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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.
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.
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
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.
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
6.
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
7.
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
8.
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
9.
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
10.
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
11.
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
12.
BMC Nephrol ; 20(1): 57, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30764800

RESUMO

BACKGROUND: Protein-bound uremic toxins are associated with poor outcomes in patients with chronic kidney disease. The aim of this study is to investigate the relationship between indoxyl sulfate (IS), a protein-bound solute, and 90-day mortality in patients with acute kidney injury. METHODS: Adults with hospital-acquired AKI (HA-AKI) were enrolled in this prospective cohort study between 2014 and 2015, according to the KDIGO creatinine criteria. The primary end point was all-cause death during follow-up. RESULTS: The mean serum IS level in patients with HA-AKI was 2.74 ± 0.75 µg/ml, which was higher than that in healthy subjects (1.73 ± 0.11 µg/ml, P < 0.001) and critically ill patients (2.46 ± 0.35 µg/ml, P = 0.016) but was lower than that in patients with chronic kidney disease (3.07 ± 0.31 µg/ml, P < 0.001). Furthermore, serum IS levels (2.83 ± 0.55 µg/ml) remained elevated in patients with HA-AKI on the seventh day after AKI diagnosis. Patients with HA-AKI were divided into the following two groups according to the median serum IS level: the low-IS group and the high-IS group. A total of 94 (35.9%) patient deaths occurred within 90 days, including 76 (29.0%) in the low-IS group and 112 (42.7%) in the high-IS group (P = 0.019). Kaplan-Meier analysis revealed that the two groups differed significantly with respect to 90-day survival (log-rank P = 0.007), and Cox regression analysis showed that an IS level ≥ 2.74 µg/ml was significantly associated with a 2.0-fold increased risk of death (adjusted hazard ratio [HR], 2.92; 95% confidence interval [CI], 1.76 to 4.86; P < 0.001) compared with an IS level < 2.74 µg/ml. CONCLUSIONS: Serum IS levels were significantly elevated in patients with HA-AKI compared to those in healthy subjects and critically ill patients and were associated with a worse prognosis of HA-AKI. TRIAL REGISTRATION: www.clinicaltrials.gov NCT 00953992. Registered 6 August 2009.


Assuntos
Lesão Renal Aguda , Estado Terminal , Indicã/sangue , Lesão Renal Aguda/sangue , Lesão Renal Aguda/diagnóstico , Lesão Renal Aguda/epidemiologia , Lesão Renal Aguda/etiologia , China/epidemiologia , Estado Terminal/mortalidade , Estado Terminal/terapia , Feminino , Mortalidade Hospitalar , Hospitalização/estatística & dados numéricos , Humanos , Testes de Função Renal/métodos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Diálise Renal/estatística & dados numéricos , Fatores de Risco
13.
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
14.
Int Urol Nephrol ; 51(3): 491-502, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30617956

RESUMO

PURPOSE: Indoxyl sulfate (IS) is one of the most potent uremic toxins involved in chronic kidney disease (CKD) progression, induction of inflammation, oxidative stress, and cardiovascular diseases occurrence. It is proved that hypertension is a common CVD complication and a major death risk factor as well as contributes for decline in a renal function. The aim of our study was to investigate how implementing of antihypertensive therapy impact IS concentrations and the associations between IS and markers of renal function, inflammation and oxidative stress. METHODS: Study was conducted on 50 patients diagnosed with CKD and hypertension, divided into three groups: without hypotensive therapy (CKD-NONE), hypotensive monotherapy (CKD-MONO), and hypotensive polypharmacotherapy (CKD-POLI), and 18 healthy volunteers. The markers of inflammation [interleukin-6, tumor necrosis factor-alpha (TNF-α), high-sensitive C-reactive protein (hs-CRP), neopterin, ferritin], oxidative status [superoxide dismutase (Cu/Zn-SOD), antibodies against oxidized low-density lipoprotein (oxLDL-abs)], and selectins were determinate using immunoenzymatic methods. IS levels were assayed using high-performance liquid chromatography and other parameters were analysed using routine laboratory techniques. Then cross-sectional analysis was performed. RESULTS: Elevated levels of IS, indicators of kidney function, markers of inflammation and blood pressure values were observed in each CKD subgroups. There was no effect of antihypertensive therapy on IS levels between studied groups, as well as there was no clear relationship between IS and blood pressure values in each studied group. The positive associations between IS and Cu/Zn SOD, neopterin, hs-CRP, creatinine and neutrophils/lymphocytes ratio were observed in CKD-NONE and CKD-POLI subgroups. Additionally, in CKD-POLI group IS positively correlated with TNF-α, ferritin and neutrophils. In CKD-MONO group, IS was positively related to oxLDL-abs, neopterin, E-selectin and creatinine, whereas it was inversely associated with hs-CRP. CONCLUSIONS: Our study showed for the first time that the antihypertensive therapy has no impact on IS levels in CKD patients with hypertension. However, the introduction of the antihypertensive therapy modified the dependencies between IS and the studied markers of kidney function, inflammation, oxidative stress and hematological parameters that are crucial for mortality and morbidity amongst the CKD patients with hypertension.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Indicã/sangue , Insuficiência Renal Crônica/sangue , Adulto , Idoso , Anticorpos/sangue , Anti-Hipertensivos/uso terapêutico , Biomarcadores/sangue , Pressão Sanguínea , Proteína C-Reativa/metabolismo , Creatinina/sangue , Quimioterapia Combinada , Selectina E/sangue , Feminino , Ferritinas/sangue , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Inflamação/sangue , Interleucina-6/sangue , Lipoproteínas LDL/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Neopterina/sangue , Neutrófilos , Estresse Oxidativo , Selectina-P/sangue , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Superóxido Dismutase-1/sangue , Fator de Necrose Tumoral alfa/sangue
15.
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
16.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(1): 113-119, 2019 Jan 30.
Artigo em Chinês | MEDLINE | ID: mdl-30692076

