IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide and a leading cause of CKD progression to end-stage renal disease. The four-hit pathogenesis model, consolidated by Wyatt & Julian in the New England Journal of Medicine (2013), describes the sequential roles of galactose-deficient IgA1 (Gd-IgA1) overproduction, autoantibody formation, immune complex deposition in the mesangium, and subsequent glomerular inflammation in driving disease progression.
The International Society of Nephrology has facilitated scientific dialogue on IgAN pathophysiology through its working groups and through KDIGO Clinical Practice Guidelines for Glomerulonephritis (2012 and 2021 update). Genome-wide association studies, including the large multicenter GWAS by Kiryluk et al. (Nature Genetics, 2014), identified 15 susceptibility loci for IgAN including variants in complement genes, cytokine networks, and HLA regions, confirming both innate and adaptive immune contributions to disease.
The role of mucosal immunity in IgAN has been further defined by research implicating APRIL and BAFF cytokines in driving overproduction of aberrantly glycosylated IgA1 by mucosal plasma cells. This mechanism provided the basis for the development of targeted-release budesonide (Nefecon), evaluated in the NefIgArd phase 3 trial (Barratt et al., New England Journal of Medicine, 2023), which demonstrated significant reductions in proteinuria and eGFR decline over two years in patients with IgAN.
Complement system inhibition has emerged as a central therapeutic strategy for IgAN. Iptacopan, a Factor B inhibitor of the alternative complement pathway, was evaluated in the APPLAUSE-IgAN trial, and sparsentan, a dual endothelin and angiotensin receptor antagonist, was studied in the PROTECT trial (Rovin et al., Lancet, 2023), demonstrating significant proteinuria reduction compared to irbesartan at 36 weeks.
ISN has underscored the importance of the Oxford MEST-C classification system (Roberts et al., Kidney International, 2009; updated 2017) for standardized biopsy reporting and enabling multinational clinical trial enrollment. The ISN-supported IgAN registry and collaborative research networks continue to provide the epidemiological and biomarker data needed to guide individualized therapeutic decision-making across diverse patient populations.