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Immunoglobulin A nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide. Up to 40% of individuals progress to develop end-stage renal disease about 20 years after diagnosis, making IgAN a leading cause of chronic kidney disease and contributing to a significant mortality rate.1 This complex autoimmune disease involves multiple pathogenic mechanisms and genetic factors that, together, shape its development and progression.2 The Multi-Hit Theory: A Cascade of Events3 The widely accepted Multi-Hit Theory explains IgAN pathogenesis through four sequential events: Hit 1: Production of Galactose-Deficient IgA1 (Gd-IgA1) The process begins with increased levels of abnormally glycosylated IgA1 molecules in circulation. Research shows that patients with IgAN have elevated serum levels of Gd-IgA1 compared to healthy individuals or patients with other kidney diseases. Hit 2: Autoantibody Formation The second hit involves the body recognizing Gd-IgA1 as foreign, triggering the production of antiglycan autoantibodies (IgG or IgA). Hit 3: Immune Complex Formation These autoantibodies (IgG and IgA) bind with Gd-IgA1, forming immune complexes that circulate in the bloodstream. Studies have demonstrated that these complexes are larger and more likely to deposit in the kidneys. Hit 4: Mesangial Deposition and Inflammation The immune complexes deposit in the glomerular mesangium, activating complement pathways and triggering local inflammation during the final stage. Genetic Factors: The Blueprint of Susceptibility4 Recent genetic studies have revolutionized the understanding of IgAN susceptibility: Genome-Wide Association Studies (GWAS) The latest GWAS meta-analysis identified 30 genome-wide significant risk loci for IgAN, including 16 novel loci, explaining approximately 11% of disease risk. These findings highlight several key pathways: • Immune system regulation Hereditary Patterns Family studies reveal: • 40%–50% estimated heritability Epigenetic Influences Beyond genetic variants, epigenetic modifications play crucial roles: • Deoxyribonucleic acid methylation patterns affect T cell activation Clinical Implications Understanding these pathogenic mechanisms and genetic factors has important clinical implications: 1. Risk Stratification: Genetic profiling may help identify high-risk patients Conclusion The Multi-Hit Theory and genetic studies have transformed the understanding of IgAN pathogenesis. This knowledge opens new avenues for targeted therapies and personalized treatment approaches. Continued research in this field promises to further unlock the mysteries of this complex disease. References ▼ 1. Rajasekaran A, Julian BA, Rizk DV. IgA nephropathy: An interesting autoimmune kidney disease. Am J Med Sci. 2021;361(2):176–194. LMRC Code: GGI-CO-A1-AQS-300027679-BANNERS-L24-0566 |