RESUMO

OBJECTIVE: To investigate the inhibitory effect of Zhenwu Decoction on ventricular hypertrophy in rats with uremic cardiomyopathy and explore the mechanism. METHODS: Cardiocytes isolated from suckling rats were divided into control group and indoxyl sulfate (IS) group, and the protein synthesis was assayed with [3H]- leucine incorporation and cellular protein expressions were detected using Western blotting. Fifty SD rats were randomly divided into sham operation group, model group, and low- and high-dose Zhenwu Decoction treatment groups, and except for those in the sham operation group, all the rats underwent 5/6 nephrectomy. Four weeks after the operation, the rats in low- and high-dose treatment groups were given Zhenwu Decoction via gavage at the dose of 4.5 g/kg and 13.5 g/kg, respectively; the rats in the sham-operated and model groups were given an equal volume of distilled water. After 4 weeks of treatment, serum levels of IS were determined, and cardiac and ventricular mass indexes were measured in the rats; cardiac ultrasound was performed and Western blotting was used to measure the expressions of BNP, p-ERK1/2, p-p38 and p-JNK in the myocardium. RESULTS: Rat cardiomyocytes treated with IS showed significantly enhanced protein synthesis and increased expression levels of BNP, p-erk1/2, and p-p38 as compared with the control cells (P < 0.01), but the expression of p-jnk was comparable between the two groups. In the animal experiment, the rats in the model group showed significantly increased serum creatinine (SCr) and urea nitrogen (BUN) levels, 24-h urine protein (24 hUpro), plasma IS level, left ventricular mass index (LVMI) and whole heart mass index (HMI) compared with those in the sham group (P < 0.01); Both LVESD and LVEDD were significantly reduced and LVAWS, LVAWD, LVPWS and LVPWD were significantly increased in the model rat, which also presented with obvious cardiomyocyte hypertrophy and increased myocardial expressions of BNP, p-ERK1/2, p-p38 and p-jnk (P < 0.01). Compared with the rats in the model group, the rats treated with low-dose and high-dose Zhenwu Decoction had significantly lowered levels of SCr, BUN, 24 hUpro and IS (P < 0.05) and decreased LVMI and HMI; LVESD, LVEDD, LVPWS, LVAWS, and LVAWD were improved more obviously in the high-dose group, and the myocardial expressions of BNP, p-ERK1/2, p-p38 and p-JNK was significantly downregulated after the treatment. CONCLUSIONS: Zhenwu Decoctin can reduce plasma IS levels and inhibit ventricular hypertrophy to delay ventricular remodeling in rats with uremic cardiomyopathy.


Assuntos
Cardiomegalia/prevenção & controle , Cardiomiopatias/complicações , Medicamentos de Ervas Chinesas/farmacologia , Ventrículos do Coração , Indicã/sangue , Miócitos Cardíacos/efeitos dos fármacos , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Indicã/farmacologia , Miócitos Cardíacos/metabolismo , Nefrectomia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
17.
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
18.
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
19.
Clin Exp Nephrol ; 23(2): 151-157, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29869756

RESUMO

Uremic toxins are linked to chronic kidney disease (CKD)-related systemic diseases. ß2-Microglobulin (ß2-m), a water-soluble, middle-sized molecule, is associated with mortality and dialysis-related amyloidosis (DRA). DRA occurs in long-term dialysis patients, with ß2-m amyloid deposited mainly in osteoarticular tissues. We investigated a model of ß2-m amyloid fibril extension at neutral pH in the presence of trifluoroethanol or sodium dodecyl sulfate. Using this model, some biological molecules, including glycosaminoglycans and lysophospholipids, were found to be chaperones for ß2-m amyloid fibril extension. Several protein-bound solutes, such as indoxyl sulfate (IS) and p-cresyl sulfate, are independent risk factors for cardiovascular disease in CKD patients, especially those undergoing dialysis. We investigated kidney injury-induced acceleration of atherosclerosis in association with macrophage phenotypic change to a proinflammatory state as well as increased IS deposition in lesions in an animal model. IS directly induced macrophage inflammation and impaired cholesterol efflux to high-density lipoprotein (HDL) in vitro. In addition, a clinical study showed that HDL isolated from CKD patients induced proinflammatory reactions and impaired cholesterol efflux to macrophages. These findings suggest that protein-bound solutes, including IS, will induce dysfunction of both macrophages and HDL in atherosclerotic lesions. To remove uremic toxins efficiently, we demonstrated the potential efficacy of oral charcoal adsorbent and hexadecyl-immobilized cellulose beads in hemodialysis patients. These findings suggest that uremic toxins induce various CKD-related systemic disorders, and further therapeutic strategies will be needed to reduce uremic toxins enough and improve life expectancy in CKD patients.


Assuntos
Amiloidose/etiologia , Aterosclerose/etiologia , Indicã/sangue , Insuficiência Renal Crônica/complicações , Uremia/sangue , Uremia/complicações , Microglobulina beta-2/sangue , Amiloidose/sangue , Amiloidose/diagnóstico , Amiloidose/terapia , Animais , Aterosclerose/sangue , Aterosclerose/diagnóstico , Aterosclerose/terapia , Distinções e Prêmios , Humanos , Lipoproteínas HDL/sangue , Macrófagos/metabolismo , Prognóstico , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/terapia , Fatores de Risco , Uremia/diagnóstico , Uremia/terapia
20.
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
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