A 28-year-old woman with biopsy-proven lupus nephritis (Class IV) presents with nephrotic syndrome (proteinuria 4.5 g/day, serum albumin 2.8 g/dL, eGFR 45 mL/min/1.73m²) and active urinary sediment. ANA is positive, anti-dsDNA titre is elevated, and C3 is low. She is currently on hydroxychloroquine and low-dose prednisolone 10 mg/day. What is the most appropriate next step in management?

Explanation

## Clinical Context This patient has **active proliferative lupus nephritis (Class IV)** with evidence of ongoing renal inflammation (low C3, elevated anti-dsDNA, active urinary sediment) and significant renal dysfunction (eGFR 45). Current therapy (hydroxychloroquine + low-dose prednisolone) is inadequate for this degree of activity. ## Treatment Strategy for Class IV Lupus Nephritis **Key Point:** Class IV (diffuse proliferative) lupus nephritis requires aggressive immunosuppression to prevent progression to ESRD. The gold standard induction regimen combines high-dose corticosteroids with either cyclophosphamide or mycophenolate mofetil. ### Induction Therapy Options | Regimen | Indication | Mechanism | Monitoring | |---------|-----------|-----------|------------| | **IV Cyclophosphamide** | Active Class III/IV, high-risk features | Alkylating agent; profound B-cell suppression | CBC, UA, bladder toxicity | | **Mycophenolate Mofetil** | Class III/IV, alternative to cyclophosphamide | IMPDH inhibitor; selective T/B suppression | CBC, LFTs | | **Azathioprine** | Maintenance, not induction | Purine antagonist; less potent | TPMT testing required | **High-Yield:** The **Euro-Lupus Nephritis Trial** and **MAINTAIN Nephritis Trial** established that **IV cyclophosphamide (0.5–0.75 g/m² monthly × 6 months)** followed by mycophenolate maintenance is superior to oral cyclophosphamide or azathioprine for Class IV disease with active features. ## Why IV Cyclophosphamide Is Correct Here 1. **Active Class IV disease** with eGFR 45 and nephrotic proteinuria requires potent induction 2. **Elevated anti-dsDNA and low C3** indicate ongoing immune complex deposition 3. **IV pulse dosing** reduces cumulative toxicity vs. daily oral therapy 4. **Concurrent high-dose corticosteroids** (0.5–1 mg/kg/day initially, then taper) are standard **Clinical Pearl:** IV cyclophosphamide is given as monthly pulses; cumulative dose should not exceed 30 g to minimize bladder cancer risk. Mesna is co-administered for uroprotection. ## Maintenance Phase After 6 months of induction, transition to **mycophenolate mofetil 1–3 g/day** for 2–3 years to consolidate remission and reduce relapse risk. **Warning:** Do not confuse induction (cyclophosphamide/mycophenolate + high-dose steroids) with maintenance (lower-dose agents, tapered steroids). This patient requires induction, not maintenance therapy.