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1.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802652

RESUMO

Red blood cells (RBCs) have been found to synthesize and release both nitric oxide (NO) and cyclic guanosine monophosphate (cGMP), contributing to systemic NO bioavailability. These RBC functions resulted impaired in chronic kidney disease (CKD). This study aimed to evaluate whether predialysis (conservative therapy, CT) and dialysis (peritoneal dialysis, PD; hemodialysis, HD) therapies used during CKD progression may differently affect NO-synthetic pathway in RBCs. Our data demonstrated that compared to PD, although endothelial-NO-synthase activation was similarly increased, HD and CT were associated to cGMP RBCs accumulation, caused by reduced activity of cGMP membrane transporter (MRP4). In parallel, plasma cGMP levels were increased by both CT and HD and they significantly decreased after hemodialysis, suggesting that this might be caused by reduced cGMP renal clearance. As conceivable, compared to healthy subjects, plasma nitrite levels were significantly reduced by HD and CT but not in patients on PD. Additionally, the increased carotid intima-media thickness (IMT) values did not reach the significance exclusively in patients on PD. Therefore, our results show that PD might better preserve the synthetic NO-pathway in CKD-erythrocytes. Whether this translates into a reduced development of uremic vascular complications requires further investigation.


Assuntos
Eritrócitos/metabolismo , Óxido Nítrico/biossíntese , Óxido Nítrico/sangue , Diálise Peritoneal , Diálise Renal , Uremia/sangue , Idoso , GMP Cíclico/sangue , GMP Cíclico/metabolismo , Feminino , Humanos , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Óxido Nítrico Sintase/metabolismo , Nitritos/sangue , Nitrosação , Fosforilação
2.
Oxid Med Cell Longev ; 2021: 6678924, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33574979

RESUMO

Deletion polymorphism of glutathione S-transferase M1 (GSTM1), a phase II detoxification and antioxidant enzyme, increases susceptibility to end-stage renal disease (ESRD) as well as the development of cardiovascular diseases (CVD) among ESRD patients and leads to their shorter cardiovascular survival. The mechanisms by which GSTM1 downregulation contributes to oxidative stress and inflammation in endothelial cells in uremic conditions have not been investigated so far. Therefore, the aim of the present study was to elucidate the effects of GSTM1 knockdown on oxidative stress and expression of a panel of inflammatory markers in human umbilical vein endothelial cells (HUVECs) exposed to uremic serum. Additionally, we aimed to discern whether GSTM1-null genotype is associated with serum levels of adhesion molecules in ESRD patients. HUVECs treated with uremic serum exhibited impaired redox balance characterized by enhanced lipid peroxidation and decreased antioxidant enzyme activities, independently of the GSTM1 knockdown. In response to uremic injury, HUVECs exhibited alteration in the expression of a series of inflammatory cytokines including retinol-binding protein 4 (RBP4), regulated on activation, normal T cell expressed and secreted (RANTES), C-reactive protein (CRP), angiogenin, dickkopf-1 (Dkk-1), and platelet factor 4 (PF4). GSTM1 knockdown in HUVECs showed upregulation of monocyte chemoattractant protein-1 (MCP-1), a cytokine involved in the regulation of monocyte migration and adhesion. These cells also have shown upregulated intracellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1). In accordance with these findings, the levels of serum ICAM-1 and VCAM-1 (sICAM-1 and sVCAM-1) were increased in ESRD patients lacking GSTM1, in comparison with patients with the GSTM1-active genotype. Based on these results, it may be concluded that incubation of endothelial cells in uremic serum induces redox imbalance accompanied with altered expression of a series of cytokines involved in arteriosclerosis and atherosclerosis. The association of GSTM1 downregulation with the altered expression of adhesion molecules might be at least partly responsible for the increased susceptibility of ESRD patients to CVD.


