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      A Multicenter Randomized Controlled Trial of Rituximab versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (MENTOR)

      research-article
      a , * , b , c , d , e , f , g , a , h , i , g , j , k , b , e , i , l , m , b , n , a , a , a , a , a , a , o , p , q , r , s , t , u , v , w , g
      Nephron
      S. Karger AG
      Idiopathic membranous nephropathy, Rituximab, Cyclosporine, Glomerular disease, Proteinuria

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          Abstract

          Background: Idiopathic membranous nephropathy remains the leading cause of nephrotic syndrome in Caucasian adults. Immunosuppressive therapy with cyclosporine (CSA) is often successful in reducing proteinuria, but its use is associated with a high relapse rate. Rituximab, a monoclonal antibody that specifically targets CD20 on the surface of B-cells, is effective in achieving a complete remission of proteinuria in patients with idiopathic membranous nephropathy. However, whether rituximab is as effective as CSA in inducing and maintaining complete or partial remission of proteinuria in these patients is unknown. The membranous nephropathy trial of rituximab (MENTOR) hypothesizes that B-cell targeting with rituximab is non-inferior to CSA in inducing long-term remission of proteinuria. Methods and Design: Patients with idiopathic membranous nephropathy, proteinuria ≥5 g/24 h, and a minimum of 3 months of Angiotensin-II blockade will be randomized into a 12-month treatment period with IV rituximab, 1,000 mg (2 infusions, 14 days apart; repeated at 6 months if a substantial reduction in proteinuria (equal to or >25%) is seen at 6 months) or oral CSA 3.5-5 mg/kg/day for 6 months (continued for another 6 months if a substantial reduction in proteinuria (equal to or >25%) is seen at 6 months). The efficacy of treatment will be assessed by the remission status (based on changes in proteinuria) at 24 months from randomization. Patient safety will be assessed via collection of adverse event data and evaluation of pre- and posttreatment laboratory data. At the 6-month post-randomization visit, patients who have been randomized to either CSA or rituximab but who do not have a reduction in proteinuria ≥25% (confirmed on repeat measurements within 2 weeks) will be considered treatment failures and exit the study. Discussion: This study will test for the first time whether treatment with rituximab is non-inferior to CSA in inducing long-term remission (complete or partial) of proteinuria in patients with idiopathic membranous nephropathy.

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          Most cited references27

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          Anti-Phospholipase A2 Receptor Antibody Titer Predicts Post-Rituximab Outcome of Membranous Nephropathy.

          Rituximab induces nephrotic syndrome (NS) remission in two-thirds of patients with primary membranous nephropathy (MN), even after other treatments have failed. To assess the relationships among treatment effect, circulating nephritogenic anti-phospholipase A2 receptor (anti-PLA2R) autoantibodies and genetic polymorphisms predisposing to antibody production we serially monitored 24-hour proteinuria and antibody titer in patients with primary MN and long-lasting NS consenting to rituximab (375 mg/m(2)) therapy and genetic analyses. Over a median (range) follow-up of 30.8 (6.0-145.4) months, 84 of 132 rituximab-treated patients achieved complete or partial NS remission (primary end point), and 25 relapsed after remission. Outcomes of patients with or without detectable anti-PLA2R antibodies at baseline were similar. Among the 81 patients with antibodies, lower anti-PLA2R antibody titer at baseline (P=0.001) and full antibody depletion 6 months post-rituximab (hazard ratio [HR], 7.90; 95% confidence interval [95% CI], 2.54 to 24.60; P<0.001) strongly predicted remission. All 25 complete remissions were preceded by complete anti-PLA2R antibody depletion. On average, 50% anti-PLA2R titer reduction preceded equivalent proteinuria reduction by 10 months. Re-emergence of circulating antibodies predicted disease relapse (HR, 6.54; 95% CI, 1.57 to 27.40; P=0.01), whereas initial complete remission protected from the event (HR, 6.63; 95% CI, 2.37 to 18.53; P<0.001). Eighteen patients achieved persistent antibody depletion and complete remission and never relapsed. Outcome was independent of PLA2R1 and HLA-DQA1 polymorphisms and of previous immunosuppressive treatment. Therefore, assessing circulating anti-PLA2R autoantibodies and proteinuria may help in monitoring disease activity and guiding personalized rituximab therapy in nephrotic patients with primary MN.
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            Antiphospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy.

