p-cresylsulfate and indoxyl sulfate level at different stages of chronic kidney disease

Lin, Cheng‐Jui; Chen, Han‐Hsiang; Pan, Chi-Feng; Chen, Chuang; Wang, Tuen-Jen; Sun, Fang‐Ju; Wu, Chih‐Jen

doi:10.1002/jcla.20456

Cited by 128 publications

(103 citation statements)

References 25 publications

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“…Of importance, the PCS concentration after administration was in the range of levels observed in patients with ESRD. 10,39 The ectopic lipid redistribution and reduction of fat accretion in PCS-treated mice were the result of a direct effect of PCS treatment rather than malnutrition because food intake and body weight were not altered. Fat mass loss should be related to the fact that we observed a decrease in the volume of adipocytes, which may reflect adipocyte dysfunction.…”

Section: Discussionmentioning

confidence: 99%

p-Cresyl Sulfate Promotes Insulin Resistance Associated with CKD

Koppe

Pillon

Vella

et al. 2013

Journal of the American Society of Nephrology

227

175

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The mechanisms underlying the insulin resistance that frequently accompanies CKD are poorly understood, but the retention of renally excreted compounds may play a role. One such compound is p-cresyl sulfate (PCS), a protein-bound uremic toxin that originates from tyrosine metabolism by intestinal microbes. Here, we sought to determine whether PCS contributes to CKD-associated insulin resistance. Administering PCS to mice with normal kidney function for 4 weeks triggered insulin resistance, loss of fat mass, and ectopic redistribution of lipid in muscle and liver, mimicking features associated with CKD. Mice treated with PCS exhibited altered insulin signaling in skeletal muscle through ERK1/2 activation. In addition, exposing C2C12 myotubes to concentrations of PCS observed in CKD caused insulin resistance through direct activation of ERK1/2. Subtotal nephrectomy led to insulin resistance and dyslipidemia in mice, and treatment with the prebiotic arabino-xylo-oligosaccharide, which reduced serum PCS by decreasing intestinal production of p-cresol, prevented these metabolic derangements. Taken together, these data suggest that PCS contributes to insulin resistance and that targeting PCS may be a therapeutic strategy in CKD.

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Section: Discussionmentioning

confidence: 99%

p-Cresyl Sulfate Promotes Insulin Resistance Associated with CKD

Koppe

Pillon

Vella

et al. 2013

Journal of the American Society of Nephrology

227

175

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“…106 Concentrations of indoxyl sulfate and p-cresyl sulfate in the serum are negatively correlated with the level of kidney function. 12 A prospective, observational study performed in 268 patients with CKD indicated that baseline levels of indoxyl sulfate and p-cresyl sulfate were predictors of CKD progression. 13 Animal studies suggest that these uremic toxins may damage renal tubular cells.…”

Section: Intestinal Dysbiosis In Ckd/ Esrdmentioning

confidence: 99%

“…[9][10][11] Preliminary evidence indicates that toxic products generated by a dysbiotic gut microbiome may contribute to progression to CKD and CKD-related complications ( Figure 1). 12,13 GUT MICROBIOTA: AN …”

mentioning

confidence: 99%

The Gut Microbiome, Kidney Disease, and Targeted Interventions

Ramezani

Raj

2014

Journal of the American Society of Nephrology

589

498

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The human gut harbors .100 trillion microbial cells, which influence the nutrition, metabolism, physiology, and immune function of the host. Here, we review the quantitative and qualitative changes in gut microbiota of patients with CKD that lead to disturbance of this symbiotic relationship, how this may contribute to the progression of CKD, and targeted interventions to re-establish symbiosis. Endotoxin derived from gut bacteria incites a powerful inflammatory response in the host organism. Furthermore, protein fermentation by gut microbiota generates myriad toxic metabolites, including p-cresol and indoxyl sulfate. Disruption of gut barrier function in CKD allows translocation of endotoxin and bacterial metabolites to the systemic circulation, which contributes to uremic toxicity, inflammation, progression of CKD, and associated cardiovascular disease. Several targeted interventions that aim to re-establish intestinal symbiosis, neutralize bacterial endotoxins, or adsorb gut-derived uremic toxins have been developed. Indeed, animal and human studies suggest that prebiotics and probiotics may have therapeutic roles in maintaining a metabolically-balanced gut microbiota and reducing progression of CKD and uremia-associated complications. We propose that further research should focus on using this highly efficient metabolic machinery to alleviate uremic symptoms.

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“…Protein-derived tryptophan is metabolized into indole, which is then absorbed into the bloodstream and oxidized into indoxyl sulfate (IS) in the liver (6). IS is normally excreted into the urine, but patients with CKD cannot effectively excrete IS because of reduced renal function (7,8). Elevated serum IS causes elevated expression of genes related to tubulointerstitial fibrosis, such as those coding for TGF-b1 and collagen (9,10).…”

Section: Introductionmentioning

confidence: 99%

A Randomized, Controlled Trial of Oral Intestinal Sorbent AST-120 on Renal Function Deterioration in Patients with Advanced Renal Dysfunction

Hui¹,

Kang²,

Park³

et al. 2016

Clinical Journal of the American Society of Nephrology

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Background and objectives The notion that oral intestinal sorbent AST-120 slows renal disease progression has not been evaluated thoroughly. In this study, we investigated the long-term effect of AST-120 on renal disease progression (doubling of serum creatinine, eGFR decrease .50%, or initiation of RRT) in patients with advanced CKD.Design, setting, participants, & measurements We prospectively recruited 579 patients (CKD stage 3 or 4) from 11 medical centers in Korea from March 4, 2009 to August 31, 2010 and randomized them into an AST-120 arm and a control arm. Patients in the AST-120 arm were given 6 g AST-120 in three divided doses per day, and those in the control arm received only standard conventional treatment (open-label design) for 36 months or until the occurrence of primary outcomes.Results Levels of serum and urine indoxyl sulfate and b2-microglobulin decreased throughout the study period in both treatment arms; however, there was not a significant difference in change in uremic toxins in the AST-120 and control arms. The two arms were not different in the occurrence of composite primary outcomes (100 events in 272 individuals in the AST-120 arm and 100 events in 266 individuals in the control arm; hazard ratio, 1.12; 95% confidence interval, 0.85 to 1.48; log-rank P=0.45). The decline in eGFR and change in proteinuria were similar in the two treatment arms over time (P randomization-time =0.64 and P randomization-time =0.16, respectively). There was no difference in mortality (nine deaths in the AST-120 arm and 11 deaths in the control arm; log-rank P=0.73) or unplanned hospitalizations (102 in the AST-120 arm and 109 in the control arm; log-rank P=0.76) in the two treatment arms. There was no significant difference of the health-related quality of life score between the two arms.Conclusions Long-term use of AST-120 added to standard treatment did not change renal disease progression, proteinuria, mortality, and health-related quality of life in patients with advanced renal dysfunction.

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p-cresylsulfate and indoxyl sulfate level at different stages of chronic kidney disease

Cited by 128 publications

References 25 publications

p-Cresyl Sulfate Promotes Insulin Resistance Associated with CKD

p-Cresyl Sulfate Promotes Insulin Resistance Associated with CKD

The Gut Microbiome, Kidney Disease, and Targeted Interventions

A Randomized, Controlled Trial of Oral Intestinal Sorbent AST-120 on Renal Function Deterioration in Patients with Advanced Renal Dysfunction

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