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1.
ACS Appl Mater Interfaces ; 11(47): 43843-43856, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31663727

RESUMO

Protein-bound uremic toxins (PBUTs) can cause noxious effects in patients suffering from renal failure as a result of inhibiting the transport of proteins and inducing their structural modification. They are difficult to remove through standard hemodialysis (HD) treatment. Herein, we report an organic bioelectronic HD device system for the effective removal of PBUTs through electrically triggered dissociation of protein-toxin complexes. To prepare this system, we employed electrospinning to fabricate electrically conductive quaternary composite nanofiber mats-comprising multiwalled carbon nanotubes (MWCNTs), poly(3,4-ethylenedioxythiophene):polystyrenesulfonate (PEDOT:PSS), poly(ethylene oxide) (PEO), and (3-glycidyloxypropyl)trimethoxysilane (GOPS)-on conventional polyethersulfone (PES) dialysis membranes. These composite nanofiber platforms exhibited (i) long-term water resistance (due to cross-linking among PSS, PEO, and GOPS), (ii) high adhesion strength on the PES membrane (due to GOPS functioning as an adhesion promoter), (iii) enhanced electrical properties [due to the MWCNTs and PEDOT:PSS promoting effective electrical stimulation (ES) operation in devices containing bioelectronic interfaces (BEI)], and (iv) good anticoagulant ability and negligible hemolysis of red blood cells. We employed this organic BEI electronic system as a novel single-membrane HD device to study the removal efficiency of four kinds of uremic toxins [p-cresol (PC), indoxyl sulfate, and hippuric acid as PBUTs; creatinine as a non-PBUT] as well as the effects of ES on lowering the protein binding ratio. Our organic BEI devices provided a high rate of removal of PC with low protein loss after 4 h of a simulated dialysis process. It also functioned with low complement activation, low contact activation levels, and lower amounts of platelet adsorption, suggesting great suitability for use in developing next-generation bioelectronic medicines for HD.


Assuntos
Nanotubos de Carbono/química , Proteínas/química , Diálise Renal/instrumentação , Toxinas Biológicas/química , Uremia/terapia , Adsorção , Cresóis/sangue , Cresóis/química , Eletrônica/instrumentação , Hipuratos/sangue , Hipuratos/química , Humanos , Indicã/sangue , Indicã/química , Polímeros/química , Toxinas Biológicas/sangue , Uremia/sangue
2.
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
3.
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
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.
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
6.
J Pharm Biomed Anal ; 167: 149-154, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30772758

RESUMO

p-Cresol is a protein-bound uremic retention solute that originates in the intestine through bacterial metabolism and accumulates throughout the body in case of kidney failure. To date, there has been no method to analyze unconjugated p-cresol concentration in the blood with a limit of detection lower than 75 pg. Thus, the aim of this study was to develop and validate a novel liquid chromatography-tandem mass spectrometry method for the determination of unconjugated p-cresol in plasma with a lower detection limit than what has been determined using previously described methods. Sample preparation included derivatization of p-cresol with dansyl chloride (derivatization reagent) showed to be a better approach to analyze the compound. The method optimization involved various pH, time of the reaction, and concentration of derivatization reagent. The validation process was performed according to the procedures prescribed by the European Medicines Agency. All analyzed validation criteria were fulfilled. The novel validated method was applied to compare the level of p-cresol in patients with chronic renal failure before and after dialysis (n = 24). Additionally, the concentration of p-cresol was determined in patients with multiple organ dysfunction syndrome (n = 23). The established method can be used for determination of p-cresol in the plasma in further clinical research.


