Medicamentos fitoterápicos são aqueles cuja matéria-prima é exclusivamente originária de vegetais, descartando-se qualquer associação que inclua em sua composição outras substâncias ativas isoladas não vegetais. A lesão renal aguda (LRA) é caracterizada pelo rápido declínio da função renal, definida por um aumento absoluto da creatinina sérica de pelo menos 0,3mg/dl, elevação de 50% (1,5 vezes) do valor basal ou redução do fluxo urinário, documentado como oligúria ou menor que 0,5ml/kg por hora por mais de seis horas. Este estudo investigou o efeito protetor do Echinodorus macrophyllus (Ema) na nefrotoxicidade induzida pela ciclofosfamida. Foram utilizados ratos da raça Wistar, machos, adultos, distribuídos nos grupos: Controle: animais que receberam solução de cloreto de sódio 0,9% por via intraperitoneal (i.p.), (1,5ml/kg, dose única), Ema: animais que receberam Echinodorus macrophyllus, (2g/kg 1 x ao dia, durante 5 dias, por gavagem), CCF: animais que receberam ciclofosfamida (150mg/kg dose única, i.p.), CCF + Ema: animais que receberam Echinodorus macrophyllus e ciclofosfamida no 5º dia (i.p.). Foram avaliadas a função renal (FR) (clearance de creatinina); a lesão oxidativa (peróxidos urinários, substâncias reativas ao ácido tiobarbitúrico TBARS e tióis no tecido renal) e feita análise histológica renal (lesão tubulointersticial). Os resultados confirmaram a lesão nefrotóxica de caráter oxidativo induzida pela ciclofosfamida. O Ema demonstrou efeito renoprotetor antioxidante, com melhora da FR, redução dos níveis de peroxidação lipídica e metabólitos oxidativos. A análise histológica indicou dano significativo ao tecido renal pela CCF, que foi reduzido nos animais tratados com Ema. Este estudo demonstra claramente a LRA induzida pela ciclofosfamida e o efeito renoprotetor do Ema / Herbal medicines are those whose raw materials are exclusively originated from vegetables, excepting any association that includes in its composition other isolated active substances. Acute kidney injury (AKI) is characterized by a rapid decline in renal function defined by an absolute increase in serum creatinine of at least 0.3 mg/dL, a 50% (1.5 times) baseline increase or urinary flow reduction, documented as oliguria or less than 0.5 ml/kg per hour for a period surpassing six hours. This study investigated the protective effect of Echinodorus macrophyllus (Ema) in cyclophosphamide-induced nephrotoxicity. We used male adults Wistar mice, divided into four groups: Control group: animals receiving sodium chloride solution 0.9 intraperitoneally (ip) (1.5 ml/kg, single dose); Ema: animals that received Echinodorus macrophyllus (2g/kg one time daily for 5 days by gavage); CCF: animals receiving cyclophosphamide (150mg/kg single dose, i.p), CCF + Ema: animals receiving Echonodorus macrophyllus and cyclophosphamide on day 5. We evaluated renal function (RF) (creatinine clearance), oxidative damage (urinary peroxides, thiobarbituric acid reactive substances - TBARS and thiols in kidney tissues) and we also carried out histologic kidney analyses (tubulointerstitial injury). Data confirmed the oxidative nephrotoxic injury induced by cyclophosphamide. Ema proved to have renoprotective and antioxidant effects, with improvement in RF, reduced levels of lipid peroxidation and oxidative metabolites. The histologic analysis indicated significant damage to renal tissue by CCF, which was reduced in animals treated with Ema. This study clearly demonstrates LRA induced by cyclophosphamide and the renoprotective effect of Ema

A sepse é uma das síndromes clínicas mais frequentes em unidades de terapia intensiva (UTI), enquanto que a lesão renal aguda (LRA) é uma complicação comum da disfunção de múltiplos órgãos (DMOs) causada pela sepse. Os mecanismos fisiopatológicos envolvidos na LRA por sepse são a hipoperfusão glomerular, as alterações microvasculares e a liberação de espécies reativas de oxigênio (EROs). Nesse contexto, o efeito antioxidante da estatina pode ser considerado. O objetivo desse estudo foi investigar a repercussão da sepse e o efeito da sinvastatina sobre a função renal dos ratos. Foram utilizados ratos Wistar, adultos e machos, pesando entre 250-300 gramas. Os animais foram distribuídos nos grupos: SHAM (controle da sepse); SHAM + Estatina (0,5 mg/kg de sinvastatina por gavagem, uma vez ao dia, durante cinco dias); Sepse (laparatomia para ligadura e punção de cécum - LPC); Sepse + Estatina (tratamento com sinvastatina e LPC). Foram avaliados os parâmetros fisiológicos (peso corporal, temperatura corporal e glicemia capilar), a presença de micro-organismos no líquido peritoneal, a função renal (clearance de creatinina, método Jaffé), os metabólitos oxidativos (peróxidos urinários - FOX-2 e substâncias reativas com o ácido tiobarbitúrico - TBARS), a gravidade da LRA e a sobrevida