Assuntos
Glutationa Transferase/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Uremia/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Biomarcadores/metabolismo , Citocinas/metabolismo , Deleção de Genes , Glutationa Peroxidase/metabolismo , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/metabolismo , Malondialdeído/metabolismo , Estresse Oxidativo , Proteoma/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Uremia/sangue
3.
PLoS One ; 16(1): e0245370, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33471852

RESUMO

BACKGROUND: Uremic pruritus (UP) is a common and frustrating symptom in patients receiving hemodialysis (HD). The majority of patients have mild to moderate itching of the skin, and a small percentage have severe itching, which seriously affects their quality of life and survival rate. However, little is known about factors that influence the intensity of itching in patients. METHODS: A cross-sectional study on uremic pruritus in male and female patients receiving HD was conducted in September 2019. This study included 148 eligible patients who received HD at the Blood Purification Center of Xinchang County People's Hospital, Zhejiang Province, China from March 2019 to June 2019. We collected general data consisted of age, sex, body mass index (BMI), place of residence, educational level, diabetes mellitus status and duration of HD; as well as clinical, biochemical indicators, including serum calcium (Ca), serum phosphorus (P), serum albumin (ALB), haemoglobin (Hb), serum intact parathyroid hormone (iPTH), pre-dialysis serum urea nitrogen (BUN), normalized protein catabolic rate (nPCR), urea nitrogen clearance index (KT/V), ferritin (FER) and pre-dialysis serum creatinine (sCR). We also assayed the inflammatory cytokine serum high sensitivity C-reactive protein (hs-CRP). The Five-Dimensional Itching Scale (5DIS) was used to evaluate the degree of skin itching (none, mild, moderate, or severe). We used multiple logistic regression to analyze influencing factors on the degree of skin itching in patients with UP. RESULTS: Of the 148 patients, 60 had uremic pruritus (incidence rate, 40.54%). These included 22 cases of mild skin itching (14.86%), 30 of moderate skin itching (20.27%), and 8 of severe skin itching (5.41%). Compared with uremia patients without skin pruritus, patients with UP had higher levels of iPTH, Hb, BUN, nPCR, and hs-CRP. The composition ratio showed significant differences between urban and rural patients with different degrees of skin itching (P = 0.017); moreover, the difference of iPTH and hs-CRP levels were statistically significant (P = 0.009 and < 0.001, respectively). Using no itching as a reference, multiple logistic regression analysis showed that as hs-CRP level increased, the patient's risks of mild skin itching (odds ratio [OR] = 1.740; 95% confidence interval [CI], 1.061-2.854; P = 0.028), moderate skin itching (OR = 2.8838 95% CI, 1.744-4.718; P < 0.001), and severe skin itching (OR = 9.440; 95% CI, 3.547-25.124; P < 0.001) all increased as well. Compared with urban residents, rural residents have a higher risk of moderate itching (OR = 3.869; 95% CI, 1.099-13.622; P = 0.035). CONCLUSION: Levels of hs-CRP were associated with the intensity of skin itching in patients with UP. Higher hs-CRP levels were closely related to severe skin itching. The relationship between the intensity of skin itching and the environment in maintenance hemodialysis patients needs further clarification.


Assuntos
Prurido/etiologia , Diálise Renal/efeitos adversos , Uremia/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/análise , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prurido/sangue , Fatores de Risco , Uremia/sangue , Adulto Jovem
4.
PLoS One ; 15(9): e0235960, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32986718

