What is the pathophysiology of Immunoglobulin A (IgA) nephropathy?

IgA Nephropathy Pathophysiology

IgA nephropathy is an autoimmune disease characterized by a multi-hit pathogenic process involving production of galactose-deficient IgA1 (Gd-IgA1), formation of immune complexes with anti-glycan autoantibodies, mesangial deposition of these complexes, and subsequent glomerular injury through mesangial cell activation and inflammation. 1, 2

The Four-Hit Hypothesis

The pathogenesis follows a sequential process:

Hit 1: Production of Galactose-Deficient IgA1

• Abnormal O-glycosylation of IgA1 occurs in the hinge region of heavy chains, resulting in IgA1 molecules with incomplete galactose residues on O-glycans 1, 3
• This aberrant glycosylation is attributed to abnormal expression and activity of key glycosyltransferases in IgA1-secreting cells 4
• Elevated circulating Gd-IgA1 is a heritable trait in IgAN patients, with genome-wide association studies identifying several immunity-related loci associated with disease 4
• Abnormal cellular signaling pathways in IgA1-producing cells drive the production of Gd-IgA1 4

Hit 2: Autoantibody Formation

• Gd-IgA1 acts as an autoantigen recognized by anti-glycan autoantibodies (IgG or IgA1) in susceptible individuals 1, 2
• These autoantibodies demonstrate restricted heterogeneity with specific molecular properties, including an A to S substitution in the complementarity-determining region 3 of the IgG heavy chain variable region 5
• The glycan-specific IgG antibody levels correlate with proteinuria severity and can differentiate IgAN patients from controls with 88% specificity and 95% sensitivity 5

Hit 3: Immune Complex Formation

• Circulating Gd-IgA1 bound by antiglycan antibodies forms pathogenic immune complexes 1, 2
• Complement activation occurs through both alternative and lectin pathways, likely happening systemically on circulating complexes and locally in glomeruli 1
• C3 frequently co-deposits with IgA in the mesangium, while C1q is less commonly present (helping distinguish IgAN from lupus nephritis) 6, 7

Hit 4: Mesangial Deposition and Glomerular Injury

• Immune complexes deposit in the glomerular mesangium, the definitive diagnostic feature being mesangial dominant or co-dominant IgA deposits on kidney biopsy 6, 7
• Deposited complexes activate mesangial cells, inducing cellular proliferation, overproduction of extracellular matrix components, and release of cytokines/chemokines 1, 3
• This leads to the mesangioproliferative glomerulonephritis characteristic of IgAN 5
• Electron microscopy reveals electron-dense deposits in the mesangium 6, 7

Genetic and Environmental Contributions

• Geographic variation in disease incidence suggests genetic influences: rare in central Africa but accounts for up to 40% of native-kidney biopsies in eastern Asia 1
• Genome-wide association studies have identified loci associated with increased IgAN prevalence, while others (such as deletion of complement factor H-related genes 1 and 3) are protective 1
• Environmental factors interact with genetic susceptibility to trigger disease, though specific inciting factors for autoantibody production remain incompletely understood 2, 3

Clinical Implications for Disease Progression

• High-risk features include proteinuria >1 g/day, uncontrolled hypertension, and impaired renal function at diagnosis 6, 7
• Up to 20-40% of patients progress to end-stage kidney disease within 20 years after disease onset 2
• The Oxford/MEST scoring system (mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis, interstitial fibrosis/tubular atrophy) provides standardized prognostic classification 8

Secondary IgA Nephropathy Considerations

• Always exclude secondary causes of IgA deposition including systemic lupus erythematosus, chronic liver disease, inflammatory bowel disease, infections, tumors, and rheumatic diseases 6, 7
• Secondary IgAN may have different pathogenic mechanisms despite similar histologic appearance 6