4-cresol-sulfate and indoleacetic-acid

Chronic kidney disease (CKD) has emerged as a global public health problem. Although the incidence and prevalence of CKD vary from one country to another, the estimated worldwide prevalence is 8-16%. The complications associated with CKD include progression to end-stage renal disease (ESRD), mineral and bone disorders, anaemia, cognitive decline and elevated all-cause and cardiovascular (CV) mortality. As a result of progressive nephron loss, patients with late-stage CKD are permanently exposed to uraemic toxins. These toxins have been classified into three groups as a function of the molecular mass: small water-soluble molecules, middle molecules and protein-bound uraemic toxins. The compounds can also be classified according to their origin (i.e. microbial or not) or their protein-binding ability. The present review will focus on the best-characterized protein-bound uraemic toxins, namely indoxylsulfate (IS), indole acetic acid (IAA) and p-cresylsulfate (PCS, a cresol metabolite). Recent research suggests that these toxins accelerate the progression of CV disease, kidney disease, bone disorders and neurological complications. Lastly, we review therapeutic approaches that can be used to decrease toxin levels.

Topics: Animals; Cardiovascular Diseases; Cresols; Humans; Indican; Indoleacetic Acids; Proteins; Renal Insufficiency, Chronic; Sulfuric Acid Esters; Uremia

Gut dysbiosis is common in patients with chronic kidney disease (CKD) and is closely related to inflammatory processes. Some nutritional strategies, such as bioactive compounds present in curcumin, have been proposed as an option to modulate the gut microbiota and decrease the production of uremic toxins such as indoxyl sulfate (IS), p-cresyl sulfate (pCS) and indole-3 acetic acid (IAA).. To evaluate the effects of curcumin supplementation on uremic toxins plasma levels produced by gut microbiota in patients with CKD on hemodialysis (HD).. The oral supplementation of curcumin for three months seems to reduce p-CS plasma levels in HD patients, suggesting a gut microbiota modulation.

Topics: Adult; Aged; Cresols; Curcumin; Dietary Supplements; Double-Blind Method; Female; Gastrointestinal Microbiome; Humans; Indican; Indoleacetic Acids; Male; Middle Aged; Pilot Projects; Renal Dialysis; Sulfuric Acid Esters; Toxins, Biological; Uremia

Generation of uremic toxins p-cresylsulfate (p-CS), indoxyl sulfate (IS) and indole 3-acetic acid (IAA) in hemodialysis (HD) individuals may be associated with the gut flora and recognized markers of disease progression. This study investigated the effect of synbiotic meal on uremic toxins in HD individuals. We conducted randomized singleblind and placebo-controlled intervention study with 58 HD subjects (20F/38M, 63.1 ± 10.9-old) who were randomly allocated in synbiotic group (SG, 40 g of extruded sorghum plus 100 mL of unfermented probiotic milk) or control group (CG, 40 g of extruded corn plus 100 mL of pasteurized milk), during 7-wk Metabolic markers and uremic toxins, fecal concentration of short chain fatty acid and pH value was determined. The SG group had decreased serum p-CS and IS, as well as decreased urea concentration (p < .05) compared to CG. SG showed higher fecal butyric acid and lower pH compared to baseline and SC (p < .05). In addition, serum p-CS and fecal pH were positively correlated to urea concentration in SG participants at the endpoint. The consumption of the synbiotic meal during 7-wk reduced colonic pH, and reduced serum uremic (p-CS and IS) toxins and urea in HD subjects.

Topics: Aged; Bifidobacterium longum; Biomarkers; Brazil; Cresols; Female; Gastrointestinal Microbiome; Humans; Hydrogen-Ion Concentration; Indican; Indoleacetic Acids; Male; Meals; Middle Aged; Probiotics; Renal Dialysis; Renal Insufficiency, Chronic; Sulfuric Acid Esters; Synbiotics; Urea; Uremia

Topics: Adsorption; Aged; Chelating Agents; Cresols; Double-Blind Method; Female; Gastrointestinal Tract; Humans; Indican; Indoleacetic Acids; Male; Middle Aged; Renal Insufficiency, Chronic; Sevelamer; Sulfuric Acid Esters; Toxins, Biological; Uremia

