Sex-Differentiated Threshold Effects of Homocysteine Levels on CKD Risk in Patients with Hypertension and Coronary...

Elevated homocysteine (Hcy) is a risk factor for hypertension and cardiovascular disease. However, whether increased Hcy elevates chronic kidney disease (CKD) risk specifically in patients with coexisting hypertension and coronary artery disease (CAD) remains unclear.

This study employed a cohort study design and included a total of 1657 patients with coexisting hypertension and CAD. Multivariate Cox regression assessed the association between Hcy and CKD risk. Kaplan-Meier curves compared CKD risk across Hcy tertiles. Restricted cubic splines explored the dose-response relationship and sex-specific threshold effects. C-index, net reclassification improvement (NRI), integrated discrimination improvement (IDI), and random forest (RF) variable importance were used to evaluate the incremental predictive value of Hcy. Mediation analysis examined the role of inflammation.

Elevated Hcy was significantly associated with increased CKD risk, with a threshold effect: risk increased notably when Hcy exceeded 18.2 μmol/L in women and 19.0 μmol/L in men. The C-index, IDI, and NRI demonstrated robust predictive performance of Hcy for CKD, and RF identified Hcy as a critical variable. Mediation analysis showed that inflammation played a crucial mediating role, with C-reactive protein and erythrocyte sedimentation rate mediating 15.04% and 6.39% of the effect, respectively.

In patients with hypertension and CAD, elevated Hcy is significantly associated with increased CKD risk with a sex-differentiated threshold effect (>18.2 μmol/L in women and >19.0 μmol/L in men). Hcy may serve as an important biomarker for CKD risk stratification. Inflammation partially mediates this process, providing a basis for future mechanistic studies.