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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.
Clin Exp Nephrol ; 23(11): 1315-1322, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31423549

RESUMO

BACKGROUND: Hemodialysis (HD) sessions induce changes in plasma electrolytes that lead to modifications of QT interval, virtually associated with dangerous arrhythmias. It is not known whether such a phenomenon occurs even during peritoneal dialysis (PD). The aim of the study is to analyze the relationship between dialysate and plasma electrolyte modifications and QT interval during a PD exchange. METHODS: In 15 patients, two manual PD 4-h exchanges were performed, using two isotonic solutions with different calcium concentration (Ca++1.25 and Ca1.75++ mmol/L). Dialysate and plasma electrolyte concentration and QT interval (ECG Holter recording) were monitored hourly. A computational model simulating the ventricular action potential during the exchange was also performed. RESULTS: Dialysis exchange induced a significant plasma alkalizing effect (p < 0.001). Plasma K+ significantly decreased at the third hour (p < 0.05). Plasma Na+ significantly decreased (p < 0.001), while plasma Ca++ slightly increased only when using the Ca 1.75++ mmol/L solution (p < 0.01). The PD exchange did not induce modifications of clinical relevance in the QT interval, while a significant decrease in heart rate (p < 0.001) was observed. The changes in plasma K+ values were significantly inversely correlated to QT interval modifications (p < 0.001), indicating that even small decreases of K+ were consistently paralleled by small QT prolongations. These results were perfectly confirmed by the computational model. CONCLUSIONS: The PD exchange guarantees a greater cardiac electrical stability compared to the HD session and should be preferred in patients with a higher arrhythmic risk. Moreover, our study shows that ventricular repolarization is extremely sensitive to plasma K+ changes, also in normal range.


Assuntos
Eletrólitos/sangue , Falência Renal Crônica/sangue , Falência Renal Crônica/terapia , Diálise Peritoneal , Uremia/terapia , Idoso , Idoso de 80 Anos ou mais , Cálcio/análise , Cálcio/sangue , Simulação por Computador , Soluções para Diálise/química , Eletrocardiografia Ambulatorial , Feminino , Frequência Cardíaca , Humanos , Soluções Isotônicas/química , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Potássio/sangue , Sódio/sangue , Uremia/sangue , Uremia/etiologia
3.
J Card Surg ; 34(10): 1137-1139, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31389631

RESUMO

Calcific uremic arteriolopathy is a rare, life-threatening syndrome of vascular calcification characterized by occlusion of microvessels that results in extremely painful skin necrosis. We present a case of sarcoidosis-associated hypercalcemia potentiating calcific uremic arteriolopathy in a patient with a left ventricular assist device. The patient's calcific uremic arteriolopathy was successfully treated with sodium thiosulfate. Clinicians should be vigilant in diagnosing calcific uremic arteriolopathy early since it is especially life-threatening in patients with multiple risk factors.


Assuntos
Cálcio/sangue , Coração Auxiliar , Hipercalcemia/complicações , Sarcoidose/complicações , Uremia/complicações , Calcificação Vascular/etiologia , Doenças Vasculares/etiologia , Cardiomiopatias/complicações , Cardiomiopatias/cirurgia , Humanos , Hipercalcemia/sangue , Masculino , Pessoa de Meia-Idade , Sarcoidose/sangue , Uremia/sangue , Uremia/diagnóstico , Calcificação Vascular/sangue , Calcificação Vascular/diagnóstico , Doenças Vasculares/sangue , Doenças Vasculares/diagnóstico
4.
Inflammation ; 42(6): 2003-2010, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31312972

