What is the treatment for membranous nephropathy?

Treatment of Membranous Nephropathy

Initial Management: Supportive Care Foundation

All patients with primary membranous nephropathy and proteinuria must receive optimal supportive care regardless of whether immunosuppression is initiated 1. This includes:

• 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
• Anticoagulation assessment based on albumin levels and thromboembolism risk 1

Anticoagulation Strategy

The KDIGO 2021 guidelines provide specific albumin thresholds for anticoagulation decisions 1:

• Serum albumin <20 g/L (bromocresol green) or <25 g/L (bromocresol purple): Consider prophylactic low-molecular-weight heparin due to high venous thromboembolism risk 1
• Serum albumin 20-30 g/L: Assess individual arterial and venous thromboembolism risk; consider aspirin for lower-risk patients 1
• Serum albumin >30 g/L: No routine anticoagulation unless other risk factors present 1

Risk Stratification: Who Requires Immunosuppression?

Immunosuppressive therapy is NOT required for low-risk patients with all of the following 1:

• Proteinuria <3.5 g/day
• Serum albumin >30 g/L (by bromocresol purple or immunometric assay)
• eGFR >60 mL/min per 1.73 m²

Immunosuppressive therapy SHOULD be initiated when any of these risk factors are present 1:

• Proteinuria ≥3.5 g/day with serum albumin ≤30 g/L
• eGFR ≤60 mL/min per 1.73 m²
• Serious nephrotic syndrome complications (AKI, infections, thromboembolic events)
• Proteinuria 4-8 g/day sustained over 6 months (medium risk) 1
• Proteinuria >8 g/day or deteriorating renal function (high risk) 1

First-Line Immunosuppressive Treatment Options

For patients requiring immunosuppression, the 2021 KDIGO guidelines recommend three equivalent first-line options (Grade 1B) 1, 2:

Option 1: Rituximab (Preferred by Most Current Evidence)

Rituximab is recommended as first-line therapy with equivalent efficacy to cyclophosphamide-based regimens and superior safety profile 2, 3, 4:

• Dosing: Either 1 gram IV on days 1 and 15, OR 375 mg/m² weekly for 4 weeks 2
• Monitoring: Evaluate proteinuria, serum albumin, and anti-PLA2R antibodies at 3 months 1, 2
• Response timeline: May take 3-6 months; do not discontinue prematurely 2
• Efficacy: Achieves remission in approximately two-thirds of patients 4
• Safety advantages: Lower infection risk, no gonadotoxicity, no malignancy risk compared to alkylating agents 4

Required prophylaxis and monitoring 2:

• Trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia prevention
• Screen for hepatitis B (surface antigen and core antibody) before treatment
• Monitor for hypogammaglobulinemia with repeated cycles
• B-cell depletion monitoring (though not sufficient alone to judge efficacy)

Option 2: Cyclophosphamide + Alternating Glucocorticoids (6 months)

The Ponticelli regimen remains highly effective for high-risk patients 1:

• Regimen: Alternate monthly between:
  • Month 1,3,5: Methylprednisolone 1g IV daily for 3 days, followed by oral prednisone 0.5 mg/kg/day
  • Month 2,4,6: Cyclophosphamide (oral or IV)
• Efficacy: 10-year renal survival 92% vs 60% untreated controls; remission rate 83% vs 38% 1
• Cumulative dose limits 1:
  • Maximum 10g if fertility preservation required
  • Maximum 36g to limit malignancy risk
• Toxicity concerns: Myelosuppression, infections, gonadotoxicity, malignancy risk 1, 4

Option 3: Tacrolimus-Based Therapy (≥6 months)

Calcineurin inhibitors are effective but have important limitations 1:

