What is the initial management for a patient with lupus nephritis class 3 plus 5?

Management of Lupus Nephritis Class 3 Plus 5

Treat lupus nephritis class 3 plus 5 (mixed proliferative and membranous) with glucocorticoids plus mycophenolic acid analogs (MPAA) as first-line therapy, following the same treatment algorithm as pure class III/IV disease since the proliferative component drives management decisions. 1

Initial Immunosuppressive Therapy

The KDIGO 2024 guidelines explicitly state that class III or IV lupus nephritis with or without a membranous component should receive identical treatment, meaning the presence of class 5 features does not change your approach. 1 You have four equally recommended options:

First-Line Treatment Options (Choose One):

1. Mycophenolic acid analogs (MPAA) - Preferred for most patients 1

   • Mycophenolate mofetil: Target 3 g/day for 6 months 2
   • Mycophenolic acid: 1080-1440 mg/day divided twice daily 1

2. Low-dose intravenous cyclophosphamide - Consider for adherence concerns 1

   • Total cumulative dose: 3 g over 3 months 2
   • Keep lifetime exposure below 36 g to minimize gonadal toxicity 1, 2

3. Belimumab + MPAA or cyclophosphamide - Preferred for high-risk patients 1

   • Use in patients with repeated flares or severe CKD at high risk for progression 1

4. MPAA + Calcineurin inhibitor (CNI) - Preferred when eGFR >45 ml/min/1.73 m² AND nephrotic-range proteinuria 1

   • The membranous component (class 5) with heavy proteinuria makes this particularly relevant 1
   • Options: voclosporin, tacrolimus, or cyclosporine 1

Glucocorticoid Regimen

Use a reduced-dose glucocorticoid protocol to minimize toxicity while maintaining efficacy: 1, 2

• Initial pulse therapy: Methylprednisolone 250-500 mg IV daily for up to 3 days 1, 2
• Oral prednisone taper (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
  • Weeks 5-6: 15 mg/day
  • Weeks 7-8: 10 mg/day
  • Weeks 9-10: 7.5 mg/day
  • Weeks 11-12: 5 mg/day
  • Continue tapering to <2.5 mg/day by week 25+ 1

Essential Adjunctive Therapies

• Hydroxychloroquine: Mandatory for all patients to reduce flares and improve long-term outcomes 2
• ACE inhibitor or ARB: Required for proteinuria control and blood pressure management 2

Special Considerations for Class 3+5

The CNI-based regimen (MPAA + CNI) deserves strong consideration in class 3+5 disease because: 1

• The membranous component typically causes nephrotic-range proteinuria from podocyte injury
• CNIs directly address podocyte dysfunction
• This approach is specifically recommended for preserved kidney function (eGFR >45) with heavy proteinuria 1

Avoid cyclophosphamide as first-line in young patients desiring fertility, as MPAA-based regimens are equally effective with better reproductive safety profiles. 1

Maintenance Therapy

After 6 months of induction: 1

• Switch to MPAA maintenance: MMF 750-1000 mg twice daily or MPA 540-720 mg twice daily 1
• Continue for ≥36 months total (induction + maintenance) 1
• Taper glucocorticoids to lowest possible dose; consider discontinuation after 12 months of complete remission 1
• If using triple therapy (belimumab or CNI), continue all three agents during maintenance 1

Monitoring Protocol

Intensive early monitoring every 2-4 weeks for the first 2-4 months: 2

• Serum creatinine and eGFR
• Urine protein-to-creatinine ratio
• Urinalysis with microscopy
• Complement levels (C3, C4)
• Anti-dsDNA antibodies
• Complete blood count
• Blood pressure and weight

Response definitions (assess at 6-12 months): 1

• Complete response: Proteinuria <0.5 g/g, stable/improved kidney function
• Partial response: ≥50% reduction in proteinuria to <3 g/g, stable/improved kidney function
• No response: Failure to achieve partial or complete response

Common Pitfalls

• Do not delay treatment waiting for "pure" class III or IV confirmation—the proliferative component requires immediate aggressive therapy regardless of membranous features 1
• Do not undertreate the class 3+5 combination; it carries the same risk as pure proliferative disease 1
• Monitor for ovarian failure with cyclophosphamide; offer gonadotropin-releasing hormone agonists or fertility preservation 1, 2
• If worsening occurs in first 3 months, switch to alternative therapy or repeat biopsy rather than continuing failing treatment 2