4-cresol-sulfate and Kidney-Failure--Chronic

Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are protein-bound uremic toxins that increase in the sera of patients with chronic kidney disease (CKD), and are not effectively removed by dialysis. The purpose of this meta-analysis was to investigate the relationships of PCS and IS with cardiovascular events and all-cause mortality in patients with CKD stage 3 and above.. Medline, Cochrane, and EMBASE databases were searched until January 1, 2014 with combinations of the following keywords: chronic renal failure, end-stage kidney disease, uremic toxin, uremic retention, indoxyl sulfate, p-cresyl sulfate. Inclusion criteria were: 1) Patients with stage 1 to 5 CKD; 2) Prospective study; 3) Randomized controlled trial; 4) English language publication. The associations between serum levels of PCS and IS and the risks of all-cause mortality and cardiovascular events were the primary outcome measures. Of 155 articles initially identified, 10 prospective and one cross-sectional study with a total 1,572 patients were included. Free PCS was significantly associated with all-cause mortality among patients with chronic renal failure (pooled OR = 1.16, 95% CI = 1.03 to 1.30, P = 0.013). An elevated free IS level was also significantly associated with increased risk of all-cause mortality (pooled OR = 1.10, 95% CI = 1.03 to 1.17, P = 0.003). An elevated free PCS level was significantly associated with an increased risk of cardiovascular events among patients with chronic renal failure (pooled OR = 1.28, 95% CI = 1.10 to 1.50, P = 0.002), while free IS was not significantly associated with risk of cardiovascular events (pooled OR = 1.05, 95% CI = 0.98 to 1.13, P = 0.196).. Elevated levels of PCS and IS are associated with increased mortality in patients with CKD, while PCS, but not IS, is associated with an increased risk of cardiovascular events.

Topics: Biomarkers; Cardiovascular Diseases; Cresols; Humans; Indican; Kidney Failure, Chronic; Risk Factors; Sulfuric Acid Esters; Toxins, Biological; Uremia

Chronic kidney disease (CKD), marked by a progressive loss in renal function, is a leading cause of hemodialysis initiation and cardiovascular disease (CVD). There are currently 13.3 million patients with CKD and 300 thousand patients are currently undergoing hemodialysis in Japan. Therefore, preventing the initiation of dialysis and reducing the risk of cardiovascular death are high-priority issues from the viewpoint of public health and economic implications. Understanding the molecular mechanism responsible for the progression of CKD and cardiovascular damage regarding crosstalk between the kidney and cardiovascular system is an important issue in controlling the pathogenesis of CKD-CVD. However, the mechanisms involved in CKD-CVD are not well understood. This hinders the development of new treatment strategies. We have been investigating the role of protein bound uremic toxins, that are difficult to remove by hemodialysis, on the onset and progression of CKD and CVD. The relationship between their redox properties and the pathogenesis of CKD-CVD was examined. In this review, we focus on two sulfate conjugated uremic toxins, namely, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), and summarize recent studies that provide new insights on the molecular mechanisms responsible for uremic toxin-induced oxidative tissue damage via a cardiovascular-renal connection.

Topics: Cardiovascular Diseases; Cresols; Humans; Indican; Kidney Failure, Chronic; Oxidation-Reduction; Oxidative Stress; Sulfuric Acid Esters

Although protein-bound uremic retention solutes are recognized as 1 of the 3 main categories of uremic retention solutes, they only recently have been submitted to thorough analysis. In vitro and ex vivo data link both p-cresyl sulfate and indoxyl sulfate, two of the main compounds of this solute group, to negative impact on the cardiovascular system and progression of kidney failure. Recent in vivo observational data also relate concentration of these compounds to survival outcome, inflammation, and vascular disease in different, even moderate, stages of chronic kidney disease. Removal by different dialysis strategies, even high-flux hemodialysis, is difficult, and only by applying convection, some improvement of removal has been obtained. The other strategy with the potential to decrease concentration is by influencing intestinal generation and/or absorption. The sorbent Kremezin (AST-120) has been shown in controlled studies to decrease protein-bound solute concentration. In pilot controlled studies, AST-120 has been shown to be superior on outcome parameters to placebo. Results from large randomized trials are awaited, before these data can be considered as solid enough to warrant the recommendation to use these compounds for overall therapeutic purposes.

Topics: Adsorption; Blood Proteins; Carbon; Cresols; Humans; Indican; Kidney Failure, Chronic; Microspheres; Oxides; Protein Binding; Renal Dialysis; Sulfuric Acid Esters; Uremia

Topics: Adult; Cresols; Drugs, Chinese Herbal; Female; Humans; Indican; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Peritoneal Dialysis; Sulfuric Acid Esters; Treatment Outcome; Uremia

Cardiovascular disease, the leading cause of mortality in hemodialysis patients, is not fully explained by traditional risk factors. To help define non-traditional risk factors, we determined the association of predialysis total p-cresol sulfate, indoxyl sulfate, phenylacetylglutamine, and hippurate with cardiac death, sudden cardiac death, and first cardiovascular event in the 1,273 participants of the HEMO Study. The results were adjusted for potential demographic, clinical, and laboratory confounders. The mean age of the patients was 58 years, 63% were Black and 42% were male. Overall, there was no association between the solutes and outcomes. However, in sub-group analyses, among patients with lower serum albumin (under 3.6 g/dl), a twofold higher p-cresol sulfate was significantly associated with a 12% higher risk of cardiac death (hazard ratio 1.12; 95% confidence interval, 0.98-1.27) and 22% higher risk of sudden cardiac death (1.22, 1.06-1.41). Similar trends were also noted with indoxyl sulfate. Trial interventions did not modify the association between these solutes and outcomes. Routine clinical and lab data explained less than 22% of the variability in solute levels. Thus, in prevalent hemodialysis patients participating in a large U.S. hemodialysis trial, uremic solutes p-cresol sulfate, indoxyl sulfate, hippurate, and phenylacetylglutamine were not associated with cardiovascular outcomes. However, there were trends of toxicity among patients with lower serum albumin.

