Causes of IgA Nephropathy
IgA nephropathy is primarily caused by abnormal galactosylation of IgA1 antibodies, leading to the formation of immune complexes that deposit in the mesangium of the glomeruli, triggering inflammation and kidney damage. 1, 2
Pathogenic Mechanisms
Primary Pathogenic Steps
IgA nephropathy develops through a multi-hit process involving several sequential pathogenic events 1, 3:
Step 1: Abnormal IgA1 Production - Increased levels of poorly O-galactosylated IgA1 in circulation, possibly related to migration of mucosal B cells to bone marrow 1, 3
Step 2: Autoantibody Formation - Generation of IgG antibodies against the poorly galactosylated IgA1, creating an autoimmune response 1, 3
Step 3: Immune Complex Formation - Development of IgG-IgA1 or IgA1-IgA1 immune complexes that circulate in the bloodstream 1, 4
Step 4: Mesangial Deposition - Deposition of these immune complexes in the mesangium of glomeruli, characterized by mesangial dominant or co-dominant IgA staining on immunofluorescence 5
Step 5: Complement Activation - Activation of mesangial IgA receptors and/or complement pathways, leading to inflammation 1, 3
Step 6: Tissue Damage - Mesangial cell damage and activation of secondary pathways that drive glomerulosclerosis and tubulointerstitial fibrosis 1, 4
Diagnostic Features
The definitive diagnostic feature is the presence of mesangial dominant or co-dominant IgA deposits on kidney biopsy 5
Electron microscopy typically reveals electron-dense deposits in the mesangium 5
C3 is often present alongside IgA deposits, while C1q is less commonly found 5
Contributing Factors
Genetic Factors
Genetic predisposition plays a significant role in determining who develops clinically significant disease 1, 3
Familial cases of IgA nephropathy have been reported, suggesting hereditary components 6
Environmental Triggers
Mucosal inflammation, particularly in the gastrointestinal tract, may trigger IgA nephropathy 6
Upper respiratory tract infections often precede episodes of gross hematuria in IgA nephropathy patients 4
Dietary and microbial antigens have been identified in circulating IgA immune complexes and mesangial deposits 6
Secondary Causes
IgA nephropathy can be secondary to liver disease, which impairs clearance of IgA complexes 6
Staphylococcal infections can lead to dominant IgA deposition in glomeruli 5
Secondary IgA nephropathy can occur in association with other autoimmune diseases 6
Disease Heterogeneity
IgA nephropathy presents with significant clinical heterogeneity, ranging from asymptomatic microscopic hematuria to rapidly progressive glomerulonephritis 2, 4
The disease may be influenced by both generic progression factors (e.g., hypertension) and specific pathogenic mechanisms 1
Progression to end-stage kidney disease occurs in approximately 20-40% of patients within 20 years of diagnosis 2, 4
Clinical Implications
Understanding the pathogenesis has led to development of targeted therapies addressing specific steps in the disease process 2, 4
Patients with proteinuria >1 g/day, hypertension, and impaired renal function at diagnosis are at high risk for disease progression 5, 2
Optimized supportive care, including RAS blockade with ACE inhibitors or ARBs, remains the cornerstone of management 5, 7
Research Directions
Current research focuses on precise identification of genetic, epigenetic, immunological, and molecular mechanisms 3
Novel therapeutic targets include mucosal immunity modulation, complement inhibition, and specific growth factor inhibitors 1, 2
Development of non-invasive biomarkers for diagnosis and monitoring is an active area of investigation 1, 3