Complement role in kidney disease: a comprehensive review and therapeutic innovations

The complement system is a vital component of innate immunity, known for its role in pathogen defense. It has been increasingly recognized as a mediator of homeostatic clearance, tissue repair, and immune-metabolic crosstalk. In the kidney, unique anatomical and hemodynamic features predispose to aberrant complement activation, rendering glomerular structures particularly vulnerable. Complement dysregulation is implicated in a broad spectrum of kidney diseases – ranging from primary complement-driven disorders (atypical hemolytic uremic syndrome, C3 glomerulopathy, and emergent C4 glomerulopathy) to secondary complement disorders, with special emphasis on classical immune complex diseases, podocytopathies, and kidney transplantation. Within glomeruli, complement activation triggers non-lytic cellular activation (including calcium influx, kinase signaling, cytokine release, and cytoskeletal remodeling), inflammation, cytotoxic injury, and maladaptive remodeling via effectors such as C3a, C5a, and the membrane attack complex (C5b-9). Genetic and autoantibody–mediated defects in complement regulators amplify this risk. Recent advances in complement-targeted therapies—including inhibitors of C3, C5, factor B, and MASP-2—are entering glomerular disease trials, with early evidence of efficacy in proteinuria reduction and slowing of glomerular injury. Nevertheless, key challenges remain: balancing infection risk, defining appropriate durations, selecting responsive patient populations based on complement pathway profiling, and achieving cost-effectiveness. Looking ahead, integration of genetic, proteomic, and histopathologic biomarkers will be essential to implement a precision-medicine approach. Complement remains a frontier in glomerular disease research, bridging fundamental immunology to translational nephrology and offering new pathways to modify disease progression.