Identification of Novel Biomarkers and Pathways for Coronary Artery Calcification in Non-diabetic Patients on Hemodialysis

Background: A better understanding of pathophysiology involving coronary artery calcification (CAC) in hemodialysis (HD) patients will help to develop new therapies. We sought to identify the differences in metabolomics profiles between HD patients with and without CAC. Methods: In this case-control study nested within a cohort of 568 incident HD patients, cases were non-diabetics with a CAC score \u003e100 (n=51), and controls were non-diabetics with a CAC score of 0 (n=48). We measured 452 serum metabolites in each participant. Metabolites and pathway scores were compared using Mann-Whitney U tests, partial least squares-discriminant analyses, and pathway enrichment analyses. Results: Compared to controls, cases were older (64±13 vs. 42±12 years) and were less likely to be African American (51% vs. 94%). We identified three metabolites in bile acid synthesis (chenodeoxycholic, deoxycholic, and glycolithocholic acids) and one pathway (arginine/proline metabolism). After adjusting for demographics, higher levels of chenodeoxycholic, deoxycholic, and glycolithocholic acids were associated with higher odds of having CAC: comparing the third with the first tertile of each bile acid, the OR (95% CI) was 6.34 (1.12-36.06), 6.73 (1.20-37.82), and 8.53 (1.50-48.49), respectively. These associations were no longer significant after further adjustment for coronary artery disease and medication use. Per 1 unit higher in the first principal component score, arginine/proline metabolism was associated with CAC after adjusting for demographics (OR: 1.83 (95% CI: 1.06-3.15)), and the association remained significant with additional adjustments for statin use (OR: 1.84 (95% CI: 1.04-3.27)). Conclusions: Among HD patients without diabetes mellitus, chenodeoxycholic, deoxycholic, and glycolithocholic acids may be potential biomarkers for CAC, and arginine/proline metabolism is a plausible mechanism to study for CAC. These findings need to be confirmed in future studies.