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1.
Molecules ; 24(20)2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618977

RESUMO

p-Cresyl sulfate is one of the bound uremic toxins whose level increases in the sera of patients with the severity of chronic kidney disease and is therefore used as a standard for clinical investigations. Our first attempts to obtain p-cresyl sulfate led exclusively to the product of sulfonation of the aromatic ring instead of sulfation on the OH moiety. Nevertheless, this initial discouraging result allowed us to handle both p-cresyl sulfate and 2-hydroxy-5-methylbenzenesulfonic acid obtained by different synthetic pathways. Interestingly, the comparison between the two isomers pointed out that the two molecules show the same fragmentation pattern and are indistinguishable by mass spectrometry. They cannot be separated on several commercially available columns. The only difference between the two compounds is a 10-fold higher ionization yield under negative ion electrospray ionization. NMR spectral studies definitely confirmed the different molecular structures. We present here an unambiguous biomimetic synthetic route for p-cresyl sulfate and the spectroscopic characterization of both the compounds by nuclear magnetic resonance and mass spectrometry.


Assuntos
Biomarcadores , Cresóis/metabolismo , Cardiopatias/metabolismo , Nefropatias/metabolismo , Ésteres do Ácido Sulfúrico/metabolismo , Toxinas Biológicas/metabolismo , Cromatografia Líquida , Cresóis/sangue , Cresóis/química , Cardiopatias/sangue , Cardiopatias/urina , Humanos , Nefropatias/sangue , Nefropatias/urina , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Ésteres do Ácido Sulfúrico/sangue , Ésteres do Ácido Sulfúrico/química , Espectrometria de Massas em Tandem , Toxinas Biológicas/sangue , Toxinas Biológicas/química
2.
J Pharm Biomed Anal ; 174: 618-624, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31276982

RESUMO

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.


Assuntos
Análise Química do Sangue/métodos , Cromatografia Líquida de Alta Pressão/métodos , Nefropatias/sangue , Espectrometria de Massas em Tandem/métodos , Uremia/diagnóstico , Cresóis/sangue , Hipuratos/sangue , Humanos , Concentração de Íons de Hidrogênio , Indicã/sangue , Nefropatias/diagnóstico , Ácido Cinurênico/sangue , Controle de Qualidade , Reprodutibilidade dos Testes , Fatores de Risco , Solventes/química , Ésteres do Ácido Sulfúrico/sangue , Fatores de Tempo
3.
Forensic Sci Int ; 302: 109857, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31284201

RESUMO

This study was conducted to understand alcohol kinetics for Koreans and to determine whether an individual is in absorption phase or elimination phase at the time of blood collection by analyzing of ethyl glucuronide and ethyl sulfate in blood. A total of 50 healthy adults was selected and assigned to drink 1g of ethanol per kg body weight of individual within 1h. Blood samples were then collected every 15min for the first 3h, 30min next 3h, and 1h last 9h. Urine samples were also collected from the individual, but not under the controlled environment. All samples were then analyzed by gas chromatography with a flame ionization detector (GC-FID) for alcohol and liquid chromatography-mass/mass spectrometry (LC-MS/MS) for EtG and EtS. The maximum BAC (Cmax) was 0.138% (g/100mL) in average under the controlled experimental condition. Alcohol elimination rates (ß) in average were 0.020% for male and 0.024% for female, respectively. It was found that the ratio of UAC and BAC was less than 1 in the absorption phase and the average ratio of UAC and BAC was 1.47 in the elimination phase. The comparison of BAC (g/L) and EtG (mg/L) absorption and elimination curves showed that the intersection time was 3.9h in average. It is shown that the ratio of EtG (mg/L)/BAC (g/L) is higher than 1, the individual would be in elimination phase of BAC. At the time of Cmax, the ratio of EtG (mg/L)/BAC (g/L) was 0.255±0.132 (SD) in average.


Assuntos
Consumo de Bebidas Alcoólicas/sangue , Depressores do Sistema Nervoso Central/farmacocinética , Etanol/farmacocinética , Glucuronatos/sangue , Ésteres do Ácido Sulfúrico/sangue , Adulto , Grupo com Ancestrais do Continente Asiático , Biomarcadores/sangue , Depressores do Sistema Nervoso Central/sangue , Depressores do Sistema Nervoso Central/urina , Cromatografia Gasosa , Cromatografia Líquida , Etanol/sangue , Etanol/urina , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , República da Coreia , Adulto Jovem
4.
Toxins (Basel) ; 11(5)2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31109001

