Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease

Liabeuf, Sophie; Barreto, Daniela Veit; Barreto, Fellype Carvalho; Meert, Natalie; Glorieux, Griet; Schepers, Eva; Temmar, M.; Choukroun, Gabriel; Vanholder, Raymond; Massy, Ziad A.

doi:10.1093/ndt/gfp592

Cited by 368 publications

(292 citation statements)

References 28 publications

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“…[16][17][18][19] Here, we showed that patients with higher IAA display higher rates of mortality and cardiovascular events. More important, we demonstrated that serum IAA is a significant predictor of cardiovascular events and mortality.…”

Section: Discussionmentioning

confidence: 71%

The Cardiovascular Effect of the Uremic Solute Indole-3 Acetic Acid

Dou

Sallée

Cérini

et al. 2015

Journal of the American Society of Nephrology

241

219

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In CKD, uremic solutes may induce endothelial dysfunction, inflammation, and oxidative stress, leading to increased cardiovascular risk. We investigated whether the uremic solute indole-3 acetic acid (IAA) predicts clinical outcomes in patients with CKD and has prooxidant and proinflammatory effects. We studied 120 patients with CKD. During the median study period of 966 days, 29 patients died and 35 experienced a major cardiovascular event. Kaplan-Meier analysis revealed that mortality and cardiovascular events were significantly higher in the higher IAA group (IAA.3.73 mM) than in the lower IAA group (IAA,3.73 mM). Multivariate Cox regression analysis demonstrated that serum IAA was a significant predictor of mortality and cardiovascular events after adjustments for age and sex; cholesterol, systolic BP, and smoking; C-reactive protein, phosphate, body mass index, and albumin; diastolic BP and history of cardiovascular disease; and uremic toxins p-cresyl sulfate and indoxyl sulfate. Notably, IAA level remained predictive of mortality when adjusted for CKD stage. IAA levels were positively correlated with markers of inflammation and oxidative stress: C-reactive protein and malondialdehyde, respectively. In cultured human endothelial cells, IAA activated an inflammatory nongenomic aryl hydrocarbon receptor (AhR)/p38MAPK/NF-kB pathway that induced the proinflammatory enzyme cyclooxygenase-2. Additionally, IAA increased production of endothelial reactive oxygen species. In conclusion, serum IAA may be an independent predictor of mortality and cardiovascular events in patients with CKD. In vitro, IAA induces endothelial inflammation and oxidative stress and activates an inflammatory AhR/p38MAPK/NF-kB pathway.

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Section: Discussionmentioning

confidence: 71%

The Cardiovascular Effect of the Uremic Solute Indole-3 Acetic Acid

Dou

Sallée

Cérini

et al. 2015

Journal of the American Society of Nephrology

241

219

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“…25 p-Cresol (acting as a surrogate for pCS) has been shown to be related to clinical outcomes. 26,27 Recent studies confirmed that free pCS levels were predictive for mortality at different stages of CKD 28 and cardiovascular and all-cause mortality in hemodialysis patients. 29 The relation between pCS and coronary artery disease in patients with no or only moderate degrees of CKD 30 extends the association of this compound with cardiovascular outcomes beyond the scope of pronounced uremia.…”

Section: Discussionmentioning

confidence: 91%

Protein-Bound Uremic Toxins Stimulate Crosstalk between Leukocytes and Vessel Wall

Pletinck

Glorieux

Schepers

et al. 2013

Journal of the American Society of Nephrology

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Leukocyte activation and endothelial damage both contribute to cardiovascular disease, a major cause of morbidity and mortality in CKD. Experimental in vitro data link several protein-bound uremic retention solutes to the modulation of inflammatory stimuli, including endothelium and leukocyte responses and cardiovascular damage, corroborating observational in vivo data. However, the impact of these uremic toxins on the crosstalk between endothelium and leukocytes has not been assessed. This study evaluated the effects of acute and continuous exposure to uremic levels of indoxylsulfate (IS), p-cresylsulfate (pCS), and p-cresylglucuronide (pCG) on the recruitment of circulating leukocytes in the rat peritoneal vascular bed using intravital microscopy. Superfusion with IS induced strong leukocyte adhesion, enhanced extravasation, and interrupted blood flow, whereas pCS caused a rapid increase in leukocyte rolling. Superfusion with pCS and pCG combined caused impaired blood flow and vascular leakage but did not further enhance leukocyte rolling over pCS alone. Intravenous infusion with IS confirmed the superfusion results and caused shedding of heparan sulfate, pointing to disruption of the glycocalyx as the mechanism likely mediating IS-induced flow stagnation. These results provide the first clear in vivo evidence that IS, pCS, and pCG exert proinflammatory effects that contribute to vascular damage by stimulating crosstalk between leukocytes and vessels.

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“…p-cresyl sulfate has also been found to be associated with the occurrence of CVD and elevated mortality in CKD patients [4,69,70]. Elevated plasma levels of p-cresyl sulfate are associated with the high concentrations of endothelial microparticles in ESRD patients [50].…”

Section: • Intestinal Microbiota and Inflammation And Cvd In Ckd Patientsmentioning

confidence: 99%

Role of Altered Intestinal Microbiota in Systemic Inflammation and Cardiovascular Disease in Chronic Kidney Disease

et al. 2014

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The normal intestinal microbiota plays a major role in the maintenance of health and disease prevention. In fact, the alteration of the intestinal microbiota has been shown to contribute to the pathogenesis of several pathological conditions, including obesity and insulin resistance, among others. Recent studies have revealed profound alterations of the gut microbial flora in patients and animals with chronic kidney disease (CKD). Alterations in the composition of the microbiome in CKD may contribute to the systemic inflammation and accumulation of gut-derived uremic toxins, which play a central role in the pathogenesis of accelerated cardiovascular disease and numerous other CKD-associated complications. This review is intended to provide a concise description of the potential role of the CKD-associated changes in the gut microbiome and its potential role the pathogenesis of inflammation and uremic toxicity. In addition, the potential efficacy of pre- and pro-biotics in the restoration of the microbiome is briefly described.

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Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease

Abstract: Serum levels of free and total p-cresylsulphate (the main in vivo circulating metabolites of p-cresol) were elevated in later CKD stages. However, only free p-cresylsulphate seems to be a predictor of survival in CKD.

Cited by 368 publications

References 28 publications

The Cardiovascular Effect of the Uremic Solute Indole-3 Acetic Acid

The Cardiovascular Effect of the Uremic Solute Indole-3 Acetic Acid

Protein-Bound Uremic Toxins Stimulate Crosstalk between Leukocytes and Vessel Wall

Role of Altered Intestinal Microbiota in Systemic Inflammation and Cardiovascular Disease in Chronic Kidney Disease

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