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Pieter Evenepoel - One of the best experts on this subject based on the ideXlab platform.
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metabolism protein binding and renal clearance of microbiota derived p Cresol in patients with ckd
Clinical Journal of The American Society of Nephrology, 2016Co-Authors: Ruben Poesen, Pieter Evenepoel, Henriette De Loor, Dirk Kuypers, Patrick Augustijns, Bjorn MeijersAbstract:Background and objectives Colonic microbial metabolism substantially contributes to uremic retention solutes in CKD. p -Cresyl sulfate is the main representative of this group of solutes, relating to adverse outcomes. Other than sulfate conjugation, p -Cresol is subjected to endogenous glucuronide conjugation. Whether the balance between sulfate and glucuronide conjugation is relevant in CKD is unexplored. Design, setting, participants, & measurements We prospectively followed 488 patients with CKD stages 1–5 (enrollment between November of 2005 and September of 2006; follow-up until December of 2010). Serum and urine levels of p -cresyl sulfate and p -cresyl glucuronide were measured using liquid chromatography-mass spectrometry. Total amount of microbial p -Cresol was calculated by the sum of serum p –cresyl sulfate and p -cresyl glucuronide. Outcome analysis was performed for mortality and cardiovascular disease. Results Serum p –cresyl sulfate was a median of 193.0-fold (interquartile range, 121.1–296.6) higher than serum p –cresyl glucuronide, with a significant correlation between eGFR and proportion of serum p –cresyl sulfate to glucuronide (rho=0.23; P =0.001). There was also a significant correlation between eGFR and proportion of 24-hour urinary excretion of p -cresyl sulfate to glucuronide (rho=0.32; P p –Cresol and lower proportion of serum p –cresyl sulfate to glucuronide were jointly and significantly associated with mortality (hazard ratio per SD higher, 1.58; 95% confidence interval, 1.10 to 2.29; P =0.01 and hazard ratio, 0.65; 95% confidence interval, 0.47 to 0.89; P P P Conclusions p -Cresol shows a preponderance of sulfate conjugation, although a relatively diminished sulfotransferase activity can be suggested in patients with advanced CKD. Along with total p –Cresol burden, a relative shift from sulfate to glucuronide conjugation is independently associated with mortality and cardiovascular disease, warranting increased focus to the dynamic interplay between microbial and endogenous metabolism.
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p Cresol and cardiovascular risk in mild to moderate kidney disease
Clinical Journal of The American Society of Nephrology, 2010Co-Authors: Bjorn Meijers, Henriette De Loor, Dirk Kuypers, Kristin Verbeke, Yves Vanrenterghem, Bert Bammens, Kathleen Claes, Liesbeth Viaene, Pieter EvenepoelAbstract:Chronic kidney disease reaches epidemic dimensions. In the recent National Health and Nutrition Examination Survey (NHANES), the overall prevalence of CKD (stages 1 to 4) increased from 10.0% in 1988 to 1994 to 13.1% in 1999 to 2004 (1). Mounting data point to the lethal synergy between chronic kidney disease (CKD) and cardiovascular disease (CVD) (2–4) and between CKD and overall mortality (5). Cardiovascular mortality in CKD patients treated with hemodialysis is more than fivefold higher than in patients in the general population, even after stratification for age, gender, race, and the presence of diabetes. The increased incidence of cardiovascular disease is not limited to patients with end-stage renal disease (6). The hazard ratio for cardiovascular events increases inversely with the estimated GFR (eGFR) (7). Individuals with earlier stages of CKD are more likely to die of CVD than to develop kidney failure. Although kidney disease-associated CVD is potentially preventable and treatable, therapies targeting traditional risk factors prove less effective in CKD. For example, two large randomized trials failed to demonstrate a benefit of statin therapy to reduce cardiovascular disease risk in hemodialysis patients (8,9). As traditional cardiovascular risk factors are insufficient to predict and treat true cardiovascular disease risk in patients with CKD (10,11), it is assumed that CKD-specific pathways contribute substantially to the high cardiovascular disease risk. Retention of organic waste solutes might be in the causal chain between CKD and cardiovascular disease. In hemodialysis patients, free serum concentrations of p-Cresol (including its sulfate and glucuronide conjugates) were found to be associated with cardiovascular disease (12). More recently, a direct association between indoxyl sulfate and cardiovascular outcomes was observed (13). Intriguingly, whereas p-cresyl sulfate and indoxyl sulfate behave similarly during dialysis and share the same albumin binding site, total serum concentrations in hemodialysis patients are unrelated (14). Whether p-Cresol is associated with cardiovascular disease in patients with chronic kidney disease not yet on dialysis is not known. We therefore performed a prospective observational study in patients with chronic kidney disease not yet on dialysis (clinical trials protocol NCT00441623). The aims were, first, to explore the relationship between chronic kidney disease and p-Cresol serum concentrations and, second, to explore the relationship between p-Cresol and cardiovascular disease and to compare the strength of this relationship relative to traditional and novel cardiovascular risk factors.
