Pathogenic Gd-IgA1

IgA nephropathy is the most common primary glomerular nephritis worldwide and remains one of the leading causes of kidney failure. Although IgA nephropathy is a heterogeneous disease, glomerular deposition of galactose-deficient IgA1 (Gd-IgA1) is considered a pathological feature shared across the disease. This pathological hallmark underpins the multihit hypothesis of IgA nephropathy and has driven the development of therapies targeting Gd-IgA1 production, several of which have recently demonstrated clinical efficacy and received regulatory approval. These advances provide a timely opportunity to re-evaluate the role of Gd-IgA1 in the pathogenesis of IgA nephropathy. Notably, analysis of longitudinal changes in serum Gd-IgA1 levels and proteinuria reported in recent therapeutic trials raises the possibility that only a subset of circulating Gd-IgA1, rather than the entire circulating Gd-IgA1 pool, may drive glomerular inflammation leading to hematuria and/or proteinuria in IgA nephropathy. In this review, we propose the concept of “pathogenic Gd-IgA1” to describe this disease-relevant subset and highlight three potential features: a mucosal origin, molecular properties that promote selective mesangial deposition, and the capacity to form immune complexes and activate the complement system. This conceptual framework may deepen our understanding of IgA nephropathy pathogenesis, help optimize the use of emerging therapies, and facilitate the development of novel therapies that selectively target pathogenic Gd-IgA1.