Membranous Nephropathy
Membranous nephropathy is a glomerular disease characterized by immune complex deposition and thickening of the glomerular basement membrane, leading to nephrotic syndrome.
Membranous Nephropathy
Membranous Nephropathy (MN) is defined by the presence of subepithelial immune deposits leading to a spectrum of glomerular capillary wall alterations, most typically the formation of intervening "GBM spikes." [1]
Let's break the name down:
- "Membranous" → refers to the thickened glomerular basement membrane (GBM) — the defining histological feature.
- "Nephropathy" → "nephro" = kidney, "pathy" = disease.
So the name literally tells you: a kidney disease characterised by membrane (GBM) thickening.
The thickening is caused by immune complex deposition on the outer (subepithelial) side of the GBM, beneath the podocyte foot processes. The body's own complement cascade then damages the podocytes, leading to massive proteinuria. Because the injury is non-inflammatory (no significant cellular proliferation), the urine sediment is typically "bland" (no dysmorphic RBCs or cellular casts), and the predominant clinical presentation is nephrotic syndrome.
Key Concept
MN is a pattern of glomerular injury, not a single disease. No single classification is ideal since it cannot always be assumed that one histologic pattern has a single etiology (e.g. the membranous pattern can be idiopathic, or due to lupus or viral hepatitis infection). [2] This is why we always separate primary (idiopathic) from secondary causes.
2. Epidemiology
- MN is commonly regarded as the most common cause of nephrotic syndrome in adults. [1]
- Accounts for ~20–30% of nephrotic syndrome in Caucasian adults [3].
- In Asian populations (including Hong Kong), MN competes with IgA nephropathy and minimal change disease as a leading cause of adult nephrotic syndrome. Local renal biopsy data suggest MN accounts for roughly 15–25% of primary glomerular diseases in Chinese adults.
- Idiopathic MN is more common in white males > 40 years. [3]
- Peak incidence: 50–60 years for primary MN.
- Male-to-female ratio: approximately 2:1 for primary MN.
- Secondary MN (e.g. lupus-associated) tends to affect younger women — always consider this in any young woman with apparent idiopathic MN [3].
| Age Group | Common Nephrotic Causes | Common Nephritic Causes |
|---|---|---|
| < 15 years | MCD, FSGS | PSGN, IgAN/HSP |
| 15–40 years | MCD, FSGS, Membranous | IgAN, PSGN, Lupus nephritis, RPGN |
| > 40 years | MCD, Membranous, DM, Amyloidosis | PSGN, IgAN, RPGN |
High Yield: In a middle-aged or elderly adult presenting with nephrotic syndrome for the first time, MN should be at the top of your differential. In a young woman, think lupus-associated (Class V) membranous nephropathy.
3. Risk Factors
- Genetic susceptibility:
- PLA2R gene variants — polymorphisms in the PLA2R1 gene increase susceptibility.
- HLA-DQA1 variants — strong GWAS association, especially HLA-DQA105:01 in European populations and HLA-DRB115:01 in East Asian populations [3].
- These genetic loci converge on the same pathogenic pathway: autoimmunity against podocyte antigens.
- Age > 40, male sex.
- Environmental triggers (largely unknown, possibly molecular mimicry or exposures that break tolerance).
- Infections: HBV, HCV, HIV, syphilis, malaria [3][4]
- HBV-associated MN is primarily seen in children and usually in the immune-tolerant phase [3] — highly relevant in Hong Kong given HBV endemicity.
- Autoimmune: SLE (Class V lupus nephritis), RA [4]
- Malignancy: especially adenocarcinoma (lung, prostate, breast, bladder, GIT), CLL, paraproteinaemia [3]
- Rule of thumb: In any patient > 60 years with MN, you must actively screen for underlying malignancy. Tumour antigens can be planted in the GBM, triggering an immune response.
- Drugs: NSAIDs, penicillamine, gold, mercury, anti-TNF agents, captopril, probenecid [3][5][6]
- Others: HSCT/GVHD, IgG4-related disease [3]
Hong Kong Focus
Given the historically high prevalence of HBV in Hong Kong (though declining with universal vaccination since 1988), HBV-associated membranous nephropathy is a critical secondary cause to consider. Always check HBsAg, anti-HBs, anti-HBc, and HBV DNA in a patient with newly diagnosed MN. Similarly, the local prevalence of lung and GI malignancies mandates thorough malignancy screening in elderly patients with MN.
4. Anatomy and Function of the Glomerular Filtration Barrier
Understanding MN requires understanding the normal glomerular capillary wall, because MN is fundamentally a disease of this barrier.
Capillary Lumen
│
▼
┌──────────────────────────────┐
│ 1. Fenestrated Endothelium │ ← 70-100 nm pores, charge barrier
├──────────────────────────────┤
│ 2. Glomerular Basement │ ← Type IV collagen, laminin, heparan
│ Membrane (GBM) │ sulfate proteoglycans (negative charge)
├──────────────────────────────┤
│ 3. Visceral Epithelial │ ← Podocytes with interdigitating foot
│ Cells (Podocytes) │ processes connected by slit diaphragms
└──────────────────────────────┘
│
▼
Bowman's Space (→ urine)- Fenestrated endothelium: Has pores (~70 nm) that allow passage of water and small solutes but restrict large proteins. The glycocalyx coating provides a negative charge barrier.
- GBM: A meshwork of type IV collagen, laminin, nidogen, and heparan sulfate proteoglycans. The negative charges repel albumin (which is also negatively charged at physiological pH). This is the size and charge barrier.
- Podocytes: Terminally differentiated epithelial cells with foot processes that interdigitate to form slit diaphragms (containing nephrin, podocin, CD2AP). The slit diaphragm is the final size-selective barrier (~4 nm gaps).
In MN, immune complexes deposit on the subepithelial side (between the GBM and the podocyte foot processes). This is the outer aspect of the GBM, directly beneath the podocytes. The complement activation (especially C5b-9 membrane attack complex) damages the podocytes → foot process effacement → loss of the slit diaphragm → massive proteinuria.
Critically, because the deposits are subepithelial (not subendothelial), they do not activate the mesangial cells or endothelium significantly → no inflammation, no cellular proliferation → bland sediment (no red cells, no casts).
Subepithelial vs Subendothelial — Why It Matters
- Subepithelial deposits (MN): Hidden from circulating inflammatory cells by the GBM → no recruitment of neutrophils/monocytes → non-proliferative, bland sediment, nephrotic presentation.
- Subendothelial deposits (e.g. lupus class III/IV, MPGN): Exposed to the circulation → activate complement in situ → recruit inflammatory cells → proliferative, active sediment, nephritic presentation.
This is the single most important concept explaining why MN is a nephrotic disease while many other glomerulonephritides are nephritic.
5. Etiology and Pathophysiology
5A. Primary (Idiopathic) Membranous Nephropathy (~75%)
~70% of primary MN is associated with IgG4-type anti-phospholipase A2 receptor (anti-PLA2R) antibodies. [3]
What is PLA2R?
- Phospholipase A2 Receptor (PLA2R) is a transmembrane glycoprotein normally expressed on the surface of podocytes.
- Its exact physiological role is not fully characterised, but it belongs to the mannose receptor family.
Pathogenic Mechanism:
- Autoantibody formation: For unknown reasons (likely a combination of genetic susceptibility + environmental trigger), the immune system generates IgG4 autoantibodies against PLA2R.
- In situ immune complex formation: Anti-PLA2R IgG4 binds to PLA2R on the podocyte surface → forms immune complexes directly at the subepithelial location (this is called "in situ" immune complex formation, as opposed to circulating immune complex deposition).
- Complement activation: The IgG4 subclass itself is a poor complement activator, but through lectin pathway activation and possibly via co-deposited IgG1/IgG3, the C5b-9 membrane attack complex (MAC) is assembled on the podocyte surface.
- Podocyte injury: MAC insertion into the podocyte membrane → sublytic injury → cytoskeletal disruption → foot process effacement and loss of slit diaphragm integrity → massive proteinuria.
- GBM response: Injured podocytes secrete excessive extracellular matrix → GBM thickens and forms "spikes" of new basement membrane material around the deposits.
Anti-PLA2R: first reported in NEJM, ~70% of cases of idiopathic MN are positive. 0% of anti-PLA2R are found in secondary MN, other diseases, and normal patients → very specific for primary MN. ROC curve 0.96. [7]
Other implicated antibodies include IgG4 vs THSD7A (~3%) [3]
- THSD7A = Thrombospondin type 1 domain-containing 7A, another podocyte-expressed protein.
- Mechanism similar to anti-PLA2R — in situ immune complex formation.
- Clinical pearl: THSD7A-positive MN has been associated with a higher rate of concurrent malignancy, so extra vigilance in cancer screening is warranted.
- Neutral endopeptidase (NEP) deficiency in the mother → maternal antibodies against fetal NEP cross the placenta → neonatal MN [3]. Extremely rare.
- PLA2R gene and HLA-DQA1 variants [3]
- GWAS studies show that the combination of PLA2R1 risk allele + HLA-DQA1 risk allele synergistically increases risk of primary MN.
In secondary MN, the immune complexes arise from:
- Planted antigens (e.g. tumour antigens, viral antigens like HBe antigen from HBV deposited in the GBM)
- Circulating immune complexes (e.g. DNA-anti-DNA complexes in SLE → can deposit subepithelially in Class V lupus nephritis)
- Drug-induced autoimmunity (e.g. penicillamine disrupting immune tolerance → autoantibody production against podocyte antigens)
Causes of Secondary MN (Detailed Table)
| Category | Specific Causes | Notes / HK Relevance |
|---|---|---|
| Autoimmune | SLE (Class V lupus nephritis) | 10–20% of lupus nephritis; can be renal-limited. Should be considered in ANY young woman with apparent idiopathic MN [3]. Characterised by full-house IF staining (IgG, IgA, IgM, C3, C1q). |
| RA | Rare, more often drug-related (gold, penicillamine) | |
| IgG4-related disease | Increasingly recognised; check serum IgG4 levels | |
| Infections | HBV | Primarily in children, usually in immune-tolerant phase [3]. Highly relevant in HK. Deposits contain HBeAg/HBsAg. |
| HCV | Less common, association unclear [3]. More commonly causes MPGN. | |
| HIV, syphilis, malaria | Consider in endemic settings | |
| Malignancy | Adenocarcinoma (lung, prostate, breast, bladder, GIT), CLL, paraproteinaemia | Screen in patients > 60 years or atypical presentations [3] |
| Drugs | Gold salts, D-penicillamine [5] | Classic associations. Gold salts rarely used now. |
| NSAIDs [5][6] | Also cause MCD and AIN — NSAIDs are versatile kidney offenders | |
| Captopril, probenecid, mercury, anti-TNF agents [3][4] | ||
| Transplant | HSCT / GVHD [3] | De novo or recurrent MN post-transplant |
HBV → polyarteritis nodosa + membranous nephropathy. HCV → cryoglobulinaemic vasculitis + MPGN. [8]
Primary vs Secondary MN — Clinical Clues
Always search for secondary causes before labelling MN as "primary":
- Age < 40, female: Think SLE → check ANA, anti-dsDNA, complement C3/C4.
- Risk factors for HBV/HCV: Think viral → check HBsAg, anti-HCV, ± HBV DNA.
- Age > 60: Think malignancy → thorough cancer screening (CXR, CT chest/abdomen/pelvis, stool occult blood, age-appropriate screening).
- Drug history: NSAIDs, penicillamine, gold, captopril.
- If anti-PLA2R is positive, it strongly supports primary MN. If anti-PLA2R is negative, the probability of secondary MN rises and biopsy + exhaustive workup is critical.
6. Classification
| Primary (Idiopathic) | Secondary | |
|---|---|---|
| Proportion | ~75% | ~25% |
| Anti-PLA2R | Positive ~70% | Negative (0%) |
| IF pattern | Granular IgG4 + C3 | Full-house (lupus), IgG subclass heterogeneity |
| Treatment | Immunosuppression | Treat underlying cause |
This staging describes the evolution of subepithelial deposits and GBM response over time:
| Stage | EM Appearance | What's Happening |
|---|---|---|
| Stage I | Scattered small subepithelial electron-dense deposits (EDDs) without any podocyte effacement | Early — deposits just arrived, GBM hasn't responded yet. GBM appears normal thickness on LM. |
| Stage II | Diffuse spiking of GBM to "surround" EDDs with diffuse podocyte effacement | GBM starts laying down new material between deposits ("spikes" visible on silver stain). This is the classic "spike and dome" pattern. |
| Stage III | GBM surrounds EDDs | Deposits are now incorporated/engulfed within the thickened GBM. The GBM looks markedly thickened. |
| Stage IV | Deposits resorbed, leaving irregular GBM thickening | Late "burnt out" stage. Deposits dissolve, leaving behind a scarred, irregularly thickened GBM. May or may not recover depending on irreversible podocyte loss. |
High Yield: Stage I may be missed on LM (GBM appears normal) and can only be diagnosed on EM. The classic "spike and dome" pattern on silver stain is Stage II.
| Feature | MN Score |
|---|---|
| Proteinuria | +++ |
| Nephrotic syndrome | ++ |
| Nephritic features | – |
| Haematuria | ± |
| ARF | – |
| CRF | ++ |
This tells you: MN is a heavy proteinuria / nephrotic disease. It does not typically present with nephritic features (because no proliferation). However, it can progress to CRF over time.
