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1.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 42(1): 124-127, 2020 Feb 28.
Artigo em Chinês | MEDLINE | ID: mdl-32131951

RESUMO

Patients with uremia can suffer from decreased renal function and endocrine and metabolism disorders,which can lead to the accumulation of toxins in the body.Accumulation of uremic toxins is a major cause of cognitive dysfunction in uremic patients.This article summarizes some of the cognitive dysfunction-related uremic toxins and their possible mechanisms.


Assuntos
Disfunção Cognitiva/fisiopatologia , Toxinas Biológicas , Uremia/fisiopatologia , Humanos
2.
Nat Commun ; 11(1): 721, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024848

RESUMO

Myo-inositol hexakisphosphate (IP6) is a natural product known to inhibit vascular calcification (VC), but with limited potency and low plasma exposure following bolus administration. Here we report the design of a series of inositol phosphate analogs as crystallization inhibitors, among which 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis(phosphate), (OEG2)2-IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG2)2-IP4 potently stabilizes calciprotein particle (CPP) growth, consistently demonstrates low micromolar activity in different in vitro models of VC (i.e., human serum, primary cell cultures, and tissue explants), and largely abolishes the development of VC in rodent models, while not causing toxicity related to serum calcium chelation. The data suggest a mechanism of action independent of the etiology of VC, whereby (OEG2)2-IP4 disrupts the nucleation and growth of pathological calcification.


Assuntos
Fosfatos de Inositol/química , Fosfatos de Inositol/farmacologia , Calcificação Vascular/tratamento farmacológico , 6-Fitase/metabolismo , Adenina/efeitos adversos , Animais , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos/métodos , Difusão Dinâmica da Luz , Etilenoglicol/química , Humanos , Injeções Subcutâneas , Fosfatos de Inositol/farmacocinética , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Ratos Sprague-Dawley , Uremia/tratamento farmacológico , Uremia/fisiopatologia , Calcificação Vascular/induzido quimicamente , Difração de Raios X
4.
BMC Neurosci ; 20(1): 52, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31585527

RESUMO

BACKGROUND: Neurological complications may occur in patients with acute or chronic renal failure; however, in cases of acute renal failure, the signs and symptoms are usually more pronounced, and progressed rapidly. Oxidative stress and nitric oxide in the hippocampus, following kidney injury may be involved in cognitive impairment in patients with uremia. Although many women continue taking hormone therapy for menopausal symptom relief, but there are also some controversies about the efficacy of exogenous sex hormones, especially estrogen therapy alone, in postmenopausal women with kidney injury. Herein, to the best of our knowledge for the first time, spatial memory and synaptic plasticity at the CA1 synapse of a uremic ovariectomized rat model of menopause was characterized by estradiol replacement alone. RESULTS: While estradiol replacement in ovariectomized rats without uremia, promotes synaptic plasticity, it has an impairing effect on spatial memory through hippocampal oxidative stress under uremic conditions, with no change on synaptic plasticity. It seems that exogenous estradiol potentiated the deleterious effect of acute kidney injury (AKI) with increasing hippocampal oxidative stress. CONCLUSIONS: Although, estrogen may have some positive effects on cognitive function in healthy subjects, but its efficacy in menopause subjects under uremic states such as renal transplantation, needs to be further investigated in terms of dosage and duration.