RESUMO

Inflammation and cardiovascular disease (CVD) are common in end-stage renal disease (ESRD) patients whose vascular endothelium is in direct contact with the uremic toxins found in the blood. These toxins are believed to affect vascular injury and repair process, which is impaired in ESRD patients. The exact mechanisms behind these interactions are not clear. So, we wanted to investigate what happens at the molecular level of endothelial cells when exposed to uremic serum from ESRD patients with diabetes and/or hypertension and its effect on the expression of molecules associated with vascular injury and repair. Cultured human endothelial cells (ECV304) were incubated in the presence of normal or uremic sera from ESRD patients with diabetes and/or hypertension. The expressions of monocyte chemoattractant protein 1 (MCP-1), vascular endothelial growth factor (VEGF), and stromal cell-derived factor 1 (SDF-1) were investigated in endothelial cells (ECV304) by real-time PCR and ELISA. The expression of MCP-1, VEGF, and SDF-1 was elevated in endothelial cells upon exposure to uremic sera from ESRD patients with diabetes and/or hypertension when compared with cells treated with healthy serum. MCP-1 expression in endothelial cells treated with uremic serum from ESRD patients with hypertension only was significantly increased compared with its expression in other cohorts. Exposure of endothelial cells to uremic serum causes endothelial injury and inflammation characterized by an increase in MCP-1 expression. This injury activates the initiation of vascular repair process in these cells by increasing the expression of VEGF and SDF-1. These molecules can be important biomarkers of chronic kidney disease-associated CVD.


Assuntos
Células Endoteliais/patologia , Inflamação/induzido quimicamente , Uremia/sangue , Células Cultivadas , Quimiocina CCL2/metabolismo , Quimiocina CXCL12/metabolismo , Diabetes Mellitus , Endotélio Vascular/metabolismo , Humanos , Hipertensão , Falência Renal Crônica/complicações , Soro , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
Pflugers Arch ; 471(8): 1079-1094, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31236663

RESUMO

Activin A is a new fascinating player in chronic kidney disease-mineral and bone disorder (CKD-MBD), which is implicated in progressive renal disease, vascular calcification, and osteodystrophy. Plasma activin A rises early in the progression of renal disease. Disruption of circadian rhythms is related to increased risk of several diseases and circadian rhythms are observed in mineral homeostasis, bone parameters, and plasma levels of phosphate and PTH. Therefore, we examined the circadian rhythm of activin A and CKD-MBD-related parameters (phosphate, PTH, FGF23, and klotho) in healthy controls and CKD rats (5/6 nephrectomy) on high-, standard- and low-dietary phosphate contents as well as during fasting conditions. Plasma activin A exhibited circadian rhythmicity in healthy control rats with fourfold higher values at acrophase compared with nadir. The rhythm was obliterated in CKD. Activin A was higher in CKD rats compared with controls when measured at daytime but not significantly when measured at evening/nighttime, stressing the importance of time-specific reference intervals when interpreting plasma values. Plasma phosphate, PTH, and FGF23 all showed circadian rhythms in control rats, which were abolished or disrupted in CKD. Plasma klotho did not show circadian rhythm. Thus, the present investigation shows, for the first time, circadian rhythm of plasma activin A. The rhythmicity is severely disturbed by CKD and is associated with disturbed rhythms of phosphate and phosphate-regulating hormones PTH and FGF23, indicating that disturbed circadian rhythmicity is an important feature of CKD-MBD.


Assuntos
Ativinas/sangue , Doenças Ósseas Metabólicas/sangue , Ritmo Circadiano , Fosfatos/sangue , Insuficiência Renal Crônica/sangue , Uremia/sangue , Animais , Doenças Ósseas Metabólicas/etiologia , Fatores de Crescimento de Fibroblastos/sangue , Glucuronidase/sangue , Masculino , Hormônio Paratireóideo/sangue , Ratos , Ratos Wistar , Insuficiência Renal Crônica/complicações , Uremia/etiologia
6.
Int J Mol Sci ; 20(12)2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31242575

