What causes IgA (Immunoglobulin A) nephropathy?

Causes of IgA Nephropathy

IgA nephropathy is caused by a "four-hit" pathogenic process involving production of galactose-deficient IgA1, formation of autoantibodies against this abnormal IgA1, immune complex formation, and mesangial deposition leading to kidney damage. 1, 2

Pathogenic Mechanism: The Four-Hit Hypothesis

1. First Hit: Production of Galactose-Deficient IgA1 (Gd-IgA1)

   • Abnormal O-glycosylation of IgA1 molecules in the hinge region
   • Results in galactose-deficient IgA1 (Gd-IgA1) 3, 2
   • Elevated serum levels of Gd-IgA1 are present in many IgAN patients 1

2. Second Hit: Production of Autoantibodies

   • Formation of autoantibodies (IgG or IgA1) against the Gd-IgA1 molecules
   • These anti-Gd-IgA1 antibodies recognize the aberrant glycosylation pattern 2
   • Autoantibody production correlates with disease activity 1

3. Third Hit: Immune Complex Formation

   • Gd-IgA1 and anti-Gd-IgA1 antibodies form immune complexes in circulation
   • These complexes are resistant to normal clearance mechanisms 3, 2

4. Fourth Hit: Mesangial Deposition and Inflammation

   • Immune complexes deposit in the glomerular mesangium
   • Deposition triggers complement activation (often C3)
   • Results in mesangial cell proliferation, inflammation, and glomerular injury 4, 2
   • Eventually leads to progressive kidney damage through inflammatory pathways 5

Contributing Factors

Genetic Factors

• Multiple genetic loci have been associated with IgAN susceptibility
• Genetic factors influence the production of Gd-IgA1 and anti-Gd-IgA1 antibodies 3

Immunological Abnormalities

• Dysregulation of mucosal immunity (gut-kidney axis)
• Abnormal B cell and plasma cell function
• CD38-positive plasma cells are the main source of pathogenic antibodies 4
• Complement pathway activation, particularly through the alternative and lectin pathways 2

Environmental Triggers

• Mucosal infections (particularly upper respiratory tract)
• Dietary antigens
• These may trigger immune responses that cross-react with self-antigens 3

Diagnostic Features

The definitive diagnosis of IgA nephropathy requires kidney biopsy showing:

• Mesangial dominant or co-dominant IgA deposits by immunofluorescence 5, 1
• Often accompanied by C3 deposition
• Electron microscopy shows electron-dense deposits in the mesangium 1
• Light microscopy may reveal various patterns including mesangial proliferation, endocapillary hypercellularity, segmental sclerosis, and crescents 1

Clinical Implications

Understanding the pathogenesis of IgA nephropathy has led to targeted therapeutic approaches:

• Targeting B cells and plasma cells to reduce production of pathogenic antibodies 4
• Complement inhibition to reduce inflammation 6
• Immunosuppressive therapies for high-risk patients 5
• Supportive care with RAS blockade to reduce proteinuria and control blood pressure 5

The complex pathogenesis explains why approximately 30% of patients progress to end-stage kidney disease within 20 years of diagnosis despite current treatments 6.