RESUMO

High serum levels of gut-derived uremic toxins, especially p-cresyl sulfate (pCS), indoxyl sulfate (IS) and indole acetic acid (IAA), have been linked to adverse outcomes in patients with chronic kidney disease (CKD). Sevelamer carbonate could represent an interesting option to limit the elevation of gut-derived uremic toxins. The aim of the present study was to evaluate the adsorptive effect of sevelamer carbonate on different gut-derived protein-bound uremic toxins or their precursors in vitro, and its impact on the serum levels of pCS, IS and IAA in patients with CKD stage 3b/4. For the in vitro experiments, IAA, p-cresol (precursor of pCS) and indole (precursor of IS), each at a final concentration of 1 or 10 µg/mL, were incubated in centrifugal 30 kDa filter devices with 3 or 15 mg/mL sevelamer carbonate in phosphate-buffered saline at a pH adjusted to 6 or 8. Then, samples were centrifuged and free uremic toxins in the filtrates were analyzed. As a control experiment, the adsorption of phosphate was also evaluated. Additionally, patients with stage 3b/4 CKD (defined as an eGFR between 15 and 45 mL/min per 1.73 m2) were included in a multicenter, double-blind, placebo-controlled, randomized clinical trial. The participants received either placebo or sevelamer carbonate (4.8 g) three times a day for 12 weeks. The concentrations of the toxins and their precursors were measured using a validated high-performance liquid chromatography method with a diode array detector. In vitro, regardless of the pH and concentration tested, sevelamer carbonate did not show adsorption of indole and p-cresol. Conversely, with 10 µg/mL IAA, use of a high concentration of sevelamer carbonate (15 mg/mL) resulted in a significant toxin adsorption both at pH 8 (mean reduction: 26.3 ± 3.4%) and pH 6 (mean reduction: 38.7 ± 1.7%). In patients with CKD stage 3b/4, a 12-week course of treatment with sevelamer carbonate was not associated with significant decreases in serum pCS, IS and IAA levels (median difference to baseline levels: -0.12, 0.26 and -0.06 µg/mL in the sevelamer group vs. 1.97, 0.38 and 0.05 µg/mL in the placebo group, respectively). Finally, in vitro, sevelamer carbonate was capable of chelating a gut-derived uremic toxin IAA but not p-cresol and indole, the precursors of pCS and IS in the gut. In a well-designed clinical study of patients with stage 3b/4 CKD, a 12-week course of treatment with sevelamer carbonate was not associated with significant changes in the serum concentrations of pCS, IS and IAA.


Assuntos
Quelantes/administração & dosagem , Cresóis/sangue , Indicã/sangue , Ácidos Indolacéticos/sangue , Insuficiência Renal Crônica/tratamento farmacológico , Sevelamer/administração & dosagem , Ésteres do Ácido Sulfúrico/sangue , Toxinas Biológicas/sangue , Adsorção , Idoso , Quelantes/química , Cresóis/química , Método Duplo-Cego , Feminino , Trato Gastrointestinal/química , Trato Gastrointestinal/metabolismo , Humanos , Indicã/química , Ácidos Indolacéticos/química , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Sevelamer/química , Ésteres do Ácido Sulfúrico/química , Uremia
5.
Nat Commun ; 10(1): 1835, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015435

RESUMO

Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.


Assuntos
Albuminúria/etiologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/sangue , Microbioma Gastrointestinal/fisiologia , Ésteres do Ácido Sulfúrico/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminúria/sangue , Albuminúria/tratamento farmacológico , Albuminúria/patologia , Animais , Animais Geneticamente Modificados , Estudos de Coortes , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/urina , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Cães , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Células Madin Darby de Rim Canino , Masculino , Metabolômica/métodos , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos/genética , Podócitos/metabolismo , Podócitos/patologia , Ratos , Estreptozocina/toxicidade , Ésteres do Ácido Sulfúrico/sangue , Tirosina Fenol-Liase/antagonistas & inibidores , Tirosina Fenol-Liase/metabolismo , Adulto Jovem
6.
J. bras. nefrol ; 41(1): 103-111, Jan.-Mar. 2019. tab
Artigo em Inglês | LILACS | ID: biblio-1002421

RESUMO

ABSTRACT One of the mechanisms proposed for chronic kidney disease (CKD)-related cognitive impairment is the accumulation of uremic toxins due to the deterioration of the renal clearance function. Cognition can be categorized into five major domains according to its information processing functions: memory, attention, language, visual-spatial, and executive. We performed a review using the terms 'uric acid', 'indoxyl sulfate', 'p-cresyl sulfate', 'homocysteine', 'interleukins' and 'parathyroid hormone'. These are the compounds that were found to be strongly associated with cognitive impairment in CKD in the literature. The 26 selected articles point towards an association between higher levels of uric acid, homocysteine, and interleukin 6 with lower cognitive performance in executive, attentional, and memory domains. We also reviewed the hemodialysis effects on cognition. Hemodialysis seems to contribute to an amelioration of CKD-related encephalopathic dysfunction, although this improvement occurs more in some cognitive domains than in others.