7. Clinical Features
MN presents overwhelmingly as nephrotic syndrome (or heavy proteinuria that may be sub-nephrotic in early stages). The clinical features are therefore dominated by:
- Consequences of massive proteinuria
- Consequences of hypoalbuminaemia
- Associated complications of the nephrotic state
- Features of the underlying cause (if secondary)
| Symptom | Pathophysiological Basis |
|---|---|
| Frothy urine | High urinary protein concentration reduces surface tension → bubbles/foam do not dissipate. Often the first symptom noticed by the patient. |
| Gradual-onset peripheral oedema (legs, periorbital, sacral) | Massive proteinuria → hypoalbuminaemia → ↓ plasma oncotic pressure → fluid shifts from intravascular to interstitial space (Starling forces). In addition, underfill triggers RAAS activation → Na+ and water retention → further oedema. An alternative "overfill" hypothesis suggests primary renal Na+ retention contributes. |
| Weight gain | Fluid retention from oedema (can be several kg). Patients may not realise until oedema becomes clinically apparent. |
| Abdominal distension / discomfort | Ascites from low oncotic pressure. Also gut wall oedema causing nausea, poor appetite, malabsorption (frusemide may not absorb well orally due to gut wall oedema [4]). |
| Dyspnoea | Pleural effusions (transudative) from low oncotic pressure. Rarely, pulmonary oedema from fluid overload. |
| Fatigue / lethargy | Multifactorial: anaemia (urinary loss of transferrin and erythropoietin), hypothyroidism (urinary loss of thyroid-binding globulin), malnutrition, chronic disease. |
| Symptoms of DVT / PE | Leg swelling (unilateral > bilateral), pleuritic chest pain, haemoptysis, sudden dyspnoea. Hypercoagulability is common in nephrotic patients; risk seems to be highest in membranous nephropathy. [10] Due to urinary loss of antithrombin III, protein C, protein S + compensatory hepatic synthesis of prothrombotic factors (fibrinogen, factors V, VIII) + platelet hyperaggregability. |
| Flank pain | Renal vein thrombosis — classically associated with MN more than other nephrotic conditions. Presents with acute flank pain, haematuria, ↑ proteinuria, or may be insidious. |
| Recurrent infections | Urinary loss of IgG → impaired opsonisation. Loss of complement factor B and D → impaired alternative complement pathway. In children, this manifests as spontaneous bacterial peritonitis (SBP). |
Symptoms of Secondary Causes (Important to Ask About)
| Secondary Cause | Suggestive Symptoms |
|---|---|
| SLE | Malar rash, photosensitivity, oral ulcers, hair loss, arthralgia, Raynaud's |
| HBV/HCV | Jaundice, RUQ pain, risk factors (IVDU, blood transfusion, endemic region, perinatal transmission in HK) |
| Malignancy | Unintentional weight loss, night sweats, change in bowel habit, haemoptysis, bone pain, new lump |
| Drug exposure | Detailed drug history: NSAIDs, penicillamine, gold, captopril, anti-TNF |
| Syphilis | Genital ulcers, rash, sexual history |
| IgG4-RD | Salivary/lacrimal gland swelling, pancreatitis, retroperitoneal fibrosis |
| Sign | Pathophysiological Basis |
|---|---|
| Pitting oedema (periorbital in morning, gravitational in legs by evening) | Interstitial fluid accumulation from ↓ oncotic pressure. Periorbital oedema is characteristic of nephrotic syndrome because periorbital tissue has low tissue pressure. |
| Anasarca (severe generalised oedema) | Severe hypoalbuminaemia (albumin typically < 20 g/L) → generalised third-spacing. |
| Ascites (shifting dullness, fluid thrill) | Transudative ascites from ↓ oncotic pressure + secondary hyperaldosteronism. |
| Pleural effusion (stony dull percussion, ↓ breath sounds, ↓ vocal resonance) | Same mechanism as ascites. Usually bilateral; if unilateral, more common on the right (anatomical reasons — right hemidiaphragm has more lymphatic drainage). |
| Xanthelasma / tendon xanthomata (in chronic nephrotic syndrome) | Hyperlipidaemia — hepatic response to ↓ oncotic pressure → liver upregulates synthesis of lipoproteins (VLDL, LDL) as part of a generalised increase in protein synthesis attempting to compensate for albumin loss. Decreased LPL activity and LCAT deficiency also contribute. |
| Leuconychia (white nails / Muehrcke's lines) | Hypoalbuminaemia → reduced protein in nail bed vasculature → white bands. |
| Normal or slightly elevated blood pressure | Unlike nephritic syndrome (where BP is markedly elevated due to salt/water retention from reduced GFR), MN usually presents with normal or mildly elevated BP. However, as disease progresses and GFR falls, hypertension develops. |
| No signs of active inflammation (no fever, no haematuria — "bland sediment") | Subepithelial deposits do not trigger inflammatory cell recruitment → no proliferative changes → no dysmorphic RBCs, no RBC casts. |
Signs of Secondary Causes
| Secondary Cause | Signs to Look For |
|---|---|
| SLE | Malar rash, discoid rash, arthritis, alopecia, oral ulcers |
| HBV | Jaundice, hepatomegaly, spider naevi, palmar erythema, polyarteritis nodosa (livedo reticularis, mononeuritis multiplex) |
| Malignancy | Cachexia, lymphadenopathy, hepatomegaly, mass on examination |
| Drugs | Withdrawal of offending drug → clinical improvement supports diagnosis |
Prognosis of primary MN: 1/3 spontaneous remission, 1/3 remain nephrotic (persistent proteinuria), 1/3 progress to ESRD [4]
This is the classic teaching and still broadly holds. It means:
- One-third of patients will spontaneously remit (especially those with lower-grade proteinuria and negative or low anti-PLA2R titres).
- One-third will have persistent nephrotic-range proteinuria but relatively preserved renal function for years.
- One-third will progressively lose renal function and reach ESRD over 10–15 years.
This natural history is the reason we don't immediately immunosuppress everyone — we observe first (6 months of conservative/supportive therapy) unless features suggest high risk of progression.
From the Nephrology Data Interpretation table:
| Proteinuria | Nephrotic | Nephritic | Haematuria | ARF | CRF | |
|---|---|---|---|---|---|---|
| Membranous GN | +++ | ++ | – | ± | – | ++ |
This confirms: heavy proteinuria, nephrotic syndrome, no nephritic features, occasional mild haematuria, no acute renal failure (usually), but CRF in the long run.
Clinical Features — What Makes MN Stand Out
- Insidious onset nephrotic syndrome in a middle-aged or elderly adult — proteinuria is often discovered incidentally.
- Bland urinary sediment — no active sediment (differentiates from IgAN, lupus nephritis, PSGN which have haematuria/casts).
- Highest risk of thromboembolic complications among all nephrotic syndromes — always think DVT, PE, or renal vein thrombosis.
- Rule of thirds for prognosis — not all patients need immunosuppression.
- Anti-PLA2R positivity can clinch the diagnosis of primary MN, potentially avoiding renal biopsy.
For completeness of clinical picture (formal diagnostic workup will be covered in the next section):
Nephrotic syndrome evaluation investigations: Full blood counts, renal biochemistry, urine protein quantification, fasting glucose, immune markers, Ig pattern, HBsAg, anti-HCV, anti-HIV, anti-PLA2R, tumour screening (CXR, stool OB, other relevant markers). [7]
Membranous nephropathy positive for anti-PLA2R can be treated WITHOUT a kidney biopsy. [7]
High Yield: Anti-PLA2R is 0% positive in secondary MN, other diseases, and normal patients → very specific. ROC 0.96. [7] A positive anti-PLA2R in a patient with nephrotic syndrome effectively diagnoses primary MN. Some guidelines now permit initiation of immunosuppressive therapy without biopsy if anti-PLA2R is positive in an appropriate clinical context.
MN is one of three primary renal diseases known to recur in the transplanted kidney (along with IgA nephropathy and FSGS) [11] — because the antibodies (anti-PLA2R) are still produced by the recipient's immune system, so the new kidney also gets attacked.
High Yield Summary
-
Definition: MN = subepithelial immune deposits → GBM thickening ("spikes") → podocyte injury → nephrotic syndrome with bland sediment.
-
Epidemiology: Most common cause of adult nephrotic syndrome. Peak > 40 years, M > F. In HK, consider HBV-associated MN.
-
Primary (~75%): Anti-PLA2R (~70%) — IgG4 against podocyte PLA2R → in situ immune complex → C5b-9 MAC → podocyte damage. Anti-THSD7A (~3%).
-
Secondary (~25%): SLE (Class V), HBV (children, immune-tolerant phase), malignancy (adenocarcinoma in elderly), drugs (gold, penicillamine, NSAIDs, captopril).
-
Histology: LM = diffuse GBM thickening without hypercellularity. EM = subepithelial EDDs → "spike and dome" (Stage II). IF = granular IgG + C3 along GBM. Full-house staining = lupus.
-
Clinical: Insidious nephrotic syndrome (frothy urine, oedema, hypoalbuminaemia, hyperlipidaemia). Bland sediment. Highest thromboembolic risk of any nephrotic syndrome.
-
Anti-PLA2R: 70% sensitivity, near 100% specificity for primary MN. Can treat WITHOUT biopsy if positive. Titres correlate with disease activity.
-
Rule of thirds: 1/3 remit spontaneously, 1/3 remain nephrotic, 1/3 → ESRD.
-
Recurs post-transplant (immune-mediated — antibodies persist).
Active Recall - Membranous Nephropathy (Definition, Epidemiology, Etiology, Clinical Features)
[1] Lecture slides: Glomerular diseases.pdf (p55) [2] Lecture slides: GC 057. Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (p10) [3] Senior notes: Ryan Ho Urogenital.pdf (p82 — Section 3.4.5 Membranous Nephropathy) [4] Senior notes: Maksim Medicine Notes.pdf (p231–232 — Nephrology, GN with predominant nephrotic features) [5] Senior notes: Block A - Drugs and the Kidney.pdf (p7 — Drug induced glomerular diseases) [6] Lecture slides: GC 043. Drugs and the Kidney.pdf [7] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (p22–23 — Anti-PLA2R, Nephrotic syndrome evaluation) [8] Senior notes: Block A - Jaundice after raw oysters_ acute hepatitis.pdf (p12 — HBV extrahepatic manifestations) [9] Senior notes: Block A – Nephrology Data Interpretation.pdf (p17 — Clinical Presentation of GN table) [10] Senior notes: Ryan Ho Fundamentals.pdf (p366 — Thromboembolism in nephrotic syndrome) [11] Senior notes: Block A - Renal Replacement Therapies.pdf (p41 — Recurrence of primary disease post-transplant)
Differential Diagnosis of Membranous Nephropathy
When you encounter a patient with suspected membranous nephropathy, the differential diagnosis operates on two levels simultaneously:
- Level 1 — Is this actually MN, or is the nephrotic syndrome caused by a different glomerular disease? (i.e., differential diagnosis of the nephrotic presentation)
- Level 2 — If it IS MN histologically, is it primary or secondary? (i.e., differential diagnosis within MN itself to identify the underlying cause)
Both levels are critical. Level 1 determines whether you need a biopsy (or whether anti-PLA2R clinches the diagnosis). Level 2 determines whether you treat with immunosuppression (primary) or treat the underlying cause (secondary).
Level 1: Differential Diagnosis of Nephrotic Syndrome (The Clinical Presentation)
A patient presenting with heavy proteinuria, hypoalbuminaemia, oedema, and hyperlipidaemia could have any cause of nephrotic syndrome. The differential is stratified by whether the sediment is bland (non-proliferative) or active (proliferative), and by age [4][12].
Non-proliferative GN is characterised by no increase in cellularity in glomerulus and is associated with nephrotic syndrome. [12]
Proliferative GN is characterised by increase in cellularity in glomerulus and is associated with nephritic syndrome. [12]
| Bland Sediment (Non-proliferative → Nephrotic) | Active Sediment (Proliferative → Nephrotic possible) | |
|---|---|---|
| Primary | Minimal change disease (MCD), FSGS, Membranous nephropathy | MPGN, MCD variants (IgM nephropathy, C1q nephropathy) |
| Secondary | Diabetic nephropathy, Amyloidosis | Lupus nephritis, Cryoglobulinaemia |
| Age | Most Likely Nephrotic Causes | Key Distinguishing Points |
|---|---|---|
| < 15 years | MCD, FSGS | MCD overwhelmingly predominant (~80% of childhood nephrotic syndrome). Respond to steroids. If steroid-resistant → biopsy → may find FSGS or (rarely) membranous nephropathy [14]. |
| 15–40 years | MCD, FSGS, Membranous | Always consider lupus-associated MN (Class V) in young women. IgAN can occasionally present nephrotic. |
| > 40 years | MCD, Membranous, DM, Amyloidosis | MN becomes the most common primary cause. Must screen for malignancy (adenocarcinoma) and diabetes. |
The Major Differentials: How to Distinguish Them from MN
| Feature | MCD | MN |
|---|---|---|
| Age | Most common in children [4]; also seen in adults | Most common cause of nephrotic syndrome in adults (30%) [12][13] |
| Onset | Often abrupt, can follow URTI | Insidious |
| Proteinuria | Highly selective (mainly albumin) | Non-selective (all proteins lost) |
| Haematuria | Absent | Absent or minimal |
| Complement | Normal | Normal (in primary MN) |
| Anti-PLA2R | Negative | Positive (~70% in primary) |
| LM | Normal [4] | Diffuse GBM thickening |
| EM | Podocyte effacement only [4] | Subepithelial EDDs with spike and dome |
| IF | Negative [4] | Granular IgG + C3 |
| Steroid response | Excellent ( > 95% in children, 80% in adults) | Poor — steroids alone are NOT effective |
| Drug associations | NSAIDs, lithium, bisphosphonates [5] | Gold salts, D-penicillamine, NSAIDs, captopril [5] |
Why it matters: In adults, if you assume nephrotic syndrome = MCD and give steroids without further workup, you will miss MN (which requires different immunosuppression). In adults: immunological screen, renal biopsy (unless diagnosis obvious e.g. DM nephropathy, PLA2R+). [4]
NSAIDs — The Double Agent
NSAIDs can cause both minimal change disease AND secondary membranous nephropathy [5][6]. The mechanism differs: MCD from NSAIDs is thought to be T-cell mediated, while MN from NSAIDs involves autoantibody generation against podocyte antigens. NSAID-induced nephrotic syndrome may also co-exist with acute tubulointerstitial nephritis (presenting as nephrotic syndrome + AKI + eosinophilia) [6]. Always take a thorough drug history.
| Feature | FSGS | MN |
|---|---|---|
| Demographics | Young adults, African descent; also secondary (obesity, HIV, reflux) | Older adults, Caucasian > Asian |
| Proteinuria | Heavy but may be sub-nephrotic | Usually nephrotic-range |
| Haematuria | May be present (microscopic) | Absent or minimal |
| Hypertension | Common (more than MN) | Less common initially |
| Renal impairment | Can be present at diagnosis | Usually preserved initially |
| Anti-PLA2R | Negative | Positive in primary MN |
| LM | Segmental sclerosis in < 50% of glomeruli; sampling error possible — "you have not picked up the affected glomeruli → FSGS characterised by < 50%" [15] | Diffuse GBM thickening |
| IF | IgM, C3 in sclerotic segments (non-specific trapping) | Granular IgG + C3 |
| Drug associations | Lithium, bisphosphonates [5] | Gold, penicillamine, NSAIDs, captopril |
| Post-transplant | Recurs post-transplant (common and rapid) [11] | Recurs post-transplant (immune-mediated) [11] |
| HIV | HIV is associated with a collapsing form of FSGS [16] | HIV → rarely MN |
Key pitfall: On biopsy, if only a few glomeruli are sampled and the focal sclerosis is missed, FSGS can be misdiagnosed as MCD. This is why repeat biopsy is considered in steroid-resistant "MCD" [4][14].
| Feature | MPGN | MN |
|---|---|---|
| Presentation | Mixed nephrotic-nephritic (haematuria + proteinuria + ↓ complement) | Predominantly nephrotic, bland sediment |
| Complement | Hypocomplementaemia (↓ C3 ± ↓ C4) — complement activation by immune deposits [16] | Normal complement (in primary MN) |
| LM | GBM thickening + hypercellularity (mesangial + endothelial proliferation) — "tram-track" appearance [12] | GBM thickening without hypercellularity |
| EM | Subendothelial deposits (Type I) or intramembranous dense deposits (Type II) [12] | Subepithelial deposits |
| Associations | HBV/HCV, cryoglobulinaemia, SLE (Class IV), CLL/MM [12] | HBV, SLE (Class V), adenocarcinoma |
Why the confusion arises: Both have GBM thickening on LM. However, MPGN has hypercellularity (proliferative component) and subendothelial deposits, while MN has no hypercellularity and subepithelial deposits. Low complement in MPGN is a key clinical discriminator.
