Association between Serum Indoxyl Sulfate Levels and Endothelial Function in Non-Dialysis Chronic Kidney Disease

Wang, Chih‐Hsien; Lai, Yu‐Hsien; Kuo, Chiu‐Huang; Lin, Yu‐Li; Tsai, Jen-Pi; Hsu, Bang‐Gee

doi:10.3390/toxins11100589

Cited by 25 publications

(27 citation statements)

References 36 publications

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“…Thus, low IS plasma levels may reflect a poor nutritional state rather than an improved uremic status. In patients with CKD, IS plasma levels are correlated with pulse wave velocity [43], vascular reactivity index [52], ankle brachial index, arteriosclerosis markers [53] and aortic calcification [43]. Moreover, the number of endothelial progenitor cells is inversely correlated with IS plasma levels [54,55].…”

Section: Indoxyl Sulfate a Uremic Endotheliotoxin: Clinical Evidencementioning

confidence: 99%

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: 99%

Indoxyl Sulfate, a Uremic Endotheliotoxin

Lano

Burtey

Sallée

2020

Toxins

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“…Furthermore, a novel study investigated the association between serum IS levels and endothelial function in patients with stages 3–5 CKD. The endothelial function, represented by the vascular reactivity index (VRI), was measured non-invasively using digital thermal monitoring and IS level was associated inversely with the VRI values demonstrating a modulating role of IS in endothelial function [ 108 ]. In future papers it would be interesting to analyze the effect on vascular dysfunction taking into account albumin and IS parameters or total and free IS levels at each CKD stage.…”

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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“…IS promotes vascular calcification [ 18 ] and inflammation [ 19 ] in vitro and in animal models of CKD [ 20 ]. Moreover, serum IS levels are associated with the surrogate markers of cardiovascular disease (intima media thickness and pulse walve velocity) in children [ 5 ] and with diminished endothelial function in adults with CKD [ 21 ]. Accordingly, the toxicity of IS in vitro and in animal models depends on its concentration, and this is reflected by the fact that those patients with IS levels in the 4th quartile have the highest risk for progression of CKD [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Serum indoxyl sulfate concentrations associate with progression of chronic kidney disease in children

et al. 2020

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The uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (pCS) accumulate in patients with chronic kidney disease (CKD) as a consequence of altered gut microbiota metabolism and a decline in renal excretion. Despite of solid experimental evidence for nephrotoxic effects, the impact of uremic toxins on the progression of CKD has not been investigated in representative patient cohorts. In this analysis, IS and pCS serum concentrations were measured in 604 pediatric participants (mean eGFR of 27 ± 11 ml/min/1.73m2) at enrolment into the prospective Cardiovascular Comorbidity in Children with CKD study. Associations with progression of CKD were analyzed by Kaplan-Meier analyses and Cox proportional hazard models. During a median follow up time of 2.2 years (IQR 4.3–0.8 years), the composite renal survival endpoint, defined as 50% loss of eGFR, or eGFR <10ml/min/1.73m2 or start of renal replacement therapy, was reached by 360 patients (60%). Median survival time was shorter in patients with IS and pCS levels in the highest versus lowest quartile for both IS (1.5 years, 95%CI [1.1,2.0] versus 6.0 years, 95%CI [5.0,8.4]) and pCS (1.8 years, 95%CI [1.5,2.8] versus 4.4 years, 95%CI [3.4,6.0]). Multivariable Cox regression disclosed a significant association of IS, but not pCS, with renal survival, which was independent of other risk factors including baseline eGFR, proteinuria and blood pressure. In this exploratory analysis we provide the first data showing a significant association of IS, but not pCS serum concentrations with the progression of CKD in children, independent of other known risk factors. In the absence of comorbidities, which interfere with serum levels of uremic toxins, such as diabetes, obesity and metabolic syndrome, these results highlight the important role of uremic toxins and accentuate the unmet need of effective elimination strategies to lower the uremic toxin burden and abate progression of CKD.

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Association between Serum Indoxyl Sulfate Levels and Endothelial Function in Non-Dialysis Chronic Kidney Disease

Cited by 25 publications

References 36 publications

Indoxyl Sulfate, a Uremic Endotheliotoxin

Indoxyl Sulfate, a Uremic Endotheliotoxin

Uremic Toxins and Vascular Dysfunction

Serum indoxyl sulfate concentrations associate with progression of chronic kidney disease in children

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