Assuntos
Lesão Renal Aguda/fisiopatologia , Região CA1 Hipocampal/fisiopatologia , Estradiol/efeitos adversos , Aprendizagem/fisiologia , Plasticidade Neuronal/fisiologia , Lesão Renal Aguda/complicações , Animais , Feminino , Menopausa/psicologia , Neurônios/fisiologia , Ovariectomia , Ratos , Memória Espacial/fisiologia , Uremia/complicações , Uremia/fisiopatologia
5.
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
6.
Clin Exp Nephrol ; 23(7): 908-919, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30895529

RESUMO

BACKGROUND: Constipation is frequently observed in patients with chronic kidney disease (CKD). Lactulose is expected to improve the intestinal environment by stimulating bowel movements as a disaccharide laxative and prebiotic. We studied the effect of lactulose on renal function in adenine-induced CKD rats and monitored uremic toxins and gut microbiota. METHODS: Wistar/ST male rats (10-week-old) were fed 0.75% adenine-containing diet for 3 weeks to induce CKD. Then, they were divided into three groups and fed as follows: control, normal diet; and 3.0- and 7.5-Lac, 3.0% and 7.5% lactulose-containing diets, respectively, for 4 weeks. Normal diet group was fed normal diet for 7 weeks. The rats were observed for parameters including renal function, uremic toxins, and gut microbiota. RESULTS: The control group showed significantly higher serum creatinine (sCr) and blood urea nitrogen (BUN) 3 weeks after adenine feeding than at baseline, with a 8.5-fold increase in serum indoxyl sulfate (IS). After switching to 4 weeks of normal diet following adenine feeding, the sCr and BUN in control group remained high with a further increase in serum IS. In addition, tubulointerstitial fibrosis area was increased in control group. On the other hand, 3.0- and 7.5-Lac groups improved sCr and BUN levels, and suppressed tubulointerstitial fibrosis, suggesting preventing of CKD progression by lactulose. Lac groups also lowered level of serum IS and proportions of gut microbiota producing IS precursor. CONCLUSION: Lactulose modifies gut microbiota and ameliorates CKD progression by suppressing uremic toxin production.


Assuntos
Adenina , Bactérias/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Rim/efeitos dos fármacos , Lactulose/farmacologia , Prebióticos , Insuficiência Renal Crônica/prevenção & controle , Uremia/prevenção & controle , Animais , Bactérias/metabolismo , Biomarcadores/sangue , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Modelos Animais de Doenças , Progressão da Doença , Fibrose , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/microbiologia , Insuficiência Renal Crônica/fisiopatologia , Uremia/induzido quimicamente , Uremia/microbiologia , Uremia/fisiopatologia
7.
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
8.
Rev Assoc Med Bras (1992) ; 65(2): 281-286, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30892456

RESUMO

INTRODUCTION: Peripheral neuropathy is a disorder that affects the cell body, axon or myelin of motor or peripheral sensory neurons and occurs in 60-100% of patients who are submitted to dialysis due to chronic kidney disease. Uremic neuropathy is attributed to the accumulation of organic waste, evident in patients with reduced glomerular filtration rate. OBJECTIVES: This review aims to make clinical characteristics of uremic neuropathy evident enabling early diagnosis and treatment. METHODS: This is a literature review of articles published on PubMed over the last 10 years using "Uremic Neuropathy" as "Title/Abstract". RESULTS: A total of nine articles that met the inclusion criteria were included. UN is a distal symmetric sensorimotor polyneuropathy that occurs due to the accumulation of uremic toxins associated with an oxidative stress-related free radical activity. Hyperkalemia is thought to play an important role in its pathophysiology. Diagnosis depends on nerve conduction studies, and treatment includes dialysis or renal transplant. CONCLUSION: Clinical presentations of UN are broad and non-specific; nonetheless, it is important to detect early changes in order to avoid its progression. The earlier UN is diagnosed and treated, the more successful are the clinical outcomes.