RESUMO Um dos mecanismos propostos para explicar o comprometimento cognitivo relacionado à doença renal crônica (DRC) é o acúmulo de toxinas urêmicas devido à deterioração da função de depuração renal. A cognição pode ser categorizada em cinco domínios principais de acordo com suas funções de processamento de informações: memória, atenção, linguagem, visual-espacial e executiva. Realizamos uma revisão usando os termos "ácido úrico", "indoxil sulfato", "p-cresil sulfato", "homocisteína", "interleucinas" e "paratormônio". Estes são os compostos que se mostraram fortemente associados ao comprometimento cognitivo na DRC na literatura. Os 26 artigos selecionados apontam para uma associação entre níveis mais elevados de ácido úrico, homocisteína e interleucina-6 com menor desempenho cognitivo nos domínios executivo, atenção e de memória. Também revisamos os efeitos da hemodiálise na cognição. A hemodiálise parece contribuir para uma melhoria da disfunção encefalopática relacionada à DRC, embora essa melhora ocorra mais em alguns domínios cognitivos do que em outros.


Assuntos
Humanos , Toxinas Biológicas/efeitos adversos , Uremia/complicações , Insuficiência Renal Crônica/complicações , Disfunção Cognitiva/etiologia , Hormônio Paratireóideo/efeitos adversos , Ésteres do Ácido Sulfúrico/efeitos adversos , Ésteres do Ácido Sulfúrico/sangue , Ácido Úrico/efeitos adversos , Ácido Úrico/sangue , Diálise Renal/efeitos adversos , Interleucina-6/efeitos adversos , Cresóis/efeitos adversos , Cresóis/sangue , Interleucina-1beta/efeitos adversos , Interleucina-1beta/sangue , Homocisteína/efeitos adversos , Homocisteína/sangue , Indicã/efeitos adversos , Indicã/sangue
7.
Clin J Am Soc Nephrol ; 14(3): 394-402, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30755453

RESUMO

BACKGROUND AND OBJECTIVES: Current hemodialysis techniques fail to efficiently remove the protein-bound uremic toxins p-cresyl sulfate and indoxyl sulfate due to their high degree of albumin binding. Ibuprofen, which shares the same primary albumin binding site with p-cresyl sulfate and indoxyl sulfate, can be infused during hemodialysis to displace these toxins, thereby augmenting their removal. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We infused 800 mg ibuprofen into the arterial bloodline between minutes 21 and 40 of a conventional 4-hour high-flux hemodialysis treatment. We measured arterial, venous, and dialysate outlet concentrations of indoxyl sulfate, p-cresyl sulfate, tryptophan, ibuprofen, urea, and creatinine before, during, and after the ibuprofen infusion. We report clearances of p-cresyl sulfate and indoxyl sulfate before and during ibuprofen infusion and dialysate concentrations of protein-bound uremic toxins normalized to each patient's average preinfusion concentrations. RESULTS: We studied 18 patients on maintenance hemodialysis: age 36±11 years old, ten women, and mean vintage of 37±37 months. Compared with during the preinfusion period, the median (interquartile range) clearances of indoxyl sulfate and p-cresyl sulfate increased during ibuprofen infusion from 6.0 (6.5) to 20.2 (27.1) ml/min and from 4.4 (6.7) to 14.9 (27.1) ml/min (each P<0.001), respectively. Relative median (interquartile range) protein-bound uremic toxin dialysate outlet levels increased from preinfusion 1.0 (reference) to 2.4 (1.2) for indoxyl sulfate and to 2.4 (1.0) for p-cresyl sulfate (each P<0.001). Although median serum post- and predialyzer levels in the preinfusion period were similar, infusion led to a marked drop in serum postdialyzer levels for both indoxyl sulfate and p-cresyl sulfate (-1.0 and -0.3 mg/dl, respectively; each P<0.001). The removal of the nonprotein-bound solutes creatinine and urea was not increased by the ibuprofen infusion. CONCLUSIONS: Infusion of ibuprofen into the arterial bloodline during hemodialysis significantly increases the dialytic removal of indoxyl sulfate and p-cresyl sulfate and thereby, leads to greater reduction in their serum levels.


Assuntos
Cresóis/sangue , Ibuprofeno/administração & dosagem , Indicã/sangue , Diálise Renal , Albumina Sérica Humana/metabolismo , Ésteres do Ácido Sulfúrico/sangue , Uremia/terapia , Adulto , Ligação Competitiva , Feminino , Humanos , Ibuprofeno/efeitos adversos , Ibuprofeno/sangue , Infusões Intra-Arteriais , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Diálise Renal/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Uremia/sangue , Uremia/diagnóstico
8.
Int Urol Nephrol ; 51(2): 293-302, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30604232

