Management of Membranous Nephropathy: Visual Infographic Guide

📊 INITIAL ASSESSMENT & RISK STRATIFICATION

All patients require immediate supportive care from diagnosis, regardless of whether immunosuppression is indicated. 1

Step 1: Confirm Diagnosis & Identify Type

Measure anti-PLA2R antibodies - high levels predict progression and poor spontaneous remission 2
Check for secondary causes - malignancy, autoimmune disease, infections, medications 3
Obtain kidney biopsy with PLA2R staining if antibody testing inconclusive 1

Step 2: Assess Disease Severity

Three key parameters determine management:

Parameter	Value	Interpretation
Proteinuria	<3.5 g/day	Low risk - supportive care only [1]
	>3.5 g/day	High risk - consider immunosuppression [1]
Serum Albumin	>30 g/L (BCP method)	Lower risk [1]
	<30 g/L	Higher risk - consider immunosuppression [1]
eGFR	>60 mL/min/1.73m²	Stable function [1]
	<60 or declining	Progressive disease - urgent immunosuppression [1]

🛡️ SUPPORTIVE CARE (ALL PATIENTS)

Initiate immediately at diagnosis - this is mandatory regardless of immunosuppression decision. 2

Blood Pressure & Proteinuria Control

ACE inhibitor or ARB - start even without hypertension to reduce proteinuria 2
Target BP: <130/80 mmHg 2
Add SGLT2 inhibitor for additional nephroprotection 4

Cardiovascular Risk Management

Statin therapy for dyslipidemia management 2
Sodium restriction: <2.0 g/day (<90 mmol/day) 2

Thromboembolism Prophylaxis

Critical decision based on albumin level: 1

Serum Albumin	Action
<20 g/L (BCG) or <25 g/L (BCP)	Prophylactic anticoagulation with LMWH [1]
20-30 g/L (BCG) or 25-32 g/L (BCP)	Aspirin prophylaxis [1]
>30 g/L (BCG) or >32 g/L (BCP)	No routine prophylaxis - assess individual VTE risk [1]

💉 IMMUNOSUPPRESSION DECISION ALGORITHM

❌ DO NOT TREAT with Immunosuppression if ALL of the following:

Proteinuria <3.5 g/day AND
Serum albumin >30 g/L (BCP method) AND
eGFR >60 mL/min/1.73m² AND
No serious NS complications (AKI, infections, thromboembolism) 1

→ Continue supportive care and monitor closely 1

✅ INITIATE IMMUNOSUPPRESSION if ANY of the following:

Proteinuria >3.5 g/day with albumin <30 g/L 1
Progressive proteinuria or rising anti-PLA2R antibodies 4, 2
eGFR declining ≥30% over 6-12 months 2
Serious NS complications (AKI, infections, thromboembolic events) 1

🎯 FIRST-LINE IMMUNOSUPPRESSION OPTIONS

Choose based on eGFR trajectory and patient factors (Grade 1B recommendation): 1

Option 1: RITUXIMAB (Preferred for Most Patients)

Dosing: 1g IV × 2 doses, given 2 weeks apart 4

Advantages:

Now standard of care with Grade 1B recommendation 4
60-80% remission rate 5
Better safety profile than alkylating agents 5

Pre-treatment Requirements: 4

Screen for HBV, HCV, HIV, tuberculosis
Update vaccinations
Consider PJP prophylaxis

Monitoring Schedule: 4

Anti-PLA2R antibodies at 3 months
Proteinuria and albumin every 1-3 months
B-cell depletion assessment

Option 2: CYCLOPHOSPHAMIDE + GLUCOCORTICOIDS (Modified Ponticelli Protocol)

Use when eGFR is declining rapidly 1

Regimen (6-month alternating protocol): 2

Months 1,3,5: Methylprednisolone 1g IV × 3 days, then prednisone 0.5 mg/kg/day × 27 days
Months 2,4,6: Cyclophosphamide 2.5 mg/kg/day (adjust for age/renal function)

