What is the NIH cyclophosphamide induction regimen for class III/IV lupus nephritis, including dosing, schedule, cumulative dose, concomitant high‑dose prednisone, and subsequent maintenance therapy?

NIH Cyclophosphamide Regimen for Lupus Nephritis

The traditional NIH high-dose cyclophosphamide protocol (0.5–1.0 g/m² monthly for six months followed by quarterly maintenance) has been replaced by the low-dose Euro-Lupus regimen (500 mg IV every two weeks for six doses) as the preferred cyclophosphamide-based treatment for class III/IV lupus nephritis, offering equivalent efficacy with markedly reduced toxicity. 1, 2

Historical NIH Protocol (No Longer Recommended)

The original NIH regimen consisted of:

• Induction: Intravenous cyclophosphamide 0.5–1.0 g/m² body surface area monthly for six doses 1
• Concomitant glucocorticoids: Intravenous methylprednisolone 0.5–1.0 g/day for 1–3 days, followed by oral prednisone up to 1 mg/kg/day (maximum 60–80 mg) with gradual taper 1
• Maintenance: Quarterly intravenous cyclophosphamide continued for 24–30 months 3, 4
• Cumulative dose: Approximately 10–15 grams over the full treatment course 5

This protocol is no longer recommended due to excessive toxicity, including sustained amenorrhea (32% incidence), severe infections (25% incidence), and high hospitalization rates 6, 4.

Current KDIGO 2024 Recommended Regimen (Euro-Lupus Protocol)

Induction Phase

Cyclophosphamide dosing:

• 500 mg IV every two weeks for six doses (total ≈3 grams over three months) 1, 2
• No body-surface-area adjustment required 2, 5

Glucocorticoid regimen:

• Initial pulse: Methylprednisolone 250–500 mg IV daily for 1–3 days, tailored to disease severity 1, 2
• Oral prednisone taper (reduced-dose protocol): 2
  • Weeks 0–2: 0.5–0.6 mg/kg/day (maximum 40 mg)
  • Weeks 3–4: 0.3–0.4 mg/kg/day
  • Weeks 5–6: 15 mg daily
  • Weeks 7–8: 10 mg daily
  • Weeks 9–10: 7.5 mg daily
  • Weeks 11–12: 5 mg daily
  • Weeks 13–24: 2.5 mg daily
  • Week 25 onward: <2.5 mg daily

Maintenance Phase

After completing six cyclophosphamide doses, transition to: 2

• Mycophenolate mofetil 750–1000 mg twice daily, OR 2
• Mycophenolic acid 540–720 mg twice daily 2
• Continue for minimum 36 months total (induction + maintenance) 2
• Alternative: Azathioprine 1–2 mg/kg/day if mycophenolate is contraindicated, though relapse rates are higher 2, 4

Mandatory Adjunctive Therapies

• Hydroxychloroquine ≤5 mg/kg/day (typically 200–400 mg daily) for all patients unless contraindicated 2
• ACE inhibitor or ARB for proteinuria control and blood pressure management 2
• Mesna co-administered with each cyclophosphamide dose to prevent hemorrhagic cystitis 2
• Pneumocystis jirovecii prophylaxis during intensive immunosuppression 2
• Gonadotropin-releasing hormone agonist (e.g., leuprolide) for women of childbearing age to preserve fertility 2

Comparative Efficacy and Safety

The Euro-Lupus low-dose regimen demonstrates: 2, 5

• Equivalent long-term renal outcomes compared to NIH high-dose protocol at 10-year follow-up
• Similar rates of lupus nephritis flares, progression to ESRD, and serum creatinine doubling
• Markedly fewer serious infections (11% vs 22% with high-dose) 6
• Lower sustained amenorrhea rates (4–8% vs 32% with NIH protocol) 6, 4
• Reduced leukopenia incidence 5

Validation caveat: The Euro-Lupus trial enrolled predominantly Caucasian (Western/Southern European) patients; comparative data for non-Caucasian racial groups are limited 2.

Patient Selection for Cyclophosphamide

Prefer cyclophosphamide when: 2

• Adherence to oral regimens is uncertain (IV administration ensures compliance)
• Severe nephritic features are present (rapid GFR decline, >25% glomeruli with crescents/necrosis)
• Prior mycophenolic acid analogue therapy has failed

Avoid cyclophosphamide when: 2

• Patient desires future fertility without prior cyclophosphamide exposure (choose mycophenolic acid analogues instead)
• Moderate-to-high cumulative prior cyclophosphamide exposure exists
• Active tuberculosis is present (cyclophosphamide increases serious infection risk 6-fold) 7

Response Assessment and Treatment Adjustment

8-week milestone: ≥25% reduction in proteinuria and/or normalization of complement C3/C4 predicts favorable response 2

3-month milestone: If serum creatinine rises or proteinuria increases ≥50%, promptly switch to alternative therapy or obtain repeat kidney biopsy 2

6-month endpoint: Approximately 50% of patients achieve definite improvement by six months, increasing to 65–80% by 12–24 months 2

Complete response definition: Proteinuria <0.5 g/g with stable or improved kidney function (within ±10–15% of baseline eGFR) 2

Critical Safety Monitoring

• Neutrophil counts: Monitor monthly during IV cyclophosphamide (versus weekly for oral formulations) 2
• Lifetime cumulative dose limit: <36 grams to reduce malignancy risk; the 3-gram Euro-Lupus course stays well below this threshold 2
• Infection screening: Test for hepatitis B, hepatitis C, HIV, and tuberculosis before initiating therapy 2
• Bone health: Supplement calcium and vitamin D; add bisphosphonates when indicated by bone-density assessment 2

Common Pitfalls to Avoid

• Using the obsolete NIH high-dose protocol: The Euro-Lupus regimen provides equivalent efficacy with superior safety 1, 2, 5
• Premature treatment switching: Continue induction for the full six months unless clear worsening occurs; most responders emerge by 12–24 months 2
• Inadequate glucocorticoid taper: Failure to reduce prednisone below 5 mg/day by 3–6 months contributes to organ-damage accumulation 2
• Omitting hydroxychloroquine: This foundational therapy reduces flares, prevents organ damage, and markedly lowers mortality 2
• Neglecting fertility preservation: Women should receive GnRH agonists; men should consider sperm banking before cyclophosphamide exposure 2