Protein-bound uremic toxins (PBUTs) are difficult to remove using conventional dialysis treatment owing to their high protein-binding affinity. As pH changes the conformation of proteins, it may be associated with the binding of uremic toxins. Albumin conformation at pH 2 to 13 was analyzed using circular dichroism. The protein binding behavior between indoxyl sulfate (IS) and albumin was examined using isothermal titration calorimetry. Albumin with IS, and serum with IS, p-cresyl sulfate, indole acetic acid or phenyl sulfate, as well as serum from hemodialysis patients, were adjusted pH of 3 to 11, and the concentration of the free PBUTs was measured using mass spectrometry. Albumin was unfolded at pH < 4 or >12, and weakened interaction with IS occurred at pH < 5 or >10. The concentration of free IS in the albumin solution was increased at pH 4.0 and pH 11.0. Addition of human serum to each toxin resulted in increased free forms at acidic and alkaline pH. The pH values of serums from patients undergoing hemodialysis adjusted to 3.4 and 11.3 resulted in increased concentrations of the free forms of PBUTs. In conclusion, acidic and alkaline pH conditions changed the albumin conformation and weakened the protein binding property of PBUTs in vitro.

Topics: Calorimetry; Circular Dichroism; Cresols; Humans; Hydrogen-Ion Concentration; Indican; Indoleacetic Acids; Protein Binding; Protein Conformation; Renal Dialysis; Renal Insufficiency, Chronic; Serum Albumin, Human; Sulfuric Acid Esters; Toxins, Biological; Uremia

We recently reported that aripiprazole (ARP), an antipsychotic drug, binds strongly to human serum albumin (HSA), the major drug binding protein in serum. It is known that uremic toxins that accumulate during renal disease affect the interaction between HSA and drug binding. In this study, the issue of how uremic toxins (indoxyl sulfate, indole acetic acid and p-cresyl sulfate) affect the binding of ARP to HSA was investigated. Equilibrium dialysis experiments revealed that all uremic toxins inhibited the binding of ARP to HSA although the inhibitory effects differed, depending on the specific uremic toxin. The potency of inhibition can be partially explained by the affinities of uremic toxins to HSA. Fluorescence displacement experiments suggested that ARP as well as all uremic toxins bind to site II of HSA. The inhibitory effects of the toxins on the binding of ARP for the drugs binding to the diazepam subsite are significantly larger, comparing with those for binding to arylpropionic acids subsite. Interestingly, induced circular dichroism (CD) spectra indicated that the spatial orientation of p-cresyl sulfate in the binding pocket is different from that for indoxyl sulfate and indole acetic acid. The limited findings obtained herein are important data in considering the effects of uremic toxins on the pharmacokinetics of ARP and the drugs that bind to site II on HSA, particularly drugs binding to diazepam binding site in site II.

Topics: Antipsychotic Agents; Aripiprazole; Binding Sites; Cresols; Humans; Indican; Indoleacetic Acids; Oleic Acid; Protein Binding; Serum Albumin, Human; Sulfuric Acid Esters; Uremia

Chronic kidney disease (CKD) is associated with high mortality rates, mainly due to cardiovascular diseases (CVD). Uremia has been considered a relevant risk factor for CVD in CKD patients, since uremic toxins (UTs) promote systemic and vascular inflammation, oxidative stress and senescence. Here, we demonstrate that uremic toxins indoxyl sulfate (IxS), p-cresyl sulfate (pCS) and indole acetic acid (IAA) are incorporated by human endothelial cells and inhibit the autophagic flux, demonstrated by cellular p62 accumulation. Moreover, isolated and mixed UTs impair the lysosomal stage of autophagy, as determined by cell imaging of the mRFP-GFP-LC3 protein. Endothelial cells exposed to UTs display accumulation of carbonylated proteins and increased sensitivity to hydrogen peroxide. Rapamycin, an autophagy activator which induces both autophagosome formation and clearance, prevented these effects. Collectively, our findings demonstrate that accumulation of oxidized proteins and enhanced cell sensitivity to hydrogen peroxide are consequences of impaired autophagic flux. These data provide evidence that UTs-induced impaired autophagy may be a novel contributor to endothelial dysfunction.