RESUMO

BACKGROUND: There is a gradual increase in serum concentrations of protein-bound colon-derived uremic toxins indoxyl sulphate (IxS) and p-cresyl sulphate (pCS) as chronic kidney disease (CKD) progresses. In acute kidney injury (AKI), up till now, the retention pattern has not been studied. METHODS: In this study, 194 adult patients admitted with sepsis to the intensive care unit were included. IxS, pCS and serum creatinine (sCrea) were quantified at inclusion (D0) and at day 4, unless follow-up ended earlier (Dend). RESULTS: Serum levels of sCrea (P < 0.001), IxS (P < 0.001) and pCS (P < 0.05) were higher in patients with AKI according to RIFLE classification at D0. In contrast with sCrea, IxS and pCS levels only increased from stage I (IxS) and F (pCS) on. When grouped according to evolution in RIFLE class from D0 to Dend, all solute concentrations were higher (P < 0.001) in the group with unfavourable evolution. In this group, there was a marked rise in sCrea (P < 0.001), a moderate one for pCS (P < 0.05), but no change for IxS (P = 0.112). There was a decrease (P < 0.001) of all solute concentrations in the group with favourable evolution. Comparing AKI with CKD patients matched for sCrea, total levels of both IxS and pCS were higher (P < 0.01) in patients with CKD. CONCLUSIONS: Although concentrations of IxS and pCS both tend to rise in sepsis patients with AKI, their evolution does not conform with that of sCrea. For the same level of sCrea, IxS and pCS concentrations are lower in AKI compared with CKD.


Assuntos
Lesão Renal Aguda , Creatinina/sangue , Cresóis/sangue , Indicã/sangue , Sepse , Ésteres do Ácido Sulfúrico/sangue , Uremia/sangue , Lesão Renal Aguda/sangue , Lesão Renal Aguda/etiologia , Idoso , Bélgica , Correlação de Dados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sepse/sangue , Sepse/complicações , Sepse/diagnóstico , Fatores de Tempo , Uremia/etiologia
9.
Toxins (Basel) ; 11(1)2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30654454

RESUMO

The protein-bound uremic toxins para-cresyl sulfate (pCS) and indoxyl sulfate (IS) are associated with cardiovascular disease in chronic renal failure, but the effect of different dialysis procedures on their plasma levels over time is poorly studied. The present prospective, randomized, cross-over trial tested dialysis efficacy and monitored pre-treatment pCS and IS concentrations in 15 patients on low-flux and high-flux hemodialysis and high-convective volume postdilution hemodiafiltration over six weeks each. Although hemodiafiltration achieved by far the highest toxin removal, only the mean total IS level was decreased at week three (16.6 ± 12.1 mg/L) compared to baseline (18.9 ± 13.0 mg/L, p = 0.027) and to low-flux dialysis (20.0 ± 12.7 mg/L, p = 0.021). At week six, the total IS concentration in hemodiafiltration reached the initial values again. Concentrations of free IS and free and total pCS remained unaltered. Highest beta2-microglobulin elimination in hemodiafiltration (p < 0.001) led to a persistent decrease of the plasma levels at week three and six (each p < 0.001). In contrast, absent removal in low-flux dialysis resulted in rising beta2-microglobulin concentrations (p < 0.001). In conclusion, this trial demonstrated that even large differences in instantaneous protein-bound toxin removal by current extracorporeal dialysis techniques may have only limited impact on IS and pCS plasma levels in the longer term.


Assuntos
Cresóis/sangue , Indicã/sangue , Falência Renal Crônica/terapia , Diálise Renal/métodos , Ésteres do Ácido Sulfúrico/sangue , Idoso , Estudos Cross-Over , Feminino , Humanos , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Microglobulina beta-2/sangue
10.
J Vet Intern Med ; 33(2): 662-669, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30561098

RESUMO

BACKGROUND: Intestinal dysbiosis has been documented in humans with chronic kidney disease (CKD) and is thought to contribute to production of the uremic toxins indoxyl sulfate (IS) and p-cresol sulfate (pCS). Characteristics of the fecal microbiome in cats with CKD and correlation to serum concentrations of uremic toxins are unknown. OBJECTIVES: To characterize the fecal microbiome and measure serum IS and pCS concentrations of cats with CKD in comparison to healthy older cats. ANIMALS: Thirty client-owned cats with CKD (International Renal Interest Society stages 2-4) and 11 older (≥8 years) healthy control cats. METHODS: Prospective, cross-sectional study. Fecal samples were analyzed by sequencing of 16S rRNA genes and Escherichia coli quantitative PCR (qPCR). Serum concentrations of IS and pCS measured using liquid chromatography tandem mass spectrometry. RESULTS: Cats with CKD had significantly decreased fecal bacterial diversity and richness. Escherichia coli qPCR showed no significant difference in bacteria count between control and CKD cats. Cats with stage 2 (P = .01) and stages 3 and 4 (P = .0006) CKD had significantly higher serum IS concentrations compared to control cats. No significant difference found between stage 2 and stages 3 and 4 CKD. The pCS concentrations were not significantly different between CKD cats and control cats. CONCLUSIONS AND CLINICAL IMPORTANCE: Decreased fecal microbiome diversity and richness is associated with CKD in cats. Indoxyl sulfate concentration is significantly increased with CKD, and cats with stage 2 CKD may suffer from a similar uremic toxin burden as do cats with later stage disease.


Assuntos
Doenças do Gato/metabolismo , Fezes/microbiologia , Insuficiência Renal Crônica/veterinária , Animais , Estudos de Casos e Controles , Doenças do Gato/sangue , Gatos , Cresóis/sangue , Estudos Transversais , Feminino , Microbioma Gastrointestinal , Indicã/sangue , Masculino , Estudos Prospectivos , RNA Ribossômico 16S/análise , Insuficiência Renal Crônica/metabolismo , Índice de Gravidade de Doença , Ésteres do Ácido Sulfúrico/sangue
11.
Artif Organs ; 43(5): 490-503, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30375673

RESUMO

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.


