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1.
Medicine (Baltimore) ; 99(45): e23008, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157946

RESUMO

Type A acute aortic dissection (TAAAD) carries a high mortality rate in the absence of surgical treatment. This study sought to determine whether combining the assessment of clinical and computed tomography (CT) findings can be used to predict the long-term all-cause mortality rate of patients with TAAAD.Eighty-five consecutive patients with TAAAD who had undergone CT imaging and surgery were retrospectively reviewed. For the clinical and CT findings, univariate testing followed by multivariate logistic regression analysis was conducted to identify independent predictors of death. Then, the area under the receiver operating characteristic curve of the combined prediction model was calculated.The long-term mortality rate was 34.1% in our cohort (a median follow-up period of 60 months). Multivariate logistic regression analysis identified the following presenting variables as predictors of death: male sex (odds ratio [OR]: 6.67; 95% confidence interval [CI]: 1.67-25.0; P = .007), kidney malperfusion (OR: 2.18; 95% CI: 1.16-4.1; P = .02), and descending aorta size (OR: 1.12; 95% CI: 1.00-1.25; P = .05). Receiver operating characteristic curve analysis revealed an area under the receiver operating characteristic curve of 0.84 when using the combined model for prediction of long-term all-cause mortality (P ≤ .01).The combined assessment of clinical and CT findings can reasonably predict the long-term prognosis of TAAAD with surgery.


Assuntos
Aneurisma Dissecante/mortalidade , Aneurisma Aórtico/mortalidade , Idoso , Aneurisma Dissecante/diagnóstico por imagem , Aneurisma Dissecante/cirurgia , Aorta Torácica/diagnóstico por imagem , Aneurisma Aórtico/diagnóstico por imagem , Aneurisma Aórtico/cirurgia , Feminino , Seguimentos , Humanos , Rim/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores Sexuais , Tomografia Computadorizada por Raios X
2.
Acta Cir Bras ; 35(9): e202000905, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33084735

RESUMO

PURPOSE: To determine the nephroprotective effect of NAC and Montelukast Sodium administration against the development of renal damage associated with long warm renal ischemia. METHODS: Twenty-seven rats were randomly divided into 3 study groups, which received NAC, montelukast and placebo, and 3 rats were included in the sham-treated control group. Medications were given 3 days before the procedure. DMSA renal scintigraphy was performed before and after surgery. The right renal pedicle was occluded for 45 min to induce ischemia and then subjected to reperfusion for 6 h (I/R groups). RESULTS: On pathological examination, the mean pathological scores of the montelukast and NAC groups were significantly lower than those of the placebo group. (p <0.05). In biochemical examination, significant differences were found in all parameter levels between the placebo group and the montelukast and NAC groups. (p <0.05) When postoperative DMSA renal scintigraphy measurements and renal function levels were compared, significant differences were found between the montelukast and NAC groups and the placebo and sham groups. CONCLUSION: The administration of NAC and montelukast sodium was seen to have a nephroprotective effect against the development of renal damage associated with warm renal ischemia.


Assuntos
Acetatos , Acetilcisteína , Quinolinas , Traumatismo por Reperfusão , Acetatos/farmacologia , Acetilcisteína/farmacologia , Animais , Rim/irrigação sanguínea , Quinolinas/farmacologia , Ratos , Ratos Wistar , Traumatismo por Reperfusão/prevenção & controle , Succímero , Tomografia Computadorizada por Raios X
3.
Medicine (Baltimore) ; 99(43): e22901, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120841

