Membranous Nephropathy
Membranous Nephropathy (MN) is the most common cause of nephrotic syndrome in non-diabetic adults over 60 years old. It is an autoimmune glomerular disease characterized by the deposition of immune complexes on the subepithelial aspect of the glomerular basement membrane (GBM).
Key Features
- Primary (70-80%): Autoimmune, most commonly due to anti-PLA2R antibodies
- Secondary (20-30%): Associated with malignancy, infections, autoimmune diseases, or drugs
- Clinical Hallmark: Nephrotic syndrome (heavy proteinuria, hypoalbuminemia, edema)
- Course: Rule of thirds (1/3 remit spontaneously, 1/3 stable proteinuria, 1/3 progress to ESRD)
Epidemiology
| Factor | Details |
|---|---|
| Incidence | 1 per 100,000/year |
| Peak age | 50-60 years |
| Gender | Male predominance (2:1) |
| Race | More common in Caucasians |
┌─────────────────────────────────────────────────────────────────────────────┐
│ MEMBRANOUS NEPHROPATHY PATHOPHYSIOLOGY │
├─────────────────────────────────────────────────────────────────────────────┤
│ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ AUTOANTIBODY FORMATION (Primary MN) │ │
│ │ • IgG4 antibodies target M-type Phospholipase A2 Receptor (PLA2R) │ │
│ │ • PLA2R is expressed on podocytes │ │
│ │ • Less common: THSD7A, NELL-1, Sema-3B │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ IN SITU IMMUNE COMPLEX FORMATION │ │
│ │ • Antibodies cross GBM and bind antigen ON PODOCYTE surface │ │
│ │ • Forms subepithelial immune deposits │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ COMPLEMENT ACTIVATION │ │
│ │ • Activation of Membrane Attack Complex (C5b-9) │ │
│ │ • BUT minimal cellular inflammation (unlike other GNs) │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ PODOCYTE INJURY │ │
│ │ • Cytoskeletal breakdown │ │
│ │ • Oxidative stress and protease release │ │
│ │ • Foot process effacement │ │
│ │ • Disruption of slit diaphragm barrier │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ │
│ ┌──────────────────────┬──────────────────┬────────────────────┐ │
│ ↓ ↓ ↓ │ │
│ ┌─────────┐ ┌─────────────┐ ┌───────────────┐ │ │
│ │ MASSIVE │ │ THICKENED │ │ HYPERCOAG- │ │ │
│ │PROTEIN- │ │ GBM │ │ ULABILITY │ │ │
│ │URIA │ │ (Spikes) │ │ (Urinary loss │ │ │
│ │ │ │ │ │ of AT-III) │ │ │
│ └─────────┘ └─────────────┘ └───────────────┘ │ │
│ │ │
└─────────────────────────────────────────────────────────────────────────────┘
Primary vs Secondary MN
Primary (80%):
- PLA2R-associated: ~70-80% of primary cases
- THSD7A-associated: ~3-5% (some associated with malignancy)
- NELL-1: Associated with malignancy but distinct antigen
Secondary (20%):
- Malignancy (Solid tumors): Lung, colon, breast, stomach (5-20% of cases >60y)
- Autoimmune: SLE (Class V Lupus Nephritis)
- Infections: Hepatitis B (classic), Malaria, Syphilis
- Drugs: NSAIDs, Penicillamine, Gold, Anti-TNF agents
Hypercoagulability
MN has the highest risk of venous thromboembolism (VTE) among all nephrotic syndromes, particularly renal vein thrombosis risk (up to 30%). This is due to urinary loss of Antithrombin III and Protein S, increased hepatic synthesis of fibrinogen, and hemoconcentration.
