Membranous Nephropathy Clinical Overview
I. The "On-Call" Snapshot
Clinical Significance in Malaysia: This is the most common cause of primary nephrotic syndrome in non-diabetic adults. You will encounter this frequently.
High-Yield Definition: MN is a glomerular disease characterised histologically by the deposition of immune complexes in the subepithelial space, leading to glomerular basement membrane (GBM) thickening and podocyte injury.
Clinical One-Liner: "Adult with new-onset anasarca and frothy urine? Think nephrotic syndrome, and put Membranous Nephropathy at the top of your differential list."
II. Etiology & Risk Factors
Etiology: The key distinction is Primary vs. Secondary.
Primary (Idiopathic) MN (~80%): Autoimmune. Caused by autoantibodies targeting podocyte antigens.
Anti-PLA2R (M-type phospholipase A2 receptor): Positive in 70-80% of primary MN.
Anti-THSD7A (Thrombospondin type-1 domain-containing 7A): Positive in 1-3%.
Secondary MN (~20%): Caused by an underlying systemic disease or exposure.
Malignancy (Crucial): Solid tumours (lung, colon, prostate, breast). This is a paraneoplastic syndrome. Always rule this out in patients >50 years.
Infections: Hepatitis B (very relevant in our population), Hepatitis C, Syphilis.
Autoimmune: Systemic Lupus Erythematosus (SLE) – this is "Lupus Nephritis Class V".
Drugs: NSAIDs, Penicillamine (rarely used now).
III. Quick Pathophysiology
Immune Complex Formation: In Primary MN, IgG4 antibodies (mainly anti-PLA2R) bind to antigens on the podocyte surface.
Complement Activation: These in-situ immune complexes activate the alternative complement pathway, forming the C5b-C9 Membrane Attack Complex (MAC).
Podocyte Injury: MAC causes direct podocyte injury and stimulates them to lay down new GBM material.
Histology: This process creates the classic "spikes" (new GBM) seen on silver stain, surrounding the subepithelial deposits (the "domes").
Proteinuria: The injured podocytes and damaged GBM lose their size and charge selectivity, leading to massive leakage of protein (mainly albumin) into the urine, causing nephrotic syndrome.
IV. Classification
The primary classification is clinical:
Primary (Idiopathic) MN: No identifiable secondary cause. Anti-PLA2R positive.
Secondary MN: Identifiable cause (e.g., Hep B-associated, malignancy-associated). Anti-PLA2R is usually negative.
Histologically, it can be staged (Ehrenreich and Churg Stages I-IV), but this is more for the pathologist. It describes the evolution from small deposits (Stage I) to the classic "spikes and domes" (Stage II/III) and eventual glomerular sclerosis (Stage IV).
V. Clinical Assessment
🚩 Red Flags & Immediate Actions
Sudden flank pain, haematuria, or oliguria: Suspect Renal Vein Thrombosis (RVT). This is a hypercoagulable state. Action: Notify senior/Nephrology, request urgent CT Angiogram or Doppler Ultrasound.
Anasarca with respiratory distress: Suspect large pleural effusion or pulmonary oedema. Action: Sit patient up, give oxygen, check CXR, notify senior for consideration of IV diuretics +/- cautious albumin infusion.
Signs of DVT/PE (swollen calf, pleuritic chest pain, haemoptysis, syncope): High risk of VTE. Action: ABCDE assessment, notify senior immediately, request CTPA.
Severe AKI on presentation: Suggests rapidly progressive disease or a complication like RVT. Action: Notify senior, hold nephrotoxins (including RAAS blockade), run fluid status assessment.
History
Key Diagnostic Clues (Classic Presentation):
Gradual onset of oedema: Starts periorbitally (worse in AM), progresses to pitting pedal oedema, and potentially ascites, pleural effusions, and scrotal/labial oedema (anasarca).
"Frothy" urine: Due to severe proteinuria (albuminuria).
Symptom Breakdown:
Common (>50%): Lethargy, fatigue, weight gain (fluid).
Less Common (10-50%): Non-specific abdominal discomfort (ascites), mild dyspnoea (pleural effusion).