RESUMO

OBJECTIVE: To investigate the effects of AMPK activation on mitochondrial inhibition by uremic serum through the AMPK-activated rat peritoneal macrophages stimulated by uremic serum, thereby providing a reference for the clinical treatment of chronic kidney disease. METHODS: Twenty-two male Sprague-Dawley (SD) rats were included as experimental subjects. Fifteen rats were constructed into chronic kidney disease models (the model group). The remaining seven rats only received renal capsule stripping instead of nephrectomy (the sham-operated group). Ten weeks after model construction, the bodyweight, blood biochemical indicators, and metabolic parameters of rats in groups were measured. Meanwhile, the expression of the M1 phenotype marker protein in peritoneal macrophages was determined. RESULTS: Ten weeks after model construction, the bodyweight of rats in the model group was significantly lower than that in the sham-operated group. The values of urea nitrogen and serum creatinine were significantly higher than those in the sham-operated group (P<0.01). The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and the monocyte chemoattractant protein 1 (MCP-1) of rats in the model group were significantly higher than those in the sham-operated group (P <0.01). After the lipopolysaccharide (LPS) stimulation, the expressions of M1 phenotype marker mRNA in the model group was significantly increased. The expression of mitochondrial structural protein mRNA in the peritoneal macrophages of rats in the model group was significantly lower than that in the sham-operated group. The expression of M1 phenotype marker mRNA was significantly decreased in the uremic serum group after AMPK agonist (P<0.01). CONCLUSION: In rats with chronic renal insufficiency, mitochondrial regeneration was dysfunctional in macrophages. By activating AMPK, the inhibitory effect of uremia serum on mitochondrial regeneration of macrophages was improved. Therefore, AMPK was a critical factor that could regulate mitochondrial regeneration of macrophages.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ativação Enzimática , Macrófagos Peritoneais/metabolismo , Mitocôndrias/metabolismo , Uremia/metabolismo , Animais , Macrófagos Peritoneais/patologia , Masculino , Mitocôndrias/patologia , Dinâmica Mitocondrial , RNA Mensageiro/metabolismo , RNA Mitocondrial/metabolismo , Ratos , Ratos Sprague-Dawley , Uremia/sangue , Uremia/patologia
5.
Int J Mol Sci ; 21(4)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32070049

RESUMO

Indoxyl sulphate (IS) and p-cresyl sulphate (PCS) are two protein bound uraemic toxins accumulated in chronic kidney disease (CKD) and associated with adverse outcomes. The purpose of this study isto evaluate the effect of the new activated charcoal, CharXgen, on renal function protection and lowering serum uraemic toxins in CKD animal model. The physical character of CharXgen was analyzed before and after activation procedure by Scanning Electron Microscope (SEM) and X-ray diffractometer (XRD). The effect of CharXgen on biochemistry and lowering uremic toxins was evaluated by in vitro binding assay and CKD animal model. CharXgen have high interior surface area analyzed by SEM and XRD and have been produced from local bamboo after an activation process. CharXgen was able to effectively absorb IS, p-cresol and phosphate in an in vitro gastrointestinal tract simulation study. The animal study showed that CharXgen did not cause intestine blackening. Serum albuminand liver function did not change after feeding with CharXgen. Moreover, renal function was improved in CKD rats fed with CharXgen as compared to the CKD group, and there were no significant differences in the CKD and the CKD + AST-120 groups. Serum IS and PCS were higher in the CKD group and lower in rats treated with CharXgen and AST-120. In rats treated with CharXgen, Fibroblast growth factor 23 was significantly decreased as compared to the CKD group. This change cannot be found in rats fed with AST-120.It indicates that CharXgen is a new safe and non-toxic activated charcoal having potential in attenuating renal function deterioration and lowering protein-bound uraemic toxins. Whether the introduction of this new charcoal could further have renal protection in CKD patients will need to be investigated further.


Assuntos
Carvão Vegetal/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Sasa/química , Toxinas Biológicas/sangue , Uremia/tratamento farmacológico , Alginatos/química , Alginatos/farmacologia , Animais , Carbono/farmacologia , Linhagem Celular , Cresóis/farmacologia , Modelos Animais de Doenças , Humanos , Indicã/farmacologia , Microscopia Eletrônica de Varredura , Microesferas , Óxidos/farmacologia , Ratos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/patologia , Ésteres do Ácido Sulfúrico/farmacologia , Uremia/sangue , Uremia/complicações , Uremia/patologia
6.
Med Sci Monit ; 26: e919086, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32040471

