Nephrotic Syndrome — Pathology
Pathology · Renal · lean revision notes
Nephrotic Syndrome — Pathology
A glomerular disease characterised by heavy proteinuria from a damaged filtration barrier. For NEET PG, the high-yield game is distinguishing the histologic types by light microscopy (LM), immunofluorescence (IF), and especially electron microscopy (EM), plus their steroid-responsiveness and clinical associations.
Definition & diagnostic criteria
Nephrotic syndrome is a clinical-pathological tetrad caused by a defect in the glomerular capillary wall (the size- and charge-selective barrier) that allows massive loss of plasma protein into urine.
The classic tetrad (mnemonic "PHHO"):
| Feature | Threshold / detail |
|---|---|
| Proteinuria | > 3.5 g/day (per 1.73 m²); "nephrotic-range" |
| Hypoalbuminaemia | Serum albumin < 3 g/dL (often < 2.5) |
| Hyperlipidaemia + lipiduria | ↑ LDL, cholesterol; oval fat bodies / Maltese cross under polarised light |
| Oedema | Periorbital → generalised (anasarca); pitting |
High-yield: The single defining lab is proteinuria > 3.5 g/24 h. Spot urine protein:creatinine ratio > 3.5 is an acceptable surrogate. Albumin < 3 g/dL is the key driver of oedema and downstream complications.
Nephrotic vs nephritic — the perennial NEET PG contrast
| Parameter | Nephrotic | Nephritic |
|---|---|---|
| Proteinuria | Heavy (> 3.5 g/day) | Mild–moderate (< 3.5 g) |
| Haematuria | Absent / mild | Dysmorphic RBCs + RBC casts |
| Oedema | Marked, due to hypoalbuminaemia | Mild, due to salt/water retention |
| Blood pressure | Usually normal | Hypertension common |
| GFR | Often preserved (early) | ↓ (azotaemia, oliguria) |
| Hallmark lesion | Podocyte / GBM injury | Endothelial / mesangial proliferation |
High-yield: Presence of RBC casts = nephritic, not nephrotic. Some lesions overlap (e.g. membranoproliferative GN, lupus nephritis) — these can present as a "nephritic-nephrotic" mixed picture.
Pathophysiology of the manifestations
The unifying defect is loss of podocyte integrity (foot-process effacement) and/or GBM damage, breaking the charge/size barrier.
Proteinuria → hypoalbuminaemia → falling oncotic pressure → oedema is the classical "underfill" model. The "overfill" model adds primary renal Na⁺ retention (activation of epithelial Na channel) as a parallel driver.
Stepwise cascade:
- Barrier injury (podocyte effacement / immune-complex deposition) → albumin leaks.
- Hypoalbuminaemia → ↓ plasma oncotic pressure → fluid into interstitium → oedema.
- Liver compensates with ↑ synthesis of albumin and lipoproteins → hyperlipidaemia; reduced lipoprotein lipase clearance adds to it.
- Urinary loss of antithrombin III, protein C/S + ↑ hepatic procoagulants → hypercoagulable state (renal vein thrombosis classically with membranous).
- Loss of immunoglobulins + complement factor B → infection risk (encapsulated organisms; Streptococcus pneumoniae peritonitis in children).
High-yield: Renal vein thrombosis is most strongly associated with membranous nephropathy. Suspect it with sudden flank pain, haematuria, and a deteriorating renal function; investigation of choice is Doppler / CT venography.
The major pathological types
1. Minimal Change Disease (MCD) — "Nil disease" / Lipoid nephrosis
- Commonest cause of nephrotic syndrome in CHILDREN (~90% under 6 years).
- LM: Normal glomeruli ("minimal change"). Proximal tubules may show lipid (foam cells) → old name "lipoid nephrosis."
- IF: Negative (no immune deposits).
- EM (the money finding): Diffuse effacement (fusion) of podocyte foot processes. No deposits.
- Pathogenesis: T-cell–derived circulating permeability factor; loss of GBM anionic charge → selective proteinuria (mainly albumin).
- Associations: Often idiopathic; secondary to NSAIDs and Hodgkin lymphoma.
High-yield: MCD is exquisitely steroid-responsive (> 90% remit). In children, empiric steroids are started without biopsy. Foot-process effacement on EM with normal LM and negative IF = MCD.
2. Focal Segmental Glomerulosclerosis (FSGS)
- Commonest cause of nephrotic syndrome in adults, especially African-American adults; rising overall incidence.
- "Focal" = some (not all) glomeruli affected; "segmental" = part of the affected glomerular tuft sclerosed.
- LM: Focal & segmental sclerosis + hyalinosis; juxtamedullary glomeruli involved earliest.
- IF: Non-specific IgM and C3 trapping in sclerotic segments.
- EM: Foot-process effacement (like MCD) + areas of GBM collapse/sclerosis.
- Pathogenesis & causes:
- Primary: circulating permeability factor (e.g. suPAR).
- Secondary/adaptive: HIV (collapsing variant), obesity, reflux nephropathy, heroin, reduced nephron mass.
