Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 264
Filtrar
1.
Yonsei Med J ; 62(1): 41-49, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33381933

RESUMO

PURPOSE: Oral adsorbents delay disease progression and improve uremic symptoms in patients with chronic kidney disease (CKD). DW-7202 is a newly developed oral adsorbent with high adsorptive selectivity for uremic toxins. We evaluated patient preference for and adherence to DW-7202 versus AST-120 therapy and compared treatment efficacy and safety in patients with pre-dialysis CKD. MATERIALS AND METHODS: A seven-center, randomized, open-label, two-way crossover, active-controlled, phase IV clinical trial was conducted. Patients with stable CKD were randomly assigned to receive DW-7202 (capsule type) or AST-120 (granule type) for 12 weeks. The groups then switched to the other adsorbent and took it for the next 12 weeks. Patient preference was the primary outcome. Secondary outcomes included changes in estimated glomerular filtration rate (eGFR) and serum creatinine, cystatin C, and indoxyl sulfate (IS) levels. RESULTS: Significantly more patients preferred DW-7202 than AST-120 (p<0.001). Patient adherence improved after switching from AST-120 to DW-7202; there was no apparent change in adherence after switching from DW-7202 to AST-120. Changes in eGFR and serum creatinine, cystatin C, and IS levels were not significantly different according to adsorbent type. There was also no significant difference in the incidences of adverse events during treatment with DW-7202 and AST-120. CONCLUSION: DW-7202 can be considered as an alternative to AST-120 in patients who cannot tolerate or show poor adherence to granule type adsorbents. Further studies to evaluate factors affecting patient preferences and improved adherence are warranted (Clinical trial registration No. NCT02681952).


Assuntos
Insuficiência Renal Crônica/tratamento farmacológico , Adsorção , Carbono/administração & dosagem , Carbono/uso terapêutico , Creatinina/sangue , Estudos Cross-Over , Cistatina C/sangue , Progressão da Doença , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Indicã/sangue , Masculino , Pessoa de Meia-Idade , Óxidos/administração & dosagem , Óxidos/uso terapêutico , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Resultado do Tratamento
2.
Cardiovasc Diabetol ; 19(1): 75, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32527273

RESUMO

BACKGROUND: Although an increased arterial stiffness has been associated with traditional coronary risk factors, the risk factors and pathology of arterial stiffness remain unclear. In this study, we aimed to identify the plasma metabolites associated with arterial stiffness in patients with type 2 diabetes mellitus. METHODS: We used the metabolomic data of 209 patients with type 2 diabetes as the first dataset for screening. To form the second dataset for validation, we enlisted an additional 31 individuals with type 2 diabetes. The non-targeted metabolome analysis of fasting plasma samples using gas chromatography coupled with mass spectrometry and the measurement of brachial-ankle pulse wave velocity (baPWV) were performed. RESULTS: A total of 65 annotated metabolites were detected. In the screening dataset, there were statistically significant associations between the baPWV and plasma levels of indoxyl sulfate (r = 0.226, p = 0.001), mannitol (r = 0.178, p = 0.010), mesoerythritol (r = 0.234, p = 0.001), and pyroglutamic acid (r = 0.182, p = 0.008). Multivariate regression analyses revealed that the plasma levels of mesoerythritol were significantly (ß = 0.163, p = 0.025) and that of indoxyl sulfate were marginally (ß = 0.124, p = 0.076) associated with baPWV, even after adjusting for traditional coronary risk factors. In the independent validation dataset, there was a statistically significant association between the baPWV and plasma levels of indoxyl sulfate (r = 0.430, p = 0.016). However, significant associations between the baPWV and plasma levels of the other three metabolites were not confirmed. CONCLUSIONS/INTERPRETATION: The plasma levels of indoxyl sulfate were associated with arterial stiffness in Japanese patients with type 2 diabetes. Although the plasma levels of mannitol, mesoerythritol, and pyroglutamic acid were also associated with arterial stiffness, further investigation is needed to verify the results.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Indicã/sangue , Doença Arterial Periférica/sangue , Rigidez Vascular , Idoso , Índice Tornozelo-Braço , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Eritritol/análogos & derivados , Eritritol/sangue , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Manitol/sangue , Metabolômica , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/fisiopatologia , Ácido Pirrolidonocarboxílico/sangue
3.
Sci Rep ; 10(1): 513, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949282