High Yield: A lecture slide MCQ asks: "What is the best diagnosis?" with options A. FSGS, B. MPGN, C. MCD, D. Membranous nephropathy, E. Lupus nephritis [1]. The answer depends on: bland sediment + diffuse GBM thickening + subepithelial deposits + granular IgG/C3 → MN.
| Feature | Diabetic Nephropathy | MN |
|---|---|---|
| Context | Long-standing diabetes (usually > 10 years), with retinopathy | No diabetes (or diabetes is coincidental) |
| Proteinuria | Progressive: microalbuminuria → macroalbuminuria → nephrotic | Often presents de novo with nephrotic-range proteinuria |
| Other diabetic complications | Retinopathy (almost always present by the time of nephropathy), neuropathy | Absent |
| Biopsy | Nodular glomerulosclerosis (Kimmelstiel–Wilson nodules), diffuse mesangial expansion | Diffuse GBM thickening, subepithelial deposits |
| Biopsy needed? | Usually NOT required if typical clinical picture (diabetes + retinopathy + progressive proteinuria + no haematuria) [4] | Anti-PLA2R+ may avoid biopsy; otherwise biopsy required |
Key principle: In a known diabetic with classic progressive proteinuria and retinopathy, you diagnose diabetic nephropathy clinically. Biopsy is reserved for atypical features (e.g. sudden nephrotic syndrome, haematuria, rapid GFR decline, no retinopathy, short diabetes duration).
| Feature | Amyloidosis | MN |
|---|---|---|
| Context | Older adult, often with paraproteinaemia (AL) or chronic inflammatory disease (AA) | Older adult, otherwise well |
| Extra-renal | Macroglossia, carpal tunnel, hepatomegaly, restrictive cardiomyopathy, purpura | No systemic features (in primary MN) |
| Labs | Monoclonal protein on serum/urine immunofixation, abnormal free light chain ratio (AL type) | Anti-PLA2R positive |
| Biopsy | Congo red stain positive (apple-green birefringence under polarised light) | IgG + C3 granular, subepithelial deposits |
This is a critically important differential because lupus Class V histologically mimics primary MN — both show subepithelial deposits and GBM thickening. The distinction is vital because treatment differs.
| Feature | Lupus Class V (Membranous) | Primary MN |
|---|---|---|
| Demographics | Young woman — should be considered in ANY young woman with apparent idiopathic MN [3] | Older male > 40 |
| Extra-renal features | Malar rash, arthralgia, serositis, cytopaenias, oral ulcers | None |
| Serology | ANA+, anti-dsDNA+, ↓ C3/C4 (complement consumption) | ANA–, anti-dsDNA–, normal complement |
| Anti-PLA2R | Negative | Positive (~70%) |
| IF | Full-house staining: IgG, IgA, IgM, C1q, C3 [3] — highly characteristic of lupus | IgG + C3 only (IgG4 dominant) |
| May co-exist with | Proliferative subtypes (Class III/IV) [3] → mixed Class III+V or IV+V | Pure membranous only |
Class V lupus nephritis: ~10–20% of lupus nephritis, can be renal-limited. [3]
Full-House Staining = Think Lupus
On IF, if you see staining for all five (IgG, IgA, IgM, C3, C1q), this is "full-house" and essentially pathognomonic for lupus nephritis, even if the patient has no obvious extra-renal lupus features. In a young woman with MN pattern + full-house IF → lupus Class V until proven otherwise.
| Condition | Key Distinguishing Feature |
|---|---|
| IgA Nephropathy | Usually nephritic (synpharyngitic haematuria), but can occasionally present nephrotic. ↑ Serum IgA. Mesangial IgA deposits on IF. |
| Fibrillary / Immunotactoid GN | Rare. EM shows organised fibrils (larger than amyloid fibrils). Congo red negative. |
| Light Chain Deposition Disease | Similar to amyloidosis but Congo red negative. Monoclonal light chains on IF (kappa predominant). |
| C3 Glomerulopathy | Dominant C3 staining on IF with minimal/no immunoglobulin. Low C3. |
Once MN is confirmed (by biopsy or by positive anti-PLA2R), you must systematically exclude secondary causes before accepting "primary/idiopathic" MN. This is because treating the underlying cause (e.g. stopping an offending drug, treating HBV, treating malignancy) can resolve the nephropathy without immunosuppression.
Secondary membranous nephropathy: infections (HBV, HCV), autoimmune conditions (SLE), drugs (gold salts, D-penicillamine), malignancy [5][8]
| Category | Specific Causes | How to Screen | Clinical Clues |
|---|---|---|---|
| Autoimmune | SLE (Class V) [3][12] | ANA, anti-dsDNA, C3/C4 | Young woman, rash, arthralgia |
| RA | RF, anti-CCP | Joint deformities; often drug-related (gold, penicillamine) | |
| MCTD [17] | Anti-U1 RNP | Raynaud, swollen fingers, myositis, characteristically NO severe renal involvement, may have membranous nephropathy [17] | |
| IgG4-related disease | Serum IgG4 | Multi-organ fibrosis, pancreatitis, orbital disease | |
| Infections | HBV [3][8] | HBsAg, HBeAg, HBV DNA | Primarily in children, usually immune-tolerant phase [3]; endemic in HK |
| HCV [3] | Anti-HCV, HCV RNA | More commonly MPGN; association with MN less clear | |
| HIV | Anti-HIV | More commonly collapsing FSGS | |
| Syphilis [3][16] | VDRL/RPR, TPHA | Congenital or secondary syphilis | |
| Malaria | Thick/thin films | Travel history | |
| Malignancy | Adenocarcinoma: lung, breast, colon, stomach, oesophagus, bladder, prostate [12][13] | CXR, CT thorax/abdomen/pelvis, stool occult blood, PSA, age-appropriate screening | Age > 60, weight loss, constitutional symptoms |
| CLL, paraproteinaemia [3][12] | CBC, serum/urine protein electrophoresis, free light chains | Lymphocytosis, anaemia, paraprotein band | |
| Drugs | Gold salts, D-penicillamine [5] | Drug history | Classic exam associations (rarely used now) |
| NSAIDs [5][6] | Drug history | May coexist with AIN | |
| Captopril [4] | Drug history | Other ACE inhibitors less associated | |
| Mercury [3][15] | Occupational/cosmetic history | Mercury toxicity and nephrotic syndrome → rare but still occur from time to time; face whitening creams [15] | |
| Anti-TNF agents [3] | Drug history | Rheumatology patients | |
| Probenecid [3] | Drug history | Gout patients | |
| Transplant | HSCT / GVHD [3] | Clinical context | De novo MN in allograft |
The Anti-PLA2R Shortcut
Anti-PLA2R: 70% of idiopathic MN positive; 0% in secondary MN, other diseases, and normal patients → very specific. ROC 0.96. [7]
- Anti-PLA2R positive → strongly favours primary MN. Still perform basic secondary screen (HBsAg, ANA, malignancy screen) but probability of secondary cause is very low.
- Anti-PLA2R negative → probability of secondary cause rises significantly → exhaustive workup mandatory (full autoimmune panel, viral serology, malignancy screening, drug review).
- Membranous nephropathy positive for anti-PLA2R can be treated WITHOUT a kidney biopsy. [7]
| Serology | Interpretation |
|---|---|
| Anti-PLA2R positive | Primary membranous nephropathy [7][14] |
| ↑ Serum IgA | IgA nephropathy |
| ANA + anti-dsDNA + ↓ C3/C4 | SLE / Lupus nephritis |
| ↓ C3 ± ↓ C4 (without ANA) | Hypocomplementaemia in MPGN, PSGN, cryoglobulinaemia [16] |
| ANCA | ANCA-associated vasculitis / pauci-immune RPGN [16] |
| Anti-GBM | Goodpasture disease [16] |
| ASO titre elevated | PSGN [16] |
| HBsAg / HBeAg positive | HBV-associated MN or MPGN |
| Anti-HCV positive | HCV-associated MPGN (rarely MN) |
| Monoclonal band on electrophoresis | Amyloidosis / light chain deposition / paraproteinaemia-associated MN |
| Anti-U1 RNP | MCTD [17] |
Patients with nephrotic syndrome have an 8 times higher risk of developing venous or arterial thrombosis compared to normal patients. [18]
Membranous nephropathy has the highest risk of thromboembolic complications among nephrotic syndromes. [10][15]
When a patient with known or suspected MN develops acute leg swelling, chest pain, or flank pain, the differential includes:
- DVT (most common thrombotic complication)
- Renal vein thrombosis (classically associated with MN — presents with flank pain, haematuria, ↑ proteinuria, ± AKI)
- Pulmonary embolism
- Arterial thrombosis (stroke, MI — less common but recognised)
Nephrotic syndrome can result in thrombosis BUT renal vein thrombosis can result in heavy proteinuria and nephrotic syndrome — chicken and egg. [18]
One-third (180 patients with nephrotic syndrome) had vascular thromboembolic events. Renal vein thrombosis, pulmonary embolism. Membranous nephropathy highest risk. [15]
Type II RPGN (granular staining, immune-complex mediated) can rarely complicate membranous nephropathy (reason unknown, but some may be ANCA-positive). [19]
If a patient with known MN develops rapidly rising creatinine, active urinary sediment (new RBC casts), and oliguria — think crescentic transformation. This is a medical emergency requiring urgent biopsy and aggressive immunosuppression.
AKI in nephrotic syndrome differential: hypovolaemia from over-diuresis, ATN, crescentic transformation (RPGN). [4]
High Yield Summary — Differential Diagnosis of MN
Level 1 (Is it MN or another cause of nephrotic syndrome?):
- MCD: Normal LM, podocyte effacement only on EM, IF negative, excellent steroid response.
- FSGS: Segmental sclerosis, steroid-resistant, sampling error possible.
- MPGN: GBM thickening WITH hypercellularity, hypocomplementaemia, subendothelial deposits.
- Diabetic nephropathy: Diabetes + retinopathy + progressive proteinuria. No biopsy usually needed.
- Amyloidosis: Congo red positive, paraproteinaemia, systemic features.
- Lupus Class V: Young woman, full-house IF staining, ↓ complement, anti-PLA2R negative.
Level 2 (Primary vs Secondary MN):
- Anti-PLA2R positive → strongly primary.
- Anti-PLA2R negative → exhaustive secondary screen: SLE, HBV/HCV, malignancy, drugs, syphilis.
- Key secondary causes: SLE (Class V), HBV, adenocarcinoma, gold/penicillamine/NSAIDs.
Critical discriminators:
- Anti-PLA2R (primary vs secondary)
- Complement levels (low in MPGN/lupus/PSGN; normal in MN)
- IF pattern (full-house = lupus; IgG+C3 only = primary MN)
- Deposit location on EM (subepithelial = MN; subendothelial = MPGN/lupus III-IV)
Active Recall - Differential Diagnosis of Membranous Nephropathy
References
[1] Lecture slides: Glomerular diseases.pdf (p54–55) [3] Senior notes: Ryan Ho Urogenital.pdf (p82 — Section 3.4.5 Membranous Nephropathy) [4] Senior notes: Maksim Medicine Notes.pdf (p231–232 — Nephrology, GN with predominant nephrotic features) [5] Senior notes: Block A - Drugs and the Kidney.pdf (p7 — Drug induced glomerular diseases) [6] Senior notes: Block A - Drugs and the Kidney.pdf (p14 — NSAID-induced nephrotic syndrome) [7] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (p22–23 — Anti-PLA2R) [8] Senior notes: Block A - Jaundice after raw oysters_ acute hepatitis.pdf (p12 — HBV extrahepatic manifestations) [10] Senior notes: Ryan Ho Fundamentals.pdf (p366 — Thromboembolism in nephrotic syndrome) [11] Senior notes: Block A - Renal Replacement Therapies.pdf (p41 — Recurrence of primary disease) [12] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p995–998 — Classification of GN, MPGN) [13] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1003–1017 — Membranous nephropathy) [14] Senior notes: Adrian Lui Pediatrics Notes.pdf (p313–315 — Classification GN, Serology markers) [15] Senior notes: Block A - Glomerular Diseases.pdf (p1 — Thromboembolic risk, mercury) [16] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p402–415 — Diagnosis serology) [17] Senior notes: Ryan Ho Rheumatology.pdf (p86 — MCTD) [18] Senior notes: Block A - Leg swelling and chest pain_ deep vein thrombosis; pulmonary embolism; Thrombophilia.pdf (p20) [19] Senior notes: Ryan Ho Fundamentals.pdf (p361 — RPGN classification)
Diagnostic Criteria, Algorithm, and Investigations for Membranous Nephropathy
Unlike many conditions (e.g. SLE with SLICC criteria, RA with ACR/EULAR criteria), membranous nephropathy does not have a single universally accepted set of diagnostic criteria with a point-scoring system. Instead, diagnosis relies on a combination of clinical, serological, and histopathological features. Think of it as a pattern-recognition exercise on three pillars:
| Pillar | What You Need |
|---|---|
| 1. Clinical | Nephrotic syndrome (or heavy proteinuria) with bland urinary sediment |
| 2. Serological | Anti-PLA2R antibody (positive in ~70% of primary MN) |
| 3. Histopathological | Renal biopsy showing characteristic LM, IF, and EM findings |
The key diagnostic question is: Do you always need a biopsy?
Membranous nephropathy positive for anti-PLA2R can be treated WITHOUT a kidney biopsy. [7]
This is a major shift in practice. The 2021 KDIGO guidelines and subsequent updates acknowledge that in the right clinical context (adult with nephrotic syndrome + positive serum anti-PLA2R + no clinical features suggesting secondary cause), a confident diagnosis of primary MN can be made serologically, and immunosuppressive therapy can be initiated without biopsy. However, biopsy remains the gold standard and is required when:
- Anti-PLA2R is negative (need histology to confirm MN and differentiate from other causes)
- Secondary cause is suspected (need IF pattern to look for full-house staining, etc.)
- Atypical clinical features (e.g. haematuria, rapid GFR decline, low complement)
- Uncertainty about diagnosis
2. Diagnostic Requirements — Summarised
All of the following:
- Clinical nephrotic syndrome or significant proteinuria ( > 3.5 g/day)
- Positive serum anti-PLA2R antibody
- No clinical or laboratory evidence of secondary causes (negative ANA, normal complement, negative HBsAg/anti-HCV, no malignancy on screening, no offending drugs)
→ This combination can establish the diagnosis without biopsy in many centres [7][4].
