A 28-year-old man with a 3-month history of nephrotic syndrome (serum albumin 1.8 g/dL, 24-hour urine protein 12 g, serum creatinine 1.2 mg/dL) undergoes kidney biopsy showing membranous nephropathy with IgG and C3 deposits. He is anti-PLA2R positive. After 8 weeks of corticosteroid monotherapy, proteinuria remains >8 g/day. What is the drug of choice for add-on therapy?

Explanation

## Steroid-Resistant Membranous Nephropathy — Add-On Therapy ### Clinical Scenario The patient has primary membranous nephropathy (anti-PLA2R positive, IgG/C3 deposits) with nephrotic syndrome that has failed to respond to 8 weeks of corticosteroid monotherapy. This defines **steroid-resistant disease** and requires escalation to combination immunosuppression. ### Drug of Choice: Rituximab **Key Point:** Rituximab (anti-CD20 monoclonal antibody) is the preferred add-on agent for steroid-resistant membranous nephropathy. It induces B-cell depletion, reducing pathogenic anti-PLA2R antibody production and immune complex deposition. **High-Yield:** Rituximab regimens in membranous nephropathy: - **Standard:** 375 mg/m² IV weekly × 4 weeks - **Alternative:** 1 g IV on days 0 and 14 (often repeated at 6 months) - Response rates: 40–60% achieve complete or partial remission within 6–12 months ### Mechanism of Action 1. Binds CD20 on B-cell surface 2. Induces B-cell apoptosis and antibody-dependent cellular cytotoxicity 3. Reduces anti-PLA2R antibody titre 4. Decreases immune complex deposition in glomerular basement membrane ### Evidence Base **MENTOR trial** and subsequent studies demonstrate rituximab + corticosteroids superior to cyclophosphamide + corticosteroids in steroid-resistant membranous nephropathy, with fewer adverse effects. ### Supportive Measures - Continue corticosteroids (0.5 mg/kg/day, taper over 6 months) - ACE-I/ARB for proteinuria reduction - Diuretics and salt restriction - Anticoagulation (serum albumin <2.0 g/dL) [cite:Harrison 21e Ch 279; Robbins 10e Ch 20]