The Role of Liver in Determining Serum Colon-Derived Uremic Solutes

Lin, Cheng‐Jui; Liou, Tai-Cherng; Pan, Chi-Feng; Wu, Pei‐Chen; Sun, Fang‐Ju; Liu, Hsuan‐Liang; Chen, Han‐Hsiang; Wu, Chih‐Jen

doi:10.1371/journal.pone.0134590

Cited by 19 publications

(28 citation statements)

References 34 publications

(37 reference statements)

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“…Our results also revealed that IS was strongly negatively correlated with FMD and pulse wave velocity after adjusting for other confounding factors in a CKD cohort. This finding was concordant with a previous study showing that IS levels were directly correlated with aortic calcification and pulse wave velocity [5]. Additionally, IS was associated with atherosclerotic factor [28,29] and was a valuable surrogate marker in predicting cardiovascular disease in pre-dialysis patients [5,15].…”

Section: Discussionsupporting

confidence: 92%

“…Previous in vitro studies showed that IS had a specific toxic effect on vascular endothelial cells [8], smooth muscle cells [9], and renal tubular cells [10,11]. Clinical outcome studies also demonstrated that IS may play a major role in cardiovascular and all-cause mortality in CKD patients, including those on hemodialysis [5,[12][13][14][15]. These adverse effects may be directly or indirectly attributed to endothelial dysfunction as a result of exposure to retained uremic toxins.…”

Section: Introductionmentioning

confidence: 99%

“…Indoxyl sulfate (IS) is a protein-bound uremic toxin that is markedly affected by liver, kidney and diet [5][6][7] and has been regarded as a nontraditional cardiovascular risk factor in CKD. Previous in vitro studies showed that IS had a specific toxic effect on vascular endothelial cells [8], smooth muscle cells [9], and renal tubular cells [10,11].…”

Section: Introductionmentioning

confidence: 99%

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Indoxyl Sulfate Impairs Endothelial Progenitor Cells and Might Contribute to Vascular Dysfunction in Patients with Chronic Kidney Disease

Lin

Wu²,

Wu³

et al. 2016

Kidney Blood Press Res

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Background/Aims: Indoxyl sulfate (IS) is a protein-bound uremic toxin that accumulates in patients with chronic kidney disease (CKD). We explored the effect of IS on human early endothelial progenitor cells (EPCs) and analyzed the correlation between serum IS levels and parameters of vascular function, including endothelial function in a CKD-based cohort. Methods: A cross-sectional study with 128 stable CKD patients was conducted. Flow-mediated dilation (FMD), pulse wave velocity (PWV), ankle brachial index, serum IS and other biochemical parameters were measured and analyzed. In parallel, the activity of early EPCs was also evaluated after exposure to IS. Results: In human EPCs, a concentration-dependent inhibitory effect of IS on chemotactic motility and colony formation was observed. Additionally, serum IS levels were significantly correlated with CKD stages. The total IS (T-IS) and free IS (F-IS) were strongly associated with age, hypertension, cardiovascular disease, blood pressure, PWV, blood urea nitrogen, creatine and phosphate but negatively correlated with FMD, the estimated glomerular filtration rate (eGFR), hemoglobin, hematocrit, and calcium. A multivariate linear regression analysis also showed that FMD was significantly associated with IS after adjusting for other confounding factors. Conclusions: In humans, IS impairs early EPCs and was strongly correlated with vascular dysfunction. Thus, we speculate that this adverse effect of IS may partly result from the inhibition of early EPCs.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Indoxyl Sulfate Impairs Endothelial Progenitor Cells and Might Contribute to Vascular Dysfunction in Patients with Chronic Kidney Disease

Lin

Wu²,

Wu³

et al. 2016

Kidney Blood Press Res

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“…He found that the dogs with surgically-removed digestive tracts given indole still had elevated indoxyl sulfate plasma levels, whereas dogs with hepatectomies did not. A more recent study by Lin et al [26] confirms the role of the liver in indoxyl sulfate production. They found that cirrhosis limited the increase in plasma indoxyl sulfate levels in patients with CKD.…”