All of the following:
- Clinical nephrotic syndrome or significant proteinuria
- Renal biopsy showing:
- Systematic exclusion of secondary causes (or identification of a specific secondary cause)
When Can You Skip the Biopsy?
In adults: immunological screen, renal biopsy (unless diagnosis obvious e.g. DM nephropathy, PLA2R+). [4]
Two situations where biopsy may be unnecessary:
- Known diabetic with retinopathy + progressive proteinuria + no haematuria → clinical diagnosis of diabetic nephropathy.
- Anti-PLA2R positive adult with nephrotic syndrome + clean secondary screen → diagnosis of primary MN.
In all other scenarios, biopsy is essential.
4. Investigation Modalities — Systematic Breakdown
The workup for suspected MN follows a logical sequence: confirm nephrotic syndrome → characterise the sediment → serological testing → screen for secondary causes → biopsy (if needed) → assess complications.
| Investigation | What to Look For | Interpretation in MN |
|---|---|---|
| Urine dipstick | Protein, blood | Protein 3+, blood negative or trace — MN gives heavy proteinuria but typically no significant haematuria [9] |
| Urine microscopy | Dysmorphic RBCs, RBC casts, WBC casts, oval fat bodies | Bland sediment expected in MN. Heavy proteinuria + NO haematuria → non-proliferative glomerular disease (nephrotic pattern) [20]. May see oval fat bodies and fatty casts (lipiduria from hyperlipidaemia). Presence of dysmorphic RBCs/RBC casts → think proliferative GN, NOT typical MN. |
| 24-hour urine protein | Total protein excretion | Gold standard for quantification. Nephrotic range ≥ 3.5 g/day; normal < 0.15 g/day [9]. MN typically presents with nephrotic-range proteinuria. |
| Urine protein-to-creatinine ratio (uPCR) | Spot urine, alternative to 24h collection | Much more convenient for the patient [21]. In QMH (Queen Mary Hospital), uPCR is used instead of UACR [21]. uPCR > 350 mg/mmol approximates nephrotic-range proteinuria. |
| Urine albumin-to-creatinine ratio (UACR) | Spot urine | Especially for diabetic patients or CKD patients — major protein is albumin anyway [21]. More sensitive for early diabetic nephropathy. Can convert between uPCR and UACR using formulas. |
Proteinuria Quantification — Practical Pearl
Gold standard is 24-hour quantification → but very cumbersome, patient hates it, may fake it by adding water. Now only used for research/studies where accuracy is most important. Urine protein-to-creatinine ratio → alternative, done for the first pee in the morning → much more convenient for patient. [21]
For clinical practice, spot uPCR (or UACR) has largely replaced 24-hour collections. But know that 24h urine protein is still the definitive reference.
| Investigation | What to Look For | Interpretation in MN |
|---|---|---|
| Renal function test (RFT) | Na+, K+, Cl–, urea, creatinine, eGFR | Creatinine usually normal or mildly elevated at presentation (MN preserves GFR initially). When creatinine rises, GFR has already been reduced by at least 50% [22]. Progressive rise → concerning for CKD progression or superimposed AKI. |
| Serum albumin | Hypoalbuminaemia | Normal albumin: 34–54 g/L [22]. In MN, typically < 30 g/L (often < 25 g/L in severe cases). Severity of hypoalbuminaemia correlates with thromboembolic risk. |
| Lipid profile | Total cholesterol, LDL, triglycerides, HDL | Hyperlipidaemia — elevated total cholesterol and LDL. This is a compensatory hepatic response to hypoalbuminaemia (liver upregulates all protein synthesis including lipoproteins). |
| Full blood count (CBC) | Hb, MCV, WCC, platelets | Usually normal. May show mild normocytic normochromic anaemia (chronic disease, or urinary transferrin loss). CBC — eosinophilia may suggest drug-induced tubulointerstitial nephritis [9]. |
| Fasting glucose / HbA1c | Screen for diabetes | To exclude diabetic nephropathy as the cause of proteinuria [7]. |
| LFT | Serum protein, albumin | Supports assessment of synthetic liver function; excludes coexisting liver disease. |
4C. Serological and Immunological Investigations
This is where you confirm primary MN and exclude secondary causes systematically.
Anti-PLA2R: first reported in NEJM (Beck LH, et al. NEJM 2009). ~70% of cases of idiopathic MN were positive. 0% in secondary MN, other diseases, and normal patients → very specific. ROC 0.96. [7][23]
| Test | Sensitivity | Specificity | Clinical Utility |
|---|---|---|---|
| Serum anti-PLA2R (ELISA or IFA) | ~70% for primary MN | ~99–100% for primary MN | Positive → strongly supports primary MN. Can diagnose without biopsy. |
| Tissue PLA2R staining (on biopsy IF) | ~80% for primary MN | Very high | More sensitive than serum anti-PLA2R (antibody may be consumed in tissue). If serum is negative but tissue PLA2R staining is positive → still primary MN. |
Additional utility of anti-PLA2R beyond diagnosis:
- Disease activity monitoring: Titres correlate with proteinuria and disease activity. Rising titres predict relapse; falling titres predict remission (often preceding clinical improvement by weeks to months).
- Post-treatment monitoring: Immunological remission (anti-PLA2R becomes negative) often precedes clinical remission (proteinuria falls). This guides duration of immunosuppressive therapy.
- Post-transplant recurrence prediction: Persistent high titres pre-transplant predict recurrence in the graft [11].
- Second target antigen identified (~3% of primary MN).
- Check when anti-PLA2R is negative and biopsy confirms MN histology.
- Association with malignancy (especially in elderly) — if anti-THSD7A positive, intensify malignancy screening.
Name the investigations you could order when working up a case of potential nephrotic syndrome: Full blood counts, renal biochemistry, urine protein quantification, fasting glucose, immune markers, Ig pattern, HBsAg, anti-HCV, anti-HIV, anti-PLA2R, tumour screening: CXR, stool OB, other relevant markers. [7]
| Test | Target Condition | Expected Finding in Primary MN | Abnormal Finding → Suggests |
|---|---|---|---|
| ANA, anti-dsDNA [14] | SLE | Negative | Positive → lupus nephritis (Class V) |
| Complement C3, C4 levels [14] | ↓ in immune complex-mediated GN (i.e. PSGN, SLE, MPGN) | Normal | Low → lupus, MPGN, cryoglobulinaemia. This is a critical discriminator — complement is normal in primary MN. |
| HBsAg, anti-HCV, anti-HIV [14] | Infection-related GN (MPGN or membranous nephropathy) | Negative | Positive → infection-associated secondary MN |
| ANCA [14] | ANCA-related vasculitis | Negative | Positive → vasculitis (rare overlap with MN, consider crescentic transformation) |
| Anti-GBM [14] | Anti-GBM disease (Goodpasture) | Negative | Positive → anti-GBM disease |
| Cryoglobulins [14] | Cryoglobulinaemia | Negative | Positive → HCV-associated MPGN/cryoglobulinaemia |
| Syphilis serology (VDRL/RPR, TPHA) | Syphilis-associated MN | Negative | Positive → secondary MN (congenital or secondary syphilis) |
| Serum Ig pattern [14] | IgA nephropathy, myeloma | Normal | ↑ IgA → IgA nephropathy. Monoclonal band → myeloma/amyloidosis |
| Serum/urine protein electrophoresis + free light chains | Amyloidosis, LCDD, paraproteinaemia | Normal | Monoclonal band/abnormal free light chain ratio → amyloid/myeloma-associated MN |
| Tumour screening (CXR, FOBT, tumour markers) [14] | Adenocarcinoma-related nephropathy | Negative | Abnormal → malignancy-associated secondary MN |
The Complement Clue
Serum complement level is important in narrowing the differential:
- ↓ C3/C4 → immune complex-mediated GN: MPGN, PSGN, lupus, cryoglobulinaemia [24]
- Normal C3/C4 → non-IC mediated GN, or primary MN [24]
If a patient has biopsy-proven MN pattern BUT low complement → think lupus Class V (± concurrent Class III/IV) or cryoglobulinaemia, NOT primary MN.
| Investigation | Finding in MN | Why Perform It |
|---|---|---|
| Ultrasound kidneys [14] | Normal size. ↑ in early DMN, ↓ in chronic GN. Mild bilateral parenchymal disease may be noted [9]. No obstruction. | Rule out post-renal obstruction. Assess kidney size (small kidneys → chronic irreversible disease, contraindication to biopsy [25]). Normal-sized kidneys in MN suggest potentially reversible disease. |
| CXR [14] | Pulmonary oedema, pleural effusion, CHF — secondary to fluid retention | Assess fluid overload. Also part of malignancy screening (lung adenocarcinoma). |
| Doppler ultrasound of renal veins | Renal vein thrombosis (RVT) | If suspected clinically (flank pain, acute ↑ proteinuria, haematuria, AKI). RVT most common in MN [4]. |
| CT angiography | Renal vein or pulmonary thromboembolism | If Doppler inconclusive or PE suspected. |
| CT thorax/abdomen/pelvis | Malignancy screening | Especially in patients > 60 years or anti-PLA2R negative MN. Looking for adenocarcinoma (lung, GI, prostate, breast, bladder). |
Ultrasonography of the kidney: Normal size — NOT likely to be chronic kidney disease. Mild bilateral parenchymal disease. No obstruction — NOT likely to be uric stone-induced obstructive uropathy. [9]
4E. Renal Biopsy — The Definitive Investigation
Renal biopsy is still essential for definitive diagnosis of a number of renal diseases including glomerulonephritis — e.g. minimal change disease, FSGS, IgAN, membranous GN, membranoproliferative GN. [26]
- All adults with nephrotic syndrome as a general principle (unless DM nephropathy or PLA2R+ primary MN) [4]
- Anti-PLA2R negative patients (need histological confirmation)
- Atypical features (haematuria, rapid GFR decline, low complement)
- Suspected secondary cause requiring histological confirmation
- Children: steroid trial first (90% MCD); renal biopsy if atypical features or failed response to steroid [4]
- Uncorrectable bleeding diathesis
- Severe uncontrolled hypertension
- Solitary native kidney
- Small kidneys indicative of chronic irreversible disease (also technically difficult)
- Hydronephrosis
- Renal or perirenal infection
- Uncooperative patient
- Multiple bilateral cysts or renal tumour [25]
Every renal biopsy specimen is processed for three complementary examinations. Think of it as three different "lenses" looking at the same tissue:
| Modality | What It Shows | Findings in MN |
|---|---|---|
| Light Microscopy (LM) | Architectural changes, cellularity, fibrosis, sclerosis | Thickening of GBM and capillaries [13]. No significant hypercellularity (non-proliferative). On silver stain (Jones methenamine silver): spike-like protrusions of GBM matrix — these are projections of new basement membrane material between and around deposits. On PAS stain: thickened, rigid capillary walls. |
| Immunofluorescence (IF) | Nature and distribution of immune deposits | Granular deposits of immunoglobulins (IgG) and complement (C3) along GBM [13]. Diffuse, global, granular pattern along capillary walls. In primary MN: predominantly IgG4 subclass. In lupus MN: full-house staining (IgG, IgA, IgM, C1q, C3) [3]. |
| Electron Microscopy (EM) | Ultrastructural detail of deposits and podocytes | Subepithelial immunoglobulin-containing electron-dense deposits (EDDs) along GBM [13]. Subepithelial surfaces consist of podocytes [13]. Effacement of podocyte foot processes [13]. Staging (I–IV) based on deposit-GBM relationship. |
| Stage | EM Description | LM Appearance | Clinical Correlate |
|---|---|---|---|
| I | Scattered small subepithelial EDDs, no/minimal foot process effacement | May appear normal — can be missed on LM alone | Early disease; diagnosis may require EM |
| II | Diffuse EDDs with GBM "spikes" surrounding deposits; diffuse foot process effacement | Spike and dome on silver stain; GBM thickened | Classic active disease; maximum proteinuria |
| III | EDDs incorporated within thickened GBM | Markedly thickened, irregular GBM | Established disease; some deposits being resorbed |
| IV | Deposits largely resorbed; irregular GBM thickening with lucent areas | Irregularly thickened GBM, sclerotic changes | "Burnt out" stage; may or may not recover. Irreversible podocyte loss → CKD |
High Yield: Stage I MN can be missed on LM because the GBM appears normal. This is why EM is essential for diagnosis of early MN. The diagnosis cannot be reliably made on LM alone.
In addition to standard IF, most centres now perform tissue PLA2R staining on the biopsy specimen:
- Positive in ~80% of primary MN (more sensitive than serum anti-PLA2R, because antibody may be consumed locally)
- If serum anti-PLA2R is negative but tissue PLA2R is positive → still consistent with primary MN
- If both serum and tissue PLA2R are negative → higher suspicion for secondary cause or anti-THSD7A-associated MN
| Complication | Investigation | Key Finding |
|---|---|---|
| Thromboembolic events | Doppler US of lower limbs/renal veins, CT pulmonary angiography, D-dimer (often elevated baseline in nephrotic syndrome — low specificity) | Renal vein thrombosis: Doppler USG, CT angiography [4]. DVT/PE on CTPA. |
| Infection | Blood cultures, urine cultures, serum immunoglobulins | Low IgG from urinary losses → susceptibility to encapsulated organisms |
| AKI | Serial creatinine, urine output monitoring | AKI differential: hypovolaemia from over-diuresis, ATN, crescentic transformation (RPGN) [4] |
| Cardiovascular risk | Lipid profile, HbA1c, BP monitoring | Accelerated atherosclerosis from chronic hyperlipidaemia and proteinuria |
Secondary causes of membranous nephropathy: Infections (HBV, HCV, syphilis); Malignancies (CA lung, CA colon, Hodgkin lymphoma); Rheumatological (SLE, Sjogren syndrome, RA); Drugs (NSAIDs, contrast, allopurinol, β-lactams, fluoroquinolones, diuretics, PPI, phenytoin, gold). [9]
| Scenario | Anti-PLA2R | Complement | Biopsy IF | Interpretation |
|---|---|---|---|---|
| Middle-aged man, nephrotic, bland sediment | Positive | Normal | IgG4 + C3 granular | Primary MN — may treat without biopsy |
| Young woman, nephrotic, arthralgia | Negative | Low C3/C4 | Full-house (IgG, IgA, IgM, C1q, C3) | Lupus Class V MN |
| Child, HBsAg positive, nephrotic | Negative | Normal or low | IgG + C3 granular ± HBeAg deposits | HBV-associated secondary MN |
| 70-year-old, weight loss, nephrotic | Negative | Normal | IgG + C3 granular (non-IgG4 dominant) | Malignancy-associated secondary MN — search for occult cancer |
| NSAID user, nephrotic + AKI + eosinophilia | Negative | Normal | Variable | NSAID-induced nephropathy (MCD + AIN or MN) [6] |
| Nephrotic, anti-PLA2R negative, anti-THSD7A positive | Negative (PLA2R) | Normal | IgG + C3 | Primary MN (THSD7A variant) — intensify malignancy screening |
| Category | Tests |
|---|---|
| Confirm nephrotic syndrome | Urine dipstick, urine microscopy, spot uPCR (or 24h urine protein), serum albumin, lipid profile |
| Assess renal function | RFT (Na, K, urea, creatinine, eGFR), serial creatinine |
| Serological — primary MN | Anti-PLA2R (serum ELISA/IFA); ± anti-THSD7A if PLA2R negative |
| Serological — exclude secondary | ANA, anti-dsDNA, C3/C4, HBsAg, anti-HCV, anti-HIV, syphilis serology, serum Ig, serum/urine protein electrophoresis, free light chains, cryoglobulins |
| Malignancy screen | CXR, CT thorax/abdomen/pelvis, FOBT, PSA (men > 50), colonoscopy if indicated |
| Drug history | Review all medications (NSAIDs, gold, penicillamine, captopril, anti-TNF, probenecid, mercury/cosmetics) |
| Imaging | US kidneys (size, parenchyma, obstruction) |
| Biopsy | If anti-PLA2R negative, secondary cause unclear, atypical features, or histological confirmation needed. Process for LM + IF + EM + tissue PLA2R |
| Complications | Doppler US renal veins/lower limbs (if thrombosis suspected), CTPA (if PE suspected), serum Ig levels |
High Yield Summary — Diagnosis of MN
-
Anti-PLA2R is the single most important serological test. ~70% sensitive, near 100% specific for primary MN. ROC 0.96. [7] Positive result in the right clinical context can establish diagnosis without biopsy.
