Pathogenesis of glomerular diseases

1. Three Approaches to Classification

Glomerular disease classification differs by specialty:

1. Clinical — what the clinician sees (labs, Sx)
2. Histological — what the pathologist sees
3. Immunological — immune mechanism

2. Clinical Classification

A) Acute nephritic syndrome

• Macroscopic painless hematuria
• Mild proteinuria
• Mild hypertension
• Some oliguria & azotemia

B) Rapidly progressive glomerulonephritis (RPGN)

• Rapid loss of renal function over days–weeks.
• Untreated → acute renal failure / death.
• Sx: oliguria/anuria, hematuria, proteinuria.
• Crescentic morphology — severe capillary damage → fibrin escape → Bowman capsule proliferation → crescents.

C) Nephrotic syndrome

• Massive proteinuria (>3.5 g/day) + hypoalbuminemia (<3.0 g/dL).
• Generalized edema (↓ oncotic pressure).
• Hyperlipoproteinemia (compensatory hepatic synthesis) → lipuria (oval fat bodies).

D) Asymptomatic hematuria / proteinuria

• No symptoms; mild urinary abnormalities only.

E) Chronic glomerulonephritis (CGN)

• End-stage kidney; prolonged uremia.

3. Histological Classification

A) Glomerular hypercellularity

• Cellular proliferation of:
  • Capillary endothelial cells
  • Epithelial cells (parietal/visceral)
  • Mesangial cells
• Leukocyte infiltration: neutrophils, monocytes, lymphocytes.

B) GBM thickening

• Linear (anti-GBM) or diffuse (immunocomplex) thickening.
• Granular deposits at subepithelial or subendothelial sites.

C) Hyalinization & sclerosis

• Capillaries replaced by hyalinic sclerotic tissue → hardening.
• Precipitation of plasma proteins (hyaline).
• Hallmark of end-stage disease.

Distribution descriptors:

Term	Meaning
Focal	Only some glomeruli affected
Diffuse	All glomeruli affected
Segmental	Only part of a glomerulus
Global	Entire glomerulus

4. Immunological Classification

Three mechanisms of antibody-mediated injury:

1. Circulating Ag-Ab immune complex deposition (type III HS)
2. In-situ antibody reaction (against fixed intrinsic OR planted antigens)
3. Antibodies against glomerular cell components

A) Circulating immune complex GN (type III HS)

• Antigen NOT of glomerular origin:
  • Endogenous: e.g., SLE (anti-DNA)
  • Exogenous: bacterial, viral, parasitic
• Complexes form in circulation → deposit in glomeruli → complement + leukocyte activation → injury.
• Deposits in subendothelial, subepithelial, or mesangial locations.
• IF: granular deposits.
• Complexes can be degraded/phagocytosed by leukocytes & mesangial cells.

B) In-situ immune complex GN

Anti-GBM antibody GN

• Antibodies against fixed antigens in GBM (component of collagen IV — α3 chain of NC1 domain).
• IF: linear pattern of IgG.
• Cross-reactivity with alveolar BM → Goodpasture syndrome (lung + kidney).

Antibodies against planted non-glomerular antigens

• Antigens deposited in glomeruli, then react with circulating Abs.
• Endogenous: DNA, IgA.
• Exogenous: bacterial antigens, aggregated proteins, drugs.
• IF: mostly granular, can be linear.

Heymann nephritis (experimental model of membranous GN)

• Brush border antigen from rabbit → rat → generates anti-brush-border antibodies → cross-react with podocyte antigens (megalin in humans = PLA2R) → membranous GN.
• IF: granular deposits.

C) Antibodies against glomerular cells

• Direct attack on endothelial, mesangial, or epithelial cells (e.g., ANCA-associated vasculitis).

5. Quick Reference — IF Pattern

IF pattern	Mechanism	Examples
Linear	Anti-GBM	Goodpasture syndrome
Granular	Immune complex	Post-strep, SLE, membranous, IgA
Pauci-immune (negative)	ANCA vasculitis	Microscopic polyangiitis, GPA

💡 High-yield: Glomerular dz → 5 clinical pictures (nephritic, RPGN, nephrotic, asymptomatic, chronic). Pathologic features = hypercellularity, GBM thickening, sclerosis; described as focal/diffuse + segmental/global. Three immune mechanisms: circulating IC (granular IF, type III), in-situ (linear IF = anti-GBM → Goodpasture; granular = Heymann/membranous), ANCA-vasculitis (pauci-immune).