Abstract
Patients with chronic kidney disease (CKD) are at a highly increased risk of cardiovascular complications, with increased vascular inflammation, accelerated atherogenesis and enhanced thrombotic risk. Considering the central role of the endothelium in protecting from atherogenesis and thrombosis, as well as its cardioprotective role in regulating vasorelaxation, this study aimed to systematically integrate literature on CKD-associated endothelial dysfunction, including the underlying molecular mechanisms, into a comprehensive overview. Therefore, we conducted a systematic review of literature describing uremic serum or uremic toxin-induced vascular dysfunction with a special focus on the endothelium. This revealed 39 studies analyzing the effects of uremic serum or the uremic toxins indoxyl sulfate, cyanate, modified LDL, the advanced glycation end products N-carboxymethyl-lysine and N-carboxyethyl-lysine, p-cresol and p-cresyl sulfate, phosphate, uric acid and asymmetric dimethylarginine. Most studies described an increase in inflammation, oxidative stress, leukocyte migration and adhesion, cell death and a thrombotic phenotype upon uremic conditions or uremic toxin treatment of endothelial cells. Cellular signaling pathways that were frequently activated included the ROS, MAPK/NF-κB, the Aryl-Hydrocarbon-Receptor and RAGE pathways. Overall, this review provides detailed insights into pathophysiological and molecular mechanisms underlying endothelial dysfunction in CKD. Targeting these pathways may provide new therapeutic strategies reducing increased the cardiovascular risk in CKD.
Highlights
As kidney function gradually declines, the risk of cardiovascular complications increases. This is reflected by the fact that approximately half of the patients with severe chronic kidney disease (CKD stage 4–5) die from cardiovascular disease (CVD) [1], compared to 26% of patients with a healthy kidney function [2,3]
Given that endothelial dysfunction is key in the initiation and progression of atherosclerosis and contributes to decreased vascular reactivity, we investigated uremic toxin-induced endothelial dysfunction and its underlying mechanisms by means of a systematic review
Uremic toxins appeared to share common signaling pathways in endothelial cells, including pathways linked to MAPK, AhR, the receptor for advanced glycation end products (RAGE) receptor or pro-inflammatory transcription factors, for example NF-κB
Summary
As kidney function gradually declines, the risk of cardiovascular complications increases. This is reflected by the fact that approximately half of the patients with severe chronic kidney disease (CKD stage 4–5) die from cardiovascular disease (CVD) [1], compared to 26% of patients with a healthy kidney function [2,3]. As main underlying mechanism of myocardial ischemia, CKD patients are at increased risk for atherosclerosis, an inflammatory process within the intimal layer of the vessel wall [5]. As CKD progresses, vascular stiffness increases [7], with vascular stiffness as an important predictor of cardiovascular mortality in CKD patients [8]
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