Assuntos
Cresóis/sangue , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência Renal Crônica/sangue , Cromatografia Líquida , Humanos , Limite de Detecção , Diálise Renal , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
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.
Nephrol Dial Transplant ; 34(11): 1876-1884, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29939302

RESUMO

BACKGROUND: Microbial-derived uremic toxins, p-cresyl sulfate (PCS), indoxyl sulfate (IS) and indole 3-acetic acid (IAA), have been associated with the burden of chronic kidney disease (CKD). Prebiotics have emerged as an alternative to modulate the gut environment and to attenuate toxin production. This trial aims to investigate the effect of a prebiotic fructooligosaccharide (FOS) on uremic toxins of non-dialysis-dependent CKD (NDD-CKD) patients. METHODS: A double-blind, placebo-controlled, randomized trial was conducted for 3 months. In all, 50 nondiabetic NDD-CKD patients [estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2], aged 18-80 years, were allocated to prebiotic (FOS, 12 g/day) or placebo (maltodextrin, 12 g/day) groups. Primary outcomes were changes in serum (total and free) and urinary (total) PCS. Secondary outcomes included changes in IS, IAA, serum markers of intestinal permeability (zonulin), gut-trophic factors (epidermal growth factor and glucagon-like peptide-2), eGFR, inflammation (high sensitive c-reactive protein and interleukin-6), homeostatic model assessment-insulin resistance, lipid profile and gastrointestinal symptoms. RESULTS: From 50 participants (54% men, 57.3 ± 14.6 years and eGFR 21.4 ± 7.6 mL/min/1.73 m2), 46 completed the follow-up. No changes in dietary intake or gastrointestinal symptoms were observed. There was a trend in the difference of serum total ΔPCS (treatment effect adjusted for baseline levels: -12.4 mg/L; 95% confidence interval (-5.6 to 0.9 mg/L; P = 0.07) and serum-free Δ%PCS [intervention -8.6 (-41.5 to 13.9%) versus placebo 3.5 (-28.8 to 85.5%); P = 0.07] between the groups. The trend in the difference of serum total ΔPCS was independent of eGFR and dietary protein:fiber ratio intake. No difference was found in urinary PCS. Aside from the decreased high-density lipoprotein cholesterol in the intervention, no differences were observed in the change of IS, IAA or other secondary outcome between the groups. CONCLUSIONS: Our result suggests the potential of FOS in reducing serum total and free PCS in nondiabetic NDD-CKD patients.


Assuntos
Trato Gastrointestinal/efeitos dos fármacos , Microbiota/fisiologia , Oligossacarídeos/administração & dosagem , Prebióticos/administração & dosagem , Insuficiência Renal Crônica/tratamento farmacológico , Toxinas Biológicas/isolamento & purificação , Uremia/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Cresóis/sangue , Proteínas na Dieta , Método Duplo-Cego , Feminino , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Taxa de Filtração Glomerular , Humanos , Inflamação/prevenção & controle , Masculino , Microbiota/efeitos dos fármacos , Pessoa de Meia-Idade , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/microbiologia , Toxinas Biológicas/metabolismo , Uremia/microbiologia , Adulto Jovem
13.
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
14.
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
15.
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
16.
Clin Nutr ESPEN ; 28: 158-164, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30390875

RESUMO

BACKGROUND: Uremic toxins such as p-cresol and phenol are suggested to be associated with higher mortality in hemodialysis patients. The aim of this study was to investigate the effects of probiotics on some serum uremic toxin levels in hemodialysis patients. METHODS: Patients undergoing hemodialysis in a university dialysis center were enrolled in this randomized controlled double blind clinical trial. The patients received probiotic (Lactobacillus Rhamnosus) for duration of 4 weeks. All data were presented as the mean ± SD. Statistical analyses were performed by SPSS statistical software. Paired t-test was used to compare pre- and post-treatment p-cresol levels. P values less than .05 were considered statistically significant. RESULTS: A total of 42 hemodialysis patients (32 male and 10 female) were enrolled in this study. The mean ± SD age of the patients in Lactobacillus Rhamnosus and placebo groups were 57.05 ± 13.96 and 59.67 ± 15.04 years, respectively. Values of uremic toxins before treatment did not differ statistically between groups but they were significantly lower in Lactobacillus Rhamnosus group compared with placebo group (P < .05). Total Phenol and p-cresol levels were associated with sodium, energy, carbohydrate, fat and protein intake and fiber consumption, accompanying by hemodialysis hours per week in linear regression analyses. CONCLUSIONS: This study demonstrated that probiotics could be a promising target in hemodialysis patients with the capability of decreasing serum phenolic uremic toxins in this population. TRIAL REGISTRATION: IRCT20154182017N21 Date:09/12/2016.


