4-cresol-sulfate and hippuric-acid

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

Total p-cresylsulfate (PCS), indoxyl sulfate (IS) and hippuric acid (HA) are harmful uremic toxins known to be elevated in patients with uremia. Serum total PCS, IS and HA levels have been associated with coronary atherosclerosis, left ventricular hypertrophy, metabolic acidosis, neurological symptoms, and accelerated renal damage associated with chronic kidney disease; however, no study has examined the effect of total PCS, IS and HA on hemodialysis (HD) quality indicators. The aim of this study was to examine associations among total PCS, IS and HA with HD quality indicators in patients undergoing HD treatment.. This study included 264 consecutive patients at a single HD center who assessed using previously demonstrated HD quality indicators including anemia, bone-mineral metabolism, dialysis dose, cardiovascular risk, and middle molecule removal area. Serum HA was measured using a capillary electrophoresis method. Serum total PCS and IS concentrations were measured using an Ultra Performance LC System.. Multiple regression analysis showed that sex, potassium, systolic blood pressure (SBP), average BP, β2-microglobulin, and creatinine were independently positively associated with IS level, and that age, total cholesterol, and estimated glomerular filtration rate (eGFR) was independently negatively associated with IS level. In addition, β2-microglobulin was independently positively associated with total PCS. Moreover, potassium, diastolic blood pressure, average BP, β2-microglobulin, dialysis vintage, and albumin were independently positively associated with HA level, and age, transferrin saturation, fasting glucose, and eGFR were independently negatively associated with HA level. When the patients were stratified by age and sex, serum IS and HA levels were still independently associated with some hemodialysis quality indicators. In addition, canonical correlation analysis also confirmed the relationship between uremic toxins (IS and HA) and HD quality indicators (potassium, β2-microglobulin, average BP, creatinine, and eGFR).. This study demonstrated that uremic toxins (IS and HA) and HD quality indicators (potassium, β2-microglobulin, average BP, creatinine, and eGFR) constructs were correlated with each other, and that there were sex and age differences in these associations among maintenance HD patients.

Topics: Cresols; Hippurates; Humans; Indican; Quality Indicators, Health Care; Renal Dialysis; Sulfuric Acid Esters; Uremia

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

Adverse physiology and antibiotic exposure devastate the intestinal microbiome in critical illness. Time and cost implications limit the immediate clinical potential of microbial sequencing to identify or treat intestinal dysbiosis. Here, we examined whether metabolic profiling is a feasible method of monitoring intestinal dysbiosis in critically ill children.. Prospective multicenter cohort study.. Three U.K.-based PICUs.. Mechanically ventilated critically ill (n = 60) and age-matched healthy children (n = 55).. Collection of urine and fecal samples in children admitted to the PICU. A single fecal and urine sample was collected in healthy controls.. Untargeted and targeted metabolic profiling using 1H-nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry or urine and fecal samples. This was integrated with analysis of fecal bacterial 16S ribosomal RNA profiles and clinical disease severity indicators. We observed separation of global urinary and fecal metabolic profiles in critically ill compared with healthy children. Urinary excretion of mammalian-microbial co-metabolites hippurate, 4-cresol sulphate, and formate were reduced in critical illness compared with healthy children. Reduced fecal excretion of short-chain fatty acids (including butyrate, propionate, and acetate) were observed in the patient cohort, demonstrating that these metabolites also distinguished between critical illness and health. Dysregulation of intestinal bile metabolism was evidenced by increased primary and reduced secondary fecal bile acid excretion. Fecal butyrate correlated with days free of intensive care at 30 days (r = 0.38; p = 0.03), while urinary formate correlated inversely with vasopressor requirement (r = -0.2; p = 0.037).. Disruption to the functional activity of the intestinal microbiome may result in worsening organ failure in the critically ill child. Profiling of bacterial metabolites in fecal and urine samples may support identification and treatment of intestinal dysbiosis in critical illness.

Topics: Adolescent; Child; Child, Preschool; Chromatography, Liquid; Cresols; Critical Illness; Dysbiosis; Fatty Acids, Volatile; Feces; Female; Formates; Gastrointestinal Microbiome; Hippurates; Humans; Infant; Intensive Care Units, Pediatric; Magnetic Resonance Imaging; Male; Mass Spectrometry; Metabolomics; Prospective Studies; Respiration, Artificial; RNA, Ribosomal, 16S; Severity of Illness Index; Sulfuric Acid Esters; Time Factors; United Kingdom; Urine

