Metabolomic search for uremic toxins as indicators of the effect of an oral sorbent AST-120 by liquid chromatography/tandem mass spectrometry

Kikuchi, Kaori; Itoh, Yoshiharu; Tateoka, Ryoko; Ezawa, Atsuko; Murakami, Kenjiro; Niwa, Toshimitsu

doi:10.1016/j.jchromb.2010.09.006

Cited by 112 publications

(75 citation statements)

References 30 publications

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“…It is very likely that this sorbent affects the concentration of not only indoxyl sulfate but also, other proteinbound uremic toxins, one of which is p-cresyl sulfate. 64 In at least two smallsized randomized controlled trials, AST-120 had a positive effect on progression of CKD. 65,66 In a recent large randomized controlled trial in the United States and Europe, however, this positive effect could not be confirmed.…”

Section: Discussionmentioning

confidence: 99%

The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate

Vanholder

Schepers

Pletinck

et al. 2014

Journal of the American Society of Nephrology

562

463

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A growing number of publications supports a biologic effect of the protein-bound uremic retention solutes indoxyl sulfate and p-cresyl sulfate. However, the use of unrealistically high free concentrations of these compounds and/or inappropriately low albumin concentrations may blur the interpretation of these results. Here, we performed a systematic review, selecting only studies in which, depending on the albumin concentration, real or extrapolated free concentrations of indoxyl sulfate and p-cresyl sulfate remained in the uremic range. The 27 studies retrieved comprised in vitro and animal studies. A quality score was developed, giving 1 point for each of the following criteria: six or more experiments, confirmation by more than one experimental approach, neutralization of the biologic effect by counteractive reagents or antibodies, use of a real-life model, and use of dose-response analyses in vitro and/or animal studies. The overall average score was 3 of 5 points, with five studies scoring 5 of 5 points and six studies scoring 4 of 5 points, highlighting the superior quality of a substantial number of the retrieved studies. In the 11 highest scoring studies, most functional deteriorations were related to uremic cardiovascular disease and kidney damage. We conclude that our systematic approach allowed the retrieval of methodologically correct studies unbiased by erroneous conditions related to albumin binding. Our data seem to confirm the toxicity of indoxyl sulfate and p-cresyl sulfate and support their roles in vascular and renal disease progression.

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Section: Discussionmentioning

confidence: 99%

The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate

Vanholder

Schepers

Pletinck

et al. 2014

Journal of the American Society of Nephrology

562

463

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“…We also reported previously that blockade of E-selectin by neutralizing antibody dramatically reduced indoxyl sulfate-enhanced leukocyte adhesion to vascular endothelium in vivo and in vitro 23) . Further, an oral adsorbent, AST-120, equivalent to that in dialysis patients 35,60) . Furthermore, stimulation with 0.02 mmol/L indoxyl sulfate, which is comparable to that in patients at Stage 4 to 5 of chronic kidney disease 12,61) , enhanced the expression of E-selectin in HUVEC (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…For the CSF-2 promoter region; F, 5´-ATAAGGGCCAGGAGATTCCA-3´, R, 5´-AGC-CACATCCTCCAGAGAACT-3´. Negative control RPL30 primers were obtained from cell signaling (CM-H2DCFDA) as previously described 13,35) . The intensity of the fluorescence was measured using an ARVO X3 plate reader.…”

Section: Chromatin Immunoprecipitation (Chip) Assaymentioning

confidence: 99%

Crucial Role of the Aryl Hydrocarbon Receptor (AhR) in Indoxyl Sulfate-Induced Vascular Inflammation

Ito

Osaka

Edamatsu

et al. 2016

JAT

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Aim:The aryl hydrocarbon receptor (AhR), a ligand-inducible transcription factor mediating toxic effects of dioxins and uremic toxins, has recently emerged as a pathophysiological regulator of immune-inflammatory conditions. Indoxyl sulfate, a uremic toxin, is associated with cardiovascular disease in patients with chronic kidney disease and has been shown to be a ligand for AhR. The aim of this study was to investigate the potential role of AhR in indoxyl sulfate-induced leukocyte -endothelial interactions. Methods: Endothelial cell-specific AhR knockout (eAhR KO) mice were produced by crossing AhR floxed mice with Tie2 Cre mice. Indoxyl sulfate was administered for 2 weeks, followed by injection of TNF-. Leukocyte recruitment to the femoral artery was assessed by intravital microscopy. Vascular endothelial cells were transfected with siRNA specific to AhR (siAhR) and treated with indoxyl sulfate, followed by stimulation with TNF-. Results: Indoxyl sulfate dramatically enhanced TNF--induced leukocyte recruitment to the vascular wall in control animals but not in eAhR KO mice. In endothelial cells, siAhR significantly reduced indoxyl sulfate-enhanced leukocyte adhesion as well as E-selectin expression, whereas the activation of JNK and nuclear factor-B was not affected. A luciferase assay revealed that the region between 153 and 146 bps in the E-selectin promoter was responsible for indoxyl sulfate activity via AhR. Mutational analysis of this region revealed that activator protein-1 (AP-1) is responsible for indoxyl sulfate-triggered E-selectin expression via AhR. Conclusion: AhR mediates indoxyl sulfate-enhanced leukocyte -endothelial interactions through AP-1 transcriptional activity, which may constitute a new mechanism of vascular inflammation in patients with renal disease.

