Plasma Proteomics in IgA Nephropathy: From Circulating Biomarkers to Molecular Endotypes

IgA nephropathy (IgAN) is a primary glomerular disease with various clinical features, disease progression, and therapeutic responses that affects people worldwide. Currently, risk stratification depends primarily on clinical variables, together with the Oxford MEST-C classification, which indicates structural damage. However, these approaches only provide a limited explanation of the molecular mechanisms responsible for the disease. Recent proteomic discoveries have enabled researchers to characterize proteins not only in blood plasma and urine but also in kidney tissues, opening new avenues for understanding the underlying biology of IgAN. Our review addresses existing findings in plasma proteomic studies and, at the same time, brings into the picture developments in urinary and tissue proteomic profiling, thereby demonstrating that molecular profiling has been essential for further understanding of IgAN pathogenesis. Several research studies highlight complement system dysregulation, immune system overactivity, extracellular matrix remodeling, and metabolic disturbances as the leading factors linked to disease activity and progression. Even after many years in biomarker discovery, the development and clinical application of single plasma-based molecules as markers for disease detection remain challenging. Proteomic signatures based on the various processes involved in a single disease consistently outperform single protein identification in describing complexity and distinguishing molecular endotypes. We also present the current status of proteomic-based profiling methods, cross-linking proteomics with other data sources, and the remaining clinical application barriers. Through the development of this technology, proteomics has not only enabled the discovery of new biomarkers but also provided a framework for viewing IgAN as a heterogeneous disease comprising distinct molecular endotypes. Overall, current evidence indicates that proteomics is evolving from biomarker discovery toward molecular disease classification, with the potential to improve prognostication, guide mechanism-based therapeutic selection, and advance precision nephrology in IgAN.