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

Gut-derived uremic toxins contribute to the uremic syndrome and are gaining attention as potentially modifiable cardiovascular disease risk factors in patients with underlying chronic kidney disease. A simple, rapid, robust, accurate and precise ultra-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous determination of a panel of four gut-derived uremic toxins in human serum. The panel was comprised of kynurenic acid, hippuric acid, indoxyl sulfate, and p-cresol sulfate. Serum samples were protein precipitated with acetonitrile containing deuterated internal standards. Chromatographic separation of analytes was accomplished with an Acquity BEH C18 (2.1 × 100 mm, 1.7 μm) column by isocratic elution at a flow rate of 0.3 mL/min with a mobile phase composed of solvent A (10 mM ammonium formate; pH 4.3) and solvent B (acetonitrile) (85:15, v/v). Analytes were detected using heated electrospray ionization and selected reaction monitoring. The total run-time was 4 min. Standard curves were linear and correlation coefficients (r) were ≥0.997 for concentration ranges of 0.01-0.5 μg/mL for kynurenic acid, 0.25-80 μg/mL for p-cresol sulfate, and 0.2-80 μg/mL for hippuric acid and indoxyl sulfate. Intra- and inter-day accuracy and precision were within 19.3% for the LLOQs and ≤10.9% for all other quality controls. Matrix effect from serum was <15% and recovery was ≥81.3% for all analytes. The method utilizes a short run-time, simple/inexpensive sample processing, has passed FDA validation recommendations, and was successfully applied to study patients with kidney disease.

Topics: Blood Chemical Analysis; Chromatography, High Pressure Liquid; Cresols; Hippurates; Humans; Hydrogen-Ion Concentration; Indican; Kidney Diseases; Kynurenic Acid; Quality Control; Reproducibility of Results; Risk Factors; Solvents; Sulfuric Acid Esters; Tandem Mass Spectrometry; Time Factors; Uremia

Equine grass sickness (EGS) is a frequently fatal disease of horses, responsible for the death of 1 to 2% of the U.K. horse population annually. The etiology of this disease is currently uncharacterized, although there is evidence it is associated with Clostridium botulinum neurotoxin in the gut. Prevention is currently not possible, and ileal biopsy diagnosis is invasive. The aim of this study was to characterize the fecal microbiota and biofluid metabolic profiles of EGS horses, to further understand the mechanisms underlying this disease, and to identify metabolic biomarkers to aid in diagnosis. Urine, plasma, and feces were collected from horses with EGS, matched controls, and hospital controls. Sequencing the16S rRNA gene of the fecal bacterial population of the study horses found a severe dysbiosis in EGS horses, with an increase in Bacteroidetes and a decrease in Firmicutes bacteria. Metabolic profiling by

Topics: Acetylcarnitine; Animals; Bacteroidetes; Biomarkers; Clostridium botulinum; Cresols; Dysbiosis; Feces; Firmicutes; Gastrointestinal Microbiome; Hippurates; Horse Diseases; Horses; Magnetic Resonance Spectroscopy; Methylamines; RNA, Ribosomal, 16S; 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

The renal proximal tubule is essential for removing organic solutes and exogenous medications from the circulation. We evaluated diurnal, prandial, and long-term biological variation of 4 candidate endogenous markers of proximal tubular secretion.. We used LC-MS to measure plasma and urine concentrations of hippurate (HA), cinnamoylglycine (CMG), indoxyl sulfate (IS), and. Plasma concentrations of secreted solutes varied over the 24-h baseline period. Diurnal variation was greatest for HA, followed by CMG, IS, and PCS. Plasma concentrations of HA (. Plasma concentrations of HA, CMG, IS, and PCS fluctuate within individuals throughout the day and over weeks. Renal clearances of these secreted solutes, which serve as estimates of renal proximal tubule secretion, are also subject to intraindividual biological variation that can be improved by additional plasma measurements.

Topics: Adult; Biomarkers; Chromatography, Liquid; Cresols; Female; Glycine; Hippurates; Humans; Indican; Kidney Tubules, Proximal; Male; Sulfuric Acid Esters; Tandem Mass Spectrometry

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

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

The kidney clears numerous solutes from the plasma; however, retention of these solutes causes uremic illness when the kidneys fail. We know remarkably little about which retained solutes are toxic and this limits our ability to improve dialysis therapies. To explore this, we employed untargeted mass spectrometry to identify solutes that are efficiently cleared by the kidney. High-resolution mass spectrometry detected 1808 features in the urine and plasma ultrafiltrate of 5 individuals with normal renal function. The estimated clearance rates of 1082 peaks were greater than the creatinine clearance indicating tubular secretion. Further analysis identified 90 features representing solutes with estimated clearance rates greater than the renal plasma flow. Quantitative mass spectrometry with stable isotope dilution confirmed that efficient clearance of these solutes is made possible by the combination of binding to plasma proteins and tubular secretion. Tandem mass spectrometry established the chemical identity of 13 solutes including hippuric acid, indoxyl sulfate, and p-cresol sulfate. These 13 efficiently cleared solutes were found to accumulate in the plasma of hemodialysis patients, with free levels rising to more than 20-fold normal for all but two of them. Thus, further analysis of solutes efficiently cleared by secretion in the native kidney may provide a potential route to the identification of uremic toxins.

