What is the recommended treatment for membranous nephropathy?

Treatment of Membranous Nephropathy

The recommended first-line treatment for membranous nephropathy with risk factors for progression is rituximab, while cyclophosphamide with glucocorticoids is preferred when renal function is declining, and calcineurin inhibitors can be used as alternatives depending on patient-specific factors. 1, 2

Risk Stratification and Treatment Indications

Immunosuppressive therapy is indicated when:

• Proteinuria ≥3.5 g/day with serum albumin <30 g/L
• Declining eGFR
• Serious complications of nephrotic syndrome (AKI, infections, thromboembolic events)

Patients without these risk factors (proteinuria <3.5 g/day, serum albumin >30 g/L, eGFR >60 ml/min/1.73 m²) should receive supportive care only. 1

Treatment Algorithm

First-Line Treatment (based on risk assessment):

1. For patients with stable renal function:

   • Rituximab (preferred in younger patients or those concerned about fertility)
     • Dosing: 375 mg/m² weekly for 4 weeks OR 1 g × 2 doses given 2 weeks apart 2

2. For patients with declining renal function:

   • Cyclophosphamide with glucocorticoids for 6 months
     • Maximum cumulative dose should not exceed 36 g (preferably limited to 25 g)
     • Limit to 10 g if preservation of fertility is required 1

3. Alternative option:

   • Calcineurin inhibitors (tacrolimus or cyclosporine) for ≥6 months
     • Target tacrolimus level: 8-10 ng/mL
     • Continue for at least 12 months if remission occurs 2

Supportive Care (for all patients):

• ACE inhibitors and/or ARBs for blood pressure control (target <120/75 mm Hg)
• Diuretics for edema management
• Dietary sodium restriction
• Lipid-lowering agents as needed 2

Management of Treatment-Resistant Disease

For patients not responding to initial therapy:

1. If initially treated with rituximab and eGFR stable:

   • Switch to calcineurin inhibitors 1

2. If initially treated with calcineurin inhibitors and eGFR stable:

   • Switch to rituximab 1

3. If eGFR is decreasing:

   • Use cyclophosphamide with glucocorticoids 1

4. For patients resistant to both rituximab and cyclophosphamide:

   • Refer to specialized center for experimental therapies (bortezomib, anti-CD38 therapy, belimumab) 1, 2

Monitoring Treatment Response

• Monitor anti-PLA2R antibody levels every 3 months in positive patients
• Continue treatment for at least 6-12 months before considering treatment failure
• Remission may be delayed for up to 18-24 months (mean time 14.7 months) 2
• Regular monitoring of proteinuria, serum albumin, and kidney function
• Consider treatment failure if no substantial reduction in proteinuria (30-50%) after 4-6 months of adequate therapy 2

Prophylactic Anticoagulation

Consider prophylactic anticoagulation in high-risk patients:

• Serum albumin <30 g/L (by bromocresol purple) or <25 g/L
• Additional risk factors for thrombosis
• Especially important in the first 6 months after diagnosis 1, 2

Special Considerations

• In patients with relapse after initial therapy, the initial treatment can be repeated or switched to rituximab if initially treated with CNIs or cyclophosphamide 1
• In transplant recipients with MN, monitor PLA2R antibody levels every 1-3 months 1
• Hydroxychloroquine should be considered for patients with lupus-associated membranous nephropathy 2
• Counsel patients to hold ACEi/ARB and diuretics when at risk for volume depletion 2
• Dihydropyridine calcium channel blockers may exacerbate edema and increase proteinuria 2

Common Pitfalls

• Failing to rule out secondary causes of membranous nephropathy before initiating treatment
• Declaring treatment failure too early (response may take up to 18-24 months)
• Not monitoring for drug-specific side effects (glucose intolerance with tacrolimus, bone marrow suppression with cyclophosphamide)
• Exceeding maximum cumulative doses of cyclophosphamide
• Neglecting thromboembolic prophylaxis in high-risk patients
• Overlooking the need for supportive care in all patients