A 38-year-old woman with systemic lupus erythematosus (SLE) develops acute lupus nephritis (Class IV) with rapidly declining renal function (creatinine rising from 0.9 to 3.2 mg/dL over 2 weeks). Kidney biopsy shows proliferative glomerulonephritis with active endocapillary proliferation and wire-loop lesions, indicating reversible glomerular injury. Which drug is the preferred first-line induction therapy to prevent progression to irreversible renal fibrosis and end-stage renal disease?

Explanation

## First-Line Induction Therapy for Proliferative Lupus Nephritis **Key Point:** Cyclophosphamide (CYC) is the gold-standard first-line induction agent for Class III and Class IV proliferative lupus nephritis, particularly when there is evidence of active, reversible glomerular injury. ### Rationale for Cyclophosphamide Cyclophosphamide is an alkylating agent that potently suppresses B and T cell proliferation, halting the immune-mediated glomerular injury at the reversible phase (before fibrinoid necrosis and crescent formation become irreversible). It is superior to other agents in preventing progression to end-stage renal disease (ESRD). ### Induction Regimen (NIH Protocol) - **Pulse IV cyclophosphamide:** 0.5–1 g/m² IV monthly for 6 months - Combined with: - **High-dose corticosteroids:** Methylprednisolone 500 mg–1 g IV daily × 3 days, then oral prednisolone 0.5–1 mg/kg/day with taper - **Antiproliferative maintenance** (azathioprine or mycophenolate) after induction ### Efficacy Data | Outcome | Cyclophosphamide | Mycophenolate Mofetil | |---------|------------------|----------------------| | Complete remission (Class IV) | 60–70% | 50–60% | | ESRD at 10 years | ~10% | ~15% | | Relapse rate | Lower | Higher | | Fertility impact | Significant (especially in ♀) | Minimal | **High-Yield:** CYC + corticosteroids is the only regimen with Level 1A evidence for preventing ESRD in proliferative lupus nephritis. ### When to Use Cyclophosphamide - Class III or IV lupus nephritis (especially with crescents or fibrinoid necrosis) - Rapidly declining renal function - Severe proteinuria (>3 g/day) - Active urinary sediment (RBC casts, dysmorphic RBCs) **Clinical Pearl:** The presence of wire-loop lesions and endocapillary proliferation indicates active, reversible immune complex deposition — the ideal window for CYC intervention before irreversible sclerosis develops. ### Adverse Effects & Monitoring - Hemorrhagic cystitis (prevent with mesna and hydration) - Infertility (counsel pre-treatment) - Infection risk (monitor CBC, prophylactic antibiotics if needed) - Secondary malignancy (long-term risk) [cite:Harrison 21e Ch 319; Robbins 10e Ch 20]