Serum protein-bound uraemic toxins and clinical outcomes in haemodialysis patients

Lin, Cheng‐Jui; Wu, Chih‐Jen; Pan, Chi-Feng; Chen, Yi-Chou; Sun, Fang‐Ju; Chen, Han‐Hsiang

doi:10.1093/ndt/gfq251

Cited by 104 publications

(81 citation statements)

References 24 publications

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“…57,58 Both indoxyl sulfate and p-cresyl sulfate per se have repeatedly been related to cardiovascular mortality. [10][11][12][13][14][15][16][17][18][19] Although strategies that more efficiently remove proteinbound solutes, such as frequent dialysis 59 and online hemodiafiltration, 60,61 in controlled studies are associated with improved outcomes, 62,63 it remains difficult to interpret these data because of the presence of confounding factors that affect the outcomes on their own and a lack of selectivity of removal, because dialysis strategies are usually not restricted to protein-bound solutes alone.…”

Section: Discussionmentioning

confidence: 99%

“…8,9 In the past decade, however, a growing number of publications documented the impact of protein-bound uremic toxins on vital processes and an association of their concentration with clinical outcome parameters. 6,[10][11][12][13][14][15][16][17][18][19] One factor blurring the interpretation of the biochemical effects of uremic toxins is the application of unrealistic concentrations compared with the concentrations observed in human CKD in in vitro testing or in vivo animal experiments. 4,20 Moreover, for protein-bound toxins, even with seemingly acceptable total concentrations, the quantities of albumin or protein present are often too low, resulting in unacceptably high and thus, irrelevant free concentrations.…”

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confidence: 99%

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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%

mentioning

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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“…1,23 In individuals with CKD, emerging evidence suggests that accumulation of uremic toxin, especially indoxyl sulfate, have repeatedly been related to cardiovascular mortality. [4][5][6] Thus it can be seen that indoxyl sulfate can significantly induce endothelial impairment and the inhibitory effect of indoxyl sulfate-induced injury turn to be a therapeutic strategy for CKD-CVD.…”

Section: Discussionmentioning

confidence: 99%

“…2,3 Indoxyl sulfate has repeatedly been related to cardiovascular mortality. [4][5][6] Dialysis is usually not powerful to remove protein-bound uremic toxins alone. 7,8 AST-120 (Kremezin), however, in a recent large randomized controlled trial in the United States and Europe, the positive effect of removing indoxyl sulfate could not be confirmed.…”

Section: Introductionmentioning

confidence: 99%

Grape seed proanthocyanidin extract protects human umbilical vein endothelial cells from indoxyl sulfate-induced injury via ameliorating mitochondrial dysfunction

Lu¹,

Lu²,

Zheng

et al. 2015

Renal Failure

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“…86 Circulating levels of p-cresol are positively associated with CV events. 87 However, p-cresol detected in humans actually represents its conjugated forms, mainly pCS (>95%) and p-cresyl glucoronide (<4%), because the conjugated bonds are hydrolyzed during acid and heat deproteinization in the sample preparation step of measurement. 88 True unconjugated p-cresol is below the limit of detection using acetone deproteinization to avoid deconjugation.…”

Section: Evidence Of Adverse CV Effects Of Protein-bound Uremic Toxinsmentioning

confidence: 99%

Cardiorenal Syndrome

Lekawanvijit

Kompa

Wang

et al. 2012

Circulation Research

149

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Cardiorenal syndrome is a condition in which a complex interrelationship between cardiac dysfunction and renal dysfunction exists. Despite advances in treatment of both cardiovascular and kidney disease, cardiorenal syndrome remains a major global health problem. Characteristic of the pathophysiology of cardiorenal syndrome is bidirectional cross-talk; mediators/substances activated by the disease state of 1 organ can play a role in worsening dysfunction of the other by exerting their biologically harmful effects, leading to the progression of the syndrome. Accumulation of uremic toxins is a hallmark of renal excretory dysfunction. Removal of some toxins by conventional dialysis is particularly problematic because of their high protein binding. In this review, we demonstrate that protein-bound uremic toxins may play an important role in progression of cardiovascular disease in the setting of chronic kidney disease. The highly protein-bound uremic toxin indoxyl sulfate has emerged as a potent toxin adversely affecting both the kidney and heart. Direct cardiac effects of this toxin have been recently demonstrated both in vitro and in vivo. Specifically, potent fibrogenic and prohypertrophic effects, as well as oxidative stress-inducing effects, appear to play a central role in both renal and cardiac pathology. Many of these adverse effects can be suppressed by use of a gut adsorbent, AST-120. Potential mechanisms underlying indoxyl sulfate−induced cardiorenal fibrosis are discussed. Future research and clinical implications conclude this review.

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Serum protein-bound uraemic toxins and clinical outcomes in haemodialysis patients

Abstract: Serum free and total p-cresol levels were significantly related to cardiovascular events. In addition, serum free p-cresol and hsCRP levels were also found to be associated with infection-related hospitalization.

Cited by 104 publications

References 24 publications

The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate

The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate

Grape seed proanthocyanidin extract protects human umbilical vein endothelial cells from indoxyl sulfate-induced injury via ameliorating mitochondrial dysfunction

Cardiorenal Syndrome

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