RESUMO

Elucidation of molecular and cellular mechanisms of the uremic syndrome is a very challenging task. More than 130 substances are now considered to be "uremic toxins" and represent a very diverse group of molecules. The toxicity of these molecules affects many cellular processes, and expectably, some of them are able to disrupt mitochondrial functioning. However, mitochondria can be the source of uremic toxins as well, as the mitochondrion can be the site of complete synthesis of the toxin, whereas in some scenarios only some enzymes of the pathway of toxin synthesis are localized here. In this review, we discuss the role of mitochondria as both the target and source of pathological processes and toxic compounds during uremia. Our analysis revealed about 30 toxins closely related to mitochondria. Moreover, since mitochondria are key regulators of cellular redox homeostasis, their functioning might directly affect the production of uremic toxins, especially those that are products of oxidation or peroxidation of cellular components, such as aldehydes, advanced glycation end-products, advanced lipoxidation end-products, and reactive carbonyl species. Additionally, as a number of metabolic products can be degraded in the mitochondria, mitochondrial dysfunction would therefore be expected to cause accumulation of such toxins in the organism. Alternatively, many uremic toxins (both made with the participation of mitochondria, and originated from other sources including exogenous) are damaging to mitochondrial components, especially respiratory complexes. As a result, a positive feedback loop emerges, leading to the amplification of the accumulation of uremic solutes. Therefore, uremia leads to the appearance of mitochondria-damaging compounds, and consecutive mitochondrial damage causes a further rise of uremic toxins, whose synthesis is associated with mitochondria. All this makes mitochondrion an important player in the pathogenesis of uremia and draws attention to the possibility of reducing the pathological consequences of uremia by protecting mitochondria and reducing their role in the production of uremic toxins.


Assuntos
Mitocôndrias/metabolismo , Ureia/metabolismo , Uremia/metabolismo , Lesão Renal Aguda/complicações , Lesão Renal Aguda/metabolismo , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Humanos , Mitocôndrias/efeitos dos fármacos , Terapia de Alvo Molecular , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Toxinas Biológicas/metabolismo , Toxinas Biológicas/toxicidade , Ureia/toxicidade , Uremia/sangue , Uremia/tratamento farmacológico , Uremia/etiologia
7.
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
8.
Am J Physiol Renal Physiol ; 317(2): F296-F302, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141401

RESUMO

The accumulation of uremic solutes in kidney failure may impair mental function. The present study profiled the accumulation of uremic solutes in the cerebrospinal fluid (CSF) in acute renal failure. CSF and plasma ultrafiltrate were obtained from rats at 48 h after sham operation (control; n = 10) or bilateral nephrectomy (n = 10) and analyzed using an established metabolomic platform. Two hundred forty-eight solutes were identified as uremic based on their accumulation in the plasma ultrafiltrate of nephrectomized compared with control rats. CSF levels of 124 of these solutes were sufficient to allow calculation of CSF-to-plasma ultrafiltrate concentration ratios. Levels of many of the uremic solutes were normally lower in the CSF than in the plasma ultrafiltrate, indicating exclusion of these solutes from the brain. CSF levels of the great majority of the uremic solutes increased in renal failure. The increase in the CSF was, however, relatively less than in the plasma ultrafiltrate for most solutes. In particular, for the 31 uremic solutes with CSF-to-plasma ultrafiltrate ratios of <0.25 in control rats, the average CSF-to-plasma ultrafiltrate ratio decreased from 0.13 ± 0.07 in control rats to 0.09 ± 0.06 in nephrectomized rats, revealing sustained ability to exclude these solutes from the brain. In summary, levels of many uremic solutes are normally kept lower in the CSF than in the plasma ultrafiltrate by the action of the blood-brain and blood-CSF barriers. These barriers remain functional but cannot prevent accumulation of uremic solutes in the CSF when the kidneys fail.


