Prospective Cohort Study of Obinutuzumab in Rituximab-Resistant Primary Membranous Nephropathy.

Introduction: Approximately 30% of patients with primary membranous nephropathy (MN) and persistent nephrotic syndrome (NS) fail rituximab therapy through mechanisms that could be overcome by obinutuzumab. Methods: In this prospective, single-arm, single-center, open-label trial, 20 consenting adults with MN and rituximab-resistant NS received three 1000 mg obinutuzumab infusions at the Bergamo Nephrology Unit (Italy) between March 2022 and February 2024 and were monitored for ≤ 12 months. The primary outcome was a composite end point of normo-albuminemia and complete (proteinuria < 0.3 g/d) or partial (proteinuria < 3.5 g/d with ≥ 50% reduction from baseline) NS remission at 12-month follow-up. Twenty-four-hour proteinuria and glomerular filtration rate (GFR) were evaluated at baseline and at 3, 6, 9, 12, 18, and 24 months posttreatment. Results: At 12 months, 16 patients met the combined end point, 4 with complete remission. No patient relapsed after remission. Median (interquartile range) 24-h proteinuria decreased from 5.7 (4.7-8.1) to 1.3 (0.5-2.7) g/24 h. Albumin and IgG fractional clearances also decreased, whereas serum albumin increased from 2.9 ± 0.6 g/dl to 3.9 ± 0.3 g/dl ( Conclusion: Obinutuzumab treatment is extremely effective and safe in patients with MN and rituximab-resistant NS and can achieve persistent remission in this population.