dos animais. Os resultados mostraram que os animais com sepse apresentaram hipertermia, hiperglicemia e crescimento microbiano em cultura do líquido peritoneal, declínio do clearance de creatinina com elevação dos níveis de peróxidos urinários e TBARS. O grupo Sepse foi classificado com LRA de maior gravidade e alta taxa de mortalidade, enquanto que o grupo que recebeu sinvastatina apresentou aumento da taxa de filtração glomerular (TFG), com atenuação da geração dos metabólitos oxidativos, associados à menor gravidade da LRA e redução da taxa de mortalidade. Os achados dessa investigação confirmam o desenvolvimento de LRA grave secundária a sepse e evidenciam a renoproteção com princípio antioxidante da sinvastatina. / Sepsis is one of the most frequent clinical syndromes in the intensive care unit (ICU), while acute kidney injury (AKI) is a common complication of multiple organ dysfunction (MODs) caused by sepsis. The pathophysiological mechanisms involved in the sepsis AKI are glomerular hypoperfusion, microvascular changes and release of reactive oxygen species (ROS). In this context, the antioxidant effect of the statin may be considered. The aim of this study was to investigate the impact of sepsis and the effect of simvastatin on renal function in rats. Wistar, adult, male rats weighing between 250-300 grams. The protocol of sepsis, consisted in a laparotomy and induced abdominal sepsis by cecal ligation and puncture (CLP). The animals were divided in groups: SHAM (sepsis control), SHAM + Statin (0.5 mg/kg of simvastatin by gavage, once daily for five days), Sepsis (laparotomy for cecal ligation and puncture - CLP), Sepsis + Statin (simvastatin treatment and CLP). We evaluated physiological parameters (body weight, body temperature and capillary glycemia blood), the presence of microorganisms in the peritoneal fluid, renal function (creatinine clearance, Jaffe method), metabolites oxidative (urinary peroxides - FOX-2 and reactive substances to thiobarbituric acid - TBARS), the severity of AKI and the animals survival. Sepsis animals presented hyperthermia, hyperglycemia and microbial growth in culture of peritoneal fluid and creatinine clearance decrease with elevated levels of urinary peroxides and TBARS. The Sepsis group was classified as the most severe AKI and high mortality rate. The animals that received simvastatin showed improvement in physiological parameters, increased glomerular filtration rate (GFR) with attenuation of the generation of oxidative metabolites, associated with lower severity of AKI and reduced mortality. The findings of this investigation confirm the development of AKI secondary to sepsis and confirm the renoprotection with simvastatin associated to its antioxidant effect

As células necessitam do contato com outras células e com a matriz extracelular, para a formação de tecidos. As junções gap são estreitos canais que conectam o citoplasma de células adjacentes, promovendo a passagem de íons orgânicos, aminoácidos, nucleotídeos e outros metabólitos. Estas junções são compostas por dois conexons ou hemicanais, que atravessam a membrana plasmática da célula a que pertencem, e são compostos por seis proteínas integrais de membrana denominadas conexinas (Cxs). A Cx43 é a mais expressa, e é fosforilada ao longo do ciclo de vida, sofrendo mudanças conformacionais, resultando em diferentes isoformas (P0, P1 e P2), apresentando propriedades distintas. A Cx43 apresenta-se distribuída em todo o rim adulto. A injúria renal aguda (IRA) é uma síndrome metabólica em que ocorre redução aguda da função renal e rápida diminuição da taxa de filtração glomerular, sendo hipóxia decorrente da isquemia sua causa principal. A restrição de oxigênio e nutrientes, e o acúmulo de metabólitos, resultam na injúria das células epiteliais tubulares. A depleção dos níveis de ATP, aumento nos níveis de cálcio intracelular, alterações na membrana e deformações no citoesqueleto caracterizam esta injúria. A reoxigenação tecidual atua como agressão adicional devido à liberação de radicais livres. Estudos sugerem que a ativação de hemicanais de Cx43, resultante da desfosforilação da proteína, durante depleção de ATP, esteja envolvida na IRA. Este trabalho verificou o envolvimento da Cx43 em modelo murino desta injúria, ocasionada por isquemia/reperfusão. Foram utilizados camundongos machos da linhagem C57BL/6J. A isquemia foi induzida por clampeamento das artérias renais por 45 minutos. A reperfusão ocorreu durante 24 horas após cirurgia. Foram utilizados 6 animais por grupo (isquêmicos, reperfundidos e controle). Após sacrifício, fragmentos dos rins foram submetidos a ensaios de western blot, PCR em tempo real, imuno-histoquímica e imunofluorescência. O modelo experimental foi validado através da dosagem de uréia e creatinina plasmática. As análises estatísticas