What is the recommended dose of cyclophosphamide (CYC) for induction therapy in a patient with lupus nephritis?

Cyclophosphamide Dosing for Induction Therapy in Lupus Nephritis

For induction therapy in lupus nephritis, use low-dose intravenous cyclophosphamide at 500 mg every 2 weeks for 6 doses (total 3 grams), which has equivalent efficacy to high-dose regimens with significantly fewer toxicities, particularly regarding fertility preservation and infection risk. 1

Recommended Dosing Regimens

The most current guidelines provide two evidence-based cyclophosphamide options:

Low-Dose "Euro-Lupus" Regimen (Preferred for Most Patients)

• 500 mg IV every 2 weeks for 6 doses (cumulative dose 3 grams) 1, 2
• This regimen achieved equivalent efficacy to high-dose protocols with 10-year follow-up showing similar rates of lupus nephritis flares, end-stage renal disease, and doubling of serum creatinine 1
• Serious infections and leukopenia were significantly less frequent compared to high-dose regimens 1
• This is the preferred regimen for Class III or IV (±V) lupus nephritis as it has the best efficacy/toxicity ratio 1

High-Dose Regimen (Reserved for High-Risk Patients)

• 500-750 mg/m² IV monthly for 6 months 1
• Consider this regimen only for patients at high risk for kidney failure, specifically those with: 1
  • Reduced GFR at presentation
  • Histological presence of crescents or fibrinoid necrosis
  • Severe interstitial inflammation on biopsy
• The dose should not exceed 1000 mg/m² per pulse 1

Concurrent Glucocorticoid Therapy

Cyclophosphamide must be combined with glucocorticoids: 1, 2

• Initial pulse therapy: IV methylprednisolone 250-500 mg daily for 1-3 days (depending on disease severity) 1, 2
• Followed by oral prednisone: 0.35-1.0 mg/kg/day (maximum 80 mg/day) 1, 2
• Taper to ≤7.5 mg/day by 3-6 months 1, 2

Maintenance Therapy Following Induction

After completing the 6-dose induction regimen: 1

• Transition to maintenance therapy with either:
  • Mycophenolate mofetil 1-2 g/day (preferred if used for induction) 1
  • Azathioprine 2 mg/kg/day (preferred if pregnancy is contemplated) 1
• Continue maintenance for at least 3-5 years in complete clinical response 1

Special Populations and Considerations

Fertility Concerns

• The low-dose Euro-Lupus regimen (3 grams cumulative) causes sustained amenorrhea in only 4.5% of patients compared to higher rates with high-dose regimens 1
• High-dose cyclophosphamide (500-1000 mg/m² monthly × 6) causes sustained amenorrhea in: 1
  • 12% of women <25 years old
  • 27% of women <30 years old
  • 62% of women ≥31 years old
• For patients with major fertility concerns, mycophenolate mofetil is preferable to any cyclophosphamide regimen 1, 2

Crescentic Lupus Nephritis

• Either cyclophosphamide or mycophenolate mofetil can be used for Class IV nephritis with cellular crescents 1
• Consider the higher-dose oral prednisone range (1 mg/kg/day) for initial therapy 1

Pure Class V (Membranous) Nephritis

• Cyclophosphamide is an alternative option but not first-line 1
• Mycophenolate mofetil 2-3 g/day is preferred for Class V nephritis with better efficacy/toxicity ratio 1

Monitoring and Response Assessment

Early Response Indicators (8 Weeks)

• Look for ≥25% reduction in proteinuria and/or normalization of C3/C4 complement levels 1, 2
• These early changes predict good long-term clinical renal responses 1

Treatment Goals by Timeline

• 3 months: At least 25% reduction in proteinuria 1
• 6 months: At least 50% reduction in proteinuria 1
• 12 months: Urine protein-to-creatinine ratio <500-700 mg/g (complete clinical response) 1

When to Continue vs. Switch Therapy

• Continue current regimen for 6 months before making major treatment changes unless clear worsening occurs (≥50% increase in proteinuria or serum creatinine at 3 months) 1
• Patients with nephrotic-range proteinuria at baseline may require an additional 6-12 months to achieve complete response 1

Critical Safety Considerations

Infection Risk

• Infection is the most common complication, occurring in approximately 29% of patients 3
• Screen for tuberculosis, hepatitis B, hepatitis C, and HIV before initiating therapy 2
• All deaths in some series were infection-related 3

Cumulative Dose Limits

• Minimize lifetime cyclophosphamide exposure to <36 grams to reduce malignancy risk 2
• The low-dose Euro-Lupus regimen (3 grams for induction) allows for potential retreatment if needed while staying well below this threshold

Hemorrhagic Cystitis Prevention

• Ensure adequate hydration with each infusion 2
• Consider mesna for bladder protection 2

Contraception Requirements

• Cyclophosphamide is teratogenic - ensure adequate contraception throughout treatment 2
• Discontinue at least 6 weeks before attempting pregnancy 1

Common Pitfalls to Avoid

• Do not use the older NIH protocol (monthly for 6 months, then quarterly for 2 years) as shorter regimens followed by maintenance therapy show equivalent long-term results with less toxicity 1
• Do not automatically choose high-dose cyclophosphamide for severe disease - the low-dose regimen is equally effective for most patients, including those with Class IV nephritis 1, 4
• Do not switch therapy prematurely - approximately 50% of patients show definite improvement by 6 months, increasing to 65-80% by 12-24 months 1
• Do not ignore racial/ethnic background - the low-dose Euro-Lupus regimen was specifically validated in Caucasian patients with Western/Southern European backgrounds, though it is now recommended more broadly 1
• Do not forget maintenance therapy - induction alone is insufficient; transition to mycophenolate mofetil or azathioprine is essential to prevent relapse 1