Critical Safety Limits: 1

Maximum cumulative dose: 10g if fertility preservation required
Maximum cumulative dose: 36g to limit malignancy risk
Reduces death/ESRD risk (RR 0.44,95% CI 0.26-0.75) 2

Option 3: TACROLIMUS-BASED THERAPY (Calcineurin Inhibitor)

Use when eGFR is stable and patient cannot tolerate other options 1

Duration: ≥6 months 1

Limitations:

High relapse rate after discontinuation 2, 6
Requires therapeutic drug monitoring 2
Alternative when rituximab/cyclophosphamide contraindicated 2

🔄 TREATMENT RESPONSE MONITORING

Timeline for Expected Response

Immunologic remission precedes clinical remission by months 3, 7

Timepoint	Assessment
3 months	Check anti-PLA2R antibodies - should be declining [4,7]
6 months	Evaluate proteinuria reduction [1]
12-24 months	Assess for complete/partial remission [7]

Remission Definitions

Complete Remission: Proteinuria <0.3 g/day with stable renal function 2, 7
Partial Remission: Proteinuria <3.5 g/day with ≥50% reduction from baseline and stable/improved renal function 2, 7

🔁 MANAGEMENT OF RELAPSE

If initial relapse occurs after achieving remission: 1

Treatment Options:

Repeat initial therapy if it was effective 1
Switch to rituximab if initially treated with CNI or cyclophosphamide 1

⚠️ TREATMENT-RESISTANT DISEASE ALGORITHM

Resistance defined as: Persistent proteinuria despite adequate treatment duration and drug levels 1

Step 1: Verify True Resistance

Before declaring resistance, check: 1

Medication compliance
Rituximab: B-cell depletion, anti-rituximab antibodies, IgG levels 1, 5
Cyclophosphamide: Leukocyte count during treatment 1
CNI: Therapeutic drug levels 1

Step 2: Reassess Disease Activity

Consider repeat biopsy if: 1

Proteinuria persists but albumin normalized (suggests secondary FSGS) 1
Anti-PLA2R antibodies disappeared but proteinuria continues 1

Step 3: Second-Line Treatment Based on eGFR Trajectory

Initial Treatment	eGFR Status	Second-Line Option
CNI	Stable	Rituximab [1]
CNI	Declining	Cyclophosphamide + glucocorticoids [1]
Rituximab	Stable	CNI (tacrolimus) [1]
Rituximab	Declining	Cyclophosphamide + glucocorticoids [1]
Cyclophosphamide	Either	Rituximab [1]

Step 4: Refractory to Multiple Agents

Refer to expert center for consideration of: 1

Bortezomib (proteasome inhibitor) 1
Anti-CD38 therapy 1
Belimumab (anti-BAFF) 1
Higher-dose conventional therapy (risk-benefit assessment required) 1

🚨 COMMON PITFALLS TO AVOID

❌ Don't:

Start immunosuppression in low-risk patients (proteinuria <3.5 g/day, albumin >30 g/L, eGFR >60) 1
Use inadequate rituximab dosing - the 1g × 2 dose regimen is evidence-based 4
Exceed cyclophosphamide cumulative dose limits (10g for fertility, 36g maximum) 1
Declare treatment failure before adequate duration (6-12 months for clinical response) 7
Ignore anticoagulation in severe hypoalbuminemia (<25 g/L BCP) 1

✅ Do:

Monitor anti-PLA2R antibodies longitudinally to guide treatment decisions 1, 4
Provide supportive care to ALL patients regardless of immunosuppression status 1, 2
Screen for infections before starting immunosuppression 4
Consider rituximab biosimilars (e.g., Riabni) as equivalent alternatives 4
Refer treatment-resistant cases to expert centers early 1

What is the best approach to manage an adult patient with membranous nephropathy (MN), including supportive care and immunosuppressive therapy, considering potential comorbid conditions and complications such as nephrotic syndrome?

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