Rituximab in Idiopathic Membranous Nephropathy

Piero Ruggenenti

Paolo Cravedi

Antonietta Chianca

Annalisa Perna

^{Mario Negri Institute for Pharmacological Research, Clinical Research Center for Rare Diseases, Aldo e Cele Daccò, Villa Camozzi, Ranica, Italy; and}

^{Units of Nephrology and}

^{Hematology, Azienda Ospedaliera, Ospedali Riuniti di Bergamo, Bergamo, Italy}

^{Corresponding author.}

P.R. and P.C. contributed equally to this work.

Correspondence: Dr. Giuseppe Remuzzi, Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Kilometro Rosso Science and Technology Park, Via Stezzano 87, 24126 Bergamo, Italy. Email: ti.irgenoiram@izzumer.eppesuig

Received 2012 Feb 16; Accepted 2012 May 18.

Abstract

Selective depletion of B cells with the mAb rituximab may benefit the autoimmune glomerular disease idiopathic membranous nephropathy (IMN). Here, we describe our experience treating 100 consecutive IMN patients with persistent nephrotic syndrome with rituximab. We defined complete remission as persistent proteinuria <0.3 g/24 h and partial remission as persistent proteinuria <3 g/24 h, each also having >50% reduction in proteinuria from baseline. During a median follow-up of 29 months after rituximab administration, 65 patients achieved complete or partial remission. The median time to remission was 7.1 months. All 24 patients who had at least 4 years of follow-up achieved complete or partial remission. Rates of remission were similar between patients with or without previous immunosuppressive treatment. Four patients died and four progressed to ESRD. Measured GFR increased by a mean 13.2 (SD 19.6) ml/min per 1.73 m^{among those who achieved complete remission. Serum albumin significantly increased and albumin fractional clearance decreased among those achieving complete or partial remission. Proteinuria at baseline and the follow-up duration each independently predicted the decline of proteinuria. Furthermore, the magnitude of proteinuria reduction significantly correlated with slower GFR decline (}P=0.0001). No treatment-related serious adverse events occurred. In summary, rituximab achieved disease remission and stabilized or improved renal function in a large cohort of high-risk patients with IMN.

Abstract

Idiopathic membranous nephropathy (IMN) is an antibody-mediated autoimmune glomerular disease that is found in the majority of adult patients with the nephrotic syndrome.¹ In an 18-year experience with 100 consecutive patients who had received no specific treatment, Schieppati et al.² found that at 5 years, 20% had achieved complete remission and 40% had some degree of proteinuria with stable or slowly declining renal function. The remainder had persistent nephrotic syndrome with progression to ESRD in most cases. More recently, Polanco et al. also found that, despite treatment with angiotensin converting enzyme (ACE) inhibitors, approximately 10% of those with persistent nephrotic syndrome die prematurely of cardiovascular events before progressing to ESRD.³

Thus far, therapeutic approaches to IMN mostly rely on nonspecific immunosuppression with steroids and alkylating agents with or without calcineurin inhibitors.⁴ In particular, steroids in combination with alkylating agents have been reported to reduce the rate of progression to ESRD more effectively that steroids alone in long-term randomized clinical trials.⁵6 Observational studies also showed that, irrespective of substantial changes in patient characteristics and concurrent advances in conservative therapies, the implementation of the above immunosuppressive regimens in IMN patients at high risk of progression has led to a substantial reduction in ESRD incidence in the everyday setting.⁷8 However, enthusiasm about more favorable outcomes achieved by steroids and alkylating agents over the last 3 decades is tempered by the side effects of these medications, which have been associated with an increased risk of lymphoproliferative disorders, cancer, infections, myelotoxicity, iatrogenic diabetes, and other serious adverse events.⁹ The oncogenic potential of alkylating agents, although at higher doses than those currently recommended for patients with IMN, is well documented and is a major concern.¹⁰12 The risk of cancer and other serious complications is further increased when patients progressing to ESRD receive a kidney transplant and are exposed to further immunosuppressive treatment to prevent allograft rejection.¹³

The possibility of a specific and hopefully safer treatment for patients with IMN emerged in 1997 when rituximab, a mAb against the CD20 antigen present on B lymphocytes, was approved by the US Food and Drug Administration for the treatment of non-Hodgkin’s lymphoma.¹⁴ Because the CD20 antigen is not expressed on hematopoietic stem cells, normal plasma cells, or other normal tissues, selective B lymphocyte depletion by rituximab therapy was expected to inhibit the production of autoantibodies involved in the pathogenesis of the disease without the toxicity of nonspecific immunosuppression.¹⁵ Thus, we initially tested the safety of rituximab in eight IMN patients with severe nephrotic syndrome unresponsive to prolonged ACE inhibitor therapy.¹⁵16 Treatment was well tolerated and led to a significant reduction in proteinuria. Other small, short-term studies confirmed these preliminary encouraging findings.¹⁷18 Thus, we decided to offer this treatment option to patients referred to our nephrology unit who were expected to progress to ESRD or to die prematurely of cardiovascular events because of persistent nephrotic syndrome.²3 Here we describe the outcome of the first 100 consecutive patients prospectively monitored for up to 10 years after rituximab administration.