foram realizadas pela análise de variância (ANOVA), seguido do teste de Bonferroni. Observou-se aumento significativo dos níveis de uréia e creatinina nos animais isquêmicos e reperfundidos, em relação ao controle. A expressão gênica apresentou aumento significativo apenas nos rins de camundongos reperfundidos (1,9 vezes; P<0,01 vs controle). No western blot verificou-se aumento na quantidade da isoforma hiperfosforilada da Cx43 (P2) em rins isquêmicos (2,73 vezes; P<0,05 vs controle), com diminuição significativa nos reperfundidos (2,37 vezes; P<0,05 vs isquêmico). Nas isoformas menos fosforiladas (P1/P0), observou-se aumento nos rins isquêmicos (2,33 vezes; P<0,05 vs controle), com diminuição nos reperfundidos (10 vezes; P<0,01 vs isquêmico). Nos ensaios imuno-histológicos verificou-se diferentes localizações da Cx43 nas células epiteliais de túbulos corticais nos grupos comparados. Nos controles verificou-se distribuição difusa, e nos isquêmicos observou-se intensa marcação em superfície celular apical. Nos rins reperfundidos, a distribuição da Cx43 foi basolateral. As alterações observadas na expressão gênica, fosforilação protéica e distribuição da Cx43 nos rins foram semelhantes às mudanças observadas na isquemia cardíaca. Este estudo mostrou pela primeira vez a regulação da Cx43 em níveis transcricionais e pós-traducionais, e sua localização celular na IRA ocasionada por isquemia/reperfusão, indicando sua participação neste processo. / The cells require contact with other cells and the extracellular matrix for tissue formation. Gap junctions are narrow channels connecting the cytoplasm of two adjacent cells, promoting the passage of inorganic ions, amino acids, nucleotides and other metabolites. These junctions are composed of two conexons or hemichannels, crossing the cell plasma membrane where they belong, and consist of six integral membrane proteins called connexins (Cxs). The Cx43 is the most expressed, and is phosphorylated throughout the life cycle, undergoing conformational changes, resulting in different isoforms (P0, P1 and P2) that have different properties. The Cx43 is distributed throughout the adult kidney. The acute kidney injury (AKI) is a metabolic syndrome that occurs in acute reduction of renal function and rapid decline in glomerular filtration rate. Hypoxia resulting from ischemia is its principal cause. The restriction of oxygen and nutrients, and accumulation of metabolites, result in the injury of tubular epithelial cells. The depletion of ATP levels, increased levels of intracellular calcium, changes in the membrane and cytoskeleton deformation characterize this injury. Reoxygenation tissue acts as additional injury due to release of free radicals. Studies suggest that activation of Cx43 hemichannels, resulting from dephosphorylation of the protein during ATP depletion, is involved in the AKI. This study investigated the involvement of Cx43 in a murine model of this injury, caused by ischemia/ reperfusion. We used male mice of strain C57BL/6J. Ischemia was induced by clamping the renal arteries for 45 minutes. Reperfusion occurred 24 hours after surgery. We used six animals per group (ischemic, reperfused, and sham). After sacrifice, kidney fragments were tested for western blot, real-time PCR, immunohistochemistry and immunofluorescence. The levels of plasma urea and creatinine were measured to validate the experimental model. Statistical analysis was performed by analysis of variance (ANOVA) followed by Bonferroni test. We observed significant increase in serum urea and creatinine in ischemic and reperfused animals compared to sham. Gene expression increased significantly only in the reperfused kidneys (1.9 fold, P <0.01 vs sham). The western blot showed an increase in the amount of hyperphosphorylated isoform of Cx43 (P2) in ischemic kidneys (2.73 times, P <0.05 vs sham), with significant reduction in reperfused (2.37 times, P <0 05 vs ischemic). In the less phosphorylated isoforms (P1/P0), we observed an increase in ischemic kidneys (2.33 times, P <0.05 vs sham), with a decrease in reperfused (10 times, P <0.01 vs ischemic). In immuno-histological tests we verified different locations of Cx43 in the epithelial cells of cortical tubules. In normal kidneys there was patchy distribution, while in ischemic there was intense staining in the apical cell surface. In the reperfused kidney, the distribution of Cx43 was basolateral. The changes in gene expression, protein phosphorylation and distribution of Cx43 in the kidney observed in this study were similar to changes observed in cardiac ischemia. This study showed for the first time the regulation of Cx43 in transcriptional and post-translational levels, and its cellular localization in acute renal failure caused by ischemia/reperfusion, indicating its involvement in this injury.