Rare (<10%): Symptoms of complications (e.g., flank pain from RVT, chest pain from PE), symptoms of secondary cause (e.g., arthralgia/rash in SLE, constitutional symptoms of malignancy).
Pertinent Negatives:
Absence of significant macroscopic haematuria or red cell casts (argues against a nephritic syndrome like IgA nephropathy or RPGN).
Absence of preceding URTI (less likely post-strep GN).
Absence of purpuric rash (less likely HSP/IgA vasculitis).
Physical Examination (OSCE Approach)
General Inspection: Patient may look pale (anaemia), comfortable at rest or breathless if fluid overloaded. Look for Muehrcke's lines on nails (transverse white bands) signifying hypoalbuminaemia. Look for xanthelasma/eruptive xanthomas (severe hyperlipidaemia).
Vitals: Blood pressure is often normal or only mildly elevated, unlike in nephritic syndromes. Tachycardia if volume depleted or in pain.
Disease-Specific Examination:
Face: Periorbital oedema.
Chest: Assess for pleural effusion (stony dull percussion note, reduced breath sounds at bases).
Abdomen: Check for ascites (shifting dullness, fluid thrill). Palpate for renal masses or hepatosplenomegaly (possible secondary causes like lymphoma or chronic hepatitis).
Limbs: Pitting oedema (check legs, sacrum). Check for signs of DVT (calf tenderness, swelling, erythema).
Examination for Differentials:
Look for malar rash, photosensitivity, or alopecia (SLE).
Palpate for lymphadenopathy (lymphoma, malignancy).
Check for jaundice (Hepatitis B/C).
Differentiating Disease Stage:
Mild Disease: Sub-nephrotic proteinuria, normal eGFR, mild oedema.
Moderate Disease: Nephrotic range proteinuria (>3.5g/day), normal eGFR, significant oedema.
Severe Disease: Persistent nephrotic syndrome, declining eGFR, or complications (e.G., VTE).
Clinical Pearl: In any adult over 50 presenting with new-onset nephrotic syndrome, your workup is not complete until you have aggressively screened for an underlying malignancy.
VI. Diagnostic Workflow
Differential Diagnosis
Diabetic Nephropathy:
Points For: Patient has a history of long-standing, poorly controlled DM.
Points Against: Absence of DM. Absence of diabetic retinopathy (retinopathy is almost always present if DM is the cause of nephropathy).
How to Differentiate: HbA1c, renal biopsy (shows nodular glomerulosclerosis, not spikes/domes).
Focal Segmental Glomerulosclerosis (FSGS):
Points For: Nephrotic syndrome.
Points Against: FSGS often presents with hypertension and microscopic haematuria.
How to Differentiate: Renal biopsy (shows segmental scarring in some glomeruli).
Minimal Change Disease (MCD):
Points For: "Bland" urine sediment, severe nephrotic syndrome.
Points Against: MCD is the #1 cause in children, but less common (10-15%) in adults.
How to Differentiate: Renal biopsy (LM is normal, EM shows podocyte foot process effacement).
Lupus Nephritis (Class V):
Points For: Nephrotic syndrome in a young-to-middle-aged female (common demographic for SLE in Malaysia).
Points Against: No other systemic features of SLE.
How to Differentiate: ANA, anti-dsDNA, C3/C4 levels. Biopsy will show "full house" immunofluorescence.
Investigations Plan
Bedside / Initial (First 15 Mins):
UFEME: This is key. Will show proteinuria (3+ or 4+), minimal or no haematuria ("bland sediment"). May see oval fat bodies and "Maltese crosses" under polarized light (lipid-laden macrophages).
ECG: Check for signs of ischaemia (CVD risk) or electrolyte disturbance if AKI.
First-Line Labs & Imaging:
Renal Profile (RP): Assess eGFR and creatinine (baseline).
Liver Function Test (LFT): Will show low serum albumin (e.g., <25 g/L) and low total protein.
Fasting Lipid Profile: Will show severe hyperlipidaemia (high total cholesterol, LDL, and triglycerides).
Urine Protein:Creatinine Ratio (UPCR) or 24h Urine Protein: To quantify proteinuria (Nephrotic-range is >350 mg/mmol or >3.5g/24h).
Full Blood Count (FBC): May show high haematocrit (haemoconcentration) or anaemia (chronic disease).