Variables expressed as mean ± SD are compared using one-way ANOVA. Variables expressed as median (IQR) are compared using the Kruskal–Wallis test. Categorical variables are expressed in percentages and compared using the chi-squared test.

The incidence of events in participants with complete remission was lower than in those with partial or no remission (P=0.037, Cochran–Armitage test for trend). MI, myocardial infarction; TIA, transitory ischemic attack.

Data are presented as n (%).

Acknowledgments

We are indebted to the staff of the Nephrology Unit of the Ospedali Riuniti and of the Clinical Research Center of the Mario Negri Institute, Bergamo, Italy, for their assistance in the selection of and care for the participants of this study. We thank Dr. Mariano Marchesi, who was alerted for acute adverse reactions during each rituximab infusion; Dr. Carlos Chiurchiu, Dr. Chiara Sghirlanzoni, and Dr. Roberto Pisoni, who were in charge of patient care and follow-up; Dr. Chiara Somma, who helped in data entry; Dr. Mario Bontempelli, who studied the lymphocyte subpopulations; and Dr. Diletta Valsecchi, who helped in data extraction and analyses. We are grateful to Manuela Passera for assistance in preparing the manuscript.

Acknowledgments

Footnotes

Published online ahead of print. Publication date available at www.jasn.org.

See related editorial, “Rituximab in Membranous Nephropathy: Is It a First-Line Treatment?,” on pages 1280–1282.

This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2012020181/-/DCSupplemental.

