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1.
Am J Physiol Renal Physiol ; 318(2): F518-F530, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31904283

RESUMO

Mucin-type O-linked glycosylation, a posttranslational modification affecting the stability and biophysical characteristics of proteins, requires C1GalT1 (T synthase) and its obligate, X-linked chaperone Cosmc. Hypomorphic C1GalT1 mutations cause renal failure via not yet established mechanisms. We hypothesize that impaired Cosmc-dependent O-glycosylation in podocytes is sufficient to cause disease. Podocyte-specific Cosmc knockout mice were generated and phenotyped to test this hypothesis. Female heterozygous mice displaying mosaic inactivation of Cosmc in podocytes due to random X-linked inactivation were also examined. Mice with podocyte-specific Cosmc deletion develop profound albuminuria, foot process effacement, glomerular sclerosis, progressive renal failure, and impaired survival. Glomerular transcriptome analysis reveals early changes in cell adhesion, extracellular matrix organization, and chemokine-mediated signaling pathways, coupled with podocyte loss. Expression of the O-glycoprotein podoplanin was lost, while Tn antigen, representing immature O-glycans, was most abundantly found on podocalyxin. In contrast to hemizygous male and homozygous female animals, heterozygous female mosaic animals developed only mild albuminuria, focal foot process effacement, and nonprogressive kidney disease. Ultrastructurally, Cosmc-deficient podocytes formed Tn antigen-positive foot processes interdigitating with those of normal podocytes but not with other Cosmc-deficient cells. This suggests a cell nonautonomous mechanism for mucin-type O-glycoproteins in maintaining podocyte function. In summary, our findings demonstrated an essential and likely cell nonautonomous role for mucin-type O-glycosylation for podocyte function.


Assuntos
Albuminúria/metabolismo , Chaperonas Moleculares/metabolismo , Mucinas/metabolismo , Podócitos/metabolismo , Insuficiência Renal/metabolismo , Albuminúria/genética , Albuminúria/patologia , Albuminúria/fisiopatologia , Animais , Antígenos Glicosídicos Associados a Tumores/metabolismo , Células Cultivadas , Feminino , Predisposição Genética para Doença , Glicosilação , Heterozigoto , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Chaperonas Moleculares/genética , Mosaicismo , Fenótipo , Podócitos/ultraestrutura , Insuficiência Renal/genética , Insuficiência Renal/patologia , Insuficiência Renal/fisiopatologia , Fatores Sexuais , Sialoglicoproteínas/metabolismo
2.
Angiology ; 71(3): 249-255, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31808357

RESUMO

Contrast-induced nephropathy (CIN) is one of the most important complications after invasive cardiovascular procedures. The neutrophil-to-lymphocyte ratio (NLR), mean platelet volume-to-lymphocyte ratio (MPVLR), and platelet-to-lymphocyte ratio (PLR) may be markers of the risk of CIN. We aimed to investigate the association of these indices with the development of CIN in patients with ST-elevation myocardial infarction and non-ST-elevation-acute coronary syndrome who underwent percutaneous coronary intervention. We retrospectively collected the data of patients with ACS after coronary angiography (CA); 564 patients were included (mean age, 62.3 ± 13.0 years; 41.1% female). We compared 62 (10.9%) patients who developed CIN and 502 patients who did not, after CA in terms of NLR, PLR, and MPVLR. Patients who developed CIN had significantly higher MPVLR, NLR, and PLR; the MPVLR (P ≤ .001) was an independent predictor of CIN. NLR, MPVLR, and PLR are simple, cheap, and easily accessible tests that can predict CIN; the MPVLR was the strongest of these predictors.


Assuntos
Síndrome Coronariana Aguda/fisiopatologia , Angiografia Coronária , Neutrófilos/citologia , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Adulto , Idoso , Plaquetas/citologia , Angiografia Coronária/métodos , Feminino , Humanos , Masculino , Volume Plaquetário Médio/métodos , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/metabolismo , Intervenção Coronária Percutânea/métodos , Insuficiência Renal/diagnóstico , Insuficiência Renal/metabolismo , Estudos Retrospectivos , Fatores de Risco
3.
Life Sci ; 239: 116868, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31682847