RESUMO

INTRODUCTION: Chemotherapeutic agents of direct cell damage play a role in initiating thrombotic microangiopathy (TMA), however still being underdiagnosed. Decitabine (DAC) is a pyrimidine analogue of the nucleoside cytidine, which can lead to injury to endothelium. Biopsy-proven DAC-induced kidney injury is rare. PATIENT CONCERNS: A 47-year-old Chinese man with membranous nephropathy presented recurrent edema and acute kidney injury after a 3-day course of low dose DAC infusion because of cyclophosphamide-relating thrombocytopenia. DIAGNOSIS: Laboratory data revealed nephrotic syndrome, hematuria, renal glycosuria and hypokalemia with hyperchloridemia. Renal pathological findings revealed TMA with secondary glomerular crescents formation (28%), partial foot process effacement and acute tubular necrosis. A diagnosis of DAC-induced renal TMA was considered. INTERVENTIONS: As DAC had been timely discontinued before admission, the patient only received supportive treatment. OUTCOMES: The patient achieved rapid remission of acute kidney injury after DAC withdrawal, and his serum creatinine further decreased to normal level after 6 months. CONCLUSION: Careful monitoring of renal function especially serum creatinine should be emphasized during DAC treatment.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Decitabina/efeitos adversos , Glomérulos Renais/patologia , Rim/patologia , Microangiopatias Trombóticas/induzido quimicamente , Lesão Renal Aguda/etiologia , Tratamento Conservador , Ciclofosfamida/efeitos adversos , Glomerulonefrite Membranosa/patologia , Humanos , Imunossupressores/efeitos adversos , Rim/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/etiologia , Trombocitopenia/induzido quimicamente , Suspensão de Tratamento
7.
PLoS One ; 15(6): e0234861, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32603330

RESUMO

OBJECTIVE: To examine whether the cardiac, renal and uterine physiological hemodynamic changes during gestation are altered in rats with an early and prolonged exposure to a high fat diet (HFD). METHODS: Arterial pressure and cardiac, renal, uterine and radial arteries hemodynamic changes during gestation were examined in adult SD rats exposed to normal (13%) (n = 8) or high (60%) (n = 8) fat diets from weaning. Plethysmography, high-resolution high-frequency ultrasonography and clearance of an inulin analog were used to evaluate the arterial pressure and hemodynamic changes before and at days 7, 14 and 19 of gestation. RESULTS: Arterial pressure was higher (P<0.05) in rats with high than in those with normal (NFD) fat diet before pregnancy (123 ±3 and 110 ±3 mmHg, respectively) and only decreased at day 14 of gestation in rats with NFD (98±4 mmHg, P<0.05). A significant increment in stroke volume (42 ±10%) and cardiac output (51 ±12%) was found at day 19 of pregnancy in rats with NFD. The changes in stroke volume and cardiac output were similar in rats with NFD and HFD. When compared to the values obtained before pregnancy, a transitory elevation in renal blood flow was found at day 14 of pregnancy in both groups. However, glomerular filtration rate only increased (P<0.05) in rats with NFD at days 14 (20 ±7%) and 19 (27 ±8%) of gestation. The significant elevations of mean velocity, and velocity time integral throughout gestation in radial (127 ±26% and 111 ±23%, respectively) and uterine (91 ±16% and 111 ±25%, respectively) arteries of rats with NFD were not found in rats with an early and prolonged HFD. SUMMARY: This study reports novel findings showing that the early and prolonged exposure to a HFD leads to a significant impairment in the renal, uterine and radial arteries hemodynamic changes associated to gestation.


Assuntos
Artérias/fisiopatologia , Vasos Coronários/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Fenômenos Fisiológicos da Nutrição Animal , Animais , Artérias/diagnóstico por imagem , Pressão Sanguínea/fisiologia , Vasos Coronários/diagnóstico por imagem , Feminino , Taxa de Filtração Glomerular/fisiologia , Rim/irrigação sanguínea , Modelos Animais , Gravidez , Ratos , Fluxo Sanguíneo Regional/fisiologia , Volume Sistólico/fisiologia , Ultrassonografia , Útero/irrigação sanguínea , Útero/diagnóstico por imagem
8.
Int J Hematol ; 112(4): 584-591, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32557125