Footnotes

References

1. Austin HA, 3rd, Antonovych TT, MacKay K, Boumpas DT, Balow JE: NIH conference. Membranous nephropathy.Ann Intern Med116: 672–682, 1992 [[PubMed]
2. Schieppati A, Mosconi L, Perna A, Mecca G, Bertani T, Garattini S, Remuzzi G: Prognosis of untreated patients with idiopathic membranous nephropathy.N Engl J Med329: 85–89, 1993 [[PubMed]
3. Polanco N, Gutiérrez E, Covarsí A, Ariza F, Carreño A, Vigil A, Baltar J, Fernández-Fresnedo G, Martín C, Pons S, Lorenzo D, Bernis C, Arrizabalaga P, Fernández-Juárez G, Barrio V, Sierra M, Castellanos I, Espinosa M, Rivera F, Oliet A, Fernández-Vega F, Praga M, Grupo de Estudio de las Enfermedades Glomerulares de la Sociedad Española de Nefrología : Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy.J Am Soc Nephrol21: 697–704, 2010
4. Ruggenenti P, Cravedi P, Remuzzi G: Latest treatment strategies for membranous nephropathy.Expert Opin Pharmacother8: 3159–3171, 2007 [[PubMed]
5. Jha V, Ganguli A, Saha TK, Kohli HS, Sud K, Gupta KL, Joshi K, Sakhuja V: A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy.J Am Soc Nephrol18: 1899–1904, 2007 [[PubMed]
6. Ponticelli C, Zucchelli P, Passerini P, Cesana B, Locatelli F, Pasquali S, Sasdelli M, Redaelli B, Grassi C, Pozzi C, Bizzarri D, Banfi G: A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy.Kidney Int48: 1600–1604, 1995 [[PubMed]
7. Cattran DC, Reich HN, Kim SJ, Troyanov S: Have we changed the outcome in membranous nephropathy? A propensity study on the role of immunosuppressive therapy.Clin J Am Soc Nephrol6: 1591–1598, 2011 [[PubMed]
8. Hofstra JM, Wetzels JF: Introduction of a cyclophosphamide-based treatment strategy and the risk of ESRD in patients with idiopathic membranous nephropathy: A nationwide survey in the Netherlands.Nephrol Dial Transplant23: 3534–3538, 2008 [[PubMed]
9. McQuarrie EP, Stirling CM, Geddes CC: Idiopathic membranous nephropathy and nephrotic syndrome: Outcome in the era of evidence-based therapy.Nephrol Dial Transplant27: 235–242, 2012 [[PubMed]
10. Lewis E: Management of the nephrotic syndrome in adults. In: The Nephrotic Syndrome. Kidney Disease, edited by Cameron JS, Glassock RJ, editors. , Vol. 8, New York, Marcel Dekker, 1988, pp 499–504 [PubMed]
11. Faurschou M, Sorensen IJ, Mellemkjaer L, Loft AG, Thomsen BS, Tvede N, Baslund B: Malignancies in Wegener’s granulomatosis: Incidence and relation to cyclophosphamide therapy in a cohort of 293 patients.J Rheumatol35: 100–105, 2008 [[PubMed]
12. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, Rottem M, Fauci AS: Wegener granulomatosis: An analysis of 158 patients.Ann Intern Med116: 488–498, 1992 [[PubMed]
13. Zeier M, Hartschuh W, Wiesel M, Lehnert T, Ritz E: Malignancy after renal transplantation.Am J Kidney Dis39: E5, 2002 [[PubMed]
14. Taylor RP, Lindorfer MA: Immunotherapeutic mechanisms of anti-CD20 monoclonal antibodies.Curr Opin Immunol20: 444–449, 2008
15. Remuzzi G, Chiurchiu C, Abbate M, Brusegan V, Bontempelli M, Ruggenenti P: Rituximab for idiopathic membranous nephropathy.Lancet360: 923–924, 2002 [[PubMed]
16. Ruggenenti P, Chiurchiu C, Brusegan V, Abbate M, Perna A, Filippi C, Remuzzi G: Rituximab in idiopathic membranous nephropathy: A one-year prospective study.J Am Soc Nephrol14: 1851–1857, 2003 [[PubMed]
17. Fervenza FC, Abraham RS, Erickson SB, Irazabal MV, Eirin A, Specks U, Nachman PH, Bergstralh EJ, Leung N, Cosio FG, Hogan MC, Dillon JJ, Hickson LJ, Li X, Cattran DC, Mayo Nephrology Collaborative Group : Rituximab therapy in idiopathic membranous nephropathy: A 2-year study.Clin J Am Soc Nephrol5: 2188–2198, 2010
18. Fervenza FC, Cosio FG, Erickson SB, Specks U, Herzenberg AM, Dillon JJ, Leung N, Cohen IM, Wochos DN, Bergstralh E, Hladunewich M, Cattran DC: Rituximab treatment of idiopathic membranous nephropathy.Kidney Int73: 117–125, 2008 [[PubMed]
19. Ponticelli C, Zucchelli P, Imbasciati E, Cagnoli L, Pozzi C, Passerini P, Grassi C, Limido D, Pasquali S, Volpini T, Sasdelli M, Locatelli F: Controlled trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy.N Engl J Med310: 946–950, 1984 [[PubMed]
20. Cattran DC, Appel GB, Hebert LA, Hunsicker LG, Pohl MA, Hoy WE, Maxwell DR, Kunis CL, North America Nephrotic Syndrome Study Group : Cyclosporine in patients with steroid-resistant membranous nephropathy: A randomized trial.Kidney Int59: 1484–1490, 2001 [[PubMed]
21. Perna A, Schieppati A, Zamora J, Giuliano GA, Braun N, Remuzzi G: Immunosuppressive treatment for idiopathic membranous nephropathy: A systematic review.Am J Kidney Dis44: 385–401, 2004 [[PubMed]
22. Lewis EJ: Idiopathic membranous nephropathy—to treat or not to treat?N Engl J Med329: 127–129, 1993 [[PubMed]
23. Ponticelli C, Altieri P, Scolari F, Passerini P, Roccatello D, Cesana B, Melis P, Valzorio B, Sasdelli M, Pasquali S, Pozzi C, Piccoli G, Lupo A, Segagni S, Antonucci F, Dugo M, Minari M, Scalia A, Pedrini L, Pisano G, Grassi C, Farina M, Bellazzi R: A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy.J Am Soc Nephrol9: 444–450, 1998 [[PubMed]
