Objective <p>To monitor the progression of chronic kidney disease to kidney failure is a pressing clinical challenge given its increasing incidence.</p> Methods <p>In a retrospective cohort of 764 patients admitted to our hospital between June 2021 and June 2024, we performed a comprehensive analysis of serum complement C3/C4 levels.</p> Results <p>Longitudinal assessment revealed a progressive, dose-dependent decline in serum C3 that correlated with disease advancement from renal insufficiency to chronic renal failure and ultimately to kidney failure. To further investigate the role of C3, we utilized an adenine-induced nephropathy model in mice. C3^−/− (C3-deficient) mice exhibited heightened susceptibility to renal injury, reflected by significant elevations in urea, uric acid, and creatinine levels. Flow cytometric analysis showed an 11% reduction in renal CD19⁺ B cell infiltration in C3^−/− mice compared with wild-type controls. Mechanistically, C3 promotes B cell recruitment via the CD21/CD35 complement receptors, and these recruited B cells upregulate IL-10 to exert a renoprotective effect. Logistic regression identified serum C3 as a candidate predictive biomarker for distinguishing kidney failure.</p> Conclusions <p>Serum C3 may represent a candidate biomarker worthy of further prospective validation for tracking the progression of CKD. Our research findings are expected to establish a novel prognostic framework for risk stratification of CKD patients through continuous serum C3 monitoring, offering a critical window for early intervention in end-stage renal disease.</p>