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.