RESUMO

Indoxyl sulfate (IS), a protein-bound uremic toxin, induces chronic kidney disease (CKD) and atrial fibrillation (AF). Catheter ablation (CA) of AF improves the renal function. However, the transition of uremic toxins is unclear. This study aimed to investigate the transition of the serum IS level in AF patients with and without CKD after CA. A total of 138 consecutive AF patients who underwent CA and maintained sinus rhythm were prospectively enrolled (paroxysmal AF 67.4%). The patients were divided into 4 groups (non-CKD/low-IS:68, non-CKD/high-IS:28, CKD/low-IS:13, and CKD/high-IS:29). The plasma IS levels and estimated glomerular filtration rate (eGFR) were determined before and 1-year after CA. CKD was defined as CKD stage III and a high-IS according to the mean IS (IS ≥ 1.1 µg/ml). CA significantly improved the eGFR in CKD patients (p < 0.001). The serum IS level in the non-CKD/high-IS group was significantly decreased (from 1.7 ± 0.7 to 1.1 ± 0.6 µg/ml, p < 0.001). However, the serum IS level in the CKD/high-IS group did not improve (from 1.9 ± 0.9 to 1.7 ± 0.7 µg/ml, p = 0.22). The change in the IS in the CKD patients significantly differed from that in those without CKD. In the CKD patients, CA did not significantly decrease the IS, a risk factor of CKD, regardless of an improved eGFR.


Assuntos
Fibrilação Atrial/cirurgia , Indicã/sangue , Rim/fisiopatologia , Insuficiência Renal Crônica/sangue , Idoso , Fibrilação Atrial/sangue , Ablação por Cateter , Eletrocardiografia , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Insuficiência Renal Crônica/fisiopatologia
4.
Clin Chim Acta ; 501: 165-173, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31726035

RESUMO

BACKGROUND: In Parkinson's disease (PD), impairment of brain to blood barrier and/or blood-cerebrospinal fluid (CSF) barrier is described. It can increase the level of uremic toxins in CSF. So far, role of these compounds in neurological disorders has not been completely understood. However, a link has been observed between chronic kidney disease and neurological disorders. We measured the concentrations of uremic toxins (i.e. indoxyl sulfate (IS), p-cresol sulfate (pCS), symmetric dimethylarginine (SDMA), asymmetric dimethylarginine (ADMA), and trimethylamine N-oxide (TMAO)) in CSF and plasma, and correlated them with inflammation and oxidative stress biomarkers. METHODS: Plasma and CSF samples were collected from 27 volunteers (18 with PD and 9 controls). The level of toxins was determined using liquid chromatography coupled with tandem mass spectrometry. RESULTS: In PD, for IS and pCS, CSF-plasma ratio was higher. Concentration of pCS in CSF was higher in PD compared to controls. TMAO level was also higher in plasma of that group. Patients with motor fluctuations had higher level of uremic toxins in CSF, but not in plasma. CONCLUSIONS: The level of pCS and IS in CSF of PD is higher than expected, based on their blood level. It can influence pathogenesis and progression of PD.


Assuntos
Cresóis/sangue , Cresóis/líquido cefalorraquidiano , Indicã/sangue , Indicã/líquido cefalorraquidiano , Doença de Parkinson/sangue , Doença de Parkinson/líquido cefalorraquidiano , Ésteres do Ácido Sulfúrico/sangue , Ésteres do Ácido Sulfúrico/líquido cefalorraquidiano , Adulto , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico
5.
Toxins (Basel) ; 11(10)2019 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614554

RESUMO

Indoxyl sulfate (IS), a product metabolized from tryptophan, is negatively correlated with renal function and cardiovascular diseases in patients with chronic kidney disease (CKD). We investigated the association between serum IS levels and endothelial function in patients with CKD. Fasting blood samples were obtained from 110 patients with stages 3-5 CKD. The endothelial function, represented by vascular reactivity index (VRI), was measured non-invasively using digital thermal monitoring. Serum IS levels were determined using liquid chromatography-mass spectrometry. Twenty-one (19.1%), 36 (32.7%), and 53 (48.2%) patients had poor (VRI < 1.0), intermediate (1.0 ≤ VRI < 2.0), and good (VRI ≥ 2.0) vascular reactivity. By univariate linear regression analysis, a higher prevalence of smoking, advanced age, higher systolic, and diastolic blood pressure (DBP), elevated levels of serum phosphorus, blood urea nitrogen, creatinine, and IS were negatively correlated with VRI values, but estimated glomerular filtration rate negatively associated with VRI values. After being adjusted by using multivariate stepwise linear regression analysis, DBP and IS levels were significantly negatively associated with VRI values in CKD patients. We concluded that IS level associated inversely with VRI values and had a modulating role in endothelial function in patients with stages 3-5 CKD.