RESUMO

BACKGROUND: Sepsis is an inflammatory response undergoing the complicate pathophysiological changes for host defense against pathogens. Previous studies suggested that dexmedetomidine (DEX) was served to controlling the over-reactive inflammatory effects to protect from the sepsis-induced organ failure via modulating histone methylation. However, the genome-wide changes of histone methylations upon DEX for sepsis treatment were poorly explored. MATERIALS AND METHODS: The acute kidney injury (AKI) mouse model were induced by lipopolysaccharide (LPS). DEX and KDM5 (H3K4 demethylases) inhibitors were used to add additionally. H3K4me3 antibody was used to conduct the ChIP-seq assay in renal cortex tissues. RESULTS: We observed that the overall H3K4me3 levels were obviously declined in AKI group compared to the normal control. We further observed that the therapeutic effect of DEX was basically equal with CPI-455 and KDM5A-IN-1 but better than PBIT. The overall H3K4me3 level was reduced in AKI group compared to DEX (p = 0.008), and KDM5A-IN-1 groups (p = 0.022). The H3K4me3 enrichment of the multiple genes associated with inflammatory cytokines such as TNF-α, NOS2 and CCL2 increased in AKI model, but decreased upon DEX or KDM5A-IN-1 treatment. Consistently, transcription and protein levels of genes such as TLR4, MYD88, MTA1, PTGS2, CASP3 associated with NF-κB signaling pathway were all compromising after treated with DEX or KDM5A-IN-1 groups compared to AKI group. CONCLUSION: Taken together, our data determined that DEX could attenuate AKI through KDM5A inhibition in sepsis.


Assuntos
Dexmedetomidina/farmacologia , Proteína 2 de Ligação ao Retinoblastoma/metabolismo , Sepse/tratamento farmacológico , Lesão Renal Aguda/prevenção & controle , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Citocinas/metabolismo , Dexmedetomidina/metabolismo , Rim/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Substâncias Protetoras/farmacologia , Insuficiência Renal/tratamento farmacológico , Insuficiência Renal/metabolismo , Insuficiência Renal/prevenção & controle , Sepse/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
4.
Rev Esp Quimioter ; 32 Suppl 3: 11-16, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31364336

RESUMO

Ceftobiprole shows many similar pharmacokinetic properties to other cephalosporins, except for not being orally bioactive, and that it is administered by IV infusion as the prodrug ceftobiprole medocaril, which is subsequently hydrolyzed in the blood into the active molecule. Distribution focus in extracellular fluid and active antibiotic concentration has been proven in different corporal tissues using dosing regimen of 500 mg intravenous infusion over 2 h every 8 h. Ceftobiprole is eliminated exclusively into the urine, thus the reason why dose adjustment is required for patients with moderate or severe renal impairment, or increased creatinine clearance. However, there is no need for dose adjustments related with other comorbidities and patients' conditions such as age, body weight. Although considering distribution features, molecular weight and dose fraction, increase dosing regimen might be necessary in patients using renal replacement therapy. The half-life of ceftobiprole is more than 3 h, allowing to easily reach optimal PK/PD parameters with the infusion time of 2 h, using the usual dosing regimen.


Assuntos
Antibacterianos/farmacocinética , Cefalosporinas/farmacocinética , Fatores Etários , Antibacterianos/administração & dosagem , Antibacterianos/urina , Área Sob a Curva , Cefalosporinas/administração & dosagem , Cefalosporinas/metabolismo , Cefalosporinas/urina , Creatinina/metabolismo , Estado Terminal , Matriz Extracelular/metabolismo , Meia-Vida , Humanos , Infusões Intravenosas , Rim/metabolismo , Método de Monte Carlo , Obesidade/metabolismo , Pró-Fármacos/administração & dosagem , Pró-Fármacos/metabolismo , Insuficiência Renal/metabolismo , Terapia de Substituição Renal
5.
Rev Esp Quimioter ; 32 Suppl 3: 17-23, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31364337

RESUMO

Ceftobiprole is a fifth-generation cephalosporin with potent antimicrobial activity against Gram positive and Gram-negative bacteria. It has been approved in major European countries for the treatment of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP), excluding ventilator-associated pneumonia (VAP). Ceftobiprole is currently in a phase 3 clinical program for registration in the U.S. In 2015, it was designated as an infectious disease product qualified for the treatment of lung and skin infections by the FDA. The efficacy of ceftobiprole in pneumonia has been demonstrated in two-phase III clinical trials conducted in patients with CAP and HAP. The recommended dose in the adult with pneumonia is 500 mg every 8 h infused in 2 h; in case of renal failure, the regimen of administration must be adjusted according to the patient's renal function. It is not necessary to adjust the dose according to gender, age, body weight or liver failure. In case of hyperfiltration, an extension to 4 h infusion of the 500mg TID is required.


