What is the pathogenesis of IgA (Immunoglobulin A) nephropathy in a patient with impaired renal function, potentially progressing to end-stage renal disease?

Pathogenesis of IgA Nephropathy

IgA nephropathy results from mesangial deposition of immune complexes containing galactose-deficient IgA1 (Gd-IgA1) bound to anti-glycan autoantibodies, triggering mesangial cell activation, complement activation, inflammatory cell recruitment, and progressive glomerular injury. 1, 2

The Four-Hit Hypothesis of Disease Development

The pathogenesis follows a sequential multi-step process:

Hit 1: Production of Galactose-Deficient IgA1

• IgA1-secreting cells produce abnormally O-glycosylated IgA1 with missing galactose residues that are normally β1,3-linked to N-acetylgalactosamine on the hinge region core 1 glycans 2
• This aberrant glycosylation occurs due to dysregulated expression and activity of several glycosyltransferases in the mucosal immune system 3, 4
• The undergalactosylation exposes N-acetylgalactosamine residues that become antigenic 2

Hit 2: Formation of Autoantibodies

• IgG (and sometimes IgA) autoantibodies develop against the exposed galactose-deficient glycan structures on IgA1 1, 3
• These anti-glycan autoantibodies specifically recognize the abnormally glycosylated hinge region of Gd-IgA1 2

Hit 3: Immune Complex Formation and Circulation

• Circulating immune complexes form when IgG autoantibodies bind to Gd-IgA1, often incorporating additional proteins such as complement C3 1, 2
• These pathogenic immune complexes persist in circulation when not adequately cleared 2

Hit 4: Mesangial Deposition and Glomerular Injury

• Immune complexes deposit in the glomerular mesangium, where they activate mesangial cells and trigger downstream inflammatory cascades 1, 4
• The definitive diagnostic feature is mesangial dominant or co-dominant IgA deposits on kidney biopsy 5, 6
• Electron microscopy reveals electron-dense deposits in the mesangium, typically with C3 co-deposition 5

Mechanisms of Progressive Kidney Damage

Direct Cellular Effects

• Mesangial cell activation leads to proliferation and increased extracellular matrix production, contributing to mesangial expansion 1, 4
• Inflammatory cell recruitment amplifies local tissue injury 1
• Podocyte damage occurs as a consequence of the inflammatory milieu 1

Complement Activation Pathways

• Multiple complement pathways are activated following immune complex deposition, including the alternative pathway, lectin pathway (MASP-2), and common pathway (C3 and C5) 1
• Complement activation drives glomerular inflammation and contributes to progressive fibrosis 4

Progression to Fibrosis

• Chronic inflammation results in tubulointerstitial fibrosis and glomerulosclerosis, the final common pathway to end-stage renal disease 4
• Approximately 20-50% of patients progress to kidney failure, with about one-third reaching end-stage kidney disease within 10-20 years 1, 3

Clinical Implications of Pathogenesis

Secondary Causes to Exclude

• Always assess for conditions that can cause secondary IgA deposition, including chronic inflammatory bowel disease, liver disease, infections, tumors, and rheumatic diseases 7, 3
• These represent shared inflammatory pathways rather than primary IgA nephropathy 6

Risk Factors for Progression

• Proteinuria >1 g/day, uncontrolled hypertension, and impaired renal function at diagnosis indicate high risk for disease progression 5
• The Oxford MEST-C histologic classification helps estimate prognosis and should always be reported 3

Common Pitfalls in Understanding Pathogenesis

• Do not assume all mesangial IgA deposition represents primary IgA nephropathy—secondary causes must be systematically excluded 7, 3
• The presence of C1q is less common in IgA nephropathy compared to lupus nephritis, helping distinguish these entities 5
• Spontaneous remission occurs in only 7% of patients, so most require active management despite the autoimmune nature 8