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the uremic retention solute p cresyl sulfate and markers of endothelial damage
American Journal of Kidney Diseases, 2009Co-Authors: Bjorn Meijers, Soetkin Van Kerckhoven, Kristin Verbeke, Wim Dehaen, Yves Vanrenterghem, Marc Hoylaerts, Pieter EvenepoelAbstract:Background Cardiovascular disease is highly prevalent in patients with chronic kidney disease. In hemodialysis patients, the protein-bound uremic retention solute p -Cresol is independently associated with cardiovascular disease. The underlying mechanisms have not been elucidated. Study Design (1) Prospective observational study of humans and (2) in vitro study in human umbilical vein endothelial cells. Setting Hemodialysis patients. Factor p -Cresol and its main derivative p -cresyl sulfate. Outcomes Endothelial dysfunction. Measurements We studied: (1) the relation between p -Cresol and blood markers of endothelial dysfunction, including soluble P-selectin and endothelial microparticles; and (2) direct effects of p -Cresol and p -cresyl sulfate on endothelial cell cultures. Results (1) In a cohort of 100 maintenance hemodialysis patients, free serum p -Cresol concentrations (median, 11.7 μmol/L; interquartile range, 15.2) were directly associated with circulating endothelial microparticles ( P = 0.007), but not with soluble P-selectin (mean, 37.7 ± 14.4 [SD] pg/mL). Other independent determinants of the degree of circulating microparticles were greater serum phosphorus (mean, 4.8 ± 1.5 mg/dL; P = 0.008) and serum calcium concentrations (mean, 9.3 ± 0.8 mg/dL; P = 0.03), whereas treatment with active vitamin D ( P = 0.008) and vintage (median, 25 months; P = 0.04) were inversely associated. (2) In vitro, p -cresyl sulfate induced a dose-dependent increase in the shedding of endothelial microparticles ( P p -cresyl sulfate–induced generation of endothelial microparticles. Limitations The relationship between p -cresyl sulfate and shedding of endothelial microparticles in vivo was not mechanistically explored. Conclusion p -Cresyl sulfate induces shedding of endothelial microparticles in the absence of overt endothelial damage in vitro and is independently associated with the number of endothelial microparticles in hemodialysis patients. These findings suggest that p -cresyl sulfate alters endothelial function in hemodialysis patients.
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the uremic retention solute p cresyl sulfate alters no signal transduction by alteration of the soluble guanylate cyclase redox state
BMC Pharmacology, 2009Co-Authors: Bjorn Meijers, Peter Gross, Constanze Meye, Johannes Peter Stasch, Pieter EvenepoelAbstract:Chronic kidney disease (CKD) is associated with excessive cardiovascular disease and mortality. Nitric oxide (NO) – soluble guanylate cyclase (sGC) signaling is impaired in CKD patients, contributing to a near ubiquitous endothelial dysfunction. Loss of kidney function induces major alterations in the blood concentration of numerous molecules. Several of these so-called uremic retention solutes are known to interfere with NO-sGC signaling. p-Cresol/p-cresyl sulfate (PCS), a prototypic representative of the protein-bound uremic retention solutes, is independently associated with overall mortality and incident cardiovascular disease in hemodialysis patients. The mechanisms underlying this association remain elusive. We hypothesized that PCS interferes with NO-sGC signaling, thereby contributing to CKD-associated endothelial dysfunction and cardiovascular mortality.