• Tacrolimus dosing: 2-3 mg/kg/day in divided doses, targeting trough levels 5-10 ng/mL 1
• Cyclosporine dosing: 3-4 mg/kg/day in divided doses, targeting C0 125-175 ng/mL 1
• Duration: Minimum 6 months; if partial remission achieved, continue 1-2 years 1
• Efficacy: 60-75% achieve complete or partial remission 1
• Major limitation: High relapse rate (40-47%) after discontinuation 1
• Nephrotoxicity risk: Requires careful monitoring of drug levels and renal function 1

Tapering strategy for CNIs 1:

• If complete remission: Taper over 3-4 months
• If partial remission: Continue full dose 1-2 years, then taper slowly or maintain at non-toxic level indefinitely

Treatment Selection Algorithm

Choose rituximab when 2, 3:

• Patient desires fertility preservation
• Concern about long-term malignancy risk
• eGFR is stable (not rapidly declining)
• Patient preference for lower toxicity profile

Choose cyclophosphamide + glucocorticoids when 1:

• eGFR is rapidly declining
• Very high-risk disease (proteinuria >8 g/day with declining function)
• Need for fastest possible response

Choose tacrolimus-based therapy when 1:

• Contraindications to rituximab and cyclophosphamide exist
• Patient can tolerate close monitoring and drug level checks
• Willing to accept potential for treatment dependence

Management of Treatment Failure or Relapse

For Initial Relapse After Successful Treatment

The initial therapy can be repeated, OR switch to rituximab if initially treated with CNIs or cyclophosphamide 1.

For Treatment-Resistant Disease

First, verify true resistance 1:

• Check compliance
• Monitor drug efficacy markers (B-cell response for rituximab, drug levels for CNIs, leukopenia for cyclophosphamide)
• Critical: Persistent proteinuria alone does NOT define resistance if serum albumin is improving 1
• Consider repeat biopsy if proteinuria persists despite normalized albumin or loss of anti-PLA2R antibodies (may indicate secondary FSGS) 1

Second-line treatment depends on eGFR trajectory 1:

• If eGFR stable and failed rituximab: Switch to cyclophosphamide + glucocorticoids 1
• If eGFR stable and failed cyclophosphamide: Switch to rituximab 1
• If eGFR stable and failed CNI: Switch to rituximab 1, 2
• If eGFR declining: Use cyclophosphamide + glucocorticoids regardless of prior therapy 1

For patients failing both rituximab and cyclophosphamide: Refer to expert center for experimental therapies (bortezomib, anti-CD38 therapy, belimumab) or higher-dose conventional immunosuppression 1.

Anti-PLA2R Antibody-Guided Treatment

Longitudinal monitoring of anti-PLA2R antibody levels is useful for treatment response evaluation and therapy adjustments 1:

• Antibody depletion predicts remission 4
• Antibody re-emergence predicts relapse 4
• Loss of antibodies despite persistent proteinuria suggests secondary FSGS rather than active membranous nephropathy 1

Special Populations

Pediatric Patients

Membranous nephropathy in children is very rare; refer all cases to expert centers 1.

Kidney Transplant Recipients

For PLA2R-associated disease 1:

• Stain native kidney biopsy for PLA2R expression
• Monitor anti-PLA2R antibody levels every 1-3 months post-transplant
• Persistent antibodies despite kidney failure increase recurrence risk
• Liberal transplant biopsy threshold if antibodies increase
• Use rituximab for documented recurrent disease

Common Pitfalls to Avoid

• Do not interpret persistent proteinuria alone as treatment failure—assess serum albumin trends and anti-PLA2R antibodies 1, 2
• Do not discontinue rituximab before 3-6 months—response is delayed 2
• Do not rely solely on B-cell depletion to assess rituximab efficacy—clinical parameters are essential 2
• Do not exceed cyclophosphamide cumulative dose limits (10g for fertility preservation, 36g maximum) 1
• Do not abruptly stop CNIs after achieving remission—taper slowly to minimize relapse risk 1
• Do not use corticosteroids as monotherapy—meta-analyses show no benefit on renal survival 1