Assuntos
Indicã/sangue , Insuficiência Renal Crônica/sangue , Idoso , Pressão Sanguínea , Creatinina/análise , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/fisiopatologia
6.
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
7.
Pediatr Nephrol ; 34(12): 2571-2582, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31428929

RESUMO

BACKGROUND: Cardiovascular disease is the leading cause of death in children with chronic kidney disease (CKD). Serum levels of gut-derived uremic toxins increase with deterioration of kidney function and are associated with cardiac comorbidities in adult CKD patients. METHODS: Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) were measured by high-performance liquid chromatography in serum of children participating in the Cardiovascular Comorbidity in Children with CKD (4C) Study. Results were correlated with measurements of the carotid intima-media thickness (cIMT), central pulse wave velocity (PWV), and left ventricular mass index (LVMI) in children aged 6-17 years with initial eGFR of 10-60 ml/min per 1.73 m2. RESULTS: The median serum levels of total IS and of pCS, measured in 609 patients, were 5.3 µmol/l (8.7) and 17.0 µmol/l (21.6), respectively. In a multivariable regression model, IS and pCS showed significant positive associations with urea and negative associations with eGFR and uric acid. Furthermore, positive associations of pCS with age, serum albumin, and non-Mediterranean residency and a negative association with glomerular disease were observed. By multivariable regression analysis, only IS was significantly associated with a higher cIMT SDS at baseline and progression of PWV SDS within 12 months, independent of other risk factors. CONCLUSIONS: Serum levels of gut-derived uremic toxins IS and pCS correlated inversely with eGFR in children. Only IS was significantly associated with surrogate markers of cardiovascular disease in this large pediatric CKD cohort.


Assuntos
Indicã/sangue , Insuficiência Renal Crônica/sangue , Adolescente , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Criança , Cresóis/sangue , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Fenótipo , Insuficiência Renal Crônica/complicações , Ésteres do Ácido Sulfúrico/sangue
8.
Sci Rep ; 9(1): 10720, 2019 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-31341259

RESUMO

Endovascular therapy is the principal therapy for haemodialysis vascular access dysfunction. Nonetheless, the incidence and determinants of post-intervention thrombotic events are unclear. This prospective cohort study evaluated the incidence and timing of thrombotic events after endovascular therapy and analysed the clinical, angiographic, and biological determinants of thrombosis. Of the 236 patients enrolled, 91 experienced post-intervention thrombotic events within 1 year. The 1-year thrombosis-free patency was 28% for thrombosed accesses, 53% for non-thrombosed grafts, and 78% for non-thrombosed fistulas. Forty-one of the 91 thrombotic events (45%) occurred within 3 months post-intervention. In the univariate analysis, early thrombosis was associated with longer haemodialysis duration (hazard ratio [HR], 1.01; 95% confidence interval [CI], 1.01-1.02), graft access (HR, 7.69; 95% CI, 3.33-20.0), multiple stenoses (HR, 2.69; 95% CI, 1.36-5.37), and high indoxyl sulphate (IS) levels (HR, 1.55; 95% CI, 1.32-1.82). Late thrombosis was associated with diabetes (HR, 1.89; 95% CI, 1.01-3.57), cardiovascular disease (HR, 2.38; 95% CI, 1.27-4.54), and endothelial progenitor cell counts (HR, 0.97; 95% CI, 0.93-0.99). After multivariate adjustment, high IS was the major predisposing factor for early post-intervention thrombosis (HR, 1.41; 95% CI, 1.18-1.69). Our findings suggest that measures to decrease IS could target the most critical period of thrombosis.