-
Complement levels are normal in primary MN. Low complement → think lupus, MPGN, cryoglobulinaemia.
-
Renal biopsy is the gold standard. Three modalities: LM (GBM thickening, spikes on silver stain), IF (granular IgG + C3), EM (subepithelial EDDs, spike and dome, podocyte effacement) [13].
-
Full-house IF staining = lupus until proven otherwise.
-
Every patient with MN needs systematic secondary cause screening: autoimmune (ANA, dsDNA, C3/C4), infection (HBV, HCV, HIV, syphilis), malignancy (especially > 60 years), drugs, paraproteinaemia.
-
Stage I MN may be missed on LM — EM is essential for early diagnosis.
-
Anti-PLA2R titres correlate with disease activity and can guide treatment response monitoring.
-
In QMH/HK: uPCR is used instead of UACR for proteinuria quantification in most glomerular diseases.
Active Recall - Diagnostic Criteria, Algorithm and Investigations for Membranous Nephropathy
References
[3] Senior notes: Ryan Ho Urogenital.pdf (p82 — Section 3.4.5 Membranous Nephropathy; p88 — Lupus nephritis diagnostic evaluation) [4] Senior notes: Maksim Medicine Notes.pdf (p231–232 — Nephrology, nephrotic syndrome evaluation and management) [5] Senior notes: Block A - Drugs and the Kidney.pdf (p7 — Drug-induced glomerular diseases) [6] Senior notes: Block A - Drugs and the Kidney.pdf (p14 — NSAID-induced nephrotic syndrome + AKI) [7] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (p22–23 — Anti-PLA2R, nephrotic evaluation) [8] Senior notes: Block A - Jaundice after raw oysters_ acute hepatitis.pdf (p12 — HBV extrahepatic manifestations) [9] Senior notes: Block A – Nephrology Data Interpretation.pdf (p7 — Secondary causes of MN, lab findings interpretation) [11] Senior notes: Block A - Renal Replacement Therapies.pdf (p41 — Recurrence of primary disease post-transplant) [13] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1003–1017 — Membranous nephropathy morphology) [14] Senior notes: Adrian Lui Pediatrics Notes.pdf (p314–315 — Investigations for glomerular disease, serology markers) [20] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p928 — Urinalysis interpretation) [21] Senior notes: Block A - Introduction to Renal Investigations (RFT, urine tests and US kidneys).pdf (p4 — uPCR, UACR, 24h urine) [22] Senior notes: Block A - Nephrology Interactive Tutorial.pdf (p3 — Normal creatinine values, AKI definition) [23] Lecture slides: GC 057. Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (p45 — Diagnostic value of anti-PLA2R) [24] Senior notes: Ryan Ho Fundamentals.pdf (p360 — Complement levels in differential diagnosis) [25] Senior notes: Ryan Ho Fundamentals.pdf (p367 — Renal biopsy indications and contraindications) [26] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (p4 — Renal biopsy for definitive diagnosis) [27] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (p770 — Renal biopsy contraindications)
Management Algorithm and Treatment Modalities for Membranous Nephropathy
The management of MN is unique among glomerular diseases because of the "rule of thirds" natural history:
Prognosis: 1/3 remit spontaneously, 1/3 remain nephrotic, 1/3 progress to ESRD. [4]
This means roughly one-third of patients will get better on their own without any immunosuppression. Exposing these patients to toxic immunosuppressive drugs (with their infection, malignancy, and metabolic side effects) would cause harm without benefit. The challenge is identifying who needs aggressive treatment and who can be safely observed.
The management therefore has two distinct layers:
- Supportive/non-immunosuppressive therapy — for ALL patients with MN
- Immunosuppressive (disease-specific) therapy — only for patients at high risk of progressive disease who fail to improve with supportive therapy alone
The second critical distinction is between primary and secondary MN:
- Primary MN → immunosuppression targeting autoantibody production
- Secondary MN → treat the underlying cause (HBV, malignancy, drug withdrawal, lupus)
3. Supportive (Non-Immunosuppressive) Therapy — For ALL Patients
These measures apply universally to every patient with MN, whether primary or secondary, and regardless of whether immunosuppression is planned.
Anti-proteinuric therapy by angiotensin inhibitor (ACEI/ARB): Indication — in ALL glomerulonephropathy. MoA: ↓ intraglomerular pressure → ↓ proteinuria, which is associated with ↓ rate of GFR decline. Goal: keep proteinuria < 1 g/day or UPCR < 0.5–1 g/g. [3][25]
| Aspect | Detail |
|---|---|
| Mechanism | ACEI/ARB dilate the efferent arteriole more than the afferent → ↓ intraglomerular hydrostatic pressure → ↓ protein filtration across the damaged GBM. Also: ↓ TGF-β → ↓ fibrosis; ↓ hepatic lipoprotein production by reducing albumin loss in urine [25]. |
| Target BP | < 125/80 mmHg [3] (or < 130/80 per 2021 KDIGO). Lower BP further reduces proteinuria. |
| Target proteinuria | < 1 g/day or UPCR < 0.5–1 g/g [3][25] |
| Titration | Start low, uptitrate to maximum tolerated dose. Combination ACEI + ARB is generally NOT recommended (↑ risk of hyperkalaemia and AKI without proven additional benefit in MN). |
| Monitoring | Check creatinine and K+ within 1–2 weeks of initiation. Acceptable: ↑ creatinine up to 30% from baseline (reflects haemodynamic effect). Discontinue if ↑ > 30% or significant hyperkalaemia. |
| Contraindications | Bilateral renal artery stenosis, pregnancy, severe hyperkalaemia, previous angioedema (ACEI). |
Why ACEI/ARB for ALL Glomerulopathies?
Even if you don't immunosuppress, reducing intraglomerular pressure is the single most important intervention for preserving long-term renal function. Think of it like this: a damaged filter under high pressure leaks more protein and sustains more damage. Lowering the pressure reduces the leak and slows the damage. ACEI/ARB for all glomerulopathies — ↓ glomerular pressure, ↓ rate of GFR decline. [4]
Note that protein restriction is NOT recommended due to heavy urinary protein loss → should have normal protein intake as ↑ albumin excretion is associated with poorer outcomes. [25] This is the opposite of what students sometimes assume — restricting protein in a patient who is already losing massive amounts makes nutritional depletion worse.
Anti-oedema: Low sodium diet + fluid restriction + diuretics. High dose frusemide ± thiazide/spironolactone. [4]
| Modality | Details | Mechanism / Rationale |
|---|---|---|
| Dietary sodium restriction | ~2 g/day [25] | Reduces Na+ retention → reduces oedema. Also enhances efficacy of ACEI/ARB and diuretics. |
| Loop diuretics (frusemide) | First-line diuretic. May need high doses (80–240 mg/day). Change to IV frusemide if gut wall oedema impairs oral absorption. [4] | Block Na-K-2Cl cotransporter in thick ascending limb → natriuresis. In nephrotic syndrome, oedematous gut wall may reduce oral bioavailability → IV route may be needed. |
| Thiazide diuretics | Add-on if loop alone insufficient | Block NCC in distal convoluted tubule. Synergistic with loop diuretics ("sequential nephron blockade"). |
| Spironolactone | Add to decrease the risk of hypokalaemia [28] and for additional natriuresis | Blocks aldosterone in collecting duct. Counteracts secondary hyperaldosteronism. Also has anti-fibrotic effects. |
| IV albumin | Only as adjunct to diuretics for diuretic-resistant oedema + oliguria/uraemia in absence of severe glomerular damage [25] | Temporarily raises plasma oncotic pressure → mobilises interstitial fluid → enhances diuretic response. Effect is transient (albumin is excreted renally within hours). |
| Fluid restriction | Generally not needed unless severe hyponatraemia. ~50% of maintenance can be considered but generally not needed. [28] |
Monitoring: I/O, vitals, BW daily (aim 1 kg/day loss), urine dipstick. [4]
Diuretic Pitfall
Frusemide — ONLY indicated in severe symptomatic oedema with normal intravascular status. May precipitate hypovolaemic shock, AKI and increased thrombosis risk in a patient with marked hypoalbuminaemia with intravascular volume depletion. [28]
Over-aggressive diuresis in a nephrotic patient → intravascular depletion (remember, fluid has shifted to the interstitium) → pre-renal AKI → worsens hypercoagulability → DVT/RVT/PE. Always assess volume status before increasing diuretics.
Statins: if hyperlipidaemia persists after treatment. [4]
Lipid-lowering drugs by statins (drug of choice). Should be considered if hyperlipidaemia persists after treatment of underlying disorder (by immunosuppressive Tx) and/or ACEI/ARB. [25]
| Detail | Explanation |
|---|---|
| Drug | Statins (e.g. atorvastatin, rosuvastatin) — first-line. |
| Rationale | Nephrotic hyperlipidaemia ↑ cardiovascular risk (accelerated atherosclerosis). Also: hyperlipidaemia may directly worsen glomerular injury (lipid-mediated toxicity to podocytes and mesangial cells). |
| When to start | If LDL remains elevated despite treating the nephrotic syndrome itself. ACEI/ARB can partially improve lipids by reducing proteinuria (less stimulus for hepatic lipoprotein overproduction). |
| Target | Per general CV risk guidelines (LDL < 2.6 mmol/L, or < 1.8 mmol/L if very high CV risk). |
DVT prophylaxis: compressive stockings ± anticoagulation if high risk. [4]
Anti-thrombotic therapy by anticoagulants and ↓ immobilisation. Indication: usually only if thromboembolic events occur. Prophylactic use: usually NOT indicated unless otherwise indicated (e.g. AF) or high risk + ↓ bleeding risk, e.g. membranous nephropathy, very low serum albumin. [25]
This is a nuanced area because MN carries the highest thromboembolic risk among nephrotic syndromes:
| Scenario | Approach | Rationale |
|---|---|---|
| No thrombotic event, low risk (albumin > 25 g/L) | Compression stockings, encourage mobilisation, avoid dehydration | Low absolute risk; anticoagulation carries bleeding risk |
| No thrombotic event, high risk (albumin < 20–25 g/L, especially in MN) | Consider prophylactic anticoagulation (warfarin or LMWH) | Membranous nephropathy + very low serum albumin = highest risk [25]. Serum albumin < 20 g/L roughly doubles VTE risk. |
| Documented DVT, PE, or RVT | LMWH/UFH → warfarin for minimum 6–12 months while still nephrotic [4] | Therapeutic anticoagulation. Continue as long as nephrotic state persists (ongoing prothrombotic drive). |
| RVT with AKI | Thrombolysis ± embolectomy [4] | Acute renal vein occlusion → acute kidney injury warrants more aggressive intervention. |
Anticoagulation in MN — High Yield
The 2021 KDIGO guidelines suggest prophylactic anticoagulation should be considered (not universally mandated) for primary MN patients with serum albumin < 20 g/L who have low bleeding risk. Some experts use a threshold of < 25 g/L. The decision is individualised. DOACs (e.g. rivaroxaban, apixaban) are increasingly used in practice but evidence is less robust than for warfarin in this specific setting.
