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PA27.5-6 | Glomerular Diseases — SDL Guide (Part 3)

Nephritic Syndrome: Overview and Pathophysiology

A multi-panel diagram explains nephritic syndrome by showing inflamed glomerular capillary injury, red cell leakage and casts, clinical features, and complement patterns used in diagnosis. — **Panel A:** Normal capillary loop, inflamed glomerular capillary, endocapillary hypercellularity, narrowed capillary lumen, disrupted glomerular basement membrane, red blood cell leakage, Bowman space, renal tubule, dysmorphic red cells, red cell cast. **Panel B:** Immune-mediated glomerular inflammation, capillary wall injury, haematuria, reduced GFR, oliguria, sodium and water retention, hypertension, azotaemia. **Panel C:** Haematuria with dysmorphic RBCs and RBC casts, oliguria, hypertension, mild to moderate proteinuria less than 3.5 g/day, azotaemia with raised BUN and creatinine. **Panel D:** Low C3 and low C4 classical pathway, Low C3 and normal C4 alternative pathway, Normal C3 and normal C4 pauci-immune GN and IgA nephropathy.

Nephritic syndrome reflects glomerular inflammation with disruption of the capillary wall, leading to haematuria and red cell leakage. Its five defining features are:
1. Haematuria — dysmorphic red cells and red cell casts in urine (the pathognomonic finding)
2. Oliguria — reduced GFR due to hypercellularity and capillary compression
3. Hypertension — sodium and water retention, renin release
4. Proteinuria — mild to moderate (< 3.5 g/day), not as heavy as nephrotic)
5. Azotaemia — elevated BUN and creatinine

Why haematuria? Inflammatory injury to the capillary wall creates gaps that allow red cells to squeeze through. As they traverse the tubules, they are moulded into red cell casts in the concentrated acidic tubular fluid. A single red cell cast on urine microscopy is sufficient to establish the diagnosis of glomerulonephritis.

Complement as a diagnostic clue:
• Low C3, low C4 → Classical pathway activation (SLE, Type I MPGN)
• Low C3, normal C4 → Alternative pathway (PSGN, Dense Deposit Disease, ANCA vasculitis — wait, ANCA is pauci-immune, see below)
• Normal C3 and C4 → Pauci-immune GN (ANCA-RPGN), IgA nephropathy

This complement profile guides the differential diagnosis even before biopsy.

Post-Streptococcal / Post-Infectious GN

Four-panel diagram showing post-streptococcal glomerulonephritis pathogenesis, light microscopy hypercellularity, lumpy-bumpy immunofluorescence, and subepithelial humps on electron microscopy. — **Panel A:** Group A beta-haemolytic Streptococcus; pharyngitis; impetigo; latent period; SPEB; GAPDH; anti-streptococcal antibodies; immune complexes; C3 activation; neutrophils; monocytes; inflamed glomerulus. **Panel B:** Low-power renal cortex; enlarged hypercellular glomeruli; pale interstitium; starry sky appearance. **Panel C:** Bowman's space; enlarged glomerular tuft; diffuse endocapillary hypercellularity; proliferating endothelial cells; proliferating mesangial cells; infiltrating neutrophils; narrowed capillary lumina. **Panel D:** Granular IgG deposits; granular C3 deposits; lumpy-bumpy capillary wall and mesangial pattern; glomerular basement membrane; podocyte epithelial side; endothelial side; subepithelial electron-dense humps.

Post-streptococcal glomerulonephritis (PSGN) is the archetype of immune-complex–mediated nephritic syndrome, caused by nephritogenic strains of Group A β-haemolytic Streptococcus.

Timing: Latent period 1-3 weeks after throat infection (pharyngitis) or 3-6 weeks after skin infection (impetigo). The latency reflects time for immune-complex formation and deposition.

Who gets it? Children 5-12 years; males > females. Now rare in high-income countries due to antibiotic use; still common in India (skin infections, crowded conditions).

Pathogenesis: Nephritogenic streptococcal antigens (SPEB — cysteine protease; GAPDH) are deposited in subepithelial space → circulating anti-streptococcal antibodies arrive and bind in situ → immune complexes activate complement (C3) → neutrophil and monocyte influx → hypercellularity and injury.

Pathology:
• LM: Diffuse endocapillary hypercellularity (proliferating endothelial and mesangial cells + infiltrating neutrophils). The glomerulus is enlarged and hypercellular, filling Bowman's space. Described as the 'starry sky' appearance on low power (hypercellular glomeruli scattered in a pale background).
• IF: Granular IgG and C3 deposits in a 'lumpy-bumpy' pattern on the capillary walls and mesangium.
• EM: Subepithelial electron-dense deposits in a hump-shaped (dome-shaped) configuration — the pathognomonic 'subepithelial humps' of PSGN. These humps sit on the epithelial side of the GBM like camel humps.

Diagram showing post-streptococcal glomerulonephritis with subepithelial hump-shaped electron-dense deposits on the GBM, adjacent endothelium and podocyte effacement, plus key laboratory correlations. — **Panel A:** Fenestrated endothelial cell, capillary lumen, glomerular basement membrane, large subepithelial hump-shaped electron-dense deposit, podocyte cell body, effaced podocyte foot processes, epithelial side of GBM. **Panel B:** Normal fenestrated endothelium, intact GBM, podocyte foot processes, filtration slits, urinary space. **Panel C:** Low C3, normal C4, raised ASO titre after pharyngitis, raised anti-DNase B after skin infection, C3 recovery within 6-8 weeks, persistent low C3 suggests MPGN or lupus nephritis.