Assuntos
Angioplastia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Trombose/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Células Progenitoras Endoteliais/citologia , Feminino , Humanos , Indicã/sangue , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Diálise Renal/métodos , Trombose/sangue , Trombose/etiologia
9.
Toxins (Basel) ; 11(7)2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31266243

RESUMO

To better understand the kinetics of protein-bound uremic toxins (PBUTs) during hemodialysis (HD), we investigated the distribution of hippuric acid (HA), indole-3-acetic acid (IAA), indoxyl sulfate (IS), and p-cresyl sulfate (pCS) in erythrocytes of HD patients. Their transport across the erythrocyte membrane was explored in the absence of plasma proteins in vitro in a series of loading and unloading experiments of erythrocytes from healthy subjects and HD patients, respectively. Furthermore, the impact of three inhibitors of active transport proteins in erythrocytes was studied. The four PBUTs accumulated in erythrocytes from HD patients. From loading and unloading experiments, it was found that (i) the rate of transport was dependent on the studied PBUT and increased in the following sequence: HA < IS < pCS < IAA and (ii) the solute partition of intra- to extra-cellular concentrations was uneven at equilibrium. Finally, inhibiting especially Band 3 proteins affected the transport of HA (both in loading and unloading), and of IS and pCS (loading). By exploring erythrocyte transmembrane transport of PBUTs, their kinetics can be better understood, and new strategies to improve their dialytic removal can be developed.


Assuntos
Cresóis/sangue , Eritrócitos/metabolismo , Hipuratos/sangue , Indicã/sangue , Ácidos Indolacéticos/sangue , Ésteres do Ácido Sulfúrico/sangue , Uremia , Transporte Biológico , Humanos , Ligação Proteica , Diálise Renal , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/terapia
10.
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
11.
Life Sci ; 231: 116570, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31207307

RESUMO

AIMS: Systemic inflammation is a main hallmark of chronic kidney disease (CKD), but the underlying mechanisms of pathogenesis of CKD-associated systemic inflammation is unclear. Current study was designed to investigate the relationship between indoxyl sulphate (IS) and CKD-associated systemic inflammation along with the protective effects of Klotho in CKD. METHODS: IS serum levels from patients were detected by high-performance liquid chromatography (HPLC), and Serum Klotho, IL-6 and TNF-α were measured separately by ELISA and Real-Time PCR analysis. Monocytes were incubated with or without Klotho, while the expressions of retinoic acid-inducible gene I (RIG-I) and NF-κB were analyzed through Western blot assay. Heterozygous kl/kl (kl/+) mice or WT mice were treated with 5/6 renal damage. Thereafter, the CKD mice were intraperitoneally injected with recombinant Klotho protein or PBS. KEY FINDINGS: It shows that in 286 CKD patients, the serum levels of inflammatory factors were positively related with IS, but negatively related with Klotho. Klotho significantly inhibited IS-induced RIG-I/NF-κB activation and productions of both IL-6 and TNF-α in cultured monocytes. In vivo, along with the increase of IS and decrease of Klotho in the serum, the activation of RIG-I/NF-κB signaling was observed in peripheral blood monocytes in both CKD mice and patients. Notably, higher levels of IL-6 and TNF-α were detected in kl+/- mice given CKD. Klotho administration has evidently attenuated RIG-I/NF-κB activation in monocytes and systemic inflammation in CKD mice. SIGNIFICANCE: The findings suggest that Klotho can suppress CKD-associated systemic inflammation through inhibiting IS-induced RIG-1/NF-κB activation and monocyte inflammatory factor release.


Assuntos
Proteína DEAD-box 58/sangue , Glucuronidase/farmacologia , Indicã/sangue , Monócitos/metabolismo , NF-kappa B/sangue , Insuficiência Renal Crônica/sangue , Uremia/sangue , Adulto , Animais , Western Blotting , Feminino , Glucuronidase/sangue , Humanos , Inflamação/sangue , Inflamação/patologia , Interleucina-6/sangue , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Monócitos/patologia , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Células THP-1 , Fator de Necrose Tumoral alfa/sangue , Uremia/patologia
12.
Blood Purif ; 48(2): 183-190, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31039561