Assuntos
Doenças do Sistema Nervoso Periférico , Uremia , Humanos , Transplante de Rim , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Doenças do Sistema Nervoso Periférico/terapia , Diálise Renal , Uremia/diagnóstico , Uremia/fisiopatologia , Uremia/terapia
9.
Medicine (Baltimore) ; 98(9): e14656, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30817588

RESUMO

The aim of this research is to evaluate the longitudinal and circumferential systolic function of the left ventricle with different configurations from endocardium, midmyocardium, and epicardium, respectively, in patients with uremia using layer-specific 2-dimensional speckle tracking echocardiography (2D-STE).According to the different left ventricular (LV) configurations, 119 patients with uremia were divided into 2 groups: LV normal group (LVN group, n = 63) and LV hypertrophy group (LVH group, n = 56). In all, 66 healthy volunteers were selected as controls. High-frame rate 2-dimensional images were recorded from the apical 4-chamber view, apical 2-chamber view, parasternal LV long-axis view, and mitral annulus, papillary muscle, and apical levels of the parasternal LV short-axis view during 3 consecutive cardiac cycles. The peak systolic longitudinal strain (LS) and circumferential strain (CS) were measured in the endocardium, midmyocardium, and epicardium.In the 3 groups, the endocardium had the highest LS and CS, whereas the epicardium had the lowest LS and CS; the LS and CS of each group gradually decreased from the endocardium to the epicardium in all the 3 sections; the LS and CS of the myocardial layers were kept gradient features, namely, endocardium > midmyocardium > epicardium. The LS of the endocardium in the LVN and LVH groups was significantly lower than that in the control group (P < .05). The LS of the midmyocardium and epicardium in the LVH group were significantly lower than those in the control group (P < .05). The LS of the endocardium significantly decreased in the LVH group compared with that in the LVN group (P < .05). The CS of the endocardium and midmyocardium in the LVH group significantly decreased compared with those in the control and LVN groups (P < .05). There were no significant differences in the CS between the LVN and control groups (P > .05).In patients with uremia, the longitudinal and circumferential systolic function in 3 myocardial layers of the LVH group, and the longitudinal systolic function in endocardium of the LVN group were found significantly impaired by layer-specific 2D-STE.


Assuntos
Ecocardiografia/métodos , Ventrículos do Coração/diagnóstico por imagem , Uremia/diagnóstico por imagem , Uremia/fisiopatologia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Adulto , Idoso , Endocárdio/diagnóstico por imagem , Endocárdio/fisiopatologia , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/etiologia , Masculino , Pessoa de Meia-Idade , Sístole , Uremia/complicações , Disfunção Ventricular Esquerda/etiologia , Função Ventricular Esquerda , Adulto Jovem
10.
Am J Physiol Renal Physiol ; 316(6): F1211-F1217, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30864840

RESUMO

The gut microbiome is composed of a diverse population of bacteria that have beneficial and adverse effects on human health. The microbiome has recently gained attention and is increasingly noted to play a significant role in health and a number of disease states. Increasing urea concentration during chronic kidney disease (CKD) leads to alterations in the intestinal flora that can increase production of gut-derived toxins and alter the intestinal epithelial barrier. These changes can lead to an acceleration of the process of kidney injury. A number of strategies have been proposed to interrupt this pathway of injury in CKD. The purpose of this review is to summarize the role of the gut microbiome in CKD, tools used to study this microbial population, and attempts to alter its composition for therapeutic purposes.


Assuntos
Bactérias/metabolismo , Microbioma Gastrointestinal , Intestinos/microbiologia , Rim/metabolismo , Insuficiência Renal Crônica/microbiologia , Ureia/metabolismo , Uremia/microbiologia , Animais , Suplementos Nutricionais , Interações Hospedeiro-Patógeno , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Intestinos/fisiopatologia , Rim/fisiopatologia , Permeabilidade , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/terapia , Uremia/metabolismo , Uremia/fisiopatologia , Uremia/terapia
11.
Nat Rev Nephrol ; 15(5): 301-316, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30728454