Assuntos
Lesão Renal Aguda/líquido cefalorraquidiano , Encefalopatias/líquido cefalorraquidiano , Uremia/líquido cefalorraquidiano , Lesão Renal Aguda/sangue , Lesão Renal Aguda/complicações , Lesão Renal Aguda/fisiopatologia , Animais , Biomarcadores/sangue , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiopatologia , Encefalopatias/sangue , Encefalopatias/etiologia , Encefalopatias/fisiopatologia , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Progressão da Doença , Rim/metabolismo , Rim/fisiopatologia , Masculino , Metabolômica/métodos , Nefrectomia , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Uremia/sangue , Uremia/etiologia , Uremia/fisiopatologia
9.
Oxid Med Cell Longev ; 2019: 8219283, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31089418

RESUMO

Chronic kidney disease (CKD) is accompanied by a disturbed redox homeostasis, especially in end-stage patients, which is associated with pathological complications such as anemia, atherosclerosis, and muscle atrophy. However, limited evidence exists about redox disturbances before the end stage of CKD. Moreover, the available redox literature has not yet provided clear associations between circulating and tissue-specific (muscle) oxidative stress levels. The aim of the study was to evaluate commonly used redox status indices in the blood and in two different types of skeletal muscle (psoas, soleus) in the predialysis stages of CKD, using an animal model of renal insufficiency, and to investigate whether blood redox status indices could be reflecting the skeletal muscle redox status. Indices evaluated included reduced glutathione (GSH), oxidized glutathione (GSSG), glutathione reductase (GR), catalase (CAT), total antioxidant capacity (TAC), protein carbonyls (PC), and thiobarbituric acid reactive substances (TBARS). Results showed that blood GSH was higher in the uremic group compared to the control (17.50 ± 1.73 vs. 12.43 ± 1.01, p = 0.033). In both muscle types, PC levels were higher in the uremic group compared to the control (psoas: 1.086 ± 0.294 vs. 0.596 ± 0.372, soleus: 2.52 ± 0.29 vs. 0.929 ± 0.41, p < 0.05). The soleus had higher levels of TBARS, PC, GSH, CAT, and GR and lower TAC compared to the psoas in both groups. No significant correlations in redox status indices between the blood and skeletal muscles were found. However, in the uremic group, significant correlations between the psoas and soleus muscles in PC, GSSG, and CAT levels emerged, not present in the control. Even in the early stages of CKD, a disturbance in redox homeostasis was observed, which seemed to be muscle type-specific, while blood levels of redox indices did not seem to reflect the intramuscular condition. The above results highlight the need for further research in order to identify the key mechanisms driving the onset and progression of oxidative stress and its detrimental effects on CKD patients.


Assuntos
Músculo Esquelético/metabolismo , Insuficiência Renal/sangue , Insuficiência Renal/metabolismo , Animais , Catalase/metabolismo , Modelos Animais de Doenças , Feminino , Dissulfeto de Glutationa/metabolismo , Oxirredução , Carbonilação Proteica , Coelhos , Uremia/sangue
10.
Kidney Blood Press Res ; 44(2): 277-285, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30959503