Workup for Secondary Causes (Mandatory):
Infection Screen: HBsAg, Anti-HCV, VDRL/TPHA.
Autoimmune Screen: ANA, anti-dsDNA, Serum C3/C4.
Malignancy Screen (Age-appropriate): CXR, Ultrasound Abdomen/Pelvis. Consider CT Thorax/Abdo/Pelvis, OGDS, Colonoscopy, PSA (male >50), Mammogram (female >40) as guided by nephrology/suspicion.
Confirmatory / Gold Standard:
1. Serology: Anti-PLA2R Antibody: A high titre (>99% specificity) in a patient with nephrotic syndrome and no evidence of a secondary cause is diagnostic of Primary MN. Per KDIGO 2021, a biopsy may be deferred if risk of biopsy is high and anti-PLA2R is strongly positive.
2. Renal Biopsy: The definitive gold standard.
Light Microscopy (LM): Diffuse thickening of the GBM, no significant cellular proliferation.
Immunofluorescence (IF): Diffuse, granular capillary wall staining for IgG (mainly IgG4 subclass) and C3.
Electron Microscopy (EM): The pathognomonic finding: subepithelial electron-dense deposits, with "spikes" of new GBM forming between them.
VII. Staging & Severity Assessment
Risk stratification (per KDIGO 2021) is crucial as it dictates management.
Low Risk:
Normal eGFR, and
Proteinuria <4 g/day, and
Stable over 6 months.
Moderate Risk:
Normal eGFR, and
Persistent proteinuria 4-8 g/day (despite 6 months of supportive care), and
Anti-PLA2R <50 RU/mL (if measured).
High Risk:
Any eGFR decline, or
Persistent proteinuria >8 g/day, or
Anti-PLA2R >50 RU/mL, or
Severe nephrotic complications.
Very High Risk:
Life-threatening complication (e.g., PE, AKI) or rapid eGFR decline.
VIII. Management Plan
A. Principle of Management
Achieve remission of proteinuria (complete or partial) to preserve renal function.
Aggressively manage the complications of nephrotic syndrome.
Identify and treat any underlying secondary cause.
B. Immediate Stabilisation (The ABCDE Plan)
Usually not applicable as MN is a chronic presentation.
If presenting with a complication (e.g., PE, anasarca with respiratory compromise), manage that complication first as per standard protocols (e.g., O2, IV diuretics, anticoagulation).
C. Definitive Treatment (The Ward Round Plan)
1. Conservative / Supportive Care (FOR ALL PATIENTS)
RAAS Blockade: ACE inhibitor or ARB. This is a cornerstone. Start low, titrate to maximum tolerated dose. Goal is BP <125/75 (if tolerated) and maximum reduction in proteinuria.
Statins: High-intensity statin (e.g., Atorvastatin 40mg ON) to manage severe hyperlipidaemia.
Diuretics: Loop diuretics (e.g., Furosemide) for oedema management. May need combination therapy (e.g., +Metolazone).
Anticoagulation: Prophylactic anticoagulation (e.g., Warfarin with target INR 2-3, or LMWH/DOAC) is indicated if serum albumin is very low (e.g., <20-25 g/L), as per local nephrology protocol, due to high VTE risk.
Lifestyle: Strict low salt diet (<2g sodium/day), fluid restriction (if oedematous).
2. Immunosuppression (For Moderate-to-High Risk Patients)
Low-Risk Patients: Receive supportive care only. ~30% undergo spontaneous remission.
Moderate/High-Risk Patients: Require immunosuppression. This is a nephrology decision.
First-Line (KDIGO 2021): Rituximab (Anti-CD20 B-cell depleting agent). Given as IV infusion (e.g., 1g on day 1 and day 15). Favourable side effect profile.
Alternative 1: Cyclophosphamide (Alkylating agent). Used in the "Modified Ponticelli Regimen" (6 months of alternating monthly IV/oral pulse steroids with oral/IV cyclophosphamide). Very effective but has significant toxicity (infection, infertility, malignancy).
Alternative 2: Calcineurin Inhibitor (CNI): Cyclosporine or Tacrolimus, usually combined with low-dose steroids. Effective at inducing remission but high relapse rate after withdrawal.