Assuntos
Soluções para Diálise/química , Lipossomos/química , Diálise Renal/métodos , Toxinas Biológicas/isolamento & purificação , Uremia/sangue , Uremia/terapia , Animais , Cresóis/sangue , Cresóis/isolamento & purificação , Desenho de Equipamento , Hipuratos/sangue , Hipuratos/isolamento & purificação , Indicã/sangue , Indicã/isolamento & purificação , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Masculino , Ratos Sprague-Dawley , Diálise Renal/instrumentação , Ésteres do Ácido Sulfúrico/sangue , Ésteres do Ácido Sulfúrico/isolamento & purificação , Toxinas Biológicas/sangue , Uremia/etiologia
12.
J Bras Nefrol ; 41(1): 103-111, 2019.
Artigo em Inglês, Português | MEDLINE | ID: mdl-30095142

RESUMO

One of the mechanisms proposed for chronic kidney disease (CKD)-related cognitive impairment is the accumulation of uremic toxins due to the deterioration of the renal clearance function. Cognition can be categorized into five major domains according to its information processing functions: memory, attention, language, visual-spatial, and executive. We performed a review using the terms 'uric acid', 'indoxyl sulfate', 'p-cresyl sulfate', 'homocysteine', 'interleukins' and 'parathyroid hormone'. These are the compounds that were found to be strongly associated with cognitive impairment in CKD in the literature. The 26 selected articles point towards an association between higher levels of uric acid, homocysteine, and interleukin 6 with lower cognitive performance in executive, attentional, and memory domains. We also reviewed the hemodialysis effects on cognition. Hemodialysis seems to contribute to an amelioration of CKD-related encephalopathic dysfunction, although this improvement occurs more in some cognitive domains than in others.


Assuntos
Disfunção Cognitiva/etiologia , Insuficiência Renal Crônica/complicações , Toxinas Biológicas/efeitos adversos , Uremia/complicações , Cresóis/efeitos adversos , Cresóis/sangue , Homocisteína/efeitos adversos , Homocisteína/sangue , Humanos , Indicã/efeitos adversos , Indicã/sangue , Interleucina-1beta/efeitos adversos , Interleucina-1beta/sangue , Interleucina-6/efeitos adversos , Hormônio Paratireóideo/efeitos adversos , Diálise Renal/efeitos adversos , Ésteres do Ácido Sulfúrico/efeitos adversos , Ésteres do Ácido Sulfúrico/sangue , Ácido Úrico/efeitos adversos , Ácido Úrico/sangue
13.
Toxins (Basel) ; 10(12)2018 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-30563136

RESUMO

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 (CPOmax), aerobic exercise capacity (VO2max), and echocardiographic parameters of cardiac morphology and evaluated their association with PBUTs. The serum total and free concentrations of indoxyl sulfate (IXS), p-cresyl sulfate (PCS), p-cresyl glucuronide, indole acetic acid, and hippuric acid showed significant negative correlation with CPOmax and VO2max. IXS and PCS were independently associated with CPOmax and VO2max even after controlling for eGFR. No correlation between left ventricular mass index (LVMI) and PBUTs was seen. The present study for the first time has demonstrated the association between subclinical cardiac dysfunction in CKD and serum levels of a panel of PBUTs. Further studies are required to evaluate the mechanism of cardiotoxicity of the individual uremic toxins.


Assuntos
Cardiopatias , Insuficiência Renal Crônica , Toxinas Biológicas/sangue , Uremia , Adulto , Pressão Arterial , Débito Cardíaco , Cresóis/sangue , Exercício Físico , Glucuronídeos/sangue , Cardiopatias/sangue , Cardiopatias/fisiopatologia , Frequência Cardíaca , Hipuratos/sangue , Humanos , Indicã/sangue , Ácidos Indolacéticos/sangue , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Ésteres do Ácido Sulfúrico/sangue , Uremia/sangue , Uremia/fisiopatologia
14.
Kidney Blood Press Res ; 43(5): 1623-1635, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30380555