RESUMO

BACKGROUND This study aimed to investigate the effects of resveratrol on kidney function in a rat model of uremia and the expression of heat shock proteins. MATERIAL AND METHODS The rat model of uremia was developed by 5/6 nephrectomy of Sprague-Dawley rats. The Hsp70 inhibitor MKT-077, a rhodacyanine dye, was used. The study groups included rats with sham surgery (the sham group), the rat model of uremia (the model group), the solvent-treated control group (the control group), the rat model treated with resveratrol group (the resveratrol group), the rat model treated with MKT-077 (the MKT-077 group), and the resveratrol+MKT-077 group. Kidney tissues were studied histologically. Renal cell apoptosis was detected by the TUNEL method. Expression of p53, Bax, and Bcl-2 mRNA and protein were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry, respectively. RESULTS Compared with the sham group, the expression levels of heat shock proteins Hsp70, Hsp90, Hsp27, Hsp25, Hsp40, and Hsp60 in the kidney of the rat model group increased to different degrees. Compared with the model group, the Hsp70 levels in the resveratrol group were significantly increased (p<0.05). Compared with the model group, treatment with MKT-077 reduced the survival rate of rats, which was increased following resveratrol treatment. Compared with the resveratrol group, renal function in the resveratrol+MKT-077 group was significantly reduced (p<0.05). CONCLUSIONS In a rat model of uremia, resveratrol reduced renal injury and improved both renal function and survival, which were associated with increased expression of Hsp70.


Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Rim/lesões , Rim/metabolismo , Resveratrol/uso terapêutico , Uremia/complicações , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Proteínas de Choque Térmico HSP70/genética , Rim/patologia , Rim/fisiopatologia , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Resveratrol/farmacologia , Análise de Sobrevida , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Uremia/sangue , Uremia/genética , Uremia/fisiopatologia , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
7.
Sci Rep ; 9(1): 15464, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664047

RESUMO

Pharmacokinetics of SN-38 in patients with end-stage kidney disease (ESKD) is partially varied because of fluctuations in transporters expression and/or function by high protein bound-uremic toxins concentration. The fluctuations may induce variations in anticancer drugs sensitivity to cancer cells. We aimed to clarify the variations in sensitivity of SN-38 to cancer patients with ESKD and investigate this mechanism, by human colon cancer cells exposed to uremic serum residue. LS180 cells were exposed to normal or uremic serum residue (LS/NSR or LS/USR cells) for a month. IC50 values of SN-38 in LS/NSR or LS/USR cells were calculated from viability of each cells treated SN-38. mRNA expression and intracellular SN-38 accumulation was evaluated by RT-PCR and HPLC-fluorescence methods, respectively. The IC50 value in LS/USR cells was higher than that in LS/NSR cells. Organic anion transporter polypeptide (OATP) 2B1 mRNA expression was lower in LS/USR cells than in LS/NSR cells, and SN-38 accumulation in LS/USR cells was lower than that in LS/NSR cells. Only co-treatment baicalin, which is OATP2B1 inhibitor, almost negated the difference in SN-38 accumulation between LS/NSR and LS/USR. Anticancer effects of substrates of OATP2B1, such as SN-38, were reduced in ESKD patients at the same plasma substrate concentration.


Assuntos
Irinotecano/farmacologia , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Inibidores da Topoisomerase I/farmacologia , Uremia/sangue , Linhagem Celular Tumoral , Células HEK293 , Humanos , Irinotecano/farmacocinética , Falência Renal Crônica/metabolismo , Inibidores da Topoisomerase I/farmacocinética
8.
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
9.
Biosci Rep ; 39(10)2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31519772