RESUMO

BACKGROUND/AIMS: Thromboembolic episodes are a frequent problem in end stage renal failure patients. The pathomechanism of the disorder is complex, including bioincompatibility of renal replacement therapy, endothelial dysfunction, increased blood level of procoagulant factors and uremic toxins. We studied changes in the functional properties of venous endothelial cells (VEC) in the presence of uremic serum and evaluated their possible modulation by N-acetylcysteine (NAC) or sulodexide (SUL). METHODS: Serum samples from 12 uremic patients treated with hemodialysis were studied ex vivo on in vitro cultured VEC. In separate experiments, NAC 1 mmol/L or SUL 0.5 LRU/mL were added to uremic serum samples. Both changes in the gene expression and secretory activity of VEC were studied. RESULTS: Uremic serum increased the expression of the following genes: IL6 +97%, p < 0.002; VEGF +28%, p < 0.002; vWF +47%, p < 0.002; PECAM +76%, p < 0.002; ICAM-1 +275%, p < 0.002; t-PA +96%, p < 0.002. Changes in gene expression were reflected by the increased secretory activity of VEC treated with the uremic serum. Exposure of VEC to uremic serum supplemented with NAC or SUL resulted in weaker stimulation of the studied genes' expression. Also, secretion of the studied solutes, with the exception of ICAM-1, was reduced in the presence of NAC: IL6 -34%, p < 0.01; VEGF -40%, p < 0.005; vWF -25%, p < 0.001; t-PA -47%, p < 0.01, and MMP9 -37%, p < 0.001. SUL reduced the uremic serum-induced secretion of all solutes: IL6 -24%, p < 0.05; ICAM-1 -43%, p < 0.01; VEGF -38%, p < 0.01; vWF -23%, p < 0.01; t-PA -49%, p < 0.01, and MMP9 -25%, p < 0.05. CONCLUSIONS: Uremic serum induces prothrombotic changes in VEC, which may cause a predisposition to thrombotic disorders in patients with renal failure. NAC and SUL reduce the effects of the uremic serum in VEC, which suggests their potential therapeutic application in uremic patients.


Assuntos
Acetilcisteína/farmacologia , Endotélio Vascular/citologia , Glicosaminoglicanos/farmacologia , Falência Renal Crônica/tratamento farmacológico , Trombose/prevenção & controle , Uremia/sangue , Acetilcisteína/uso terapêutico , Anticoagulantes , Coleta de Amostras Sanguíneas , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Feminino , Depuradores de Radicais Livres , Glicosaminoglicanos/uso terapêutico , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Masculino , Uremia/tratamento farmacológico
11.
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
12.
Neurotoxicology ; 73: 85-91, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30826344

RESUMO

Patients receiving hemodialysis (HD) have a higher risk of cognitive impairment and dementia than the general population. The accumulation of uremic toxins in the brain causes uremic encephalopathy, however, limited data exists to elucidate the effect of protein-bound uremic toxins on cognitive function. Here we investigate the effect of indole-3 acetic acid (IAA) and hippuric acid (HA), two different protein-bound uremic toxins from amino acid derivatives, on cognitive function by Silico and in a clinical study. Prevalent HD patients were enrolled in two independent hospitals. Serum IAA and HA were measured using mass spectrometry. Cognitive performance was measured using Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Cognitive Abilities Screening Instrument (CASI) by trained psychologists. Using silico data to predict the effect of blood-brain barrier penetration was performed. The silico data demonstrated that IAA and HA had positive blood-brain barrier penetration ability. Amongst the 230 HD patients, serum IAA was associated with poor MMSE score (ß= -0.90, 95% CI -1.61 to -0.19) and poor CASI score (ß= -3.29, 95% CI -5.69 to -0.88) in stepwise multiple linear regression analysis. In logistic regression model, Serum IAA was also associated with cognitive impairment based on MMSE definition (OR, 1.96, 95% CI 1.10, 3.5) and CASI definition (OR, 2.09, 95% CI 1.21, 3.61). There was no correlation between Serum HA levels and cognitive function status. In conclusion, IAA, not HA, was associated with cognitive impairment in HD patients. Further large scale and prospective studies are needed to confirm our findings.


Assuntos
Encéfalo/metabolismo , Cognição , Disfunção Cognitiva/etiologia , Ácidos Indolacéticos/sangue , Falência Renal Crônica/terapia , Diálise Renal , Uremia/terapia , Idoso , Biomarcadores/sangue , Barreira Hematoencefálica/metabolismo , Permeabilidade Capilar , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Feminino , Hipuratos/sangue , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/diagnóstico , Masculino , Pessoa de Meia-Idade , Diálise Renal/efeitos adversos , Medição de Risco , Fatores de Risco , Taiwan , Resultado do Tratamento , Uremia/sangue , Uremia/complicações , Uremia/diagnóstico
13.
J Immunol ; 202(8): 2372-2383, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30833349