- Genetic: podocyte gene mutations — podocin (NPHS2), nephrin (NPHS1), APOL1 (risk allele in African ancestry).
High-yield: HIV-associated nephropathy = collapsing FSGS with tubular microcysts. Obesity → secondary FSGS. FSGS is the classic cause of steroid-resistant nephrotic syndrome; progresses to ESRD and recurs in transplants.
3. Membranous Nephropathy (MN) — "Membranous glomerulonephritis"
- A leading cause of primary nephrotic syndrome in older / Caucasian adults.
- LM: Diffuse GBM thickening; no proliferation. Silver stain → "spike and dome" / basement-membrane spikes projecting between subepithelial deposits.
- IF: Granular subepithelial IgG + C3 along the capillary wall.
- EM: Subepithelial electron-dense deposits with intervening GBM "spikes."
- Pathogenesis: In-situ immune-complex formation. Primary disease driven by autoantibodies to anti-PLA2R (phospholipase A2 receptor) — positive in ~70–80% of primary MN; THSD7A is a second antigen.
| Cause class | Examples |
|---|---|
| Primary | Anti-PLA2R antibody (idiopathic) |
| Infections | Hepatitis B (and C), syphilis, malaria |
| Drugs | Penicillamine, gold, NSAIDs, captopril |
| Malignancy | Solid tumours — lung, colon, breast (esp. elderly) |
| Autoimmune | SLE class V (membranous lupus nephritis) |
High-yield: Anti-PLA2R antibody = serologic marker of primary membranous nephropathy; its titre tracks disease activity and can spare a biopsy. "Spike and dome" on silver/EM and subepithelial deposits are the buzz phrases. MN is the commonest cause of renal vein thrombosis.
4. Membranoproliferative GN (MPGN) — mixed nephritic/nephrotic
- LM: "Tram-track" / double-contour GBM from mesangial interposition; lobular hypercellularity.
- Type I: subendothelial deposits; immune-complex driven (HCV, cryoglobulinaemia, SLE) → low C3 via classical pathway.
- Dense Deposit Disease (old type II): intramembranous dense deposits; C3 nephritic factor, persistently low C3 (alternative pathway). Now grouped under C3 glomerulopathy.
High-yield: Tram-track GBM = MPGN. Type I → subendothelial deposits; Dense deposit disease → C3 nephritic factor + intramembranous deposits.
5. Amyloid Nephropathy
- A systemic deposition disease causing nephrotic syndrome, classically in older adults with AL (light-chain, myeloma) or AA (chronic inflammation — RA, TB, chronic infection) amyloid.
- LM: Acellular, amorphous, eosinophilic mesangial/capillary deposits.
- Special stain: Congo red → apple-green birefringence under polarised light; EM shows non-branching fibrils ~8–12 nm.
- Renal involvement → massive proteinuria, enlarged kidneys, progressive renal failure.
High-yield: Congo red + apple-green birefringence + 8–10 nm fibrils = amyloid. Think multiple myeloma (AL) or chronic inflammation/RA (AA).
6. Diabetic Nephropathy
- The commonest cause of nephrotic-range proteinuria overall (because diabetes is so prevalent).
- LM: Diffuse mesangial expansion → Kimmelstiel-Wilson nodules (nodular glomerulosclerosis); hyaline arteriolosclerosis (afferent and efferent).
- Clinical sequence: hyperfiltration → microalbuminuria → overt proteinuria → declining GFR.
High-yield: Kimmelstiel-Wilson nodules are pathognomonic-sounding for diabetic nodular glomerulosclerosis. First clinical clue = microalbuminuria (30–300 mg/day).
EM & IF quick-distinguish table (the single most tested matrix)
| Disease | LM | IF | EM (deposit location) | Steroid response |
|---|---|---|---|---|
| MCD | Normal | Negative | Foot-process effacement, no deposits | Excellent |
| FSGS | Focal segmental sclerosis | IgM/C3 (non-specific) | Effacement + sclerosis | Poor (resistant) |
| Membranous | GBM thickening, spikes | Granular IgG/C3 | Subepithelial deposits | Variable / poor |
| MPGN I | Tram-track | Granular C3, Ig | Subendothelial | Variable |
| Dense deposit dz | Tram-track | C3 only | Intramembranous dense | Poor |
| Amyloid | Amorphous, Congo-red⁺ | Negative (λ light chain in AL) | Fibrils 8–12 nm | None (treat cause) |
| Diabetic | KW nodules | Linear (non-specific) | Diffuse GBM thickening | None |
High-yield mnemonic for deposit sites — "SEEN": Subepithelial = Membranous (humps if post-strep). Endo/subEndothelial = MPGN-I & lupus. INtramembranous = Dense deposit disease.
Diagnosis & investigation of choice
Workup flow: Urinalysis (proteinuria, oval fat bodies, Maltese cross) → 24-h urine protein or spot UPCR → serum albumin + lipid profile → serology (ANA, anti-dsDNA, HBsAg/HCV, complement C3/C4, anti-PLA2R, serum/urine electrophoresis, HIV) → renal biopsy (LM + IF + EM).