Topics: Adult; Aged; Cardiovascular Diseases; Cresols; Female; Glutamine; Hippurates; Humans; Indican; Kidney Failure, Chronic; Longitudinal Studies; Male; Middle Aged; Renal Dialysis; Risk Factors; Serum Albumin; Sulfuric Acid Esters; Uremia

The Frequent Hemodialysis Network Daily Trial compared conventional three-times weekly treatment to more frequent treatment with a longer weekly treatment time in patients receiving in-center hemodialysis. Evaluation at one year showed favorable effects of more intensive treatment on left ventricular mass, blood pressure, and phosphate control, but modest or no effects on physical or cognitive performance. The current study compared plasma concentrations of uremic solutes in stored samples from 53 trial patients who received three-times weekly in-center hemodialysis for an average weekly time of 10.9 hours and 30 trial patients who received six-times weekly in-center hemodialysis for an average of 14.6 hours. Metabolomic analysis revealed that increased treatment frequency and time resulted in an average reduction of only 15 percent in the levels of 107 uremic solutes. Quantitative assays confirmed that increased treatment did not significantly reduce levels of the putative uremic toxins p-cresol sulfate or indoxyl sulfate. Kinetic modeling suggested that our ability to lower solute concentrations by increasing hemodialysis frequency and duration may be limited by the presence of non-dialytic solute clearances and/or changes in solute production. Thus, failure to achieve larger reductions in uremic solute concentrations may account, in part, for the limited benefits observed with increasing frequency and weekly treatment time in Frequent Hemodialysis Daily Trial participants.

Topics: Adult; Cresols; Female; Humans; Indican; Kidney Failure, Chronic; Male; Metabolomics; Middle Aged; Renal Dialysis; Sulfuric Acid Esters; Time Factors; Uremia

Protein-bound uraemic retention solutes, including p-cresyl sulfate and indoxyl sulfate, contribute substantially to the uraemic syndrome. These and several other uraemic retention solutes originate from intestinal bacterial protein fermentation. We investigated whether the prebiotic oligofructose-enriched inulin reduced serum concentration of p-cresyl sulfate and indoxyl sulfate, through interference with intestinal generation.. We performed a single centre, non-randomized, open-label phase I/II study in maintenance HD patients with a 4-week, escalating dose regimen of oligofructose-enriched inulin (ORAFTI Synergy 1, Tienen, Belgium) (www.clinicaltrials.gov NCT00695513). Changes in p-cresyl sulfate and indoxyl sulfate serum concentrations as well as changes in p-cresyl sulfate and indoxyl sulfate generation rates were analysed.. Compliance with therapy was excellent. p-Cresyl sulfate serum concentrations at 4 weeks were significantly reduced by 20% (intention to treat, P = 0.01; per protocol, P = 0.03). Also p-cresyl sulfate generation rates were reduced (P = 0.007). In contrast, neither indoxyl sulfate generation rates (P = 0.9) nor serum concentrations (P = 0.4) were significantly changed.. The prebiotic oligofructose-inulin significantly reduced p-cresyl sulfate generation rates and serum concentrations in haemodialysis patients. Whether reduction of p-cresyl sulfate serum concentrations, an independent predictor of cardiovascular disease in HD patients, will result in improved cardiovascular outcomes remains to be proven.

Topics: Administration, Oral; Aged; Cresols; Female; Humans; Indican; Inulin; Kidney Failure, Chronic; Male; Middle Aged; Oligosaccharides; Prebiotics; Renal Dialysis; Sulfuric Acid Esters

Protein-bound solutes are poorly cleared by peritoneal dialysis. We examined the hypothesis that plasma concentrations of bound solutes would therefore rise as residual renal function is lost.. Clearances of urea indican and p-cresol sulfate were measured in peritoneal dialysis patients with and without residual function.. In patients with residual function, protein binding restricted the peritoneal indican and p-cresol sulfate clearances to 0.3 +/- 0.1 ml/min, as compared to the peritoneal urea clearance of 5.5 +/- 1.1 ml/min. The urinary indican and p-cresol sulfate clearances of 2.7 +/- 2.5 and 1.3 +/- 1.0 ml/min were closer to the urinary urea clearance of 3.9 +/- 2.2 ml/min, reflecting the superior ability of native kidney function to clear bound solutes. Urinary clearance thus provided the majority of the total indican and p-cresol sulfate clearances of 3.0 +/- 2.5 and 1.6 +/- 1.0 ml/min in patients with residual function but the minority of total urea clearance of 9.4 +/- 2.2 ml/min. Loss of residual function lowered the total clearances for indican and p-cresol sulfate to 0.5 +/- 0.2 and 0.4 +/- 0.2 ml/min, whereas the urea clearance fell only slightly. However there was only a modest increase in the plasma indican level and no increase in the plasma p-cresol sulfate level in patients with no residual function because reduction in the daily removal of these solutes accompanied the reduction in their total clearance rates.. Reduction in the removal of indican and p-cresol sulfate kept plasma levels from rising markedly when residual function was lost.

Topics: Adult; Aged; Blood Proteins; Cresols; Dialysis Solutions; Female; Humans; Indican; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Sulfuric Acid Esters; Treatment Outcome

The binding of drugs to plasma protein is frequently altered in certain types of renal diseases. We recently reported on the effects of oxidation and uremic toxins on the binding of aripiprazole (ARP) to human serum albumin. In our continuing investigations, we examined the binding of ARP to plasma pooled from patients with chronic renal dysfunction. We examined the issue of the molecular basis for which factors affect the changes in drug binding that accompany renal failure. The study was based on the statistical relationships between ARP albumin binding and biochemical parameters such as the concentrations of oxidized albumin and uremic toxins. The binding of ARP to plasma from chronic renal patients was significantly lower than healthy volunteers. A rational relationship between the ARP binding rate and the concentration of toxins, including indoxyl sulphate (IS) and p-cresyl sulphate (PCS), was found, particularly for IS. Moreover, multiple regression analyses that involved taking other parameters such as PCS or oxidized albumin ratio to IS into account supports the above hypothesis. In conclusion, the limited data reported in this present study indicates that monitoring IS in the blood is a very important determinant in the dosage plan for the administration of site II drugs such as ARP, if the efficacy of the drug in renal disease is to be considered.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Aripiprazole; Blood Proteins; Case-Control Studies; Cresols; Female; Humans; Indican; Kidney Failure, Chronic; Male; Protein Binding; Retrospective Studies; Serum Albumin, Human; Sulfuric Acid Esters; Young Adult

Topics: Aged; Blood Pressure; C-Reactive Protein; Chromatography, High Pressure Liquid; Cresols; Diabetes Mellitus; Female; Humans; Kidney Failure, Chronic; Male; Mass Spectrometry; Middle Aged; Predictive Value of Tests; Pulse Wave Analysis; Renal Dialysis; Risk Factors; Sulfuric Acid Esters; Vascular Stiffness

Protein-bound uremic toxins (PBUTs) accumulate at high plasma levels and cause various deleterious effects in end-stage renal disease patients because their removal by conventional hemodialysis is severely limited by their low free-fraction levels in plasma. Here, we assessed the extent to which solute removal can be increased by adding liposomes to the dialysate. The uptake of liposomes by direct incubation in vitro showed an obvious dose-response relationship for p-cresyl sulfate (PCS) and indoxyl sulfate (IS) but not for hippuric acid (HA). The percent removal of both PCS and IS but not of HA was gradually increased with the increased concentration of liposomes in a rapid equilibrium dialysis setup. In vitro closed circulation showed that adding liposomes to the dialysate markedly increased the dialysances of PBUTs without greatly altering that of urea and creatinine. In vivo experiments in uremic rats demonstrated that adding liposomes to the dialysate resulted in higher reduction ratios (RRs) and more total solute removal (TSR) for several PBUTs compared to the conventional dialysate, which was approximately similar to the addition of bovine serum albumin to the dialysate. These findings highlight that as an adjunct to conventional hemodialysis, addition of liposomes to the dialysate could significantly improve the removal of protein-bound uremic solutes without greatly altering the removal of small, water-soluble solutes.