Pneumococcal vaccinations: indicated for ALL as pneumococcal infection is common. [25]
| Measure | Rationale |
|---|---|
| Pneumococcal vaccine (PCV13 then PPSV23) | Urinary IgG loss → impaired opsonisation → susceptibility to encapsulated organisms (especially Streptococcus pneumoniae). |
| Avoid unnecessary immunosuppressant exposure | Only immunosuppress when genuinely indicated — balances infection risk. |
| Monitor for infection | Low threshold for investigation/treatment of infections. In children: watch for spontaneous bacterial peritonitis (SBP). |
| Intervention | For Whom | Goal |
|---|---|---|
| ACEI/ARB | ALL | BP < 125/80, proteinuria < 1 g/day |
| Salt restriction (~2 g/day) | ALL | Reduce oedema, enhance ACEI/ARB |
| Diuretics (frusemide ± thiazide ± spironolactone) | Symptomatic oedema | BW loss ~1 kg/day |
| Statins | Persistent hyperlipidaemia | LDL target |
| Anticoagulation (prophylactic) | MN + albumin < 20–25 g/L + low bleeding risk | Prevent VTE |
| Pneumococcal vaccine | ALL | Prevent pneumococcal infection |
After initiating supportive therapy, primary MN patients are observed for 3–6 months (KDIGO 2021 recommends at least 3 months; some extend to 6 months if disease is stable). During this period:
- Monitor proteinuria (uPCR or 24h urine) every 1–3 months
- Monitor renal function (creatinine, eGFR) every 1–3 months
- Monitor anti-PLA2R titres (if initially positive) every 3–6 months
Risk factors for progressive idiopathic MN: Clinical — > 50 years onset, male, nephrotic proteinuria, ↑ serum Cr at onset. Histologic — ↑ glomerular scarring (segmental sclerosis), ↑ tubulointerstitial disease. [3]
| Risk Category | Features | Action |
|---|---|---|
| Low risk | Proteinuria declining, anti-PLA2R falling/negative, eGFR stable | Continue supportive therapy. Many will achieve spontaneous remission. |
| Moderate risk | Persistent nephrotic-range proteinuria but stable eGFR | Extended observation up to 6–12 months; some will still remit. |
| High risk | Persistent nephrotic syndrome > 6 months despite supportive Rx, OR declining eGFR, OR life-threatening complications (massive oedema, thromboembolic events), OR very high anti-PLA2R titre | Immunosuppressive therapy indicated |
5. Immunosuppressive Therapy — For High-Risk Primary MN
Immunosuppressive therapy: only in patients with poor prognostic factors. [3]
Per KDIGO 2021 (updated from 2012), immunosuppression is indicated when:
- Nephrotic syndrome persists ≥ 3–6 months despite optimal supportive therapy, AND at least one of:
- Proteinuria > 4 g/day (some use > 3.5 g/day) and remains unchanged or ↑ over observation
- eGFR declining
- Life-threatening nephrotic complications (severe oedema, thromboembolic events)
- Serum albumin persistently < 20 g/L
- OR at very high risk from the outset (serum creatinine rising at presentation, very high anti-PLA2R titres)
Do NOT immunosuppress if:
- Patient is improving on supportive therapy
- Secondary MN (treat underlying cause instead — unless it's lupus Class V, which has its own IS protocol)
- Anti-PLA2R titres are already declining (immunological remission preceding clinical remission)
5B. First-Line Immunosuppressive Regimens
The 2021 KDIGO guideline marks a paradigm shift: Rituximab is now recommended as first-line, displacing the traditional cyclophosphamide-steroid regimen. However, the older regimens remain valid and widely used, and are still featured prominently in exam material.
| Aspect | Detail |
|---|---|
| Drug name | Rituximab — "Ritux" = derived from "chimeric" monoclonal antibody; anti-CD20 |
| Mechanism | Chimeric anti-CD20 monoclonal antibody → depletes B lymphocytes (CD20+ cells) → ↓ autoantibody production (including anti-PLA2R) → ↓ immune complex formation → ↓ podocyte injury |
| Regimen | Typically 1 g IV on days 1 and 15 (or 375 mg/m² × 4 weekly doses). Some protocols use a "treat-to-target" approach based on anti-PLA2R titres. |
| Advantages | Less toxic than cyclophosphamide (no gonadal toxicity, no bladder toxicity). Can be guided by anti-PLA2R monitoring. Generally well-tolerated. |
| Response | ~60–70% achieve complete or partial remission within 12–24 months. Immunological remission (anti-PLA2R becomes negative) often precedes proteinuria reduction by months. |
| Side effects | Infusion reactions (pre-medicate with hydrocortisone + antihistamine + paracetamol), ↑ infection risk (especially reactivation of HBV — screen before starting!), rare progressive multifocal leukoencephalopathy (PML), late-onset neutropaenia. |
| Contraindications | Active severe infection, HBV carrier without antiviral cover, severe immunodeficiency, hypersensitivity. |
| Monitoring | Anti-PLA2R titres, CD19/CD20 cell counts (to confirm B-cell depletion), proteinuria, creatinine, immunoglobulin levels. |
High Yield (2021+ Update): The MENTOR trial (2019) and RI-CYCLO trial (2021) demonstrated that rituximab is non-inferior (and in some analyses superior) to cyclosporine and comparable to cyclophosphamide-steroid regimens, with a better safety profile. KDIGO 2021 now lists rituximab as the preferred first-line agent.
Treatment: Steroids + Cyclophosphamide/Cyclosporine/MMF/Chlorambucil. [13]
| Aspect | Detail |
|---|---|
| Regimen | Alternating monthly cycles over 6 months: Month 1, 3, 5: IV methylprednisolone 1 g/day × 3 days → oral prednisolone 0.5 mg/kg/day for remainder of month. Month 2, 4, 6: oral cyclophosphamide 2–2.5 mg/kg/day. |
| Mechanism | Steroids: broad immunosuppression (↓ T-cell activation, ↓ cytokine production, ↓ inflammatory gene transcription). Cyclophosphamide ("cyclo" = cycle, "phosphamide" = alkylating phosphoramide): alkylates DNA → kills rapidly dividing cells (especially lymphocytes) → ↓ autoantibody production. |
| Advantages | Extensively studied (Ponticelli trial, 1990s). Proven efficacy: ~70–80% remission rates. Lower relapse rate than CNI-based regimens. |
| Side effects | Cyclophosphamide: bone marrow suppression (leucopaenia), haemorrhagic cystitis (prevent with adequate hydration), gonadal toxicity (especially in males — discuss sperm banking), ↑ risk of malignancy (bladder cancer, lymphoma with cumulative dose), infection. Steroids: Cushingoid features, hyperglycaemia, osteoporosis, AVN, cataracts, psychosis, infection. |
| Contraindications | Active infection, pregnancy (teratogenic), leucopaenia (WCC < 3.0), previous excessive cumulative cyclophosphamide dose. |
| Monitoring | FBC weekly during cyclophosphamide (for leucopaenia), RFT, glucose, urinalysis for haematuria (cyclophosphamide bladder toxicity). |
Classic Exam Framing
Senior notes and older lecture material consistently list steroids + cyclophosphamide/cyclosporine/MMF/chlorambucil [13] as treatment options for MN. For in-house exams, know ALL of these agents. For current practice (2021+), rituximab is first-line per KDIGO. Chlorambucil (an older alkylating agent used in the original Ponticelli regimen) has largely been replaced by cyclophosphamide due to a more favourable toxicity profile.
| Aspect | Detail |
|---|---|
| Drugs | Cyclosporine A (CsA) or tacrolimus |
| Mechanism | Inhibit calcineurin → block IL-2 transcription → ↓ T-cell activation. Also: direct podocyte-stabilising effect (stabilise the cytoskeleton of podocyte foot processes via synaptopodin). |
| Regimen | Cyclosporine: 3.5–5 mg/kg/day in divided doses, ± low-dose prednisolone. Tacrolimus: 0.05–0.1 mg/kg/day. Treatment for 12–24 months with slow taper. |
| Advantages | Effective in CNI-sensitive patients (~70–80% remission). Direct podocyte-stabilising effect (↓ proteinuria independent of immunosuppression). Non-alkylating (no gonadal toxicity). |
| Disadvantages | High relapse rate when CNI is stopped (~40–50%). Nephrotoxicity (chronic CNI nephrotoxicity → arteriolar hyalinosis, interstitial fibrosis — this is the major concern, especially in a patient whose kidneys are already compromised). Hypertension, hyperkalaemia, tremor, gingival hypertrophy (CsA), new-onset diabetes (tacrolimus). |
| Role | Used as alternative first-line (if rituximab unavailable or contraindicated) or second-line after rituximab/cyclophosphamide failure. Also used in steroid-sparing strategies. Steroid-sparing agents: tacrolimus, steroid + mycophenolate. [15] |
| Monitoring | Trough drug levels (CsA: 100–175 ng/mL; tacrolimus: 5–8 ng/mL), RFT (creatinine must not rise > 30% from baseline — if it does, reduce dose), BP, glucose, lipids. |
| Aspect | Detail |
|---|---|
| Mechanism | Inhibits inosine monophosphate dehydrogenase (IMPDH) → blocks de novo purine synthesis in lymphocytes (lymphocytes are uniquely dependent on this pathway) → ↓ T- and B-cell proliferation. |
| Role in MN | NOT a standard first-line agent. Used as: steroid-sparing maintenance after induction, or as alternative agent in patients who cannot tolerate cyclophosphamide or rituximab. Steroid + mycophenolate [15] is an option in some protocols. |
| Side effects | GI upset (diarrhoea, nausea), bone marrow suppression, teratogenic (strict contraception required). |
| Regimen | Remission Rate | Relapse Rate | Major Toxicities | Current Role |
|---|---|---|---|---|
| Rituximab | 60–70% | 30–40% (retreatable) | Infusion reactions, infection, HBV reactivation | KDIGO 2021 first-line |
| Cyclophosphamide + steroids (modified Ponticelli) | 70–80% | 25–30% | Gonadal toxicity, leucopaenia, haemorrhagic cystitis, steroid SE | Traditional first-line; remains valid |
| CNI (CsA/tacrolimus) | 70–80% | 40–50% on withdrawal | Nephrotoxicity, HTN, DM (tacrolimus) | Alternative first-line or second-line |
| MMF ± steroids | 50–60% | Variable | GI, teratogenic | Adjunct/alternative |
If first-line immunosuppression fails (no response after 6–12 months):
- Switch regimen class (e.g. rituximab failure → cyclophosphamide + steroid, or vice versa)
- CNI-based regimen if not already tried
- Repeat rituximab with higher doses or more frequent dosing if anti-PLA2R still positive (may have had insufficient B-cell depletion)
- Experimental/emerging agents: Obinutuzumab (anti-CD20 next-generation), anti-complement therapies, BAFF/APRIL inhibitors — under investigation
The fundamental principle: immunosuppression for the MN itself is usually NOT needed if you treat the underlying cause successfully.
| Secondary Cause | Specific Treatment |
|---|---|
| Drug-induced (gold, penicillamine, NSAIDs, captopril) | Stop the offending drug. Proteinuria typically resolves over weeks to months. Supportive therapy (ACEI/ARB) while waiting. |
| HBV-associated | Antiviral therapy (entecavir or tenofovir). Spontaneous remission is uncommon; response to IFN was poor; many patients develop progressive renal failure: 29% CKD and 10% ESRD at 60 months. [29] Do NOT immunosuppress (can reactivate HBV → fulminant hepatitis). The nephropathy often improves when viral replication is suppressed. |
| HCV-associated | Direct-acting antivirals (DAAs) — sofosbuvir-based regimens. Treat the virus; nephropathy may improve. |
| Malignancy-associated | Treat the underlying malignancy (surgery, chemotherapy, etc.). MN may remit with successful cancer treatment. Recurrence of MN may signal tumour recurrence. |
| SLE Class V (membranous lupus nephritis) | HCQ for all SLE patients unless C/I [30]. For pure Class V: ACEI/ARB + immunosuppression if nephrotic (MMF or cyclosporine or rituximab per KDIGO lupus nephritis guidelines). For mixed Class V + III/IV: treat as proliferative lupus nephritis (induction with MMF or cyclophosphamide + steroids, then maintenance). |
HBV and MN — Critical Hong Kong Point
HBV-related membranous GN: 21 adult patients with biopsy-proven HBV-related MN; mean follow-up 60 months; spontaneous remission uncommon; response to IFN was poor; many patients develop progressive renal failure: 29% CKD and 10% ESRD at 60 months. [29]
This HKU study (Lai KN, NEJM 1991) demonstrated that HBV-associated MN has a poor natural history. Modern management uses nucleos(t)ide analogues (entecavir/tenofovir) rather than interferon. Never give immunosuppression without antiviral cover in HBV+ patients — risk of fulminant hepatic failure from viral reactivation.
Management of complications: [4]
| Complication | Pathophysiology | Management |
|---|---|---|
| Resistant oedema/anasarca | Poor drug/diet compliance; frusemide malabsorption due to gut wall oedema | Change to IV frusemide; add thiazide/potassium-sparing diuretics; IV albumin [4] |
| AKI | Hypovolaemia due to over-diuresis; ATN; crescentic transformation (RPGN) | Lower dose/withhold diuretics; rehydration. If RPGN: urgent biopsy + pulse methylprednisolone [4] |
| Renal vein thrombosis | Hypercoagulability by compensatory production of clotting factors by liver | Doppler USG, CT angiography. If AKI: thrombolysis ± embolectomy. If non-AKI: LMWH/UFH → warfarin for minimum 6–12 months while still nephrotic [4] |
| SBP (only in children) | Loss of Ig | Antibiotics [4] |
| CV disease | Long-term complications | CV risk modifications [4] (statins, BP control, smoking cessation, diabetes control) |
| Parameter | Frequency | Purpose |
|---|---|---|
| Proteinuria (uPCR or 24h) | Every 1–3 months | Track treatment response |
| Serum albumin | Every 1–3 months | Improving albumin = improving nephrosis |
| RFT (creatinine, eGFR) | Every 1–3 months | Detect progression or drug nephrotoxicity (esp. CNI) |
| Anti-PLA2R titres | Every 3–6 months | Immunological remission often precedes clinical remission. Falling titres = good sign. Persistently high titres = consider treatment escalation. |
| FBC | Weekly during cyclophosphamide; monthly otherwise | Detect leucopaenia, bone marrow suppression |
| CD19/CD20 counts | After rituximab | Confirm B-cell depletion |
| CNI trough levels | If on CsA/tacrolimus | Ensure therapeutic range, avoid toxicity |
| Immunoglobulin levels | Every 6–12 months on IS | Detect hypogammaglobulinaemia → infection risk |
| Body weight, BP, dipstick | Daily while inpatient; every visit as outpatient [4] | Track fluid status and proteinuria trend |
| Response | Definition |
|---|---|
| Complete remission | Proteinuria < 0.3 g/day [3] + normal serum albumin + stable eGFR |
| Partial remission | Proteinuria ≤ 2 g/day (or ≥ 50% reduction from baseline) + stable or improving eGFR |
| No response | Persistent nephrotic-range proteinuria or worsening eGFR despite ≥ 6 months of IS |
| Relapse | Return of nephrotic-range proteinuria after having achieved complete or partial remission |
Attainment of complete remission (proteinuria < 0.3 g/d) is associated with good long-term outcomes. [3]
10. Special Populations
- MN is uncommon in children (< 5% of childhood nephrotic syndrome).
- Membranous nephropathy in children: can be primary or secondary (associated with HBV, SLE, etc., which may precede by many years). Most remit spontaneously within 5 years. [14]
- Always screen for HBV (highly relevant in HK paediatric population).
- Supportive therapy + observation is the mainstay; immunosuppression only if progressive.
- MN is one of three primary renal diseases that recur in the transplanted kidney (along with IgA nephropathy and FSGS) — because the antibodies are still being produced. [11]
- Recurrence rate: ~30–40% for primary MN. Risk predicted by pre-transplant anti-PLA2R titres.
- Management of recurrence: rituximab (often effective given the anti-PLA2R mechanism).
High Yield Summary — Management of MN
-
ALL patients: Supportive therapy — ACEI/ARB (goal: proteinuria < 1 g/day, BP < 125/80), salt restriction, diuretics, statins, thromboprophylaxis (esp. if albumin < 20–25 g/L), pneumococcal vaccine. [3][4][25]
-
Primary MN — observe 3–6 months: 1/3 remit spontaneously. Risk-stratify using proteinuria trend, eGFR, anti-PLA2R titres.
-
High risk primary MN — immunosuppress:
- 1st line (KDIGO 2021): Rituximab (anti-CD20) — preferred due to better safety profile.
- Alternative 1st line: Modified Ponticelli — cyclophosphamide + steroids (alternating 6-month regimen).