Laboratory: Low C3 (alternative pathway consumption), normal C4 in most. Anti-streptolysin O (ASO) titre raised after pharyngitis; anti-DNase B after skin infection. Elevated.

Clinical course: Self-limiting in children — 95%+ full recovery. Elderly patients and those with pre-existing kidney disease have a worse prognosis. Steroids not indicated. Treat the streptococcal infection with penicillin (to stop spread, not to alter renal course).

CLINICAL PEARL

In PSGN the complement drops early and recovers within 6-8 weeks. If C3 remains low beyond 8 weeks, reconsider the diagnosis — think MPGN (persistent low complement) or lupus nephritis (both C3 and C4 low). This 'complement recovery rule' is a high-yield clinical pearl used in differential diagnosis of low-complement nephritic syndrome.

Rapidly Progressive GN (RPGN) / Crescentic GN

Diagram of rapidly progressive crescentic glomerulonephritis showing crescent formation, diagnostic criteria, and the three immunological types with immunofluorescence patterns and serology. — **Panel A:** Crescent in Bowman's space, Bowman's capsule, parietal epithelial cell proliferation, fibrin leakage, ruptured GBM, macrophages, compressed glomerular tuft, normal Bowman's space inset. **Panel B:** RPGN, clinical criterion: >50% GFR loss in weeks to months, pathological criterion: crescents in >=50% glomeruli, kidney emergency. **Panel C:** Type I Anti-GBM: linear IgG, anti-GBM Ab positive, complement normal or mildly decreased; Type II Immune-complex: granular IgG/C3, variable serology, low complement; Type III Pauci-immune: little/no IF staining, ANCA often positive, complement usually normal.

Rapidly progressive glomerulonephritis (RPGN) is defined clinically as a loss of > 50% GFR within weeks to months, and pathologically by the presence of crescents in ≥ 50% of glomeruli.

What is a crescent? Fibrin and proliferating parietal epithelial cells of Bowman's capsule fill Bowman's space in a crescent shape in response to fibrin leakage through ruptured GBM. Macrophages also contribute. Crescents are a morphological marker of severe, destructive glomerular injury — a kidney emergency.

Three immunological types — memorise IF + serology:

Type	Mechanism	IF Pattern	Serology	Complement
Type I (Anti-GBM)	Anti-GBM antibodies (Goodpasture)	Linear IgG	Anti-GBM Ab (+)	Normal or mildly ↓
Type II (Immune-complex)	IC deposition (post-infectious, lupus, IgA)	Granular IgG/C3	Variable	Low
Type III (Pauci-immune)	ANCA vasculitis (MPA, GPA)	Negative (pauci = few/none)	ANCA (+): MPO (p-ANCA) or PR3 (c-ANCA)	Normal

Type III is the most common (~60%) and is associated with ANCA-associated small vessel vasculitis — microscopic polyangiitis (MPO/p-ANCA) or granulomatosis with polyangiitis/Wegener's (PR3/c-ANCA).

A four-panel medical diagram shows crescentic glomerulonephritis histology, anti-GBM antibody cross-reactivity in Goodpasture syndrome, linear IgG immunofluorescence, and key clinical treatment steps. — **Panel A:** Light microscopy view of crescentic GN showing cellular crescent, Bowman’s space, compressed glomerular tuft, parietal epithelial cell proliferation, and Bowman’s capsule.. **Panel B:** Anti-GBM antibodies targeting α3 type IV collagen in glomerular basement membrane and cross-reacting with pulmonary alveolar basement membrane.. **Panel C:** Immunofluorescence pattern showing continuous linear IgG staining along glomerular capillary loops, characteristic of Type I RPGN.. **Panel D:** Clinical clue and treatment pathway: young male with haemoptysis, haematuria, rapidly rising creatinine; Goodpasture syndrome treated with pulse steroids, cyclophosphamide, and plasmapheresis..

Goodpasture syndrome (Type I): Anti-GBM antibodies cross-react with pulmonary alveolar basement membrane (same α3 type IV collagen) → pulmonary haemorrhage + RPGN. HLA-DR15 predisposition. Young males. Haemoptysis + haematuria = Goodpasture until proven otherwise.

Treatment principle: All RPGN types require aggressive immunosuppression (pulse steroids + cyclophosphamide). Type I adds plasmapheresis to remove anti-GBM antibodies. Without treatment, ESRD within weeks.

SELF-CHECK

A 25-year-old man presents with haemoptysis and rapidly worsening renal function. Renal biopsy shows crescents in 70% of glomeruli with LINEAR IgG on immunofluorescence. Which serology is most likely positive?

A. Anti-neutrophil cytoplasmic antibodies (ANCA/MPO)

B. Anti-GBM antibodies

C. Anti-dsDNA antibodies

D. Anti-streptolysin O titre

Reveal Answer

Answer: B. Anti-GBM antibodies

Linear IgG on IF is the hallmark of anti-GBM antibody disease (Type I RPGN). The combination of pulmonary haemorrhage and rapidly progressive GN in a young male with linear IgG is classic Goodpasture syndrome — caused by autoantibodies against the NC1 domain of the α3 chain of type IV collagen. ANCA is associated with pauci-immune (Type III) RPGN, which shows a NEGATIVE IF.