Topics: Animals; Cresols; Dialysis Solutions; Equipment Design; Hippurates; Indican; Kidney Failure, Chronic; Liposomes; Male; Rats, Sprague-Dawley; Renal Dialysis; Sulfuric Acid Esters; Toxins, Biological; Uremia

The variability of molecular signatures and predictive low molecular weight markers of chronic kidney disease (CKD) in different populations are poorly understood. Thus, in a large sample with 4763 people we compare the molecular signatures and metabolites with diagnostic relevance in plasma and urine of CKD patients of different geographical origins. From an integrated model based on dynamic networks and multivariate statistics, metabolites with predictive value obtained from targeted and untargeted molecular analysis, interactions between metabolic pathways affected by CKD, and the methodological quality of metabolomic studies were analyzed. The metabolites 3-methylhistidine, citrulline, kynurenine, p-cresol sulfate, urea, and citrate presented consistent expression in all population groups. Only increased kynurenine and p-cresol sulfate in plasma samples obtained acceptable scores as CKD biomarkers, independent of geographic origin. Metabolites such as leucine, alanine, isoleucine, serine, histidine, and citrate were nodal points, indicating that protein metabolism pathways are similarly impaired in Asian, European and North American patients. Based on our integrated model, we show that the metabolome of CKD patients exhibits a strong geographic influence, leading to unique metabolic signatures. Contrary to the likelihood of molecular similarities between geographically distinct populations, metabolic convergences in protein metabolism pathways and the molecules kynurenine and p-cresol sulfate were relevant as general predictors of CKD. In general, the quality assessment indicated that the current evidence is based on research models with variable methodological quality, whose limitations described in this study should be considered in the refinement of molecular approaches.

Topics: Biomarkers; Case-Control Studies; Cresols; Female; Humans; Kidney Failure, Chronic; Kynurenine; Male; Metabolomics; Multivariate Analysis; Oxidative Stress; Population Surveillance; Sulfuric Acid Esters

Observational studies have suggested a relationship between the plasma concentration of indoxyl sulfate (IS) and p-cresyl sulfate (PCS), small gut-derived 'uremic solutes', and the high incidence of uremic cardiomyopathy in patients with end-stage renal disease (ESRD). IS and PCS are derived from the metabolism of dietary components (tryptophan and tyrosine) by gut bacteria. This pilot study was designed to examine the effects of a poorly absorbable antibiotic (vancomycin) on the plasma concentration of two gut-derived 'uremic solutes', IS and PCS, and on the composition of the gut microbiome.. Plasma concentrations of IS and PCS were measured by MS-HPLC. The gut microbiome was assessed in stool specimens sequenced for the 16S rRNA gene targeting the V4 region.. The pre-dialysis mean plasma concentrations of both IS and PCS were markedly elevated. Following the administration of vancomycin (Day 0), the IS and PCS concentrations decreased at Day 2 or Day 5 and returned to baseline by Day 28. Following vancomycin administration, several changes in the gut microbiome were observed. Most striking was the decrease in diversity, a finding that was evident on Day 7 and was still evident at Day 28. There was little change at the phylum level but at the genus level, broad population changes were noted. Changes in the abundance of several genera appeared to parallel the concentration of IS and PCS.. These findings suggest that alteration of the gut microbiome, by an antibiotic, might provide an important strategy in reducing the levels of IS and PCS in ESRD.

Topics: Administration, Oral; Adult; Aged; Anti-Bacterial Agents; Biomarkers; Cresols; Female; Gastrointestinal Microbiome; Humans; Indican; Kidney Failure, Chronic; Male; Metagenome; Middle Aged; Molecular Typing; Pilot Projects; RNA, Ribosomal, 16S; Sulfuric Acid Esters; Vancomycin

Topics: Administration, Oral; Adsorption; Animals; Carbon; Chromatography, Liquid; Cresols; Indican; Kidney Failure, Chronic; Male; Mice, Inbred C57BL; Oxides; Sulfuric Acid Esters; Tandem Mass Spectrometry; Toxins, Biological; Uremia

p-Cresyl sulfate (PCS) is a risk factor of cardiovascular disease in patients with chronic kidney disease. Here we tested whether serum PCS levels were related to the rate and evolution of carotid atherosclerosis in hemodialysis patients and identified a potential mechanism. A total of 200 hemodialysis patients were categorized as with or without carotid atherosclerotic plaque and followed for 5 years. Serum PCS levels were found to be higher in patients with than without carotid atherosclerotic plaque and positively correlated with increased total plaque area during follow-up. Multiple logistic regression and mixed effects model analyses showed that serum PCS levels were independently associated with the incidence and progression of carotid atherosclerotic plaque. PCS induced inflammatory factor and adhesion molecule expression in endothelial cells and macrophages. In addition, PCS triggered monocyte-endothelial cell interaction in vitro and in vivo through increased production of reactive oxygen species. Compared with controls, increase of PCS levels produced by gavage promoted atherogenesis in 5/6-nephrectomized apoE-/- mice; a process attenuated by NADPH oxidase inhibitors. Thus, increased serum PCS levels are associated with the occurrence and progression of carotid atherosclerosis in hemodialysis patients and promote atherogenesis through increased reactive oxygen species production.