- Alternative: CNI (cyclosporine/tacrolimus) — effective but high relapse rate and nephrotoxicity.
- Senior notes list: steroids, cyclophosphamide, cyclosporine, MMF, chlorambucil. [13]
-
Secondary MN: treat the underlying cause — stop drug, antivirals for HBV (NEVER immunosuppress without antiviral cover), treat malignancy, lupus protocol for Class V LN.
-
Complications: Resistant oedema → IV frusemide ± thiazide ± albumin. RVT → anticoagulation (thrombolysis if AKI). AKI → reduce diuretics, rehydrate, biopsy if RPGN.
-
Monitoring: Anti-PLA2R titres = best biomarker for disease activity and treatment response.
Active Recall - Management of Membranous Nephropathy
References
[3] Senior notes: Ryan Ho Urogenital.pdf (p76 — General approach to management; p83 — MN management, risk factors for progression; p88 — Lupus nephritis management) [4] Senior notes: Maksim Medicine Notes.pdf (p231–232 — General management of nephrotic syndrome, complications management) [5] Senior notes: Block A - Drugs and the Kidney.pdf (p7 — Drug-induced glomerular diseases) [7] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (p22–23 — Anti-PLA2R significance) [11] Senior notes: Block A - Renal Replacement Therapies.pdf (p41 — Recurrence post-transplant) [13] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1003–1017 — MN treatment options) [14] Senior notes: Adrian Lui Pediatrics Notes.pdf (p322 — MN in childhood, steroid-resistant NS) [15] Senior notes: Block A - Glomerular Diseases.pdf (p1 — Steroid-sparing agents, thromboembolic risk) [25] Senior notes: Ryan Ho Fundamentals.pdf (p368 — General approach to management of nephrotic syndrome) [28] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p435 — General management of nephrotic syndrome) [29] Lecture slides: Glomerular diseases.pdf (p68 — HBV-related membranous GN, Lai KN NEJM 1991) [30] Senior notes: Ryan Ho Rheumatology.pdf (p76 — SLE management)
Complications of Membranous Nephropathy
The complications of MN arise from two main sources: (1) the nephrotic state itself (consequences of massive proteinuria and hypoalbuminaemia), and (2) progression of the underlying renal disease (CKD and ESRD). Additionally, there are (3) complications of treatment (immunosuppressive drug toxicity). Understanding the "why" behind each complication is essential — they all trace back to what the kidney is losing or what the liver is overproducing in compensation.
1. Thromboembolic Complications
This is the single most important and clinically dangerous complication of MN, and the one that distinguishes MN from other nephrotic syndromes in terms of risk.
Hypercoagulability is common in nephrotic patients, with 1.5%/year risk of arterial thrombosis and 1.0%/year risk of venous thrombosis. Risk seems to be highest in membranous nephropathy. [10]
180 patients with nephrotic syndrome, one-third had vascular thromboembolic events — renal vein thrombosis, pulmonary embolism. Membranous nephropathy highest risk. [15]
The hypercoagulable state in nephrotic syndrome is multifactorial, but MN amplifies every component:
| Factor | Mechanism | Why Worse in MN |
|---|---|---|
| Urinary loss of anticoagulants | Antithrombin III (AT-III, MW ~58 kDa), protein C, protein S are lost in urine. AT-III is the most important — it is the major physiological inhibitor of thrombin and factor Xa. | MN has the most severe and prolonged proteinuria among nephrotic conditions → more anticoagulant loss. |
| Hepatic overproduction of procoagulants | Liver responds to ↓ oncotic pressure by ↑ synthesis of all proteins → including procoagulant factors (fibrinogen, factors V, VIII, vWF). | The compensatory hepatic response is proportional to the degree of hypoalbuminaemia — MN patients often have very low albumin for months to years. |
| Platelet abnormalities | Thrombocytosis (↑ thrombopoietin production), ↑ platelet aggregability, ↑ thromboxane A2 generation. | |
| Hyperviscosity / haemoconcentration | Intravascular volume depletion (fluid shifts to interstitium) → haemoconcentration. Hyperlipidaemia ↑ blood viscosity. | |
| Immobility | Patients with severe oedema/anasarca are often immobile. |
Mechanism unclear, probably due to a combination of ↑ hepatic clotting factor synthesis with ↑ urinary loss of anticoagulants and platelet abnormalities. [10]
| Event | Frequency | Presentation | Investigation |
|---|---|---|---|
| Deep vein thrombosis (DVT) | Most common venous event | Unilateral leg swelling, pain, warmth, distended veins | Doppler US of lower limbs |
| Renal vein thrombosis (RVT) | Classic and almost pathognomonic association with MN | Flank pain, haematuria, acute ↑ proteinuria, ± AKI. Can be insidious and asymptomatic. | Doppler USG, CT angiography [4] |
| Pulmonary embolism (PE) | May follow DVT or RVT propagation | Acute dyspnoea, pleuritic chest pain, tachycardia, haemoptysis | CT pulmonary angiography (CTPA) |
| Arterial thrombosis | Less common (stroke, MI, peripheral arterial occlusion) | Neurological deficits, chest pain, limb ischaemia | CT angiography, coronary angiography |
Pulmonary embolism: especially in lupus membranous nephropathy or antiphospholipid syndrome. [31]
Renal vein thrombosis: Hypercoagulability by compensatory production of clotting factors by liver. Doppler USG, CT angiography. If AKI: thrombolysis ± embolectomy. If non-AKI: LMWH/UFH → warfarin for minimum 6–12 months while still nephrotic. [4]
Anticoagulant prophylaxis should be considered in MN patients with albumin < 20–25 g/L and low bleeding risk [15][25].
Thromboembolic Complications — The Most Testable Complication of MN
MN = highest thromboembolic risk among nephrotic syndromes. The combination of AT-III loss + ↑ fibrinogen + platelet hyperactivity creates a "perfect storm" for thrombosis. Renal vein thrombosis is the classic association — always consider it when a MN patient develops sudden flank pain, haematuria, or unexplained AKI.
2. Infection
Altered humoral immunity due to defective complement-dependent opsonisation and loss of IgG and its subclasses. Altered cell-mediated immunity due to altered T-cell function and immunosuppressive treatment. Mechanical factors, e.g. oedema, ascites, may also play a role. [10]
| Mechanism | Explanation |
|---|---|
| Urinary IgG loss | IgG (MW ~150 kDa) is lost through the damaged glomerular filtration barrier → ↓ opsonisation capacity → poor bacterial clearance, especially of encapsulated organisms (S. pneumoniae, H. influenzae, E. coli). |
| Complement factor loss | Factors B and D of the alternative complement pathway (low MW) are lost in urine → impaired alternative pathway activation → ↓ innate immune defence. |
| Impaired T-cell function | Multifactorial: uraemic toxins, malnutrition, zinc/iron deficiency from urinary losses. |
| Immunosuppressive therapy | Rituximab → B-cell depletion → hypogammaglobulinaemia. Cyclophosphamide → leucopaenia. Steroids → suppress all immune limbs. CNIs → ↓ T-cell function. |
| Mechanical factors | Oedematous tissues have poor lymphatic drainage and act as culture medium. Ascites fluid provides a warm, protein-rich environment for bacterial growth. |
| Infection | Pathogen | Notes |
|---|---|---|
| Spontaneous bacterial peritonitis (SBP) | S. pneumoniae, E. coli, Klebsiella | SBP — only in children [4]. Occurs because ascitic fluid is a poor defence environment + ↓ IgG. In adults with MN, SBP is less common than in children with MCD. |
| Cellulitis | S. aureus, Streptococcus | Oedematous skin stretches, cracks, and has impaired perfusion → portal of entry for skin flora. |
| Pneumonia | S. pneumoniae | Especially if immunosuppressed. Pleural effusions further predispose. |
| Opportunistic infections (on immunosuppression) | Pneumocystis jirovecii, CMV, BK virus, TB | Particularly relevant for patients on cyclophosphamide or rituximab. PJP prophylaxis (cotrimoxazole) is standard during intense immunosuppression. |
Pneumococcal vaccinations: indicated for ALL nephrotic syndrome patients as pneumococcal infection is common. [25]
Additionally: influenza vaccination annually; HBV vaccination if non-immune (check anti-HBs); PJP prophylaxis during immunosuppression; monitor immunoglobulin levels and consider IVIG replacement if severely hypogammaglobulinaemic.
AKI in nephrotic syndrome — differential: hypovolaemia due to over-diuresis, ATN, crescentic transformation (RPGN). [4]
AKI can develop in MN through several mechanisms, each requiring different management:
| Cause | Mechanism | Clinical Clues | Management |
|---|---|---|---|
| Hypovolaemia from over-diuresis | Aggressive diuretic use → depletes already reduced intravascular volume (remember: fluid has shifted to interstitium) → pre-renal AKI | Postural hypotension, tachycardia, rising urea:creatinine ratio, concentrated urine (high osmolality, low Na) | Lower dose/withhold diuretics; rehydration [4] |
| Acute tubular necrosis (ATN) | Severe hypovolaemia → ischaemic tubular injury. Also: NSAID use, contrast nephropathy, aminoglycosides | Muddy brown granular casts on urine microscopy, non-oliguric or oliguric AKI | Supportive: IV fluids, stop nephrotoxins, ± dialysis if severe |
| Crescentic transformation (RPGN) | Can rarely complicate membranous nephropathy (reason unknown, but some may be ANCA-positive) [19] | Sudden onset of active sediment (dysmorphic RBCs, RBC casts), rapid creatinine rise, possible haemoptysis | Emergency: Urgent renal biopsy + pulse IV methylprednisolone ± cyclophosphamide/rituximab. Can give empirical pulse IV methylprednisolone before renal biopsy if indicated [19]. |
| Renal vein thrombosis | Acute venous outflow obstruction → congestion → ↓ GFR | Flank pain, haematuria, sudden ↑ proteinuria | If AKI: thrombolysis ± embolectomy [4] |
| Bilateral oedema compressing renal parenchyma | Severe anasarca → external compression (rare) | Severe generalised oedema | Diuresis, albumin infusion |
| Drug nephrotoxicity | CNI nephrotoxicity (cyclosporine/tacrolimus), NSAID-induced haemodynamic AKI | Rising creatinine while on CNI, ↑ trough drug levels | Reduce or stop offending agent |
In some patients, there may be collapsing FSGS and crescentic membranous nephropathy where the primary glomerular lesion is thought to play a major role. [10]
Crescentic Transformation — Rare but Devastating
If a patient with known MN suddenly develops active urinary sediment (new RBC casts), rapid creatinine rise, and oliguria — do not assume it is simply progression of MN. Think crescentic transformation (Type II RPGN with granular IF, or occasionally ANCA-positive). This is a medical emergency requiring urgent biopsy and aggressive treatment. Failure to recognise this leads to irreversible ESRD.
4. Resistant Oedema / Anasarca
Resistant oedema/anasarca: Poor drug/diet compliance; frusemide malabsorption due to gut wall oedema. Management: Change to IV frusemide; add thiazide/potassium-sparing diuretics; IV albumin. [4]
| Reason | Explanation |
|---|---|
| Poor compliance | Patient not adhering to sodium restriction or diuretic regimen. |
| Gut wall oedema | Severe hypoalbuminaemia → oedema of intestinal mucosa → reduced oral absorption of frusemide. The drug simply isn't getting into the bloodstream. |
| Diuretic resistance | Chronic loop diuretic use → compensatory Na+ reabsorption in distal nephron (post-diuretic NaCl retention, distal tubule hypertrophy). |
| Severe hypoalbuminaemia | Albumin < 15–20 g/L → oncotic pressure so low that fluid cannot be mobilised from the interstitium back into the vasculature, even with diuretics. |
- Verify compliance (dietary Na+ and medication)
- Switch to IV frusemide (bypass gut wall absorption issue)
- Add sequential nephron blockade: thiazide (e.g. metolazone) to block distal Na+ reabsorption that compensates for loop diuretic action
- Add spironolactone to counteract secondary hyperaldosteronism
- IV albumin infusion — temporarily ↑ oncotic pressure to mobilise interstitial fluid → enhances diuretic response. Only for diuretic-resistant patients with oliguria/uraemia in absence of severe glomerular damage [25]. Effect is transient (albumin rapidly excreted renally).
