Epidemiology & Definition
Membranous nephropathy (MN) = Most common cause of nephrotic syndrome in adults (25-30% of adult nephrotic syndrome)
- Peak age: 40-60 years
- M:F ratio: 1.5-2:1
- Primary (idiopathic) MN: 70-80% of cases
- Secondary MN: 20-30% (hepatitis B, lupus, malignancy, drugs, infections)
- Spontaneous remission rate: 25-30% over 5 years (monitor before treating)
MN is THE most common cause of nephrotic syndrome you’ll see in clinical practice. Most patients present with asymptomatic proteinuria discovered on routine screening.
Pathophysiology: Primary MN (Autoimmune)
The Two-Hit Mechanism
Hit 1: Circulating Autoantibodies - ~70% of primary MN: Anti-PLA2R antibodies (Phospholipase A2 receptor) - IgG4 dominant subclass - Serum anti-PLA2R titer correlates with disease activity and proteinuria - ~3% of primary MN: Anti-THSD7A antibodies (Thrombospondin type-1 domain-containing protein 7A) - IgG4 dominant; younger age at presentation - ~25% of primary MN: Seronegative (neither anti-PLA2R nor anti-THSD7A detected) - Likely other unknown antigens; worse prognosis
Hit 2: In-Situ Immune Complex Deposition - Circulating IgG4 antibodies bind to PLA2R (expressed on podocyte surface) - Immune complex deposits in subepithelial space (“spike and dome” pattern on EM) - Complement activation (C5b-9, MAC) → podocyte injury, proteinuria
Primary vs. Secondary MN
PRIMARY MEMBRANOUS NEPHROPATHY (Idiopathic)
- ~75% of MN cases
- Serology: Anti-PLA2R positive (70%), anti-THSD7A positive (3%), seronegative (25%)
- Pathology: Isolated MN without systemic features
- Clinical: Adults >40 years typically
- Prognosis: ~30% spontaneous remission; ~40% progressive to ESRD
SECONDARY MEMBRANOUS NEPHROPATHY (Associated Conditions)
| Cause |
Frequency |
Key Features |
| Hepatitis B |
Most common globally |
Endemic in Asia; HBsAg+ patients; often children |
| Lupus (Class V) |
10-15% of SLE |
Nephrotic + serologies (anti-dsDNA, low C3) |
| Malignancy |
5-10% in adults |
Lung (most common), colon, gastric, ovary; resolves if cancer treated |
| NSAIDs |
Chronic use |
Especially naproxen; proteinuria may resolve after cessation |
| Antibiotics |
Penicillamine, rifampicin |
Penicillamine for Wilson disease; drug-induced immune complex |
| Infections |
Syphilis, malaria, schistosomiasis |
Regional prevalence; parasitic endemic areas |
| SLE + MN (Class V+III/IV) |
Overlap syndrome |
Rare; treated as proliferative class |
Secondary MN screening: If adult >60 years with MN and no anti-PLA2R antibodies, or if clinical features suggest secondary cause (weight loss, night sweats, positive serologies), screen for: hepatitis B/C, malignancy (CT chest/abdomen/pelvis), active SLE (ANA, anti-dsDNA, complement), occult infection.