RESUMO

Uraemic syndrome (also known as uremic syndrome) in patients with advanced chronic kidney disease involves the accumulation in plasma of small-molecule uraemic solutes and uraemic toxins (also known as uremic toxins), dysfunction of multiple organs and dysbiosis of the gut microbiota. As such, uraemic syndrome can be viewed as a disease of perturbed inter-organ and inter-organism (host-microbiota) communication. Multiple biological pathways are affected, including those controlled by solute carrier (SLC) and ATP-binding cassette (ABC) transporters and drug-metabolizing enzymes, many of which are also involved in drug absorption, distribution, metabolism and elimination (ADME). The remote sensing and signalling hypothesis identifies SLC and ABC transporter-mediated communication between organs and/or between the host and gut microbiota as key to the homeostasis of metabolites, antioxidants, signalling molecules, microbiota-derived products and dietary components in body tissues and fluid compartments. Thus, this hypothesis provides a useful perspective on the pathobiology of uraemic syndrome. Pathways considered central to drug ADME might be particularly important for the body's attempts to restore homeostasis, including the correction of disturbances due to kidney injury and the accumulation of uraemic solutes and toxins. This Review discusses how the remote sensing and signalling hypothesis helps to provide a systems-level understanding of aspects of uraemia that could lead to novel approaches to its treatment.


Assuntos
Insuficiência Renal Crônica/fisiopatologia , Transdução de Sinais , Uremia/etiologia , Biomarcadores/metabolismo , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/microbiologia , Uremia/imunologia , Uremia/microbiologia , Uremia/fisiopatologia
12.
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
13.
Echocardiography ; 36(1): 87-93, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30411403

RESUMO

OBJECTIVE: To study ventricular-arterial coupling(VAC) in uremic patients by application of two-dimensional speckle tracing imaging (2DSTI). METHODS: One hundred uremic patients were divided into two groups based on left ventricular ejection fraction (LVEF): group 1 with LVEF ≥ 5%, and group 2 with LVEF < 55%. Forty healthy subjects were recruited as a control group. Conventional echocardiography was performed; VAC components and myocardial performance index were calculated. Longitudinal strain (LS) of 17 segments was measured using 2DSTI. Mean base (LSBA ), papillary muscle (LSPM ), and apex values (LSAP ) were calculated. RESULTS: Compared to subjects in the control group and group 1, subjects in group 2 exhibited decreased LV end-diastolic volume (EDV), end-systolic volume (ESV), LV mass index (LVMI), and VAC (P < 0.05). EF, fractional shortening (FS), end-systolic elastance (Ees) were significantly higher in group 2 (P < 0.05). SLBA , SLPM , and SLAP differed significantly among the groups (all P < 0.05). SLBA , SLPM , and SLAP correlated positively with Ees, EF, and FS (all P < 0.05) but negatively with arterial elastance (Ea), VAC, systemic vascular resistance index (SVRI), and rate-pressure product (RPP) (all P < 0.05). Multiple regression analysis revealed that relative wall thickness (RWT), LVMI, LSAP , and stroke works (SW) were independent predictors of VAC (b' = -0.443, 0.537, -0.470, and -0.491, all P < 0.05). CONCLUSIONS: In patients with uremia, LV myocardial LS gradually decreased as LV systolic dysfunction decreased. VAC correlated negatively with left ventricular LS, and LSAP was an independent predictor for VAC.


Assuntos
Ecocardiografia/métodos , Uremia/complicações , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/diagnóstico por imagem , Adulto , Estudos de Viabilidade , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Uremia/fisiopatologia , Rigidez Vascular/fisiologia , Disfunção Ventricular Esquerda/fisiopatologia , Adulto Jovem
14.
Am J Hypertens ; 32(1): 34-44, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30329020