Renal ischaemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) which is in turn the leading cause of morbidity and mortality in hospitalized patients. The principle aim of this thesis was to evaluate potential new therapies that might afford protection against IRI in both in vitro and in vivo settings. Recent evidence suggests that nitrite (NO2-) may play an important role in protecting the myocardium from IRI. Our initial work into the role of NO2- in an in vitro model of renal IRI in proximal tubular epithelial cells provided evidence that NO2- can prevent apoptosis and preserve cell viability. This lead to an in vivo study where high NO2- concentrations (50 mg/L) were given orally to rats for 7 days prior to inducing renal IRI but no beneficial effects of this treatment were observed. Another potential treatment identified was thiamine (vitamin B1) and this, like NO2-was investigated to see if it had the potential to protect rats from AKI injury. It has been previously recognized that in renal IRI the high energy phosphate ATP is found to be severely depleted whilst is is known that thiamine can play a pivotal role in generating ATP. Furthermore, thiamine has previously been demonstrated to protect against myocardial ischaemic injury and has the ability to reduce myocardial infarct size. In vitro, thiamine was found to reduce the degree of apoptosis in cultured HK-2 cells caused by ischaemia whilst in vivo it afforded protection against AKI caused by renal IRI by anti-apoptotic, anti-inflammatory and anti-oxidant mechanisms. Finally, a study into the possible therapeutic role of gene therapy with bone morphogenic protein 7 (BMP-7) in renal IRI was undertaken. Previous work has established that i.v. BMP-7 is able to protect against renal IRI but it has also been associated with ectopic bone formation at the site of injection. Therefore another method to increase circulating BMP-7 was sought. We initially found that BMP-7 gene therapy could attenuate apoptosis and preserves cell viability in an in vitro model of renal IRI. However, whilst in vivo gene therapy with electroporation of BMP-7 plasmid DNA increased BMP-7 expression in mice serum 2 days post electroporation, it was unable to protect the animals against IRI induced AKI. In rats the direct injection of naked DNA BMP-7 plasmid systematic 2 days prior to renal IRI was able to upregulate BMP-7 expression 4 days later in kidney tissue. Despite this it was unable to afford protection against renal IRI. Apoptosis and necrosis play a crucial role in the pathogenesis of renal IRI induced AKI. In this thesis we investigated the role of three putative therapeutic agents and their role in apoptosis and necrosis in vitro in PTECs and in vivo against renal IRI induced AKI. All three therapeutic drugs were able to attenuate apoptosis in PTECs but were unable to protect against necrosis, whilst against renal IRI induced AKI only thiamine was found to be protective. Thiamine appears to hold the most promise and more work needs to be undertaken so that its potential benefit in AKI can be realised.

Orientador: Daniela Ponce / Resumo: Introdução: A sepse caracteriza-se por intensa resposta inflamatória associada à infecção sistêmica, comumente acompanhada de Lesão Renal Aguda (LRA). A determinação do gasto energético de repouso (GER) em pacientes críticos é essencial para evitar complicações decorrentes da hipo e hiperalimentação. Objetivos: Ao estudar pacientes sépticos, este estudo tem como objetivos descrever o GER, analisar comparativamente o GER estimado pela equação de Harris-Benedict (HB) e o aferido pela calorimetria indireta (CI) e avaliar evolutivamente o GER. Métodos: Estudo tipo coorte prospectivo que avaliou pacientes admitidos em Unidade de Terapia Intensiva do HC-FMB, durante 18 meses consecutivos. Foram incluídos pacientes sépticos, maiores de 18 anos, admitidos em UTI e em ventilação mecânica, com e sem LRA definida pelos critérios do KDIGO. O GER foi estimado pela equação de HB e determinado pela CI até 72 horas após o diagnóstico de sepse e após sete dias da primeira aferição. Resultados foram expressos em média e desvio padrão ou mediana com intervalo interquartílico. Para a comparação entre variáveis categóricas utilizou-se o Teste Qui-Quadrado, entre variáveis continuas de distribuição normal o Teste T e na ausência de distribuição normal foi utilizado o Mann-Whitney, com p<0,05. A análise de regressão logística foi realizada pelo método de Stepwise, considerando p<0,1. Para a avaliação evolutiva do GER de toda a população e de acordo com a presença ou não de LRA foi utilizada análise... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Abstract Background: The determination of resting energy expenditure (REE) in critically ill patients is essential to prevent complications such as hypo and hyper alimentation. Objectives: This study aims to describe the REE in septic patients with and without acute kidney injury (AKI) and compare the REE estimated by the Harris-Benedict equation (HB) with the REE measured by indirect calorimetry (IC). Methods: Prospective and observational study was performed for 18 consecutive months. Septic patients older than 18 years, undergoing mechanical ventilation, with or without AKI defined by KDIGO criteria, and admitted to the Intensive Care Unit of University Hospital from Brazil were included. The REE was estimated by HB equation and measured by the IC within 72 hours after the diagnosis of sepsis and seven days after the initial measure. The chi-square test was used to compare categorical variables and t-test to compare parametric variables. For non-parametric variables, the Mann-Whitney test was used, p<0.05. Variables with significant univariate associations (p<0.10) were candidates for multivariable analysis, which was performed using stepwise variable selection. Repeated measures analysis using the mixed procedure was used for the evolutional REE. Results: Sixty-eight patients were evaluated, age was 62.49 ± 16.6 years, 64.7% were male, 63.2% had AKI, and SOFA was 9.81 ± 2.35. The measured REE was 1857.53 ± 685.32 kcal, while the estimated REE was 1514.87 ± 356.72 kc... (Complete abstract click electronic access below) / Mestre