5. Hyperlipidaemia and Accelerated Cardiovascular Disease
CV disease — long-term complications. Management: CV risk modifications. [4]
Massive proteinuria → ↓ plasma oncotic pressure → liver attempts to compensate by upregulating all protein synthesis, including:
- VLDL and LDL → ↑ total cholesterol, ↑ LDL cholesterol, ↑ triglycerides
- Lipoprotein(a) → highly atherogenic
- ↓ HDL (urinary loss of HDL and apolipoproteins)
- ↓ lipoprotein lipase (LPL) activity and ↓ LCAT (lecithin-cholesterol acyltransferase) → impaired lipid clearance
This creates a highly atherogenic lipid profile that, when sustained over months to years (as in MN, which often has a prolonged course), accelerates:
- Coronary artery disease (MI, angina)
- Cerebrovascular disease (stroke)
- Peripheral arterial disease
- Statins — first-line (atorvastatin, rosuvastatin)
- ACEI/ARB — indirectly improves lipid profile by reducing proteinuria (less stimulus for hepatic overproduction) [25]
- Treat underlying MN — successful immunosuppression → remission of proteinuria → normalisation of lipids
- Lifestyle modifications — exercise, healthy diet, smoking cessation
6. Progression to Chronic Kidney Disease (CKD) and ESRD
Prognosis: 1/3 remit, 1/3 remain nephrotic, 1/3 progress to ESRD. [4]
The MN presentation table confirms: CRF ++ in Membranous GN. [9]
- Persistent proteinuria → tubular reabsorption of filtered proteins → tubular injury → tubulointerstitial inflammation and fibrosis
- Chronic podocyte injury → irreversible podocyte loss (podocytes are terminally differentiated and cannot regenerate) → segmental sclerosis → progressive nephron loss
- Glomerular scarring → reduced total filtering surface area → adaptive hyperfiltration of remaining nephrons → further damage (vicious cycle)
- Tubulointerstitial fibrosis → the final common pathway of all progressive renal disease
Risk factors for progressive idiopathic MN: Clinical — > 50 years onset, male, nephrotic proteinuria, ↑ serum Cr at onset. Histologic — ↑ glomerular scarring (segmental sclerosis), ↑ tubulointerstitial disease. [3]
Once MN progresses to CKD (stages 3–5), the patient develops the standard CKD complications:
Complications of chronic kidney disease: Fluid retention, metabolic acidosis, high blood pressure, normochromic normocytic anaemia, secondary hyperparathyroidism, bone disease. [32]
Full blood counts: NcNc anaemia — anaemia of chronic disease → normochromic normocytic. Renal biochemistry: ↑ serum urea, creatinine, PO₄, ↓ Ca ± ↑ K⁺ and metabolic acidosis. [7]
| CKD Complication | Mechanism | Management |
|---|---|---|
| Anaemia (NcNc) | ↓ EPO production by damaged kidneys; urinary loss of transferrin and EPO in nephrotic state | EPO-stimulating agents (ESA), IV iron supplementation |
| Mineral bone disease (CKD-MBD) | ↓ 1,25-(OH)₂ vitamin D production, ↑ phosphate retention → ↑ PTH → secondary hyperparathyroidism → renal osteodystrophy | Phosphate binders, active vitamin D (calcitriol), calcimimetics (cinacalcet) |
| Metabolic acidosis | ↓ H⁺ excretion, ↓ NH₄⁺ production | Oral sodium bicarbonate supplementation |
| Hyperkalaemia | ↓ K⁺ excretion + ACEI/ARB use + metabolic acidosis | Dietary restriction, loop diuretics, sodium polystyrene sulphonate/patiromer, reduce ACEI/ARB dose |
| Fluid overload / hypertension | ↓ Na⁺ and water excretion | Salt restriction, diuretics, antihypertensives |
| Uraemic symptoms | Accumulation of uraemic toxins (urea, creatinine, phosphate, etc.) | Preparation for renal replacement therapy if approaching stage 5 CKD [7] |
MN is one of three primary renal diseases that recur in the transplanted kidney (along with IgA nephropathy and FSGS) — because the antibodies are still being produced. [11]
Recurrence of primary disease: especially in IgAN, membranous nephropathy, FSGS. NOT a contraindication to transplant → still can be treated despite recurrence. [33]
- Recurrence rate of MN post-transplant: ~30–40%
- Predicted by persistent high anti-PLA2R titres pre-transplant
- Manageable with rituximab in most cases
- Despite recurrence risk, transplantation remains the best option for ESRD — graft survival is acceptable
Immunosuppressive therapy introduces its own set of complications:
| Treatment | Complications | Mechanism |
|---|---|---|
| Corticosteroids | Cushingoid features, DM, osteoporosis, AVN, cataracts, psychosis, growth retardation (children), infection | Broad metabolic effects of chronic glucocorticoid excess |
| Cyclophosphamide | Gonadal toxicity (especially males — azoo/oligospermia), haemorrhagic cystitis (acrolein metabolite irritates bladder urothelium — prevent with hydration/mesna), leucopaenia, ↑ malignancy risk (bladder cancer, lymphoma) | Alkylating agent → damages DNA in all rapidly dividing cells |
| Rituximab | Infusion reactions, infection (especially HBV reactivation), late-onset neutropaenia, hypogammaglobulinaemia, PML (extremely rare) | B-cell depletion → ↓ antibody production → ↓ humoral immunity |
| Calcineurin inhibitors (CsA, tacrolimus) | Nephrotoxicity (chronic CNI nephrotoxicity → arteriolar hyalinosis, interstitial fibrosis — ironic in a kidney disease!), hypertension, hyperkalaemia, tremor, gingival hypertrophy (CsA), new-onset DM (tacrolimus) | Direct vasoconstriction of afferent arteriole → chronic ischaemia; metabolic effects |
| MMF | GI upset (diarrhoea, nausea), leucopaenia, teratogenic | Inhibits purine synthesis → affects all rapidly dividing cells (GI epithelium, bone marrow) |
CNI Nephrotoxicity — The Ironic Complication
Using cyclosporine or tacrolimus to treat MN can itself cause progressive kidney damage through chronic CNI nephrotoxicity. This is why CNI use must be monitored with trough levels, and duration should be limited (12–24 months). If creatinine rises > 30% from baseline on CNI, the dose must be reduced or the drug stopped. This ironic complication is a major reason why KDIGO 2021 prefers rituximab (which has no direct nephrotoxicity) as first-line.
| Complication | Pathophysiology | Key Management | Source |
|---|---|---|---|
| Thromboembolism (DVT, RVT, PE) | Loss of AT-III + ↑ procoagulants + platelet abnormalities; highest risk in MN | Prophylactic anticoagulation if albumin < 20–25 g/L; therapeutic anticoagulation if event occurs | [4][10][15] |
| Infection | Loss of IgG + complement + immunosuppressive Rx | Pneumococcal vaccine, PJP prophylaxis on IS, monitor Ig levels | [10][25] |
| AKI | Over-diuresis, ATN, crescentic transformation, RVT | Withhold diuretics if hypovolaemic; urgent biopsy if RPGN; thrombolysis if RVT with AKI | [4][10][19] |
| Resistant oedema | Gut wall oedema → frusemide malabsorption; poor compliance | IV frusemide, add thiazide/spironolactone, IV albumin | [4] |
| Hyperlipidaemia / CVD | ↑ Hepatic lipoprotein synthesis, ↓ LPL activity | Statins, CV risk modification | [4][25] |
| CKD / ESRD | Progressive podocyte loss, tubulointerstitial fibrosis; 1/3 progress to ESRD | ACEI/ARB, immunosuppression if indicated, RRT preparation | [3][4][32] |
| Post-transplant recurrence | Antibodies still produced → ~30–40% recurrence | Rituximab, monitor anti-PLA2R; NOT a C/I to transplant | [11][33] |
| Treatment toxicity | Drug-specific (steroids, CyP, CNI, RTX, MMF) | Monitoring, dose adjustment, switch agents | Multiple |
High Yield Summary — Complications of MN
-
Thromboembolism is the most dangerous acute complication. MN carries the highest thromboembolic risk of any nephrotic syndrome. Classic: renal vein thrombosis (flank pain, haematuria, AKI). Also DVT, PE. Mechanism: urinary loss of AT-III/protein C/S + hepatic overproduction of procoagulants.
-
Infection from IgG/complement loss + immunosuppressive therapy. Encapsulated organisms. Pneumococcal vaccine for all. SBP classically in children.
-
AKI — differentiate: over-diuresis (pre-renal), ATN, crescentic transformation (RPGN — emergency!), renal vein thrombosis.
-
Resistant oedema — gut wall oedema reduces frusemide absorption → switch to IV; sequential nephron blockade; IV albumin for diuretic resistance.
-
Hyperlipidaemia → accelerated CVD. Statins + treat underlying disease.
-
CKD/ESRD — 1/3 of patients. Standard CKD complications (anaemia, MBD, acidosis). RRT needed; MN recurs post-transplant (~30–40%) but transplant is NOT contraindicated.
-
Treatment toxicity — cyclophosphamide (gonadal, bladder, marrow), CNI (nephrotoxicity — ironic!), rituximab (infections, HBV reactivation), steroids (metabolic).
Active Recall - Complications of Membranous Nephropathy
References
[3] Senior notes: Ryan Ho Urogenital.pdf (p83 — Risk factors for progressive MN) [4] Senior notes: Maksim Medicine Notes.pdf (p232 — Management of complications table) [7] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (p28 — Chronic GN investigations, NcNc anaemia) [9] Senior notes: Block A – Nephrology Data Interpretation.pdf (p17 — Clinical Presentation of GN table) [10] Senior notes: Ryan Ho Fundamentals.pdf (p366 — Thromboembolism, infection in nephrotic syndrome) [11] Senior notes: Block A - Renal Replacement Therapies.pdf (p41 — Recurrence post-transplant) [15] Senior notes: Block A - Glomerular Diseases.pdf (p1 — 180 patients, thromboembolic events, MN highest risk) [19] Senior notes: Ryan Ho Fundamentals.pdf (p361 — RPGN, crescentic transformation of MN) [25] Senior notes: Ryan Ho Fundamentals.pdf (p368 — General approach to management, pneumococcal vaccination) [31] Senior notes: Ryan Ho Respiratory.pdf (p128 — PE in lupus membranous nephropathy) [32] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf (p23 — Complications of CKD) [33] Senior notes: Ryan Ho Urogenital.pdf (p120 — Post-transplant recurrence)
High Yield Summary
-
Definition: MN = subepithelial immune deposits → GBM thickening ("spikes") → podocyte injury → nephrotic syndrome with bland sediment.
-
Epidemiology: Most common cause of adult nephrotic syndrome. Peak > 40 years, M > F. In HK, consider HBV-associated MN.
-
Primary (~75%): Anti-PLA2R (~70%) — IgG4 against podocyte PLA2R → in situ immune complex → C5b-9 MAC → podocyte damage. Anti-THSD7A (~3%).
-
Secondary (~25%): SLE (Class V), HBV (children, immune-tolerant phase), malignancy (adenocarcinoma in elderly), drugs (gold, penicillamine, NSAIDs, captopril).
-
Histology: LM = diffuse GBM thickening without hypercellularity. EM = subepithelial EDDs → "spike and dome" (Stage II). IF = granular IgG + C3 along GBM. Full-house staining = lupus.
-
Clinical: Insidious nephrotic syndrome (frothy urine, oedema, hypoalbuminaemia, hyperlipidaemia). Bland sediment. Highest thromboembolic risk of any nephrotic syndrome.
-
Anti-PLA2R: 70% sensitivity, near 100% specificity for primary MN. Can treat WITHOUT biopsy if positive. Titres correlate with disease activity.
-
Rule of thirds: 1/3 remit spontaneously, 1/3 remain nephrotic, 1/3 → ESRD.
-
Recurs post-transplant (immune-mediated — antibodies persist).
High Yield Summary — Differential Diagnosis of MN
Level 1 (Is it MN or another cause of nephrotic syndrome?):
- MCD: Normal LM, podocyte effacement only on EM, IF negative, excellent steroid response.
- FSGS: Segmental sclerosis, steroid-resistant, sampling error possible.
- MPGN: GBM thickening WITH hypercellularity, hypocomplementaemia, subendothelial deposits.
- Diabetic nephropathy: Diabetes + retinopathy + progressive proteinuria. No biopsy usually needed.
- Amyloidosis: Congo red positive, paraproteinaemia, systemic features.
- Lupus Class V: Young woman, full-house IF staining, ↓ complement, anti-PLA2R negative.
Level 2 (Primary vs Secondary MN):
- Anti-PLA2R positive → strongly primary.
- Anti-PLA2R negative → exhaustive secondary screen: SLE, HBV/HCV, malignancy, drugs, syphilis.
- Key secondary causes: SLE (Class V), HBV, adenocarcinoma, gold/penicillamine/NSAIDs.
Critical discriminators:
- Anti-PLA2R (primary vs secondary)
- Complement levels (low in MPGN/lupus/PSGN; normal in MN)
- IF pattern (full-house = lupus; IgG+C3 only = primary MN)
- Deposit location on EM (subepithelial = MN; subendothelial = MPGN/lupus III-IV)
High Yield Summary — Diagnosis of MN
-
Anti-PLA2R is the single most important serological test. ~70% sensitive, near 100% specific for primary MN. ROC 0.96. [7] Positive result in the right clinical context can establish diagnosis without biopsy.
-
Complement levels are normal in primary MN. Low complement → think lupus, MPGN, cryoglobulinaemia.
-
Renal biopsy is the gold standard. Three modalities: LM (GBM thickening, spikes on silver stain), IF (granular IgG + C3), EM (subepithelial EDDs, spike and dome, podocyte effacement) [13].
-
Full-house IF staining = lupus until proven otherwise.
-
Every patient with MN needs systematic secondary cause screening: autoimmune (ANA, dsDNA, C3/C4), infection (HBV, HCV, HIV, syphilis), malignancy (especially > 60 years), drugs, paraproteinaemia.
-
Stage I MN may be missed on LM — EM is essential for early diagnosis.
-
Anti-PLA2R titres correlate with disease activity and can guide treatment response monitoring.
-
In QMH/HK: uPCR is used instead of UACR for proteinuria quantification in most glomerular diseases.
High Yield Summary — Management of MN
-
ALL patients: Supportive therapy — ACEI/ARB (goal: proteinuria < 1 g/day, BP < 125/80), salt restriction, diuretics, statins, thromboprophylaxis (esp. if albumin < 20–25 g/L), pneumococcal vaccine. [3][4][25]
-
Primary MN — observe 3–6 months: 1/3 remit spontaneously. Risk-stratify using proteinuria trend, eGFR, anti-PLA2R titres.
-
High risk primary MN — immunosuppress:
- 1st line (KDIGO 2021): Rituximab (anti-CD20) — preferred due to better safety profile.
- Alternative 1st line: Modified Ponticelli — cyclophosphamide + steroids (alternating 6-month regimen).
- Alternative: CNI (cyclosporine/tacrolimus) — effective but high relapse rate and nephrotoxicity.
- Senior notes list: steroids, cyclophosphamide, cyclosporine, MMF, chlorambucil. [13]
-
Secondary MN: treat the underlying cause — stop drug, antivirals for HBV (NEVER immunosuppress without antiviral cover), treat malignancy, lupus protocol for Class V LN.
-
Complications: Resistant oedema → IV frusemide ± thiazide ± albumin. RVT → anticoagulation (thrombolysis if AKI). AKI → reduce diuretics, rehydrate, biopsy if RPGN.
-
Monitoring: Anti-PLA2R titres = best biomarker for disease activity and treatment response.
High Yield Summary — Complications of MN
-
Thromboembolism is the most dangerous acute complication. MN carries the highest thromboembolic risk of any nephrotic syndrome. Classic: renal vein thrombosis (flank pain, haematuria, AKI). Also DVT, PE. Mechanism: urinary loss of AT-III/protein C/S + hepatic overproduction of procoagulants.
-
Infection from IgG/complement loss + immunosuppressive therapy. Encapsulated organisms. Pneumococcal vaccine for all. SBP classically in children.
-
AKI — differentiate: over-diuresis (pre-renal), ATN, crescentic transformation (RPGN — emergency!), renal vein thrombosis.
-
Resistant oedema — gut wall oedema reduces frusemide absorption → switch to IV; sequential nephron blockade; IV albumin for diuretic resistance.
-
Hyperlipidaemia → accelerated CVD. Statins + treat underlying disease.
-
CKD/ESRD — 1/3 of patients. Standard CKD complications (anaemia, MBD, acidosis). RRT needed; MN recurs post-transplant (~30–40%) but transplant is NOT contraindicated.
-
Treatment toxicity — cyclophosphamide (gonadal, bladder, marrow), CNI (nephrotoxicity — ironic!), rituximab (infections, HBV reactivation), steroids (metabolic).
Focal Segmental Glomerulosclerosis
Focal segmental glomerulosclerosis is a pattern of glomerular injury characterized by sclerosis affecting some glomeruli (focal) and only portions of the glomerular tuft (segmental), commonly presenting with nephrotic syndrome.
Diabetic Nephropathy
Diabetic nephropathy is a progressive kidney disease caused by long-standing diabetes mellitus, characterized by glomerular hyperfiltration, thickening of the glomerular basement membrane, mesangial expansion, and nodular glomerulosclerosis (Kimmelstiel-Wilson lesions), ultimately leading to proteinuria and declining renal function.