RESUMO

Vascular calcification (VC) is common in subjects with chronic kidney disease (CKD) and is associated with increased cardiovascular risk. It is an active process involving transdifferentiation of arterial smooth muscle cells (SMCs) into osteogenic phenotype. We investigated the ability of serum from CKD subjects to induce calcification in human SMCs in vitro (calcific potential of sera: CP), and associated changes in expression of Runt-related transcription factor 2 (RUNX2), SM22α, and Klotho. Sera from subjects with CKD (18 stage 3, 17 stage 4/5, and 29 stage 5D) and 20 controls were added to human cultured SMCs and CP quantified. The CP of CKD sera was greater (P<0.01) than that of controls, though not influenced by CKD stage. Modification of diet in renal disease estimated glomerular filtration rate (MDRD-4 eGFR) (P<0.001), serum phosphate (P=0.042), receptor activator of nuclear factor κappa-B ligand (RANKL) (P=0.001), parathyroid hormone (PTH) (P=0.014), and high-density lipoprotein (HDL)/cholesterol ratio (P=0.026) were independent predictors of CP accounting for 45% of variation. Adding calcification buffer (CB: calcium chloride [7 mM] and ß-glycerophosphate [7 mM]) increased the CP of control sera to approximate that of CKD sera. CP of CKD sera was unchanged. CKD sera increased RUNX2 expression (P<0.01) in human SMCs and decreased SM22α expression (P<0.05). Co-incubating control but not CKD serum with CB further increased RUNX2 expression (P<0.01). Both SM22α and Klotho expression decreased significantly (P<0.01) in the presence of CKD serum, and were virtually abolished with stage 5D sera. These findings support active regulation by CKD serum of in vitro VC by induction of RUNX2 and suppression of SM22α and Klotho.


Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Glucuronidase/metabolismo , Miócitos de Músculo Liso/metabolismo , Soro/química , Uremia/sangue , Calcificação Vascular/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Aorta/citologia , Células Cultivadas , Meios de Cultura/química , Meios de Cultura/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Ratos , Insuficiência Renal Crônica/sangue , Calcificação Vascular/induzido quimicamente
10.
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
11.
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
12.
Biosci Rep ; 39(10)2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31427482

RESUMO

BACKGROUND: Regulatory T (Treg) cells are of critical functionality in immune activation and inflammation in uremic patients undergoing hemodialysis (HD). A disruption in balance of Treg cells has potency to elicit infectious disease progression. Here, we examined possible association between ratio imbalance of Th22/Treg cells and microinflammation in uremic patients undergoing HD. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated to allow measurement of the percentage of Th22 cells and Treg cells using flow cytometry. Subsequently, serum levels of related cytokines, interleukin (IL) 22 (IL-22) and IL-10 and inflammatory factors, C-reactive protein (CRP), (TNF-α), IL-6 were determined via enzyme-linked immunosorbent assay (ELISA). Then relationships among dialysis time, microinflammation status (CRP) and dialysis adequacy (immunoreactive parathyroid hormone (iPTH), urea clearance index (Kt/V), ß2-MG, serum calcium, and serum phosphorus) were evaluated. Finally, correlation between microinflammation status and dialysis adequacy was analyzed with Pearson's correlation coefficient. RESULTS: An increased percentage of Th22 and a decreased percentage of Treg cells were evident in uremic patients undergoing HD. Serum levels of IL-22, CRP, TNF-α, and IL-6 were increased, while IL-10 serum level was reduced. An imbalance of Th22/Treg cells was associated with microinflammation status in uremic patients undergoing HD. Furthermore, prolongation of the dialysis time, the microinflammation status and dialysis adequacy were changed. Increased dialysis adequacy was observed to correlate with alleviated microinflammation of uremic patients undergoing HD. CONCLUSIONS: Conjointly, an imbalance of Th22/Treg cells may be a potential cause responsible for uremia occurrence, which in turn indicates that uremia could be effectively alleviated by altering the ratio of Th22/Treg cells.


Assuntos
Inflamação/imunologia , Interleucinas/imunologia , Diálise Renal/métodos , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Uremia/terapia , Adulto , Idoso , Proteína C-Reativa/imunologia , Proteína C-Reativa/metabolismo , Células Cultivadas , Feminino , Humanos , Inflamação/sangue , Inflamação/metabolismo , Interleucina-10/sangue , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-6/sangue , Interleucina-6/imunologia , Interleucina-6/metabolismo , Interleucinas/sangue , Interleucinas/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/metabolismo , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Uremia/sangue , Uremia/imunologia
13.
JCI Insight ; 4(13)2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31292298