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removal of the uremic retention solute p Cresol using fractionated plasma separation and adsorption
Artificial Organs, 2008Co-Authors: Bjorn Meijers, Kristin Verbeke, Wim Dehaen, Viktoria Weber, Bert Bammens, Dieter Falkenhagen, Pieter EvenepoelAbstract:Removal of protein-bound uremic retention solutes, including p-Cresol, by peritoneal dialysis and hemodialysis (HD) is limited. p-Cresol, mainly circulating as sulfate conjugate (p-cresyl sulfate [PCS]), is independently associated with mortality. Fractionated plasma separation and adsorption (FPSA) is a nonbiologic detoxification system for the treatment of liver failure. The FPSA clearance of uremic retention solutes is unknown. We studied PCS clearance by FPSA, using the Prometheus system. The neutral resin adsorbent and the anion exchange adsorbent bind PCS in vitro (reduction ratios [RRs] 37 and 70%). Ex vivo, the adsorbent mass removal (MR) (median 47.5 mg) contributes more than half to total MR (median 89.6 mg). In vivo, PCS RR during FPSA (50%) exceeded the RR during high flux HD (30%). We halted the study after four inclusions due to repeated thrombosis of the arterio-venous conduit. In conclusion, FPSA is a promising technique to improve clearance of protein-bound uremic retention solutes.
Bjorn Meijers - One of the best experts on this subject based on the ideXlab platform.
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metabolism protein binding and renal clearance of microbiota derived p Cresol in patients with ckd
Clinical Journal of The American Society of Nephrology, 2016Co-Authors: Ruben Poesen, Pieter Evenepoel, Henriette De Loor, Dirk Kuypers, Patrick Augustijns, Bjorn MeijersAbstract:Background and objectives Colonic microbial metabolism substantially contributes to uremic retention solutes in CKD. p -Cresyl sulfate is the main representative of this group of solutes, relating to adverse outcomes. Other than sulfate conjugation, p -Cresol is subjected to endogenous glucuronide conjugation. Whether the balance between sulfate and glucuronide conjugation is relevant in CKD is unexplored. Design, setting, participants, & measurements We prospectively followed 488 patients with CKD stages 1–5 (enrollment between November of 2005 and September of 2006; follow-up until December of 2010). Serum and urine levels of p -cresyl sulfate and p -cresyl glucuronide were measured using liquid chromatography-mass spectrometry. Total amount of microbial p -Cresol was calculated by the sum of serum p –cresyl sulfate and p -cresyl glucuronide. Outcome analysis was performed for mortality and cardiovascular disease. Results Serum p –cresyl sulfate was a median of 193.0-fold (interquartile range, 121.1–296.6) higher than serum p –cresyl glucuronide, with a significant correlation between eGFR and proportion of serum p –cresyl sulfate to glucuronide (rho=0.23; P =0.001). There was also a significant correlation between eGFR and proportion of 24-hour urinary excretion of p -cresyl sulfate to glucuronide (rho=0.32; P p –Cresol and lower proportion of serum p –cresyl sulfate to glucuronide were jointly and significantly associated with mortality (hazard ratio per SD higher, 1.58; 95% confidence interval, 1.10 to 2.29; P =0.01 and hazard ratio, 0.65; 95% confidence interval, 0.47 to 0.89; P P P Conclusions p -Cresol shows a preponderance of sulfate conjugation, although a relatively diminished sulfotransferase activity can be suggested in patients with advanced CKD. Along with total p –Cresol burden, a relative shift from sulfate to glucuronide conjugation is independently associated with mortality and cardiovascular disease, warranting increased focus to the dynamic interplay between microbial and endogenous metabolism.