RESUMO

BACKGROUND: In uremic animals, vitamin D receptor (VDR) agonists like paricalcitol (Pc) attenuate cardiac hypertrophy, but this effect has not been replicated consistently in humans with chronic kidney disease. Elevated fibroblast growth factor 23 (FGF23) levels cause cardiac hypertrophy with activation of the myocardial calcineurin/nuclear factor of activated T cell (NFAT) axis and may antagonize the cardioprotective effects of VDR agonist therapy. We hypothesized that the effectiveness of Pc may depend on the prevailing circulating levels of FGF23 and could be potentiated by the combined administration of a pan-FGF23 receptor (FGFR) blocker agent (PD173074). METHODS: In rats with 5/6 nephrectomy treated with Pc or PD173074 or both agents concurrently, myocardial mRNA expression of renin-angiotensin system, VDR, FGFR4, and calcineurin/NFAT target genes was determined. In adolescents on hemodialysis, we analyzed sequential echocardiograms, blood pressures and serial FGF23 measurements, and their relations to the cumulative administered dose of parenteral Pc. RESULTS: The ratio of Pc dose/plasma levels of FGF23 correlated inversely (P < 0.005) with the cardiac mass in uremic rats and in hemodialysis patients, independently of hypertension. Despite persistently elevated FGF23 levels and myocardial FGFR4 activation, Pc suppressed upregulated myocardial calcineurin/NFAT target genes, and the effects were amplified by coadministration of PD173074. CONCLUSIONS: The beneficial effects of Pc on uremic cardiac hypertrophy are counterbalanced by the increased FGF23 levels. Blockade of FGF23-mediated signaling increased the Pc-induced suppression of the myocardial calcineurin/NFAT system. Higher doses of Pc should be considered in the treatment of patients with uremic cardiomyopathy.


Assuntos
Síndrome Cardiorrenal/prevenção & controle , Cardiomiopatias/prevenção & controle , Ergocalciferóis/farmacologia , Fatores de Crescimento de Fibroblastos/sangue , Ventrículos do Coração/efeitos dos fármacos , Falência Renal Crônica/tratamento farmacológico , Pirimidinas/farmacologia , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Calcitriol/agonistas , Adolescente , Animais , Síndrome Cardiorrenal/metabolismo , Síndrome Cardiorrenal/fisiopatologia , Cardiomiopatias/metabolismo , Cardiomiopatias/fisiopatologia , Criança , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Humanos , Falência Renal Crônica/metabolismo , Falência Renal Crônica/fisiopatologia , Masculino , Ratos Sprague-Dawley , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores de Calcitriol/metabolismo , Estudos Retrospectivos , Transdução de Sinais , Uremia/tratamento farmacológico , Uremia/metabolismo , Uremia/patologia , Uremia/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
15.
Expert Rev Clin Pharmacol ; 12(1): 61-90, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30501441

RESUMO

Introduction: Uremic syndrome of chronic kidney disease (CKD) is a term used to describe clinical, metabolic, and hormonal abnormalities associated with progressive kidney failure. It is a rapidly growing public health problem worldwide. Nervous system complications occur in every patient with uremic syndrome of CKD. Areas covered: This review summarized central and peripheral nervous system complications of uremic syndrome of CKD and their pathogenic mechanisms. They include cognitive deterioration, encephalopathy, seizures, asterixis, myoclonus, restless leg syndrome, central pontine myelinolysis, stroke, extrapyramidal movement disorders, neuropathies, and myopathy. Their pathogenic mechanisms are complex and multiple. They include (1) accumulation of uremic toxins resulting in neurotoxicity, blood-brain barrier injury, neuroinflammation, oxidative stress, apoptosis, brain neurotransmitters imbalance, ischemic/microvascular changes, and brain metabolism dysfunction (e.g. dopamine deficiency), (2) metabolic derangement (as acidosis, hypocalcemia, hyperphosphatemia, hypomagnesemia, and hyperkalemia); (3) secondary hyperparathyroidism, (4) erythropoietin and iron deficiency anemia, (5) thiamin, vitamin D, and other nutritional deficiencies, (6) hyperhomocysteinemia, and (7) coagulation problems. Expert commentary: Nervous system complications of uremia contribute to the patients' morbidity and mortality. Optimizing renal replacement therapy, correction of associated metabolic and medical conditions, and improved understanding of possible pathogenic mechanisms of these complications is a major target for their prevention and treatment.