Orientador: Magda Cristina Queiroz Dell'Acqua / Resumo: Introdução: A lesão renal aguda (LRA) é caracterizada pela perda abrupta da função renal, com redução da taxa de filtração glomerular, acúmulo de produtos nitrogenados e presença de distúrbios hidroeletrolíticos e ácido-básico. Quando há alteração da função renal a equipe de enfermagem é requerida de forma intensa. Contribui sobremaneira com a segurança e a qualidade da assistência o uso de ferramenta metodológica, o Processo de Enfermagem (PE). A utilização de linguagem padronizada corrobora para a operacionalização do PE, como a taxonomia da Nanda Internacional (NANDA-I), Classificação dos Resultados de Enfermagem (NOC) e Classificação das Intervenções de Enfermagem (NIC). Objetivo geral: Identificar o perfil clínico e sociodemográfico dos pacientes com lesão renal aguda em terapia dialítica em unidade de terapia intensiva, a prevalência e o perfil dos diagnósticos, resultados e intervenções de enfermagem, com a utilização da NANDA-I, NOC e NIC. Método: Estudo transversal com pacientes com LRA em tratamento dialítico em UTI. O local do estudo foram as UTIs do Instituto Central do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (IC- HCFMUSP). Amostra de 98 pacientes e a coleta de dados foram de março a julho de 2016, por meio de consulta de enfermagem, composta por anamnese, exame físico e dados do prontuário. Houve a aprovação pelo comitê de ética conforme o parecer n° 1.440.974. Foi utilizado software SPSS v21.0 para estimação da prevalência, co... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

Acute kidney injury (AKI) is a major risk factor for chronic kidney disease (CKD). For patients who recover from AKI, there is a 25% increase in the risk of CKD, and a mortality rate of up to 50% after 10 years. Nuclear factor kappa-B (NF-κB) is a family of transcription factors that regulates the transcription of many proteins that play a key role in inflammation. Inhibitor of IκB kinase (IKK) is directly upstream of NF-κB. My aim was to investigate a) the role of IKK in the progression of AKI to CKD, and b) whether its inhibition attenuates renal fibrosis. In this thesis I used a model of unilateral renal ischaemia-reperfusion injury with contralateral nephrectomy, to firstly map the acute time course of AKI. From the data generated from the time course, I decided to treat the animals at 24 h post reperfusion with the IKK inhibitor, IKK16, as i) this was at the peak of renal dysfunction (24 h post reperfusion), and ii) prior to the activation of NF-κB (48 h post reperfusion). The inhibition of IKK at 24 hours post reperfusion, as a delayed treatment, successfully attenuated renal dysfunction, NF-κB activation and renal structural damage. I subsequently increased the recovery time after ischaemia-reperfusion in my rat model to 28 days to study the development of fibrosis post AKI. The inhibition of IKK at 24 hours post reperfusion successfully attenuated the development of fibrosis, formation of myofibroblasts, macrophage infiltration, the expression of pro-fibrotic markers and the deposition of extracellular matrix components at 28 days post reperfusion. In addition, the delayed inhibition of IKK at days 7-13 post unilateral ureteral obstruction in a rat model, successfully attenuated the development of fibrosis, formation of myofibroblasts, macrophage infiltration, the expression of pro-fibrotic markers and the deposition of extracellular matrix components. These data indicate that the activation of the IKK complex drives tubulointerstitial fibrosis, and suggests that the inhibition of IKK could be a useful pharmacological tool for the creation of therapies to combat AKI and the subsequent development of fibrosis, via the reduction of both inflammation and the prevention of the expression of pro-fibrotic markers.

L’insuffisance rénale aiguë (IRA) représente une complication fréquente de lachirurgie cardiaque pédiatrique sous circulation extracorporelle (CEC). Son traitement resteessentiellement conservateur, visant à prévenir l’aggravation de l’atteinte rénale, ousubstitutif, par épuration extrarénale (EER). L’EER précoce améliore le pronostic des adultesen défaillance multiviscérale, mais ceci n’a pas été montré chez l’enfant après chirurgiecardiaque. Le diagnostic de l’IRA repose actuellement sur une diminution du débit defiltration glomérulaire (DFG), reflété par la hausse de la créatinine sérique (sCr), et laréduction de la diurèse. Ces critères traduisent une perte de la fonction glomérulaire ; orl’atteinte initiale dans l’IRA post-chirurgicale se situe au niveau tubulaire. Ces critères sontpeu spécifiques et tardifs, et risquent de retarder le diagnostic et la prise en charge de l’IRA.Des nouveaux biomarqueurs rénaux, traduisant la présence d’une lésion tubulaire, dont leNeutrophil Gelatinase-Associated Lipocaline urinaire (NGALu) est le plus populaire,permettraient un diagnostic plus précoce.Objectif. L’objectif de ce travail est triple : (i) explorer l’association entre le délai de la miseen route de l’EER et le pronostic à court et moyen terme chez le patient < 1an qui développeune IRA post-chirurgie cardiaque ; (ii) explorer les performances diagnostiques desvariations précoces de la sCr pour l’IRA sévère ; et (iii) explorer les performancesdiagnostiques de l’élévation de NGALu pour l’IRA sévère dans des populations similaires depatients < 1an.Méthode. Une cohorte monocentrique rétrospective de patients < 1an constituée sur 10 ansa servi pour étudier l’association entre le délai de la mise en route de l’EER et la survie àcourt et moyen terme. La technique de pondération