Predicting Remission in Anti-PLA2R Antibody-Associated Membranous Nephropathy: A Secondary Analysis of the GEMRITUX, MENTOR and STARMEN Trials

Background: In patients with anti-phospholipase A2 receptor (PLA2R) antibody associated membranous nephropathy, there is currently no accepted method to predict an individual’s probability of remission after treatment with immunosuppression or supportive therapy using changes in antibody levels and clinical variables during the first 3-6 months of therapy. Methods: Using a cohort of 187 patients from the GEMRITUX, MENTOR and STARMEN clinical trials with antibody levels at baseline ≥14 RU/ml, we derived logistic regression models to predict proteinuria remission at 12 months that can be used at baseline or after three or six months of treatment. Treatment exposures in the trials included supportive therapy, rituximab, calcineurin inhibitors and cyclophosphamide. Predictors in the models included male sex, and baseline and changes in serum albumin, proteinuria, and antibody levels, with or without changes in eGFR. Results: Proteinuria remission at 12 months was achieved in 107 patients. Compared to the model at baseline, the three- and six-month models had better model fit with lower Akaike Information Criterion (186/158 vs 225) and higher R2 (52.7%/62.4% vs 25.8%), better discrimination with higher C-statistic (0.87 and 0.91 vs 0.75, P<0.001), and better calibration with lower integrated calibration index (0.89%/2.22% vs 2.51%). The three- and six-month models had no consistent difference in prediction performance and decision curve analysis demonstrated similar net benefit for treatment decisions based on either model up to a threshold probability of 31%. Prediction performance was similar after internal validation using optimism correction. Prediction performance was maintained within subgroups of different treatment regimens, including supportive therapy, rituximab, calcineurin inhibitors and cyclophosphamide. Conclusions: Either the three- or six-month models can be used in patients with anti-PLA2R antibody associated membranous nephropathy after three or six months of treatment with a variety of immunosuppression or supportive therapy to predict remission status at 12 months.