different from that of the original article. Letters must not exceed 250 words (excluding references, maximum number 10) and contain no more than 1 figure or table. Letters are subject to editing and abridgment without notice and there is no guarantee that your letter will be published. Submitting the letter constitutes your permission for its publication in any current or subsequent issue or edition of AJKD, in any form or media, now known or hereafter developed. Immunosuppressive treatment for idiopathic membranous nephropathy: A systematic reviewAmerican Journal of Kidney DiseasesVol. 44Issue 3PreviewBackground: This study aims to assess whether immunosuppression is beneficial in the treatment of idiopathic membranous nephropathy (IMN). Methods: We reviewed randomized controlled trials (RCTs) addressing the effect of immunosuppression on histologically proven IMN in adults with nephrotic syndrome followed up for at least 6 months. The literature was searched according to Cochrane Collaboration guidelines. Four therapeutic classes were considered: (1) steroids (alone), (2) alkylating agents (alone or in combination with steroids), (3) calcineurin inhibitors (alone or in combination with steroids), and (4) antiproliferative agents (alone). Full-Text PDF In replyAmerican Journal of Kidney DiseasesVol. 45Issue 4PreviewThe remarks by Hebert et al concerning the apparent paradox between the observation by Perna et al1 that alkylating agent therapy of idiopathic membranous nephropathy is associated with a higher frequency of complete remissions yet does not protect from end-stage renal disease (ESRD) are quite appropriate. In my editorial,2 I suggested some possible reasons for the paradox, including the duration of follow-up for some studies included in the systematic review. Full-Text PDF