RESUMO

BACKGROUND/AIMS: Dysbiosis of the intestinal microbiota may accelerate the progression of chronic kidney disease (CKD) by increasing the levels of urea toxins. In recent years, probiotics have been recognized to maintain the physiological balance of the intestinal microbiota. In this study, we aim to assess the therapeutic effects of probiotics on CKD patients with and without dialysis via meta-analysis. METHODS: We conducted a meta-analysis of randomized controlled trials (RCTs) by searching the databases of Pubmed, EMBASE and Cochrane Library (No. CRD42018093080). Studies on probiotics for treatment of CKD adults lasting for at least 4 weeks were selected. The primary outcomes were the levels of urea toxins, and the second outcomes were the levels of interleukin (IL)-6, C-reactive protein (CRP) and hemoglobin (Hb). The risk of bias was assessed by Cochrane Collaboration' tool, and the quality of evidence was appraised with the Grading of Recommendation Assessment. Means and standard deviations were analyzed by random effects analysis. Stratified analysis was done and sensitivity analysis was performed when appropriate. RESULTS: Totally, eight studies with 261 patients at CKD stage 3 to 5 with and without dialysis were included. We found a decrease of p-cresyl sulfate (PCS) of 3 studies with 125 subjects (P = 0.01, SMD -0.57, 95% CI, -0.99 to -0.14, I2 = 25%) and an increase of IL-6 in 3 studies with 134 subjects (P = 0.03, 95% CI, SMD 0.37, 0.03 to 0.72, I2 = 0%) in the probiotics groups. Analysis of serum creatinine (P = 0.47), blood urine nitrogen (P = 0.73), CRP (P = 0.55) and Hb (P = 0.49) yielded insignificant difference. CONCLUSION: Limited number of studies and small sample size are limitations of our study. Probiotics supplementation may reduce the levels of PCS and elevate the levels of IL-6 whereby protecting the intestinal epithelial barrier of patients with CKD.


Assuntos
Probióticos/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Cresóis/sangue , Diálise , Suplementos Nutricionais , Humanos , Interleucina-6/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/terapia , Ésteres do Ácido Sulfúrico/sangue
15.
Toxins (Basel) ; 10(10)2018 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-30249039

RESUMO

Uremic toxin (UT) retention in chronic kidney disease (CKD) affects biological systems. We aimed to identify the associations between UT, inflammatory biomarkers and biomarkers of the uremic cardiovascular response (BUCVR) and their impact on cardiovascular status as well as their roles as predictors of outcome in CKD patients. CKD patients stages 3, 4 and 5 (n = 67) were recruited and UT (indoxyl sulfate/IS, p-cresil sulfate/pCS and indole-3-acetic acid/IAA); inflammatory biomarkers [Interleukin-6 (IL-6), high sensitivity C reactive protein (hsCRP), monocyte chemoattractant protein-1 (MCP-1), soluble vascular adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble Fas (sFas)] and BUCVRs [soluble CD36 (sCD36), soluble receptor for advanced glycation end products (sRAGE), fractalkine] was measured. Patients were followed for 5.2 years and all causes of death was used as the primary outcome. Artery segments collected at the moment of transplantation were used for the immunohistochemistry analysis in a separate cohort. Estimated glomerular filtration rate (eGFR), circulating UT, plasma biomarkers of systemic and vascular inflammation and BUCVR were strongly interrelated. Patients with plaque presented higher signs of UT-induced inflammation and arteries from CKD patients presented higher fractalkine receptor (CX3CR1) tissue expression. Circulating IS (p = 0.03), pCS (p = 0.007), IL-6 (p = 0.026), sFas (p = 0.001), sCD36 (p = 0.01) and fractalkine (p = 0.02) were independent predictors of total mortality risk in CKD patients. Our results reinforce the important role of uremic toxicity in the pathogenesis of cardiovascular disease (CVD) in CKD patients through an inflammatory pathway.


Assuntos
Doenças Cardiovasculares/metabolismo , Cresóis/sangue , Indicã/sangue , Ácidos Indolacéticos/sangue , Inflamação/metabolismo , Insuficiência Renal Crônica/metabolismo , Ésteres do Ácido Sulfúrico/sangue , Toxinas Biológicas/sangue , Uremia/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Antígenos CD36/metabolismo , Doenças Cardiovasculares/fisiopatologia , Citocinas/metabolismo , Feminino , Taxa de Filtração Glomerular , Humanos , Inflamação/fisiopatologia , Masculino , Pessoa de Meia-Idade , Artéria Renal/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Uremia/fisiopatologia
16.
Biol Pharm Bull ; 41(8): 1170-1177, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30068866

RESUMO

Patients with chronic kidney disease (CKD) have increased blood levels of phenyl sulfate (PS), a circulating uremic toxin. In this study, we produced anti-PS monoclonal antibodies (mAbs) and characterized their cross-reactivity to structural PS analogs. To induce PS-specific mAbs, we synthesized 4-mercaptophenyl sulfate with a sulfhydryl group at the para-position of PS and conjugated it to carrier proteins via bifunctional linkers. Using these PS conjugates as immunogens and as antigens for enzyme-linked immunosorbent assay (ELISA) screening, we produced by a hybridoma method two novel mAbs (YK33.1 and YKS19.2) that react with PS conjugates independent of carrier and linker structures. Although all of the PS analogs tested, with the exception of indoxyl sulfate, were cross-reactive to both mAbs in phosphate buffered saline (PBS), PS specificity for YKS19.2 was enhanced in human plasma and serum. YKS19.2 mAb was cross-reactive only with o-cresyl sulfate, which is absent in human blood. PS sensitivity for YKS19.2 mAb increased to an IC50 of 10.4 µg/mL when 0.1% Tween 20 was added in a primary competitive reaction. To explore potential clinical applications, we determined concentrations of PS in serum samples from 19 CKD patients by inhibition ELISA using YKS19.2 mAb and compared them to those found using an LC-MS/MS method. A good correlation was observed between each value (R2=0.825). Therefore, the unique antigen specificity of YKS19.2 mAb could be useful for prescreening of patients with accumulated PS or for comprehensive analysis of uremic toxins that have a PS-like structure.