24. Ponticelli C, Zucchelli P, Passerini P, Cesana B, The Italian Idiopathic Membranous Nephropathy Treatment Study Group : Methylprednisolone plus chlorambucil as compared with methylprednisolone alone for the treatment of idiopathic membranous nephropathy.N Engl J Med327: 599–603, 1992 [[PubMed]
25. Gea-Banacloche JC: Rituximab-associated infections.Semin Hematol47: 187–198, 2010 [[PubMed]
26. Lanini S, Molloy AC, Fine PE, Prentice AG, Ippolito G, Kibbler CC: Risk of infection in patients with lymphoma receiving rituximab: Systematic review and meta-analysis.BMC Med9: 36, 2011
27. Tan CS, Koralnik IJ: Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: Clinical features and pathogenesis.Lancet Neurol9: 425–437, 2010
28. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ: Cancer statistics, 2006.CA Cancer J Clin56: 106–130, 2006 [[PubMed]
29. Bomback AS, Derebail VK, McGregor JG, Kshirsagar AV, Falk RJ, Nachman PH: Rituximab therapy for membranous nephropathy: A systematic review.Clin J Am Soc Nephrol4: 734–744, 2009
30. Winter MC, Hancock BW: Ten years of rituximab in NHL.Expert Opin Drug Saf8: 223–235, 2009 [[PubMed]
31. Salliot C, Dougados M, Gossec L: Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: Meta-analyses of randomised placebo-controlled trials.Ann Rheum Dis68: 25–32, 2009
32. Tony HP, Burmester G, Schulze-Koops H, Grunke M, Henes J, Kötter I, Haas J, Unger L, Lovric S, Haubitz M, Fischer-Betz R, Chehab G, Rubbert-Roth A, Specker C, Weinerth J, Holle J, Müller-Ladner U, König R, Fiehn C, Burgwinkel P, Budde K, Sörensen H, Meurer M, Aringer M, Kieseier B, Erfurt-Berge C, Sticherling M, Veelken R, Ziemann U, Strutz F, von Wussow P, Meier FM, Hunzelmann N, Schmidt E, Bergner R, Schwarting A, Eming R, Hertl M, Stadler R, Schwarz-Eywill M, Wassenberg S, Fleck M, Metzler C, Zettl U, Westphal J, Heitmann S, Herzog AL, Wiendl H, Jakob W, Schmidt E, Freivogel K, Dörner T, GRAID investigators : Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: Experience from a national registry (GRAID).Arthritis Res Ther13: R75, 2011
33. Gürcan HM, Keskin DB, Stern JN, Nitzberg MA, Shekhani H, Ahmed AR: A review of the current use of rituximab in autoimmune diseases.Int Immunopharmacol9: 10–25, 2009 [[PubMed]
34. Kerjaschki D: Pathogenetic concepts of membranous glomerulopathy (MGN).J Nephrol13Suppl 3]: S96–S100, 2000 [[PubMed]
35. Debiec H, Guigonis V, Mougenot B, Decobert F, Haymann JP, Bensman A, Deschênes G, Ronco PM: Antenatal membranous glomerulonephritis due to anti-neutral endopeptidase antibodies.N Engl J Med346: 2053–2060, 2002 [[PubMed]
36. Beck LH, Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, Klein JB, Salant DJ: M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.N Engl J Med361: 11–21, 2009
37. Beck LH, Jr, Fervenza FC, Beck DM, Bonegio RG, Malik FA, Erickson SB, Cosio FG, Cattran DC, Salant DJ: Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy.J Am Soc Nephrol22: 1543–1550, 2011
38. Cravedi P, Ruggenenti P, Remuzzi G: Circulating anti-PLA2R autoantibodies to monitor immunological activity in membranous nephropathy.J Am Soc Nephrol22: 1400–1402, 2011 [[PubMed]
39. Gaspari F, Perico N, Matalone M, Signorini O, Azzollini N, Mister M, Remuzzi G: Precision of plasma clearance of iohexol for estimation of GFR in patients with renal disease.J Am Soc Nephrol9: 310–313, 1998 [[PubMed]
40. Ruggenenti P, Cravedi P, Sghirlanzoni MC, Gagliardini E, Conti S, Gaspari F, Marchetti G, Abbate M, Remuzzi G: Effects of rituximab on morphofunctional abnormalities of membranous glomerulopathy.Clin J Am Soc Nephrol3: 1652–1659, 2008
41. Remuzzi G, Benigni A, Remuzzi A: Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes.J Clin Invest116: 288–296, 2006
42. Mathieson PW: The UK Randomised Controlled Trial of Immunosuppression for Progressive Membranous Nephropathy [Abstract].J Am Soc Nephrol22: 11A, 2011 [PubMed]
43. Cravedi P, Ruggenenti P, Sghirlanzoni MC, Remuzzi G: Titrating rituximab to circulating B cells to optimize lymphocytolytic therapy in idiopathic membranous nephropathy.Clin J Am Soc Nephrol2: 932–937, 2007 [[PubMed]
44. Ruggenenti P, Perticucci E, Cravedi P, Gambara V, Costantini M, Sharma SK, Perna A, Remuzzi G: Role of remission clinics in the longitudinal treatment of CKD.J Am Soc Nephrol19: 1213–1224, 2008
45. Ng HJ, Lim LC: Fulminant hepatitis B virus reactivation with concomitant listeriosis after fludarabine and rituximab therapy: Case report.Ann Hematol80: 549–552, 2001 [[PubMed]
46. Troyanov S, Wall CA, Miller JA, Scholey JW, Cattran DC, Toronto Glomerulonephritis Registry Group : Idiopathic membranous nephropathy: Definition and relevance of a partial remission.Kidney Int66: 1199–1205, 2004 [[PubMed]