KDIGO Guideline for Membranous Nephrotic Syndrome
Initial Management Strategy
For patients with membranous nephropathy and nephrotic syndrome, the 2021 KDIGO guidelines recommend starting with at least 6 months of optimal supportive care before initiating immunosuppressive therapy, unless severe complications or declining kidney function are present. 1
Supportive Care Requirements (All Patients)
- RAS blockade with ACE inhibitors or ARBs for antiproteinuric effect 2, 3
- Blood pressure control to target <130/80 mmHg 4, 2
- Prophylactic anticoagulation should be strongly considered when serum albumin <25 g/L (bromocresol purple) or <20 g/L (bromocresol green) due to high thromboembolism risk 4, 2, 3
- Management of hyperlipidemia and edema 1
Indications for Immunosuppressive Therapy
Initiate immunosuppression only when patients meet at least one of these criteria after 6 months of supportive care: 1
- Persistent proteinuria >4 g/day that remains >50% of baseline despite optimal supportive therapy 1
- Severe, disabling, or life-threatening symptoms related to nephrotic syndrome 1
- Serum creatinine risen by ≥30% within 6-12 months from diagnosis (but eGFR still >25-30 ml/min/1.73 m²) 1
Absolute Contraindications to Immunosuppression
Do not use immunosuppressive therapy in patients with: 1
- Serum creatinine persistently ≥3.5 mg/dL (or eGFR ≤30 ml/min/1.73 m²) AND reduced kidney size on ultrasound (<8 cm) 1
- Concomitant severe or potentially life-threatening infections 1
First-Line Immunosuppressive Treatment Options
For patients with membranous nephropathy and at least one risk factor for disease progression, KDIGO 2021 recommends rituximab, cyclophosphamide with alternate-month glucocorticoids, or tacrolimus-based therapy, with the choice depending on risk stratification and patient factors. 1
Treatment Algorithm by Risk and Clinical Context
Option 1: Rituximab (Preferred by Most Clinicians)
- Dosing: Either 1 gram on days 1 and 15, OR 375 mg/m² weekly for 4 weeks 4
- Advantages: More favorable safety profile compared to cyclophosphamide; equivalent efficacy 4
- Monitoring: Assess proteinuria and serum albumin at 3 months; anti-PLA2R antibody levels to guide adjustments 4
- Safety requirements: Prophylactic trimethoprim-sulfamethoxazole to prevent Pneumocystis jirovecii pneumonia; screen for hepatitis B before initiation 4
- Important caveat: Response may take 3-6 months; do not discontinue prematurely 4
Option 2: Cyclophosphamide with Glucocorticoids (Modified Ponticelli Regimen)
- Regimen: 6-month course of alternating monthly cycles of oral/IV corticosteroids and oral cyclophosphamide 1, 2
- Preferred alkylating agent: Cyclophosphamide rather than chlorambucil 1
- Indication: Particularly when kidney function is declining 3
- Post-treatment observation: Manage conservatively for at least 6 months after completion before declaring treatment failure, unless kidney function deteriorating or severe symptoms present 1, 2
Option 3: Calcineurin Inhibitors (Tacrolimus or Cyclosporine)
- Tacrolimus dosing: 0.05-0.1 mg/kg/day, targeting therapeutic blood levels 5
- Cyclosporine dosing: 3-5 mg/kg/day in divided doses 1
- Duration: Continue for at least 6 months if achieving partial or complete remission 2
- Consideration: Higher relapse rates after discontinuation compared to cyclophosphamide 6, 7
Risk Stratification for Treatment Selection
Low Risk (No Immunosuppression Needed)
Patients with proteinuria <3.5 g/day, serum albumin >30 g/L, and eGFR >60 ml/min/1.73 m² do not require immunosuppressive therapy 1, 3
High Risk (Immunosuppression Indicated)
Most physicians and patients prefer rituximab or CNI over cyclophosphamide initially, but well-informed patients with very high risk of kidney failure may choose cyclophosphamide 1
Second-Line Treatment After Initial Failure
For patients who fail calcineurin inhibitor-based therapy with stable eGFR, rituximab is the recommended next treatment option. 4, 3
For resistant disease with declining eGFR, cyclophosphamide with glucocorticoids is recommended. 3
Assessment of Treatment Response
Timeline for Response Evaluation
- At 3 months: Assess proteinuria and serum albumin for early clinical response 4
- At 6 months post-treatment: Manage conservatively before declaring treatment failure 1, 2
- Partial remission rates: 39% at 1 year, 70% at 3 years, 83% at 5 years with restrictive treatment strategy 8
- Complete remission rates: 5% at 1 year, 24% at 3 years, 38% at 5 years 8
Critical Pitfall to Avoid
Do not interpret persistent proteinuria alone as treatment failure—proteinuria may persist for months after immunologic remission; anti-PLA2R antibody levels are more reliable indicators of disease activity 4, 3
Long-Term Outcomes with Restrictive Strategy
A large cohort study supporting the KDIGO restrictive treatment approach demonstrated: 8
- 10-year cumulative incidence: 3% for renal replacement therapy, 10% for death 8
- Serious adverse events: Occurred in 23% of patients receiving immunosuppression 8
- Most notable complications: Infections (17%), leukopenia (18%), cardiovascular events (13%), malignancies (8%) 8
These outcomes validate the conservative approach of limiting immunosuppression to high-risk patients only. 8
Special Considerations for Secondary Membranous Nephropathy
The initial approach should focus on identifying and treating the underlying cause (malignancy, autoimmune disease, infections, drugs) before considering immunosuppression. 3
- Screen for malignancy, especially in elderly patients 9
- For lupus membranous nephropathy (Class V), treat with glucocorticoids plus mycophenolic acid analogs, low-dose IV cyclophosphamide, or belimumab combinations 3
- Anti-PLA2R antibodies help establish primary disease, though screening for secondary causes should still be performed 9
Key Safety Monitoring
For All Immunosuppressive Regimens
- Regular monitoring of proteinuria, serum albumin, and kidney function 2
- Infection surveillance and prophylaxis 4
- Avoid cyclophosphamide cumulative doses exceeding 36 grams due to malignancy and infertility risks 3