Assuntos
Antibacterianos/uso terapêutico , Cefalosporinas/uso terapêutico , Infecção Hospitalar/tratamento farmacológico , Pneumonia Bacteriana/tratamento farmacológico , Antibacterianos/administração & dosagem , Antibacterianos/metabolismo , Cefalosporinas/administração & dosagem , Cefalosporinas/metabolismo , Ensaios Clínicos como Assunto , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , Estado Terminal , Infecção Hospitalar/microbiologia , Esquema de Medicação , Humanos , Pneumonia Bacteriana/microbiologia , Insuficiência Renal/metabolismo
6.
Biomed Pharmacother ; 117: 109154, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387184

RESUMO

Gentamicin, an aminoglycoside drug, used for the treatment of Gram-negative bacterial infections. Despite its potency against bacterial infections, its clinical use is limited owing to nephrotoxicity effect. However, the study investigated the nephroprotective effect of fatty acids from ethanolic extract of Moringa oleifera seeds (EEMOS) against gentamicin-induced kidney injury in rats. Forty-five male Wistar rats, 100-160 g, were divided into 5 groups as follows: Group 1 (control), 5 rats, received 0.2 ml/100 g/day of propylene glycol orally for 28 days. Group 2, 10 rats, received 100 mg/kg/day (i.p) of gentamicin (GENT) for 8 days. Group 3-5, 10 rats each, treated with EEMOS orally for 28 days at graded doses of 100, 200 and 400 mg/kg respectively after GENT treatment. Twenty four after treatment, five rats from each group were sacrificed. The remaining 5 rats were sacrificed after 2 weeks recovery period from the drugs. The result showed that GENT elicited polyuria, elevated plasma creatinine, urea, and lower plasma electrolytes and creatinine clearance levels. Measurements of 24 h urinary output demonstrated marked decrease in creatinine and potassium levels in the GENT-treated group, whereas sodium level remain unchanged. Also, GENT caused significant decrease in superoxide dismutase and an increase in malondialdehyde levels in the kidney of the rats. Histopathological examination revealed evidence of necrosis of the kidney. Treatment with EEMOS significantly ameliorated the alterations caused by GENT in the plasma, urine and kidney homogenate of the rats. Hence, the mono- and poly-unsaturated fatty acids present in EEMOS were responsible for its renoprotective ability.


Assuntos
Ácidos Graxos/farmacologia , Rim/efeitos dos fármacos , Moringa oleifera/química , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Insuficiência Renal/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Creatinina/metabolismo , Etanol/química , Gentamicinas/farmacologia , Rim/metabolismo , Testes de Função Renal/métodos , Masculino , Malondialdeído/metabolismo , Ratos , Ratos Wistar , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/metabolismo , Sementes/química , Superóxido Dismutase/metabolismo
7.
Biopharm Drug Dispos ; 40(8): 307-311, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31426119

RESUMO

Plasma protein binding (PPB) can be different depending on the status of hepatic or renal functions. In this study, the PPB of lenvatinib was determined using equilibrium dialysis in plasma from healthy volunteers and from subjects with mild, moderate, or severe hepatic impairment or renal impairment. Plasma from these subjects, fortified with lenvatinib at four concentrations (20, 200, 500, or 1200 ng/ml), was dialysed against phosphate buffered saline (PBS), and then determinations of the total concentrations of lenvatinib in plasma and unbound concentrations in PBS were made. In addition, the binding of lenvatinib was determined in human serum albumin (HSA), α1 -acid glycoprotein (AAG), and human γ-globulin (HG) in order to identify major binding proteins in human plasma. The PPB of lenvatinib in subjects with HI or RI ranged from 97.5% to 98.2% in hepatic impairment and 98.0% to 98.4% in renal impairment, which was similar to that of healthy volunteers. The binding of lenvatinib to HSA, AAG, and HG was 96.6%-97.1%, 46.4%-69.9%, and 19.1%-23.9%, respectively. These findings suggest that lenvatinib mainly binds to HSA and neither renal nor hepatic impairment impacts the PPB of lenvatinib.


Assuntos
Antineoplásicos/administração & dosagem , Hepatopatias/metabolismo , Compostos de Fenilureia/administração & dosagem , Quinolinas/administração & dosagem , Insuficiência Renal/metabolismo , Adulto , Idoso , Antineoplásicos/farmacocinética , Proteínas Sanguíneas/metabolismo , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Humanos , Pessoa de Meia-Idade , Orosomucoide , Compostos de Fenilureia/farmacocinética , Ligação Proteica , Quinolinas/farmacocinética , Albumina Sérica/metabolismo , gama-Globulinas/metabolismo
8.
Clin Drug Investig ; 39(11): 1117-1123, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31435905