Topics: Acetophenones; Adult; Aged; Animals; Aorta; Apolipoproteins E; Carotid Artery Diseases; Case-Control Studies; Cresols; Disease Progression; Endothelial Cells; Female; Humans; Kidney Failure, Chronic; Macrophages; Male; Mice; Middle Aged; NADPH Oxidases; Reactive Oxygen Species; Sulfuric Acid Esters

A significant number of patients with chronic kidney disease (CKD) have cardiac abnormalities, and left ventricular systolic dysfunction (LVSD) is a common manifestation. p-Cresylsulfate (PCS), a protein-bound uraemic retention solute, is known to cause endothelial dysfunction and possibly plays a role in coronary atherosclerosis. Furthermore, the associations among serum total PCS, major adverse cardiovascular events, all-cause mortality, and QTc prolongation have also been found in previous studies. We thus investigated the association of total PCS and CKD with LVSD in the clinical setting.. We included 403 consecutive patients with stable angina. To evaluate LV function, all patients underwent echocardiography. To measure the serum total PCS concentrations and estimated glomerular filtration rate (eGFR), blood samples were obtained.. Multiple regression analysis showed that left atrium diameter, left ventricular mass index, end diastolic interventricular septal thickness, left ventricular end-systolic diameter, left ventricular end-systolic volume, stroke volume, left ventricular end-systolic volume index, left ventricular ejection fraction (LVEF), and the interventricular septum/posterior wall of the left ventricle were independently associated with total PCS (all p<0.05). In addition, a significantly decreased LVEF was present in patients with lower and higher serum total PCS and with CKD, and with higher serum total PCS and without CKD than from those with lower serum total PCS concentrations and without CKD (p=0.004). In the multivariate logistic regression analysis, when patients without CKD and lower PCS were used as reference group, patients with the higher total PCS concentration and without CKD had an odds ratio of 3.59 for the risk of LVSD, the lower total PCS concentration and with CKD had an odds ratio of 3.89 for the risk of LVSD, and the higher total PCS concentration and with CKD had an odds ratio of 4.04 for the risk of LVSD (p=0.039, p=0.038, and p=0.020, respectively).. High serum concentrations of total PCS or CKD, or both, represent an increased risk of impaired LV systolic function in stable angina patients.

Topics: Aged; Aged, 80 and over; Cresols; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Sulfuric Acid Esters; Ventricular Dysfunction, Left

End-stage renal disease (ESRD) is associated with uremia and increased systemic inflammation. Alteration of the intestinal microbiota may facilitate translocation of endotoxins into the systemic circulation leading to inflammation. We hypothesized that children with ESRD have an altered intestinal microbiota and increased serum levels of bacterially derived uremic toxins.. Four groups of subjects were recruited: peritoneal dialysis (PD), hemodialysis (HD), post-kidney transplant and healthy controls. Stool bacterial composition was assessed by pyrosequencing analysis of 16S rRNA genes. Serum levels of C-reactive protein (CRP), D-lactate, p-cresyl sulfate and indoxyl sulfate were measured.. Compared to controls, the relative abundance of Firmicutes (P = 0.0228) and Actinobacteria (P = 0.0040) was decreased in PD patients. The relative abundance of Bacteroidetes was increased in HD patients (P = 0.0462). Compared to HD patients the relative abundance of Proteobacteria (P = 0.0233) was increased in PD patients. At the family level, Enterobacteriaceae was significantly increased in PD patients (P = 0.0020) compared to controls; whereas, Bifidobacteria showed a significant decrease in PD and transplant patients (P = 0.0020) compared to control. Alpha diversity was decreased in PD patients and kidney transplant using both phylogenetic and non-phylogenetic diversity measures (P = 0.0031 and 0.0003, respectively), while beta diversity showed significant separation (R statistic = 0.2656, P = 0.010) between PD patients and controls. ESRD patients had increased serum levels of p-cresyl sulfate and indoxyl sulfate (P < 0.0001 and P < 0.0001, respectively). The data suggests that no significant correlation exists between the alpha diversity of the intestinal microbiota and CRP, D-lactate, or uremic toxins. Oral iron supplementation results in expansion of the phylum Proteobacteria.. Children with ESRD have altered intestinal microbiota and increased bacterially derived serum uremic toxins.

Topics: Actinobacteria; Adolescent; Bacterial Load; Bacteroidetes; C-Reactive Protein; Child; Child, Preschool; Cresols; Feces; Female; Firmicutes; Gastrointestinal Microbiome; Humans; Indican; Intestines; Kidney Failure, Chronic; Kidney Transplantation; Lactic Acid; Male; Peritoneal Dialysis; Proteobacteria; RNA, Ribosomal, 16S; Sulfuric Acid Esters; Uremia; Verrucomicrobia

Numerous substances accumulate in the body in uremia but those contributing to cardiovascular morbidity and mortality in dialysis patients are still undefined. We examined the association of baseline free levels of four organic solutes that are secreted in the native kidney - p-cresol sulfate, indoxyl sulfate, hippurate and phenylacetylglutamine - with outcomes in hemodialysis patients.. We measured these solutes in stored specimens from 394 participants of a US national prospective cohort study of incident dialysis patients. We examined the relation of each solute and a combined solute index to cardiovascular mortality and morbidity (first cardiovascular event) using Cox proportional hazards regression adjusted for demographics, comorbidities, clinical factors and laboratory tests including Kt/VUREA.. Mean age of the patients was 57 years, 65% were white and 55% were male. In fully adjusted models, a higher p-cresol sulfate level was associated with a greater risk (HR per SD increase; 95% CI) of cardiovascular mortality (1.62; 1.17-2.25; p=0.004) and first cardiovascular event (1.60; 1.23-2.08; p<0.001). A higher phenylacetylglutamine level was associated with a greater risk of first cardiovascular event (1.37; 1.18-1.58; p<0.001). Patients in the highest quintile of the combined solute index had a 96% greater risk of cardiovascular mortality (1.96; 1.05-3.68; p=0.04) and 62% greater risk of first cardiovascular event (1.62; 1.12-2.35; p=0.01) compared with patients in the lowest quintile. Results were robust in sensitivity analyses.. Free levels of uremic solutes that are secreted by the native kidney are associated with a higher risk of cardiovascular morbidity and mortality in incident hemodialysis patients.

Topics: Adult; Aged; Biomarkers; Cardiovascular Diseases; Cause of Death; Cresols; Female; Glutamine; Hippurates; Humans; Indican; Kidney Failure, Chronic; Male; Middle Aged; Morbidity; Mortality; Patient Outcome Assessment; Renal Dialysis; Sulfuric Acid Esters; United States

To identify blood markers for early stages of chronic kidney disease (CKD), blood samples were collected from rats with adenine-induced CKD over 28 days. Plasma samples were subjected to metabolomic profiling by liquid chromatography-mass spectrometry, followed by multivariate analyses. In addition to already-identified uremic toxins, we found that plasma concentrations of N6-succinyl adenosine, lysophosphatidylethanolamine 20:4, and glycocholic acid were altered, and that these changes during early CKD were more sensitive markers than creatinine concentration, a universal indicator of renal dysfunction. Moreover, the increase in plasma indoxyl sulfate concentration occurred earlier than increases in phenyl sulfate and p-cresol sulfate. These novel metabolites may serve as biomarkers in identifying early stage CKD.