RESUMO

A 66-year-old man with hypertension was diagnosed with chronic myelogenous leukemia in 1996. Treatment was started with hydroxycarbamide and imatinib 400 mg in 1996 + 6, which was increased to 600 mg. Although he achieved a complete cytogenic response in 1996 + 9, he could not continue imatinib because of edema; the regimen was changed to nilotinib 800 mg in 1996 + 13. After he achieved a molecular response better than 4.5 in 1996 + 19, he was referred to our hospital. His urinalysis had shown urine protein since 1996 + 13, and his creatinine level increased in 1996 + 16. Renal biopsy, performed in 1996 + 20, revealed abdominal distention and massive ascites. After the nilotinib dosage was reduced to 400 mg, liver biopsy, also performed in 1996 + 20, revealed hypertrophy of renal small blood vessels and endothelial cells of the hepatic artery and loss of endothelial cells of the renal glomeruli, portal vein, and hepatic sinusoids. Both renal and liver biopsies revealed marked pathological vascular damage. The patient took oral imatinib for approximately 3.5 years and nilotinib for 11 years. Pathological findings indicated a tendency for thrombosis, which could induce vascular occlusive disease. Accumulation of cases, such as the present case, is needed to further analyze the pathophysiological processes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Mesilato de Imatinib/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/efeitos adversos , Idoso , Substituição de Medicamentos , Humanos , Hidroxiureia/administração & dosagem , Mesilato de Imatinib/administração & dosagem , Rim/irrigação sanguínea , Rim/patologia , Fígado/irrigação sanguínea , Fígado/patologia , Masculino , Pirimidinas/administração & dosagem , Fatores de Tempo , Resultado do Tratamento
9.
Transplant Proc ; 52(5): 1544-1546, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32505503

RESUMO

BACKGROUND: Double kidney transplantation allows the use of marginal kidneys with a significant improvement in the recovery of renal function expected after transplantation, although with a greater anesthesiologic and surgical risk. One-sided positioning, more cautious in the event of functional exhaustion, can be complex due to vascular anomalies. MATERIALS AND METHODS: We report the case of 2 double unilateral kidney transplants with vascular reconstructions. The first is a double kidney transplant from a 83-year-old donor. Both kidneys (score 5) had 2 arteries and the arterial patch was not usable. A cryopreserved arterial graft was used for the packaging of an arterial axis with which a single T-L anastomosis was performed; the 2 veins were also joined with the packaging of a single anastomosis. The second case is a double kidney transplant from a cadaveric donor performed on a recipient suffering from severe diffuse atheromasia. The right kidney had 2 arteries and the left kidney had 3 arteries (both score 5). The aortic patches and veins of the 2 kidneys were joined together and a single arterial and venous anastomosis was performed. RESULTS: The course has been uneventful. In both cases there were no perioperative vascular complications. CONCLUSIONS: The use of marginal organs is an increasingly common reality. Bench vascular reconstructions can further increase donation resources, safely enhancing the transplantation of already marginal organs that would otherwise not be usable and allowing the contralateral vascular axis to be kept intact.


Assuntos
Transplante de Rim/métodos , Rim/irrigação sanguínea , Rim Único/cirurgia , Transplantes/irrigação sanguínea , Malformações Vasculares/cirurgia , Procedimentos Cirúrgicos Vasculares/métodos , Idoso , Idoso de 80 Anos ou mais , Anastomose Cirúrgica , Feminino , Humanos , Rim/cirurgia , Masculino , Pessoa de Meia-Idade , Reoperação/métodos , Transplantes/cirurgia
10.
Am J Kidney Dis ; 76(3): 431-435, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32479921

RESUMO

Coronavirus disease 2019 (COVID-19) is a contagious life-threatening infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent findings indicate an increased risk for acute kidney injury during COVID-19 infection. The pathophysiologic mechanisms leading to acute kidney injury in COVID-19 infection are unclear but may include direct cytopathic effects of the virus on kidney tubular and endothelial cells, indirect damage caused by virus-induced cytokine release, and kidney hypoperfusion due to a restrictive fluid strategy. In this report of 2 cases, we propose an additional pathophysiologic mechanism. We describe 2 cases in which patients with COVID-19 infection developed a decrease in kidney function due to kidney infarction. These patients did not have atrial fibrillation. One of these patients was treated with therapeutic doses of low-molecular-weight heparin, after which no further deterioration in kidney function was observed. Our findings implicate that the differential diagnosis of acute kidney injury in COVID-19-infected patients should include kidney infarction, which may have important preventive and therapeutic implications.


