Glomerulonephritis
Pathology · Renal · lean revision notes
Glomerulonephritis
Glomerulonephritis (GN) is a group of immune-mediated disorders producing inflammation of the glomerulus. For NEET PG, the single highest-yield skill is pattern recognition: linking a clinical syndrome (nephritic vs nephrotic) to a light-microscopy picture, an immunofluorescence (IF) pattern, an electron-microscopy (EM) finding, and a serum complement level. Master those four axes and most one-liners become free marks.
Two master syndromes: nephritic vs nephrotic
Every glomerular disease pushes the patient towards one of two clinical poles. Knowing the pole instantly narrows the differential.
| Feature | Nephritic syndrome | Nephrotic syndrome |
|---|---|---|
| Core lesion | Inflammatory, proliferative | Podocyte/GBM injury (non-inflammatory) |
| Proteinuria | Sub-nephrotic (<3.5 g/day) | Heavy (>3.5 g/1.73 m²/day) |
| Haematuria | Marked, dysmorphic RBCs + RBC casts | Absent/mild |
| Hypertension | Common, often prominent | Variable |
| Oedema | Mild, periorbital | Marked, generalised (anasarca) |
| Oliguria / azotaemia | Common | Uncommon early |
| Hypoalbuminaemia | Mild | Marked (<3 g/dL) |
| Hyperlipidaemia/lipiduria | No | Yes (oval fat bodies, Maltese cross) |
High-yield: RBC casts and dysmorphic (acanthocytic) RBCs = glomerular bleeding = nephritic. Oval fat bodies with "Maltese cross" appearance under polarised light = nephrotic.
The nephritic causes most tested: PSGN, IgA nephropathy, rapidly progressive GN (RPGN), lupus nephritis, MPGN (can be mixed). The nephrotic causes: minimal change disease, FSGS, membranous nephropathy, diabetic nephropathy, amyloidosis. MPGN classically gives a mixed nephritic-nephrotic picture.
The complement compass
Serum C3/C4 is one of the most frequently examined discriminators.
| Low complement (consumed) | Normal complement |
|---|---|
| Post-streptococcal GN (transient, C3 ↓) | IgA nephropathy |
| MPGN types I, II/DDD, III | Anti-GBM (Goodpasture) disease |
| Lupus nephritis (C3 and C4 ↓) | ANCA-associated (pauci-immune) GN |
| Cryoglobulinaemic/HCV-related GN | Henoch-Schönlein purpura nephritis |
| Subacute bacterial endocarditis GN | — |
High-yield: Mnemonic for LOW-complement GN — "Post-streptococcal, MPGN, Lupus, Endocarditis, Cryoglobulinaemia." Everything else (pauci-immune, anti-GBM, IgA/HSP) runs with normal complement.
High-yield: Lupus nephritis is the classic cause where both C3 and C4 fall (classical pathway). PSGN and DDD lower C3 with relatively preserved C4 (alternative pathway, C3 nephritic factor in DDD).
Immunofluorescence: three buckets
The IF pattern is the spine of GN classification.
- Granular ("lumpy-bumpy") deposits → immune-complex GN: PSGN, IgA nephropathy, lupus, MPGN, membranous, cryoglobulinaemic.
- Linear deposits along GBM → anti-GBM disease (Goodpasture). IgG ribbon-like.
- Pauci-immune (scant/no deposits) → ANCA-associated vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic GPA).
High-yield: Linear IF = anti-GBM. Granular = immune complex. Pauci-immune = ANCA. This single line answers many IF questions.
Individual disease profiles
Post-streptococcal glomerulonephritis (PSGN)
The prototype acute nephritic syndrome and a favourite in paediatrics/medicine.
- Trigger: Nephritogenic strains of group A β-haemolytic Streptococcus (e.g. M-type 12 after pharyngitis, M-type 49 after impetigo).
- Latent period: ~1–3 weeks after pharyngitis; ~3–6 weeks after skin infection. This lag distinguishes it from IgA nephropathy (synpharyngitic, see below).
- Pathophysiology: Immune-complex deposition + in-situ formation; nephritogenic antigens NAPlr (nephritis-associated plasmin receptor) and SPeB (streptococcal pyrogenic exotoxin B). Complement activated via alternative pathway → C3 ↓, normalises within 6–8 weeks.
- Clinical: Child with cola-coloured urine, periorbital puffiness, hypertension, oliguria.
- Light microscopy: Diffuse endocapillary proliferative GN, hypercellular glomeruli, neutrophil infiltration.
- IF: Granular IgG + C3 — "starry sky" pattern.
- EM: Subepithelial "humps."
