IgA nephropathy: gut microbiome insights and unmet needs in pediatrics

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulopathy worldwide and a leading cause of chronic kidney disease and kidney failure in children and young adults. Well-established pathogenic pathways include genetic susceptibility, intrinsic B-cell glycosylation abnormalities, complement activation, and immune dysregulation, and accumulating evidence further places the gut microbiome at the center of IgAN pathogenesis via the gut-kidney axis. A critical evidence gap defines the field: no prospective cohort has characterized the gut microbiome in pediatric primary IgAN. This conceptual narrative review synthesizes well-validated mechanistic data from adult cohorts-most notably microbial-mediated IgA1 deglycosylation-and extrapolates these findings to pediatric populations through the lens of the developmental entanglement framework, which accounts for the synchronized maturation of the gut microbiome, mucosal immunity, and renal structure in early life. Using an adapted Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, we separately rate evidence quality for adult and pediatric populations, explicitly mark all pediatric extrapolations as unvalidated, and cautiously appraise indirect evidence from pediatric IgA vasculitis with nephritis (IgAVN). We further evaluate the translational potential of microbiome-guided strategies, and conclude with a pragmatic, stepwise research agenda centered on foundational cohort studies and emerging technologies to address the evidence gap. Closing this deficit will enable the development of non-invasive biomarkers and safe, mechanism-targeted therapies to prevent progressive renal failure in children with IgAN.