Chronic Kidney Disease, Circulating Ceramides, and Coronary Microvascular Dysfunction: Insights from the CRUISE-MET Study

INTRODUCTION: Ceramides and chronic kidney disease (CKD) independently associate with coronary microvascular dysfunction (CMD), but their combined association remains unestablished, warranting investigation. METHODS: This cross-sectional analysis included coronary artery disease (CAD) patients from the CRUISE-MET trial (NCT06383208) who underwent coronary angiography and ceramide profiling measurement. The microvascular resistance was assessed in all patients using the angiography-derived microcirculatory resistance (AMR). CKD was classified based on both estimated glomerular filtration rate and urine albumin-to-creatinine ratio. The combined associations and statistical mediation of ceramides and renal dysfunction on CMD was examined, with sensitivity analyses to ensure the robustness. RESULTS: In this analysis of 794 CAD patients, CKD patients demonstrated significantly higher AMR values (2.56 ± 0.51 vs. 2.46 ± 0.48, p = 0.003) and CMD prevalence (57.1% vs. 41.7%, p < 0.001). Three ceramide species - Cer(18:1/16:0), Cer(18:1/18:0), and Cer(18:1/24:1) - showed strong positive correlations with AMR (all p < 0.05). LASSO regression identified 14 factors associated with CMD, with E/e', CKD, and Cer(18:1/16:0) emerging as top correlates. Cer(18:1/16:0) demonstrated superior predictive performance (area under the curve [AUC] = 0.609, 95% CI: 0.570-0.648, p < 0.001), with its addition to baseline models significantly improving reclassification (δAUC = 0.03, p = 0.010; cNRI>0 = 0.23, p < 0.001; integrated discrimination improvement = 0.03, p < 0.001). Notably, patients with concurrent CKD and elevated Cer(18:1/16:0) exhibited significantly higher odds of CMD (OR = 3.74, 95% CI: 2.39-5.84). Statistical mediation analysis suggested that Cer(18:1/16:0) mediated 13.8% of the association between CKD and CMD. CONCLUSION: Ceramides, particularly Cer(18:1/16:0), partially mediated the statistical association between CKD and CMD. These findings highlight the potential role of sphingolipid metabolism in cardiorenal pathophysiology.