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p Cresol and cardiovascular risk in mild to moderate kidney disease
Clinical Journal of The American Society of Nephrology, 2010Co-Authors: Bjorn Meijers, Henriette De Loor, Dirk Kuypers, Kristin Verbeke, Yves Vanrenterghem, Bert Bammens, Kathleen Claes, Liesbeth Viaene, Pieter EvenepoelAbstract:Chronic kidney disease reaches epidemic dimensions. In the recent National Health and Nutrition Examination Survey (NHANES), the overall prevalence of CKD (stages 1 to 4) increased from 10.0% in 1988 to 1994 to 13.1% in 1999 to 2004 (1). Mounting data point to the lethal synergy between chronic kidney disease (CKD) and cardiovascular disease (CVD) (2–4) and between CKD and overall mortality (5). Cardiovascular mortality in CKD patients treated with hemodialysis is more than fivefold higher than in patients in the general population, even after stratification for age, gender, race, and the presence of diabetes. The increased incidence of cardiovascular disease is not limited to patients with end-stage renal disease (6). The hazard ratio for cardiovascular events increases inversely with the estimated GFR (eGFR) (7). Individuals with earlier stages of CKD are more likely to die of CVD than to develop kidney failure. Although kidney disease-associated CVD is potentially preventable and treatable, therapies targeting traditional risk factors prove less effective in CKD. For example, two large randomized trials failed to demonstrate a benefit of statin therapy to reduce cardiovascular disease risk in hemodialysis patients (8,9). As traditional cardiovascular risk factors are insufficient to predict and treat true cardiovascular disease risk in patients with CKD (10,11), it is assumed that CKD-specific pathways contribute substantially to the high cardiovascular disease risk. Retention of organic waste solutes might be in the causal chain between CKD and cardiovascular disease. In hemodialysis patients, free serum concentrations of p-Cresol (including its sulfate and glucuronide conjugates) were found to be associated with cardiovascular disease (12). More recently, a direct association between indoxyl sulfate and cardiovascular outcomes was observed (13). Intriguingly, whereas p-cresyl sulfate and indoxyl sulfate behave similarly during dialysis and share the same albumin binding site, total serum concentrations in hemodialysis patients are unrelated (14). Whether p-Cresol is associated with cardiovascular disease in patients with chronic kidney disease not yet on dialysis is not known. We therefore performed a prospective observational study in patients with chronic kidney disease not yet on dialysis (clinical trials protocol NCT00441623). The aims were, first, to explore the relationship between chronic kidney disease and p-Cresol serum concentrations and, second, to explore the relationship between p-Cresol and cardiovascular disease and to compare the strength of this relationship relative to traditional and novel cardiovascular risk factors.
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the uremic retention solute p cresyl sulfate and markers of endothelial damage
American Journal of Kidney Diseases, 2009Co-Authors: Bjorn Meijers, Soetkin Van Kerckhoven, Kristin Verbeke, Wim Dehaen, Yves Vanrenterghem, Marc Hoylaerts, Pieter EvenepoelAbstract:Background Cardiovascular disease is highly prevalent in patients with chronic kidney disease. In hemodialysis patients, the protein-bound uremic retention solute p -Cresol is independently associated with cardiovascular disease. The underlying mechanisms have not been elucidated. Study Design (1) Prospective observational study of humans and (2) in vitro study in human umbilical vein endothelial cells. Setting Hemodialysis patients. Factor p -Cresol and its main derivative p -cresyl sulfate. Outcomes Endothelial dysfunction. Measurements We studied: (1) the relation between p -Cresol and blood markers of endothelial dysfunction, including soluble P-selectin and endothelial microparticles; and (2) direct effects of p -Cresol and p -cresyl sulfate on endothelial cell cultures. Results (1) In a cohort of 100 maintenance hemodialysis patients, free serum p -Cresol concentrations (median, 11.7 μmol/L; interquartile range, 15.2) were directly associated with circulating endothelial microparticles ( P = 0.007), but not with soluble P-selectin (mean, 37.7 ± 14.4 [SD] pg/mL). Other independent determinants of the degree of circulating microparticles were greater serum phosphorus (mean, 4.8 ± 1.5 mg/dL; P = 0.008) and serum calcium concentrations (mean, 9.3 ± 0.8 mg/dL; P = 0.03), whereas treatment with active vitamin D ( P = 0.008) and vintage (median, 25 months; P = 0.04) were inversely associated. (2) In vitro, p -cresyl sulfate induced a dose-dependent increase in the shedding of endothelial microparticles ( P p -cresyl sulfate–induced generation of endothelial microparticles. Limitations The relationship between p -cresyl sulfate and shedding of endothelial microparticles in vivo was not mechanistically explored. Conclusion p -Cresyl sulfate induces shedding of endothelial microparticles in the absence of overt endothelial damage in vitro and is independently associated with the number of endothelial microparticles in hemodialysis patients. These findings suggest that p -cresyl sulfate alters endothelial function in hemodialysis patients.
