Complement Activation in Primary IgA Nephropathy (CAIGAN): study protocol for an international prospective multicenter observational cohort study

Background IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and a leading cause of chronic kidney disease and kidney failure. Increasing evidence supports a central role for complement activation in disease severity and crescent formation. With the emergence of complement-targeted therapies, biomarkers identifying patients with active complement dysregulation are increasingly needed. Methods CAIGAN (Complement Activation in IgA Nephropathy) is an international, prospective, observational multicenter cohort study involving adult and pediatric nephrology centers in Switzerland, Italy, France, and Spain. Consecutive patients undergoing clinically indicated native kidney biopsy for suspected IgAN will be screened, and those with biopsy-proven primary IgAN will be enrolled. Clinical, laboratory, and histopathological data will be collected at baseline, with clinical and laboratory follow-up at 1, 2, and 3 years. Blood and urine samples for complement analyses will generally be obtained after histopathological confirmation of IgAN, within 4 weeks after kidney biopsy and before initiation of immunosuppressive therapy. In patients with a rapidly progressive clinical course requiring prompt immunosuppressive treatment, sampling may precede histopathological confirmation and will be performed after informed consent and before administration of immunosuppressive agents. Complement profiling will include circulating complement proteins and activation products, functional pathway assessment, and optional complement-related genetic analyses. Kidney biopsies will be characterized using the Oxford MEST-C classification, with intrarenal complement deposition and exploratory transcriptomic analyses of residual kidney tissue performed in a subgroup. The primary objective is to validate prospectively the association observed in our retrospective pilot study between circulating sC5b-9 concentrations and the percentage of active glomerular crescents. Secondary exploratory objectives include characterization of the mechanisms underlying complement activation and dysregulation and evaluation of their associations with clinical phenotype, histopathological findings, renal tissue complement activation, genetic and transcriptomic profiles, and longitudinal kidney outcomes. Discussion CAIGAN will integrate complement phenotyping, genetics, histopathology, and prospective clinical follow-up to characterize complement activation across the spectrum of primary IgAN and possibly support the development of biomarker-guided therapeutic strategies.