RESUMO

Decreased inflammation and cardiovascular mortality are evident in patients with end-stage chronic kidney disease treated by online hemodiafiltration. Extracellular vesicles (EV) are mediators of cell-to-cell communication and contain different RNA types. This study investigated whether mixed online hemodiafiltration (mOL-HDF) beneficial effects associate with changes in the RNA content of plasma EV in chronic kidney disease patients. Thirty bicarbonate hemodialysis (BHD) patients were randomized 1:1 to continue BHD or switch to mOL-HDF. Concentration, size, and microRNA content of plasma EV were evaluated for 9 mo; we then studied EV effects on inflammation, angiogenesis, and apoptosis of endothelial cells (HUVEC) and on osteoblast mineralization of vascular smooth muscle cells (VSMC). mOL-HDF treatment reduced different inflammatory markers, including circulating CRP, IL-6, and NGAL. All hemodialysis patients showed higher plasma levels of endothelial-derived EV than healthy subjects, with no significant differences between BHD and mOL-HDF. However, BHD-derived EV had an increased expression of the proatherogenic miR-223 with respect to healthy subjects or mOL-HDF. Compared with EV from healthy subjects, those from hemodialysis patients reduced angiogenesis and increased HUVEC apoptosis and VSMC calcification; however, all these detrimental effects were reduced with mOL-HDF with respect to BHD. Cell transfection with miR-223 mimic or antagomiR proved the role of this microRNA in EV-induced HUVEC and VSMC dysfunction. The switch from BHD to mOL-HDF significantly reduced systemic inflammation and miR-223 expression in plasma EV, thus improving HUVEC angiogenesis and reducing VSMC calcification.


Assuntos
Endotélio Vascular/imunologia , Vesículas Extracelulares , Regulação da Expressão Gênica/imunologia , Hemodiafiltração , MicroRNAs , Insuficiência Renal Crônica , Uremia , Calcificação Vascular , Adulto , Idoso , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Vesículas Extracelulares/imunologia , Vesículas Extracelulares/metabolismo , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/sangue , Inflamação/imunologia , Inflamação/patologia , Inflamação/terapia , Masculino , MicroRNAs/sangue , MicroRNAs/imunologia , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/terapia , Uremia/sangue , Uremia/imunologia , Uremia/patologia , Uremia/terapia , Calcificação Vascular/sangue , Calcificação Vascular/imunologia , Calcificação Vascular/patologia , Calcificação Vascular/terapia
14.
Blood Purif ; 48(2): 142-149, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30726841

RESUMO

BACKGROUND/AIMS: Uremic patients experience premature vascular ageing that causes cardiovascular morbidity. In this study, we investigated the relationship between uremic serum calcific potential induced by high phosphate (Pi) and vascular calcification score (VCS). METHODS: Vascular smooth muscle cells (VSMCs) were cultured with 3.5 mM Na3PO4 (Pi) with 10% uremic serum and calcium deposition, markers of osteoblastic transformation, and apoptosis were evaluated. RESULTS: Culture with uremic serum and high-Pi significantly induced calcification (0.21 ± 0.03 vs. 8.05 ± 0.6; ctr vs. Pi; OD/mg protein; p < 0.01). We next stratified patients with respect of the degree of VCS in 2 groups: absence of vascular calcification (VC) "no VC group" and presence of VC "VC group". We found that there was a significant correlation between VCS and uremic serum calcific potential induced by high Pi in vitro (p < 0.01). Interestingly, uremic sera of the "VC group" were more effective than sera from the "no VC group", in downregulating α-actin and SM22α, after treatment with high-Pi (41.3 ± 4.7 vs. 23.3 ± 2.9 and 25.6 ± 6.8 vs. 8.14 ± 2.3; VC vs. no VC group, α-actin and SM22α respectively; Δ intensity area; p < 0.01). Similarly, sera from "VC group" were more effective than sera from "no VC group" in adjuvanting the high-Pi effect of increasing osteoblastic markers, such as bone morphogenic protein 2 (BMP2), osteocalcin (OC), and runt-related transcription factor 2 (RUNX2; 39.1 ± 11.3 vs. 5.0 ± 2.6 BMP2; 12.2 ± 4.2 vs. 1.7 ± 0.3 OC; 2.9 ± 0.4 vs. 1.2 ± 0.2 RUNX2; VC vs. no VC group respectively; p < 0.05). We found a similar pattern with significantly higher apoptosis and necrosis induction by sera from the "VC group" compared to the "no VC group" (2.05 ± 0.33 vs. 1.29 ± 0.13 and 54.1 ± 19.5 vs. 27.4 ± 10.6; Pi; VC group vs. no VC group; enrichment factor of apoptotic or necrotic fragments, respectively; p < 0.05). CONCLUSIONS: We conclude that VCS of end-stage renal disease patients significantly correlates with serum-calcific potential induced by high Pi. In addition, uremic patients with higher VCS have sera with a higher potential to induce VSMC osteoblastic trans-differentiation, apoptosis, and necrosis.


