Xiaoman Wang
Introduction and aim Immune-mediated nephropathies are a mechanistically diverse group of kidney disorders in which dysregulated innate and adaptive immunity drive sustained inflammation, tissue injury, and progressive fibrosis. The kidney is not a passive target of these processes but an active immunological organ, where crosstalk between resident parenchymal cells and infiltrating leukocytes shapes both initiation and progression of disease. Advances in immunogenetics and molecular pathology have allowed several previously idiopathic entities—lupus nephritis, IgA nephropathy, ANCA-associated vasculitis, membranous nephropathy, and complement-mediated glomerulopathies—to be reclassified along mechanism-based lines. This review synthesizes the current understanding of their immunopathology, with emphasis on convergent signaling networks and on translational implications for diagnosis, risk stratification, and targeted therapy. Methodology We adopted an evidence-based narrative approach, integrating clinical and experimental findings from immunology, nephrology, immunogenetics, and multi-omics. Key domains examined included immune tolerance, immune-complex biology, complement dysregulation, the renal immune microenvironment, cytokine and chemokine networks, non-coding RNA regulation, and immune-derived renal biomarkers. Comparative analysis was used to distinguish shared immune programs from disease-specific cascades across the major nephritic syndromes. Results and Discussion Synthesizing evidence from over 150 peer-reviewed publications (2015–2025) across five major immune-mediated nephropathies, several recurrent immune modules emerge: autoantibody generation, complement activation, macrophage M1/M2 repolarization, and NLRP3 inflammasome priming. These converge on canonical signaling axes (TLR–MyD88, NF-κB, JAK–STAT, cGAS–STING, TGF-β/Smad), linking immune activation to glomerular injury and interstitial fibrosis. Established biomarkers (anti-dsDNA, anti-PLA2R, Gd-IgA1) guide diagnosis and risk stratification, while lncRNA signatures and exosomal cargo represent emerging non-invasive monitoring tools. Mechanism-targeted therapies—B-cell depletion, complement inhibition, and inflammasome modulation—are reshaping the treatment landscape. Conclusion Immune-mediated nephropathies arise from the interaction between systemic immune dysregulation and a nephron-specific immune microenvironment. Distinguishing the shared immune programs from disease-defining cascades provides a rational basis for stratification and precision medicine. Integrated serologic, urinary, histologic, genetic, and multi-omics biomarkers can support earlier diagnosis and dynamic treatment adjustment. Therapy that targets the dominant pathogenic axis in each patient—rather than broad immunosuppression—offers the most realistic route to delaying end-stage renal disease, reducing toxicity, and improving long-term outcomes.