What is the initial treatment for lupus nephritis in patients with Systemic Lupus Erythematosus (SLE)?

Initial Treatment for Lupus Nephritis in SLE Patients

For patients with active Class III or IV lupus nephritis, initiate treatment with glucocorticoids combined with mycophenolic acid analogs (MPAA) as the preferred first-line regimen, particularly in patients concerned about fertility preservation. 1

Treatment Algorithm for Active Proliferative Lupus Nephritis (Class III/IV)

First-Line Immunosuppressive Options

The KDIGO 2024 guidelines provide four equally recommended initial treatment combinations with glucocorticoids (all Grade 1B recommendations): 1

1. Mycophenolic acid analogs (MPAA) - Target dose of 3 g/day for 6 months 2

   • Preferred for patients at high risk of infertility or with prior cyclophosphamide exposure 1
   • Mycophenolate mofetil (MMF) 750-1000 mg twice daily or mycophenolic acid 540-720 mg twice daily 3

2. Low-dose intravenous cyclophosphamide - Total dose of 3 g over 3 months 2

   • Consider for patients with difficulty adhering to oral regimens 1
   • Lifetime cumulative exposure must remain below 36 g to minimize cancer risk 1

3. Belimumab combined with either MPAA or low-dose cyclophosphamide 1

   • Emerging option with additional B-cell targeting mechanism

4. MPAA plus calcineurin inhibitor (CNI) - Only when eGFR >45 ml/min/1.73 m² 1, 2

   • Options include voclosporina, tacrolimus, or cyclosporine 2
   • Avoid in severely impaired kidney function 1

Glucocorticoid Regimens

Reduced-dose glucocorticoid protocols are now preferred to minimize toxicity while maintaining efficacy: 1, 2

• Initial pulse therapy: Methylprednisolone IV 500-750 mg/day for up to 3 days 2
• Oral prednisone (reduced-dose scheme): 1
  • Weeks 0-2: 0.5-0.6 mg/kg/day (maximum 40 mg)
  • Weeks 3-4: 0.3-0.4 mg/kg/day
  • Week 5-6: 15 mg/day
  • Progressive taper to ≤5 mg/day by week 12-24
  • Maintenance: <2.5 mg/day after week 25

This represents a significant departure from older high-dose protocols (0.8-1.0 mg/kg/day) that carried substantially greater toxicity burden. 1

Essential Adjunctive Therapies

Universal Recommendations for All Patients

Hydroxychloroquine is mandatory for all lupus nephritis patients to improve outcomes, reduce renal flares, and limit cardiovascular damage. 2

Renin-angiotensin-aldosterone system (RAAS) blockade with ACE inhibitors or ARBs for patients with proteinuria or hypertension. 1, 2

Complication Prevention Measures

The following adjunctive interventions must be implemented from treatment initiation: 1

• Infection prophylaxis:

  • Screen for HBV, HCV, HIV; provide HBV vaccination 1
  • Pneumocystis jirovecii prophylaxis during intensive immunosuppression 1
  • Consider recombinant zoster vaccine 1

• Bone protection:

  • Calcium and vitamin D supplementation 1
  • Bone density assessment with bisphosphonates when appropriate 1

• Fertility preservation (for patients receiving cyclophosphamide):

  • GnRH agonists (leuprolide) 1
  • Sperm/oocyte cryopreservation 1, 2

• Cardiovascular risk reduction:

  • Blood pressure optimization 1
  • Dyslipidemia management 1
  • Low-dose aspirin during pregnancy 1

• UV protection: Broad-spectrum sunscreen and limit exposure 1

Monitoring Protocol

Intensive monitoring is required during the first 2-4 months: 2

• Frequency: Every 2-4 weeks initially, then adjusted based on treatment response 2
• Parameters to track: 2
  • Weight, blood pressure
  • Serum creatinine, eGFR, albumin
  • 24-hour proteinuria or spot urine protein-to-creatinine ratio
  • Urine sediment analysis
  • Complement levels (C3, C4)
  • Anti-dsDNA antibodies
  • Complete blood count

Critical Clinical Considerations

When to Choose Specific Regimens

MPAA-based therapy is strongly preferred when: 1, 2

• Patient is of reproductive age with fertility concerns
• Prior cyclophosphamide exposure exists
• Patient can reliably adhere to oral medication

Cyclophosphamide is indicated when: 1, 2

• Severe disease with adverse prognostic factors present
• Crescentic glomerulonephritis with rapidly declining renal function
• Medication adherence to oral regimens is questionable

CNI combination therapy requires: 1, 2

• Preserved kidney function (eGFR >45 ml/min/1.73 m²)
• Close monitoring for nephrotoxicity

Common Pitfalls to Avoid

Do not delay treatment initiation - Early aggressive therapy improves long-term renal outcomes and reduces progression to ESRD, which still occurs in 5-20% of patients within 10 years despite treatment. 4

Do not use high-dose glucocorticoid protocols routinely - The reduced-dose schemes provide equivalent efficacy with substantially lower toxicity burden. 1, 2

Do not exceed 36 g lifetime cyclophosphamide exposure - This threshold minimizes malignancy risk. 1, 2

Do not discontinue immunosuppression during intercurrent infections unless severe infection is present or worsening despite appropriate antibiotics - maintain established regimens during acute infections with close monitoring. 3