Assuntos
Doenças do Sistema Nervoso/etiologia , Insuficiência Renal Crônica/complicações , Uremia/etiologia , Animais , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Humanos , Doenças do Sistema Nervoso/fisiopatologia , Doenças do Sistema Nervoso/terapia , Insuficiência Renal Crônica/terapia , Terapia de Substituição Renal/métodos , Síndrome , Uremia/fisiopatologia , Uremia/terapia
16.
J Nephrol ; 32(1): 27-37, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30069677

RESUMO

In chronic kidney disease (CKD), the progressive decline in the renal excretory function leads to accumulation of urea and toxins in the blood. The CKD-associated dysbiosis of gut microbiota further contributes to uremia by increasing intestinal toxins production. Gut microbiota is involved in a complex network of human organs, mediated by microbial metabolites: in CKD, gut-heart and gut-brain axes may have a role in increased cardiovascular risk and neuropsychiatric disorders. While the cardiovascular toxicity of some microbial molecules is well known, their presumptive neurotoxicity needs to be confirmed by specific studies. In this review, we describe gut-heart and gut-brain axes in CKD, with an overview of the experimental and human studies characterizing CKD-associated gut microbiota, and we discuss the benefits coming from new approaches aimed at gut manipulation. Microbiota metabolism is emerging as a modifiable non-traditional risk factor in nephrology. In order to take advantage of this issue, it is necessary to consider the microbiota manipulation as part of the nutritional management of CKD. Integrating the low-protein nutritional approach with prebiotic, probiotic and synbiotic supplementation is a promising tool to control disease progression and comorbidities, though an extensive validation in large-scale clinical trials is still required.


Assuntos
Bactérias/metabolismo , Microbioma Gastrointestinal , Intestinos/microbiologia , Rim/fisiopatologia , Eliminação Renal , Insuficiência Renal Crônica/microbiologia , Ureia/sangue , Uremia/microbiologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Dieta com Restrição de Proteínas , Disbiose , Interações Hospedeiro-Patógeno , Humanos , Prebióticos , Probióticos/uso terapêutico , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/dietoterapia , Insuficiência Renal Crônica/fisiopatologia , Simbióticos , Uremia/sangue , Uremia/dietoterapia , Uremia/fisiopatologia
18.
J Bone Miner Metab ; 37(2): 212-223, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29603070

RESUMO

A link between vascular calcification and bone anomalies has been suggested in chronic kidney disease (CKD) patients with low bone turnover disease. We investigated the vascular expression of osteocyte markers in relation to bone microarchitecture and mineralization defects in a model of low bone turnover CKD rats with vascular calcification. CKD with vascular calcification was induced by 5/6 nephrectomy followed by high calcium and phosphate diet, and vitamin D supplementation (Ca/P/VitD). CKD + Ca/P/VitD group (n = 12) was compared to CKD + normal diet (n = 12), control + normal diet (n = 8) and control + Ca/P/VitD supplementation (n = 8). At week 6, tibia, femurs and the thoracic aorta were analysed by Micro-Ct, histomorphometry and for expression of osteocyte markers. High Ca/P/VitD treatment induced vascular calcification only in CKD rats, suppressed serum parathyroid hormone levels and led to higher sclerostin, DKK1 and FGF23 serum levels. Expression of sclerostin, DKK1 and DMP1 but not FGF23 were increased in calcified vessels from CKD + Ca/P/VitD rats. Despite low parathyroid hormone levels, tibia bone cortical thickness was significantly lower in CKD + Ca/P/VitD rats as compared to control rats fed a normal diet, which is likely the result of radial growth impairment. Finally, Ca/P/VitD treatment in CKD rats induced a bone mineralization defect, which is likely explained by the high calcitriol dose. In conclusion, Ca/P/VitD supplementation in CKD rats induces expression of osteocyte markers in vessels and bone mineralisation anomalies. Further studies should evaluate the mechanisms of high dose calcitriol-induced bone mineralisation defects in CKD.