- Labs: ↑ ASO titre (post-pharyngitis), ↑ anti-DNase B (best for post-skin), low C3.
- Management: Supportive — salt/water restriction, loop diuretics, antihypertensives; treat residual streptococcal infection with penicillin. Excellent prognosis in children; adults recover less completely.
High-yield: EM subepithelial humps + IF starry sky + transient low C3 = PSGN. C3 returning to normal by 8 weeks confirms it; persistently low C3 should make you reconsider MPGN.
IgA nephropathy (Berger disease)
The commonest primary GN worldwide.
- Clinical hallmark: Synpharyngitic haematuria — gross haematuria occurring within 1–2 days of an upper respiratory (or GI) infection, i.e. no lag, contrasting with PSGN.
- Pathophysiology: Deposition of galactose-deficient IgA1 immune complexes in the mesangium.
- IF: Dominant mesangial IgA deposits (± C3). Normal complement.
- Light microscopy: Mesangial proliferation; graded by the Oxford MEST-C classification.
- Course: Often relapsing micro/macroscopic haematuria; up to a third progress to CKD over decades.
- Management: ACE inhibitors/ARBs for proteinuria + BP control; corticosteroids/immunosuppression in progressive disease.
High-yield: PSGN = haematuria after a latent period with low C3; IgA nephropathy = haematuria with/within 1–2 days of infection and normal C3. This contrast is examined relentlessly.
High-yield: Henoch-Schönlein purpura (IgA vasculitis) is the systemic counterpart of IgA nephropathy — palpable purpura on buttocks/legs, arthralgia, abdominal pain, GN; same mesangial IgA on biopsy.
Membranous nephropathy
Leading cause of primary nephrotic syndrome in adults (especially Caucasians/elderly).
- Pathophysiology: In-situ subepithelial immune complexes. Anti-PLA2R (phospholipase A2 receptor) antibodies in ~70–80% of primary cases.
- Secondary causes: Solid tumours (lung, colon — think malignancy in the elderly), hepatitis B, SLE (class V), drugs (gold, penicillamine, NSAIDs).
- Light microscopy: Diffuse GBM thickening; silver stain shows "spike and dome."
- IF: Granular IgG + C3 along the GBM.
- EM: Subepithelial deposits between basement-membrane spikes.
- Complication: Highest risk of renal vein thrombosis among nephrotic states.
- Management: ACEi/ARB + supportive; immunosuppression (rituximab, or cyclophosphamide + steroids per Ponticelli regimen) for high-risk disease.
High-yield: "Spike and dome" on silver stain + anti-PLA2R positivity = membranous nephropathy. Subepithelial deposits without humps — humps belong to PSGN.
Minimal change disease (MCD)
Most common nephrotic syndrome in children.
- Light microscopy: Normal glomeruli (hence "minimal change").
- EM: Diffuse podocyte foot-process effacement.
- IF: Negative.
- Associations: Hodgkin lymphoma; NSAIDs.
- Management: Exquisitely steroid-responsive — corticosteroids are first line; relapsers may need calcineurin inhibitors/cyclophosphamide.
Focal segmental glomerulosclerosis (FSGS)
- Leading cause of nephrotic syndrome in adults overall in many series, and especially common in Indian and African ancestry populations and HIV.
- Light microscopy: Focal (some glomeruli) and segmental (part of tuft) sclerosis; collapsing variant in HIV.
- EM: Foot-process effacement.
- IF: Often negative or non-specific IgM/C3 in sclerotic segments.
- Secondary: obesity, reflux nephropathy, heroin, sickle cell.
- Management: ACEi/ARB; steroids ± calcineurin inhibitors; often steroid-resistant with risk of progression to ESRD.
Membranoproliferative GN (MPGN) / C3 glomerulopathy
The classic mixed nephritic-nephrotic picture with persistently low complement.
- Light microscopy / silver stain: GBM "double contour" — "tram-track" appearance from mesangial interposition.
- Classification (modern, by IF):
- Immune-complex MPGN (old type I) — subendothelial deposits; driven by chronic antigenaemia (HCV with cryoglobulins, endocarditis, lupus). IF: Ig + C3.
- C3 glomerulopathy — includes Dense deposit disease (DDD, old type II); driven by alternative-pathway dysregulation. C3 nephritic factor stabilises C3 convertase. EM of DDD: ribbon-like intramembranous dense deposits. IF: C3 dominant, scant Ig.
- Management: Treat underlying cause (e.g. HCV); immunosuppression/eculizumab in selected C3 glomerulopathy.
