Prospective Pilot Study of Plasma Cell-Targeted Therapy With Bortezomib in Refractory IgA Nephropathy

IgA nephropathy (IgAN) is a leading cause of kidney failure, characterized by galactose-deficient IgA1 (Gd-IgA1) deposition and immune complex formation. Aberrant trafficking of IgA+ plasma cells and autoantibody production (IgG or IgA) contribute to disease pathogenesis. Proteasome inhibitors such as bortezomib may modulate B or plasma cell activity and reduce pathogenic antibody production.

This open-label, prospective, uncontrolled trial evaluated bortezomib in adults with biopsy-confirmed IgAN, proteinuria > 1.5 g/d, and estimated glomerular filtration rate (eGFR) ≥ 30 ml/min per 1.73 m² despite optimized care. Patients received 4 to 8 doses of i.v. bortezomib at 1.1 to 1.3 mg/m² per dose. The primary end point was achieving 24-hour proteinuria (24 h-UP) < 300 mg/24 h at 12 months. Secondary end points included changes in eGFR and adverse event monitoring.

Sixteen patients completed the study. Median time from diagnosis to treatment was 63 months (range: 10-192). Baseline proteinuria was 2.719 g/24 h (95% confidence interval [CI]: 2.169-3.408), and mean eGFR was 51.1 ml/min per 1.73 m² (95% CI: 41.3-60.8). At 12 months, proteinuria decreased by 44.67%, with 6.25% achieving complete remission and 43.75% achieving ≥ 50% reduction. Proteinuria reduction persisted at 24 months (mean: 1.411 g/24 h: 48.09% reduction). The annual eGFR slope was -4.275 ml/min per 1.73 m². No serious treatment-related adverse events were reported.

Short course bortezomib therapy led to sustained proteinuria reduction in patients with IgAN, with an acceptable safety profile. These results support further evaluation in larger, controlled trials.