Many prospective studies and a recent randomized controlled trial have shown that the B-cell-depleting monoclonal antibody, rituximab, safely promotes the remission of nephrotic syndrome in approximately 65% of patients with membranous nephropathy (MN). Mechanistic studies have indicated that rituximab-induced proteinuria reduction is associated with clearance of anti-podocyte antigens phospholipase 2 receptor autoantibodies and subepithelial immune complexes, the hallmarks of the disease. A recently published study reported results which, at first sight, looked less favorable and implied that, due to a publication bias against negative results, the efficacy of rituximab in MN might be overestimated. Since patients received only one or 2 rituximab administrations, the authors suggest that when rituximab is used, higher doses and longer treatments should be considered. In this study, we highlight limitations of the study and warn against an oversimplified interpretation of the data. Though information on the optimal dose of rituximab to use in MN is still limited, available data from studies with predefined rituximab administration protocols collectively support the concept of titrating rituximab to the number of circulating B-cells that are invariably depleted after the first or second administration. Additional doses may increase the risk of adverse effects and related costs without augmenting efficacy. Importantly, underpowered studies with inconclusive results should not be confused with negative studies formally proving a neutral effect of a treatment. Until data from ad hoc designed clinical trials are available, the B-cell-driven protocol should be the preferred regimen, since it is similarly effective, but safer and more cost effective than other protocols employing multiple rituximab administrations.

1.
Radhakrishnan J, Cattran DC: The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines - application to the individual patient. Kidney Int 2012;82:840-856.
2.
Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, et al: M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009;361:11-21.
3.
Tomas NM, Beck LH Jr, Meyer-Schwesinger C, Seitz-Polski B, Ma H, Zahner G, et al: Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med 2014;371:2277-2287.
4.
Ronco P, Debiec H: Pathophysiological advances in membranous nephropathy: time for a shift in patient's care. Lancet 2015;385:1983-1992.
5.
Cohen CD, Calvaresi N, Armelloni S, Schmid H, Henger A, Ott U, et al: CD20-positive infiltrates in human membranous glomerulonephritis. J Nephrol 2005;18:328-333.
6.
Remuzzi G, Chiurchiu C, Abbate M, Brusegan V, Bontempelli M, Ruggenenti P: Rituximab for idiopathic membranous nephropathy. Lancet 2002;360:923-924.
7.
Beck LH Jr, Fervenza FC, Beck DM, Bonegio RG, Malik FA, Erickson SB, et al: Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. J Am Soc Nephrol 2011;22:1543-1550.
8.
Bomback AS, Derebail VK, McGregor JG, Kshirsagar AV, Falk RJ, Nachman PH: Rituximab therapy for membranous nephropathy: a systematic review. Clin J Am Soc Nephrol 2009;4:734-744.
9.
Fervenza FC, Abraham RS, Erickson SB, Irazabal MV, Eirin A, Specks U, et al: Rituximab therapy in idiopathic membranous nephropathy: a 2-year study. Clin J Am Soc Nephrol 2010;5:2188-2198.
10.
Ruggenenti P, Cravedi P, Chianca A, Perna A, Ruggiero B, Gaspari F, et al: Rituximab in idiopathic membranous nephropathy. J Am Soc Nephrol 2012;23:1416-1425.
11.
Cravedi P, Sghirlanzoni MC, Marasà M, Salerno A, Remuzzi G, Ruggenenti P: Efficacy and safety of rituximab second-line therapy for membranous nephropathy: a prospective, matched-cohort study. Am J Nephrol 2011;33:461-468.
12.
Ruggenenti P, Debiec H, Ruggiero B, Chianca A, Pellé T, Gaspari F, et al: Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy. J Am Soc Nephrol 2015;26:2545-2558.
13.
Beck LH Jr, Fervenza FC, Beck D, Bonegio R, Erickson SB, Cosio FG, et al: Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. J Am Soc Nephrol 2011;22:1543-1550.
14.
Ruggenenti P, Cravedi P, Sghirlanzoni MC, Gagliardini E, Conti S, Gaspari F, et al: Effects of rituximab on morphofunctional abnormalities of membranous glomerulopathy. Clin J Am Soc Nephrol 2008;3:1652-1659.
15.
Dahan K, Debiec H, Plaisier E, Cachanado M, Rousseau A, Wakselman L, et al: Rituximab for severe membranous nephropathy: a 6-month trial with extended follow-up. J Am Soc Nephrol 2016;pii:ASN.2016040449.
16.
Cravedi P, Remuzzi G, Ruggenenti P: Rituximab in primary membranous nephropathy: first-line therapy, why not? Nephron Clin Pract 2014;128:261-269.
17.
Moroni G, Depetri F, Del Vecchio L, Gallelli B, Raffiotta F, Giglio E, et al: Low-dose rituximab is poorly effective in patients with primary membranous nephropathy. Nephrol Dial Transplant 2016;pii:gfw251.
18.
Ruggenenti P, Cravedi P, Remuzzi G: Rituximab for membranous nephropathy and immune disease: less might be enough. Nat Clin Pract Nephrol 2009;5:76-77.
19.
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 Nephrol 2007;2:932-937.
20.
Ruggenenti P, Chiurchiu C, Abbate M, Perna A, Cravedi P, Bontempelli M, et al: Rituximab for idiopathic membranous nephropathy: who can benefit? Clin J Am Soc Nephrol 2006;1:738-748.
21.
Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R: Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008;358:252-260.
22.
Luijendijk HJ, Koolman X: The incentive to publish negative studies: how beta-blockers and depression got stuck in the publication cycle. J Clin Epidemiol 2012;65:488-492.
23.
Joober R, Schmitz N, Annable L, Boksa P: Publication bias: what are the challenges and can they be overcome? J Psychiatry Neurosci 2012;37:149-152.
24.
Ponticelli C, Zucchelli P, Passerini P, Cesana BL: Methylprednisolone plus chlorambucil as compared with methylprednisolone alone for the treatment of idiopathic membranous nephropathy. The Italian idiopathic membranous nephropathy treatment study group. N Engl J Med 1992;327:599-603.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication 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.
You do not currently have access to this content.