Layered immune biomarker monitoring in IgA nephropathy: from mucosal IgA dysregulation to precision therapeutic response assessment

Abstract

IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and remains a major cause of chronic kidney disease and kidney failure. Conventional monitoring still depends largely on proteinuria, estimated glomerular filtration rate (eGFR), hematuria, blood pressure and biopsy-based pathological classification. These measures are clinically indispensable, but they mainly capture downstream kidney injury and may lag behind the mucosal and systemic immune events that drive active disease. In the targeted-therapy era, this limitation has become more consequential. Targeted-release budesonide, BAFF/APRIL dual inhibitors, APRIL inhibitors and complement-directed therapies act at different levels of the IgAN immunopathogenic cascade. Galactose-deficient IgA1 (Gd-IgA1) remains central to disease biology, yet its standalone value as a marker of disease activity or prognosis is limited by assay heterogeneity, ethnic and clinical variability, treatment exposure and differences in histopathological context. Increasing evidence suggests that the pathogenicity of IgA depends not only on Gd-IgA1 concentration, but also on mucosal origin, polymeric state, autoantibody binding, immune-complex formation, mesangial retention and complement activation. This Review synthesizes recent advances in immune biomarker monitoring in IgAN, with emphasis on mucosal immune activity, Gd-IgA1, polymeric IgA, IgA-containing immune complexes, complement activation and kidney injury biomarkers. Its contribution is not another undifferentiated catalog of candidate markers. Instead, biomarkers are organized according to their position in the disease cascade and their relationship to treatment mechanism: upstream mucosal immune activation, pathogenic IgA immune-complex burden, complement-mediated intrarenal amplification and tissue injury, and conventional clinical outcomes. The framework is intended to support mechanistic research, trial enrichment and longitudinal pharmacodynamic assessment, while distinguishing established clinical measures from biomarkers that remain investigational. Its use for treatment selection or routine precision monitoring requires prospective validation and assay standardization.