RESUMO

BACKGROUND/AIMS: To compare the serum concentration of Indoxyl sulfate (IS) in patients on continuous ambulatory peritoneal dialysis (CAPD) and low-flux hemodialysis (HD), and analyze the risk factors associated with IS. METHODS: We performed a single-center, cross-sectional observational study including 169 patients on CAPD and 115 patients on low-flux HD. Patients were divided into the anuric HD group, anuric peritoneal dialysis (PD) group, and non-anuric PD group on the basis of dialysis modality and residual urinary output. Serum concentration of IS was determined by high-performance liquid chromatography electrospray tandem mass spectrometry. RESULTS: After matching the urinary volume and dialysis vintage, 58 anuric patients on PD and 58 anuric patients on HD were enrolled. The serum level of IS was significantly lower in patients on PD than that in those on HD (28.05 ± 13.98 vs. 39.64 ± 18.25 µg/mL; p < 0.001). This result persisted even after adjustment for confounding risk factors including nutritional status (ß = 0.338, p < 0.001). In addition, the serum level of IS was significantly lower in non-anuric PD patients than that anuric PD patients (18.70 ± 11.21 vs. 28.05 ± 13.98 µg/mL; p < 0.001). After the adjustment for risk factors such as dialysis vintage, IS serum concentration in patients on PD was still significantly correlated with residual renal function (RRF; ß = -0.355, p < 0.001). CONCLUSIONS: Dialysis modality is the independent risk factor of IS serum concentration and it is substantially lower in patients on CAPD than that in those on low-flux HD. Additionally, RRF was independently associated with IS serum concentration in CAPD patients, and the better the RRF is, the lower IS serum concentration.


Assuntos
Indicã/sangue , Diálise Peritoneal , Diálise Renal , Insuficiência Renal Crônica/sangue , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Peritoneal/efeitos adversos , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/terapia
13.
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
14.
J Formos Med Assoc ; 118(7): 1099-1106, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30928187

RESUMO

BACKGROUND/PURPOSE: Indoxyl sulfate (IS) is a protein-binding molecule that exhibits cardiovascular (CV) toxicity. This study determined whether the serum IS level can be used to predict the risk of major adverse CV events (MACEs) in patients with chronic kidney disease (CKD). METHODS: We studied 147 patients with CKD stage 1-5 over a 3-year follow-up period. IS was measured through mass spectrometry. Patients' demographics were collected and analyzed to predict outcomes by using multivariable Cox regression. RESULTS: Forty-seven (32.0%) patients had MACEs. IS remained significantly associated with MACEs after multivariable regression analysis. The area under the receiver operating characteristic curve for IS levels was 0.708 (95% confidence interval: 0.618-0.798). CONCLUSION: IS may have a critical role in the prediction of CV disease in patients with CKD. Further large-scale investigations are warranted and suggested.


Assuntos
Doenças Cardiovasculares/diagnóstico , Indicã/sangue , Insuficiência Renal Crônica/sangue , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/complicações , Progressão da Doença , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Análise Multivariada , Curva ROC , Insuficiência Renal Crônica/complicações , Taiwan , Centros de Atenção Terciária
15.
J Food Drug Anal ; 27(2): 502-509, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30987721

RESUMO

Chronic kidney disease (CKD) is a complex disorder that affects multiple organs and increases the risk of cardiovascular complications. CKD affects approximately 12% of the population in Taiwan. Loss of kidney function leads to accumulation of potentially toxic compounds such as indoxyl sulfate (IS) and p-cresyl sulfate (pCS), two protein-bound uremic solutes that can stimulate the progression of CKD. The aim of this study was to assess whether IS and pCS levels were correlated with CKD stage. We developed and validated a method for quantitating total and free IS and pCS in serum by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Serum samples were pretreated using protein precipitation with acetonitrile containing stable isotope-labeled IS and pCS as internal standards. After centrifugation, the supernatant was diluted and injected into a UPLC-MS/MS system. Analyte concentrations were calculated from the calibration curve and ion ratios between the analyte and the internal standard. The calibration curves were linear with a correlation coefficient of >0.999; the analytical measurement range was 0.05-5 mg/L. The limit of quantitation of this assay was 0.05 mg/L for both analytes. The reference interval was ≤0.05-1.15 mg/L for total-form IS, ≤0.05-5.33 mg/L for total-form pCS, ≤0.05 mg/L for free-form IS, and ≤0.12 mg/L for free-form pCS. A positive correlation was observed between analyte concentration and CKD stage. Our sensitive UPLC-MS/MS method for quantifying total and free-form IS and pCS in serum can be used to monitor the progression of CKD in clinical settings, identify patients at risk, and facilitate development of further therapies for this devastating disease.


