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

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.

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.

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 (P < 0.0001 for all changes). Dyslipidemia, hypocalcemia, and hypo-gammaglobulinemia improved significantly and GFR stabilized. At 12 months, total B cells and circulating anti-phospholipase A₂ receptor (PLA₂R) antibodies were depleted. Similar findings were observed in the cohort of 10 patients who completed 24 months of follow-up. However, total B cells reemerged in the circulation without an increase in anti-PLA₂R antibodies and proteinuria, or relapses. Treatment was safe and well-tolerated.

Obinutuzumab treatment is extremely effective and safe in patients with MN and rituximab-resistant NS and can achieve persistent remission in this population.