Topics: Adenine; Adenosine; Animals; Biomarkers; Chromatography, Liquid; Cresols; Early Diagnosis; Glycocholic Acid; Indican; Kidney Failure, Chronic; Lysophospholipids; Male; Metabolomics; Multivariate Analysis; Rats; Rats, Sprague-Dawley; Sulfuric Acid Esters; Tandem Mass Spectrometry

Removal of protein-bound uremic toxins by dialysis therapy is limited. The effect of oral adsorbent AST-120 in chronic dialysis patients has rarely been investigated.. AST-120 was administered 6.0 g/day for 3 months in 69 chronic dialysis patients. The blood concentrations of indoxyl sulfate, p-cresol sulfate and biomarkers of cardiovascular risk were determined before and after AST-120 treatment.. AST-120 significantly decreased both the total and free forms of indoxyl sulfate and p-cresol sulfate ranging from 21.9 to 58.3%. There were significant simultaneous changes of the soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK, 24% increase), malondialdehyde (14% decrease) and interleukin-6 (19% decrease). A significant association between the decrease of indoxyl sulfate and changes of sTWEAK and interleukin-6 was noted.. AST-120 effectively decreased indoxyl sulfate and p-cresol sulfate levels in both total and free forms. AST-120 also improved the profile of cardiovascular biomarkers.

Topics: Adsorption; Adult; Biomarkers; Carbon; Cardiovascular Diseases; Cresols; Cytokine TWEAK; Female; Humans; Indican; Interleukin-6; Kidney Failure, Chronic; Male; Malondialdehyde; Middle Aged; Oxides; Protein Binding; Renal Dialysis; Risk Factors; Sulfuric Acid Esters; Tumor Necrosis Factors; Uremia

Intestinal microbiome constitutes a symbiotic ecosystem that is essential for health, and changes in its composition/function cause various illnesses. Biochemical milieu shapes the structure and function of the microbiome. Recently, we found marked differences in the abundance of numerous bacterial taxa between ESRD and healthy individuals. Influx of urea and uric acid and dietary restriction of fruits and vegetables to prevent hyperkalemia alter ESRD patients' intestinal milieu. We hypothesized that relative abundances of bacteria possessing urease, uricase, and p-cresol- and indole-producing enzymes is increased, while abundance of bacteria containing enzymes converting dietary fiber to short-chain fatty acids (SCFA) is reduced in ESRD.. Reference sets of bacteria containing genes of interest were compiled to family, and sets of intestinal bacterial families showing differential abundances between 12 healthy and 24 ESRD individuals enrolled in our original study were compiled. Overlap between sets was assessed using hypergeometric distribution tests.. Among 19 microbial families that were dominant in ESRD patients, 12 possessed urease, 5 possessed uricase, and 4 possessed indole and p-cresol-forming enzymes. Among 4 microbial families that were diminished in ESRD patients, 2 possessed butyrate-forming enzymes. Probabilities of these overlapping distributions were <0.05.. ESRD patients exhibited significant expansion of bacterial families possessing urease, uricase, and indole and p-cresol forming enzymes, and contraction of families possessing butyrate-forming enzymes. Given the deleterious effects of indoxyl sulfate, p-cresol sulfate, and urea-derived ammonia, and beneficial actions of SCFA, these changes in intestinal microbial metabolism contribute to uremic toxicity and inflammation.

Topics: Adult; Aged; Ammonia; Cresols; Diet; Fatty Acids, Volatile; Female; Humans; Indican; Indoles; Inflammation; Intestines; Kidney Failure, Chronic; Male; Microbiota; Middle Aged; Sulfuric Acid Esters; Urate Oxidase; Urea; Urease

There is a growing body of evidence supporting the nephrovascular toxicity of indoxyl sulphate (IS) and p-cresyl sulphate (PCS). Nonetheless, a comprehensive description of how these toxins accumulate over the course of chronic kidney disease (CKD) is lacking.. This cross-sectional observational study included a convenience sample of 327 participants with kidney function categorised as normal, non-dialysis CKD and end-stage kidney disease (ESKD). Participants underwent measurements of serum total and free IS and PCS and assessment of cardiovascular history and structure (carotid intima-media thickness [cIMT, a measure of arterial stiffness]), and endothelial function (brachial artery reactivity [flow-mediated dilation (BAR-FMD); glyceryl trinitrate (BAR-GTN)]). Across the CKD spectrum there was a significant increase in both total and free IS and PCS and their free fractions, with the highest levels observed in the ESKD population. Within each CKD stage, concentrations of PCS, total and free, were significantly greater than IS (all p < 0.01). Both IS and PCS, free and total, were correlated with BAR-GTN (ranging from r = -0.33 to -0.44) and cIMT (r = 0.19 to 0.21), even after adjusting for traditional risk factors (all p < 0.01). Further, all toxins were independently associated with the presence of cardiovascular disease (all p < 0.02).. More advanced stages of CKD are associated with progressive increases in total and free serum IS and PCS, as well as increases in their free fractions. Total and free serum IS and PCS were independently associated with structural and functional markers of cardiovascular disease. Studies of therapeutic interventions targeting these uraemic toxins are warranted.

Topics: Aged; Biomarkers; Brachial Artery; Cardiovascular Diseases; Carotid Intima-Media Thickness; Cresols; Cross-Sectional Studies; Female; Follow-Up Studies; Humans; Indican; Kidney Failure, Chronic; Logistic Models; Male; Middle Aged; Multivariate Analysis; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Sulfuric Acid Esters; Vascular Stiffness

Cardiovascular disease is the leading cause of mortality in hemodialysis patients and is associated with chronic inflammation. Elevation of uremic toxins, particular protein-bound uremic toxins, is a possible cause of hyper-inflammation in hemodialysis patients. But the association between uremic toxins and inflammatory markers in hemodialysis is still unclear.. We conducted a cross-sectional study to evaluate the association of the serum uremic toxins and inflammatory markers in hemodialysis patients.. The uremic toxins were not associated with inflammatory markers--including high sensitivity C-reactive protein, IL(Interleukin) -1β, IL-6, tumor necrosis factor-α. In multiple linear regression, serum levels of total p-cresol sulfate (PCS) were independently significantly associated with serum total indoxyl sulfate (IS) (standardized coefficient: 0.274, p<0.001), and co-morbidity of diabetes mellitus (DM) (standardized coefficient: 0.342, p<0.001) and coronary artery disease (CAD) (standardized coefficient: 0.128, p = 0.043). The serum total PCS levels in hemodialysis with co-morbidity of DM and CAD were significantly higher than those without co-morbidity of DM and CAD (34.10±23.44 vs. 16.36±13.06 mg/L, p<0.001). Serum levels of total IS was independently significantly associated with serum creatinine (standardized coefficient: 0.285, p<0.001), total PCS (standardized coefficient: 0.239, p = 0.001), and synthetic membrane dialysis (standardized coefficient: 0.139, p = 0.046).. The study showed that serum levels of total PCS and IS were not associated with pro-inflammatory markers in hemodialysis patients. Besides, serum levels of total PCS were independently positively significantly associated with co-morbidity of CAD and DM.