Assuntos
Lesão Renal Aguda/diagnóstico por imagem , Betacoronavirus , Infecções por Coronavirus/diagnóstico por imagem , Infarto/diagnóstico por imagem , Rim/irrigação sanguínea , Rim/diagnóstico por imagem , Pneumonia Viral/diagnóstico por imagem , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/etiologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Diagnóstico Diferencial , Heparina de Baixo Peso Molecular/farmacologia , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Infarto/tratamento farmacológico , Infarto/etiologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico
11.
Vasc Endovascular Surg ; 54(6): 553-557, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32476618

RESUMO

Renal arteriovenous shunts are direct communications between the supplying artery and draining vein without the presence of an intervening capillary bed. They can be traumatic or nontraumatic. Coils can be used for embolization of feeding arteries; however, they do not treat the nidus directly. We report a case in which proximal coil placement in feeding arteries led to recanalization of the renal AV shunt through collaterals, resulting in recurrent hematuria. The case was subsequently managed by embolizing the nidus by N-butyl 2-cyanoacrylate glue.


Assuntos
Malformações Arteriovenosas/terapia , Embolização Terapêutica , Embucrilato/administração & dosagem , Hematúria/etiologia , Rim/irrigação sanguínea , Malformações Arteriovenosas/complicações , Malformações Arteriovenosas/diagnóstico por imagem , Embolização Terapêutica/instrumentação , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva , Retratamento , Resultado do Tratamento
12.
Am J Physiol Renal Physiol ; 319(2): F149-F154, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32567347

RESUMO

Ischemia-reperfusion injury of the kidney is caused by the sudden and temporary obstruction of blood flow to the organ. Renal ischemia-reperfusion injury is associated with high morbidity and mortality, but effective therapies are lacking. Sexual dimorphism in renal injury has been acknowledged since the 1940s, and the possible role of sex hormones has been intensively investigated in the past decades. Clinical and experimental data demonstrate sexual differences in renal anatomy, physiology, and susceptibility to renal diseases including but not limited to ischemia-reperfusion injury. Some data suggest the protective role of female sex hormones, whereas others highlight the detrimental effect of male hormones in renal ischemia-reperfusion injury. Although the important role of sex hormones is evident, the exact underlying mechanisms remain to be elucidated. This review focuses on collecting the current knowledge about sexual dimorphism of renal ischemia-reperfusion injury, with emphasis on molecular mechanisms and potential novel therapeutic strategies.


Assuntos
Lesão Renal Aguda/fisiopatologia , Rim/irrigação sanguínea , Rim/fisiopatologia , Traumatismo por Reperfusão/fisiopatologia , Caracteres Sexuais , Animais , Hormônios Esteroides Gonadais/metabolismo , Humanos
13.
Am J Physiol Renal Physiol ; 319(1): F76-F83, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32475131

RESUMO

Acutely increased renal venous pressure (RVP) impairs renal function, but the long-term impact is unknown. We investigated whether chronic RVP elevation impairs baseline renal function and prevents exacerbation of renal dysfunction and cardiovascular instability upon further RVP increase. RVP elevation (20-25 mmHg) or sham operation (sham) was performed in rats. After 1 wk (n = 17) or 3 wk (n = 22), blood pressure, RVP, renal blood flow (RBF), renal vascular conductance (RVC), and glomerular filtration rate (GFR) were measured at baseline and during superimposed RVP increase. Chronic RVP elevation induced extensive renal venous collateral formation. RVP fell to 6 ± 1 mmHg at 1 wk and 3 ± 1 mmHg at 3 wk. Baseline blood pressure and heart rate were unaltered compared with sham. RBF, RVC, and GFR were reduced at 1 wk but normalized by 3 wk. Upon further RVP increase, the drop in mean arterial pressure was attenuated at 3 wk compared with 1 wk (P < 0.05), whereas heart rate fell comparably across all groups; the mean arterial pressure-heart rate relationship was disrupted at 1 and 3 wk. RBF fell to a similar degree as sham at 1 wk (-2.3 ± 0.7 vs. -3.9 ± 1.2 mL/min, P = 0.066); however, at 3 wk, this was attenuated compared with sham (-1.5 ± 0.5 vs. -4.2 ± 0.7 mL/min, P < 0.05). The drop in RVC and GFR was attenuated at 1 and 3 wk (P < 0.05). Thus, chronic RVP elevation induced by partial renal vein ligation elicits extensive renal venous collateral formation, and although baseline renal function is impaired, chronic RVP elevation in this manner induces protective adaptations in kidneys of healthy rats, which attenuates the hemodynamic response to further RVP increase.


Assuntos
Taxa de Filtração Glomerular/fisiologia , Hipertensão Renal/fisiopatologia , Rim/fisiopatologia , Circulação Renal/fisiologia , Veias Renais/fisiopatologia , Animais , Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Hemodinâmica/fisiologia , Rim/irrigação sanguínea , Masculino , Ratos , Ratos Endogâmicos Lew
14.
Adv Gerontol ; 33(2): 360-366, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32593253

RESUMO

The aim of the work was to assess the dynamics of ultrasound parameters of renal blood flow in patients with chronic obstructive pulmonary disease (COPD)and initial stages of chronic kidney disease (CKD) during treatment with inactive vitamin D. The study included 264 patients with COPD of 2-4 degrees of severity in combination with CKD of 1-2 stages: 135 patients of the main group and 129 patients of the control group. Each group was divided into 4 subgroups according to the value of FEV1 and vitamin D level. In the main group, the native vitamin D was prescribed according to the scheme providing maintenance of vitamin D level >34,3 ng/ml during the year, in the control group - according to the recommendations of the Russian Association of Endocrinologists. An ultrasound of the kidneys with the calculation of the resistance index (RI) and albuminuria level were carried out in all patients at inclusion into the study and after its completion. A decrease in the severity of albuminuria from A3 to A2 was revealed in 24,1% (16), and an increase in GFR - in 42,9% (58) patients of all patients in the main group. A statistically significant decrease in the renal artery resistance index was recorded in the group of patients with moderate COPD (GOLD 2) and vitamin D deficiency in the main group (p<0,05). The maintaining of vitamin D levels more than 34,3 ng/ml over 12 months in patients with COPD in combination with CKD stage 1-2 was associated with a decrease in the severity of albuminuria, with an increase in GFR, and statistically significant decrease of resistance index in renal arteries of patients with moderate clinical course of COPD (GOLD 2) and lack of vitamin D.


Assuntos
Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Fluxo Sanguíneo Regional/efeitos dos fármacos , Vitamina D/farmacologia , Vitamina D/uso terapêutico , Humanos , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/etiologia , Federação Russa , Índice de Gravidade de Doença , Deficiência de Vitamina D/fisiopatologia
15.
Life Sci ; 256: 117860, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32534037

RESUMO

Optimal tissue oxygenation is essential for its normal function. Suboptimal oxygenation or ischemia contributes to increased mortalities during various pathological conditions such as stroke, acute kidney injury (AKI), cardiac failure. Despite the rapid progression of renal tissue injury, the mechanism underlying renal ischemia/reperfusion injury (IRI) remains highly unclear. Experimental in vitro and in vivo models epitomizing the fundamental process is critical to the research of the pathogenesis of IRI and the development of plausible therapeutics. In this review, we describe the in vitro and in vivo models of IRI, ranges from proximal tubular cell lines to surgery-based animal models like clamping of both renal pedicles (bilateral IRI), clamping of one renal pedicle (unilateral IRI), clamping of one/or both renal arteries/or vein, or unilateral IRI with contralateral nephrectomy (uIRIx). Also, advanced technologies like three-dimensional kidney organoids, kidney-on-a-chip are explained. This review provides thoughtful information for establishing reliable and pertinent models for studying IRI-associated acute renal pathologies.


Assuntos
Nefropatias/fisiopatologia , Rim/fisiopatologia , Traumatismo por Reperfusão/fisiopatologia , Lesão Renal Aguda/fisiopatologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Humanos , Rim/irrigação sanguínea , Oxigênio/metabolismo , Artéria Renal/metabolismo , Reprodutibilidade dos Testes
16.
J Trauma Acute Care Surg ; 88(6): 783-788, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32459446

