What is the stepwise treatment approach for all classes of lupus nephritis?

Stepwise Treatment for All Classes of Lupus Nephritis

For Class III and IV lupus nephritis, initiate treatment with glucocorticoids plus mycophenolic acid analogs (MPAA) as the preferred first-line regimen, followed by maintenance MPAA for at least 3 years. 1

Class III and IV Lupus Nephritis (Proliferative Disease)

Initial Treatment Options (Choose One)

The KDIGO 2024 guidelines provide four equally effective first-line regimens, all combined with glucocorticoids 1:

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

   • Preferred for patients at high risk of infertility 1
   • Preferred for patients with prior cyclophosphamide exposure 1

2. Low-dose intravenous cyclophosphamide - Total dose 3 g over 3 months 1, 2

   • Preferred for patients with difficulty adhering to oral regimens 1
   • Consider higher doses (0.5-0.75 g/m² monthly for 6 months) for patients at high risk for kidney failure (reduced GFR, crescents, fibrinoid necrosis, severe interstitial inflammation) 2

3. Belimumab plus either MPAA or low-dose cyclophosphamide 1

   • Preferred for patients with repeated kidney flares or high risk for progression to kidney failure due to severe chronic kidney disease 1
   • FDA-approved data shows 43% achieved primary efficacy renal response at Week 104 versus 32% with placebo 3

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

   • Preferred for patients with relatively preserved kidney function and nephrotic-range proteinuria due to extensive podocyte injury 1
   • Preferred for patients who cannot tolerate standard-dose MPAA or are unfit for cyclophosphamide 1

Glucocorticoid Regimen

Reduced-dose scheme (preferred when disease shows satisfactory improvement) 1:

• Methylprednisolone IV pulses: 0.25-0.5 g/day for up to 3 days initially 1, 4
• 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 1
  • Weeks 5-6: 15 mg 1
  • Weeks 7-8: 10 mg 1
  • Weeks 9-10: 7.5 mg 1
  • Weeks 11-12: 5 mg 1
  • Weeks 13-14: 2.5 mg 1
  • Week >25: <2.5 mg 1

Target: ≤5 mg/day by 6 months 4, 2

Recent pooled analysis demonstrates that low-dose oral glucocorticoids (up to 0.5 mg/kg/day) following IV pulse therapy achieve equivalent renal responses to high-dose regimens (1.0 mg/kg/day) but with significantly fewer serious adverse events (19.4% vs 31.6%, p<0.001) and infection-related serious adverse events (9.8% vs 16.5%, p=0.012) 5

Maintenance Therapy (After 6 Months Initial Treatment)

Mycophenolic acid (MPA) - 1-2 g/day for at least 3 years 1, 4, 2

Alternative: Azathioprine 2 mg/kg/day 1, 2

• For patients who cannot tolerate MPA 1
• For patients planning pregnancy 1, 2

Essential Adjunctive Therapies for All Patients

• Hydroxychloroquine: Dose not to exceed 5 mg/kg/day, adjusted for GFR 4, 2
• ACE inhibitors or ARBs: For all patients with UPCR >500 mg/g or hypertension 4, 2

Treatment Goals and Monitoring Timeline

• 3 months: ≥25% reduction in proteinuria 4, 2
• 6 months: ≥50% reduction in proteinuria to subnephrotic levels 1, 4
• 12 months: Complete clinical response (UPCR <50 mg/mmol with normal or near-normal renal function) 1, 4

Management of Treatment Failure

If inadequate response by 6-12 months 1, 4:

• Switch from MPA to cyclophosphamide or vice versa 1, 4
• Add rituximab 1
• Assess medication adherence 4
• Consider re-biopsy to evaluate for transformation to chronic disease 4

Class V Lupus Nephritis (Membranous)

Pure Class V with Nephrotic-Range Proteinuria

Initial Treatment: MPA (target dose 3 g/day for 6 months) plus oral prednisone 0.5 mg/kg/day 1

Alternative options 1:

• Cyclophosphamide
• Calcineurin inhibitors (ciclosporin, tacrolimus)
• Rituximab

Pure Class V with Proteinuria <1 g/24h

No immunosuppressive treatment required 1

• Optimize renin-angiotensin-aldosterone system blockers 1
• Monitor closely for disease progression 1

Class I and II Lupus Nephritis (Minimal/Mesangial)

No specific immunosuppressive therapy required 6

• Careful surveillance to recognize possible transformation to more severe disease classifications 6
• Supportive care with ACE inhibitors/ARBs as needed 4

Important Caveats

Renal biopsy is essential before initiating immunosuppressive therapy to confirm diagnosis and classify disease severity using the ISN/RPS 2003 classification system 1, 4, 2

Alternative agents with inferior efficacy (azathioprine or leflunomide combined with glucocorticoids) may be considered only in situations of patient intolerance, lack of availability, or excessive cost of standard drugs, but these are associated with increased rate of disease flares and/or drug toxicities 1