What is the initial treatment approach for idiopathic membranous nephropathy?

Initial Treatment Approach for Idiopathic Membranous Nephropathy

All patients with idiopathic membranous nephropathy should begin with optimal supportive care including RAS blockade, and immunosuppressive therapy should only be initiated in high-risk patients after risk stratification, with rituximab, cyclophosphamide plus alternating corticosteroids, or tacrolimus-based therapy as equivalent first-line options. 1

Mandatory Supportive Care for All Patients

Every patient with idiopathic membranous nephropathy requires foundational supportive management regardless of disease severity 1:

• RAS blockade with ACE inhibitors or ARBs targeting blood pressure <130/80 mmHg 1
• Statin therapy for dyslipidemia management 1
• Diuretics for edema control 1
• Anticoagulation assessment based on albumin levels and thromboembolism risk, with strong consideration for prophylactic anticoagulation when serum albumin <2.5 g/dL (25 g/L) due to high thromboembolism risk 2

Risk Stratification: Who Needs Immunosuppression?

Low-risk patients do NOT require immunosuppressive therapy 1:

• Proteinuria <3.5 g/day
• Serum albumin >30 g/L
• eGFR >60 mL/min per 1.73 m²
• Continue supportive care and monitor 1

High-risk patients requiring immunosuppression must have at least 6 months of conservative management first, then initiate immunosuppression when ANY of the following are present 1:

• Proteinuria ≥3.5 g/day with serum albumin ≤30 g/L
• eGFR ≤60 mL/min per 1.73 m²
• Serious nephrotic syndrome complications (AKI, infections, thromboembolic events) 1
• Persistent severe proteinuria despite maximum conservative therapy 1
• Deteriorating renal function over 2-3 months 2

First-Line Immunosuppressive Options

The 2025 KDIGO guidelines establish three equivalent first-line options (Grade 1B recommendation) 1:

Option 1: Rituximab

• Preferred by the American Society of Nephrology due to superior safety profile with equivalent efficacy 1
• Standard dosing: either two 1000-mg doses given 2 weeks apart OR four weekly doses of 375 mg/m² 3
• Requires baseline screening: immunoglobulin levels, hepatitis B and C antibody testing, latent tuberculosis screening 3

Option 2: Cyclophosphamide Plus Alternating Corticosteroids

• Recommended by the European Society of Nephrology for high-risk patients with rapidly declining eGFR or very high-risk disease (proteinuria >8 g/day with declining function) 1
• 6-month cyclical regimen alternating monthly between corticosteroids and cyclophosphamide 2
• Can be administered as oral cyclophosphamide (1.5-2 mg/kg/day) or pulse IV cyclophosphamide (500-750 mg/m²/month) 4, 5
• Critical limitation: This regimen should only be repeated ONCE for relapse treatment 2

Option 3: Tacrolimus-Based Therapy

• Initial dose 0.1 mg/kg/day adjusted to blood trough level 5-10 ng/mL for 6 months, then reduced to 2-5 ng/mL for subsequent 3 months 6
• Alternative: Cyclosporine 3-4 mg/kg/day with target C0 125-200 ng/mL 2
• Faster remission induction: Tacrolimus achieves significantly higher remission rates at 1-2 months compared to cyclophosphamide (p<0.01) 7
• Continue for at least 6 months; if partial remission achieved, continue for at least 1-2 years 2
• Monitor CNI blood levels regularly during initial treatment and whenever unexplained rise in creatinine (>20%) occurs 2
• Important caveat: Higher risk of glucose intolerance/diabetes, infection, and hypertension compared to cyclophosphamide 6

Important Contraindications and Warnings

Corticosteroid monotherapy should NOT be used for initial therapy of idiopathic membranous nephropathy (Grade 1B) 2

Mycophenolate mofetil monotherapy should NOT be used for initial therapy (Grade 2C) 2

Long-term CNI use warning: Avoid prolonged calcineurin inhibitor therapy as it is associated with immune complex-negative angiopathy MPGN and thrombotic microangiopathy 2

Treatment Duration and Monitoring

• Minimum treatment duration: At least 6 months for all immunosuppressive regimens 2
• CNI tapering protocol: If partial remission achieved, reduce CNI dosage at 4-8 week intervals to approximately 50% of starting dose, provided remission is maintained and no treatment-limiting nephrotoxicity occurs 2
• Discontinuation criteria: Stop CNIs if no complete or partial remission after 6 months 2
• Anti-PLA2R antibody monitoring: Check levels every 1-3 months to predict remission, relapse, and treatment response 1

Management of Treatment Failure

If no response after 3-6 months at non-toxic dose 2:

• If resistant to alkylating agent/steroid-based therapy: Switch to CNI-based regimen 2
• If resistant to CNI-based therapy: Switch to alkylating agent/steroid-based therapy or rituximab 2
• Verify true resistance by checking compliance, monitoring drug efficacy markers, and consider repeat biopsy if proteinuria persists despite normalized albumin or loss of anti-PLA2R antibodies 1

Management of Relapse

For relapse after successful treatment 1:

• Reinstitute the same therapy that resulted in initial remission 2
• Alternative: Switch to rituximab if initially treated with CNIs or cyclophosphamide 1
• Critical restriction: If 6-month cyclical corticosteroid/alkylating-agent regimen was used initially, repeat only ONCE for relapse 2

Special Populations

Children: Follow adult treatment recommendations, but give no more than one course of cyclical corticosteroid/alkylating-agent regimen, and refer all pediatric cases to expert centers 2, 1

Kidney transplant recipients: Monitor anti-PLA2R antibody levels every 1-3 months post-transplant in patients with PLA2R-associated disease 1