Section: Characteristicsmentioning

confidence: 82%

Indoxyl Sulfate—Review of Toxicity and Therapeutic Strategies

Leong

Sirich

2016

Toxins

208

178

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Indoxyl sulfate is an extensively studied uremic solute. It is a small molecule that is more than 90% bound to plasma proteins. Indoxyl sulfate is derived from the breakdown of tryptophan by colon microbes. The kidneys achieve high clearances of indoxyl sulfate by tubular secretion, a function not replicated by hemodialysis. Clearance by hemodialysis is limited by protein binding since only the free, unbound solute can diffuse across the membrane. Since the dialytic clearance is much lower than the kidney clearance, indoxyl sulfate accumulates to relatively high plasma levels in hemodialysis patients. Indoxyl sulfate has been most frequently implicated as a contributor to renal disease progression and vascular disease. Studies have suggested that indoxyl sulfate also has adverse effects on bones and the central nervous system. The majority of studies have assessed toxicity in cultured cells and animal models. The toxicity in humans has not yet been proven, as most data have been from association studies. Such toxicity data, albeit inconclusive, have prompted efforts to lower the plasma levels of indoxyl sulfate through dialytic and non-dialytic means. The largest randomized trial showed no benefit in renal disease progression with AST-120. No trials have yet tested cardiovascular or mortality benefit. Without such trials, the toxicity of indoxyl sulfate cannot be firmly established.

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“…The biotransformation of indoxyl sulfate requires CYP2E1 and SULT1A1 hepatic enzymes and demonstrates the importance of these pathways in microbiota-derived uremic toxin formation (Figure 2). Formation of p-cresol sulfate and indoxyl sulfate is decreased in chronic kidney disease patients and animal models with advanced liver cirrhosis (and thus impaired hepatic metabolism) [28]. Cirrhotic patients also exhibit higher serum concentrations of metabolic precursors like phenol and indole, suggesting decreased metabolic conjugation [29,30].…”

Section: Intestinal Microbiota-host Liver Interactionsmentioning

confidence: 99%

Microbiota-derived uremic retention solutes: perpetrators of altered nonrenal drug clearance in kidney disease

Prokopienko

Nolin

2017

Expert Review of Clinical Pharmacology

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Introduction Scientific interest in the gut microbiota is increasing due to improved understanding of its implications in human health and disease. In patients with kidney disease, gut microbiota-derived uremic toxins directly contribute to altered nonrenal drug clearance. Microbial imbalances, known as dysbiosis, potentially increase formation of microbiota-derived toxins, and diminished renal clearance leads to toxin accumulation. High concentrations of microbiota-derived toxins such as indoxyl sulfate and p-cresol sulfate perpetrate interactions with drug metabolizing enzymes and transporters, which provides a mechanistic link between increases in drug-related adverse events and dysbiosis in kidney disease. Areas Covered This review summarizes the effects of microbiota-derived uremic toxins on hepatic phase I and phase II drug metabolizing enzymes and drug transporters. Research articles that tested individual toxins were included. Therapeutic strategies to target microbial toxins are also discussed. Expert Commentary Large interindividual variability in toxin concentrations may explain some differences in nonrenal clearance of medications. Advances in human microbiome research provide unique opportunities to systematically evaluate the impact of individual and combined microbial toxins on drug metabolism and transport, and to explore microbiota-derived uremic toxins as potential therapeutic targets.

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The Role of Liver in Determining Serum Colon-Derived Uremic Solutes

Cited by 19 publications

References 34 publications

Indoxyl Sulfate Impairs Endothelial Progenitor Cells and Might Contribute to Vascular Dysfunction in Patients with Chronic Kidney Disease

Indoxyl Sulfate Impairs Endothelial Progenitor Cells and Might Contribute to Vascular Dysfunction in Patients with Chronic Kidney Disease

Indoxyl Sulfate—Review of Toxicity and Therapeutic Strategies

Microbiota-derived uremic retention solutes: perpetrators of altered nonrenal drug clearance in kidney disease

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