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      Anti-Phospholipase A 2 Receptor Antibody Titer Predicts Post-Rituximab Outcome of Membranous Nephropathy

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          Abstract

          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 A 2 receptor (anti-PLA 2R) 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-PLA 2R antibodies at baseline were similar. Among the 81 patients with antibodies, lower anti-PLA 2R 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-PLA 2R antibody depletion. On average, 50% anti-PLA 2R 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-PLA 2R autoantibodies and proteinuria may help in monitoring disease activity and guiding personalized rituximab therapy in nephrotic patients with primary MN.

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          Author and article information

          Journal
          J Am Soc Nephrol
          J. Am. Soc. Nephrol
          jnephrol
          jnephrol
          ASN
          Journal of the American Society of Nephrology : JASN
          American Society of Nephrology
          1046-6673
          1533-3450
          October 2015
          24 March 2015
          : 26
          : 10
          : 2545-2558
          Affiliations
          [* ]IRCCS—Istituto di Ricerche Farmacologiche Mario Negri, and
          []Unit of Nephrology, Azienda Ospedaliera Ospedale Papa Giovanni XXIII, Bergamo, Italy;
          []Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche UMR_S1155, Paris, France;
          [§ ]Sorbonne Universités, Universitè Pierre and Marie Curie University, Paris 06, Paris, France; and
          []Assistance Publique-Hôpitaux de Paris, Department of Nephrology and Dialysis, Tenon Hospital, Paris, France
          Author notes

          P.R., H.D., and B.R. contributed equally to this work as the first author.

          P.Ro. and G.R. contributed equally to this work as the last author.

          Correspondence: Dr. Giuseppe Remuzzi, IRCCS—Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano, 87, 24126 Bergamo, Italy. Email: Giuseppe.remuzzi@ 123456marionegri.it
          Article
          PMC4587688 PMC4587688 4587688 2014070640
          10.1681/ASN.2014070640
          4587688
          25804280
          Copyright © 2015 by the American Society of Nephrology
          Page count
          Pages: 14
          Categories
          Clinical Research
          Custom metadata
          October 2015

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