- Renal biopsy is the definitive investigation for adults and atypical children; EM is required to subtype.
- Children 1–10 yr with typical nephrotic syndrome: no biopsy — start prednisolone empirically; biopsy reserved for steroid resistance, atypical features (haematuria, hypertension, low complement, age outside range).
High-yield: Selectivity index — MCD shows selective proteinuria (mostly albumin); FSGS/membranous show non-selective (albumin + larger globulins).
Management / drug of choice
| Type | First-line / DOC |
|---|---|
| MCD (children) | Oral corticosteroids (prednisolone) — DOC; relapsers/steroid-dependent → levamisole, cyclophosphamide, calcineurin inhibitors, MMF |
| FSGS (primary) | High-dose, prolonged steroids; resistant → calcineurin inhibitors (cyclosporine/tacrolimus) |
| Membranous (primary) | Supportive + immunosuppression (steroids + cyclophosphamide "Ponticelli regimen", or rituximab anti-CD20) for high-risk |
| Lupus / infection / drug | Treat underlying cause; withdraw offending drug |
| Amyloid | Treat plasma-cell dyscrasia (AL) or inflammation (AA) |
Universal supportive measures: ACE inhibitor / ARB (reduce proteinuria + intraglomerular pressure), salt restriction + loop diuretics for oedema, statins for hyperlipidaemia, anticoagulation if albumin very low / thrombosis, pneumococcal vaccination.
High-yield: Rituximab is now a first-line/preferred agent for primary (anti-PLA2R) membranous nephropathy. ACEi/ARB is the antiproteinuric backbone for all chronic glomerular disease.
Complications
- Thromboembolism — renal vein thrombosis (membranous), DVT, PE (loss of antithrombin III).
- Infection — spontaneous bacterial peritonitis, cellulitis; encapsulated organisms (loss of Ig).
- Hyperlipidaemia → accelerated atherosclerosis.
- Acute kidney injury (intravascular volume depletion, interstitial oedema).
- Protein malnutrition, vitamin-D deficiency (loss of binding proteins), iron-refractory anaemia (transferrin loss).
- Progression to CKD/ESRD — especially FSGS, membranous, diabetic.
Key differentials & "spot the lesion" pearls
- Child + selective proteinuria + steroid response → MCD.
- Adult / African ancestry + steroid resistance + segmental scarring → FSGS. HIV → collapsing variant.
- Older adult + subepithelial spikes + anti-PLA2R → membranous. Screen for malignancy if elderly.
- Tram-track + low C3 → MPGN.
- Congo-red apple-green + myeloma → amyloid.
- Long-standing diabetic + KW nodules + retinopathy → diabetic nephropathy.
High-yield: Hodgkin lymphoma → MCD; solid tumours → membranous. Memorise this malignancy-association split.
Recently asked / exam angle
- EM correlation MCQs are perennial: "Diffuse foot-process effacement with normal LM and negative IF" → MCD; "subepithelial deposits with spikes" → membranous; "subendothelial deposits + tram-tracking" → MPGN-I.
- Anti-PLA2R as the antibody for primary membranous — repeatedly tested image/marker question.
- HIV → collapsing FSGS, and obesity → secondary FSGS.
- Renal vein thrombosis ↔ membranous association.
- Steroid responsiveness pattern: MCD (responsive) vs FSGS (resistant) is a favourite "best answer" distractor set.
- Congo red apple-green birefringence and fibril diameter (8–12 nm) for amyloid.
- Kimmelstiel-Wilson nodules and microalbuminuria as earliest diabetic marker.
- Silver-stain "spike and dome" image identification for membranous nephropathy.
Rapid revision
- Nephrotic syndrome = proteinuria > 3.5 g/day + albumin < 3 g/dL + oedema + hyperlipidaemia/lipiduria.
- RBC casts → nephritic, not nephrotic.
- MCD = commonest in children, normal LM, negative IF, foot-process effacement on EM, steroid-responsive; linked to Hodgkin lymphoma & NSAIDs.
- FSGS = commonest in adults; HIV (collapsing), obesity, APOL1; steroid-resistant; recurs post-transplant.
- Membranous = subepithelial deposits, "spike and dome," granular IgG/C3, anti-PLA2R; commonest cause of renal vein thrombosis.
- Membranous causes: HBV, drugs (penicillamine/gold), solid tumours, SLE class V.
- MPGN = tram-track GBM; type I subendothelial (HCV); dense deposit disease → C3 nephritic factor, low C3.
- Amyloid = Congo red apple-green birefringence, 8–12 nm fibrils; AL (myeloma) / AA (chronic inflammation).
- Diabetic nephropathy = Kimmelstiel-Wilson nodules; earliest sign microalbuminuria.
- Deposit sites — Subepithelial = membranous; subendothelial = MPGN/lupus; intramembranous = dense deposit disease.
- DOC: MCD → prednisolone; primary membranous → rituximab / Ponticelli; all → ACEi/ARB for proteinuria.
- Biopsy with EM is the gold standard to subtype; children with typical disease are treated empirically without biopsy.