Topics: Aged; Comorbidity; Coronary Artery Disease; Creatinine; Cresols; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Indican; Inflammation; Inflammation Mediators; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Sulfuric Acid Esters

P-cresyl sulfate (PCS) and indoxyl sulfate (IS) were not only novel but essential factors associated with cardiovascular disease and mortality in patients with chronic kidney disease and hemodialysis. However, little evidence exams the effect in peritoneal dialysis (PD) patients.. This pilot study recruited 46 stable PD patients in a single medical center. Serum levels of IS, PCS and biochemistry were measured concurrently. Clinical outcomes including cardiovascular, all-cause mortality and PD failure event were recorded during a 5-year follow-up.. Serum levels of free and total PCS were lower in patients with residual renal function (11.67 ± 6.92, p = 0.014, 0.77 ± 0.48, p = 0.046, respectively). Multivariate Cox regression analysis showed age (HR: 1.07, p = 0.01), serum CO2 (HR: 0.67, p = 0.02) and total PCS (HR: 1.05, p <0.01) were independently associated with cardiovascular events; only free PCS (HR: 1.42, p <0.01) reached significant correlation with all-cause mortality. Total IS (HR: 1.27, p = 0.03) significantly correlated with PD failure event after adjusting other confounding factors. Kaplan-Meier analysis revealed that patients with higher total and free PCS levels had higher cardiovascular events (log rank p <0.01, log rank p = 0.05, respectively) and mortality event (log rank p = 0.02, log rank p = 0.03, respectively) than those with lower levels. In addition, total IS (log rank p = 0.04), total PCS (log rank p = 0.01) and free PCS (log rank p <0.01) could independently predict PD failure event during the study period.. Our findings suggest PCS and IS may be a valuable surrogate in predicting poor clinical outcomes in PD patients.

Topics: Adult; Cardiovascular Diseases; Cresols; Female; Follow-Up Studies; Humans; Indican; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Pilot Projects; Prognosis; Sulfuric Acid Esters

Indoxyl sulfate and p-cresyl sulfate are two uremic retention solutes implicated in the uremic syndrome. Removal during dialysis is limited, mainly due to protein binding. Binding characteristics to healthy albumin have recently been characterized. Whether uremia alters the binding characteristics of albumin is currently unknown. Moreover, protein binding values previously determined with ultrafiltration are in sharp contrast to recently reported values based on microcalorimetry. In the present study, indoxyl sulfate and p-cresyl sulfate binding were therefore quantified using both equilibrium dialysis and ultrafiltration. Deming regression demonstrated good agreement between equilibrium dialysis and ultrafiltration. Free serum concentrations of indoxyl sulfate (+26.6%) and p-cresyl sulfate (+19.7%) were slightly higher at body temperature compared with at room temperature. To investigate binding kinetics, the plasma of healthy individuals or hemodialysis patients was titrated with albumin solutions. Theoretical models of protein binding were fitted to observed titration curves. Binding coefficients of both toxins were highest in purified albumin, and were reduced from healthy to uremic plasma. In conclusion, the ultrafiltration-HPLC technique reliably measures free serum concentrations of indoxyl sulfate and p-cresyl sulfate. Albumin is the main binding protein, both in health and in advanced stages of chronic kidney disease. Modeling suggests that albumin contains two binding sites for both toxins, a single high affinity binding site and a second low affinity binding site. The high affinity binding site accounts for at least 90% of overall binding. Competition for this binding site could be used to augment free solute concentrations during dialysis, thus improving epuration.

Topics: Binding Sites; Cresols; Humans; Indican; Kidney Failure, Chronic; Models, Biological; Protein Binding; Renal Dialysis; Serum Albumin; Sulfuric Acid Esters; Ultrafiltration

The mortality rate of elderly hemodialysis (HD) patients is high. Serum p-cresyl sulfate (PCS) and indoxyl sulfate (IS) are associated with cardiovascular (CV) disease and mortality in renal patients. The association between such biomarkers and mortality in elderly HD patients has a high clinical value but remains unclear.. This prospective cohort study investigated the association of serum IS and PCS with all-cause and CV mortality in elderly HD patients. Multivariate Cox regression analysis was used to estimate the risk of all-cause and CV mortality in this prospective cohort.. Of 112 patients, 45 deaths (18 CV deaths) were identified after a mean follow-up of 33.2 months. The cumulative and CV survival of patients with lower free PCS was significantly better than high free PCS patients. In multivariate Cox regression analysis, serum free PCS was associated with all-cause and CV mortality after various adjustments, including age, gender and diabetes status (Model 1), albumin (Model 2), Ca × P product and intact parathyroid hormone (Model 3), hemoglobin and high-sensitivity C-reactive protein (Model 4) and hierarchically selected covariates (age, diabetes status and albumin, Model 5).. Serum free PCS levels may help in predicting risk of all-cause and CV mortality in elderly HD patients beyond traditional and uremia related risk factors.

Topics: Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Case-Control Studies; Cresols; Female; Humans; Kidney Failure, Chronic; Male; Prognosis; Prospective Studies; Renal Dialysis; Sulfuric Acid Esters; Survival Rate

Uremic toxins are considered to have a determinant pathological role in the progression of chronic kidney disease. The aim of this study was to define the putative pathological roles of the renal renin-angiotensin-aldosterone system (RAAS) and renal tubular epithelial-to-mesenchymal transition (EMT) in kidney fibrosis induced by (indoxyl sulfate) IS and (p-cresol sulfate) PCS.. Mouse proximal renal tubular cells (PKSV-PRs) treated with IS or PCS were used. Half-nephrectomized B-6 mice were treated with IS or PCS for 4 weeks. In the losartan treatment study, the study animal was administrated with IS+losartan or PCS+losartan for 4 weeks.. IS and PCS significantly activated the intrarenal RAAS by increasing renin, angiotensinogen, and angiotensin 1 (AT1) receptor expression, and decreasing AT2 receptor expression in vitro and in vivo. IS and PCS significantly increased transforming growth factor-β1 (TGF-β1) expression and activated the TGF-β pathway by increasing Smad2/Smad2-P, Smad3/Smad3-P, and Smad4 expression. The expression of the EMT-associated transcription factor Snail was increased by IS and PCS treatment. IS and PCS induced the phenotype of EMT-like transition in renal tubules by increasing the expression of fibronectin and α-smooth muscle actin and decreasing the expression of E-cadherin. Losartan significantly attenuated the expression of TGF-β1 and Snail, and decreased kidney fibrosis induced by IS and PCS in vivo.. Activating the renal RAAS/TGF-β pathway has an important pathological role in chronic kidney injury caused by IS and PCS. IS and PCS may increase Snail expression and induce EMT-like transition.

