Accumulation of indoxyl sulfate, an inhibitor of drug-binding, in uremic serum as demonstrated by internal-surface reversed-phase liquid chromatography.

Niwa, Toshimitsu; Takeda, Naohlto; Tatematsu, Akira; Maeda, Kenji

doi:10.1093/clinchem/34.11.2264

Cited by 168 publications

(59 citation statements)

References 3 publications

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“…Based on previous reports, the concentrations of the uraemic solutes used in this study (1-100 μg ml −1 ) are in the range of those reported in CKD (Duranton et al 2012;Zhu et al 2012). It has been observed that in CKD patients, serum levels of IS and pc increased by approximately 50-to 90-fold (Niwa et al 1988;Vanholder et al 2003) and10-fold (De Smet et al 1998), respectively. In this regard, Itoh et al (2012) measured uraemic toxins in haemodialysis patients by liquid chromatography/tandem mass spectrometry.…”

Section: Discussionsupporting

confidence: 55%

Effect of uraemia on endothelial cell damage is mediated by the integrin linked kinase pathway

García-Jérez

Luengo

Carracedo

et al. 2014

The Journal of Physiology

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Key pointsr Patients with chronic kidney disease have a higher risk of developing cardiovascular diseases than the general population. Their vascular endothelium is dysfunctional, among other things, because it is permanently exposed to uraemic toxins, several of which have poor clearance by conventional dialysis.r Recent studies have demonstrated the important role of integrin-linked kinase (ILK) in the maintenance of endothelial integrity and in this study we investigate the involvement of ILK in the mechanism underlying vascular endothelial damage that occurs in uraemia.r For the first time, we demonstrate the implication of ILK in the protection against endothelial cell damage (inhibition of proliferation, toxicity, oxidative stress and programed cell death) induced by uraemic serum from chronic kidney disease patients and uraemic toxins.r This molecular mechanism may have clinical relevance because it highlights the importance of maintaining high levels of ILK activity to help preserve endothelial integrity, at least in early stages of chronic kidney disease.Abstract Patients with chronic kidney disease (CKD) have a higher risk of developing cardiovascular diseases. Their vascular endothelium is dysfunctional, among other things, because it is permanently exposed to uraemic toxins, several of which, mostly protein-bound compounds such as indoxyl sulfate (IS) and p-cresyl sulphate, having poor clearance by conventional dialysis, induce endothelial toxicity. However, the molecular mechanism by which uraemic toxins regulate early stages of endothelial dysfunction remains unclear. Recent studies have demonstrated the important role of integrin-linked kinase (ILK) in the maintenance of endothelial integrity. In this study, we investigate the involvement of ILK in the mechanism underlying vascular endothelial damage that occurs in uraemia. First, we show that incubation of EA.hy926 cells with human uraemic serum from CKD patients upregulates ILK activity. This ILK activation also occurs when the cells are exposed to IS (25-100 μg ml −1 ), p-cresol (10-100 μg ml −1 ) or both combined, compared to human serum control. Next, we observed that high doses of both toxins together induce a slight decrease in cell proliferation and increase apoptosis and reactive oxygen species production. Interestingly, these toxic effects displayed a strong increase when the ILK protein is knocked down by small interfering RNA, even at low doses of uraemic toxins. Abrogation of AKT has demonstrated the ILK/AKT signalling pathway involved in these processes. This study has demonstrated the implication of ILK in the protection against endothelial cell damage induced by uraemic toxins, a molecular mechanism that could play a protective role in the early stages of endothelial dysfunction observed in uraemic patients.

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Section: Discussionsupporting

confidence: 55%

Effect of uraemia on endothelial cell damage is mediated by the integrin linked kinase pathway

García-Jérez

Luengo

Carracedo

et al. 2014

The Journal of Physiology

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“…Blood indoxyl sulfate is progressively accumulated in accordance with a decline of GFR in patients with renal insufficiency. 9,11 The glomerular filtration of indoxyl sulfate is considered to be minimal because >96% is bound to albumin. 12 Indoxyl sulfate significantly inhibits para-aminohippuric acid (PAH) uptake by isolated renal tubules 13 and it reduces the renal clearance of PAH.…”

Section: Discussionmentioning

confidence: 99%

“…8 Recently, the serum level of indoxyl sulfate was found to be high in patients with chronic renal impairment. 9 In the present study we investigated whether these serum markers are effective in detecting CsA-induced chronic renal toxicity.…”

mentioning

confidence: 99%

Serum indoxyl sulfate as an early marker for detecting chronic cyclosporine nephrotoxicity

Umino

Ohtomo

Hara

et al. 2010

Pediatrics International

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“…12,13 Indoxyl sulphate (IS) is a protein-bound uremic toxin, whose excretion is reduced in CKD patients. [14][15][16] We previously reported that this gut bacteria-derived substance is a potent nephrovascular toxin in CKD patients. [17][18][19][20] Impact of gut microbiome and its derived inflammatory reaction on human health is an emerging research field.…”

Section: Introductionmentioning

confidence: 99%

Diet, gut microbiome and indoxyl sulphate in chronic kidney disease patients

Yang

Tarng

2018

Nephrology

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Emerging evidence suggests that intestinal dysbiosis plays an important role in host inflammation locally and systemically. Such pathological condition is even more prevailing in patients with chronic kidney disease (CKD). Of note, indoxyl sulphate (IS), a gut‐derived uremic toxin, is notorious for its pro‐inflammatory feature in CKD patients. IS accumulates in the body as the urinary excretion of uremic toxins is impaired, and further worsens the kidney function in a vicious cycle to CKD. Dietary restriction in vegetables, fruits and yogurt leads to the predominance of indole‐producing intestinal microbial flora and further exaggerates the accumulation of IS in CKD patients. Recently, interventional studies have shown that circulating IS can be reduced by dietary prebiotic and/or probiotic supplements. However, further randomized controlled trials are warranted to examine whether such beneficial effect of dietary prebiotic/probiotic supplements could be extrapolated to better hard outcomes in CKD population. In this review, we would also like to emphasize the importance of achieving sufficient intake of dietary fibre by proper vegetable pre‐treatment and accurate fruit selection, instead of directly avoiding these potassium‐rich yet fibre‐rich and base‐producing foods.

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Accumulation of indoxyl sulfate, an inhibitor of drug-binding, in uremic serum as demonstrated by internal-surface reversed-phase liquid chromatography.

Cited by 168 publications

References 3 publications

Effect of uraemia on endothelial cell damage is mediated by the integrin linked kinase pathway

Effect of uraemia on endothelial cell damage is mediated by the integrin linked kinase pathway

Serum indoxyl sulfate as an early marker for detecting chronic cyclosporine nephrotoxicity

Diet, gut microbiome and indoxyl sulphate in chronic kidney disease patients

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