Efficacy and safety of modified-dose obinutuzumab in the treatment of refractory membranous nephropathy

Introduction: Primary membranous nephropathy (MN) is an autoimmune kidney disease, and the main autoantibody is directed against the M-type phospholipase A2 receptor (PLA2R). Approximately 20-40% of patients with MN do not respond to standard immunosuppressive therapy, termed refractory MN. Previous studies suggest obinutuzumab's efficacy in refractory MN, but the optimal dosing regimen remains undefined. Methods: This single-center retrospective study investigated the efficacy and safety of a B-cell reconstitution-guided regimen of obinutuzumab in patients with refractory MN. All patients were followed at 3-month intervals for up to 18 months. The primary outcome was a composite of complete or partial remission. The secondary outcomes included complete remission, B-cell depletion, immunological remission, and safety profiles. Results: A total of 33 patients with refractory MN were included (81.8% were rituximab-refractory), with a mean age of 46.1 ± 12.1 years. At baseline, these patients had a mean 24-hour urinary protein of 6.7 ± 4.9 g, a mean serum albumin of 30.0 ± 8.3 g/L, and positive anti-PLA2R in 19 (57.6%) cases. The median total obinutuzumab dose was 2 g (IQR: 2-3). Following treatment, the cumulative remission rate during the 18-month follow-up period reached 84.8%. B cells were depleted in all patients at month 3, and the median duration of sustained B-cell depletion was 12 months (95% CI: 9.5-14.5). Among the 19 anti-PLA2R-positive patients, 84.2% achieved immunological remission at month 18. No patients experienced severe adverse events. Conclusion: This study demonstrates that B-cell reconstitution-guided modified-dose obinutuzumab is associated with favorable efficacy and a safety profile in refractory MN. The individualized strategy minimized drug exposure while maintaining efficacy, but the conclusions warrant further validation in controlled studies.