Topics: Angiotensinogen; Animals; Cresols; Epithelial-Mesenchymal Transition; Fibrosis; Gene Expression Regulation; Indican; Kidney; Kidney Failure, Chronic; Kidney Tubules; Losartan; Male; Mice; Models, Biological; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Snail Family Transcription Factors; Sulfuric Acid Esters; Transcription Factors; Transforming Growth Factor beta1; Uremia

Recently, p-cresyl sulfate (PCS) has been identified as a protein-bound uremic toxin. Moreover, the serum-free concentration of PCS, which is associated with its efficacy of hemodialysis, appears to be a good predictor of survival in chronic kidney disease (CKD). We previously found that PCS interacts with indoxyl sulfate (IS), another sulfate-conjugated uremic toxin, during renal excretion via a common transporter. The purpose of this study was to further investigate the interaction between PCS and IS on the binding to human serum albumin (HSA). Here, we used ultrafiltration to show that there is only one high-affinity binding site for PCS, with a binding constant on the order of 10(5) M(-1) (i.e., comparable to that of IS). However, a binding constant of the low-affinity binding site for PCS is 2.5-fold greater than that for IS. Displacement of a fluorescence probe showed that PCS mainly binds to site II, which is the high-affinity site for PCS, on HSA. This finding was further supported by experiments using mutant HSA (R410A/Y411A) that displayed reduced site II ligand binding. A Klotz analysis showed that there could be competitive inhibition between PCS and IS on HSA binding. A similar interaction between PCS and IS on HSA was also observed under the conditions mimicking CKD stage 4 to 5. The present study suggests that competitive interactions between PCS and IS in both HSA binding and the renal excretion process could contribute to fluctuations in their free serum concentrations in patients with CKD.

Topics: Binding Sites; Biological Transport; Cresols; Humans; Immunotoxins; Indican; Kidney Failure, Chronic; Mutation; Protein Binding; Serum Albumin; Sulfates; Sulfuric Acid Esters; Ultrafiltration; Uremia

Chronic renal failure patients accumulate in the blood molecules that are normally excreted into the urine. p-Cresol Sulphate (pCS), the most representative retained toxin, shows a high level of toxicity. Therefore, its quantification could represent a prediction factor to determine the risk of endothelial dysfunction and cardiovascular complication and response to the haemodialysis treatment. The aim of this study was to evaluate the suitability of the multiple reaction monitoring (MRM) technique in order to improve the sensibility, the selectivity and the timing of pCS detection in a small amount of plasma. Deproteinized plasma of uremic patients was concentrated and dissolved in liquid chromatography (LC) mobile phase solution. pCS was quantified by LC coupled to tandem mass spectrometry (LC-MS/MS) on a triple-quadrupole mass spectrometer. Selective and sensitive detection of pCS was achieved by selecting the specific parent ion and monitoring two specific fragment ions. The MRM assay was carried out using the following transitions: m/z 187 → 80.00 and m/z 187 → 107.00. A good linearity was observed for each calibration curve. The intra-day and inter-day results showed a good precision and repeatability. The percentage recoveries indicate an optimal selectivity of the analytical method. The MRM assay to quantify pCS in a small amount of human plasma is rapid, highly sensitive, selective and with a good repeatability.

Topics: Chromatography, High Pressure Liquid; Cresols; Humans; Kidney Failure, Chronic; Renal Dialysis; Sulfuric Acid Esters; Tandem Mass Spectrometry

Protein-bound uremic toxins indoxyl sulfate (IS) and p-cresol sulfate (p-CS) have been implicated as an important factor in uremic syndrome. Recent evidence indicates that both IS and p-CS are predictors of cardiovascular as well as all-cause mortality among chronic dialysis patients. We conducted a study to analyze the relationship between IS and p-CS and vascular access (VA) outcome in chronic hemodialysis (HD) patients.. A total of 91 chronic stable HD patients were divided into groups according to survival of VA and frequency of VA dysfunction. Demographic and biochemical data were reviewed and recorded. Serum levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1, and the total and free forms of IS and p-CS were determined.. Patients with a history of frequent VA failure and dysfunction had lower albumin and higher levels of ICAM-1, free IS, free and total p-CS. Diabetes was associated with higher IS and p-CS. Logistic regression revealed that diabetes and free p-CS were independent factors associated with poor outcome of VA.. Endothelial dysfunction and uremic toxins were associated with survival and function of VA. Diabetes and free p-CS were significantly related to the outcome of VA among chronic HD patients.

Topics: Biomarkers; Cresols; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Retrospective Studies; Sulfuric Acid Esters; Vascular Access Devices

Indoxyl sulphate (IS) and p-cresyl sulphate (PCS) are uraemic toxins that have similar protein binding, dialytic clearance and proinflammatory features. However, only a few prospective studies have evaluated possible associations between these two retained solutes and renal disease progression in chronic kidney disease (CKD) patients.. This prospective observational study evaluated independent associations between serum total IS and PCS with renal progression in a selected cohort of patients having different stages of CKD. Baseline PCS and IS were correlated with renal progression [defined as decrements in estimated glomerular filtration rate (eGFR) > 50% from baseline or progression to end-stage renal disease (ESRD)] and death during a follow-up period of 24 months.. Of 268 patients, 35 (13.1%) had renal progression and 14 (5.2%) died after a mean follow-up of 21 ± 3 months. Univariate Cox regression analysis followed by multivariate analysis showed that high-serum PCS levels were associated with renal progression and all-cause mortality independent of age, gender, diabetes status, albumin levels, serum IS, serum creatinine, Ca × P product, intact parathyroid hormone, haemoglobin or high-sensitivity C-reactive protein level. Serum IS was only associated with renal progression; however, the predictive power of serum IS was weakened when serum PCS was also present in the analytical model.. In addition to traditional and uraemia-related risk factors such as renal function, serum IS and PCS levels may help in predicting the risk of renal progression in patients having different stages of CKD.

Topics: Aged; Biomarkers; Cohort Studies; Creatinine; Cresols; Disease Progression; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Indican; Kidney Failure, Chronic; Kidney Function Tests; Male; Prognosis; Prospective Studies; Risk Factors; Sulfuric Acid Esters; Survival Rate; Uremia

Indoxyl sulfate and p-cresylsulfate was associated with poor clinical outcome of uremia. We explored the relationship between the two toxins and renal function in chronic kidney disease (CKD) patients. This study enrolled 103 stable CKD patients (stage 3-5 and hemodialysis (HD) patients). Serum levels of indoxyl sulfate and p-cresylsulfate were measured using ultra performance liquid chromatography. General laboratory results and patient background were also checked. Patients with advanced CKD had higher serum indoxyl sulfate, p-cresylsulfate based on ANOVA test. There were significant correlation between indoxyl sulfate and p-cresylsulfate and serum creatinine after multivariate regression analysis (B=3.59, P<0.01; B=0.93, P=0.04, respectively). In addition, there was a positive correlation between indoxyl sulfate and p-cresylsulfate level (r=0.61, P<0.01). Indoxyl sulfate and p-cresylsulfate level increased gradually while renal function declined and reached the peak at the stage of HD. Serum indoxyl sulfate level was closely associated with p-cresylsulfate level in CKD patients.

