Kynurenine pathway metabolites predict subclinical atherosclerotic disease and new cardiovascular events in chronic kidney disease

Abstract

Introduction Inflammation and oxidative stress contribute to the disproportionate burden of cardiovascular disease (CVD) in chronic kidney disease (CKD). Disordered catabolism of tryptophan via the kynurenine and indole pathways is linked to CVD in both CKD and dialysis patients. However, the association between specific kynurenine and indole metabolites to subclinical CVD and time to new CV events in CKD has not been studied. Methods We measured kynurenine and indole pathway metabolites using targeted mass spectrometry in a cohort of 325 patients with moderate to severe CKD and a median follow-up of 2 years. Multiple linear regression and Cox regression analyses were used to assess the relationship between these tryptophan metabolites and subclinical CVD, including calcium scores, carotid intima-media thickness, and time to new CV events. Results Elevated quinolinic and anthranilic acid were independently associated with reduced time to new CVD (Hazard ratio [HR]: 1.28, p = 0.01; HR: 1.02, p = 0.02, respectively). Low tryptophan levels were associated with reduced time to new CV events when adjusting for demographics and CVD history (HR: 0.30, p = 0.03). Low tryptophan levels were also associated with aortic calcification in a fully adjusted linear regression model (β = -1983, p = 0.006). Similarly, high levels of several kynurenine pathway metabolites predicted increased coronary, aortic, and composite calcification scores. Conclusions We demonstrate the association of kynurenine pathway metabolites, and not indole derivatives, with subclinical and new CV events in an advanced CKD cohort. Our findings support a possible role for altered tryptophan immune metabolism in the pathogenesis of CKD associated atherosclerosis.

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