High-yield: Tram-track GBM + persistently low C3 = MPGN/C3 glomerulopathy. C3 nephritic factor and partial lipodystrophy are linked to dense deposit disease.
Rapidly progressive GN (RPGN) / crescentic GN
A clinical-pathological emergency: loss of renal function over days to weeks with crescents on biopsy.
- Defining lesion: Glomerular crescents (proliferating parietal epithelial cells, monocytes, fibrin) in >50% of glomeruli.
- Three immunopathologic types:
| Type | IF pattern | Disease | Complement | Key serology |
|---|---|---|---|---|
| Type I | Linear | Anti-GBM / Goodpasture | Normal | Anti-GBM Ab |
| Type II | Granular | Immune-complex (PSGN, lupus, IgA, HSP) | Often low | Disease-specific |
| Type III | Pauci-immune | ANCA vasculitis (GPA, MPA, EGPA) | Normal | c-ANCA/PR3, p-ANCA/MPO |
- Anti-GBM (Goodpasture): Antibody to the α3 chain of type IV collagen; lung (haemoptysis) + kidney. Bimodal age. Plasmapheresis + steroids + cyclophosphamide.
- ANCA-associated: GPA (c-ANCA/anti-PR3, upper + lower airway + kidney) and MPA (p-ANCA/anti-MPO). Induction with steroids + rituximab or cyclophosphamide.
High-yield: Crescents = RPGN. Decide the type by IF — linear = anti-GBM, granular = immune complex, pauci-immune = ANCA. Anti-GBM targets the α3 chain of collagen IV.
A stepwise diagnostic approach
A clean approach for a stem with haematuria/proteinuria and renal impairment:
Step 1 — Define the syndrome → nephritic vs nephrotic vs mixed (urine microscopy: RBC casts vs oval fat bodies). → Step 2 — Quantify proteinuria (spot urine protein:creatinine or 24-h) and check renal function/rate of rise. → Step 3 — Send serum complement (C3, C4) → splits low-complement from normal-complement causes. → Step 4 — Targeted serology: ASO/anti-DNase B, ANA/anti-dsDNA + C3/C4, ANCA (PR3/MPO), anti-GBM, anti-PLA2R, hepatitis B/C, cryoglobulins. → Step 5 — Renal biopsy (LM + IF + EM) for definitive diagnosis when the picture is unclear, RPGN is suspected, or there is significant proteinuria/declining function.
High-yield: Renal biopsy with immunofluorescence and electron microscopy is the investigation of choice for classifying GN. Urgent biopsy is mandated when RPGN/crescentic disease is suspected because treatment is time-critical.
EM and LM quick-match table
| Disease | LM / special stain | IF | EM | Complement |
|---|---|---|---|---|
| PSGN | Endocapillary proliferative | Granular IgG/C3 "starry sky" | Subepithelial humps | ↓ C3 (transient) |
| IgA nephropathy | Mesangial proliferation | Mesangial IgA | Mesangial deposits | Normal |
| Membranous | "Spike and dome" (silver) | Granular IgG/C3 on GBM | Subepithelial deposits | Normal |
| MCD | Normal | Negative | Foot-process effacement | Normal |
| FSGS | Focal/segmental sclerosis | IgM/C3 (segmental) | Foot-process effacement | Normal |
| MPGN type I | Tram-track | Ig + C3 | Subendothelial deposits | ↓ |
| DDD (C3 GP) | Tram-track | C3 dominant | Intramembranous dense deposits | ↓ (C3 NeF) |
| Anti-GBM | Crescents | Linear IgG | No deposits | Normal |
| ANCA GN | Crescents | Pauci-immune | No deposits | Normal |
| Lupus (class IV) | Diffuse proliferative, wire loops | "Full house" (IgG/IgA/IgM/C3/C1q) | Subendo deposits | ↓ C3 and C4 |
High-yield: Lupus nephritis IF = "full house" staining; class IV LM shows wire-loop lesions. This is a recurrent single-best-answer.
Management & drugs of choice — at a glance
- PSGN: Supportive (diuretics, BP control); penicillin for active infection. No steroids routinely.
- MCD: Corticosteroids (first line, highly responsive).
- FSGS: ACEi/ARB + steroids; calcineurin inhibitors if resistant.
- Membranous (high risk): Rituximab or Ponticelli (cyclophosphamide + steroids).
- IgA nephropathy: ACEi/ARB for BP and proteinuria; steroids if progressive.
- Anti-GBM: Plasmapheresis + steroids + cyclophosphamide.
- ANCA GN: Steroids + rituximab or cyclophosphamide.