3. Management of Secondary MN
Treat the underlying cause.
Hep B: Start antiviral therapy (e.g., Tenofovir/Entecavir).
Malignancy: Treat the cancer (surgery, chemo, radiation).
SLE: Treat the lupus (e.g., MMF, steroids).
Drug-induced: Stop the offending drug.
D. Long-Term & Discharge Plan
Follow-up: Lifelong follow-up in the Nephrology clinic.
Monitoring: Regular BP, UFEME (for proteinuria), RP (for eGFR), and lipid profile. Anti-PLA2R titres can be monitored to assess treatment response and predict relapse.
Vaccinations: Pneumococcal and annual influenza vaccine (especially if on immunosuppression).
IX. Complications
Immediate / Short-Term:
Thromboembolism (RVT, DVT, PE): Due to urinary loss of anticoagulant proteins (Antithrombin III). Action: High index of suspicion. Prophylactic or therapeutic anticoagulation.
Infection (e.g., Spontaneous Bacterial Peritonitis (SBP), cellulitis): Due to urinary loss of immunoglobulins (IgG). Action: Low threshold to start antibiotics. Diagnostic ascitic tap if SBP is suspected.
Acute Kidney Injury (AKI): Often pre-renal (over-diuresis) or from the disease itself. Action: Review fluid status, hold diuretics/RAASi if pre-renal.
Long-Term:
End-Stage Kidney Disease (ESKD): The main long-term fear. Risk at 10 years is ~10-15% in treated patients, but up to 40% if untreated.
Atherosclerotic Cardiovascular Disease (CVD): Due to chronic severe hyperlipidaemia and hypertension. Action: Aggressive statin therapy and BP control.
Complications of Immunosuppression: Opportunistic infections, bone marrow suppression, secondary malignancy.
X. Prognosis
Prognosis has improved significantly.
The old "rule of thirds" (1/3 remission, 1/3 proteinuria, 1/3 ESKD) is outdated.
With modern risk-stratified treatment, ESKD rates are much lower.
Good Prognostic Factors: Female, younger age, normal eGFR, sub-nephrotic proteinuria, anti-PLA2R negative or low titre, remission of proteinuria (spontaneous or treated).
Poor Prognostic Factors: Male, older age (>50), elevated creatinine at presentation, persistent nephrotic-range proteinuria (>8g/day), hypertension, high anti-PLA2R titre.
XI. How to Present to Your Senior
"Dr, I'm calling to refer a new admission, Mr. Tan, a 48-year-old gentleman in Bed 10, admitted for new-onset anasarca.
Situation: He is haemodynamically stable, BP 130/85, saturating 97% on room air. He has significant pitting oedema up to his mid-thighs and mild ascites.
Background: No known medical illness. Presented with 2 weeks of frothy urine and progressive swelling.
Assessment: Initial labs show nephrotic syndrome: UFEME protein 4+, UPCR is 1100 mg/mmol, serum albumin is 18 g/L, and creatinine is normal with eGFR 90. My top differential is primary nephrotic syndrome, likely Membranous Nephropathy.
Recommendation: I have sent off the full workup including anti-PLA2R, Hep B/C screen, and an autoimmune screen. I've also initiated supportive care with salt restriction and subcutaneous Clexane 40mg OD for VTE prophylaxis given albumin <20. I have not started an ACEi yet pending your review. Requesting nephrology review for further management and to discuss the plan for a renal biopsy."
XII. Summary & Further Reading
Top 3 Takeaways
MN is the #1 cause of primary nephrotic syndrome in adults.
Your initial workup must include two things: Anti-PLA2R (to confirm primary MN) and a screen for secondary causes (Malignancy, Hepatitis B, SLE).
Management is risk-stratified: All patients get supportive care (ACEi/ARB, statin, diuretic). Only moderate-to-high-risk patients (e.g., declining eGFR, proteinuria >8g/day) get immunosuppression (usually Rituximab first-line).
Key Resources
Primary Guideline: KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases (Chapter 7: Membranous Nephropathy).
UpToDate: "Membranous nephropathy: Pathogenesis and etiology" and "Membranous nephropathy: Treatment and prognosis".
Amboss: "Membranous nephropathy".
