Piero Ruggenenti * , † , Hanna Debiec ‡ , § , Barbara Ruggiero * , Antonietta Chianca * , Timothee Pellé ‡ , § , Flavio Gaspari * , Flavio Suardi * , Elena Gagliardini * , Silvia Orisio * , Ariela Benigni * , Pierre Ronco ‡ , § , ‖ , Giuseppe Remuzzi , * , †
24 March 2015
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.