- Lupus nephritis (class III/IV): Steroids + mycophenolate mofetil or cyclophosphamide; maintenance with MMF/azathioprine.
High-yield: Plasmapheresis is specifically indicated in anti-GBM (Goodpasture) disease and in ANCA vasculitis with severe renal failure/pulmonary haemorrhage. Linking plasmapheresis to anti-GBM is a classic answer.
Complications
- Acute kidney injury / progression to CKD and ESRD (especially FSGS, MPGN, untreated RPGN).
- Hypertensive emergency, pulmonary oedema, hypertensive encephalopathy in acute nephritic states.
- Thromboembolism in nephrotic syndrome (loss of antithrombin III); renal vein thrombosis highest in membranous nephropathy.
- Infection from urinary loss of immunoglobulins; spontaneous bacterial peritonitis in nephrotic children (pneumococcus).
- Hyperlipidaemia and accelerated atherosclerosis in chronic nephrotic syndrome.
- Pulmonary-renal syndrome (anti-GBM, ANCA) — life-threatening alveolar haemorrhage.
Key differentials & traps
- Glomerular vs non-glomerular haematuria: dysmorphic RBCs/RBC casts and proteinuria point glomerular; isomorphic RBCs/clots suggest urological (stone, tumour).
- PSGN vs IgA nephropathy: latency and complement (covered above).
- Membranous vs MCD vs FSGS as the cause of adult nephrotic syndrome — distinguish by LM/EM and anti-PLA2R.
- Alport syndrome: hereditary nephritis (type IV collagen mutation) with sensorineural deafness + anterior lenticonus; EM shows basket-weave/lamellated GBM — do not confuse with anti-GBM (both involve collagen IV but mechanism differs).
- Thin basement membrane disease (benign familial haematuria): isolated persistent microscopic haematuria, uniformly thin GBM, benign course.
Recently asked / exam angle
- "Subepithelial humps on EM" → PSGN (and the transient low C3, ASO/anti-DNase B linkage).
- "Spike and dome on silver stain / anti-PLA2R positive" → membranous nephropathy; remember malignancy/HBV as secondary causes.
- "Tram-track GBM with persistently low complement" → MPGN/C3 glomerulopathy; C3 nephritic factor with partial lipodystrophy for DDD.
- "Linear IF along GBM + haemoptysis" → anti-GBM disease, antigen = α3 chain of type IV collagen, treat with plasmapheresis.
- "Pauci-immune crescentic GN, c-ANCA/PR3" → granulomatosis with polyangiitis.
- "Full-house IF / wire-loop lesions / low C3 and C4" → lupus nephritis (class IV).
- "Synpharyngitic gross haematuria, normal C3" → IgA nephropathy; palpable purpura added → HSP/IgA vasculitis.
- "Child, normal LM, foot-process effacement, steroid-responsive" → minimal change disease.
- Investigation of choice question → renal biopsy with IF + EM.
- Commonest primary GN worldwide → IgA nephropathy; commonest cause of nephrotic syndrome in children → MCD.
Rapid revision
- Nephritic = RBC casts + dysmorphic RBCs, HTN, oliguria; nephrotic = >3.5 g/day proteinuria, hypoalbuminaemia, oedema, lipiduria (Maltese cross).
- Low-complement GN: PSGN, MPGN, Lupus, Endocarditis, Cryoglobulinaemia; everything else normal.
- Lupus nephritis lowers both C3 and C4; "full house" IF + wire-loop lesions (class IV).
- PSGN: subepithelial humps, starry-sky IF, transient low C3, post-infection latent period; ASO (throat), anti-DNase B (skin).
- IgA nephropathy: commonest primary GN; synpharyngitic haematuria, mesangial IgA, normal complement.
- Membranous: adult nephrotic, spike and dome, anti-PLA2R, highest renal-vein-thrombosis risk; screen for malignancy/HBV.
- MCD: child, normal LM, foot-process effacement, steroid-responsive; FSGS: focal/segmental sclerosis, HIV (collapsing), often steroid-resistant.
- MPGN/C3 glomerulopathy: tram-track GBM, persistently low C3; DDD has dense intramembranous deposits + C3 nephritic factor + partial lipodystrophy.
- RPGN = crescents: linear (anti-GBM), granular (immune complex), pauci-immune (ANCA).
- Anti-GBM targets α3 chain of type IV collagen; treat with plasmapheresis + steroids + cyclophosphamide.
- Investigation of choice for GN classification = renal biopsy (LM + IF + EM); urgent in suspected RPGN.
- Alport = collagen IV mutation + sensorineural deafness + lenticonus + basket-weave GBM; distinct from anti-GBM.