Assuntos
Músculo Liso Vascular/patologia , Osteoblastos/patologia , Uremia/patologia , Calcificação Vascular/patologia , Idoso , Idoso de 80 Anos ou mais , Diferenciação Celular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Uremia/sangue , Uremia/complicações , Calcificação Vascular/sangue , Calcificação Vascular/complicações
17.
Food Res Int ; 116: 241-248, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30716942

RESUMO

Generation of uremic toxins p-cresylsulfate (p-CS), indoxyl sulfate (IS) and indole 3-acetic acid (IAA) in hemodialysis (HD) individuals may be associated with the gut flora and recognized markers of disease progression. This study investigated the effect of synbiotic meal on uremic toxins in HD individuals. We conducted randomized singleblind and placebo-controlled intervention study with 58 HD subjects (20F/38M, 63.1 ±â€¯10.9-old) who were randomly allocated in synbiotic group (SG, 40 g of extruded sorghum plus 100 mL of unfermented probiotic milk) or control group (CG, 40 g of extruded corn plus 100 mL of pasteurized milk), during 7-wk Metabolic markers and uremic toxins, fecal concentration of short chain fatty acid and pH value was determined. The SG group had decreased serum p-CS and IS, as well as decreased urea concentration (p < .05) compared to CG. SG showed higher fecal butyric acid and lower pH compared to baseline and SC (p < .05). In addition, serum p-CS and fecal pH were positively correlated to urea concentration in SG participants at the endpoint. The consumption of the synbiotic meal during 7-wk reduced colonic pH, and reduced serum uremic (p-CS and IS) toxins and urea in HD subjects.


Assuntos
Refeições , Diálise Renal , Simbióticos , Ureia/toxicidade , Uremia/sangue , Idoso , Bifidobacterium longum , Biomarcadores/sangue , Brasil , Cresóis , Feminino , Microbioma Gastrointestinal , Humanos , Concentração de Íons de Hidrogênio , Indicã , Ácidos Indolacéticos , Masculino , Pessoa de Meia-Idade , Probióticos/uso terapêutico , Insuficiência Renal Crônica , Ésteres do Ácido Sulfúrico , Ureia/sangue
18.
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
19.
Ren Fail ; 41(1): 47-56, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30732506