RESUMO

BACKGROUND: The orally active dual endothelin receptor antagonist aprocitentan targets a novel pathway in the treatment of hypertension and could be a key player in the treatment of salt/volume-dependent hypertension. Its pharmacokinetic profile supports a once-daily dosing strategy. OBJECTIVE: As hypertensive patients may also experience concomitant renal disease, the objectives of this study were to evaluate the pharmacokinetics and tolerability of aprocitentan in subjects with severe renal function impairment (SRFI) and compare these with matched healthy subjects. DESIGN, SETTING, PARTICIPANTS: In this open-label, single-center, phase 1 study (NCT03165071) eight subjects with SRFI (mean estimated glomerular filtration rate [eGFR] 21.9 mL/min/1.73 m2) and eight healthy subjects (mean eGFR 94.9 mL/min/1.73 m2) received a single dose of 50 mg of aprocitentan followed by an observation period of up to 17 days. Plasma pharmacokinetic parameters of aprocitentan were derived by noncompartmental analysis of the plasma concentration-time profiles. Differences in pharmacokinetic parameters were explored using geometric means ratio (GMR) and 90% confidence intervals (CIs) with SRFI subjects as test group and healthy subjects as reference group. Safety and tolerability evaluations included adverse events (AEs), electrocardiograms, vital signs, and clinical laboratory tests. RESULTS: All 16 subjects received aprocitentan and completed the study. The pharmacokinetics of aprocitentan were similar in SRFI and healthy subjects with maximum plasma concentrations reached at 7.6 h and 5.0 h, respectively. Maximum plasma concentrations did not differ as indicated by a GMR (90% CI) of 1.04 (0.85-1.28). Due to a slightly lower observed clearance in SRFI subjects, half-life was longer (53.2 h compared to 47.4 h in healthy subjects), while exposure expressed as area under the curve was 34% higher (GMR 90% CI 1.13-1.58). There were no differences in plasma protein binding (> 99% bound). Aprocitentan was well tolerated in subjects with SRFI with no notable difference compared to healthy subjects. CONCLUSIONS: Based on these single-dose results, subjects with mild, moderate, or severe renal function can be included in clinical studies without the need for dose adjustment.


Assuntos
Antagonistas dos Receptores de Endotelina/farmacocinética , Rim/efeitos dos fármacos , Pirimidinas/farmacocinética , Insuficiência Renal/metabolismo , Sulfonamidas/farmacocinética , Adulto , Antagonistas dos Receptores de Endotelina/uso terapêutico , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Humanos , Rim/fisiologia , Masculino , Pessoa de Meia-Idade , Pirimidinas/uso terapêutico , Insuficiência Renal/tratamento farmacológico , Sulfonamidas/uso terapêutico
9.
Int J Mol Sci ; 20(15)2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357488

RESUMO

The use of donors deceased after brain death (DBD) with extended criteria in response to the shortage of grafts leads to the removal of more fragile kidneys. These grafts are at greater risk of not being grafted or delayed function. A better knowledge of the pathophysiology of DBDs would improve this situation. There is a difference between the results from animal models of DBD and the clinical data potentially explained by the kinetics of brain death induction. We compared the effect of the induction rate of brain death on the recovery of post-transplant renal function in a pig model of DBD followed by allografts in nephrectomized pigs. Resumption of early function post-transplant was better in the rapidly generated brain death group (RgBD) and graft fibrosis at three months less important. Two groups had identical oxidative stress intensity but a greater response to this oxidative stress by SIRT1, PGC1-α and NRF2 in the RgBD group. Modulation of mechanistic target of rapamycin (mTOR) stimulation by NRF2 would also regulate the survival/apoptosis balance of renal cells. For the first time we have shown that an allostatic response to oxidative stress can explain the impact of the rapidity of brain death induction on the quality of kidney transplants.


Assuntos
Morte Encefálica/metabolismo , Transplante de Rim , Rim/metabolismo , Animais , Biomarcadores , Função Retardada do Enxerto , Endotélio Vascular/metabolismo , Fibrose , Rim/patologia , Túbulos Renais/metabolismo , Modelos Animais , Estresse Oxidativo , Insuficiência Renal/etiologia , Insuficiência Renal/metabolismo , Insuficiência Renal/patologia , Suínos , Fatores de Tempo , Doadores de Tecidos , Transplante Homólogo
10.
Eur J Clin Pharmacol ; 75(10): 1355-1360, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31243478

