Efficacy and safety of obinutuzumab as rescue therapy for rituximab-resistant and rituximab-recurrent primary membranous nephropathy: a retrospective cohort study.

Objectives: With the recognition of membranous nephropathy as an autoimmune disease, targeting B-cells has emerged as an effective therapeutic agent for primary membranous nephropathy (PMN). About up to 40 % of patients fail to respond to rituximab (RTX). Obinutuzumab is a humanized and glycoengineered type II anti-CD20 monoclonal antibody which demonstrates more powerful and prolonged B-cell depletion to rituximab in certain hematologic malignancies. Our aim was to observe the efficacy and safety of Obinutuzumab in rituximab-resistant and recurrent membranous nephropathy and to find the factors associated with a poor response to Obinutuzumab. Methods: We conducted a retrospective analysis of consecutive patients with biopsy-proven primary membranous nephropathy who received Obinutuzumab as rescue therapy for rituximab-resistant or rituximab-recurrent disease between September 2022 and March 2025. Obinutuzumab was administered as two separate 1 g intravenous infusions over two to four weeks, with a subsequent 1 g infusion at approximately six months in most patients. The treatment regimen was determined by the medical team based on the patient's clinical condition and laboratory findings. We assessed the following outcomes: clinical remission rate, immunological remission rate, relapse rate, and incidence of adverse events. Additionally, we explored potential factors associated with treatment response. Results: The mean age at initiation of Obinutuzumab treatment was 46.5 ± 12.0 years. Patients with CKD stages 1-4 were48 %, 24 %, 20 % and 8 % respectively. Renal pathological findings revealed 15 cases of stage I membranous nephropathy, 6 cases of stage II membranous nephropathy, and 4 cases of atypical membranous nephropathy. Of the 25 patients, 20 were identified as rituximab-resistant, while 5 had recurrent disease after an initial response. During a median follow-up of nine months (range 6-30), complete or partial remission of proteinuria was achieved in 20 of the 25 participants (80 %). The time to achieve clinical remission was four months (range 1-14). Among the 21 patients with anti-phospholipase A2 receptor antibody-associated primary membranous nephropathy, 13 simultaneously achieved immunologic remission. Relapse occurred in two patients following a nine-month period off medication. No clinically severe adverse events were observed during the treatment period. Higher baseline proteinuria (p=0.001) and serum creatinine levels (p=0.03) were associated with a poorer response. Conclusions: Obinutuzumab may represent a promising treatment strategy for rituximab-resistant and recurrent membranous nephropathy, including in cases with severe renal impairment. A poorer response to obinutuzumab may be associated with higher baseline proteinuria and serum creatinine levels.