What is the initial treatment approach for a patient with 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 after at least 6 months of observation, with rituximab, cyclophosphamide plus alternating glucocorticoids, or tacrolimus-based therapy as equivalent first-line options. 1, 2

Step 1: Exclude Secondary Causes and Initiate Supportive Care

• Immediately investigate all biopsy-proven membranous nephropathy cases to exclude secondary causes (malignancy, autoimmune disease, infections, drugs) before considering immunosuppression. 3

• Start all patients on optimal supportive care regardless of disease severity:

  • RAS blockade (ACE inhibitors or ARBs) targeting blood pressure <130/80 mmHg 1, 2
  • Statin therapy for dyslipidemia management 1
  • Diuretics for edema control 1
  • Prophylactic anticoagulation when serum albumin <20-25 g/L due to high thromboembolism risk 1, 2

Step 2: Risk Stratification - Determine Who Needs Immunosuppression

Low-Risk Patients (No Immunosuppression Required)

• Do NOT use immunosuppressive therapy if ALL of the following are present:
  • Proteinuria <3.5 g/day 1, 2
  • Serum albumin >30 g/L 1, 2
  • eGFR >60 mL/min per 1.73 m² 1, 2
  • Continue supportive care and monitor closely 1

High-Risk Patients (Immunosuppression Indicated)

• Initiate immunosuppressive therapy ONLY after at least 6 months of observation with optimal supportive care when ANY of the following criteria are met: 3, 1
  • Proteinuria persistently >4 g/day AND remains at >50% of baseline AND shows no progressive decline despite 6 months of supportive therapy 3
  • Severe, disabling, or life-threatening nephrotic syndrome symptoms 3
  • Serum creatinine risen by ≥30% within 6-12 months from diagnosis (but eGFR not <25-30 mL/min per 1.73 m²) 3

Absolute Contraindications to Immunosuppression

• Do NOT use immunosuppressive therapy if:
  • Serum creatinine persistently ≥3.5 mg/dL (or eGFR ≤30 mL/min per 1.73 m²) AND reduced kidney size on ultrasound (<8 cm) 3
  • Concomitant severe or life-threatening infections 3

Step 3: Select First-Line Immunosuppressive Therapy

Three regimens are considered equivalent first-line options - choice depends on kidney function stability and patient factors: 3, 1, 2

Option 1: Rituximab (Preferred for Most Patients)

• Use rituximab as first-line when eGFR is stable - it has equivalent efficacy to cyclophosphamide-based regimens with superior safety profile 1, 2
• Dosing: 1-2 infusions of 1 g each, administered 2 weeks apart 3
• Monitor anti-PLA2R antibody levels every 1-3 months to guide treatment response 1, 2
• Evaluate proteinuria and anti-PLA2R antibodies at 3 months - response typically occurs within 3 months 3, 2
• Critical safety measures:
  • Prophylactic trimethoprim-sulfamethoxazole to prevent Pneumocystis jirovecii pneumonia 2
  • Screen for hepatitis B before treatment 2
  • Monitor for hypogammaglobulinemia with repeated cycles 2
  • Counsel about reduced vaccine efficacy during treatment 2

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

• Use cyclophosphamide-based therapy when eGFR is declining or in very high-risk disease (proteinuria >8 g/day with declining function) 3, 1, 2
• Dosing: 6-month course of alternating monthly cycles of oral/IV corticosteroids and oral cyclophosphamide 3
• Prefer cyclophosphamide over chlorambucil for initial therapy 3
• Adjust dose according to age and eGFR 3
• Critical dose limits:
  • Cumulative dose should NOT exceed 36 g (risk of malignancy) 3
  • Maximum 10 g if preservation of fertility is required 3
• Wait at least 6 months after completion before declaring treatment failure unless kidney function is rapidly deteriorating 3

Option 3: Calcineurin Inhibitor-Based Therapy (Tacrolimus or Cyclosporine)

• Use CNI therapy for at least 6 months in patients who refuse or have contraindications to cyclophosphamide 3, 1, 2
• Dosing: Cyclosporine 3-5 mg/kg/day in divided doses OR tacrolimus (dose adjusted to target levels) 3
• Monitor CNI blood levels regularly during initial treatment and whenever unexplained rise in creatinine (>20%) occurs 3
• If remission achieved: Continue for at least 12 months, then taper slowly to 50% of starting dose 3
• Discontinue if no complete or partial remission after 6 months 3
• Major limitation: High relapse rate after withdrawal and risk of CNI nephrotoxicity 4, 5

Step 4: Monitor Treatment Response

• Assess clinical response at 3 months: Evaluate proteinuria, serum albumin, and anti-PLA2R antibody levels 3, 2
• Define immunologic remission: Anti-PLA2R antibodies <2 RU/mL or negative immunofluorescence 3
• Clinical remission typically lags behind immunologic remission by months - persistent proteinuria alone does NOT define treatment failure 3, 1

Step 5: Management of Treatment Failure or Relapse

For Resistant Disease (No Response After Adequate Trial)

• If eGFR stable and resistant to CNI: Switch to rituximab 3, 1
• If eGFR stable and resistant to rituximab: Switch to CNI or cyclophosphamide 3, 1
• If eGFR declining: Use cyclophosphamide plus glucocorticoids 3, 1
• Before declaring resistance: Verify compliance, check drug efficacy markers (B-cell depletion, CNI levels, leukocytopenia), and consider repeat biopsy if proteinuria persists despite normalized albumin 3, 1

For Relapse After Initial Remission

• Repeat the initial therapy that achieved remission OR switch to rituximab if initially treated with CNI or cyclophosphamide 3, 1
• Critical limitation: Only repeat cyclical cyclophosphamide/corticosteroid regimen ONCE for relapse due to cumulative toxicity 3

Common Pitfalls to Avoid

• Starting immunosuppression too early - always observe for at least 6 months with optimal supportive care unless severe complications present 3, 1
• Interpreting persistent proteinuria as treatment failure - proteinuria may persist for months after immunologic remission; check anti-PLA2R antibodies and serum albumin 3, 1
• Exceeding cyclophosphamide cumulative dose limits - increases malignancy and infertility risk 3
• Using corticosteroid monotherapy - this is NOT recommended for initial therapy of membranous nephropathy 3
• Using mycophenolate mofetil monotherapy - this is NOT recommended for initial therapy 3
• Judging rituximab efficacy by B-cell depletion alone - insufficient marker; must monitor anti-PLA2R antibodies and proteinuria 3, 2