The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate

Vanholder, Raymond; Schepers, Eva; Pletinck, Anneleen; Nagler, Evi; Glorieux, Griet

doi:10.1681/asn.2013101062

Cited by 543 publications

(482 citation statements)

References 85 publications

(256 reference statements)

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“…It is important to consider the concentration of free uremic toxins on their biological activity, which means that the experiments need to be conducted using the correct albumin concentrations or with the correct free concentration. Vanholder et al previously pointed out that the use of unrealistically high free concentrations of uremic toxins compared with the concentrations observed in human CKD and/or inappropriately low albumin concentrations may blur the interpretation of the biochemical effects of uremic toxins 43. On this point, the IS concentration used in this cell culture study may have been unusually high and the free concentration irrelevant.…”

Section: Discussionmentioning

confidence: 89%

Potential therapeutic interventions for chronic kidney disease‐associated sarcopenia via indoxyl sulfate‐induced mitochondrial dysfunction

Enoki

Watanabe

Arake

et al. 2017

J cachexia sarcopenia muscle

127

132

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BackgroundChronic kidney disease (CKD) patients experience skeletal muscle wasting and decreased exercise endurance. Our previous study demonstrated that indoxyl sulfate (IS), a uremic toxin, accelerates skeletal muscle atrophy. The purpose of this study was to examine the issue of whether IS causes mitochondria dysfunction and IS‐targeted intervention using AST‐120, which inhibits IS accumulation, or mitochondria‐targeted intervention using L‐carnitine or teneligliptin, a dipeptidyl peptidase‐4 inhibitor which retains mitochondria function and alleviates skeletal muscle atrophy and muscle endurance in chronic kidney disease mice.MethodsThe in vitro effect of IS on mitochondrial status was evaluated using mouse myofibroblast cells (C2C12 cell). The mice were divided into sham or 5/6‐nephrectomized (CKD) mice group. Chronic kidney disease mice were also randomly assigned to non‐treatment group and AST‐120, L‐carnitine, or teneligliptin treatment groups.ResultsIn C2C12 cells, IS induced mitochondrial dysfunction by decreasing the expression of PGC‐1α and inducing autophagy in addition to decreasing mitochondrial membrane potential. Co‐incubation with an anti‐oxidant, ascorbic acid, L‐carnitine, or teneligliptine restored the values to their original state. In CKD mice, the body and skeletal muscle weights were decreased compared with sham mice. Compared with sham mice, the expression of interleukin‐6 and atrophy‐related factors such as myostatin and atrogin‐1 was increased in the skeletal muscle of CKD mice, whereas muscular Akt phosphorylation was decreased. In addition, a reduced exercise capacity was observed for the CKD mice, which was accompanied by a decreased expression of muscular PCG‐1α and increased muscular autophagy, as reflected by decreased mitochondria‐rich type I fibres. An AST‐120 treatment significantly restored these changes including skeletal muscle weight observed in CKD mice to the sham levels accompanied by a reduction in IS levels. An L‐carnitine or teneligliptin treatment also restored them to the sham levels without changing IS level.ConclusionsOur results indicate that IS induces mitochondrial dysfunction in skeletal muscle cells and provides a potential therapeutic strategy such as IS‐targeted and mitochondria‐targeted interventions for treating CKD‐induced muscle atrophy and decreased exercise endurance.

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Section: Discussionmentioning

confidence: 89%

Potential therapeutic interventions for chronic kidney disease‐associated sarcopenia via indoxyl sulfate‐induced mitochondrial dysfunction

Enoki

Watanabe

Arake

et al. 2017

J cachexia sarcopenia muscle

127

132

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“…29 Little is known about potential toxicity of CMG and HA, and to our knowledge, our study is the first to evaluate associations of the renal clearances of any secreted solutes with clinical outcomes. This study includes several important limitations.…”

