nÃo hà / IntroduÃÃo: A lesÃo renal aguda (LRA) à um achado comum em pacientes internados em unidade de terapia intensiva (UTI) e està associada a altos Ãndices de mortalidade. O perfil da UTI, o diagnÃstico categÃrico na admissÃo, os fatores socioeconÃmicos da regiÃo e as caracterÃsticas epidemiolÃgicas exercem influÃncia no resultado do tratamento de pacientes com LRA. Objetivo: Determinar a incidÃncia, os fatores associados, e a mortalidade da LRA em pacientes vÃtimas ou nÃo de trauma, que estiveram internados em uma UTI geral de uma regiÃo de baixa renda. MÃtodos: Estudamos consecutivamente 279 pacientes internados em uma UTI durante o perÃodo de um ano. Pacientes com menos de 24 horas de permanÃncia na unidade e com doenÃa renal crÃnica foram excluÃdos. A LRA foi classificada de acordo com os critÃrios propostos pelo Kidney Disease: Improving Global Outcomes (KDIGO) - âAcute Kidney Injury Work Groupâ em trÃs estÃgios. As anÃlises estatÃsticas foram realizadas pelo teste t de Student e de Mann-Whitney para variÃveis contÃnuas, com e sem distribuiÃÃo normal respectivamente. Para comparaÃÃo de frequÃncias foi utilizado o teste de Fisher. A regressÃo logÃstica multivariada foi utilizada para testar variÃveis como preditores de LRA e morte. Resultados: O diagnÃstico categÃrico na admissÃo da UTI foi dividido proporcionalmente em 51.6% nÃo relacionados ao trauma e 48.4% relacionados ao trauma. A maioria dos diagnÃsticos de trauma estava associada ao traumatismo crÃnio encefÃlica (TCE) 79.5%. A incidÃncia global de LRA foi de 32,9% distribuÃdos em trÃs estÃgios: 33,7% LRA estÃgio I; 29,4% LRA estÃgio II e 36,9% LRA estÃgio III. Os pacientes que desenvolveram LRA eram mais idosos, apresentaram maior Ãndice de diabetes mellitus, permaneceram por maior tempo internados em UTI, demonstraram maior valor no escore APACHE II e necessitaram com maior freqÃÃncia de ventilaÃÃo mecÃnica e uso de drogas vasopressoras. Em comparaÃÃo com os pacientes que nÃo tiveram trauma, os que tiveram apresentaram maior prevalÃncia do sexo masculino, maior pontuaÃÃo no escore APACHE II, maior dÃbito urinÃrio e eram mais jovens. NÃo houve diferenÃa no desenvolvimento de LRA e na mortalidade entre pacientes com trauma e sem trauma. A idade, presenÃa de diabetes, escore APACHE II e uso de drogas vasopressoras foram preditores independentes para a LRA. O risco de morte aumentou em dez vezes na presenÃa de LRA (OR = 14.51; IC95% = 7.94-26.61; p<0,001). ConclusÃes: Existe uma alta incidÃncia de LRA nesse estudo. A LRA foi fortemente associada com mortalidade, tanto entre pacientes com trauma, como em pacientes sem trauma. O trauma, especialmente o vinculado com lesÃo cerebral por TCE, devido a acidentes de trÃnsito envolvendo veÃculos motorizados de duas rodas, deve ser visto como uma importante causa evitÃvel de LRA. / Background: Acute kidney injury (AKI) is common among intensive care unit (ICU) patients and is associated with high mortality. Type of ICU, category of admission diagnosis, and socioeconomic characteristics of the region can impact AKI outcomes. We aimed to determine incidence, associated factors and mortality of AKI among trauma and non-trauma patients in a general ICU from a low-income area. Methods: We studied 279 consecutive patients in an ICU during a follow-up of one year. Patients with less than24-hour stay in the ICU and with chronic kidney disease were excluded. AKI was classified according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria in three stages. Comparisons were performed by the Student-t and MannâWhitney tests for continuous variables, respectively with and without normal distribution. Comparisons of frequencies were carried out by the Fisher test. Multivariate logistic regression was used to test variables as predictors for AKI and death. Results: Admission categories were proportionally divided into 51.6% of non-trauma diagnosis and 48.4% of trauma cases. Most trauma cases involved brain injury (79.5%). The overall incidence of AKI was 32.9%, distributed among the three stages: 33.7% stage 1, 29.4% stage 2 and 36.9% stage-3. Patients who developed AKI were older, had more diabetes, stayed longer in the ICU, presented higher APACHE II and more often needed mechanical ventilation and use of vasopressors. In comparison with non-trauma cases, trauma patients had a greater prevalence of males, higher APACHE II score, higher urine output, and younger age. There was no difference concerning development of AKI and crude mortality between trauma and non-trauma patients. Age, presence of diabetes, APACHE score and use of vasopressors were independent predictors for AKI, and AKI increased the risk of death ten-fold (OR = 14.51; CI 95% = 7.94-26.61; p<0.001). Conclusions: There was a high incidence of AKI in this study. AKI was strongly associated with mortality both among trauma and non-trauma patients. Trauma cases, especially brain injury due to traffic accidents involving motorized two-wheeled vehicles, should be seen as an important preventable cause of AKI.

CoordenaÃÃo de AperfeÃoamento de Pessoal de NÃvel Superior / IntroduÃÃo. A leptospirose à uma doenÃa endÃmica no Nordeste, sendo caracterizada por complicaÃÃes potencialmente fatais como a lesÃo renal aguda (LRA). O objetivo deste estudo foi avaliar as manifestaÃÃes clÃnicas, a classificaÃÃo da LRA e os fatores de risco para Ãbito em pacientes com a forma grave de leptospirose. MÃtodos. Foi realizado estudo retrospectivo em pacientes com a forma grave de leptospirose internados em hospitais terciÃrios na cidade de Fortaleza, nordeste do Brasil. Foram avaliadas as manifestaÃÃes clÃnicas, os exames laboratoriais na admissÃo e durante a internaÃÃo e o tratamento instituÃdo. LRA foi definida de acordo com as classificaÃÃes RIFLE e AKIN, sendo comparados os pacientes nas diferentes classes. Foram comparados os pacientes que usaram com aqueles que nÃo usaram penicilina, assim como os pacientes que sobreviveram com os que foram a Ãbito. AnÃlises univariada e multivariada foram usadas para a investigaÃÃo dos fatores de risco para Ãbito. A anÃlise estatÃstica foi feita pelo programa SPSS versÃo 10.0. Resultados. Foram incluÃdos 287 pacientes, com mