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1.
Cell Physiol Biochem ; 55(S4): 68-95, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34523304

RESUMO

Protein homeostasis strongly depends on the targeted and selective removal of unneeded or flawed proteins, of protein aggregates, and of damaged or excess organelles by the two main intracellular degradative systems, namely the ubiquitin proteasomal system (UPS) and the autophagosomal lysosomal system. Despite representing completely distinct mechanisms of degradation, which underlie differing regulatory mechanisms, growing evidence suggests that the UPS and autophagy strongly interact especially in situations of overwhelming and impairment, and that both are involved in podocyte proteostasis and in the pathogenesis of podocyte injury. The differential impact of autophagy and the UPS on podocyte biology and on podocyte disease development and progression is not understood. Recent advances in understanding the role of the UPS and autophagy in podocyte biology are reviewed here.


Assuntos
Autofagia , Nefropatias , Podócitos , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , Animais , Autofagossomos/metabolismo , Autofagossomos/patologia , Humanos , Nefropatias/metabolismo , Nefropatias/patologia , Nefropatias/fisiopatologia , Lisossomos/metabolismo , Lisossomos/patologia , Podócitos/metabolismo , Podócitos/patologia
2.
Best Pract Res Clin Anaesthesiol ; 35(3): 449-459, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34511232

RESUMO

Coronavirus disease (COVID-19) causes many deleterious effects throughout the body. Prior studies show that the incidence of acute kidney injury in COVID-19 patients could be as high as 25%. There are also autopsy reports showing evidence of viral tropism to the renal system. In this regard, COVID-19 can damage the kidneys and increase a patient's risk of requiring dialysis. Available evidence suggests that renal involvement in COVID-19 infection is not uncommon, and there has been an increased incidence of chronic kidney disease related to the pandemic. In this literature analysis, we address COVID-19 and its effects on the renal system, including the pathophysiologic mechanisms. We also address current studies on the causes of injury to the renal system, the cause of kidney failure, its effect on mortality, the impact on dialysis patients, and the impact on renal transplant patients. COVID-19 disease may have unique features in individuals on chronic dialysis and kidney transplant recipients, requiring increased vigilance in limiting viral transmission in perioperative, in-patient, and dialysis center settings.


Assuntos
COVID-19/fisiopatologia , Nefropatias/fisiopatologia , Rim/fisiopatologia , COVID-19/epidemiologia , COVID-19/terapia , Humanos , Rim/virologia , Nefropatias/epidemiologia , Nefropatias/terapia , Nefropatias/virologia , Diálise Renal/métodos , Diálise Renal/tendências , Resultado do Tratamento
3.
Int J Public Health ; 66: 1603966, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335140

RESUMO

Objective: This study aimed to evaluate the associations between lifestyle factors and the estimated glomerular filtration rate (eGFR) levels in older adults by analyzing the United States National Health and Nutrition Examination Survey data (1999-2016). Methods: A total of 10,052 eligible participants were divided into two groups: reduced eGFR group (eGFR < 60 ml/min/1.73 m2) and normal group (eGFR ≥ 60 ml/min/1.73 m2). The primary factors were physical activity, alcohol consumption, smoking, and comorbidities. Results: Multivariable analysis revealed that older age, proteinuria, cardiovascular disease, diabetes, hyperuricemia, and hypertension were significantly associated with higher odds of reduced kidney function. Sufficient physical activity, current alcohol consumption, and being a current smoker were significantly associated with lower odds of reduced kidney function. However, subgroup analysis by sex revealed that the effects of proteinuria, current alcohol consumption, and sufficient physical activity were sex-specific. Conclusion: Several risk and beneficial factors for reduced kidney function in adults aged 65 and above in the United States were identified, but some of them might be sex-specific. Further studies are warranted to confirm these findings in other populations and countries.


Assuntos
Taxa de Filtração Glomerular , Nefropatias , Estilo de Vida , Idoso , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Nefropatias/epidemiologia , Nefropatias/fisiopatologia , Masculino , Inquéritos Nutricionais , Fatores de Risco , Estados Unidos/epidemiologia
4.
BMC Cancer ; 21(1): 894, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34353305

RESUMO

BACKGROUND: Because lenvatinib is well known to induce proteinuria by blocking the vascular endothelial growth factor (VEGF) pathway, renal function is a concern with long-term administration of lenvatinib. The long-term effects of lenvatinib on renal function in patients with advanced differentiated thyroid carcinoma (DTC) were analyzed. METHOD: This study involved 40 DTC patients who continued lenvatinib therapy for ≥6 months. Estimated glomerular filtration rate (eGFR) was calculated as an indicator of renal function. The temporal course of eGFR, effects of baseline eGFR on eGFR changes, and factors affecting renal impairment were investigated. RESULTS: The overall cohort showed sustainable decreases in eGFR, with decreased values of 11.4, 18.3, and 21.0 mL/min/1.73 m2 at 24, 36, and 48 months after starting treatment, respectively. No differences in eGFR decrease every 6 months were seen for three groups classified by baseline eGFR ≥90 mL/min/1.73 m2 (n = 6), < 90 but ≥60 mL/min/1.73 m2 (n = 26), or < 60 but ≥45 mL/min/1.73 m2 (n = 8). Grade 3 proteinuria was associated with declines in eGFR (p = 0.0283). Long observation period was also associated with decreases in eGFR (p = 0.0115), indicating that eGFR may decrease in a time-dependent manner. CONCLUSION: Lenvatinib can induce declines in eGFR, particularly with treatment duration > 2 years, regardless of baseline eGFR. Proteinuria is a risk factor for declines in eGFR. Patients who start lenvatinib with better renal function show a renal reserve capacity, prolonging clinical outcomes. Decision-making protocols must balance the benefits of lenvatinib continuation with acceptable risks of harm.


Assuntos
Antineoplásicos/efeitos adversos , Rim/efeitos dos fármacos , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Adulto , Idoso , Antineoplásicos/uso terapêutico , Feminino , Taxa de Filtração Glomerular , Humanos , Nefropatias/diagnóstico , Nefropatias/epidemiologia , Nefropatias/etiologia , Nefropatias/fisiopatologia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/epidemiologia , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
5.
Int J Mol Sci ; 22(16)2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34445179

RESUMO

The aim of the present study was to perform kidney messenger ribonucleic acid (mRNA) analysis in normotensive, Hannover Sprague-Dawley (HanSD) rats and hypertensive, Ren-2 renin transgenic rats (TGR) after doxorubicin-induced heart failure (HF) with specific focus on genes that are implicated in the pathophysiology of HF-associated cardiorenal syndrome. We found that in both strains renin and angiotensin-converting enzyme mRNA expressions were upregulated indicating that the vasoconstrictor axis of the renin-angiotensin system was activated. We found that pre-proendothelin-1, endothelin-converting enzyme type 1 and endothelin type A receptor mRNA expressions were upregulated in HanSD rats, but not in TGR, suggesting the activation of endothelin system in HanSD rats, but not in TGR. We found that mRNA expression of cytochrome P-450 subfamily 2C23 was downregulated in TGR and not in HanSD rats, suggesting the deficiency in the intrarenal cytochrome P450-dependent pathway of arachidonic acid metabolism in TGR. These results should be the basis for future studies evaluating the pathophysiology of cardiorenal syndrome secondary to chemotherapy-induced HF in order to potentially develop new therapeutic approaches.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Doxorrubicina/efeitos adversos , Insuficiência Cardíaca/induzido quimicamente , Hipertensão/genética , Nefropatias/induzido quimicamente , Rim/efeitos dos fármacos , Renina/genética , Animais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Hipertensão/complicações , Hipertensão/fisiopatologia , Rim/fisiopatologia , Nefropatias/genética , Nefropatias/fisiopatologia , Masculino , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Sistema Renina-Angiotensina/efeitos dos fármacos
6.
Nutrients ; 13(7)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34371925

RESUMO

Renal dysfunction and sarcopenia are important prognostic factors in patients with chronic liver disease (CLD). Muscle atrophy can cause the overestimation of renal function based on serum creatinine. However, the frequency of overestimated renal function in Japanese patients with CLD and its relationship with sarcopenia are unclear. In present study, we evaluated the frequency of overestimated renal function, defined as a >20% higher eGFR using creatinine than using cystatin C, in 307 patients with CLD as well as its relationship with indicators of sarcopenia. In total, 24.8% of patients had overestimated renal function. In a multivariate regression analysis, liver cirrhosis (p = 0.004) and psoas muscle mass index (p = 0.049) were significantly associated with overestimated renal function. Loss of skeletal muscle mass was significantly more frequent in both male and female patients with overestimated renal function than without. In males, the loss of muscle strength and rate of sarcopenia, defined as loss of muscle mass and strength, were significantly higher in patients with than without overestimated renal function. The high frequency of overestimated renal function in Japanese patients suggests that indicators of renal function should be carefully considered; furthermore, monitoring and interventions for both renal function and sarcopenia are needed in patients with CLD.


Assuntos
Composição Corporal , Taxa de Filtração Glomerular , Nefropatias/fisiopatologia , Rim/fisiopatologia , Hepatopatias/fisiopatologia , Músculos Psoas/fisiopatologia , Sarcopenia/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doença Crônica , Creatinina/sangue , Cistatina C/sangue , Feminino , Humanos , Japão/epidemiologia , Nefropatias/diagnóstico , Nefropatias/epidemiologia , Hepatopatias/diagnóstico , Hepatopatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Músculos Psoas/diagnóstico por imagem , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sarcopenia/diagnóstico por imagem , Sarcopenia/epidemiologia , Tomografia Computadorizada por Raios X , Adulto Jovem
7.
Br J Anaesth ; 127(3): 415-423, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34246461

RESUMO

BACKGROUND: Remimazolam is a new benzodiazepine for procedural sedation and general anaesthesia. The aim of this study was to characterise its pharmacokinetic properties and safety in renally and hepatically impaired subjects. METHODS: Two separate trials were conducted in patients with hepatic (n=11) or renal impairment (n=11) compared with matched healthy subjects (n=9 and n=12, respectively). The hepatic impairment trial was an open-label adaptive 'Reduced Design' trial, using a single bolus of remimazolam 0.1 mg kg-1 i.v., whereas the renal impairment trial was an open-label trial of a single bolus dose of remimazolam 1.5 mg i.v. Remimazolam plasma concentrations over time were analysed by population pharmacokinetic modelling. RESULTS: Remimazolam pharmacokinetic properties were adequately described by a three-compartment, recirculatory model. Exposure in subjects with severe hepatic impairment was 38.1% higher (i.e. clearance was 38.1% lower) compared with healthy volunteers. This increase caused a slightly delayed recovery (8.0 min for healthy, 12.1 min for moderate, and 16.7 min for severe hepatic impairment). With renal impairment, plasma clearance was comparable with that measured in healthy subjects. Simulations of Cmax after a bolus dose of 10 mg showed no relevant impact of hepatic or renal impairment. The overall incidence of adverse events was low, and all adverse events were mild. CONCLUSIONS: As Cmax after a remimazolam bolus i.v. was not affected by hepatic or renal impairment, no dose adjustments are required. No unexpected adverse events related to remimazolam were seen in subjects with renal or hepatic impairment. CLINICAL TRIAL REGISTRATION: Hepatic impairment trial: ClinicalTrials.gov, NCT01790607 (https://clinicaltrials.gov/ct2/show/NCT01790607). Renal impairment trial: EudraCT Number: 2014-004575-23.


Assuntos
Benzodiazepinas/farmacocinética , Taxa de Filtração Glomerular , Hipnóticos e Sedativos/farmacocinética , Nefropatias/fisiopatologia , Rim/fisiopatologia , Hepatopatias/fisiopatologia , Fígado/fisiopatologia , Adulto , Benzodiazepinas/administração & dosagem , Benzodiazepinas/efeitos adversos , Benzodiazepinas/sangue , Simulação por Computador , Monitoramento de Medicamentos , Feminino , Humanos , Hungria , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/sangue , Injeções Intravenosas , Nefropatias/diagnóstico , Hepatopatias/diagnóstico , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Estados Unidos
8.
Pediatr Rheumatol Online J ; 19(1): 104, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193201

RESUMO

BACKGROUND: H syndrome (HS) is a rare autoinflammatory disease caused by a mutation in the solute carrier family 29, member 3 (SCL29A3) gene. It has a variable clinical presentation and little phenotype-genotype correlation. The pathognomonic sign of HS is cutaneous hyperpigmentation located mainly in the inner thighs and often accompanied by other systemic manifestations. Improvement after tocilizumab treatment has been reported in a few patients with HS. We report the first patient with HS who presented cardiogenic shock, multiorgan infiltration, and digital ischemia. CASE PRESENTATION: 8-year-old boy born to consanguineous parents of Moroccan origin who was admitted to the intensive care unit during the Coronavirus Disease-2019 (COVID-19) pandemic with tachypnoea, tachycardia, and oliguria. Echocardiography showed dilated cardiomyopathy and severe systolic dysfunction compatible with cardiogenic shock. Additionally, he presented with multiple organ dysfunction syndrome. SARS-CoV-2 polymerase chain reaction (PCR) and antibody detection by chromatographic immunoassay were negative. A previously ordered gene panel for pre-existing sensorineural hearing loss showed a pathological mutation in the SCL29A3 gene compatible with H syndrome. Computed tomography scan revealed extensive alveolar infiltrates in the lungs and multiple poor defined hypodense lesions in liver, spleen, and kidneys; adenopathy; and cardiomegaly with left ventricle subendocardial nodules. Invasive mechanical ventilation, broad antibiotic and antifungal coverage showed no significant response. Therefore, Tocilizumab as compassionate use together with pulsed intravenous methylprednisolone was initiated. Improvement was impressive leading to normalization of inflammation markers, liver and kidney function, and stabilising heart function. Two weeks later, he was discharged and has been clinically well since then on two weekly administration of Tocilizumab. CONCLUSIONS: We report the most severe disease course produced by HS described so far in the literature. Our patient's manifestations included uncommon, new complications such as acute heart failure with severe systolic dysfunction, multi-organ cell infiltrate, and digital ischemia. Most of the clinical symptoms of our patient could have been explained by SARS-CoV-2, demonstrating the importance of a detailed differential diagnosis to ensure optimal treatment. Although the mechanism of autoinflammation of HS remains uncertain, the good response of our patient to Tocilizumab makes a case for the important role of IL-6 in this syndrome and for considering Tocilizumab as a first-line treatment, at least in severely affected patients.


Assuntos
Cardiomiopatia Dilatada/fisiopatologia , Doenças Hereditárias Autoinflamatórias/fisiopatologia , Isquemia/fisiopatologia , Insuficiência de Múltiplos Órgãos/fisiopatologia , Choque Cardiogênico/fisiopatologia , Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19 , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/terapia , Criança , Glucocorticoides/uso terapêutico , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/terapia , Humanos , Isquemia/terapia , Nefropatias/diagnóstico por imagem , Nefropatias/fisiopatologia , Nefropatias/terapia , Hepatopatias/diagnóstico por imagem , Hepatopatias/fisiopatologia , Hepatopatias/terapia , Pneumopatias/diagnóstico por imagem , Pneumopatias/fisiopatologia , Pneumopatias/terapia , Linfadenopatia/diagnóstico por imagem , Linfadenopatia/fisiopatologia , Linfadenopatia/terapia , Masculino , Metilprednisolona/uso terapêutico , Insuficiência de Múltiplos Órgãos/terapia , Proteínas de Transporte de Nucleosídeos/genética , Pulsoterapia , Respiração Artificial , SARS-CoV-2 , Choque Cardiogênico/terapia , Esplenopatias/diagnóstico por imagem , Esplenopatias/fisiopatologia , Esplenopatias/terapia , Dedos do Pé/irrigação sanguínea , Tomografia Computadorizada por Raios X , Resultado do Tratamento
9.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299260

RESUMO

The CD73 pathway is an important anti-inflammatory mechanism in various disease settings. Observations in mouse models suggested that CD73 might have a protective role in kidney damage; however, no direct evidence of its role in human kidney disease has been described to date. Here, we hypothesized that podocyte injury in human kidney diseases alters CD73 expression that may facilitate the diagnosis of podocytopathies. We assessed the expression of CD73 and one of its functionally important targets, the C-C chemokine receptor type 2 (CCR2), in podocytes from kidney biopsies of 39 patients with podocytopathy (including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous glomerulonephritis (MGN) and amyloidosis) and a control group. Podocyte CD73 expression in each of the disease groups was significantly increased in comparison to controls (p < 0.001-p < 0.0001). Moreover, there was a marked negative correlation between CD73 and CCR2 expression, as confirmed by immunohistochemistry and immunofluorescence (Pearson r = -0.5068, p = 0.0031; Pearson r = -0.4705, p = 0.0313, respectively), thus suggesting a protective role of CD73 in kidney injury. Finally, we identify CD73 as a novel potential diagnostic marker of human podocytopathies, particularly of MCD that has been notorious for the lack of pathological features recognizable by light microscopy and immunohistochemistry.


Assuntos
5'-Nucleotidase/genética , Nefropatias/metabolismo , Podócitos/metabolismo , 5'-Nucleotidase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Humanos , Rim/metabolismo , Rim/patologia , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Podócitos/fisiologia , Proteinúria , Receptores CCR2/genética , Receptores CCR2/metabolismo
10.
Biomolecules ; 11(6)2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34207942

RESUMO

Blood pressure (BP) follows a circadian rhythm, it increases on waking in the morning and decreases during sleeping at night. Disruption of the circadian BP rhythm has been reported to be associated with worsened cardiovascular and renal outcomes, however the underlying molecular mechanisms are still not clear. In this review, we briefly summarized the current understanding of the circadian BP regulation and provided therapeutic overview of the relationship between circadian BP rhythm and cardiovascular and renal health and disease.


Assuntos
Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/fisiopatologia , Ritmo Circadiano/fisiologia , Nefropatias/fisiopatologia , Doenças Cardiovasculares/metabolismo , Sistema Cardiovascular/fisiopatologia , China , Humanos , Hipertensão/fisiopatologia , Rim/fisiopatologia , Nefropatias/metabolismo
11.
BMC Cardiovasc Disord ; 21(1): 359, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330222

RESUMO

BACKGROUND: It is difficult to evaluate the risk of patients with severe renal dysfunction before surgery due to various limitations despite high postoperative cardiac events. This study aimed to investigate the value of a newly reclassified Revised Cardiac Risk Index (RCRI) that incorporates QRS fragmentation (fQRS) as a predictor of postoperative cardiac events in patients with severe renal dysfunction. METHODS: Among the patients with severe renal dysfunction, 256 consecutive patients who underwent both a nuclear stress test and noncardiac surgery were evaluated. We reclassified RCRI as fragmented RCRI (FRCRI) by integrating fQRS on electrocardiography. We defined postoperative major adverse cardiac event (MACE) as a composite of cardiac death, nonfatal myocardial infarction, and pulmonary edema. RESULTS: Twenty-eight patients (10.9%) developed postoperative MACE, and this was significantly frequent in patients with myocardial perfusion defect (41.4% vs. 28.0%, p = 0.031). fQRS was observed 84 (32.8%) patients, and it was proven to be an independent predictor of postoperative MACE after adjusting for the RCRI (odds ratio 3.279, 95% confidence interval (CI) 1.419-7.580, p = 0.005). Moreover, fQRS had an incremental prognostic value for the RCRI (chi-square = 7.8, p = 0.005), and to the combination of RCRI and age (chi-square = 9.1, p = 0.003). The area under curve for predicting postoperative MACE significantly increased from 0.612 for RCRI to 0.667 for FRCRI (p = 0.027) and 23 patients (32.4%) originally classified as RCRI 2 were reclassified as FRCRI 3. CONCLUSIONS: A newly reclassified FRCRI that incorporates fQRS, is a valuable predictor of postoperative MACE in patients with severe renal dysfunction undergoing noncardiac surgery.


Assuntos
Técnicas de Apoio para a Decisão , Eletrocardiografia , Cardiopatias/etiologia , Nefropatias/complicações , Rim/fisiopatologia , Isquemia Miocárdica/diagnóstico , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Feminino , Cardiopatias/diagnóstico , Cardiopatias/fisiopatologia , Humanos , Nefropatias/diagnóstico , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/complicações , Isquemia Miocárdica/fisiopatologia , Imagem de Perfusão do Miocárdio , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Tomografia Computadorizada de Emissão de Fóton Único , Resultado do Tratamento
12.
Nat Rev Drug Discov ; 20(10): 770-788, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34262140

RESUMO

Loss of normal kidney function affects more than 10% of the population and contributes to morbidity and mortality. Kidney diseases are currently treated with immunosuppressive agents, antihypertensives and diuretics with partial but limited success. Most kidney disease is characterized by breakdown of the glomerular filtration barrier (GFB). Specialized podocyte cells maintain the GFB, and structure-function experiments and studies of intercellular communication between the podocytes and other GFB cells, combined with advances from genetics and genomics, have laid the groundwork for a new generation of therapies that directly intervene at the GFB. These include inhibitors of apolipoprotein L1 (APOL1), short transient receptor potential channels (TRPCs), soluble fms-like tyrosine kinase 1 (sFLT1; also known as soluble vascular endothelial growth factor receptor 1), roundabout homologue 2 (ROBO2), endothelin receptor A, soluble urokinase plasminogen activator surface receptor (suPAR) and substrate intermediates for coenzyme Q10 (CoQ10). These molecular targets converge on two key components of GFB biology: mitochondrial function and the actin-myosin contractile machinery. This Review discusses therapies and developments focused on maintaining GFB integrity, and the emerging questions in this evolving field.


Assuntos
Barreira de Filtração Glomerular/efeitos dos fármacos , Barreira de Filtração Glomerular/fisiologia , Nefropatias/tratamento farmacológico , Nefropatias/fisiopatologia , Animais , Barreira de Filtração Glomerular/fisiopatologia , Humanos
14.
Int J Mol Sci ; 22(13)2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34281243

RESUMO

BACKGROUND: Bisphenol A (BPA) is a ubiquitous environmental toxin that accumulates in chronic kidney disease (CKD). Our aim was to explore the effect of chronic exposition of BPA in healthy and injured kidney investigating potential mechanisms involved. METHODS: In C57Bl/6 mice, administration of BPA (120 mg/kg/day, i.p for 5 days/week) was done for 2 and 5 weeks. To study BPA effect on CKD, a model of subtotal nephrectomy (SNX) combined with BPA administration for 5 weeks was employed. In vitro studies were done in human proximal tubular epithelial cells (HK-2 line). RESULTS: Chronic BPA administration to healthy mice induces inflammatory infiltration in the kidney, tubular injury and renal fibrosis (assessed by increased collagen deposition). Moreover, in SNX mice BPA exposure exacerbates renal lesions, including overexpression of the tubular damage biomarker Hepatitis A virus cellular receptor 1 (Havcr-1/KIM-1). BPA upregulated several proinflammatory genes and increased the antioxidant response [Nuclear factor erythroid 2-related factor 2 (Nrf2), Heme Oxygenase-1 (Ho-1) and NAD(P)H dehydrogenase quinone 1 (Nqo-1)] both in healthy and SNX mice. The autophagy process was modulated by BPA, through elevated autophagy-related gene 5 (Atg5), autophagy-related gene 7 (Atg7), Microtubule-associated proteins 1A/1B light chain 3B (Map1lc3b/Lc3b) and Beclin-1 gene levels and blockaded the autophagosome maturation and flux (p62 levels). This autophagy deregulation was confirmed in vitro. CONCLUSIONS: BPA deregulates autophagy flux and redox protective mechanisms, suggesting a potential mechanism of BPA deleterious effects in the kidney.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/farmacologia , Fenóis/efeitos adversos , Fenóis/farmacologia , Insuficiência Renal Crônica/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Compostos Benzidrílicos/metabolismo , Linhagem Celular , Feminino , Humanos , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/fisiopatologia , Túbulos Renais/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Fenóis/metabolismo , Insuficiência Renal Crônica/fisiopatologia
15.
Am J Kidney Dis ; 78(3): 442-458, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34275659

RESUMO

Medications are an important part of the management of patients with kidney disease. When used appropriately, pharmacotherapy can slow disease progression and reduce morbidity and mortality. Unfortunately, reduced kidney function can significantly alter the pharmacokinetics and pharmacodynamics of many medications, putting patients at risk for drug toxicity if modifications to therapy are not appropriately managed. Adding complexity to the appropriateness of medication and dosage selection is the difficulty in estimating kidney function and the discordance between the Cockcroft-Gault-derived dosing cut points in most medication package inserts and the estimations of glomerular filtration rate by newer and generally more accurate guideline-recommended equations. This installment of the AJKD Core Curriculum in Nephrology provides recent updates and practical considerations for designing optimal medication regimens. Given the prevalence of abnormal kidney function and its importance in medication selection and dose adjustment, additional focus and specific recommendations are provided for anticoagulant, anti-infective, analgesic, antidiabetic, and antihypertensive agents.


Assuntos
Currículo , Taxa de Filtração Glomerular/fisiologia , Nefropatias/tratamento farmacológico , Rim/fisiopatologia , Nefrologistas/normas , Humanos , Nefropatias/fisiopatologia
16.
Expert Rev Clin Pharmacol ; 14(9): 1173-1182, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34181499

RESUMO

Background: Arsenic trioxide (ATO) was successfully applied to treat acute promyelocytic leukemia (APL).Methods: Inorganic arsenic (iAs), monomethylarsonic acid (MMAV) and dimethyarsinic acid (DMAV) in plasma of 143 APL patients with different renal function were determined. Arsenic methylation capacity was evaluated by iAs%, MMAV%, DMAV%, primary methylation index (PMI, MMAV/iAs), and secondary methylated index (SMI, DMAV/MMAV). Arsenic accumulation with administration frequency were explored. Moreover, safety assessments were performed.Results: Compared with normal renal function, MMAV and DMAV concentrations increased 1.5-4 fold in moderate and severe renal impairment groups, iAs increased 1.3-1.7 fold. APL patients with renal impairment showed lower iAs%, but higher DMAV% and PMI in plasma than those with normal renal function (P < 0.05). MMAV, DMAV, and tAs apparently accumulated with administration frequency in moderate and severe renal dysfunction groups. The incidence of QTc interval prolongation and liver injury increased with the increasing severity of renal impairment.Conclusion: Renal dysfunction may increase exposure to arsenic and arsenic accumulation and affect methylation capacity, then the clinical safety in APL patients treated with ATO. Arsenic-level monitoring and dosing regimen adjustment should be considered in APL patients with moderate and severe renal dysfunction.


Assuntos
Antineoplásicos/administração & dosagem , Trióxido de Arsênio/administração & dosagem , Nefropatias/fisiopatologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Trióxido de Arsênio/efeitos adversos , Trióxido de Arsênio/farmacocinética , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Feminino , Humanos , Testes de Função Renal , Síndrome do QT Longo/induzido quimicamente , Masculino , Metilação , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
17.
Toxicol Appl Pharmacol ; 426: 115615, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102242

RESUMO

Current therapies for preeclampsia (PE) and its complications are limited and defective. Considering the importance of endothelin (ET) and thromboxane A2 (TXA2) signaling in PE pathophysiology, we tested the hypothesis that prenatal blockade of endothelin ETA or thromboxane TXA2 receptors favorably reprograms preeclamptic cardiovascular and renal insults. PE was induced by daily oral administration of L-NAME (50 mg/kg) to pregnant rats for 7 consecutive days starting from gestational day 14. The effects of co-exposure to atrasentan (ETA receptor blocker, 10 mg/kg/day) or terutroban (TXA2 receptor blocker, 10 mg/kg/day) on cardiovascular and renal anomalies induced by PE were assessed on gestational day 20 (GD20) and at weaning time and compared with those evoked by the sympatholytic drug α-methyldopa (α-MD, 100 mg/kg/day), a prototypic therapy for PE management. Among all drugs, terutroban was basically the most potent in ameliorating PE-evoked increments in blood pressure and decrements in creatinine clearance. Cardiorenal tissues of PE rats exhibited significant increases in ETA and TXA2 receptor expressions and these effects disappeared after treatment with atrasentan and to a lesser extent by terutroban or α-MD. Atrasentan was also the most effective in reversing the reduced ETB receptor expression in renal tissues of PE rats. Signs of histopathological damage in cardiac and renal tissues of PE rats were mostly improved by all therapies. Together, pharmacologic elimination of ETA or TXA2 receptors offers a relatively better prospect than α-MD in controlling perinatal cardiorenal irregularities sparked by PE.


Assuntos
Atrasentana/uso terapêutico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Cardiopatias/prevenção & controle , Nefropatias/prevenção & controle , Naftalenos/uso terapêutico , Pré-Eclâmpsia/tratamento farmacológico , Propionatos/uso terapêutico , Receptores de Tromboxano A2 e Prostaglandina H2/antagonistas & inibidores , Animais , Atrasentana/farmacologia , Antagonistas do Receptor de Endotelina A/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Cardiopatias/genética , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/genética , Nefropatias/patologia , Nefropatias/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Naftalenos/farmacologia , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Propionatos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/genética , Receptores de Tromboxano A2 e Prostaglandina H2/genética
18.
Int J Mol Sci ; 22(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064558

RESUMO

The discovery and characterization of sirtuins as NAD+-dependent deacylases have transformed our understanding of post-translational protein regulation [...].


Assuntos
Inflamação/fisiopatologia , Nefropatias/fisiopatologia , Neoplasias/fisiopatologia , Sirtuínas/metabolismo , Animais , Humanos , Inflamação/metabolismo , Nefropatias/metabolismo , Neoplasias/metabolismo
19.
Angiology ; 72(8): 762-769, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33966501

RESUMO

This study evaluated the impact of the baseline estimated glomerular filtration rate (eGFR) on clinical and angiographic outcomes and long-term in-stent restenosis (ISR) rates in patients undergoing elective carotid artery stenting (CAS) procedures. Consecutive patients who underwent CAS were retrospectively enrolled (n = 456). At the end of 3 years of follow-up, patients who had died or were lost follow-up were excluded from the study and a final analysis was performed using data from the remaining 405 patients. The study population (n = 405) was divided into 3 tertiles based on the tertile values of the eGFR level (T1, T2, and T3); then, clinical and procedural characteristics and 3-year ISR rates were compared between the groups. An ISR of 50% was detected in 49 (12%) surviving patients. The 3-year ISR was higher among patients with the lowest eGFR values (T1) by 3.7 times (95% CI: 2.01-11.38) than that among patients with the highest eGFR values (T3). These significant relationships persisted following adjustment for confounders. A lower baseline eGFR level was significantly associated with an increased ISR rate. Decreased renal function may be a predictor of ISR after CAS using first-generation stents.


Assuntos
Angioplastia com Balão/efeitos adversos , Angioplastia com Balão/instrumentação , Estenose das Carótidas/terapia , Taxa de Filtração Glomerular , Nefropatias/fisiopatologia , Rim/fisiopatologia , Stents , Idoso , Idoso de 80 Anos ou mais , Estenose das Carótidas/complicações , Estenose das Carótidas/diagnóstico por imagem , Bases de Dados Factuais , Feminino , Humanos , Nefropatias/complicações , Nefropatias/diagnóstico , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Desenho de Prótese , Recidiva , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
20.
Int Heart J ; 62(3): 546-551, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34053999

RESUMO

Severe aortic stenosis (AS) is often accompanied by renal dysfunction, which portends a poor prognosis. Trans-catheter aortic valve replacement (TAVR) is an accepted therapy for patients with severe AS, whereas the prediction of persistent renal dysfunction following TAVR remains challenging. In this study, we aimed to evaluate the pre-procedural score to assess the reversibility of renal dysfunction following TAVR. A total of 2,588 patients with severe AS who received TAVR and were enrolled in the Optimized transCathEter vAlvular iNtervention (OCEAN-TAVI) multicenter registry (UMIN000020423) were retrospectively investigated and those with serum creatinine (Cre) data at baseline and one year following TAVR were included. The Cre score was calculated using the formula: 0.2 × (age [years]) + 3.6 × (baseline serum Cre [mg/dL]). This score was evaluated to assess the risk of persistent renal dysfunction defined as serum Cre level > 1.5 mg/dL at one year following TAVR. Of the 1705 patients (84.3 ± 5.0 years old) included, 246 (14%) had persistent renal dysfunction following TAVR. The Cre score predicted the incidence of persistent renal dysfunction with an adjusted incidence rate ratio of 1.48 (95% confidence interval 1.42-1.56) with a cutoff of 21.4 (43% versus 5%, P < 0.001). The Cre score also predicted 4-year survival following TAVR (70% versus 52%, P < 0.001) with an adjusted hazard ratio of 1.75 (95% confidence interval 1.29-2.37). In conclusion, the Cre score identified those with a high risk of one-year persistent renal dysfunction following TAVR. The implication of Cre score-guided therapeutic strategy is the next concern.


Assuntos
Estenose da Valva Aórtica/cirurgia , Creatinina/sangue , Nefropatias/fisiopatologia , Substituição da Valva Aórtica Transcateter/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/complicações , Feminino , Humanos , Incidência , Japão/epidemiologia , Nefropatias/sangue , Nefropatias/epidemiologia , Nefropatias/etiologia , Masculino , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Sistema de Registros , Estudos Retrospectivos , Índice de Gravidade de Doença , Substituição da Valva Aórtica Transcateter/mortalidade
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