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“…Oral administration of AST-120 has been shown to result in a dose-dependent decrease in serum IS and PCS in both human [46][47][48] and animal studies [19,49], and its use is associated with slower progression of renal dysfunction [44,50] and reduction of proteinuria [43,44] in animal models of CKD. It has also been demonstrated to slow progression of renal dysfunction in early non-randomized and randomized studies in pre-dialysis patients [51][52][53].…”

Section: Gastrointestinal Sequestrationmentioning

confidence: 99%

The Roles of Indoxyl Sulphate and p-Cresyl Sulphate in Patients with Chronic Kidney Disease: A Review of Therapeutic Options

Nataatmadja¹,

Cho²,

Campbell³

et al. 2018

Chronic Kidney Disease - From Pathophysiology to Clinical Improvements

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Indoxyl sulphate (IS) and p-cresyl sulphate (PCS) are products of proteolytic bacterial fermentation by gut microbiota. They accumulate in the sera of patients with chronic kidney disease (CKD) and have been associated with CKD progression and cardiovascular and all-cause mortality. Therapeutic strategies for lowering IS and PCS include increased clearance (enhanced dialysis), gastrointestinal sequestration (oral adsorbents), reduced synthesis (dietary protein restriction, dietary ibre augmentation and pre-, pro-or synbiotics), antioxidants and organic anion transporter modulators. This review will discuss the roles of IS and PCS as therapeutic targets and examine the clinical evidence for diferent treatment options and their efects on CKD and cardiovascular disease risk. We will include our group's research with pre-, pro-and synbiotic interventions to mitigate serum uraemic toxin accumulation and modify cardiovascular and renal risk.Keywords: indoxyl sulphate, p-cresyl sulphate, uraemic toxins, chronic kidney disease, gut microbiome IntroductionThe reciprocal relationship observed between gut microbiota and chronic kidney disease (CKD) has led to the recent recognition of the 'gut-kidney axis'. Patients with CKD, including those with end-stage kidney disease (ESKD), often experience impaired uraemic toxin clearance, salt and water retention, dietary restrictions, anorexia, dysgeusia and malnutrition, © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.which in turn leads to quantitative and qualitative alterations in gut microbiome composition (gut dysbiosis). Further efects include gut wall oedema, intestinal barrier impairment, translocation of bacteria and endotoxins across the intestinal wall and resultant systemic inlammation [1][2][3]. Gut dysbiosis may in turn lead to the production of various toxins and metabolites that contribute to uraemic toxicity, cardiovascular disease and progressive kidney scarring and failure [4][5][6]. The central role of the gut microbiome in kidney health therefore makes it an appealing therapeutic target in patients with CKD [7,8].Two key nephrovascular toxins produced by proteolytic bacterial fermentation in the gut are indoxyl sulphate (IS) and p-cresyl sulphate (PCS). IS is produced by tryptophan metabolism facilitated by Escherichia coli and Clostridium sporogenes, while PCS is generated by break down of tyrosine and phenylalanine by intestinal anaerobes, such as Clostridium diicile, Faecalibacterium prausnizii, Subdoligranulum and selected strains within the Biidobacterium and Lactobacillus genus [8]. IS and PCS are both solely produced by the gut microbiota [9][10][11][12] and accumulate in the serum of patients with CKD due to both increased intestinal production and reduced glomerular iltration and proximal tubular sec...

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Metabolomic search for uremic toxins as indicators of the effect of an oral sorbent AST-120 by liquid chromatography/tandem mass spectrometry

Cited by 112 publications

References 30 publications

The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate

The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate

Crucial Role of the Aryl Hydrocarbon Receptor (AhR) in Indoxyl Sulfate-Induced Vascular Inflammation

The Roles of Indoxyl Sulphate and p-Cresyl Sulphate in Patients with Chronic Kidney Disease: A Review of Therapeutic Options

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