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the uremic retention solute p cresyl sulfate alters no signal transduction by alteration of the soluble guanylate cyclase redox state
BMC Pharmacology, 2009Co-Authors: Bjorn Meijers, Peter Gross, Constanze Meye, Johannes Peter Stasch, Pieter EvenepoelAbstract:Chronic kidney disease (CKD) is associated with excessive cardiovascular disease and mortality. Nitric oxide (NO) – soluble guanylate cyclase (sGC) signaling is impaired in CKD patients, contributing to a near ubiquitous endothelial dysfunction. Loss of kidney function induces major alterations in the blood concentration of numerous molecules. Several of these so-called uremic retention solutes are known to interfere with NO-sGC signaling. p-Cresol/p-cresyl sulfate (PCS), a prototypic representative of the protein-bound uremic retention solutes, is independently associated with overall mortality and incident cardiovascular disease in hemodialysis patients. The mechanisms underlying this association remain elusive. We hypothesized that PCS interferes with NO-sGC signaling, thereby contributing to CKD-associated endothelial dysfunction and cardiovascular mortality.
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removal of the uremic retention solute p Cresol using fractionated plasma separation and adsorption
Artificial Organs, 2008Co-Authors: Bjorn Meijers, Kristin Verbeke, Wim Dehaen, Viktoria Weber, Bert Bammens, Dieter Falkenhagen, Pieter EvenepoelAbstract:Removal of protein-bound uremic retention solutes, including p-Cresol, by peritoneal dialysis and hemodialysis (HD) is limited. p-Cresol, mainly circulating as sulfate conjugate (p-cresyl sulfate [PCS]), is independently associated with mortality. Fractionated plasma separation and adsorption (FPSA) is a nonbiologic detoxification system for the treatment of liver failure. The FPSA clearance of uremic retention solutes is unknown. We studied PCS clearance by FPSA, using the Prometheus system. The neutral resin adsorbent and the anion exchange adsorbent bind PCS in vitro (reduction ratios [RRs] 37 and 70%). Ex vivo, the adsorbent mass removal (MR) (median 47.5 mg) contributes more than half to total MR (median 89.6 mg). In vivo, PCS RR during FPSA (50%) exceeded the RR during high flux HD (30%). We halted the study after four inclusions due to repeated thrombosis of the arterio-venous conduit. In conclusion, FPSA is a promising technique to improve clearance of protein-bound uremic retention solutes.
Robert C. Lindsay - One of the best experts on this subject based on the ideXlab platform.
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Volatile Branched-chain Fatty Acids and Phenolic Compounds in Aged Italian Cheese Flavors
Journal of Food Science, 1991Co-Authors: J.k. Ha, Robert C. LindsayAbstract:Analysis of cheeses by capillary gas chromatography (GC) revealed adequate concentrations of certain branched-chain fatty acids (BCFAs) and phenols present to contribute distinctive flavors. Butyric acid-like flavors in cow's milk Romano cheese were modified by 2-methyl-butanoic and 2-ethylbutanoic acids which provided sweet, fruity notes. 4-Ethyloctanoic acid provided a characterizing goaty note to Romano cheese made from mixed goats’and cows’milk. 4-Methyloctanoic and 4-ethyloctanoic acids along with p-Cresol, m-Cresol, and 3,4-Di-methylphenol appeared responsible for sheepy notes in sheep milk Romano cheese. Phenol and Cresols (o, m, p) strongly contributed phenolic and medicinal flavor notes to smoked Provolone cheese. Low concentrations of BCFAs and phenols appeared to provide desirable background flavors to Parmesan cheeses.