Clinical Presentation
| Feature |
Frequency |
Significance |
| Asymptomatic proteinuria |
40-50% |
Discovered on routine screening; may have stable disease |
| Nephrotic syndrome (full) |
30-40% |
Proteinuria ≥3.5 g/day, hypoalbuminemia, edema, hyperlipidemia |
| Hematuria |
10-20% |
Usually microscopic; gross rare (suggests proliferative component) |
| Hypertension |
30-40% |
Present at diagnosis; worsens prognosis |
| Acute kidney injury |
<5% |
Indicates thrombotic event (renal vein thrombosis) or rapidly progressive disease |
Renal Vein Thrombosis (RVT) in MN
- 5-10% of MN patients develop RVT (higher in nephrotic subgroup)
- Mechanism: Proteinuria → loss of anticoagulant proteins (protein C, S, antithrombin), nephrotic state hypercoagulability
- Presentation: Acute rise in Cr, hematuria, flank pain (can be asymptomatic)
- Diagnosis: CT/MRI angiography (contrast ultrasound if CKD)
- Management: Anticoagulation (warfarin INR 2-3 or DOAC); resolve underlying MN
Diagnosis: Kidney Biopsy
When to Biopsy
- ANY nephrotic syndrome in adult → biopsy for diagnosis
- Nephrotic proteinuria (≥3.5 g/day) even if no edema
Light Microscopy (LM)
- Normal or minimal changes (hallmark of MN)
- Glomeruli appear normal to slightly thickened
- Distinguish from other nephrotic causes
- “Spike and dome” appearance on PAS stain (subepithelial deposits creating spikes)
Immunofluorescence (IF)
- Granular IgG deposits along capillary wall (predominantly IgG, not IgM/IgA)
- C3 granular deposits along capillary wall
- If IgG4 staining available: IgG4 predominance (80-90% of IgG) in primary MN
Electron Microscopy (EM) — Gold Standard
- “Spike and dome” lesions: Subepithelial electron-dense deposits with interpositioned GBM
- Stage I (early): Sparse subepithelial deposits
- Stage II (progressive): Abundant deposits with spike formation
- Stage III (advanced): Spikes merging with deposits; GBM rarefaction
- Diffuse foot process effacement (podocytopathy)
Anti-PLA2R & Anti-THSD7A Testing
Anti-PLA2R Antibody
- Serum testing: ELISA or immunofluorescence on PLA2R-transfected cells
- Positive in ~70% of primary MN
- Titer correlation:
- High titer (≥20 RU/mL) → active disease, higher proteinuria, slower remission
- Low titer (5-20 RU/mL) → milder disease or treatment response
- Negative conversion → predictor of remission (especially on rituximab/tacrolimus)
- Seronegative MN (~25-30% of primary MN): Likely other antigens; variable prognosis
Anti-THSD7A Antibody
- Serum testing: Similar platforms as PLA2R
- Positive in 3-5% of primary MN
- Clinical significance: Younger patients; IgG4-predominant
Anti-PLA2R negative doesn’t rule out primary MN: 25-30% of primary MN are seronegative. Clinical-pathologic diagnosis sufficient. Don’t assume secondary cause without systemic features.
Natural History & Risk Stratification
KDIGO 2021 Risk Stratification for MN Progression
| Risk Category |
Proteinuria |
Anti-PLA2R |
eGFR |
10-Year ESRD Risk |
| Low risk |
<4 g/day |
Negative |
>60 |
<15% |
| Low-intermediate |
<4 g/day |
Positive |
>60 |
15-25% |
| High-intermediate |
4-8 g/day |
Any |
>60 |
35-50% |
| High risk |
>8 g/day |
Any |
<60 |
>50% |
Risk assessment guides treatment: Low-risk patients can be observed. Intermediate/high-risk require immunosuppression. Re-assess risk every 6 months.