RESUMO

OBJECTIVE: Renal insufficiency may influence the pharmacokinetics of drugs. We have investigated the pharmacokinetic parameters of imrecoxib and its two main metabolites in individuals with osteoarthritis (OA) with normal renal function and renal insufficiency, respectively. METHODS: This was a prospective, parallel, open, matched-group study in which 24 subjects were enrolled (renal insufficiency group, n = 12; healthy control group, n = 12). Blood samples of subjects administered 100 mg imrecoxib were collected at different time points and analyzed. Plasma concentrations of imrecoxib and its two metabolites (M1 and M2) were determined by the liquid chromatography-tandem mass spectrometry method, and pharmacokinetic parameters (clearance [CL], apparent volume of distribution [Vd], maximum (or peak) serum concentration [Cmax], amount of time drug is present in serum at Cmax [Tmax], area under the curve [AUC; total drug exposure across time], mean residence time [MRT] and elimination half-life [t1/2]) were calculated. RESULTS: The demographic characteristics of the two groups were not significantly different, with the exception of renal function. The mean Cmax and AUC0-t (AUC from time 0 to the last measurable concentration) of imrecoxib in the renal insufficiency group were 59 and 70%, respectively, of those of the healthy control volunteers with normal renal function, indicating a significant decline in the former group (P < 0. 05). The mean pharmacokinetic parameters of Ml in the renal insufficiency and healthy control groups did not significantly differ. In contrast, the mean Cmax and AUC0-t of M2 in the renal insufficiency group were 233 and 367%, respectively, of those of the normal renal function group, indicating a significant increase in the former group (P < 0.05). The mean CL/F (clearance/bioavailability) of M2 of the renal insufficiency group was 37% of that of the normal renal function group, indicating a notable reduction in the former group (P < 0.05). CONCLUSION: The exposure of imrecoxib in OA patients with renal insufficiency showed a decline compared to that in healthy subjects. However, in patients with renal insufficiency the exposure of M2 was markedly increased and the CL was noticeably reduced. These results indicate that the dosage of imrecoxib should be reduced appropriately in patients with renal insufficiency.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacocinética , Pirróis/farmacocinética , Insuficiência Renal/metabolismo , Sulfetos/farmacocinética , Adulto , Idoso , Inibidores de Ciclo-Oxigenase 2/sangue , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Pirróis/sangue , Pirróis/uso terapêutico , Insuficiência Renal/tratamento farmacológico , Sulfetos/sangue , Sulfetos/uso terapêutico
11.
Environ Res ; 174: 143-151, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31077989

RESUMO

Associations between selected perfluoroalkyl acids (PFAAs) and biomarkers of renal function were evaluated for US adult aged ≥ 20 years (N = 8220) in the National Health and Nutrition Examination Survey for 2005-2014. Glomerular filtration (GF) stage-stratified regression models were classified by estimated glomerular filtration rate (eGFR) with GF-1 (eGFR > 90 mL/min/1.73 m2), GF-2 (eGFR 60-89 mL/min/1.73 m2), GF-3A (45-59 mL/min/1.73 m2), and GF-3B/4 (15-44 mL/min/1.73 m2). For GF-1, PFOA, PFOS, and PFHxS were positively and significantly associated with serum creatinine. Serum albumin levels were positively associated with the PFAA considered at all stages and most associations were significant. Further, PFAS serum concentration associations to serum albumin were about 2-3 times stronger at GF-3B/4 than at GF-1. In contrast, urine albumin was negatively and significantly associated with PFOA and PFHxS serum concentrations at all stages of renal function, while, PFOS and PFNA were negatively and significantly associated to urine albumin at GF-3A and GF-3B/4. Urine albumin/creatinine ratios were negatively and significantly associated with PFOA, PFOS, and, and PFHxS serum concentrations at all stages of renal function, as well as with PFNA and PFDA at GF-3A and GF-3B/4. Recent work revealed that serum PFAAs have an inverted U-shaped association to the calculated stages of renal failure based on eGFR; this work adds that albuminuria makes additional negative contributions to already existing negative associations of PFAA to eGFR in advancing stages of renal failure. We hypothesize that both progressive renal failure per se and especially renal failure with albuminuria cause the kidneys to reabsorb less and to excrete more of the PFAAs studied. We suspect this finding may generalize to some other perfluoroalkyl substances (PFAS). The findings also imply study design considerations for evaluating associations to diseases and biomarkers associated with renal failure, such as diabetes.