inverse par le score de propension a étéutilisée afin de réduire le biais associé aux changements des pratiques inhérents à la longuepériode d’inclusion. Une deuxième cohorte monocentrique rétrospective de patients < 1anconstituée sur 3 ½ ans a servi pour étudier les performances diagnostiques des variationsprécoces de la sCr pour l’IRA sévère. Enfin, une troisième cohorte monocentriqueprospective de patients < 1an constituée sur 18 mois a servi pour étudier les performancesdiagnostiques de NGALu pour l’IRA sévère. Pour l’étude des deux biomarqueurs, sCr etNGALu, la méthodologie utilisée a été similaire : partition des trajectoires individuelles devariation, puis analyse de l’association avec un critère composite (recours à l’EER et/oudécès postopératoire) et définition du profil à faible risque d’IRA; enfin, utilisation de laméthodologie des courbes ROC et des tables de reclassification pour quantifier leursperformances diagnostiques respectives.Résultats. La mise en route de l’EER le jour de la chirurgie ou le lendemain a été associéeavec une augmentation d’environ 45% de la survie à 30 et 90 jours. La variation de la sCrdans les 2 jours suivant la chirurgie a été spécifique mais peu sensible et peu discriminantepour le diagnostic de l’IRA sévère ; le profil à faible risque, rencontré chez près de 50% despatients a été une diminution durable d’environ 25% de la sCr par rapport à la valeur basale.NGALu a été discriminant et prédictif pour le critère composite ; la concentration de NGALu aaugmenté dans les 2 heures suivant la chirurgie, et est restée élevée chez les patientsprésentant le critère composite.Discussion et conclusions. Si la prise en charge précoce par EER de l’IRA sévère est unepriorité en termes de pronostic chez le patient < 1an, alors il faut se munir de moyensdiagnostiques précoces et performants. La variation précoce de la sCr est peu sensible etpeu discriminante. En revanche, l’élévation précoce de l’NGALu présente d’excellentesperformances diagnostiques pour l’IRA sévère, faisant de NGALu un marqueur rénalprometteur dans la population < 1an bénéficiant d’une chirurgie cardiaque. / Acute kidney injury (AKI) is common following congenital cardiac surgery withcardiopulmonary bypass (CPB). To date, no prophylactic intervention has proved to beuseful for the prevention of postoperative AKI. When AKI occurs, treatment is mainlysupportive and, when severe, requires renal replacement therapy (RRT). Several reportshave shown better outcome with early RRT in adults with multiorgan failure. No such data isavailable in children undergoing cardiac surgery, and criteria for RRT vary among centres.The definition of AKI is a reduction in the glomerular filtration rate (GFR), and the diagnosis isbased on an increase in serum creatinine (sCr) and a reduction in urine output; these arefunctional criteria, translating the consequences of glomerular injury. However, it iscommonly admitted that the first pathophysiologic finding in AKI following cardiac surgery istubular injury. Besides, the functional criteria are late, are not specific, and may delay thediagnosis of AKI. Novel AKI biomarkers, specific of tubular injury are available nowadays,with urine Neutrophil Gelatinase-Associated Lipocaline (uNGAL) being the most popular –they may allow for an early diagnosis of AKI.Objectifs. The aim of this work was: (i) explore associations between the delay to RRT, earlyand mid-term outcome in patients younger than 1 year of age who develop AKI followingcardiac surgery; (ii) assess the accuracy of early sCr variations and (iii) of uNGAL for severeAKI in two similar populations aged < 1 year.Methods. A single centre retrospective cohort of patients aged < 1 year undergoing surgeryover 10 years was used to asses the association between the delay to RRT et short and midtermsurvival. Inverse probability of treatment weighting was used to reduce bias due tochanges in practices that occurred during the long study period. A second retrospectivecohort of patients aged < 1 year undergoing surgery over 3 ½ years was used to asses theaccuracy of early sCr variations for the diagnosis of severe AKI. Finally, a third prospectivecohort of patients aged < 1 year undergoing surgery over 18 month was used to asses theaccuracy of uNGAL for the diagnosis of severe AKI. The study of both sCr and uNGAL useda similar methodology: first clustering of all individual trajectories of variation, enablingassessment of the association with a composite outcome (need for RRT and/or death) andidentification of the « normally expected » postoperative evolution of both sCr an uNGAL,associated with the best outcome; second, use of ROC curves and reclassification tables toassess the accuracy of each biomarker for the diagnosis of AKI.Results. Early RRT, initiated on the day of surgery or on day 1 following surgery, wasassociated with a 45% increase in 30-days and 90-days survival. Early sCr variation, within 2days of surgery, had a good specificity but was lacking sensitivity and discrimination for thediagnosis of severe AKI; the « expected » sCr evolution was a persistent 25% postoperativereduction relative to baseline. uNGAL had good discrimination and predictive ability for thecomposite outcome; uNGAL concentration increased within 2 hours of surgery, andremained high in patients with the composite outcome.Discussion and conclusions. If early RRT improves outcome in patients aged < 1 yearswith AKI following cardiac surgery, then it becomes important to perform an early diagnosisof severe AKI. To date, diagnosis of AKI is based on early sCr variations, but such variationslack sensitivity and discrimination for the diagnosis of severe AK. On the other hand, theincrease in uNGAL within hours of surgery has excellent accuracy for the diagnosis of severeAKI, making uNGAL a promising AKI biomarker in patients aged < 1 year undergoing cardiacsurgery with cardiopulmonary bypass.