RESUMO

BACKGROUND: Delayed graft function (DGF), the need for dialysis in the first week following kidney transplant, affects approximately one quarter of deceased-donor kidney transplant recipients. Donor demographics, donor serum creatinine, and graft cold ischemia time are associated with DGF. However, there is no consensus on the optimal management of hemodynamic instability in organ donors after brain death (DBDs). Our objective was to determine the relationship between vasopressor selection during donor management and the development of DGF. METHODS: Prospective observational data, including demographic and critical care parameters, were collected for all DBDs managed by 17 organ procurement organizations from nine Organ Procurement and Transplantation Network Regions between 2012 and 2018. Recipient outcome data were linked with donor data through donor identification numbers. Donor critical care parameters, including type of vasopressor and doses, were recorded at three standardized time points during donor management. The analysis included only donors who received at least one vasopressor at all three time points. Vasopressor doses were converted to norepinephrine equivalent doses and analyzed as continuous variables. Univariate analyses were conducted to determine the association between donor variables and DGF. Results were adjusted for known predictors of DGF using binary logistic regression. RESULTS: Complete data were available for 5,554 kidney transplant recipients and 2,985 DBDs. On univariate analysis, donor serum creatinine, donor age, donor subtype, kidney donor profile index, graft cold ischemia time, phenylephrine dose, and dopamine dose were associated with DGF. After multivariable analysis, increased donor serum creatinine, donor age, kidney donor profile index, graft cold ischemia time, and phenylephrine dose remained independent predictors of DGF. CONCLUSION: Higher doses of phenylephrine were an independent predictor of DGF. With the exception of phenylephrine, the selection and dose of vasopressor during donor management did not predict the development of DGF. LEVEL OF EVIDENCE: Prognostic study, Level III.


Assuntos
Morte Encefálica/fisiopatologia , Cuidados Críticos/estatística & dados numéricos , Função Retardada do Enxerto/epidemiologia , Transplante de Rim/efeitos adversos , Rim/efeitos dos fármacos , Vasoconstritores/efeitos adversos , Adulto , Fatores Etários , Isquemia Fria/efeitos adversos , Cuidados Críticos/métodos , Função Retardada do Enxerto/etiologia , Função Retardada do Enxerto/prevenção & controle , Relação Dose-Resposta a Droga , Feminino , Humanos , Rim/irrigação sanguínea , Rim/fisiopatologia , Transplante de Rim/métodos , Transplante de Rim/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Fenilefrina/administração & dosagem , Fenilefrina/efeitos adversos , Estudos Prospectivos , Medição de Risco , Obtenção de Tecidos e Órgãos/métodos , Obtenção de Tecidos e Órgãos/estatística & dados numéricos , Vasoconstritores/administração & dosagem , Adulto Jovem
17.
Lab Invest ; 100(9): 1184-1196, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32366943

RESUMO

Acute kidney injury triggers a complex cascade of molecular responses that can culminate in maladaptive repair and fibrosis. We have previously reported that the matrix protein thrombospondin-1 (TSP1), binding its high affinity its receptor CD47, promotes acute kidney injury. However, the role of this pathway in promoting fibrosis is less clear. Hypothesizing that limiting TSP1-CD47 signaling is protective against fibrosis, we interrogated this pathway in a mouse model of chronic ischemic kidney injury. Plasma and renal parenchymal expression of TSP1 in patients with chronic kidney disease was also assessed. We found that CD47-/- mice or wild-type mice treated with a CD47 blocking antibody showed clear amelioration of fibrotic histological changes compared to control animals. Wild-type mice showed upregulated TSP1 and pro-fibrotic markers which were significantly abrogated in CD47-/- and antibody-treated cohorts. Renal tubular epithelial cells isolated from WT mice showed robust upregulation of pro-fibrotic markers following hypoxic stress or exogenous TSP1, which was mitigated in CD47-/- cells. Patient sera showed a proportionate correlation between TSP1 levels and worsening glomerular filtration rate. Immunohistochemistry of human kidney tissue demonstrated tubular and glomerular matrix localization of TSP1 expression in patients with CKD. These data suggest that renal tubular epithelial cells contribute to fibrosis by activating TSP1-CD47 signaling, and point to CD47 as a potential target to limit fibrosis following ischemic injury.


Assuntos
Antígeno CD47/metabolismo , Rim/metabolismo , Transdução de Sinais , Trombospondina 1/metabolismo , Animais , Antígeno CD47/genética , Células Cultivadas , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Fibrose , Humanos , Isquemia , Rim/irrigação sanguínea , Rim/patologia , Túbulos Renais/citologia , Túbulos Renais/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout
18.
PLoS One ; 15(5): e0233109, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32437461

