What is the treatment for membranous nephropathy?

Treatment of Membranous Nephropathy

Initial Conservative Management (All Patients)

All patients with membranous nephropathy and proteinuria require optimal supportive care before considering immunosuppression, including RAS blockade, blood pressure control to <130/80 mmHg, statin therapy, diuretics for edema, and thromboembolism risk assessment. 1

• Start ACE inhibitors or ARBs targeting blood pressure <130/80 mmHg regardless of proteinuria level 1
• Initiate statin therapy for dyslipidemia management 1
• Use diuretics for edema control 1
• Assess anticoagulation needs: strongly consider prophylactic anticoagulation when serum albumin <25 g/L (or <20 g/L) due to high thromboembolism risk 2, 1, 3

Risk Stratification: Who Needs Immunosuppression?

Immunosuppressive therapy should be initiated only in patients with nephrotic syndrome who meet specific high-risk criteria after at least 6 months of conservative management. 2

Low-Risk Patients (Conservative Management Only):

• Proteinuria <3.5 g/day AND
• Serum albumin >30 g/L AND
• eGFR >60 mL/min/1.73 m² 1

These patients do NOT require immunosuppression and should continue conservative therapy 1

High-Risk Patients (Immunosuppression Indicated):

Start immunosuppressive therapy when ANY of the following criteria are met:

• Persistent severe proteinuria: >4 g/day remaining at >50% of baseline after 6 months of optimal conservative therapy 2
• Declining kidney function: Serum creatinine risen by ≥30% within 6-12 months BUT eGFR still ≥25-30 mL/min/1.73 m² 2
• Severe nephrotic complications: Life-threatening or disabling symptoms (acute kidney injury, serious infections, thromboembolic events) 2, 1

Important caveat: Spontaneous remission can occur in >20% of patients even with proteinuria 8-12 g/day, and remission may take 12-24 months 2. Consider extending observation beyond 6 months if proteinuria is progressively declining and kidney function remains stable 2

Absolute Contraindications to Immunosuppression:

• Serum creatinine persistently ≥3.5 mg/dL (eGFR ≤30 mL/min/1.73 m²) with small echogenic kidneys on ultrasound 2
• Active severe or life-threatening infections 2

First-Line Immunosuppressive Treatment Options

Three regimens are considered equivalent first-line options: rituximab, cyclophosphamide plus alternating corticosteroids, or tacrolimus-based therapy. 1, 3

Option 1: Rituximab (Preferred for Most Patients)

Rituximab is recommended as first-line therapy with equivalent efficacy to cyclophosphamide-based regimens but superior safety profile. 1, 3

Dosing: 1 gram IV on days 1 and 15, OR 375 mg/m² weekly for 4 weeks (both regimens clinically equivalent) 3

Advantages:

• More favorable safety profile compared to alkylating agents 1, 3
• Particularly appropriate when eGFR is stable 3

Monitoring requirements:

• Proteinuria and serum albumin at 3 months to assess response 3
• Anti-PLA2R antibody levels for treatment guidance 1, 3
• B-cell depletion (though not sufficient alone to judge efficacy) 3

Safety considerations:

• Prophylactic trimethoprim-sulfamethoxazole to prevent Pneumocystis jirovecii pneumonia 3
• Screen for hepatitis B (risk of reactivation) 3
• Risk of hypogammaglobulinemia with repeated cycles 3
• Reduced vaccine efficacy during treatment 3

Common pitfall: Do not discontinue rituximab prematurely—response may take 3-6 months 3

Option 2: Cyclophosphamide + Alternating Corticosteroids (Ponticelli Regimen)

A 6-month course of alternating monthly cycles of oral/IV corticosteroids and oral alkylating agents is recommended for initial therapy. 2

Regimen details: See KDIGO Table 15 for specific dosing 2

Preference: Use cyclophosphamide rather than chlorambucil 2

Best suited for: High-risk patients with rapidly declining eGFR or very high-risk disease (proteinuria >8 g/day with declining function) 1

Important timing consideration: Manage conservatively for at least 6 months AFTER completing this regimen before declaring treatment failure (unless kidney function deteriorating or severe symptoms present), as immunologic remission lags behind clinical remission 2

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

CNI-based therapy can be used as initial treatment, with CNI blood levels monitored regularly during initial treatment and whenever unexplained rise in creatinine occurs. 2

• Continue for at least 12 months if remission maintained and no treatment-limiting nephrotoxicity 2
• Tacrolimus combined with corticosteroids may have better short-term efficacy than cyclophosphamide 4

Limitations:

• High relapse rate after discontinuation 5
• Risk of CNI-related nephrotoxicity requiring monitoring 2

Corticosteroid and MMF Monotherapy

Do NOT use corticosteroid monotherapy or mycophenolate mofetil (MMF) monotherapy for initial therapy of membranous nephropathy. 2

These agents as monotherapy are not recommended based on lack of efficacy 2

Management of Treatment Failure or Relapse

For Initial Treatment Failure:

If resistant to alkylating agent/steroid-based therapy, switch to a CNI-based regimen. 2

If resistant to CNI-based therapy, switch to alkylating agent/steroid-based therapy OR rituximab. 2, 1, 3

Before declaring treatment failure:

• Verify medication compliance 1
• Monitor drug efficacy markers (anti-PLA2R antibodies) 1
• Consider repeat biopsy if proteinuria persists despite normalized albumin or loss of anti-PLA2R antibodies 1

For Relapse After Successful Treatment:

Reinstitute the same therapy that resulted in initial remission. 2

Critical limitation: If a 6-month cyclical corticosteroid/alkylating-agent regimen was used initially, repeat it only ONCE for relapse treatment 2

Anti-PLA2R Antibody-Guided Treatment

Monitor anti-PLA2R antibody levels longitudinally for treatment response evaluation and therapy adjustments. 1

Anti-PLA2R antibodies predict:

• Remission likelihood 1
• Relapse risk 1
• Treatment response 1

Special Populations

Children:

• Follow adult treatment recommendations 2
• Give no more than ONE course of cyclical corticosteroid/alkylating-agent regimen 2
• Refer all pediatric cases to expert centers 1

Kidney Transplant Recipients:

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

Treatment Algorithm Summary

1. All patients: Start conservative management (RAS blockade, BP control, statins, assess anticoagulation)
2. Observe 6 months (can extend if proteinuria declining and stable kidney function)
3. If high-risk criteria met: Choose first-line immunosuppression
   • Rituximab (preferred for most): 1g IV days 1 and 15
   • Cyclophosphamide + steroids: 6-month alternating regimen (for rapidly declining eGFR)
   • Tacrolimus-based: Alternative option
4. If treatment fails: Switch to different class (CNI ↔ alkylating agent, or add rituximab)
5. If relapse occurs: Repeat initial successful therapy (cyclophosphamide regimen only once)