RESUMO

We induced chronic kidney disease (CKD) with adenine in WT mice, mice with osteocyte-specific deletion of Cyp27b1, encoding the 25-hydroxyvitamin D 1(OH)ase [Oct-1(OH)ase-/-], and mice with global deletion of Cyp27b1 [global-1α(OH)ase-/-]; we then compared extraskeletal calcification. After adenine treatment, mice displayed increased blood urea nitrogen, decreased serum 1,25(OH)2D, and severe hyperparathyroidism. Skeletal expression of Cyp27b1 and of sclerostin and serum sclerostin all increased in WT mice but not in Oct-1α(OH)ase-/- mice or global-1α(OH)ase-/- mice. In contrast, skeletal expression of BMP2 and serum BMP2 rose in the Oct-1α(OH)ase-/- mice and in the global-1α(OH)ase-/- mice. Extraskeletal calcification occurred in muscle and blood vessels of mice with CKD and was highest in Oct-1α(OH)ase-/-mice. In vitro, recombinant sclerostin (100 ng/mL) significantly suppressed BMP2-induced osteoblastic transdifferentiation of vascular smooth muscle A7r5 cells and diminished BMP2-induced mineralization. Our study provides evidence that local osteocytic production of 1,25(OH)2D stimulates sclerostin and inhibits BMP2 production in murine CKD, thus mitigating osteoblastic transdifferentiation and mineralization of soft tissues. Increased osteocytic 1,25(OH)2D production, triggered by renal malfunction, may represent a "primary defensive response" to protect the organism from ectopic calcification by increasing sclerostin and suppressing BMP2 production.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína Morfogenética Óssea 2/metabolismo , Calcinose/patologia , Calcitriol/metabolismo , Insuficiência Renal Crônica/complicações , Uremia/complicações , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/sangue , Adenina/toxicidade , Animais , Nitrogênio da Ureia Sanguínea , Proteína Morfogenética Óssea 2/sangue , Osso e Ossos/citologia , Osso e Ossos/metabolismo , Calcinose/sangue , Calcinose/etiologia , Calcitriol/sangue , Transdiferenciação Celular , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Masculino , Camundongos , Osteócitos/metabolismo , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/induzido quimicamente , Uremia/sangue , Uremia/induzido quimicamente
14.
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
15.
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
16.
Heart ; 105(17): 1302-1309, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31239278

RESUMO

The syndrome of uraemic cardiomyopathy, characterised by left ventricular hypertrophy, diffuse fibrosis and systolic and diastolic dysfunction, is common in chronic kidney disease and is associated with an increased risk of cardiovascular morbidity and mortality. The pathophysiological mechanisms leading to uraemic cardiomyopathy are not fully understood. We suggest that coronary microvascular dysfunction may be a key mediator in the development of uraemic cardiomyopathy, a phenomenon that is prevalent in other myocardial diseases that share phenotypical similarities with uraemic cardiomyopathy such as hypertrophic cardiomyopathy and heart failure with preserved ejection fraction. Here, we review the current understanding of uraemic cardiomyopathy, highlight different methods of assessing coronary microvascular function and evaluate the current evidence for coronary microvascular dysfunction in chronic kidney disease.


Assuntos
Cardiomiopatias/etiologia , Doença da Artéria Coronariana/etiologia , Vasos Coronários/fisiopatologia , Rim/fisiopatologia , Microvasos/fisiopatologia , Uremia/complicações , Animais , Cardiomiopatias/sangue , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/fisiopatologia , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/fisiopatologia , Circulação Coronária , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/metabolismo , Fibrose , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Microcirculação , Microvasos/diagnóstico por imagem , Microvasos/metabolismo , Prognóstico , Medição de Risco , Fatores de Risco , Uremia/sangue , Uremia/diagnóstico , Uremia/fisiopatologia , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda , Remodelação Ventricular
17.
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 , Injúria Renal Aguda/complicações , Injúria 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
18.
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
19.
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
Injúria Renal Aguda/líquido cefalorraquidiano , Encefalopatias/líquido cefalorraquidiano , Uremia/líquido cefalorraquidiano , Injúria Renal Aguda/sangue , Injúria Renal Aguda/complicações , Injúria 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
20.
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
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