RESUMO

Normalisation to standard reference gene(s) is essential for quantitative real-time polymerase chain reaction (RT-qPCR) to obtain reproducible and comparable results of a gene of interest (GOI) between subjects and under varying experimental conditions. There is limited evidence to support selection of the commonly used reference genes in rat ischaemic and toxicological kidney models. Employing these models, we determined the most stable reference genes by comparing 4 standard methods (NormFinder, qBase+, BestKeeper and comparative ΔCq) and developed a new 3-way linear mixed-effects model for evaluation of reference gene stability. This new technique utilises the intra-class correlation coefficient as the stability measure for multiple continuous and categorical covariates when determining the optimum normalisation factor. The model also determines confidence intervals for each candidate normalisation gene to facilitate selection and allow sample size calculation for designing experiments to identify reference genes. Of the 10 candidate reference genes tested, the geometric mean of polyadenylate-binding nuclear protein 1 (PABPN1) and beta-actin (ACTB) was the most stable reference combination. In contrast, commonly used ribosomal 18S and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were the most unstable. We compared the use of PABPN1×ACTB and 2 commonly used genes 18S and GAPDH on the expression of 4 genes of interest know to vary after renal injury and expressed by different kidney cell types (KIM-1, HIF1α, TGFß1 and PECAM1). The less stable reference genes gave varying patterns of GOI expression in contrast to the use of the least unstable reference PABPN1×ACTB combination; this improved detection of differences in gene expression between experimental groups. Reduced within-group variation of the now more accurately normalised GOI may allow for reduced experimental group size particularly for comparison between various models. This objective selection of stable reference genes increased the reliability of comparisons within and between experimental groups.


Assuntos
Regulação da Expressão Gênica , Isquemia/metabolismo , Nefropatias/metabolismo , Rim/irrigação sanguínea , Rim/metabolismo , Reação em Cadeia da Polimerase em Tempo Real/normas , Reação em Cadeia da Polimerase Via Transcriptase Reversa/normas , Actinas/biossíntese , Animais , Isquemia/patologia , Rim/patologia , Nefropatias/patologia , Proteína I de Ligação a Poli(A)/biossíntese , RNA Ribossômico 18S/biossíntese , Ratos , Padrões de Referência
20.
Am J Physiol Renal Physiol ; 319(1): F19-F28, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32463728

RESUMO

Scattered tubular-like cells (STCs) are dedifferentiated surviving tubular epithelial cells that repair neighboring injured cells. Experimental renal artery stenosis (RAS) impairs STC reparative potency by inducing mitochondrial injury, but the exact mechanisms of mitochondrial damage remain unknown. We hypothesized that RAS alters expression of mitochondria-related genes, contributing to mitochondrial structural damage and dysfunction in swine STCs. CD24+/CD133+ STCs were isolated from pig kidneys after 10 wk of RAS or sham (n = 3 each). mRNA sequencing was performed, and nuclear DNA (nDNA)-encoded mitochondrial genes and mitochondrial DNA (mtDNA)-encoded genes were identified. Mitochondrial structure, ATP generation, biogenesis, and expression of mitochondria-associated microRNAs were also assessed. There were 96 nDNA-encoded mitochondrial genes upregulated and 12 mtDNA-encoded genes downregulated in RAS-STCs versus normal STCs. Functional analysis revealed that nDNA-encoded and mtDNA-encoded differentially expressed genes were primarily implicated in mitochondrial respiration and ATP synthesis. Mitochondria from RAS STCs were swollen and showed cristae remodeling and loss and decreased ATP production. Immunoreactivity of the mitochondrial biogenesis marker peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and expression of the mitochondria-associated microRNAs miR-15a, miR-181a, miR-196a, and miR-296-3p, which target several mtDNA genes, were higher in RAS-STCs compared with normal STCs, suggesting a potential modulation of mitochondria-related gene expression. These results demonstrate that RAS induces an imbalance in mtDNA- and nDNA-mitochondrial gene expression, impairing mitochondrial structure and function in swine STCs. These observations support development of gene gain- and loss-of-function strategies to ameliorate mitochondrial damage and preserve the reparative potency of STCs in patients with renal ischemia.


Assuntos
Expressão Gênica , Genes Mitocondriais , Isquemia/genética , Rim/irrigação sanguínea , Mitocôndrias/metabolismo , Obstrução da Artéria Renal/metabolismo , Animais , Feminino , Isquemia/metabolismo , Biogênese de Organelas , Obstrução da Artéria Renal/genética , Suínos
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