What is the initial treatment for lupus nephritis?

Initial Treatment for Lupus Nephritis

For patients with active Class III or IV lupus nephritis, initial treatment should consist of glucocorticoids plus mycophenolic acid analogs (MPAA) or low-dose intravenous cyclophosphamide, as these regimens have the best efficacy/toxicity ratio for preserving renal function and improving survival. 1

Diagnostic Approach Before Treatment

• Renal biopsy is essential before initiating treatment as clinical and laboratory tests cannot accurately predict histological findings
• Treatment should be guided by the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification system 1

Induction Therapy Options

1. First-line options (for Class III/IV lupus nephritis):

   • Mycophenolic acid analogs (MMF target dose: 3 g/day for 6 months) plus glucocorticoids 1
   • Low-dose intravenous cyclophosphamide (total dose 3 g over 3 months) plus glucocorticoids 1

2. Alternative options:

   • Belimumab plus either MPAA or low-dose intravenous cyclophosphamide plus glucocorticoids 1
   • MPAA plus calcineurin inhibitor (when eGFR >45 ml/min/1.73 m²) plus glucocorticoids 1

Glucocorticoid Regimen

• Begin with IV methylprednisolone pulses (500-750 mg for 3 consecutive days)
• Follow with oral prednisone 0.5 mg/kg/day for 4 weeks
• Taper to ≤10 mg/day by 4-6 months 1
• Higher initial prednisone doses (median 45 mg/day) have been shown to achieve significantly better rates of complete renal response at 12 months in new-onset lupus nephritis 2

Treatment Selection Considerations

• Patients with adverse prognostic factors (acute deterioration in renal function, substantial cellular crescents, fibrinoid necrosis) may benefit from higher-dose cyclophosphamide regimens 1
• Patients at high risk of infertility should preferentially receive MPAA-based therapy rather than cyclophosphamide 1
• Patients with adherence concerns may benefit from intravenous cyclophosphamide 1
• Azathioprine may be considered as an alternative when MPAA or cyclophosphamide are contraindicated, not tolerated, or unavailable, but carries a higher flare risk 1

Adjunctive Therapies

• Hydroxychloroquine should be given to all SLE patients to reduce flares and improve outcomes 1
• ACE inhibitors or ARBs should be used for patients with proteinuria or hypertension 1
• Statins should be prescribed for persistent dyslipidemia 1
• Calcium and vitamin D supplementation is recommended 1
• Appropriate vaccinations (non-live vaccines) should be administered 1

Treatment Goals and Monitoring

• Aim for complete renal response (proteinuria <50 mg/mol and normal/near-normal renal function) 1
• Target partial response by 6 months and complete response by 12 months 1
• Regular monitoring should include:
  • Serum creatinine and eGFR
  • Proteinuria
  • Urinary sediment
  • Complement levels (C3, C4)
  • Anti-dsDNA antibody levels
  • Complete blood count
  • Blood pressure 1

Common Pitfalls and Caveats

• Delaying treatment initiation can lead to worse outcomes and increased risk of progression to end-stage renal disease
• Inadequate initial immunosuppression may result in treatment failures and disease progression 3
• Excessive immunosuppression increases risk of infections and other adverse effects
• Approximately 35% of patients will experience at least one episode of renal relapse despite appropriate initial treatment 4
• Membranous lupus nephritis (Class V) may have a more benign course than proliferative forms but still requires appropriate immunosuppression 5, 6