Known Causes of IgA Nephropathy (IgAN)
IgAN is primarily an autoimmune disease characterized by the production of aberrantly glycosylated IgA1 (undergalactosylated IgA1), followed by formation of IgG autoantibodies against this abnormal IgA1, leading to immune complex formation and glomerular deposition 1.
Primary Pathogenic Mechanism
The pathogenesis follows a multi-hit hypothesis involving:
- Overproduction of undergalactosylated IgA1: Galactose-deficient O-linked glycans in the hinge region of IgA1 molecules, likely due to dysregulation of the mucosal immune system 1, 2
- Autoantibody formation: Development of glycan-specific IgA and IgG autoantibodies that recognize the undergalactosylated IgA1 1
- Immune complex circulation and deposition: These IgG-IgA immune complexes circulate and deposit in the glomerular mesangium 2
- Glomerular inflammation: Mesangial cell activation leads to local overproduction of cytokines, chemokines, and complement (particularly alternative pathway activation), causing podocyte and tubulointerstitial injury 1, 3
Important caveat: Aberrant glycosylation alone is insufficient to cause disease—the formation of autoantibodies against the abnormal IgA1 is required for renal injury 1.
Genetic Factors
- Common genetic variants contribute to IgAN susceptibility, with genome-wide association studies identifying multiple risk loci 4
- Rare complement pathway variants: Pathogenic variants in complement regulatory genes (e.g., cofactor I) can lead to more aggressive IgAN phenotypes with membranoproliferative patterns and resistance to immunosuppression 3
- Familial clustering occurs, suggesting heritable components 3
Secondary Causes to Exclude
Before diagnosing primary IgAN, the following secondary causes must be ruled out, as they can produce identical histologic findings of IgA-dominant mesangial deposits 5, 2:
- Chronic inflammatory bowel disease (Crohn's disease, ulcerative colitis)
- Liver disease: Cirrhosis from any cause (impaired IgA clearance) 6
- Autoimmune hepatitis (immune dysregulation) 6
- Infections: Viral hepatitis, HIV, chronic bacterial infections 5
- Celiac disease
- Rheumatic diseases: Axial spondyloarthritis, other autoimmune conditions 5
- Malignancies/tumors 2
- IgA vasculitis (Henoch-Schönlein purpura)
- IgA-dominant infection-related glomerulonephritis (particularly staphylococcal infections) 7, 5
Diagnostic Confirmation
Kidney biopsy is mandatory for diagnosis 5. The diagnosis requires:
- IgA-dominant or co-dominant mesangial immune deposits on immunofluorescence 7
- Exclusion of all secondary causes listed above
- Histologic scoring using the MEST-C classification system (mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis, tubular atrophy/interstitial fibrosis, crescents) 8, 9
Critical pitfall: Do not diagnose primary IgAN without systematically excluding secondary causes through appropriate clinical history, serologic testing (hepatitis panel, HIV, autoimmune markers), and evaluation for systemic diseases 5, 2.