Treatment for Membranous Nephropathy
Initial therapy for membranous nephropathy should consist of a 6-month course of alternating monthly cycles of oral and intravenous corticosteroids with oral alkylating agents, preferably cyclophosphamide, in patients who meet specific criteria for treatment initiation. 1
When to Start Treatment
Treatment should only be initiated in patients with:
- Nephrotic syndrome AND at least one of the following:
- Urinary protein excretion persistently >4 g/day AND remaining at >50% of baseline value without progressive decline during 6 months of conservative therapy 1
- Severe, disabling, or life-threatening symptoms related to nephrotic syndrome 1
- Serum creatinine rise ≥30% within 6-12 months (but eGFR not less than 25-30 ml/min/1.73 m²) 1
Risk Stratification Approach
Patients should be stratified by 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 1
First-Line Treatment Options
Cyclical Corticosteroid/Alkylating Agent Regimen (preferred first-line) 1:
- Alternating monthly cycles of oral and IV corticosteroids with oral cyclophosphamide for 6 months
- Cyclophosphamide is preferred over chlorambucil due to better safety profile
Calcineurin Inhibitors (alternative first-line) 1:
- Cyclosporine (3-4 mg/kg/day in divided doses) ± low-dose corticosteroids for at least 6 months
- Target trough levels (C0): 125-175 ng/ml
- Particularly effective for patients with nephrotic-range proteinuria
Treatment Monitoring and Duration
- Monitor for at least 6 months after completing therapy before declaring treatment failure 1
- For cyclosporine:
Contraindications to Immunosuppressive Therapy
Do NOT use immunosuppressive therapy in patients with:
- Serum creatinine persistently ≥3.5 mg/dl (or eGFR ≤30 ml/min/1.73 m²) AND reduced kidney size on ultrasound
- Concomitant severe or potentially life-threatening infections 1
Treatment of Resistant Disease
- If resistant to alkylating agent/steroid therapy: try calcineurin inhibitor 1
- If resistant to calcineurin inhibitor therapy: try alkylating agent/steroid therapy 1
- Rituximab may be considered for resistant cases, as recent evidence shows it can improve remission rates and reduce anti-PLA2R antibody levels 2, 3
Treatment of Relapses
- Reinstitute the same therapy that resulted in initial remission 1
- If cyclical corticosteroid/alkylating agent regimen was used initially, repeat only once for relapse 1
Supportive Care
All patients should receive conservative management with:
Consider prophylactic anticoagulation with warfarin in patients with:
- Marked reduction in serum albumin (<2.5 g/dl)
- Additional risk factors for thrombosis 1
Special Considerations
- Rule out secondary causes of membranous nephropathy (medications, malignancy) before initiating treatment 1
- Limit malignancy workup to age-appropriate cancer screening unless specific risk factors or symptoms suggest additional testing 1
- Consider prophylactic trimethoprim-sulfamethoxazole in patients receiving high-dose immunosuppression 1
Emerging Therapies
Recent evidence suggests rituximab may be effective as it targets B-cells responsible for producing pathogenic antibodies (anti-PLA2R), with fewer adverse effects than traditional immunosuppressants 2, 3. First-line rituximab therapy appears to achieve higher remission rates than second-line use 2.