Topics: Animals; Apoptosis; Cell Survival; Cells, Cultured; Cresols; Endothelial Cells; Humans; Hydrogen Peroxide; Indican; Indoleacetic Acids; Lysosomes; Mice; NIH 3T3 Cells; Oxidative Stress; RNA-Binding Proteins; Sulfuric Acid Esters; Toxins, Biological

In chronic kidney disease (CKD), impaired kidney function results in accumulation of uremic toxins, which exert deleterious biological effects and contribute to inflammation and cardiovascular morbidity and mortality. Protein-bound uremic toxins (PBUTs), such as

Topics: Amino Acids, Aromatic; Bacteria; Cresols; Feces; Gastrointestinal Microbiome; Humans; Indican; Indoleacetic Acids; Renal Insufficiency, Chronic; Sulfuric Acid Esters; Toxins, Biological

To better understand the kinetics of protein-bound uremic toxins (PBUTs) during hemodialysis (HD), we investigated the distribution of hippuric acid (HA), indole-3-acetic acid (IAA), indoxyl sulfate (IS), and

Topics: Biological Transport; Cresols; Erythrocytes; Hippurates; Humans; Indican; Indoleacetic Acids; Protein Binding; Renal Dialysis; Renal Insufficiency, Chronic; Sulfuric Acid Esters; Uremia

To evaluate the effects of low-protein diet (LPD) on uremic toxins and the gut microbiota profile in nondialysis chronic kidney disease (CKD) patients.. Longitudinal study with 30 nondialysis CKD patients (stage 3-4) undergoing LPD for 6 months. Adherence to the diet was evaluated based on the calculation of protein equivalent of nitrogen appearance from the 24-hour urine analysis. Good adherence to LPD was considered when protein intake was from 90% to 110% of the prescribed amount (0.6 g/kg/day). Food intake was analyzed by the 24-hour recall method. The anthropometric, biochemical and lipid profile parameters were measured according to standard methods. Uremic toxin serum levels (indoxyl sulfate, p-cresyl sulfate, indole-3-acetic acid) were obtained by reversed-phase high-performance liquid chromatography (RP-HPLC). Fecal samples were collected to evaluate the gut microbiota profile through polymerase chain reaction and denaturing gradient gel electrophoresis. Statistical analysis was performed by the SPSS 23.0 program software.. Patients who adhered to the diet (n = 14) (0.7 ± 0.2 g/kg/day) presented an improvement in renal function (nonsignificant) and reduction in total and low-density lipoprotein cholesterol (183.9 ± 48.5-155.7 ± 37.2 mg/dL, P = .01; 99.4 ± 41.3-76.4 ± 33.2 mg/dL, P = .01, respectively). After 6 months of nutricional intervention, p-cresyl sulfate serum levels were reduced significantly in patients who adhered to the LPD (19.3 [9.6-24.7] to 15.5 [9.8-24.1] mg/L, P = .03), and in contrast, the levels were increased in patients who did not adhere (13.9 [8.0-24.8] to 24.3 [8.1-39.2] mg/L, P = .004). In addition, using the denaturing gradient gel electrophoresis technique, it was observed change in the intestinal microbiota profile after LPD intervention in both groups, and the number of bands was positively associated with protein intake (r = 0.44, P = .04).. LPD seems be a good strategy to reduce the uremic toxins production by the gut microbiota in nondialysis CKD patients.

