A 28-year-old woman with biopsy-proven lupus nephritis (WHO Class IV) presents with proteinuria of 3.5 g/day, serum creatinine 1.8 mg/dL, and active urinary sediment. She has been on prednisolone 1 mg/kg/day for 2 weeks. What is the drug of choice to add for induction therapy of lupus nephritis?

Explanation

## Induction Therapy for Lupus Nephritis (WHO Class III/IV) **Key Point:** Cyclophosphamide (CYC) combined with corticosteroids remains the gold standard for induction therapy in proliferative lupus nephritis (Class III and IV), particularly when there is significant renal dysfunction and active disease. ### Evidence Base The NIH and Euro-Lupus protocols both established cyclophosphamide as the induction agent of choice: - **NIH protocol:** IV CYC 0.5–1 g/m² monthly × 6 months + IV methylprednisolone + oral prednisolone - **Euro-Lupus protocol:** IV CYC 500 mg fixed dose (not weight-based) × 6 weeks + IV methylprednisolone + oral prednisolone Both achieve remission rates of 60–80% in proliferative nephritis. ### Why Cyclophosphamide in This Case 1. **WHO Class IV (diffuse proliferative)** — most aggressive form; requires potent immunosuppression 2. **Significant proteinuria (3.5 g/day) + elevated creatinine** — indicates advanced renal involvement 3. **Active urinary sediment** — ongoing glomerulonephritis; CYC targets B and T cells most effectively 4. **Early intervention window** — starting within 2–4 weeks of diagnosis optimizes renal preservation ### Mechanism Cyclophosphamide is an alkylating agent that causes irreversible cross-linking of DNA, leading to: - Profound B and T cell lymphopenia - Suppression of anti-dsDNA and anti-nucleosome antibodies - Reduction in immune complex deposition in glomeruli **Clinical Pearl:** Mesna (2-mercaptoethanesulfonate) must be co-administered IV with CYC to prevent hemorrhagic cystitis. Adequate hydration and frequent urinalysis are mandatory. **High-Yield:** CYC is more effective than mycophenolate mofetil (MMF) for **induction** in Class IV nephritis, though MMF is increasingly used for maintenance after CYC induction or as an alternative in resource-limited settings or when CYC is contraindicated. ### Maintenance Phase (After Induction) Once remission is achieved (typically at 6 months), switch to a less toxic maintenance agent: - Mycophenolate mofetil (1–3 g/day) OR - Azathioprine (1–2 mg/kg/day) [cite:Harrison 21e Ch 297]