Anti-PLA2R Antibody Levels and Clinical Risk Factors for Treatment Nonresponse in Membranous Nephropathy

Abstract

Background: The 2021 KDIGO guidelines recommend following anti-PLA2R antibody levels as a marker of treatment response in membranous nephropathy, however the optimal timing to evaluate antibody levels and how to combine them with other clinical variables are currently unknown. Methods: We used a cohort of 85 patients from the MENTOR trial with anti-PLA2R antibodies ≥14 RU/ml to identify risk factors for not experiencing proteinuria remission after 12 months of treatment with cyclosporine or rituximab. Three landmark times were considered: at baseline, and after 3 and 6 months of treatment. Logistic regression model performance was evaluated using C-statistics and model fit (Akaike Information Criterion (AIC), R2). Results: The model at baseline that best predicted no remission included anti-PLA2R antibodies >323 RU/ml and creatinine clearance; the best model after 3 months included the change from baseline in both antibody and albumin levels; and the best model after 6 months included antibody levels >14 RU/ml, creatinine clearance, and the change from baseline in albumin. Compared to the model at baseline, the model at 3 months had better model fit (AIC 70.9 vs 96.4, R2 51.8% vs 30.1%) and higher C-statistic (0.93 vs 0.83, p=0.008). The model at 6 months had no difference in performance compared to the model at 3 months (AIC 68.6, R2 53.0%, C-statistic 0.94 p=0.67). Conclusions: Using the MENTOR clinical trial cohort of patients with membranous nephropathy treated with standardized cyclosporine or rituximab, we found that the optimal method to evaluate risk factors for the probability of treatment response was to use anti-PLA2R antibody levels combined with albumin levels after 3 months of treatment, which was significantly better than using antibody levels alone or risk factor evaluation at baseline, with no added benefit of waiting until 6 months of treatment.

Ten tips on immunosuppression in primary membranous nephropathy

“…Cases with immunologic remission not followed by remission of NS have been described [ 69 ] and recent evidence suggests that baseline anti-PLA2R titres do not predict disease progression with such confidence after adjusting for proteinuria and kidney function [ 75 , 76 ]. A subanalysis of the MENTOR trial (NCT01180036) showed that anti-PLA2R antibody titres combined with serum albumin levels after 3 months of treatment was the best method to evaluate the probability of remission [ 77 ]. Serum albumin levels are of great value considering that proteinuria can show fluctuations caused by haemodynamic changes or inaccurate urine collection.…”

Membranous nephropathy: pathogenesis and treatments

“… 164 Furthermore, studies have showcased its capacity to reverse epitope spread. 165 , 166 After undergoing RTX treatment, a significant majority of individuals with IMN experience either complete or partial remission (CR or PR), 167 with an impressive overall remission rate of 83.12%. 168 Remarkably, it has demonstrated superiority over cyclosporine in sustaining the remission of proteinuria.…”