Assuntos
Calcificação Fisiológica/efeitos dos fármacos , Calcitriol/efeitos adversos , Cálcio/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Osteócitos/patologia , Fosfatos/efeitos adversos , Uremia/complicações , Calcificação Vascular/induzido quimicamente , Animais , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Osso Cortical/efeitos dos fármacos , Osso Cortical/patologia , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Rim/fisiopatologia , Masculino , Minerais/metabolismo , Osteócitos/efeitos dos fármacos , Osteócitos/metabolismo , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Uremia/sangue , Uremia/patologia , Uremia/fisiopatologia , Calcificação Vascular/sangue , Calcificação Vascular/complicações , Calcificação Vascular/fisiopatologia , Via de Sinalização Wnt
19.
Am J Kidney Dis ; 73(1): 90-101, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29784616

RESUMO

There are 2 major categories of patients with seizures and chronic kidney disease (CKD): patients who develop acute symptomatic seizures in the setting of CKD and patients with epilepsy who at some point develop CKD. The incidence of uremic seizures with kidney failure is ∼10%. These seizures are often nonconvulsive and may mimic uremic encephalopathy. Recognition and management of such situations may be challenging for treating physicians who are non-neurologists. Furthermore, practitioners caring for patients with seizures with or without an established diagnosis of epilepsy in the setting of CKD frequently encounter challenges in the selection, loading, titration, and maintenance of antiepileptic drugs (AEDs) due to potentially altered pharmacokinetics of the AEDs. We review the pathophysiology of uremia, uremic seizures, and other neurologic complications of kidney failure; management approaches to the treatment of such complications; the relevant mechanisms of action and pharmacokinetics of AEDs with their use in CKD; and in particular, the management of AEDs in patients requiring hemodialysis therapy.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/complicações , Epilepsia/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Convulsões/complicações , Convulsões/tratamento farmacológico , Anticonvulsivantes/farmacocinética , Humanos , Uremia/etiologia , Uremia/metabolismo , Uremia/fisiopatologia
20.
Microvasc Res ; 122: 101-110, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30448400

RESUMO

Fluid homeostasis is required for life. Processes involved in fluid balance are strongly related to exchanges at the microvascular level. Computational models have been presented in the literature to analyze the microvascular-interstitial interactions. As far as we know, none of those models consider a physiological description for the lymphatic drainage-interstitial pressure relation. We develop a computational model that consists of a network of straight cylindrical vessels and an isotropic porous media with a uniformly distributed sink term acting as the lymphatic system. In order to describe the lymphatic flow rate, a non-linear function of the interstitial pressure is defined, based on literature data on the lymphatic system. The proposed model of lymphatic drainage is compared to a linear one, as is typically used in computational models. To evaluate the response of the model, the two are compared with reference to both physiological and pathological conditions. Differences in the local fluid dynamic description have been observed using the non-linear model. In particular, the distribution of interstitial pressure is heterogeneous in all the cases analyzed. The resulting averaged values of the interstitial pressure are also different, and they agree with literature data when using the non-linear model. This work highlights the key role of lymphatic drainage and its modeling when studying the fluid balance in microcirculation for both to physiological and pathological conditions, e.g. uremia.


Assuntos
Simulação por Computador , Linfa/fisiologia , Vasos Linfáticos/fisiologia , Modelos Anatômicos , Análise Numérica Assistida por Computador , Equilíbrio Hidroeletrolítico , Análise de Elementos Finitos , Humanos , Modelos Lineares , Linfa/metabolismo , Vasos Linfáticos/anatomia & histologia , Vasos Linfáticos/metabolismo , Dinâmica não Linear , Porosidade , Pressão , Uremia/metabolismo , Uremia/fisiopatologia
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