What is the initial treatment approach for membranous nephropathy?

Initial Treatment Approach for Membranous Nephropathy

All patients with membranous nephropathy should receive optimal supportive care first, and immunosuppressive therapy should only be initiated in high-risk patients meeting specific criteria after an observation period of at least 6 months. 1

Immediate Supportive Care for All Patients

Every patient with membranous nephropathy requires the following baseline interventions regardless of disease severity:

• RAS blockade with ACE inhibitors or ARBs targeting blood pressure <130/80 mmHg 1, 2
• 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 is <20-25 g/L 1, 3

Risk Stratification: Who NOT to Treat with Immunosuppression

Low-risk patients do NOT require immunosuppressive therapy and should be managed with supportive care alone. Low-risk criteria include: 1

• Proteinuria <3.5 g/day
• Serum albumin >30 g/L
• eGFR >60 mL/min per 1.73 m²

These patients should be monitored closely for 6-12 months with continued supportive care. 2

Criteria for Starting Immunosuppressive Therapy

Initiate immunosuppression ONLY when the patient has nephrotic syndrome AND meets at least one of these conditions: 2

1. Persistent severe proteinuria: Urinary protein excretion persistently exceeds 4 g/day AND remains at >50% of baseline value AND does not show progressive decline during 6 months of optimal supportive care 2

2. Severe nephrotic complications: Presence of severe, disabling, or life-threatening symptoms related to nephrotic syndrome (e.g., AKI, severe infections, thromboembolic events) 2, 1

3. Declining renal function: Serum creatinine has risen by ≥30% within 6-12 months from diagnosis, BUT eGFR remains ≥25-30 mL/min per 1.73 m², AND this change is not explained by other complications 2

Absolute Contraindications to Immunosuppression

Do NOT use immunosuppressive therapy in patients with: 2

• Serum creatinine persistently ≥3.5 mg/dL (or eGFR ≤30 mL/min per 1.73 m²) AND reduced kidney size on ultrasound (<8 cm in length)
• Concomitant severe or potentially life-threatening infections

First-Line Immunosuppressive Treatment Options

The 2025 KDIGO guidelines recognize three equivalent first-line options for patients requiring immunosuppression: 1

Option 1: Rituximab (Preferred by Most Guidelines)

Rituximab is increasingly recognized as the preferred first-line agent due to equivalent efficacy to cyclophosphamide-based regimens with a superior safety profile. 1, 3

• Dosing: Either 1 gram on days 1 and 15, OR 375 mg/m² weekly for 4 weeks (both regimens are clinically equivalent) 3
• Monitoring: Assess proteinuria and serum albumin at 3 months; monitor anti-PLA2R antibody levels to guide treatment adjustments 1, 3
• Response timeline: Clinical response may take 3-6 months; do not discontinue prematurely 3
• Safety requirements: Prophylactic trimethoprim-sulfamethoxazole to prevent Pneumocystis jirovecii pneumonia 3

Option 2: Cyclophosphamide + Alternating Glucocorticoids (Modified Ponticelli Regimen)

This regimen is recommended for high-risk patients with rapidly declining eGFR or very high-risk disease (proteinuria >8 g/day with declining function). 2, 1

• Protocol: 6-month course of alternating monthly cycles 2
  • Months 1,3,5: IV methylprednisolone 1 gram daily for 3 days, followed by oral prednisone 0.4-0.5 mg/kg/day for the remainder of the month
  • Months 2,4,6: Oral cyclophosphamide 2-2.5 mg/kg/day (dose adjusted for age and eGFR)
• Preferred alkylating agent: Use cyclophosphamide rather than chlorambucil 2
• Post-treatment observation: Manage conservatively for at least 6 months after completing the regimen before considering treatment failure, unless kidney function is deteriorating or severe symptoms are present 2

Option 3: Tacrolimus-Based Therapy (Calcineurin Inhibitor)

CNIs are appropriate for patients with contraindications to cyclophosphamide or as an alternative first-line option. 2, 1

• Dosing: Tacrolimus targeting trough levels 8-10 ng/mL, often combined with low-dose prednisone 2
• Duration: Continue for at least 12 months if partial or complete remission is achieved; taper only after remission is obtained 2
• Response assessment: Do not automatically discontinue at 6 months if no remission; consider ineffective only if <30-50% reduction in proteinuria after 4-6 months with therapeutic trough levels 2
• Monitoring: Watch closely for acute increases in serum creatinine indicating nephrotoxicity 2

Important Clinical Pitfalls to Avoid

The observation period may need to be longer than 6 months. Spontaneous remission can occur even with proteinuria >8-12 g/day, and mean time to remission is 14.7 ± 11.4 months. 2 A conservative approach should be maintained in patients showing progressive decline in proteinuria during the first year, provided renal function remains stable. 2

Do not interpret persistent proteinuria alone as treatment failure. Response to immunosuppression may be delayed for 18-24 months after treatment completion. 2, 3

Do not use corticosteroid monotherapy or mycophenolate mofetil monotherapy as initial therapy for membranous nephropathy—these approaches are ineffective. 2

Anti-PLA2R Antibody-Guided Management

Longitudinal monitoring of anti-PLA2R antibody levels should guide treatment decisions: 1

• Use antibody levels to predict remission, relapse, and treatment response
• Monitor every 1-3 months during and after treatment
• Declining antibody levels predict clinical remission even before proteinuria improves
• Loss of antibodies despite persistent proteinuria may indicate structural damage rather than active immunologic disease