What is the treatment for membranous nephropathy?

Treatment of Membranous Nephropathy

Immunosuppressive therapy for membranous nephropathy should be initiated with rituximab, cyclophosphamide with corticosteroids, or calcineurin inhibitors based on patient risk factors, with rituximab preferred in younger patients due to its better safety profile. 1, 2

Patient Risk Assessment and Treatment Initiation

Treatment decisions should be based on risk stratification:

• Low risk: Normal renal function with proteinuria <3.5 g/day

  • Conservative management only
  • No immunosuppression needed

• Medium risk: Proteinuria 3.5-8 g/day, stable renal function

  • Consider immunosuppression if persistent >6 months

• High risk: Proteinuria >8 g/day and/or deteriorating renal function

  • Prompt immunosuppression recommended

Immunosuppressive therapy is indicated when:

• Proteinuria persistently >3.5 g/day despite 6 months of conservative therapy
• Severe complications of nephrotic syndrome occur
• Serum creatinine rises by 30% within 6-12 months (with eGFR >30 ml/min/1.73m²) 1, 2

Conservative Management (All Patients)

All patients should receive:

• ACE inhibitors and/or ARBs for blood pressure control (target <120/75 mmHg)
• Diuretics for edema management
• Dietary sodium restriction
• Lipid-lowering agents as needed 2

First-Line Immunosuppressive Options

1. Rituximab

• Preferred in younger patients or those concerned about fertility
• Dosing: 375 mg/m² weekly for 4 weeks OR 1 g × 2 doses given 2 weeks apart
• Better safety profile compared to cyclophosphamide 1, 2

2. Cyclophosphamide with Corticosteroids

• 6-month course of alternating monthly cycles
• Initial IV methylprednisolone (500-2500 mg total dose)
• Followed by oral prednisone (0.3-0.5 mg/kg/day, reducing to ≤7.5 mg/day by 3-6 months)
• Cyclophosphamide dose: 1.5-2.0 mg/kg/day
• Maximum cumulative dose: 36 g (preferably limit to 25 g)
• Limit to 10 g if fertility preservation is required 1, 2

3. Calcineurin Inhibitors (CNIs)

• Tacrolimus (target levels 8-10 ng/mL) or cyclosporine
• Continue for at least 12 months if remission occurs
• Particularly effective for nephrotic-range proteinuria
• May be used as monotherapy or combined with MMF ("multitarget" approach) 1, 2

Monitoring and Treatment Duration

• Anti-PLA2R antibody levels should be monitored every 3 months in positive patients
• Continue treatment for at least 6-12 months before considering treatment failure
• Remission may be delayed for up to 18-24 months (mean time 14.7 months)
• Treatment failure: No substantial reduction in proteinuria (30-50%) after 4-6 months 1, 2

Management of Resistant Disease

For patients not responding to initial therapy:

1. If initial treatment was CNI and eGFR is stable: Switch to rituximab
2. If initial treatment was rituximab and eGFR is stable: Switch to CNI
3. If eGFR is decreasing: Consider cyclophosphamide with glucocorticoids
4. For patients resistant to both rituximab and cyclophosphamide: Refer to expert center for experimental therapies 1

Thrombosis Prophylaxis

• Consider prophylactic anticoagulation in high-risk patients:
  • Serum albumin <30 g/L (by bromocresol purple) or <25 g/L (by bromocresol green)
  • Additional risk factors for thrombosis
  • Especially important in first 6 months after diagnosis 1, 2

Important Considerations

• Secondary causes of membranous nephropathy must be ruled out before initiating treatment
• Spontaneous remission occurs in 20-30% of cases, justifying observation in low-risk patients
• Nephrotoxicity and other side effects of CNIs should be monitored when using these agents
• Cyclophosphamide is preferred over chlorambucil due to better safety profile 2, 3
• Hydroxychloroquine should be considered for patients with lupus-associated membranous nephropathy 1