Uremic Toxins Activate Macrophages: Implications for Atherosclerosis in Chronic Kidney Disease

Abstract

Chronic kidney disease is accompanied by a remarkably high risk for coronary artery disease, myocardial infarction, stroke, and congestive heart failure.1 In fact, cardiovascular disease is accountable for half of all fatalities in endstage renal disease, which, despite improvements in care over the last 2 decades, has an overall mortality of ≈15% to 20% per year.2,3 Chronic kidney disease is a prevalent and challenging disorder affecting 14.8% of the adult general population in the United States.2 Also, the incidence of end-stage renal disease remains high, with 124 114 newly reported cases receiving renal replacement therapy in the United States in 2015, 87% of which were treated by hemodialysis.2 Although cardiovascular and chronic kidney disease share many risk factors such as diabetes mellitus and hypertension, which may explain their frequent association, it recently became clear that the increased cardiovascular risk in patients with chronic kidney disease is at least partly mediated by factors specifically linked to renal insufficiency.1 For instance, isolated impairment in renal function elevates the risk for future coronary events, which equals or exceeds the risk of traditional risk factors.4 However, statins fail to attenuate cardiovascular mortality despite a significant low-density lipoprotein cholesterol reduction in patients on hemodialysis.5 Mechanisms that enhance vascular inflammation in chronic kidney disease may include modification of low-density lipoprotein or fibroblast growth factor 23 signaling, which contributes to vascular calcification.1 Overall, the reason for rapidly progressing atherosclerosis in patients with chronic kidney disease remains incompletely understood. In recent years, the toxicity of uremic retention solutes has been increasingly recognized.6 More than 150 molecules have been cataloged so far.7 Although hemodialysis removes the majority of small-sized and nonprotein-bound solutes, binding to albumin (66 kDa) impedes the diffusion across the membrane pores, which only allow passage up to a size of ≈20 kDa.7 Indoxyl sulfate, one of the most studied protein-bound uremic toxins, is independently associated with cardiovascular events.8,9 Other studies also suggest a role of indoxyl sulfate in the progression of renal fibrosis, bone remodeling, and neurological impairment.6 Colon microbiota convert dietary tryptophan to indole, which is further processed in the liver, and cleared via secretion in the proximal tubules involving organic anion transporters, a mechanism compromised in chronic kidney disease.7 Because indoxyl sulfate is bound 90% to albumin, it readily accumulates despite regular hemodialysis.10 In this issue of Circulation, Nakano and colleagues11 demonstrate how indoxyl sulfate connects chronic kidney disease with vascular inflammation and atherosclerosis. Macrophages essentially contribute to the progression of atherosclerotic lesions.12 In this study, the authors report that indoxyl sulfate induces the expression of interleukin 1-β and other inflammatory cytokines in human primary mac© 2019 American Heart Association, Inc.