Topics: Adult; Aged; Aged, 80 and over; Chromatography, Liquid; Cresols; Female; Hippurates; Humans; Indican; Kidney; Kidney Diseases; Male; Metabolic Clearance Rate; Middle Aged; Protein Binding; Renal Dialysis; Sulfuric Acid Esters; Tandem Mass Spectrometry

In end stage renal disease (ESRD) waste solutes accumulate in body fluid. Removal of protein bound solutes using conventional renal replacement therapies is currently very poor while their accumulation is associated with adverse outcomes in ESRD. Here we investigate the application of a hollow fiber mixed matrix membrane (MMM) for removal of these toxins. The MMM hollow fiber consists of porous macro-void free polymeric inner membrane layer well attached to the activated carbon containing outer MMM layer. The new membranes have permeation properties in the ultrafiltration range. Under static conditions, they adsorb 57% p-cresylsulfate, 82% indoxyl sulfate and 94% of hippuric acid from spiked human plasma in 4 h. Under dynamic conditions, they adsorb on average 2.27 mg PCS/g membrane and 3.58 mg IS/g membrane in 4 h in diffusion experiments and 2.68 mg/g membrane PCS and 12.85 mg/g membrane IS in convection experiments. Based on the dynamic experiments we estimate that our membranes would suffice to remove the daily production of these protein bound solutes.

Topics: Adsorption; Cresols; Hippurates; Humans; Indican; Membranes, Artificial; Microscopy, Electron, Scanning; Sulfuric Acid Esters; Toxins, Biological; Ultrafiltration

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

This study evaluated the contribution of residual function to the removal of solutes for which protein binding limits clearance by hemdialysis.. Solute concentrations were measured in 25 hemodialysis patients with residual urea clearances ranging from 0.1 to 6.2 ml/min per 1.73 m2. Mathematical modeling assessed the effect of residual function on time-averaged solute concentrations.. Dialytic clearances of the protein-bound solutes p-cresol sulfate, indoxyl sulfate, and hippurate were reduced in proportion to the avidity of binding and averaged 8±2, 10±3, and 44±13% of the dialytic urea clearance. For each bound solute, the residual clearance was larger in relation to the residual urea clearance. Residual kidney function therefore removed a larger portion of each of the bound solutes than of urea. Increasing residual function was associated with lower plasma levels of p-cresol sulfate and hippurate but not indoxyl sulfate. Wide variation in solute generation tended to obscure the dependence of plasma solute levels on residual function. Mathematical modeling that corrected for this variation indicated that increasing residual function will reduce the plasma level of each of the bound solutes more than the plasma level of urea.. In comparison to urea, solutes than bind to plasma proteins can be more effectively cleared by residual function than by hemodialysis. Levels of such solutes will be lower in patients with residual function than in patients without residual function even if the dialysis dose is reduced based on measurement of residual urea clearance in accord with current guidelines.

Topics: Adult; Aged; Cresols; Female; Glomerular Filtration Rate; Hippurates; Humans; Indican; Kidney; Kidney Diseases; Linear Models; Male; Middle Aged; Models, Biological; Practice Guidelines as Topic; Protein Binding; Renal Dialysis; Sulfuric Acid Esters; Time Factors; Treatment Outcome; Urea

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

Distinguishing between the inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC) is important for both management and prognostic reasons. Discrimination using noninvasive techniques could be an adjunct to conventional diagnostics. Differences have been shown between the intestinal microbiota of CD and UC patients and controls; the gut bacteria influence specific urinary metabolites that are quantifiable using proton high-resolution nuclear magnetic resonance (NMR) spectroscopy. This study tested the hypothesis that such metabolites differ between IBD and control cohorts, and that using multivariate pattern-recognition analysis, the cohorts could be distinguished by urine NMR spectroscopy.. NMR spectra were acquired from urine samples of 206 Caucasian subjects (86 CD patients, 60 UC patients, and 60 healthy controls). Longitudinal samples were collected from 75 individuals. NMR resonances specific for metabolites influenced by the gut microbes were studied, including hippurate, formate, and 4-cresol sulfate. Multivariate analysis of all urinary metabolites involved principal components analysis (PCA) and partial least squares discriminant analysis (PLS-DA).. Hippurate levels were lowest in CD patients and differed significantly between the three cohorts (P<0.0001). Formate levels were higher and 4-cresol sulfate levels lower in CD patients than in UC patients or controls (P=0.0005 and P=0.0002, respectively). PCA revealed clustering of the groups; PLS-DA modeling was able to distinguish the cohorts. These results were independent of medication and diet and were reproducible in the longitudinal cohort.. Specific urinary metabolites related to gut microbial metabolism differ between CD patients, UC patients, and controls. The emerging technique of urinary metabolic profiling with multivariate analysis was able to distinguish these cohorts.

Topics: Adolescent; Adult; Aged; Biomarkers; Colitis, Ulcerative; Cresols; Crohn Disease; Female; Formates; Hippurates; Humans; Inflammatory Bowel Diseases; Magnetic Resonance Spectroscopy; Male; Middle Aged; Prognosis; Sulfuric Acid Esters; Young Adult