INTRODUÇÃO: O corte manual da cana-de-açúcar é uma atividade que impõe ao cortador uma elevada carga física, pois requer a execução de movimentos vigorosos, rápidos e repetitivos. Trabalham em condições de elevadas temperaturas ambientais e baixa umidade relativa do ar que, com o uso de vestimentas aumenta risco de sobrecarga térmica, bem como se expõem aos poluentes gerados pela queima da cana-de-açúcar. OBJETIVO: avaliar os efeitos agudos e em longo prazo do trabalho na colheita de cana-de-açúcar queimada nas concentrações da proteína CC16, na função renal e em marcadores inflamatórios sistêmicos, em um grupo de cortadores de cana-de-açúcar. MÉTODOS: Foram avaliados 78 homens, cortadores de cana-de-açúcar empregados em uma usina de açúcar e álcool localizada na Região Oeste do Estado de São Paulo. Eles foram submetidos a avaliações clínicas e à coleta de amostras de sangue e de urina, utilizadas para análises de marcador de toxicidade pulmonar (proteína CC16), de marcadores renais e inflamatórios sistêmicos, em três momentos distintos ao longo do ano: 1) Pré-Safra, (Abril de 2014), no início da jornada de trabalho (7h00min); 2) Três meses após o início da safra, antes e após uma jornada diária de trabalho (7h00min e 16h00min); 3) Após seis meses do início da safra, antes do início da jornada de trabalho (7h00min). Foram realizados registros da concentração de material particulado (MP2,5), temperatura e umidade relativa do ar. RESULTADOS: A concentração de MP2,5 foi de 27,0 (23,0-33,0) ug/m3 e 101,0 (31,0-139,5) ?g/m3 no período da pré-safra e na safra respectivamente. A mediana da temperatura e umidade relativa do ar no período da pré-safra foram de 32,6 (25,4-37,4)°C e 45,4 (35,0-59,7)% respectivamente; no período da Safra foram de 29,7 (24,1-34,0)°C e 54,9 (34,7-63,2)% respectivamente. A idade dos trabalhadores foi de 37,9±11,0 anos, eles cortam, em média, nove toneladas de cana-de-açúcar/dia. Foram observadas reduções agudas e ao longo da safra nas concentrações plasmáticas e urinárias da proteína CC16. Após uma jornada diária de trabalho observou-se evidências de desidratação, queda da filtração glomerular, aumento de biomarcadores de injúria e reparação tubular renal (NGAL, KIM-1, IL-18, calbindina, MCP-1, osteopontina, e TFF-3) e aumento de marcadores inflamatórios sistêmicos (leucócitos, ácido úrico, LDH). Ao longo da safra observou-se aumento significante de cistatina C, ureia, CPK, NGAL e monócitos no sangue e de marcadores urinários como NGAL, MCP-1, TFF-3, fósforo, magnésio e densidade. CONCLUSÃO: O trabalho no corte manual de cana-de-açúcar submete os trabalhadores à sobrecarga física, exposição a poluentes e à elevadas temperaturas. Foi observado efeito agudo e ao longo da safra nas concentrações da proteína CC16, na alteração de biomarcadores inflamatórios sistêmicos, de equilíbrio hidroeletrolítico e na função renal, incluindo alterações de marcadores que sugerem lesão estrutural renal / INTRODUCTION: The manual sugarcane harvesting is an activity that requires considerable physical exertion, involves vigorous, quick, repetitive cutting movements. They work under conditions of high temperatures and low relative air humidity that, with the use of clothing, increases the risk of thermal overload, as well as expose themselves to the pollutants from burning of sugarcane. AIM: To evaluate the short and long-term effects of harvesting burnt sugarcane on the CC16 protein concentrations, renal function, and systemic inflammatory markers in a group of sugarcane cutters. METHODS: A total of 78 sugarcane cutters employed in a sugar-alcohol mill in the state of São Paulo, Brazil were evaluated. They underwent clinical evaluations and the collection of both blood and urine samples, used for analysis of pulmonary toxicity (CC16 protein), renal markers and systemic inflammatory markers performed at three different times throughout the year: 1) In the pre-harvest period (April 2014), at the onset of the working shift (7h00 am); 2) Three months after the onset of the harvest, before and after the daily work shift (7h00 a.m. and 4h00 p.m.); 3) Six months after the onset of the harvest, before the work shift (7h00 am). The concentrations of particulate matter (MP2.5), temperature and relative air humidity were recorded. RESULTS: The concentrations of PM2.5 were 27.0 (23.0-33.0) and 101.0 (31.0-139.5) ?g/m3 in the pre-harvest and harvest periods, respectively. The medians temperature and relative air humidity in the pre-harvest period were 32.6 (25.4-37.4) °C