Spontaneous Remission
- ~25-35% of MN patients achieve spontaneous complete remission over 5-10 years
- Predictors of remission: Female sex, younger age, low baseline proteinuria (<4 g/day), low anti-PLA2R
- Monitoring period: Observation for 6-12 months off treatment acceptable for low-risk patients
Treatment Algorithm (KDIGO 2021)
Baseline Therapy (All Patients)
- ACE-I or ARB: First-line; titrate to maximum tolerated dose
- Reduces proteinuria 30-50% in most patients
- Target: Proteinuria <1 g/day if possible
- Examples: Lisinopril 40 mg daily, Losartan 100 mg daily
- Recheck K+, Cr 1-2 weeks after initiation
- Diuretics: Loop diuretics for edema management
- Furosemide 40-120 mg daily (adjust for volume status)
- Goal: 0.5-1 kg/day weight loss initially
- Statins: Pravastatin 80 mg or atorvastatin 80 mg daily
- Indicated in all nephrotic syndrome patients (dyslipi
demia + proteinuria)
- NSAIDs: Avoid (↓ renal perfusion, worsens proteinuria, ↑ HTN)
Immunosuppression: Decide Based on Risk Stratification
Low-Risk MN (Proteinuria <4 g/day, anti-PLA2R negative or low, eGFR >60)
- Observation for 6-12 months
- Continue ACE-I/ARB, monitor proteinuria q 3 months
- If proteinuria remains <1-2 g/day: Continue observation
- If proteinuria increases to high-risk category: Escalate to treatment
High-Risk MN (Proteinuria >8 g/day OR eGFR <60)
- Aggressive immunosuppression required
- Combination therapy: Rituximab + CNI (cyclosporine or tacrolimus) ± steroids
- Superior response rates vs. monotherapy
- Response: 60-70% complete remission + 20-30% partial remission
- Timeline: Expect response at 3-6 months; allow 6-12 months for full remission
Secondary MN Management
Hepatitis B-Associated MN
- Lamivudine or entecavir (nucleos(t)ide reverse transcriptase inhibitor)
- Proteinuria improves in 80-90% after viral suppression
- Don’t add immunosuppression unless poor viral response (can worsen HBV replication)
- Target: HBV DNA <2000 IU/mL (undetectable)
Lupus Class V MN (±III/IV)
- Pure Class V: RAAS blockade + low-dose corticosteroids ± rituximab
- Class III/IV+V: Use induction therapy (MMF or cyclophosphamide) targeting proliferative component
- See: Lupus Nephritis Student Handout
Malignancy-Associated MN
- Primary intervention: Cancer treatment (surgery, chemotherapy, radiation)
- Proteinuria may resolve completely after tumor resection
- Immunosuppression decision: If cancer remission achieved, hold immunosuppression; restart if MN persists
Drug-Induced MN (NSAIDs, Penicillamine)
- Discontinue offending agent
- Proteinuria may resolve within weeks-months
- Supportive care during remission period
Monitoring & Response Assessment
During Treatment (Every 3 Months)
- Proteinuria (UPCR or 24-hr UP): Expected to decline 0.5-2 g/day per month
- Serum Cr and eGFR: Monitor for acute kidney injury
- Albumin and lipid panel: Assess nutritional status
- Anti-PLA2R titer (if rituximab used): Declining titer = favorable response predictor
- K+, BP, medication side effects
Remission End-Points
- Complete remission: Proteinuria <0.3 g/day, normal Cr, normal UA
- Partial remission: ≥50% ↓ proteinuria or proteinuria <3.5 g/day, stable Cr
- No remission: <50% ↓ proteinuria or worsening Cr
Delayed remission in rituximab: 50% of patients remit by 6 months, 80% by 12 months. Don’t switch therapy before month 6 unless clinical deterioration.
Clinical Pearls & Pitfalls
Seronegative primary MN: Look for malignancy screening (especially >60 years). Seronegative patients more likely to have secondary cause or aggressive course.
Renal vein thrombosis in MN: Suspect if sudden rise in Cr or acute flank pain. Anticoagulate even if stable (prevent progression to bilateral thrombosis). Controversial whether to screen asymptomatic patients (many advocate screening if proteinuria >10 g/day).
Rituximab relapse in MN: 30-40% of rituximab responders relapse within 2-3 years. Retreatment effective; don’t assume treatment failure. Anti-PLA2R positive patients more likely to relapse.
CNI + steroid combination: Often used for rapid proteinuria reduction in high-risk patients. CNI added for anti-inflammatory effect + steroid taper allows lower cumulative steroid dose.
MN in pregnant patient: Proteinuria often increases during pregnancy (hormonal effects). Manage with RAAS blockade (ACE-I/ARB contraindicated 2nd/3rd trimester); steroids safe; defer immunosuppression if possible until postpartum.
Landmark Trials
[1] GEMRITUX Trial (2017): Rituximab plus non-immunosuppressive antiproteinuric treatment vs. that treatment alone in severe membranous nephropathy. JASN. 2017;28(1):348–358. PMID: 27352623
[2] MENTOR Trial (2019): Rituximab vs. cyclosporine for primary membranous nephropathy. NEJM. 2019;381(1):36–46. PMID: 31269364