Assuntos
Cresóis/sangue , Falência Renal Crônica/terapia , Lactobacillus rhamnosus , Fenol/sangue , Probióticos/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Falência Renal Crônica/sangue , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Diálise Renal , Resultado do Tratamento
17.
Asia Pac J Clin Nutr ; 27(5): 1067-1076, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30272855

RESUMO

BACKGROUND AND OBJECTIVES: Obesity is linked to metabolic diseases characterized by insulin resistance, such as diabetes and cardiovascular disease. In this study, we investigated the metabolic disorders of uncomplicated obesity to identify early alterations in biological systems. METHODS AND STUDY DESIGN: Metabolic differences between overweight/obese (n=36) and normal-weight (n=35) young Chinese men without known metabolic disorders were assessed. Metabolic profiling of the serum and urine was performed using ultra-performance liquidchromatography quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Partial least squares discriminant analysis (PLS-DA) was undertaken to reveal and classify the differences between the two groups. RESULTS: Compared to normal-weight men, obese men had higher levels of the serum metabolites phenylalanine, Phe-Phe, and L-tryptophan, whereas those of p-cresol sulfate and p-cresol were less in obesity. Urinary metabolites phenylacetamide, L-glutamine, phenylacetylglutamine, indoxyl sulfate, p-cresol, and p-cresol sulfate were greater in obese men. CONCLUSIONS: These findings indicate that disorders involving aromatic amino acids and the tricarboxylic acid cycle (TCA) have microbiomic involvement in the uncomplicated phase of obesity.


Assuntos
Metabolômica/métodos , Sobrepeso/sangue , Sobrepeso/urina , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Cromatografia Líquida de Alta Pressão , Cresóis/sangue , Cresóis/urina , Análise Discriminante , Glutamina/análogos & derivados , Glutamina/urina , Humanos , Indicã/urina , Masculino , Espectrometria de Massas , Obesidade/sangue , Obesidade/urina , Fenilalanina/sangue , Triptofano/sangue , Adulto Jovem
18.
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
19.
Leg Med (Tokyo) ; 34: 27-35, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30103078

RESUMO

In some forensic autopsy cases there are high concentrations of p-cresol in the blood. In vivo, p-cresol is the only isomer yielded by intestinal bacteria and is excreted into urine. We investigated the diagnostic meaning of p-cresol in the blood of forensic autopsy cases. Blood samples from 110 autopsy cases within 48 h of the postmortem interval (PMI) and 10 healthy adults were examined. Blood with p-cresol-d8 as an internal standard was analyzed using a GC-MS/MS method. Using acid and heat deproteinization, free (F) and conjugated (non-protein bound: C; protein bound: PC) p-cresol were individually analyzed. The p-cresol concentrations were 1.39 ±â€¯0.86 µg/ml [mean ±â€¯SD] and 1.18 (0.19-18.80) µg/ml [median (range)] in healthy adults and autopsy cases, respectively. The p-cresol showed no significant relationship to age, sex, fasting duration, survival duration, or PMI. No significant differences were found between causes of death. Significantly higher levels of C p-cresol were found in cases with atherosclerosis in the basilar or renal arteries, or stenosis in the coronary artery. Significantly higher levels of p-cresol except F were found in cases with hyalinosis of the kidney. Cases with low BMI also showed significantly higher p-cresol concentrations. The 22 cases of abnormally high total p-cresol were investigated. It was considered that high concentrations of p-cresol could be an indicator of certain diseases and physical conditions that effect the production, absorption, metabolism, circulation, and excretion of p-cresol. Measuring the levels of p-cresol may provide valuable information about the antemortem physical conditions.


Assuntos
Autopsia , Cresóis/sangue , Medicina Legal , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/diagnóstico , Biomarcadores/sangue , Índice de Massa Corporal , Estenose Coronária/diagnóstico , Jejum , Feminino , Glomerulosclerose Segmentar e Focal/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Mudanças Depois da Morte , Espectrometria de Massas em Tandem , Fatores de Tempo , Adulto Jovem
20.
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
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