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
• International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification system should guide therapy 1
• Treatment approach differs based on histological classification

Induction Therapy Options

1. First-line options (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 induction options:

   • Belimumab plus either MPAA or low-dose IV cyclophosphamide plus glucocorticoids 1
   • MPAA plus calcineurin inhibitor (when eGFR >45 ml/min/1.73 m²) plus glucocorticoids 1
   • Azathioprine may be considered when MPAA or cyclophosphamide are contraindicated, not tolerated, or unavailable (note: higher flare risk) 1

Glucocorticoid Regimen

• Begin with IV methylprednisolone pulses (500-750 mg for 3 consecutive days) 1
• Follow with oral prednisone 0.5 mg/kg/day for 4 weeks 1
• Taper to ≤10 mg/day by 4-6 months 1
• Consider reduced-dose regimens when kidney and extrarenal manifestations show improvement 1

Recent research suggests higher initial prednisone doses (≥40 mg/day) may achieve better complete renal response rates at 12 months compared to medium doses (≤30 mg/day) 2, though the guidelines still recommend the tapering schedule above.

Special Considerations for Treatment Selection

• 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

Adjunctive Therapies (Start Concurrently)

• Hydroxychloroquine for all SLE patients to reduce flares and improve outcomes 1
• ACE inhibitors or ARBs for patients with proteinuria or hypertension 1
• Calcium and vitamin D supplementation 1
• Statins for persistent dyslipidemia 1
• Appropriate non-live vaccinations 1

Treatment Goals and Monitoring

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

Maintenance Therapy (After Achieving Improvement)

• Continue with MPAA at lower doses (MMF 2 g/day) or azathioprine (2 mg/kg/day) for at least 3 years 1
• Maintain low-dose prednisone (5-7.5 mg/day) during maintenance therapy 1
• Patients who responded to MPAA should remain on MPAA unless pregnancy is contemplated 1

Clinical Pearls and Pitfalls

• Despite advances in understanding lupus nephritis pathogenesis, the current standard of care still relies on broad-spectrum immunosuppression plus corticosteroids 3
• Treatment failures remain common, with 35% of patients experiencing at least one episode of renal relapse 4
• For pure membranous lupus nephritis (Class V), some evidence suggests that prednisone monotherapy may be effective in inducing remission in certain patients 5, though the guidelines recommend immunosuppressive therapy for this class as well
• Long-term follow-up is essential as renal flares can occur years after initial treatment 6