Abstract: Objective:To explore the efficacy and safety of Obinutuzumab for the treatment of phospholipase A2 receptor (PLA2R) associated membranous nephropathy (MN) with very high risk and analyzed factors associated with clinical efficacy. Methods:This was a retrospective study which included PLA2R associated membranous nephropathy with very high risk treated with Obinutuzumab from September 2022 to December 2024.All patients received OBZ 1g×1~2 for induction and maintained with another dose of OBZ 1g at month 6 or once B cell reconstituted.The primary endpoints were remission and complete remission rate during follow up.K-M survival curve and COX regression models were used for remission and factors association analysis.Correlation test was used for renal function improvement influencing factors analysis. Results:35 patients were enrolled in the present study.Baseline proteinuria,serum creatinine,albumin and estimated glomerular filtration rate (eGFR) was 11.8±3.9g/24h,168±44μmol/L,23.5±4.5g/L and 40.7±12.3mL/(min・1.73m²). Following OBZ treatment, proteinuria was significantly decreased while serum albumin and eGFR were significantly increased.After a median follow up of 13 months,a total of 30 patients (86%) achieved remission,including 7 patients (20%) achieving complete remission. Complete immunological remission (anti-PLA2R antibody<2RU/mL) was achieved in all patients,and the median time to complete immunological remission was 3 months.In Cox regression analysis, serum albumin at baseline (HR=1.090, 95% CI 1.004~1.183) was associated with clinical remission. Compared to baseline, eGFR was increased by 13.7mL/(min・1.73m²) at month 6. In correlation test, baseline urine N-acetyl-β-D-glucosaminidase (NAG) enzyme (r=0.341,95% CI 0.009-0.606) and proteinuria decline at month 3 (r=0.583,95% CI 0.310~0.767) was associated with eGFR increase at month 6.Infusion-related adverse event was revealed in 26% patients and mostly mild.Severe infection rate was 2.9%. Conclusion:Obinutuzumab is a promising treatment option for PLA2R-associated membranous nephropathy with very high risk.Renal function was significantly improved following OBZ treatment.

Key words: Obinutuzumab,membranous nephropathy,phospholipase A2 receptor,very high risk,immunological complete remission