History Taking
Presentation:
- Edema (80%): Independent, often severe (anasarca)
- Frothy urine: Sign of heavy proteinuria
- Fatigue: Often profound
- Asymptomatic: Found on routine dipstick (20%)
Screening for Secondary Causes:
- Weight loss, night sweats, bowel habit change (Malignancy screen)
- Joint pains, rash, photosensitivity (SLE)
- Drug history (NSAIDs, biologic agents)
- Risk factors for Hepatitis B/C
Physical Examination
| System | Findings | Significant |
|---|---|---|
| General | Edema | Pitting edema (legs, sacrum), periorbital edema |
| Resipratory | Pleural effusions | "Transudate" from hypoalbuminemia |
| Abdominal | Ascites | Shifting dullness |
| Skin | Xanthelasma | Due to hyperlipidemia |
| Nails | Muehrcke's lines | White bands (hypoalbuminemia) |
| Vascular | DVT signs | Suspect if unilateral leg swelling |
Diagnostic Approach
Steps:
- Confirm Nephrotic Syndrome
- Determine Etiology (Primary vs Secondary)
- Assess Risk of Progression
Laboratory Investigations
| Test | Typical Findings | Notes |
|---|---|---|
| Urinalysis | ++++ Protein | Lipid casts, oval fat bodies |
| Urine PCR/ACR | Nephrotic range (>.5 g/day) | Often >-10 g/day |
| Serum Albumin | Low (<30 g/L) | Often very low (<20 g/L) |
| Anti-PLA2R Ab | Positive in 70-80% | Highly specific for Primary MN |
| Secondary Screen | ANA, Hepatitis, HIV | Rule out secondary causes |
| Malignancy Screen | Age-appropriate | CT CAP often required in elderly |
Anti-PLA2R Antibody
- Diagnostic Utility: A positive anti-PLA2R antibody in a patient with nephrotic syndrome and preserved eGFR may obviate the need for renal biopsy (KDIGO 2021).
- Prognostic Utility: Titers correlate with disease activity and response to treatment. Disappearance of antibody usually precedes proteinuria remission by months (Immunological Remission).
Renal Biopsy (Gold Standard)
Indications:
- Anti-PLA2R negative
- Anti-PLA2R positive but:
- Rapidly declining eGFR
- Suspected secondary cause (e.g., SLE features)
- Not responding to therapy
Histological Stages:
| Stage | Light Microscopy | Electron Microscopy |
|---|---|---|
| I | Normal/mild thickening | Small subepithelial deposits |
| II | Spikes (silver stain) | GBM grows between deposits |
| III | Thickened GBM ("chain link") | Deposits incorporated into GBM |
| IV | Severe thickening/sclerosis | Resorbing deposits (radiolucent) |
┌─────────────────────────────────────────────────────────────────────────────┐
│ MEMBRANOUS NEPHROPATHY MANAGEMENT │
├─────────────────────────────────────────────────────────────────────────────┤
│ │
│ DIAGNOSIS CONFIRMED (Primary MN / PLA2R+) │
│ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ SECONDARY CAUSE SCREENING │ │
│ │ • Age appropriate malignancy screen │ │
│ │ • Review medications │ │
│ │ • Autoimmune/Infectious screen │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ Negative │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ RISK STRATIFICATION │ │
│ │ Based on Proteinuria, Albumin, eGFR, PLA2R Titer │ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ ↓ ↓ ↓ │
│ ┌────────────┐ ┌─────────────┐ ┌──────────────┐ ┌────────────┐ │
│ │ LOW RISK │ │MODERATE RISK│ │ HIGH RISK │ │ VERY HIGH │ │
│ └────────────┘ └─────────────┘ └──────────────┘ └────────────┘ │
│ ↓ ↓ ↓ ↓ │
│ ┌────────────┐ ┌─────────────┐ ┌──────────────┐ ┌────────────┐ │
│ │ WAIT & SEE │ │ WAIT & SEE │ │ TREAT NOW │ │ TREAT NOW │ │
│ │ │ │ (3-6 mo) │ │ │ │ (Urgent) │ │
│ └────────────┘ └─────────────┘ └──────────────┘ └────────────┘ │
│ ↓ ↓ ↓ ↓ │
│ ┌─────────────────────────────────────────────────────────────────────┐ │
│ │ MAXIMAL SUPPORTIVE CARE (ALL PATIENTS) │ │
│ │ • ACEi/ARB (Target BP <120/80) │ │
│ │ • Diuretics for edema │ │
