What is the cyclophosphamide (Urolupus) regimen for severe proliferative lupus nephritis, including dosing schedules and adjunctive therapy?

Cyclophosphamide Regimen for Severe Proliferative Lupus Nephritis

The low-dose intravenous cyclophosphamide (Euro-Lupus) regimen—500 mg IV every 2 weeks for 6 doses (total ≈3 g over 3 months)—combined with glucocorticoids is the recommended cyclophosphamide protocol for severe proliferative lupus nephritis, offering efficacy equivalent to older high-dose regimens with markedly reduced toxicity. 1

Induction Phase: Cyclophosphamide Dosing

Low-Dose (Euro-Lupus) Protocol - Preferred

• Administer 500 mg IV cyclophosphamide every 2 weeks for 6 doses (total cumulative dose ≈3 g over 3 months). 1
• This regimen has replaced the older NIH high-dose protocol because it provides comparable long-term efficacy with fewer serious infections and less leukopenia. 1
• Ten-year follow-up data demonstrate similar rates of lupus nephritis flares, progression to end-stage renal disease, and doubling of serum creatinine compared to high-dose regimens. 1

Patient Selection for Cyclophosphamide

• Choose cyclophosphamide when adherence to oral medications is a concern, as IV administration ensures compliance. 2, 1
• Select cyclophosphamide for severe nephritic features: rapid GFR decline or >25% of glomeruli showing crescents/necrosis. 1
• Use cyclophosphamide after documented failure of mycophenolic acid analogs. 1
• Avoid cyclophosphamide as first-line in patients desiring future fertility without prior exposure; mycophenolic acid analogs are preferred in this setting. 2, 1

Glucocorticoid Co-Therapy

Initial Pulse Therapy

• Administer IV methylprednisolone 250-500 mg daily for up to 3 consecutive days at treatment initiation. 2, 1
• The pulse dose should be tailored to disease severity (range 250-1000 mg). 1

Oral Glucocorticoid Taper

The KDIGO 2024 guidelines provide three glucocorticoid dosing schemes; the reduced-dose scheme is preferred to minimize toxicity while maintaining efficacy: 2

Reduced-Dose Glucocorticoid Protocol:

• Weeks 0-2: 0.5-0.6 mg/kg/day oral prednisone (maximum 40 mg) 2
• Weeks 3-4: 0.3-0.4 mg/kg/day 2
• Weeks 5-6: 15 mg daily 2
• Weeks 7-8: 10 mg daily 2
• Weeks 9-10: 7.5 mg daily 2
• Weeks 11-12: 5 mg daily 2
• Weeks 13-14: 2.5 mg daily 2
• Weeks 15-24: Maintain 2.5 mg daily 2
• Week 25 onward: <2.5 mg daily 2

Mandatory Adjunctive Therapies

Essential Co-Medications

• Hydroxychloroquine ≤5 mg/kg/day (typically 200-400 mg daily) for all patients unless contraindicated to reduce flares and improve long-term outcomes. 3, 1
• ACE inhibitor or ARB for proteinuria control and blood pressure management. 3, 1

Safety Measures During Cyclophosphamide

• Mesna co-administration with each IV cyclophosphamide dose to prevent hemorrhagic cystitis. 1
• Pneumocystis jirovecii prophylaxis (typically trimethoprim-sulfamethoxazole). 1
• Screen for hepatitis B, hepatitis C, HIV, and tuberculosis before initiating therapy. 1
• Calcium and vitamin D supplementation; add bisphosphonates when indicated by bone density assessment. 1

Fertility Preservation

• Women should receive gonadotropin-releasing hormone agonists (e.g., leuprolide) during cyclophosphamide exposure. 1
• Men should consider sperm banking before treatment initiation. 1
• Limit total lifetime cyclophosphamide exposure to <36 g to reduce malignancy risk; the 3 g Euro-Lupus induction course stays well below this threshold. 1

Monitoring Protocol

During Induction

• Monitor neutrophil counts monthly during IV cyclophosphamide therapy. 1
• Assess every 2-4 weeks for the first 2-4 months: serum creatinine, eGFR, urine protein-to-creatinine ratio, urinalysis with microscopy, complement levels (C3/C4), anti-dsDNA antibodies, complete blood count, blood pressure, and weight. 4

Response Assessment Milestones

• 8-week milestone: ≥25% reduction in proteinuria and/or normalization of complement C3/C4 predicts favorable response. 1
• 3-month milestone: If renal function worsens (rising serum creatinine or increasing proteinuria), promptly switch to alternative therapy or obtain repeat kidney biopsy. 1
• 6-month milestone: Continue induction for full 6 months unless clear clinical deterioration occurs; approximately 50% achieve definite improvement by 6 months, increasing to 65-80% by 12-24 months. 1

Maintenance Therapy After Induction

Transition to Maintenance

• After completing 6 doses of cyclophosphamide, transition to mycophenolic acid analog maintenance. 2, 1
• Mycophenolate mofetil 750-1000 mg twice daily or mycophenolic acid 540-720 mg twice daily. 2
• Continue maintenance therapy for ≥36 months total (induction plus maintenance). 2

Alternative Maintenance

• Azathioprine 1-2 mg/kg/day is an alternative for patients who cannot tolerate mycophenolic acid analogs, who lack access, or who are considering pregnancy. 2
• Note that azathioprine is associated with higher disease relapse rates compared to mycophenolic acid analogs. 2, 3

Response Definitions

Complete Response

• Proteinuria <0.5 g/g (50 mg/mmol) measured as urine protein-to-creatinine ratio 2
• Stabilization or improvement in kidney function (±10-15% of baseline eGFR) 2

Partial Response

• ≥50% reduction in proteinuria to subnephrotic levels (<3 g/g) 3
• Stable or improved kidney function 3

Critical Pitfalls to Avoid

• Do not use high-dose cyclophosphamide unnecessarily: The Euro-Lupus low-dose regimen (≈3 g total) provides equivalent efficacy with superior safety compared to the NIH high-dose protocol (0.5-1 g/m² monthly for 6 months). 1
• Do not exceed 36 g lifetime cumulative cyclophosphamide exposure: This increases infertility and malignancy risk substantially. 3, 1
• Do not switch therapy prematurely: Continue induction for the full 6 months unless clear worsening occurs, as 65-80% of responders emerge by 12-24 months. 1
• Do not omit hydroxychloroquine: This foundational therapy reduces flares, prevents organ damage, and markedly lowers mortality. 1
• Do not delay fertility preservation counseling: Discuss gonadotropin-releasing hormone agonists and gamete cryopreservation before initiating cyclophosphamide. 1

Special Considerations

Triple Therapy Option

• Belimumab 10 mg/kg IV every 2 weeks for 3 doses, then every 4 weeks combined with glucocorticoids and reduced-dose cyclophosphamide may be preferred in patients with repeated kidney flares or high risk for progression to kidney failure. 2

Active Tuberculosis Context

• Cyclophosphamide should be avoided during active tuberculosis because it markedly raises the risk of serious infections (13.5% vs 2% without cyclophosphamide). 3
• If lupus nephritis progresses during TB treatment, increase mycophenolate mofetil to maximum tolerated dose (up to 3 g/day) rather than switching to cyclophosphamide. 3