Assuntos
Albuminas/metabolismo , Ácidos Alcanossulfônicos/sangue , Exposição Ambiental/estatística & dados numéricos , Poluentes Ambientais/sangue , Fluorcarbonetos/sangue , Insuficiência Renal/metabolismo , Adulto , Biomarcadores/metabolismo , Caprilatos , Creatinina/metabolismo , Humanos , Inquéritos Nutricionais , Estados Unidos , Adulto Jovem
12.
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
13.
Clin Sci (Lond) ; 133(9)2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988131

RESUMO

Renal vasoconstriction, an early manifestation of ischemic acute kidney injury (AKI), results in renal hypoperfusion and a rapid decline in kidney function. The pathophysiological mechanisms that underlie ischemia-reperfusion (IR)-induced renal insufficiency are poorly understood, but possibilities include alterations in ion channel-dependent renal vasoregulation. In the present study, we show that pharmacological activation of TRPV4 channels constricted preglomerular microvessels and elicited renal hypoperfusion in neonatal pigs. Bilateral renal ischemia followed by short-term reperfusion increased TRPV4 protein expression in resistance size renal vessels and TRPV4-dependent cation currents in renal vascular smooth muscle cells (SMCs). Selective TRPV4 channel blockers attenuated IR-induced reduction in total renal blood flow (RBF), cortical perfusion, and glomerular filtration rate (GFR). TRPV4 inhibition also diminished renal IR-induced increase in AKI biomarkers. Furthermore, the level of angiotensin II (Ang II) was higher in the urine of IR- compared with sham-operated neonatal pigs. IR did not alter renal vascular expression of Ang II type 1 (AT1) receptors. However, losartan, a selective AT1 receptor antagonist, ameliorated IR-induced renal insufficiency in the pigs. Blockade of TRPV4 channels attenuated Ang II-evoked receptor-operated Ca2+ entry and constriction in preglomerular microvessels. TRPV4 inhibition also blunted Ang II-induced increase in renal vascular resistance (RVR) and hypoperfusion in the pigs. Together, our data suggest that SMC TRPV4-mediated renal vasoconstriction and the ensuing increase in RVR contribute to early hypoperfusion and renal insufficiency elicited by renal IR in neonatal pigs. We propose that multimodal signaling by renal vascular SMC TRPV4 channels controls neonatal renal microcirculation in health and disease.


Assuntos
Losartan/farmacologia , Circulação Renal/efeitos dos fármacos , Insuficiência Renal/tratamento farmacológico , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Animais Recém-Nascidos , Pressão Sanguínea/efeitos dos fármacos , Taxa de Filtração Glomerular/efeitos dos fármacos , Isquemia/tratamento farmacológico , Isquemia/fisiopatologia , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Substâncias Protetoras/farmacologia , Receptores de Angiotensina/efeitos dos fármacos , Receptores de Angiotensina/metabolismo , Insuficiência Renal/metabolismo , Suínos , Canais de Cátion TRPV/metabolismo , Vasoconstrição/efeitos dos fármacos
14.
Curr Drug Metab ; 20(5): 361-376, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30947665

RESUMO

BACKGROUND: Evidence has revealed that renal impairment can affect the systemic exposure of drugs which are predominantly eliminated via the liver. The modulation of drug-metabolizing enzymes and transporters expressed in the liver and/or small intestine by diverse entities, including uremic toxins, in systemic circulation of patients with severe renal failure is considered as the cause of atypical pharmacokinetics, which sometimes induce undesirable adverse events that are especially critical for drugs with narrow therapeutic window such as anticancer drugs. A dosing strategy for anticancer drugs in these patients needs to be established. METHODS: The effects of renal impairment on the systemic exposure and safety of anticancer drugs were summarized. The proposed mechanisms for the alterations in the pharmacokinetics of these anticancer drugs were also discussed. RESULTS: Changes in pharmacokinetics and clinical response were reported in 9 out of 10 cytotoxic anticancer drugs investigated, although available information was limited and sometimes controversial. Systemic exposure of 3 out of 16 tyrosine kinase inhibitors was higher in patients with severe renal failure than that in patients with normal kidney function. An increase in systemic exposure of anticancer drugs in patients with renal impairment is likely to be observed for substrates of OATP1B1, despite the limited evidence. CONCLUSION: The molecular basis for the effect of uremia on non-renal drug elimination still needed to be clarified with further studies to generate generalizable concepts, which may provide insights into establishing better clinical usage of anticancer drugs, i.e. identifying patients at risk and dose adjustment.


