Treatment Approach for Lupus Nephritis
Diagnostic Evaluation
All patients with clinical evidence of lupus nephritis should undergo renal biopsy (unless strongly contraindicated) to guide treatment decisions using the ISN/RPS classification system. 1
- Indications for biopsy: Reproducible proteinuria ≥0.5 g/24h, especially with glomerular hematuria and/or cellular casts 1
- Pathological assessment: Use ISN/RPS 2003 classification with evaluation of active/chronic glomerular and tubulointerstitial changes 1
Initial Treatment by Class
Class III/IV Proliferative Lupus Nephritis (±V)
The 2024 KDIGO guidelines represent the most current evidence and recommend glucocorticoids PLUS one of four equally acceptable options 1:
| Treatment Option | Specific Regimen | Key Considerations |
|---|---|---|
| Mycophenolic Acid Analogs (MPAA) | MMF 1.0-1.5 g PO BID or MPA sodium 0.72-1.08 g BID [1] | First-line option with favorable efficacy/toxicity ratio [1] |
| Low-dose IV Cyclophosphamide | 500 mg IV q2wk × 6 doses OR oral 1.0-1.5 mg/kg/day × 3 months [1] | Alternative to MPAA; higher doses (0.75-1 g/m²) for adverse prognostic factors [1] |
| Belimumab + MPAA or Cyclophosphamide | Belimumab 10 mg/kg IV q2wk × 3 doses, then q4wk + MPAA or cyclophosphamide 500 mg q2wk × 6 [1] | Newest addition to guidelines; duration up to 2.5 years [1] |
| Calcineurin Inhibitor + MPAA | Voclosporin 23.7 mg PO BID + MPAA (if eGFR >45 ml/min/1.73m²) [1] | Caution: Avoid in significantly impaired kidney function due to nephrotoxicity risk [1]; consider cyclosporine when voclosporin/tacrolimus unavailable [1] |
Glucocorticoid regimen (all patients):
- Methylprednisolone IV 0.25-0.50 g/day × 1-3 days (or 500-750 mg × 3 consecutive pulses) 1
- Followed by prednisone PO 0.35-1.0 mg/kg/day (max 80 mg/day), tapering to ≤10 mg/day by 4-6 months 1
Adverse prognostic factors requiring higher cyclophosphamide doses: Acute deterioration in renal function, substantial cellular crescents, and/or fibrinoid necrosis 1
Class V Membranous Lupus Nephritis (Pure)
For nephrotic-range proteinuria (>1 g/24h despite RAAS blockade):
| First-Line | Alternatives |
|---|---|
| MPAA (MMF 3 g/day × 6 months) + oral prednisone 0.5 mg/kg/day [1] | Cyclophosphamide, calcineurin inhibitors (cyclosporine, tacrolimus), or rituximab for non-responders [1] |
Maintenance/Subsequent Treatment
After achieving response to initial therapy, continue immunosuppression for at least 3 years 1:
| Maintenance Options | Dosing | Notes |
|---|---|---|
| MPAA (preferred if initial MPAA) | MMF 2 g/day (lower than induction) [1] | Initial treatment with MPAA should be followed by MPAA [1] |
| Azathioprine | 2 mg/kg/day [1] | Alternative option; associated with higher flare risk [1] |
| Low-dose prednisone | 5-7.5 mg/day [1] | Combine with either MPAA or azathioprine [1] |
| CNI continuation | Up to 3 years if used initially [1] | - |
| Belimumab continuation | Up to 2.5 years if used initially [1] | - |
Treatment Goals and Response Criteria
Primary goal: Complete renal response, defined as:
- UPCR <50 mg/mol (or proteinuria <0.5 g/24h) 1
- Normal or near-normal renal function (within 10% of normal GFR if previously abnormal) 1
Acceptable alternative: Partial renal response by 6 months (no later than 12 months):
Ultimate goals: Long-term preservation of renal function, prevention of flares, avoidance of treatment-related harms, improved quality of life and survival 1
Management of Treatment Failures
For MPAA or cyclophosphamide failures:
- Switch to the alternative agent (MPAA ↔ cyclophosphamide) 1
- Consider rituximab as third-line option 1
Adjunctive Therapies (All Patients)
| Intervention | Indication | Evidence Level |
|---|---|---|
| Hydroxychloroquine | All lupus nephritis patients (unless contraindicated) [1] | Reduces flare rates and damage accrual [1] |
| RAAS blockade (ACEi or ARB) | Proteinuria ≥0.5 g/24h [1] | Reduces proteinuria ~30% and delays CKD progression [1]; contraindicated in pregnancy [1] |
Special Populations
Pregnancy planning:
- Switch to pregnancy-appropriate medications (e.g., azathioprine) without reducing treatment intensity 1
Pediatric patients:
- No evidence suggests management should differ from adults 1
Class I/II (minimal/mesangial):
- Generally does not require immunosuppressive treatment 1
Class VI (advanced sclerosis):
- Prepare for renal replacement therapy rather than immunosuppression 1
Key Pitfalls to Avoid
- Do not delay biopsy: Clinical/serological tests cannot accurately predict histology 1
- Avoid azathioprine as first-line: Higher flare risk; reserve for patients without adverse prognostic factors or when MPAA/cyclophosphamide contraindicated 1
- CNI nephrotoxicity: Exercise extreme caution with calcineurin inhibitors in patients with significantly impaired kidney function 1
- Inadequate steroid taper: Failure to reduce to ≤10 mg/day by 4-6 months increases toxicity without added benefit 1
- Premature discontinuation: Maintain immunosuppression for minimum 3 years even with good response 1