What is the optimal treatment for membranous glomerulonephritis?

Optimal Treatment for Membranous Glomerulonephritis

Initial Risk Stratification and Treatment Decision

All patients with primary membranous nephropathy require optimal supportive care, but immunosuppressive therapy should be reserved for those with proteinuria ≥3.5 g/day, serum albumin <30 g/L, or eGFR <60 mL/min/1.73 m², or when serious nephrotic syndrome complications occur. 1

Who Does NOT Need Immunosuppression

• Patients with proteinuria <3.5 g/day AND serum albumin >30 g/L (by bromocresol purple) AND eGFR >60 mL/min/1.73 m² can be managed with supportive care alone 1
• These patients should be observed for 6 months before considering immunosuppression unless severe symptoms or declining kidney function develop 2, 3

Who DOES Need Immunosuppression

Immunosuppressive therapy is indicated when at least one risk factor for disease progression is present, including: 1

• Nephrotic-range proteinuria with low serum albumin
• Declining eGFR
• Serious complications of nephrotic syndrome (AKI, infections, thromboembolic events)

First-Line Immunosuppressive Therapy

For patients requiring immunosuppression, rituximab or cyclophosphamide with alternate-month glucocorticoids for 6 months, or tacrolimus-based therapy for ≥6 months are the recommended first-line options (Grade 1B). 1

Treatment Selection Algorithm

Choose based on disease severity and patient factors: 1

• Rituximab: Preferred for most patients requiring immunosuppression, particularly those with stable eGFR 1

• Cyclophosphamide + alternating glucocorticoids: Consider when eGFR is decreasing or for more aggressive disease 1

  • Use 6-month course of alternating monthly cycles of oral and IV corticosteroids with oral cyclophosphamide 2, 3
  • Cumulative cyclophosphamide dose should not exceed 10 g if fertility preservation is required, or 36 g maximum to limit malignancy risk 1

• Tacrolimus-based therapy: Alternative for patients who cannot receive or have contraindications to rituximab or cyclophosphamide 1

  • Minimum duration of 6 months 1

Critical Monitoring Point

Monitor anti-PLA2R antibody levels longitudinally after starting therapy to evaluate treatment response and guide therapy adjustments. 1 When rituximab is used, evaluate proteinuria and anti-PLA2R antibodies after 3 months 1

Universal Supportive Care Measures

All patients with membranous nephropathy and proteinuria require: 1, 2, 3

Blood Pressure and Proteinuria Management

• ACE inhibitors or ARBs at maximally tolerated doses as first-line therapy 2, 3
• Target systolic blood pressure <120 mmHg using standardized office measurement 2, 3
• Hold RAS inhibitors during intercurrent illnesses with volume depletion risk 2

Dietary Modifications

• Restrict sodium to <2.0 g/day 2, 3
• Protein intake 0.8-1 g/kg/day for nephrotic-range proteinuria, with additional protein (up to 5 g/day) to compensate for losses 2
• For eGFR <60 mL/min/1.73 m² with nephrotic proteinuria, limit to 0.8 g/kg/day 2

Edema Management

• Use diuretics as first-line agents, adding mechanistically different diuretics if response is insufficient 2, 3
• Monitor for hyponatremia, hypokalemia, GFR reduction, and volume depletion 2, 3

Thromboembolism Prophylaxis

Base anticoagulation decisions on serum albumin levels and thromboembolic risk: 1

• Serum albumin <20 g/L (bromocresol green) or <25 g/L (bromocresol purple): Consider prophylactic anticoagulation with low-molecular-weight heparin if low bleeding risk 1
• Serum albumin 20-30 g/L: Assess individual arterial and venous thromboembolic risk; consider aspirin for lower-risk patients 1
• Serum albumin >30 g/L: No routine anticoagulation needed 1

Management of Treatment-Resistant Disease

For patients not responding to initial therapy, compliance and treatment efficacy must be verified before declaring resistance. 1

Evaluation of Apparent Resistance

• Check compliance with medications 1
• Monitor B-cell response and anti-rituximab antibodies (for rituximab) 1
• Check IgG levels and leukocytopenia (for cyclophosphamide) 1
• Consider repeat kidney biopsy if proteinuria persists with normal/near-normal serum albumin or despite loss of anti-PLA2R antibodies to document active disease versus secondary FSGS 1

Second-Line Treatment Algorithm

If eGFR is stable: 1

• Switch to rituximab if not previously used
• Evaluate response at 3 months

If eGFR is decreasing: 1

• Use cyclophosphamide with glucocorticoids if not previously used
• Respect cumulative dose limits

For patients failing both rituximab and cyclophosphamide: 1

• Consultation with expert center is mandatory
• Expert centers may consider experimental therapies (bortezomib, anti-CD38 therapy, belimumab) or higher doses of conventional immunosuppression 1

Management of Relapse

For initial relapse of nephrotic syndrome after therapy: 1

• Repeat the initial therapy that achieved remission, OR
• Switch to rituximab if initially treated with calcineurin inhibitors or cyclophosphamide 1

Infection Prevention During Immunosuppression

Before and during immunosuppressive therapy: 2, 3, 4

• Screen for latent tuberculosis, hepatitis B, hepatitis C, HIV, and syphilis 2, 3, 4
• Administer pneumococcal vaccine 2, 3
• Ensure influenza vaccine for patients and household contacts 2, 3
• Provide herpes zoster vaccination (Shingrix) 2, 3
• Consider prophylactic trimethoprim-sulfamethoxazole for patients receiving high-dose prednisone or other immunosuppressive agents 2, 3

Common Pitfalls to Avoid

Do not start immunosuppression prematurely: Up to 40-50% of patients may achieve spontaneous remission, but waiting too long in high-risk patients can lead to irreversible kidney damage 5, 6. The 6-month observation period balances these risks 2, 3

Do not ignore persistent proteinuria alone as treatment failure: If serum albumin has increased despite persistent proteinuria, consider secondary FSGS rather than active membranous nephropathy 1. Loss of anti-PLA2R antibodies with persistent proteinuria also suggests alternative pathology 1

Do not exceed cyclophosphamide cumulative dose limits: Fertility preservation requires limiting to 10 g cumulative dose, and malignancy risk increases substantially above 36 g 1

Do not continue calcineurin inhibitors indefinitely without monitoring: These agents can reduce proteinuria through non-immunological mechanisms and may not reflect true histologic quiescence 1