Serum indoxyl sulfate predicts adverse cardiovascular events in patients with chronic kidney disease

Fan, Pei‐Chun; Chang, Jason C.; Lin, Chieh‐Mo; Lee, Cheng‐Chia; Chen, Yi-Ting; Chu, Pao-Hsien; Kou, George; Lu, Yueh-An; Yang, Chih‐Wei; Chen, Yung‐Chang

doi:10.1016/j.jfma.2019.03.005

Cited by 34 publications

(34 citation statements)

References 32 publications

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“…First, Barreto et al [43] demonstrated that IS concentration is a strong predictor of mortality and cardiovascular events in patients with different stages of CKD (from stage one to five days). More recently, Fan et al [44] confirmed this association before the dialysis stage, independently of eGFR and nutritional status. Shafi et al [45] studied this association in hemodialysis patients: in a post hoc analysis of the HEMO study, IS plasma levels were predictive of cardiac and sudden cardiac death in the subgroup of patients with lower albumin.…”

Section: Indoxyl Sulfate a Uremic Endotheliotoxin: Clinical Evidencementioning

confidence: 85%

Indoxyl Sulfate, a Uremic Endotheliotoxin

Lano

Burtey

Sallée

2020

Toxins

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Chronic kidney disease (CKD) is associated with a high prevalence of cardiovascular diseases. During CKD, the uremic toxin indoxyl sulfate (IS)—derived from tryptophan metabolism—accumulates. IS is involved in the pathophysiology of cardiovascular complications. IS can be described as an endotheliotoxin: IS induces endothelial dysfunction implicated in cardiovascular morbidity and mortality during CKD. In this review, we describe clinical and experimental evidence for IS endothelial toxicity and focus on the various molecular pathways implicated. In patients with CKD, plasma concentrations of IS correlate with cardiovascular events and mortality, with vascular calcification and atherosclerotic markers. Moreover, IS induces a prothrombotic state and impaired neovascularization. IS reduction by AST-120 reverse these abnormalities. In vitro, IS induces endothelial aryl hydrocarbon receptor (AhR) activation and proinflammatory transcription factors as NF-κB or AP-1. IS has a prooxidant effect with reduction of nitric oxide (NO) bioavailability. Finally, IS alters endothelial cell and endothelial progenitor cell migration, regeneration and control vascular smooth muscle cells proliferation. Reducing IS endothelial toxicity appears to be necessary to improve cardiovascular health in CKD patients.

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Section: Indoxyl Sulfate a Uremic Endotheliotoxin: Clinical Evidencementioning

confidence: 85%

Indoxyl Sulfate, a Uremic Endotheliotoxin

Lano

Burtey

Sallée

2020

Toxins

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“…The continuous loss of functional nephrons leads to a decrease in the renal elimination of this compound and contributes to an increase in serum concentrations of this uremic toxin [ 103 ]. In patients with CKD, the IS level was a predictor of mortality [ 104 , 105 ]. The observational nature of the present studies prevented authors from demonstrating a causal relationship.…”

Section: The Role Of Uremic Toxin In Vascular Dysfunctionmentioning

confidence: 99%

Uremic Toxins and Vascular Dysfunction

Six

Flissi

Lenglet

et al. 2020

Toxins

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Vascular dysfunction is an essential element found in many cardiovascular pathologies and in pathologies that have a cardiovascular impact such as chronic kidney disease (CKD). Alteration of vasomotricity is due to an imbalance between the production of relaxing and contracting factors. In addition to becoming a determining factor in pathophysiological alterations, vascular dysfunction constitutes the first step in the development of atherosclerosis plaques or vascular calcifications. In patients with CKD, alteration of vasomotricity tends to emerge as being a new, less conventional, risk factor. CKD is characterized by the accumulation of uremic toxins (UTs) such as phosphate, para-cresyl sulfate, indoxyl sulfate, and FGF23 and, consequently, the deleterious role of UTs on vascular dysfunction has been explored. This accumulation of UTs is associated with systemic alterations including inflammation, oxidative stress, and the decrease of nitric oxide production. The present review proposes to summarize our current knowledge of the mechanisms by which UTs induce vascular dysfunction.

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“…Of several varieties of UTs, protein bound uremic toxins (PBUTs) are particularly toxic to the cardiovascular system [4][5][6]. Specifically, indoxyl sulfate (IS) [7,8], p-cresol/p-cresyl sulfate (PCS) [9,10], trimethylamine N-oxide (TMAO) [11], kynurenine (Kyn) [12], and indole-3-acetic acid (IAA) [13] have been well characterized for their cardiovascular toxicity. These uremic solutes are generated by mammalian processing of metabolites of gut microbial catabolism, and are excreted by renal tubular secretion [14,15].…”

Section: Uremic Solutesmentioning

confidence: 99%

Molecular Mechanisms Underlying the Cardiovascular Toxicity of Specific Uremic Solutes

Ravid

Chitalia

2020

Cells

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Mounting evidence strongly suggests a causal link between chronic kidney disease (CKD) and cardiovascular disease (CVD). Compared with non-CKD patients, patients with CKD suffer disproportionately from CVD and derive suboptimal benefits from interventions targeting conventional CVD risk factors. Uremic toxins (UTs), whose plasma levels rapidly rise as CKD progresses, represent a unique risk factor in CKD, which has protean manifestations on CVD. Among the known UTs, tryptophan metabolites and trimethylamine N-oxide are well-established cardiovascular toxins. Their molecular mechanisms of effect warrant special consideration to draw translational value. This review surveys current knowledge on the effects of specific UTs on different pathways and cell functions that influence the integrity of cardiovascular health, with implication for CVD progression. The effect of UTs on cardiovascular health is an example of a paradigm in which a cascade of molecular and metabolic events induced by pathology in one organ in turn induces dysfunction in another organ. Deciphering the molecular mechanisms underlying such cross-organ pathologies will help uncover therapeutic targets to improve the management of CVD in patients with CKD.

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Serum indoxyl sulfate predicts adverse cardiovascular events in patients with chronic kidney disease

Cited by 34 publications

References 32 publications

Indoxyl Sulfate, a Uremic Endotheliotoxin

Indoxyl Sulfate, a Uremic Endotheliotoxin

Uremic Toxins and Vascular Dysfunction

Molecular Mechanisms Underlying the Cardiovascular Toxicity of Specific Uremic Solutes

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