Section: Discussionmentioning

confidence: 99%

Tubular Secretion in CKD

Suchy‐Dicey¹,

Laha²,

Hoofnagle³

et al. 2015

JASN

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Renal function generally is assessed by measurement of GFR and urinary albumin excretion. Other intrinsic kidney functions, such as proximal tubular secretion, typically are not quantified. Tubular secretion of solutes is more efficient than glomerular filtration and a major mechanism for renal drug elimination, suggesting important clinical consequences of secretion dysfunction. Measuring tubular secretion as an independent marker of kidney function may provide insight into kidney disease etiology and improve prediction of adverse outcomes. We estimated secretion function by measuring secreted solute (hippurate, cinnamoylglycine, p-cresol sulfate, and indoxyl sulfate) clearance using liquid chromatography-tandem mass spectrometric assays of serum and timed urine samples in a prospective cohort study of 298 patients with kidney disease. We estimated GFR by mean clearance of creatinine and urea from the same samples and evaluated associations of renal secretion with participant characteristics, mortality, and CKD progression to dialysis. Tubular secretion rate modestly correlated with eGFR and associated with some participant characteristics, notably fractional excretion of electrolytes. Low clearance of hippurate or p-cresol sulfate associated with greater risk of death independent of eGFR (hazard ratio, 2.3; 95% confidence interval, 1.1 to 4.7; hazard ratio, 2.5; 95% confidence interval, 1.0 to 6.1, respectively). Hazards models also suggested an association between low cinnamoylglycine clearance and risk of dialysis, but statistical analyses did not exclude the null hypothesis. Therefore, estimates of proximal tubular secretion function correlate with glomerular filtration, but substantial variability in net secretion remains. The observed associations of net secretion with mortality and progression of CKD require confirmation.

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“…8 In addition to the lack of an animal model, this study has limitations. First, the concentrations of IS and HSA used to treat cells corresponded to the levels found in ESRD patients 25,[38][39][40][41] and this combination of HSA and IS is expected to result in 10% of the free form of IS, a biologically active form. Although lack of direct measurement of free IS represents a limitation of the study, the conditions used were sufficient to activate AHR signaling and TF stabilization.…”

Section: Discussionmentioning

confidence: 99%

The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia

Shivanna

Kolandaivelu

Shashar

et al. 2016

Journal of the American Society of Nephrology

146

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Patients with CKD suffer high rates of thrombosis, particularly after endovascular interventions, yet few options are available to improve management and reduce thrombotic risk. We recently demonstrated that indoxyl sulfate (IS) is a potent CKD-specific prothrombotic metabolite that induces tissue factor (TF) in vascular smooth muscle cells (vSMCs), although the precise mechanism and treatment implications remain unclear. Because IS is an agonist of the aryl hydrocarbon receptor (AHR), we first examined the relationship between IS levels and AHR-inducing activity in sera of patients with ESRD. IS levels correlated significantly with both vSMC AHR activity and TF activity. Mechanistically, we demonstrated that IS activates the AHR pathway in primary human aortic vSMCs, and further, that AHR interacts directly with and stabilizes functional TF. Antagonists directly targeting AHR enhanced TF ubiquitination and degradation and suppressed thrombosis in a postinterventional model of CKD and endovascular injury. Furthermore, AHR antagonists inhibited TF in a manner dependent on circulating IS levels. In conclusion, we demonstrated that IS regulates TF stability through AHR signaling and uncovered AHR as an antithrombotic target and AHR antagonists as a novel class of antithrombotics. Together, IS and AHR have potential as uremia-specific biomarkers and targets that may be leveraged as a promising theranostic platform to better manage the elevated thrombosis rates in patients with CKD.

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The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate

Cited by 543 publications

References 85 publications

Potential therapeutic interventions for chronic kidney disease‐associated sarcopenia via indoxyl sulfate‐induced mitochondrial dysfunction

Potential therapeutic interventions for chronic kidney disease‐associated sarcopenia via indoxyl sulfate‐induced mitochondrial dysfunction

Tubular Secretion in CKD

The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia

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