What is the recommended treatment regimen for lupus nephritis according to the National Institutes of Health (NIH)?

Lupus Nephritis NIH Regimen

The historical "NIH regimen" for lupus nephritis referred to high-dose intravenous cyclophosphamide (0.75–1 g/m² monthly for 6 months), but current evidence-based guidelines have moved beyond this single approach to offer multiple equally effective first-line options with better safety profiles. 1

Current First-Line Treatment Options for Proliferative Lupus Nephritis (Class III/IV)

The 2024 KDIGO guidelines recommend any one of the following regimens combined with glucocorticoids for initial therapy: 1

Option 1: Mycophenolic Acid Analogs (MPAA)

• Mycophenolate mofetil (MMF) 1.0–1.5 g twice daily or mycophenolic acid sodium 0.72–1.08 g twice daily for 6 months 1
• This may be the preferred option as it probably increases complete disease remission compared to IV cyclophosphamide (though evidence certainty is low) and has fewer side effects 2
• Significantly less alopecia (170 fewer cases per 1000 people) and ovarian toxicity compared to cyclophosphamide 2

Option 2: Low-Dose Intravenous Cyclophosphamide

• 500 mg IV every 2 weeks for 6 doses (total 3 g over 3 months) 1
• This is the modern "low-dose" evolution of the original NIH regimen, with substantially reduced cumulative exposure 1
• Alternative dosing: 0.75–1 g/m² monthly for 6 months or oral 1.0–1.5 mg/kg/day for 3 months 1
• Lifetime cumulative cyclophosphamide exposure should remain below 36 g to minimize toxicity 1

Option 3: Triple Therapy with Belimumab

• Belimumab (10 mg/kg IV every 2 weeks for 3 doses, then every 4 weeks) combined with either MPAA or low-dose cyclophosphamide 1
• May be preferred in patients with repeated kidney flares or high risk for progression to kidney failure 1
• Duration up to 2.5 years in clinical trials 1

Option 4: Calcineurin Inhibitor + MPAA

• Voclosporin 23.7 mg twice daily plus MPAA when eGFR >45 ml/min/1.73 m² 1
• Alternative CNIs: tacrolimus or cyclosporine when voclosporin unavailable 1
• Preferred in patients with relatively preserved kidney function and nephrotic-range proteinuria due to extensive podocyte injury 1
• CNI duration up to 3 years 1

Glucocorticoid Regimens (Essential Component of All Options)

Three dosing schemes are available, with reduced-dose regimens increasingly preferred: 1

Reduced-Dose Scheme (Preferred for Lower Toxicity)

• Methylprednisolone IV pulses: 0.25–0.5 g/day for up to 3 days initially 1
• Oral prednisone equivalent:
  • Weeks 0–2: 0.5–0.6 mg/kg/day (max 40 mg) 1
  • Weeks 3–4: 0.3–0.4 mg/kg/day 1
  • Weeks 5–6: 15 mg/day 1
  • Progressive taper to ≤2.5 mg/day by week 21–24 1

Moderate-Dose Scheme

• Initial oral prednisone 0.6–0.7 mg/kg/day (max 50 mg), tapering to <5 mg/day by week 21–24 1

High-Dose Scheme (Reserved for Severe Cases)

• Initial oral prednisone 0.8–1.0 mg/kg/day (max 80 mg), tapering to <5 mg/day by week 25+ 1

The EULAR/ERA-EDTA guidelines recommend: 3 consecutive pulses of IV methylprednisolone 500–750 mg, followed by oral prednisone 0.5 mg/kg/day for 4 weeks, reducing to ≤10 mg/day by 4–6 months 1

Maintenance Therapy (After 6 Months of Induction)

MPAA is the recommended maintenance agent: 1

• MMF approximately 750–1000 mg twice daily (or MPA sodium 540–720 mg twice daily) 1
• Continue for at least 36 months total (induction plus maintenance) 1
• Patients who responded to MPAA induction should remain on MPAA for maintenance 1

Azathioprine 2 mg/kg/day is an alternative for patients who cannot tolerate MPAA or are planning pregnancy, but is associated with higher disease relapse rates (75% increased risk compared to MMF) 1, 2

Special Considerations and Treatment Selection

When to Prefer Cyclophosphamide Over MPAA:

• Patients with adverse prognostic factors: acute deterioration in renal function, substantial cellular crescents, and/or fibrinoid necrosis 1
• Patients who may have difficulty adhering to an oral regimen (IV cyclophosphamide preferred) 1

When to Prefer MPAA Over Cyclophosphamide:

• Patients at high risk of infertility or with moderate-to-high prior cyclophosphamide exposure 1
• Most patients without severe adverse prognostic factors, given comparable efficacy and better toxicity profile 2

When to Consider CNI-Based Regimens:

• Relatively preserved kidney function (eGFR >45 ml/min/1.73 m²) with nephrotic-range proteinuria 1
• Patients who cannot tolerate standard-dose MPAA or are unfit for cyclophosphamide 1

Essential Adjunctive Therapies

All patients with lupus nephritis should receive: 1

• Hydroxychloroquine to reduce renal flares and limit accrual of renal and cardiovascular damage 1
• ACE inhibitors or ARBs for proteinuria (UPCR >50 mg/mmol) or hypertension 1
• Statins for persistent dyslipidemia (target LDL <100 mg/dl) 1

Monitoring Strategy

Initial intensive monitoring (first 2–4 months): 1

• Every 2–4 weeks: serum creatinine, eGFR, urinalysis, urine protein-to-creatinine ratio, C3/C4, anti-dsDNA antibodies, complete blood count 1, 3

Treatment goals: 1

• Complete renal response: UPCR <50 mg/mmol and normal or near-normal GFR 1
• Partial response: ≥50% reduction in proteinuria to subnephrotic levels, preferably by 6 months but no later than 12 months 1

Management of Treatment Failure

For patients who fail initial therapy: 1

• Switch from MPAA to cyclophosphamide, or cyclophosphamide to MPAA 1
• Consider rituximab for persistent disease activity or inadequate response 1
• Repeat kidney biopsy may guide further treatment decisions 3

Critical Pitfalls to Avoid

• Delaying kidney biopsy can lead to undertreatment and irreversible kidney damage 3
• Excessive cumulative cyclophosphamide exposure (>36 g lifetime) increases infertility and malignancy risk 1
• Premature discontinuation of maintenance therapy before 36 months increases relapse risk 1
• Inadequate glucocorticoid tapering prolongs toxicity exposure unnecessarily 1