            The phospholipase A(2) receptor (PLA(2)R) is the major target antigen in idiopathic membranous nephropathy. The technique for measuring antibodies against PLA(2)R and the relationship between antibody titer and clinical characteristics are not well established. Here, we measured anti-PLA(2)R (aPLA(2)R) antibody titer and subclass in a well defined cohort of 117 Caucasian patients with idiopathic membranous nephropathy and nephrotic-range proteinuria using both indirect immunofluorescence testing (IIFT) and ELISA. We assessed agreement between tests and correlated antibody titer with clinical baseline parameters and outcome. In this cohort, aPLA(2)R antibodies were positive in 74% and 72% of patients using IIFT and ELISA, respectively. Concordance between both tests was excellent (94% agreement, κ=0.85). Among 82 aPLA(2)R-positive patients, antibody titer significantly correlated with baseline proteinuria (P=0.02). Spontaneous remissions occurred significantly less frequently among patients with high antibody titers (38% versus 4% in the lowest and highest tertiles, respectively; P<0.01). IgG4 was the dominant subclass in the majority of patients. Titers of IgG4, but not IgG1 or IgG3, significantly correlated with the occurrence of spontaneous remission (P=0.03). In summary, these data show high agreement between IIFT and ELISA assessments of aPLA(2)R antibody titer and highlight the pathogenetic role of these antibodies, especially the IgG4 subclass, given the observed relationships between aPLA(2)R titer, baseline proteinuria, and outcome.
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              Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial.

              Membranous nephropathy is a common cause of nephrotic syndrome in adults. Although some patients with membranous nephropathy achieve a spontaneous remission, renal function continues to deteriorate in others. We conducted a prospective randomized trial evaluating monotherapy with tacrolimus to achieve complete or partial remission in patients with biopsy-proven membranous nephropathy. Twenty-five patients received tacrolimus (0.05 mg/kg/day) over 12 months with a 6-month taper, whereas 23 patients were in the control group. The probability of remission in the treatment group was 58, 82, and 94% after 6, 12, and 18 months but only 10, 24, and 35%, respectively in the control group. The decrease in proteinuria was significantly greater in the treatment group. Notably, six patients in the control group and only one in the treatment group reached the secondary end point of a 50% increase in their serum creatinine. No patient in the tacrolimus group showed a relapse during the taper period. Nephrotic syndrome reappeared in almost half of the patients who were in remission by the 18th month after tacrolimus withdrawal. We conclude that tacrolimus is a very useful therapeutic option for patients with membranous nephropathy and preserved renal function. The majority of patients experienced remission with a significant reduction in the risk for deteriorating renal function.
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                Author and article information

                Journal
                NEF
                Nephron
                10.1159/issn.1660-8151
                Nephron
                S. Karger AG
                1660-8151
                2235-3186
                2015
                July 2015
                12 June 2015
                : 130
                : 3
                : 159-168
                Affiliations
                aDivision of Nephrology and Hypertension, Mayo Clinic, Rochester, Minn., bDivision of Nephrology, Columbia University, New York, N.Y., USA; cDivision of Nephrology, University of British Columbia, Vancouver, B.C., Canada; dDivision of Nephrology and Hypertension, Stanford University Medical Center, Sanford, Calif., eDivision of Nephrology, Ohio State University, Columbus, Ohio, fDivision of Nephrology and Hypertension, Mayo Clinic, Jacksonville, Fla., USA; gUniversity Health Network, Toronto General Hospital, Toronto, Ont., Canada; hDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minn., USA; iDivision of Nephrology, University of Michigan, Ann Arbor, Mich., jManchester Royal Infirmary, Manchester, UK; kInternal Medicine/Nephrology and Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Mich., lDivision of Nephrology and Hypertension, Mayo Clinic, Scottsdale, Ariz., mDivision of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, Kans., and nDivision of Nephrology, University of Washington Medical Center, Seattle, Wash., oDepartment of Medicine and Physiology &amp; Biophysics, Case Western Reserve University, Cleveland, Ohio, pDivision of Nephrology, University of Alabama, Birmingham, Ala., qDivision of Nephrology, Medical College of Wisconsin, Milwaukee, Wis., rDivision of Nephrology, New York University, New York, N.Y., sDivision of Nephrology, University of Mississippi Medical Center, Jackson, Miss., tDivision of Nephrology and Hypertension, University of Miami, Miami, Fla., uDepartment of Nephrology and Hypertension, Cleveland Clinic, Cleveland, Ohio, vDivision of Nephrology, University of Arizona, Tucson, Ariz., USA; wCentre Hospitalier Universitaire de Québec, Quebec City, Que., Canada
                Author notes
                *Dr. Fernando C. Fervenza, Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 (USA), E-Mail fervenza.fernando@mayo.edu, Dr. Daniel C. Cattran, University Health Network, Toronto General Hospital, 610 University Avenue, Toronto, ON M5G 2M9 (Canada), E-Mail daniel.cattran@uhn.ca
                Article
                430849 Nephron 2015;130:159-168
                10.1159/000430849
                26087670
                abb94829-8b17-48f3-8ed0-8a2f15652a8f
                © 2015 S. Karger AG, Basel

                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.

                History
                : 29 January 2015
                : 17 April 2015
                Page count
                Figures: 1, Tables: 4, References: 52, Pages: 10
                Categories
                Clinical Practice: Original Paper

                Cardiovascular Medicine,Nephrology
                Idiopathic membranous nephropathy,Rituximab,Cyclosporine,Proteinuria,Glomerular disease

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