and 45.4 (35.0-59.7) % respectively; in the harvest period were 29.7 (24.1-34.0) °C and 54.9 (34.7-63.2) % respectively. The age of the workers was 37.9 ± 11.0 years, they cut, on average, nine tons of sugarcane/day. Short and long-term reductions in plasmatic and urinary concentrations of CC16 protein were observed. There was an acute increase in the concentrations of markers suggestive of dehydration, decreased glomerular filtration, increased biomarkers of injury and renal tubular repair (NGAL, KIM-1, IL-18, calbindin, MCP-1, osteopontin, and TFF-3 ) and increased systemic inflammatory markers (leukocytes, uric acid, DHL). Six months after the onset of the harvest, a significant increase of cystatin C, urea, CPK, NGAL and monocytes in the blood and urinary markers such as NGAL, MCP-1, TFF-3, phosphorus, magnesium and density were observed. CONCLUSION: The manual sugarcane harvesting exposes workers to physical overload, pollutants and high temperatures. It was observed an acute and chronic effects in the concentrations of CC16 protein, in systemic inflammatory biomarkers, hydroelectrolytic balance and renal function, including changes in markers that suggest renal structural damage

A Lesão Renal Aguda (LRA) é a complicação mais grave da rabdomiólise. Nessa síndrome, a liberação do pigmento heme desencadeia uma lesão que se caracteriza por vasoconstrição glomerular e toxicidade celular direta com componente oxidativo. A lesão oxidativa desencadeada é uma das linhas fisiopatológicas mais intrigantes. A renoproteção com antioxidantes tem demonstrado efeito satisfatório. As proantocianidinas são antioxidantes naturais encontrados no extrato da semente da uva. O objetivo deste estudo foi avaliar o efeito antioxidante da Vitis vinifera (extrato da semente de uva) sobre a função renal de ratos submetidos à lesão por rabdomiólise. Foram utilizados ratos Wistar, adultos machos, pesando entre 250-300 gramas. A LRA foi induzida pela administração de glicerol 50% i.m (intramuscular). Os animais foram distribuídos em 4 grupos: grupo Salina (6ml/Kg de NaCl 0,9% via intraperitoneal (i.p) 1 vez ao dia), grupo Glicerol (6ml/Kg de glicerol i.m, cada região femoral recebeu 3ml/Kg de glicerol, 1 vez ao dia), grupo Vitis vinifera (3mg/Kg v.o por 5 dias) e grupo Glicerol+Vitis vinifera que recebeu Vitis vinifera por 5 dias antes do glicerol. Foram avaliados o marcador de lesão muscular (CK), a função renal (FR), a função tubular (FENa e FEK), o perfil oxidativo (peróxidos urinários-FOX-2 e MDA-TBARS) , a histologia e morfometria renal. O grupo Glicerol tratado com Vitis vinifera apresentou melhora da FR e tubular, redução dos níveis da peroxidação lipídica e melhora da histologia renal. Os resultados deste estudo confirmaram a proteção antioxidante, com repercussão histológica, da Vitis vinifera na LRA induzida por glicerol. / The Acute Kidney Injury (AKI) is the worst complication of rhabdomyolysis. In this syndrome, the delivery of heme pigment induces an injury that distinguishes itself by glomerular vasoconstriction and direct cellular toxicity with oxidative component. The oxidative injury is an intriguing one of the pathophysiological mechanism. The renoprotection with antioxidants has demonstrated satisfactory effect. The proanthocyanidins are natural antioxidants found in grape seed extract. The aim of this study was to evaluate the antioxidant effect of Vitis vinifera (grape seed extract) on the renal function of rats submitted to the injury by rhabdomyolysis. Wistar rats, male, adults, weight ranging from 250-300 g were used. The AKI was induced intramuscular (i.m.) administration of glycerol 50%. The animals were distributed in 4 groups: Saline group (6ml/Kg of NaCl 0,9% intraperitoneal (i.p) once a day), Glycerol group (6ml/Kg of glycerol i.m, each femoral region received 3ml/Kg of glycerol, once a day), Vitis vinifera group (3mg/Kg v.o by 5 days) and Glycerol+Vitis vinifera group that has received Vitis vinifera by 5 days before glycerol. Marker of muscular injury (CK), renal function (RF), the tubular function (FENa and FEK), the oxidative profile (urinary peroxides -FOX-2 and MDA-TBARS), the histological and kidney morphometric were evaluated. The Glycerol group treated with Vitis vinifera has shown improvements in RF and tubular, reduction of levels of lipid peroxidation and amelioration of kidney histology. The results of this study have confirmed the antioxidant protection, with histological repercussion of Vitis vinifera in AKI induced by glycerol.