Assuntos
Antineoplásicos/farmacocinética , Fígado/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Insuficiência Renal/metabolismo , Animais , Humanos
15.
Biopharm Drug Dispos ; 40(5-6): 176-187, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30985942

RESUMO

We previously verified a physiologically based pharmacokinetic (PBPK) model for mirabegron in healthy subjects using the Simcyp Simulator by incorporating data on the inhibitory effect on cytochrome P450 (CYP) 2D6 and a multi-elimination pathway mediated by CYP3A4, uridine 5'-diphosphate-glucuronosyltransferase (UGT) 2B7 and butyrylcholinesterase (BChE). The aim of this study was to use this PBPK model to assess the magnitude of drug-drug interactions (DDIs) in an elderly population with severe renal impairment (sRI), which has not been evaluated in clinical trials. We first determined the system parameters, and meta-analyses of literature data suggested that the abundance of UGT2B7 and the BChE activity in an elderly population with sRI was almost equivalent to and 20% lower than that in healthy young subjects, respectively. Other parameters, such as the CYP3A4 abundance, for an sRI population were used according to those built into the Simcyp Simulator. Second, we confirmed that the PBPK model reproduced the plasma concentration-time profile for mirabegron in an sRI population (simulated area under the plasma concentration-time curve (AUC) was within 1.5-times that of the observed value). Finally, we applied the PBPK model to simulate DDIs in an sRI population. The PBPK model predicted that the AUC for mirabegron with itraconazole (a CYP3A4 inhibitor) was 4.12-times that in healthy elderly subjects administered mirabegron alone, and predicted that the proportional change in AUC for desipramine (a CYP2D6 substrate) with mirabegron was greater than that in healthy subjects. In conclusion, the PBPK model was verified for the purpose of DDI assessment in an elderly population with sRI.


Assuntos
Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Modelos Biológicos , Insuficiência Renal/metabolismo , Tiazóis/farmacocinética , Acetanilidas/sangue , Adolescente , Agonistas de Receptores Adrenérgicos beta 3/sangue , Adulto , Idoso , Envelhecimento/metabolismo , Butirilcolinesterase/metabolismo , Inibidores do Citocromo P-450 CYP2D6/sangue , Inibidores do Citocromo P-450 CYP2D6/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/sangue , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Desipramina/sangue , Desipramina/farmacocinética , Interações Medicamentosas , Feminino , Genfibrozila/sangue , Genfibrozila/farmacocinética , Glucuronosiltransferase/metabolismo , Humanos , Itraconazol/sangue , Itraconazol/farmacocinética , Lorazepam/sangue , Lorazepam/farmacocinética , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/sangue , Tiazóis/sangue , Adulto Jovem , Zidovudina/sangue , Zidovudina/farmacocinética
16.
Cancer Sci ; 110(6): 1987-1994, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30989775

RESUMO

Although dose reduction of S-1 is recommended for patients with impaired renal function, dose modification for such patients has not been prospectively evaluated. The aim of the present study was to investigate the pharmacokinetic parameters of 5-fluorouracil, 5-chloro-2,4 dihydroxypyridine and oteracil potassium, and to review the recommended dose modification of S-1 in patients with renal impairment. We classified patients receiving S-1 into 4 groups according to their renal function, as measured using the Japanese estimated glomerular filtration rate (eGFR) equation. The daily S-1 dose was adjusted based on the patient's eGFR and body surface area. Blood samples were collected for pharmacokinetic analysis. A total of 33 patients were enrolled and classified into 4 groups as follows: 10 patients in cohort 1 (eGFR ≥ 80 mL/min/1.73 m2 ), 10 patients in cohort 2 (eGFR = 50-79 mL/min/1.73 m2 ), 10 patients in cohort 3 (eGFR = 30-49 mL/min/1.73 m2 ), and 3 patients in cohort 4 (eGFR < 30 mL/min/1.73 m2 ). Those in cohorts 3 and 4 treated with an adjusted dose of S-1 showed a similar area under the curve for 5-fluorouracil (941.9 ± 275.6 and 1043.5 ± 224.8 ng/mL, respectively) compared with cohort 2 (1034.9 ± 414.3 ng/mL). Notably, while there was a statistically significant difference between cohort 1 (689.6 ± 208.8 ng/mL) and 2 (P = 0.0474) treated with an equal dose of S-1, there was no significant difference observed in the toxicity profiles of the cohorts. In conclusion, dose adjustment of S-1 in patients with impaired renal function using eGFR is appropriate and safe.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Insuficiência Renal/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Estudos de Coortes , Combinação de Medicamentos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/farmacocinética , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Ácido Oxônico/farmacocinética , Insuficiência Renal/complicações , Insuficiência Renal/metabolismo , Neoplasias Gástricas/complicações , Neoplasias Gástricas/metabolismo , Tegafur/administração & dosagem , Tegafur/efeitos adversos , Tegafur/farmacocinética
17.
Int J Mol Sci ; 20(3)2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30736366