Topics: Adult; Aged; Cresols; Diet, Protein-Restricted; Feces; Female; Gastrointestinal Microbiome; Humans; Indican; Indoleacetic Acids; Longitudinal Studies; Male; Middle Aged; Patient Compliance; Renal Insufficiency, Chronic; Sulfuric Acid Esters

Although the relationship between protein-bound uremic toxins (PBUTs) and cardiac structure and cardiac mortality in chronic kidney disease (CKD) has been studied in the past, the association between cardiac dysfunction and PBUTs has not yet been studied. We therefore evaluated the association between impaired peak cardiac performance and the serum free and total concentrations of potentially cardiotoxic PBUTs. In a cross-sectional study of 56 male CKD patients (stages 2⁻5 (pre-dialysis)) who were asymptomatic with no known cardiac diseases or diabetes we measured peak cardiac power (CPO

Topics: Adult; Arterial Pressure; Cardiac Output; Cresols; Exercise; Glucuronides; Heart Diseases; Heart Rate; Hippurates; Humans; Indican; Indoleacetic Acids; Male; Middle Aged; Renal Insufficiency, Chronic; Sulfuric Acid Esters; Toxins, Biological; Uremia

Little is known about potential differences in binding characteristics of protein-bound uremic toxins (PBUTs) in patients with chronic kidney disease (CKD) versus healthy controls. The question arises whether eventual differences are attributed to (i) the elevated levels of competing uremic toxins, and/or (ii) post-translational modifications of albumin. We evaluated the binding characteristics of hippuric acid (HA), indole-3-acetic acid (IAA), indoxyl sulfate (IS), and p-cresylsulfate (pCS) by deriving a binding curve in three distinct conditions: (i) serum from healthy controls (healthy serum), (ii) blank serum from hemodialysis patients (blank HD serum; i.e. cleared from uremic toxins), and (iii) non-treated serum from HD patients (HD serum). Additionally, the mutual binding competition of these uremic toxins was studied in blank HD in pairs. In both experiments, equilibrium dialysis (37 °C, 5 h) was used to separate the free and bound fractions of each PBUT. Free and total PBUT concentrations were quantified by an ultra-high performance liquid chromatography method with tandem mass spectrometer detection and the percentage protein binding (%PB) of each PBUT was calculated. For all four compounds, the binding capacity of healthy serum was higher than blank HD serum, which was comparable to non-treated HD serum, except for HA. The competition experiments revealed that at high uremic concentrations, mutual competition was observed for the strongly bound PBUTs IS and pCS. The %PB of the weakly bound HA and IAA was lower (trend) only for the addition to blank HD serum containing the strongly bound IS or pCS. There is an intrinsic impact on protein binding in uremia, revealing a lower binding capacity, as compared to healthy controls. Competitive binding is only relevant for the strongly bound PBUTs at high uremic concentrations. In addition, at least part of the effect on binding capacity can be attributed to post-translational modifications of albumin.

Topics: Binding, Competitive; Case-Control Studies; Chromatography, High Pressure Liquid; Cresols; Hippurates; Humans; Indican; Indoleacetic Acids; Protein Binding; Protein Processing, Post-Translational; Renal Dialysis; Renal Insufficiency, Chronic; Serum Albumin; Sulfuric Acid Esters; Tandem Mass Spectrometry; Toxins, Biological; Uremia

As protein binding of uremic toxins is not well understood, neither in chronic kidney disease (CKD) progression, nor during a hemodialysis (HD) session, we studied protein binding in two cross-sectional studies. Ninety-five CKD 2 to 5 patients and ten stable hemodialysis patients were included. Blood samples were taken either during the routine ambulatory visit (CKD patients) or from blood inlet and outlet line during dialysis (HD patients). Total (CT) and free concentrations were determined of p-cresylglucuronide (pCG), hippuric acid (HA), indole-3-acetic acid (IAA), indoxyl sulfate (IS) and p-cresylsulfate (pCS), and their percentage protein binding (%PB) was calculated. In CKD patients, %PB/CT resulted in a positive correlation (all p < 0.001) with renal function for all five uremic toxins. In HD patients, %PB was increased after 120 min of dialysis for HA and at the dialysis end for the stronger (IAA) and the highly-bound (IS and pCS) solutes. During one passage through the dialyzer at 120 min, %PB was increased for HA (borderline), IAA, IS and pCS. These findings explain why protein-bound solutes are difficult to remove by dialysis: a combination of the fact that (i) only the free fraction can pass the filter and (ii) the equilibrium, as it was pre-dialysis, cannot be restored during the dialysis session, as it is continuously disturbed.