│ │ • Statins for hyperlipidemia │ │
│ │ • Anticoagulation (Prophylactic if Albumin <20 & High bleeding risk)│ │
│ └─────────────────────────────────────────────────────────────────────┘ │
│ ↓ ↓ ↓ ↓ │
│ Monitor Consider Rx Rituximab OR Cyclophos- │
│ 6 monthly if persists Cyclophosphamide phamide + │
│ (Ponticelli) Steroids │
│ (Ponticelli) │
│ + Rituximab │
└─────────────────────────────────────────────────────────────────────────────┘
Risk Stratification Criteria (KDIGO 2021)
| Risk Category | Criteria |
|---|---|
| Low Risk | Proteinuria <4 g/d AND Normal eGFR |
| Moderate Risk | Proteinuria > g/d but <8 g/d despite 6mo supportive care |
| High Risk | Proteinuria >8 g/d OR Anti-PLA2R >0 OR eGFR decreasing |
| Very High Risk | Life-threatening nephrosis OR Rapid eGFR decline |
Immunosuppression Regimens
Rituximab (First Line for Moderate/High Risk):
- B-cell depletion therapy
- Better safety profile than cyclophosphamide
- MENTOR trial showed non-inferiority to cyclosporine with better sustained remission
Cyclophosphamide + Steroids (Example: Modified Ponticelli Regimen):
- Alternating months of steroids (Month 1, 3, 5) and oral cyclophosphamide (Month 2, 4, 6)
- Most effective for preserving renal function in high/very high risk
- Higher toxicity (infertility, infection, malignancy risk)
Calcineurin Inhibitors (Tacrolimus/Cyclosporine):
- Second line or adjunctive
- High relapse rate upon discontinuation
Risk Assessment
Thrombotic Risk Factors:
- Serum Albumin <20-25 g/L (Main factor)
- Proteinuria >10 g/day
- BMI >35
- HF NYHA III/IV
Bleeding Risk Factors:
- Prior bleeding
- Peptic ulcer disease
- Age >75
- Hypertension
Recommendations
- Represents a balance of risk vs benefit.
- Consider Prophylactic Anticoagulation (Warfarin or DOAC) if:
- Serum Albumin <20 g/L (KDIGO suggests <20-25 g/L)
- AND Low bleeding risk
- CONTINUE until albumin >30 g/L
The Rule of Thirds (Untreated)
- Spontaneous Remission (1/3): Usually within first 6-12 months. More likely if low-level proteinuria.
- Persistent Proteinuria (1/3): Stable renal function but ongoing nephrotic syndrome.
- Progression (1/3): Decline in eGFR to ESRD over 5-10 years.
Monitoring Response via PLA2R
Immunological Remission precedes Clinical Remission:
- Immunological Remission: Anti-PLA2R antibodies disappear (Months)
- Proteinuria Remission: Proteinuria falls (Months to Years after antibody clearance)
Clinical Pearl: Don't change treatment too early if proteinuria is slow to fall but anti-PLA2R has disappeared. The podocytes take time to heal.
Disease Complications:
- Thromboembolism: RVT, PE, DVT (Highest risk of all GNs)
- Infections: Due to urinary loss of immunoglobulins
- Hyperlipidemia: Accelerated atherosclerosis
- Acute Kidney Injury: Can occur from over-diuresis or bilateral/severe RVT
Treatment Complications:
- Infections: Pneumocystis jirovecii (Prophylaxis needed with Cyclophosphamide)
- Infertility: Cyclophosphamide risk
- Malignancy: Bladder cancer, leukemia (long term Cyclophosphamide risk)
Pregnancy
- High risk of thrombosis - prophylaxis essential
- Avoid teratogens (ACEi/ARB, Cyclophosphamide, MMF)
- Calcineurin inhibitors (Tacrolimus) generally safe
- High risk of pre-eclampsia
Elderly Patients
- Higher malignancy risk (requires thorough screening)
- Higher risk of infection with immunosuppression
- Often favor Rituximab over Cyclophosphamide due to tolerability
- Conservative management ("Wait and See") may be prolonged if symptoms manageable
Renal Transplantation
- Recurrence in 30-40% of transplants
- Risk predicted by high pre-transplant anti-PLA2R titers
- Treat recurrence with Rituximab
Exam-Focused Points
- Most Common: Primary GN causing nephrotic syndrome in non-diabetic elderly.