Assuntos
Cresóis/sangue , Indicã/sangue , Insuficiência Renal Crônica/sangue , Ésteres do Ácido Sulfúrico/sangue , Adulto , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Testes de Função Renal , Masculino , Insuficiência Renal Crônica/diagnóstico , Espectrometria de Massas em Tandem , Adulto Jovem
16.
Ren Fail ; 41(1): 284-293, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31014150

RESUMO

OBJECTIVE: We investigate the mechanism of neutrophil/lymphocyte ratio (NLR) elevation, a useful prognostic marker in patients with cardiovascular diseases (CVDs). METHODS: In this clinical study, we retrospectively searched for factors associated with NLR elevation in cardiovascular outpatients. In animal experiments using mice with adenine-induced nephropathy, we further examined the hematopoietic process in bone marrow and explored the mechanism of NLR elevation. RESULT: In patients with CVDs or their risk factors, multiple regression analysis revealed that decrease in estimated glemerular filtration rate and increase in white blood cell count were significantly associated with increase in NLR. In mice with adenine-induced nephropathy, NLR and serum indoxyl sulfate (IS) levels were increased. Fluorescence-activated cell sorting revealed the increase in the number of myeloid progenitors and decrease in the number of common lymphoid progenitors, suggesting biased granulocyte side in the hematopoietic process in bone marrow. Treatment with oral charcoal adsorbent AST-120 decreased serum concentration of IS and normalized NLR and bone marrow abnormalities in mice with adenine-induced nephropathy. CONCLUSION: Renal function was a strong determinant of NLR in cardiovascular outpatients. NLR elevation due to renal impairment is caused by distortion of the hematopoietic process in bone marrow. IS plays a significant role in these processes.


Assuntos
Doenças Cardiovasculares/etiologia , Nefropatias/complicações , Linfócitos , Neutrófilos , Adenina/toxicidade , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores/sangue , Medula Óssea/patologia , Carbono/farmacologia , Carbono/uso terapêutico , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/prevenção & controle , Modelos Animais de Doenças , Feminino , Taxa de Filtração Glomerular , Hematopoese/efeitos dos fármacos , Hematopoese/fisiologia , Humanos , Indicã/sangue , Indicã/metabolismo , Nefropatias/sangue , Nefropatias/induzido quimicamente , Nefropatias/fisiopatologia , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Óxidos/farmacologia , Óxidos/uso terapêutico , Prognóstico , Estudos Retrospectivos , Fatores de Risco
17.
Cardiovasc Drugs Ther ; 33(3): 277-286, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30903544

RESUMO

PURPOSE: Several lines of evidence suggest that renal dysfunction is associated with cardiovascular toxicity through the action of uremic toxins. The levels of those uremic toxins can be reportedly reduced by the spherical carbon adsorbent AST-120. Because heart failure (HF) causes renal dysfunction by low cardiac output and renal edema, the removal of uremic toxins could be cardioprotective. METHOD: To determine whether blood levels of the uremic toxin indoxyl sulfate (IS) increase in HF and whether AST-120 can reduce those levels and improve HF. We induced HF in 12 beagle dogs by 6 weeks of rapid right ventricular pacing at 230 beats per min. We treated six dogs with a 1-g/kg/day oral dosage of AST-120 for 14 days from week 4 after the start of rapid ventricular pacing. The other six dogs did not receive any treatment (control group). RESULTS: In the untreated dogs, IS levels increased as cardiac function deteriorated. In contrast, plasma IS levels in the treated dogs decreased to baseline levels, with both left ventricular fractional shortening and pulmonary capillary wedge pressure also improving when compared with untreated dogs. Finally, AST-120 treatment was shown to reduce both myocardial apoptosis and fibrosis along with decreases in extracellular signal-regulated kinase phosphorylation, the Bax/Bcl-2 ratio, and TGF-ß1 expression and increases in AKT phosphorylation. CONCLUSIONS: IS levels are increased in HF. AST-120 treatment reduces the levels of IS and improves the pathophysiology of HF in a canine model. AST-120 could be a novel candidate for the treatment of HF.


