Anti-PLA2R IgG4-to-IgG Ratio Helps to Predict Remission of PLA2R-Associated Primary Membranous Nephropathy

Background and Aims: PLA2R-associated primary membranous nephropathy (PMN) was classified as IgG4-associated autoimmune disease in which anti-PLA2R antibody is predominantly IgG4 subclass. Our objective was to explore the capability of anti-PLA2R IgG4-to-IgG ratio for predicting remission in PLA2R-associated PMN patients. Methods: 143 patients with anti-PLA2R IgG ≥14 RU/ml were biopsy-confirmed as PLA2R-associated PMN. Serum samples collected at the time of renal biopsy were tested for anti-PLA2R IgG and anti-PLA2R IgG4 using time-resolved fluoroimmunoassay. The anti-PLA2R IgG4-to-IgG ratio was calculated as anti-PLA2R IgG4 (ng/ml) divided by anti-PLA2R IgG (RU/ml). Patients were divided into high ratio and low ratio groups by cutoff value of 31.5 ng/RU determined by the maximally selected log-rank statistic. The relationship between anti-PLA2R IgG4-to-IgG ratio and remission was analyzed using Cox proportional hazard regression. Results: Compared to the low ratio group, patients in the high ratio group were significantly younger (52 [40-60] vs. 58 [51-61] years, p=0.035), had higher eGFR (102 [88-111] vs. 94 [72-100] ml/min/1.73m2, p=0.004), obtained higher 6-month partial remission rates (64.6% vs. 30.0%, p=0.001) and 1-year complete remission rates (38.3% vs. 7.7%, p=0.003). The higher remission rates with high ratio remained in both moderate-low risk and high risk subgroups categorized according to KDIGO 2021 guidelines. Anti-PLA2R IgG4-to-IgG ratio had a significant positive relation with partial remission (HR [95%CI] = 2.09 [1.27-3.46], p=0.004), which also persisted across both risk subgroups. Kaplan-Meier survival curves confirmed the significantly higher partial remission in high ratio group. Conclusion: An elevated anti-PLA2R IgG4-to-IgG ratio may be a supplementary predictor for remission in PLA2R-associated PMN.