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Volatile Branched‐chain Fatty Acids and Phenolic Compounds in Aged Italian Cheese Flavors
Journal of Food Science, 1991Co-Authors: Robert C. LindsayAbstract:Analysis of cheeses by capillary gas chromatography (GC) revealed adequate concentrations of certain branched-chain fatty acids (BCFAs) and phenols present to contribute distinctive flavors. Butyric acid-like flavors in cow's milk Romano cheese were modified by 2-methyl-butanoic and 2-ethylbutanoic acids which provided sweet, fruity notes. 4-Ethyloctanoic acid provided a characterizing goaty note to Romano cheese made from mixed goats’and cows’milk. 4-Methyloctanoic and 4-ethyloctanoic acids along with p-Cresol, m-Cresol, and 3,4-Di-methylphenol appeared responsible for sheepy notes in sheep milk Romano cheese. Phenol and Cresols (o, m, p) strongly contributed phenolic and medicinal flavor notes to smoked Provolone cheese. Low concentrations of BCFAs and phenols appeared to provide desirable background flavors to Parmesan cheeses.
C Valla - One of the best experts on this subject based on the ideXlab platform.
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determination of urinary ortho and meta Cresol in humans by headspace spme gas chromatography mass spectrometry
Journal of Chromatography B, 2005Co-Authors: Silvia Fustinoni, Rosa Mercadante, Laura Campo, L Scibetta, C VallaAbstract:Abstract ortho-Cresol (o-C) and meta-Cresol (m-C) are minor urinary metabolites of toluene, a widely used chemical with neurotoxicological properties. A new assay for their determination in human urine is here proposed. Urinary Cresol sulphates and glucuronates are submitted to acid hydrolysis, urine is neutralized, added with o-Cresols-d8, and analytes are sampled in the headspace of urine by SPME using a polydimethylsiloxane fiber. Analysis is performed by GC/MS using, for separation, either a SupelcoWax10 (for o-C) or a chiral CP Cresol (for o-C and m-C) column. The method is very specific, with a range of linearity 0–5.0 mg/l, within- and between-run precision, as coefficient of variation,
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Determination of urinary ortho- and meta-Cresol in humans by headspace SPME gas chromatography/mass spectrometry.
Journal of Chromatography B, 2005Co-Authors: Silvia Fustinoni, Rosa Mercadante, Laura Campo, L Scibetta, C VallaAbstract:Abstract ortho-Cresol (o-C) and meta-Cresol (m-C) are minor urinary metabolites of toluene, a widely used chemical with neurotoxicological properties. A new assay for their determination in human urine is here proposed. Urinary Cresol sulphates and glucuronates are submitted to acid hydrolysis, urine is neutralized, added with o-Cresols-d8, and analytes are sampled in the headspace of urine by SPME using a polydimethylsiloxane fiber. Analysis is performed by GC/MS using, for separation, either a SupelcoWax10 (for o-C) or a chiral CP Cresol (for o-C and m-C) column. The method is very specific, with a range of linearity 0–5.0 mg/l, within- and between-run precision, as coefficient of variation,
Indu Mehrotra - One of the best experts on this subject based on the ideXlab platform.
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treatment of phenol and Cresols in upflow anaerobic sludge blanket uasb process a review
Water Research, 2005Co-Authors: Gali S Veeresh, Pradeep Kumar, Indu MehrotraAbstract:Abstract Upflow anaerobic sludge blanket (UASB) process has been successfully applied in the treatment of municipal and industrial wastewaters. Several researchers have investigated the suitability of the process for the treatment of phenols and phenolic wastewaters. The anaerobic treatment of phenols is still at an investigative stage. With increasing recognition of the UASB process, feasibility studies on the treatment of wastewater containing phenol and Cresols ( o -, m - and p - isomers) in UASB have been reviewed. It is reported that phenol concentration up to a range of 500–750 mg/L is generally not inhibitory to the UASB process. Phenol concentrations greater than 500 mg/L can be effectively treated with acclimatization of inocula, recirculation of the treated effluent and/or supplementing with co-substrates such as glucose, VFA and dilute molasses. The degradability of phenol is more than p -Cresol, which in turn is more than m - and o -Cresol.