- Anti-PLA2R: The game-changer biomarker. Diagnostic (usually no biopsy needed) and prognostic.
- Rule of Thirds: 1/3 remit, 1/3 stable, 1/3 progress. justifies "wait and see" for low risk.
- Clot Risk: Highest VTE risk of any GN. Prophylax if Albumin <20.
- Renal Vein Thrombosis: Suspect if new flank pain + haematuria + worsening renal function.
- Secondary Causes: Remember the "Cs" - Cancer (solid tumors), Carcinoma, Colon, Captopril, Cat-scratch (not really, but Hep B/SLE/Drugs).
- Ponticelli Regimen: The classic "heavy hitter" cyclophosphamide/steroid cycle for high risk.
Common Exam Scenarios
- 60yo man with leg swelling, proteinuria 6g/d. Next step? (Anti-PLA2R).
- Patient with MN develops breathlessness and chest pain. Diagnosis? (PE/RVT).
- Patient on treatment has falling PLA2R titers but persistent proteinuria. Action? (Continue and wait - immunological remission precedes clinical).
What is Membranous Nephropathy?
"Membranous Nephropathy is an autoimmune kidney disease. 'Autoimmune' means your body's immune system mistakenly attacks healthy tissue. In this case, it produces antibodies that attack the filters (glomeruli) in your kidneys.
This attack damages the filters, causing them to become leaky. This allows protein, which should stay in your blood, to leak into your urine. Loss of protein leads to fluid retention (swelling) and high cholesterol."
What Caused It?
"In about 75% of cases, it happens on its own (Primary) related to a specific antibody called anti-PLA2R. In the other 25% (Secondary), it can be triggered by another condition like a medication, infection like Hepatitis B, or sometimes a cancer. We will do thorough checks to rule these out."
Will I Need Dialysis?
"Not necessarily. We follow the 'Rule of Thirds':
- One-third of patients get better on their own without strong drugs.
- One-third stay stable with some protein leakage but stable kidney function.
- One-third get worse over time.
We use blood tests (anti-PLA2R) and urine tests to determine your risk level and decide if you need strong immune-suppressing medication or if we can monitor you safely."
Why do I need Blood Thinners?
"Because you are losing protein in your urine, you are also losing natural blood thinners. This makes your blood 'sticky' and prone to clots. If your albumin level gets very low, we use blood thinners to prevent dangerous clots in your legs or lungs."
Key Guidelines
| Guideline | Organization | Year | Key Points |
|---|---|---|---|
| KDIGO Glomerular Diseases | KDIGO | 2021 | Major update. Anti-PLA2R allows non-biopsy diagnosis. Risk-based treatment. |
| Glomerulonephritis | UK Renal Association | 2019 | Similar to KDIGO. Emphasizes VTE prophylaxis. |
Landmark Trials
MENTOR Trial (2019):
- Rituximab vs Cyclosporine for MN.
- Rituximab was non-inferior at 12 months and superior at 24 months for maintaining remission.
- Established Rituximab as a preferred first-line agent.
GEMRITUX Trial (2017):
- Rituximab + supportive care vs supportive care alone.
- Rituximab increased remission rates significantly.
Modified Ponticelli Regimen Studies:
- Establish the efficacy of alternating steroids/cyclophosphamide for preserving renal function long-term (10-year data).
Evidence-Based Recommendations
| Recommendation | Evidence Level |
|---|---|
| Use Anti-PLA2R for diagnosis | Moderate |
| Wait-and-see for Low Risk | Moderate |
| Rituximab for Moderate/High Risk | High (MENTOR) |
| Cyclophosphamide for Very High Risk | High |
| Prophylactic Anticoagulation | Low (Expert Consensus) |
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Beck LH Jr, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11-21.
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Ponticelli C, et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney Int. 1995;48(5):1600-1604.
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Dahan K, et al. Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up (GEMRITUX). J Am Soc Nephrol. 2017;28(1):348-358.
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Cattran DC, et al. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int Suppl. 2012;2:139-274.