What is the treatment for membranous nephropathy?

Treatment of Membranous Nephropathy

For patients with primary membranous nephropathy (MN) and nephrotic syndrome with risk factors for disease progression, initial treatment should be rituximab, cyclophosphamide with alternate month glucocorticoids, or calcineurin inhibitors, with rituximab preferred due to its better safety profile. 1

Patient Selection for Treatment

Treatment should be initiated only when at least one of the following conditions is met:

• Persistent nephrotic syndrome with:

  • Urinary protein excretion >4 g/day that remains >50% of baseline value despite 6 months of conservative therapy 2
  • Severe, disabling, or life-threatening symptoms related to nephrotic syndrome 2
  • Serum creatinine rise ≥30% within 6-12 months (with eGFR >30 ml/min/1.73m²) 2

• Contraindications to immunosuppressive therapy:

  • Serum creatinine persistently ≥3.5 mg/dl or eGFR ≤30 ml/min/1.73m² 2
  • Reduced kidney size on ultrasound 2
  • Severe or potentially life-threatening infections 2

Risk Stratification

Patients should be stratified according to risk of progression:

• Low risk: Normal renal function despite conservative therapy
• Medium risk: Proteinuria 4-8 g/day observed for up to 6 months
• High risk: Deteriorating renal function over 2-3 months and/or proteinuria >8 g/day 2

First-Line Treatment Options

1. Rituximab

• Preferred option for most patients, especially younger patients or those concerned about fertility 1
• Dosing: 375 mg/m² weekly for 4 weeks or 1 g × 2 doses given 2 weeks apart 1
• Better safety profile than cyclophosphamide 1, 3
• Significantly improves remission rates (OR=3.06) and reduces relapse rates (OR=0.06) compared to other treatments 3
• First-line rituximab therapy achieves higher remission rates than second-line therapy 3

2. Cyclical Corticosteroid/Alkylating Agent Regimen

• 6-month course of alternating monthly cycles of oral and IV corticosteroids with oral cyclophosphamide 2
• Cyclophosphamide preferred over chlorambucil due to better safety profile 2
• Reserved for patients with high risk of progression 2, 4

3. Calcineurin Inhibitors (CNIs)

• Cyclosporine or tacrolimus 2, 1
• Initial cyclosporine dose: 3-4 mg/kg/day with progressive reduction to smallest effective dose 2
• Target tacrolimus levels: 8-10 ng/mL 1
• Continue for at least 12 months if remission occurs 1

Conservative Management

All patients should receive supportive care:

• ACE inhibitors and/or ARBs 2, 5
• Diuretics for edema management 5
• Blood pressure control (target <120/75 mm Hg) 2
• Lipid-lowering agents 6
• Consider prophylactic anticoagulation with warfarin in patients with serum albumin <2.5 g/dl and additional risk factors for thrombosis 1

Monitoring and Treatment Duration

• Monitor proteinuria, serum albumin, and kidney function regularly 1
• For anti-PLA2R positive patients, monitor antibody levels every 3 months 1
• Continue treatment for at least 6-12 months before considering treatment failure 1
• Consider treatment failure if no substantial reduction in proteinuria (30-50%) after 4-6 months of adequate therapy 1

Response Assessment and Follow-up

Complete Remission

• Taper cyclosporine dose over at least 2-4 months 2

Partial Remission

• Continue cyclosporine for at least 1-2 years 2
• May need to maintain at non-toxic level indefinitely if renal function is stable 2

No Response

• After 3-6 months at a non-toxic dose, consider alternative treatment 2
• If response obtained but with significant adverse effects, switch to alternative treatment 2

Special Considerations

• Spontaneous remission occurs in 20-30% of cases, more likely in patients with subnephrotic proteinuria and in women 2
• Remission may be delayed for as long as 18-24 months (mean time 14.7 ± 11.4 months) 2
• Secondary causes of MN should always be ruled out before initiating treatment 1
• Anti-PLA2R antibody status can help confirm primary MN and monitor treatment response 1, 6