Assuntos
Anticorpos Monoclonais/imunologia , Insuficiência Renal Crônica/sangue , Ésteres do Ácido Sulfúrico/sangue , Ésteres do Ácido Sulfúrico/imunologia , Animais , Antígenos/química , Antígenos/imunologia , Linhagem Celular Tumoral , Cromatografia Líquida , Ensaio de Imunoadsorção Enzimática , Feminino , Hemocianinas/química , Hemocianinas/imunologia , Humanos , Imunoconjugados/química , Imunoconjugados/imunologia , Camundongos Endogâmicos BALB C , Ovalbumina/química , Ovalbumina/imunologia , Soroalbumina Bovina/química , Soroalbumina Bovina/imunologia , Ésteres do Ácido Sulfúrico/química , Espectrometria de Massas em Tandem
17.
Biosci Rep ; 38(5)2018 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-29921575

RESUMO

Clearance of protein-bound uremic toxins (PBUTs) by dialysis is a challenge in the treatment of uremic patients. Shen-Shuai-Ning (SSN), a traditional Chinese medicine formulation, has been used commonly in China to retard kidney disease progression and decrease uremic toxins in chronic kidney disease (CKD) patients, but the effects of SSN on serum PBUTs in dialysis patients were not investigated. We conducted a randomized controlled trial in patients on peritoneal dialysis (PD) at dialysis center of Changzheng Hospital to evaluate the effects of SSN on serum PBUTs. Participants with SSN intervention took 5 g SSN granule three times daily for 12 weeks, while the baseline medications and dialysis prescriptions remained during the study in all patients. The serum concentrations of indoxyl sulphate (IS) and p-cresol sulphate (PCS) were determined by HPLC/MS/MS and biochemical parameters were assessed during the study. Sixty PD patients were enrolled and randomly allocated into SSN group and control group. Total IS level was significantly lower in SSN group than in control group at week 4, 8, and 12 (27.28 ± 18.19, 29.73 ± 19.10, and 29.41 ± 17.61 mg/l compared with 39.25 ± 20.23, 44.86 ± 23.91, and 45.34 ± 33.52 mg/l, respectively). However, there were no statistical difference of total PCS, free forms of IS and PCS concentrations between SSN group and control group during 12 weeks follow-up. Administration of SSN granule orally decreased serum total IS level effectively in uremic patients on PD with good tolerance. Benefits of PD patients' outcomes from IS reduction by SSN awaits further large size and long duration clinical trials to verify.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Indicã/sangue , Diálise Peritoneal , Uremia/tratamento farmacológico , Adulto , Cresóis/sangue , Feminino , Humanos , Falência Renal Crônica/terapia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Diálise Peritoneal/efeitos adversos , Ésteres do Ácido Sulfúrico/sangue , Resultado do Tratamento , Uremia/sangue
18.
Toxicol Lett ; 295: 173-178, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29908303

RESUMO

Furfuryl alcohol (FFA) is a heat-induced food contaminant. Conversion by sulfotransferases (SULT) yields 2-sulfoxymethylfuran, which is prone to react with DNA and proteins. In order to monitor the internal FFA exposure we developed a technique for the mass spectrometric quantification of the adduct N-((furan-2-yl)methyl)-valine (FFA-Val) after cleavage from the N-termini of hemoglobin. In the current study the method was applied to investigate the influence of different SULT forms on the adduct formation in wild-type mice and three genetically modified mouse models treated with FFA. Two lines were devoid of endogenous Sult1a1 or Sult1d1, while another mouse line carried a transgene of human SULT1A1/1A2 in the Sult1a1/1d1 double knockout background. The Sult1d1 knockout did not influence adduct formation, whereas the lack of Sult1a1 reduced mean FFA-Val levels by 80% and 58% in male and female mice, respectively, in comparison to FFA-treated wild-type mice. The levels of FFA-Val in the humanized mice were elevated by factors of 2.7 (males) and 2.2 (females) as compared to the wild-type, indicating that SULT1A1/1A2 play a central role for FFA bioactivation also in humans. The excellent correlation between adduct levels in hepatic DNA and hemoglobin (r2 = 0.97) indicated that 2-sulfoxymethylfuran of hepatic origin is sufficiently stable to enter circulation and pass the cellular membrane of erythrocytes. This is a prerequisite for the application of FFA-Val as a biomarker of internal FFA exposure.