Topics: Aged; Aged, 80 and over; Cresols; Cross-Sectional Studies; Female; Glucuronides; Hippurates; Humans; Indican; Indoleacetic Acids; Male; Middle Aged; Protein Binding; Renal Dialysis; Renal Insufficiency, Chronic; Serum Albumin; Severity of Illness Index; Sulfuric Acid Esters; Uremia

Hemodialysis aims at removing uremic toxins thus decreasing their concentrations. The present study investigated whether Kt/V(urea), used as marker of dialysis adequacy, is correlated with these concentrations. Predialysis blood samples were taken before a midweek session in 71 chronic HD patients. Samples were analyzed by colorimetry, HPLC, or ELISA for a broad range of uremic solutes. Solute concentrations were divided into four groups according to quartiles of Kt/V(urea), and also of different other parameters with potential impact, such as age, body weight (BW), Protein equivalent of Nitrogen Appearance (PNA), Residual Renal Function (RRF), and dialysis vintage. Dichotomic concentration comparisons were performed for gender and Diabetes Mellitus (DM). Analysis of Variance in quartiles of Kt/V(urea) did not show significant differences for any of the solute concentrations. For PNA, however, concentrations showed significant differences for urea (P<0.001), uric acid (UA), p-cresylsulfate (PCS), and free PCS (all P<0.01), and for creatinine (Crea) and hippuric acid (HA) (both P<0.05). For RRF, concentrations varied for β₂-microglobulin (P<0.001), HA, free HA, free indoxyl sulfate, and free indole acetic acid (all P<0.01), and for p-cresylglucuronide (PCG), 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), free PCS, and free PCG (all P<0.05). Gender and body weight only showed differences for Crea and UA, while age, vintage, and diabetes mellitus only showed differences for one solute concentration (UA, UA, and free PCS, respectively). Multifactor analyses indicated a predominant association of concentration with protein intake and residual renal function. In conclusion, predialysis concentrations of uremic toxins seem to be dependent on protein equivalent of nitrogen appearance and residual renal function, and not on dialysis adequacy as assessed by Kt/V(urea). Efforts to control intestinal load of uremic toxin precursors by dietary or other interventions, and preserving RRF seem important approaches to decrease uremic solute concentration and by extension their toxicity.

Topics: Aged; Aged, 80 and over; beta 2-Microglobulin; Biomarkers; Creatinine; Cresols; Diabetes Mellitus; Female; Furans; Glucuronides; Hippurates; Humans; Indican; Indoleacetic Acids; Male; Middle Aged; Multivariate Analysis; Propionates; Renal Dialysis; Sulfuric Acid Esters; Treatment Outcome; Urea; Uremia; Uric Acid

Chronic kidney disease (CKD) is a devastating illness characterized by accumulation of uremic retention solutes in the body. The objective of this study was to develop and validate a simple, rapid, and robust UPLC-MS-MS method for simultaneous determination, in serum, of seven organic acid uremic retention toxins, namely uric acid (UA), hippuric acid (HA), indoxylsulfate (IS), p-cresylglucuronide (pCG), p-cresylsulfate (pCS), indole-3-acetic acid (IAA), and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF). Isotopically labeled internal standards (d(5)-HA; 1,3-(15)N(2)-UA, and d(5)-IAA) were used to correct for variations in sample preparation and system performance. Separation on a C18 column was followed by negative electrospray ionization and tandem mass spectrometric detection. Accuracy was below the 15 % threshold. Within-day precision varied from 0.60 to 4.54 % and between-day precision was below 13.33 % for all compounds. The applicability of the method was evaluated by analyzing 78 serum samples originating both from healthy controls and from patients at different stages of CKD. These results were compared with those obtained by use of conventional HPLC-PDA-FLD methods. A good correlation was obtained between both methods for all compounds.

Topics: Cardiovascular Diseases; Case-Control Studies; Chromatography, High Pressure Liquid; Cresols; Female; Furans; Glucuronides; Hippurates; Humans; Indican; Indoleacetic Acids; Male; Propionates; Renal Insufficiency, Chronic; Severity of Illness Index; Sulfuric Acid Esters; Tandem Mass Spectrometry; Uremia; Uric Acid

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