Topics: Cohort Studies; Cresols; Female; Humans; Indican; Kidney Failure, Chronic; Linear Models; Male; Middle Aged; Multivariate Analysis; Sulfuric Acid Esters

During chronic kidney disease (CKD), solutes called uremic solutes, accumulate in blood and tissues of patients. We developed an HPLC method for the simultaneous determination of several uremic solutes of clinical interest in biological fluids: phenol (Pol), indole-3-acetic acid (3-IAA), p-cresol (p-C), indoxyl sulfate (3-INDS) and p-cresol sulfate (p-CS). These solutes were separated by ion-pairing HPLC using an isocratic flow and quantified with a fluorescence detection. The mean serum concentrations of 3-IAA, 3-INDS and p-CS were 2.12, 1.03 and 13.03 μM respectively in healthy subjects, 3.21, 17.45 and 73.47 μM in non hemodialyzed stage 3-5 CKD patients and 5.9, 81.04 and 120.54 μM in hemodialyzed patients (stage 5D). We found no Pol and no p-C in any population. The limits of quantification for 3-IAA, 3-INDS, and p-CS were 0.83, 0.72, and 3.2 μM respectively. The within-day CVs were between 1.23 and 3.12% for 3-IAA, 0.98 and 2% for 3-INDS, and 1.25 and 3.01% for p-CS. The between-day CVs were between 1.78 and 5.48% for 3-IAA, 1.45 and 4.54% for 3-INDS, and 1.19 and 6.36% for p-CS. This HPLC method permits the simultaneous and quick quantification of several uremic solutes for daily analysis of large numbers of samples.

Topics: Aged; Chromatography, High Pressure Liquid; Cresols; Female; Humans; Indican; Indoleacetic Acids; Kidney Failure, Chronic; Male; Middle Aged; Phenol; Phenols; Sulfuric Acid Esters; Uremia

Uraemic toxins are considered to be emerging mortality risk factors in chronic kidney disease (CKD) patients. p-Cresol (a prototype protein-bound uraemic retention solute) has been shown to exert toxic effects in vitro. Recently, it has been demonstrated that p-cresol is present in plasma as its sulphate conjugate, p-cresylsulphate. The present study evaluated the distribution of free and total p-cresylsulphate and sought to determine whether these parameters were associated with vascular calcification, arterial stiffness and mortality risk in a cohort of CKD patients.. One hundred and thirty-nine patients (mean +/- SD age: 67 +/- 12; males: 60%) at different stages of CKD (8% at Stage 2, 26.5% at Stage 3, 26.5% at Stage 4, 7% at Stage 5 and 32% at Stage 5D) were enrolled in this study.. Baseline total and free p-cresylsulphate presented an inverse relationship with renal function and were significantly associated with vascular calcification. During the study period (mean follow-up period: 779 +/- 185 days), 38 patients died [including 22 from cardiovascular (CV) causes]. In crude survival analyses, free (but not total) p-cresylsulphate was shown to be a predictor of overall and CV death. Higher free p-cresylsulphate levels (>0.051 mg/100 mL; median) were associated with mortality independently of well-known predictors of survival such as age, vascular calcification, anaemia and inflammation.. 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.

Topics: Aged; Biomarkers; Cresols; Female; Humans; Kidney Failure, Chronic; Male; Predictive Value of Tests; Sulfuric Acid Esters; Survival Rate

We applied the metabolomic analysis of comprehensive small-molecular metabolites using liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS/MS) and principal component analysis to identify uremic toxins accumulated in the serum of chronic renal failure (CRF) rats. CRF rats were produced by 5/6-nephrectomy. Indoxyl sulfate was demonstrated to be the first principal serum metabolite which differentiates CRF from normal, followed by phenyl sulfate, hippuric acid and p-cresyl sulfate. Then, we measured the serum levels of indoxyl sulfate, phenyl sulfate, hippuric acid and p-cresyl sulfate by the selected reaction monitoring (SRM) of LC/ESI-MS/MS, and demonstrated that these serum levels were markedly increased in CRF rats as compared with normal rats. As creatinine clearance decreased, the serum levels of the metabolites increased.

Topics: Animals; Chromatography, Liquid; Cresols; Disease Models, Animal; Hippurates; Humans; Indican; Kidney; Kidney Failure, Chronic; Male; Metabolomics; Rats; Rats, Sprague-Dawley; Spectrometry, Mass, Electrospray Ionization; Sulfuric Acid Esters; Toxins, Biological

Indoxyl sulfate and p-cresyl sulfate are important representatives of the protein-bound uremic retention solutes. Serum levels of p-cresyl sulfate and indoxyl sulfate are linked to cardiovascular outcomes and chronic kidney disease progression, respectively. They share important features such as the albumin-binding site, low dialytic clearance, and both originate from protein fermentation. Whether serum concentrations are related is, however, not known.. In an observational study in 75 maintenance hemodialysis patients, we studied agreement between indoxyl sulfate and p-cresyl sulfate serum concentrations, dialytic reduction rates, and dialytic clearances. Concentrations were determined by HPLC. Dialytic clearances were determined from total spent dialysate collections. In vitro spiking experiments were performed to explore protein binding characteristics.. Indoxyl sulfate and p-cresyl sulfate total serum concentrations were not related (r = 0.02, P = 0.9), whereas free serum concentrations were only moderately related (r = 0.53, P < 0.001). Indoxyl sulfate and p-cresyl sulfate share the same albumin binding site, for which they are competitive binding inhibitors. Intriguingly, indoxyl sulfate and p-cresyl sulfate reduction rates (r = 0.91, P < 0.001) and dialytic clearances (r = 0.97, P < 0.001) correlated tightly.. Indoxyl sulfate and p-cresyl sulfate serum concentrations are not associated, suggesting different metabolic pathways. Indoxyl sulfate and p-cresyl sulfate are both valid markers to monitor behavior of protein-bound solutes during dialysis. Finally, they are competitive binding inhibitors for the same albumin binding site.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Cohort Studies; Cresols; Female; Humans; Indican; Kidney Failure, Chronic; Male; Middle Aged; Models, Biological; Renal Dialysis; Serum Albumin; Sulfuric Acid Esters; Urea