RESUMO

Pemafibrate (K-877) is a novel selective peroxisome proliferator-activated receptor-α modulator (SPPARMα) with a favorable benefit-risk balance. Previous clinical trials of pemafibrate used stringent exclusion criteria related to renal functions. Therefore, we investigated its safety and efficacy in a broader range of patients, including those with chronic kidney disease (CKD). In this multicenter, single-arm, open-label, phase III trial, 0.2⁻0.4 mg/day pemafibrate was administered for 52 weeks to 189 patients with hypertriglyceridemia and an estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m² on statin or regardless of eGFR when statin was not administered. Post-hoc analyses were performed on subgroups stratified by baseline eGFR. Triglyceride levels decreased by 45.9% at week 52 (last-observation-carried-forward). These reductions were not correlated with baseline eGFR. The eGFR < 30 mL/min/1.73 m² subgroup showed the greatest reduction in chylomicron, very low-density lipoprotein, small low-density lipoprotein cholesterol levels, and an increase in high-density lipoprotein cholesterol levels. The incidences of adverse events and adverse drug reactions were 82.0% and 31.7%, respectively, and these were not associated with baseline eGFR. In CKD patients, pemafibrate blood concentrations were not elevated. Pemafibrate showed a good safety profile and efficacy in correcting lipid abnormalities in a broad range of patients, including those with CKD.


Assuntos
Benzoxazóis/uso terapêutico , Butiratos/uso terapêutico , Dislipidemias/complicações , Dislipidemias/tratamento farmacológico , PPAR alfa/antagonistas & inibidores , Insuficiência Renal/complicações , Idoso , Benzoxazóis/administração & dosagem , Benzoxazóis/efeitos adversos , Biomarcadores , Butiratos/administração & dosagem , Butiratos/efeitos adversos , Dislipidemias/diagnóstico , Dislipidemias/metabolismo , Feminino , Humanos , Testes de Função Renal , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , PPAR alfa/metabolismo , Insuficiência Renal/diagnóstico , Insuficiência Renal/metabolismo , Resultado do Tratamento
18.
Med Hypotheses ; 124: 95-97, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30798927

RESUMO

In this article, we hypothesize that eating a low acid (and particularly a low phosphate) diet and/or supplementing the diet with base precursors such as bicarbonate would have a number of helpful effects on aging, by:Although the present data is mainly from studies in invertebrate and small animal models, extrapolation of these results, as well as some associated results in human studies, suggests that low acid diets, or neutralization of the low grade metabolic acidosis seen in aging human subjects would possibly allow us to live longer and remain healthier.


Assuntos
Acidose/fisiopatologia , Envelhecimento , Bicarbonatos/metabolismo , Dieta , Rim/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Estudos de Coortes , Creatinina , Regulação para Baixo , Glucuronidase/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Pessoa de Meia-Idade , Fosfatos/metabolismo , Ratos , Insuficiência Renal/metabolismo , Telomerase/metabolismo , Telômero/metabolismo , Adulto Jovem
20.
Ageing Res Rev ; 49: 144-164, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30391754

RESUMO

There are numerous theories of aging, a process which still seems inevitable. Aging leads to cancer and multi-systemic disorders as well as chronic diseases. Decline in age- associated cellular functions leads to neurodegeneration and cognitive decline that affect the quality of life. Accumulation of damage, mutations, metabolic changes, failure in cellular energy production and clearance of altered proteins over the lifetime, and hyperhomocysteinemia, ultimately result in tissue degeneration. The decline in renal functions, nutritional deficiencies, deregulation of methionine cycle and deficiencies of homocysteine remethylation and transsulfuration cofactors cause elevation of homocysteine with advancing age. Abnormal accumulation of homocysteine is a risk factor of cardiovascular, neurodegenerative and chronic kidney disease. Moreover, approximately 50% of people, aged 65 years and older develop hypertension and are at a high risk of developing cardiovascular insufficiency and incurable neurodegenerative disorders. Increasing evidence suggests inverse relation between cognitive impairment, cerebrovascular and cardiovascular events and renal function. Oxidative stress, inactivation of nitric oxide synthase pathway and mitochondria dysfunction associated with impaired homocysteine metabolism lead to aging tissue degeneration. In this review, we examine impact of high homocysteine levels on changes observed with aging that contribute to development and progression of age associated diseases.


Assuntos
Envelhecimento/metabolismo , Doença Crônica , Homocisteína/metabolismo , Idoso , Doenças Ósseas/etiologia , Doenças Ósseas/metabolismo , Perda Auditiva/etiologia , Perda Auditiva/metabolismo , Humanos , Hiper-Homocisteinemia , Metionina/metabolismo , Qualidade de Vida , Insuficiência Renal/etiologia , Insuficiência Renal/metabolismo , Fatores de Risco
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