What is IgA (Immunoglobulin A) nephropathy?

IgA Nephropathy: Definition and Pathophysiology

IgA nephropathy is the most common primary glomerulonephritis worldwide, characterized by mesangial dominant or co-dominant IgA deposits in the glomeruli, which can lead to progressive kidney damage and potentially end-stage kidney disease. 1

Pathophysiology

IgA nephropathy follows a "four-hit" pathogenic process:

1. Production of galactose-deficient IgA1 (Gd-IgA1) - Abnormally glycosylated IgA1 molecules
2. Formation of autoantibodies - Anti-Gd-IgA1 IgG or IgA antibodies develop
3. Immune complex formation - Gd-IgA1 and autoantibodies form immune complexes
4. Mesangial deposition - These complexes deposit in the glomerular mesangium, triggering inflammation 2

Diagnostic Features

Histopathology

• Immunofluorescence: Mesangial dominant or co-dominant IgA deposits (defining feature) 1
• Light microscopy: Various patterns including:
  • Mesangial proliferation
  • Endocapillary hypercellularity
  • Segmental sclerosis
  • Crescents (in severe cases) 1
• Electron microscopy: Electron-dense deposits in the mesangium 1

Oxford Classification (MEST-C Score)

• M: Mesangial hypercellularity
• E: Endocapillary hypercellularity
• S: Segmental glomerulosclerosis
• T: Tubular atrophy/interstitial fibrosis
• C: Crescents 1

Clinical Presentation

• Most common: Asymptomatic microscopic hematuria with varying degrees of proteinuria
• Less common: Macroscopic hematuria during upper respiratory infections
• Variable: Hypertension, reduced kidney function
• Long-term: 20-40% of patients develop end-stage kidney disease within 20 years 3, 2

Risk Factors for Progression

1. Proteinuria >1 g/day - Major modifiable risk factor
2. Hypertension - Second major modifiable risk factor
3. Reduced eGFR at diagnosis
4. Unfavorable histological features (high MEST-C score)
5. Persistent hematuria (though its independent significance remains uncertain) 4, 3, 5

Epidemiology

• Most prevalent primary glomerulonephritis worldwide
• Higher prevalence in Asian-Pacific populations
• Relatively rare in people of African descent
• Can affect all ages, but often diagnosed in young adults 5

Pathogenic Mechanisms

• Mucosal immune dysregulation: Abnormal IgA production at mucosal surfaces
• B-cell and plasma cell dysfunction: Production of pathogenic antibodies
• Complement activation: Both alternative and lectin pathways involved
• Mesangial cell activation: Leading to inflammation and fibrosis 6, 2

Biomarkers

• Serum Gd-IgA1 levels: Elevated in many patients
• Anti-Gd-IgA1 antibodies: Associated with disease activity
• Urinary biomarkers: Under investigation for non-invasive monitoring
• No validated non-invasive diagnostic test: Kidney biopsy remains the gold standard 3

Distinguishing Features

IgA nephropathy must be distinguished from:

• Secondary causes of IgA deposition (liver disease, inflammatory bowel disease)
• IgA vasculitis (Henoch-Schönlein purpura)
• Other forms of glomerulonephritis
• Lupus nephritis (which can have "full house" immune deposits including IgA) 1

Emerging Understanding

Recent research has expanded our understanding of IgA nephropathy as an autoimmune disorder with complex pathophysiology involving mucosal immunity, complement activation, and genetic factors. This has led to the development of targeted therapies addressing specific pathogenic mechanisms rather than relying solely on non-specific immunosuppression 7, 6.