Gender-specific associations between serum indirect bilirubin and chronic kidney disease risk: a prospective cohort study highlighting a protective effect confined to males.

BACKGROUND: Current evidence remains limited regarding associations between serum indirect bilirubin (IBIL) levels and chronic kidney disease (CKD) risk, particularly in gender-stratified analyses. This study investigated the gender-specific relationship between serum IBIL and CKD incidence. METHODS: Using data from a prospective cohort in northwestern China, we followed 25,684 CKD-free participants. Cox proportional hazards models and restricted cubic spline regression were employed to assess IBIL-CKD associations. The discriminatory performance of IBIL was evaluated through ROC curve analysis. Robustness of results was examined via subgroup and sensitivity analyses. RESULTS: Over 122,401.17 person-years of follow-up, 1,219 incident CKD cases were identified. Adjusted hazard ratios (95% CIs) for CKD were 0.799 (0.679–0.940) overall and 0.718 (0.693–0.869) among males. Area under the curve (AUC) values were 0.710 (0.704–0.715; p < 0.001) overall, 0.710 (0.703–0.718; p < 0.001) for males, and 0.679 (0.670–0.688; p < 0.001) for females. A formal test for interaction confirmed that the association was significantly modified by sex (p for interaction < 0.001). A linear dose-response pattern was observed exclusively in males. Results remained consistent across subgroup and sensitivity analyses. CONCLUSIONS: Our findings reveals a significant sex interaction in the association between serum IBIL and CKD. The inverse association is robust, exhibits a linear dose-response relationship, and is statistically significant exclusively in males. These findings position serum IBIL as a sexually dimorphic factor linked to CKD risk, underscoring the necessity of considering gender in both the research and potential risk assessment of oxidative stress-related pathways in renal disease.