RESUMO

AST-120 (KREMEZIN®) consists of oral, spherical carbon particles that adsorb uremic toxins and their precursors within the gastrointestinal tract, allowing them to be excreted in the feces. Uremic toxins such as indoxyl sulfate and p-cresyl sulfate are abundant in the blood of chronic kidney disease (CKD) patients and are related to the progression of both CKD and cardiovascular disease. AST-120 was approved in Japan in 1991 followed by Korea (2004), Taiwan (2007) and the Philippines (2010) for treating uremic symptoms and prolonging the time to initiation of dialysis in patients with progressive CKD. In this review, we provide an overview of the past clinical data on AST-120 from 1982 to 2013. The effect of AST-120 for renal events was not supported in the primary analysis of randomized clinical trials. However, post-hoc analyses revealed significant differences between the AST-120 and control groups in the second Japanese phase III trial and in the multinational Evaluating Prevention of Progression in CKD (EPPIC) trials. Furthermore, inhibitory effects on the progression of CKD, as represented by amelioration in the estimated glomerular filtration rate (eGFR) decline and serum creatinine (sCr) elevation were suggested. These results suggest that AST-120 delays the decline in renal function. In addition, AST-120 may prolong the time to the initiation of dialysis, especially in patients with progressive CKD. For further verification of the clinical efficacy of AST-120, future study inclusion criteria should be determined carefully, defining progressive CKD using markers such as declines in eGFR and sCr elevation.


Assuntos
Carbono/uso terapêutico , Óxidos/uso terapêutico , Insuficiência Renal Crônica/terapia , Sequestrantes/uso terapêutico , Toxinas Biológicas/toxicidade , Uremia/terapia , Adsorção , Biomarcadores/análise , Carbono/farmacologia , Creatinina/sangue , Progressão da Doença , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Absorção Intestinal/efeitos dos fármacos , Rim/fisiopatologia , Óxidos/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Diálise Renal , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Sequestrantes/farmacologia , Fatores de Tempo , Toxinas Biológicas/química , Resultado do Tratamento , Uremia/sangue , Uremia/fisiopatologia
20.
J Am Heart Assoc ; 8(2): e010805, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30646802

RESUMO

Background Micro RNA -125b (miR-125b) has been shown to regulate vascular calcification ( VC ), and serum miR-125b levels are a potential biomarker for estimating the risk of uremic VC status. However, it is unknown whether clinical features, including chronic kidney disease-mineral bone disorder molecules, affect serum miR-125b levels. Methods and Results Patients receiving chronic dialysis for ≥3 months were recruited from different institutes. Serum miR-125b and chronic kidney disease-mineral bone disorder effectors, including intact parathyroid hormone, 25- OH -D, fibroblast growth factor-23, osteoprotegerin, and fetuin-A, were quantified. We used multivariate regression analyses to identify factors associated with low serum miR-125b levels and an area under receiver operating characteristic curve curve to derive optimal cutoffs for factors exhibiting close associations. Further regression analyses evaluated the influence of miR-125b on VC risk. Among 223 patients receiving chronic dialysis (mean age, 67.3 years; mean years of dialysis, 5.2), 54 (24.2%) had high serum miR-125b levels. Osteoprotegerin ( P=0.013), fibroblast growth factor-23 ( P=0.006), and fetuin-A ( P=0.036) were linearly associated with serum miR-125b levels. High osteoprotegerin levels independently correlated with high serum miR-125 levels. Adding serum miR-125b levels and serum osteoprotegerin levels (≥400 pg/mL) into models estimating the risk of uremic VC increased the area under receiver operating characteristic curve values (for models without miR-125b/osteoprotegerin, with miR-125b, and both: 0.74, 0.79, and 0.81, respectively). Conclusions Serum osteoprotegerin levels ≥400 pg/mL and serum miR-125b levels synergistically increased the accuracy of estimating VC risk among patients receiving chronic dialysis. Taking miR-125b and osteoprotegerin levels into consideration when estimating VC risk may be recommended.


Assuntos
Falência Renal Crônica/sangue , MicroRNAs/sangue , Uremia/complicações , Calcificação Vascular/sangue , Idoso , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Masculino , Osteoprotegerina/sangue , Estudos Prospectivos , Radiografia , Radioimunoensaio , Diálise Renal , Fatores de Risco , Uremia/sangue , Uremia/terapia , Calcificação Vascular/diagnóstico , Calcificação Vascular/etiologia
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