Assuntos
Carbono/administração & dosagem , Síndrome Cardiorrenal/terapia , Insuficiência Cardíaca/terapia , Indicã/sangue , Nefropatias/prevenção & controle , Óxidos/administração & dosagem , Desintoxicação por Sorção/métodos , Uremia/prevenção & controle , Adsorção , Animais , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Síndrome Cardiorrenal/sangue , Síndrome Cardiorrenal/fisiopatologia , Estado de Consciência , Modelos Animais de Doenças , Cães , Fibrose , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica , Nefropatias/sangue , Nefropatias/etiologia , Nefropatias/fisiopatologia , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Transdução de Sinais , Uremia/sangue , Uremia/etiologia , Uremia/fisiopatologia , Função Ventricular Esquerda
18.
Pharmacol Rep ; 71(2): 276-281, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30826567

RESUMO

BACKGROUND: Phenoconversion is a phenomenon whereby some genotypic extensive metabolizers transiently exhibit drug metabolizing enzyme activity at similar level as that of poor metabolizers. Renal failure is known to decrease CYP3A activity in humans. Indoxyl sulfate, parathyroid hormone (PTH), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) have been reported to cause CYP3A downregulation in renal failure. We measured plasma concentrations of the above compounds in stable kidney transplant recipients, and evaluated their relations with phenoconversion of CYP3A evaluated by plasma concentration of 4ß-hydroxycholesterol, a biomarker of CYP3A activity. Phenoconversion was defined as a genotypic extensive/intermediate metabolizer exhibiting CYP3A activity below the cutoff value that discriminates extensive/intermediate from poor metabolizers. METHODS: Sixty-three Japanese kidney transplant recipients who underwent transplantation more than 180 days prior to the study were included. Morning blood samples were collected, and CYP3A5 polymorphism as well as plasma concentrations of 4ß-hydroxycholesterol, indoxyl sulfate, intact-PTH, IL-6 and TNF-α were determined. RESULTS: Significantly higher plasma 4ß-hydroxycholesterol concentration was observed in recipients with CYP3A5*1 allele (n = 23) compared to those without the allele (n = 40), and the cut-off value was 40.0 ng/mL. Ten recipients with CYP3A5*1 allele exhibited CYP3A activity below 40.0 ng/mL (phenoconversion). Only plasma indoxyl sulfate concentration was significantly higher in recipients with CYP3A phenoconversion compared to those without phenoconversion. CONCLUSIONS: These findings suggest that higher plasma indoxyl sulfate concentration may be involved in CYP3A phenoconversion. Dose adjustment of drugs metabolized by CYP3A may be needed in patients with CYP3A5*1 allele and high blood indoxyl sulfate.


Assuntos
Citocromo P-450 CYP3A/genética , Hidroxicolesteróis/metabolismo , Indicã/sangue , Transplante de Rim , Adulto , Idoso , Alelos , Citocromo P-450 CYP3A/metabolismo , Feminino , Genótipo , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Polimorfismo Genético , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
19.
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
20.
J Vet Intern Med ; 33(2): 686-693, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30779214

RESUMO

BACKGROUND: Indoxyl sulfate (IS) has been reported not only to increase with the severity of impaired renal function, but also possibly to be a factor associated with bone abnormalities linked to fibroblast growth factor-23 (FGF-23) in humans with chronic kidney disease (CKD). It is not yet known whether this correlation between IS and FGF-23 holds true for cats with CKD. HYPOTHESIS: Accumulation of IS is related to FGF-23 secretion in cats with CKD. ANIMALS: Twenty clinically healthy cats and 73 cats with CKD cases were evaluated retrospectively. METHODS: The concentrations of IS and FGF-23 in plasma were determined by high-performance liquid chromatography and ELISA, respectively. Progression was defined as an increment of 0.5 mg/dL of serum creatinine concentration within 3 months. RESULTS: Plasma IS and FGF-23 concentrations were significantly increased concurrently with decreasing renal function. Higher concentration of FGF-23 was significantly associated with higher concentration of IS after adjusting for various confounding factors including creatinine and phosphate. Furthermore, the correlation between IS and phosphate was higher than that between FGF-23 and phosphate. When the renal progression group was compared with the non-progression group, both IS and FGF-23 were found to be significantly increased (P < .05). In addition, the area under receiver operator curve of the combination of IS and FGF-23 predicted renal progression at a level >0.9. CONCLUSIONS AND CLINICAL IMPORTANCE: Both FGF-23 and IS are associated with phosphate metabolism and CKD progression.


Assuntos
Doenças do Gato/sangue , Fatores de Crescimento de Fibroblastos/sangue , Indicã/sangue , Insuficiência Renal Crônica/veterinária , Animais , Estudos de Casos e Controles , Gatos , Cromatografia Líquida de Alta Pressão/veterinária , Progressão da Doença , Ensaio de Imunoadsorção Enzimática/veterinária , Feminino , Masculino , Insuficiência Renal Crônica/sangue , Estudos Retrospectivos , Índice de Gravidade de Doença
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...