Assuntos
Arilsulfotransferase/metabolismo , Furanos/sangue , Hemoglobinas/metabolismo , Fígado/enzimologia , Sulfotransferases/metabolismo , Ésteres do Ácido Sulfúrico/sangue , Ativação Metabólica , Animais , Arilsulfotransferase/deficiência , Arilsulfotransferase/genética , Biomarcadores/sangue , Cromatografia Líquida , Feminino , Genótipo , Humanos , Masculino , Camundongos Knockout , Camundongos Transgênicos , Fenótipo , Sulfotransferases/deficiência , Sulfotransferases/genética , Espectrometria de Massas em Tandem
19.
J Am Soc Nephrol ; 29(7): 1992-1999, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29728422

RESUMO

Background Most patients on hemodialysis are treated thrice weekly even if they have residual kidney function, in part because uncertainty remains as to how residual function should be valued and incorporated into the dialysis prescription. Recent guidelines, however, have increased the weight assigned to residual function and thus reduced the treatment time required when it is present. Increasing the weight assigned to residual function may be justified by knowledge that the native kidney performs functions not replicated by dialysis, including solute removal by secretion. This study tested whether plasma concentrations of secreted solutes are as well controlled in patients with residual function on twice weekly hemodialysis as in anuric patients on thrice weekly hemodialysis.Methods We measured the plasma concentration and residual clearance, dialytic clearance, and removal rates for urea and the secreted solutes hippurate, phenylacetylglutamine, indoxyl sulfate, and p-cresol sulfate in nine patients on twice weekly hemodialysis and nine patients on thrice weekly hemodialysis.Results Compared with anuric patients on thrice weekly dialysis with the same standard Kt/Vurea, patients on twice weekly hemodialysis had lower hippurate and phenylacetylglutamine concentrations and similar indoxyl sulfate and p-cresol sulfate concentrations. Mathematical modeling revealed that residual secretory function accounted for the observed pattern of solute concentrations.Conclusions Plasma concentrations of secreted solutes can be well controlled by twice weekly hemodialysis in patients with residual kidney function. This result supports further study of residual kidney function value and the inclusion of this function in dialysis adequacy measures.


Assuntos
Falência Renal Crônica/fisiopatologia , Falência Renal Crônica/terapia , Diálise Renal/métodos , Idoso , Idoso de 80 Anos ou mais , Cresóis/sangue , Feminino , Glutamina/análogos & derivados , Glutamina/sangue , Hipuratos/sangue , Humanos , Indicã/sangue , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica , Ésteres do Ácido Sulfúrico/sangue , Ureia/sangue
20.
Dtsch Arztebl Int ; 115(18): 309-315, 2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29807559

RESUMO

BACKGROUND: Biomarkers of alcohol consumption are important not only in forensic contexts, e.g., in child custody proceedings or as documentation of alcohol abstinence after temporary confiscation of a driver's license. They are increasingly being used in clinical medicine as well for verification of abstinence or to rule out the harmful use of alcohol. METHODS: This review is based on pertinent publications that were retrieved by a selective literature search in PubMed concerning the direct and indirect alcohol markers discussed here, as well as on the authors' experience in laboratory analysis and clinical medicine. RESULTS: Alongside the direct demonstration of ethanol, the available markers of alcohol consumption include the classic indirect markers carbohydrate-deficient transferrin (CDT), gamma-glutamyltransferase (GGT), and mean corpuscular volume (MCV) as well as direct alcohol markers such as ethyl glucuronide (EtG) and ethyl sulfate (EtS) in serum and urine and EtG and fatty acid ethyl esters (FAEE) in hair. Phosphatidylethanol (PEth) is a promising parameter that com - plements the existing spectrum of tests with high specificity (48-89%) and sensi - tivity (88-100%). In routine clinical practice, the demonstration of positive alcohol markers often leads patients to admit previously denied alcohol use. This makes it possible to motivate the patient to undergo treatment for alcoholism. CONCLUSION: The available alcohol biomarkers vary in sensitivity and specificity with respect to the time period over which they indicate alcohol use and the minimum extent of alcohol use that they can detect. The appropriate marker or combination of markers should be chosen in each case according to the particular question that is to be answered by laboratory analysis.


Assuntos
Consumo de Bebidas Alcoólicas/sangue , Pesos e Medidas/normas , Consumo de Bebidas Alcoólicas/metabolismo , Consumo de Bebidas Alcoólicas/urina , Biomarcadores/análise , Biomarcadores/sangue , Biomarcadores/urina , Etil-Éteres/análise , Etil-Éteres/metabolismo , Ciências Forenses/métodos , Ciências Forenses/normas , Glucuronatos/análise , Glucuronatos/sangue , Glicerofosfolipídeos/análise , Glicerofosfolipídeos/sangue , Cabelo/enzimologia , Cabelo/metabolismo , Cabelo/patologia , Humanos , Jurisprudência , Pessoa de Meia-Idade , Ésteres do Ácido Sulfúrico/análise , Ésteres do Ácido Sulfúrico/sangue , Ésteres do Ácido Sulfúrico/urina , Fatores de Tempo , Transferrina/análogos & derivados , Transferrina/análise , gama-Glutamiltransferase/análise , gama-Glutamiltransferase/sangue
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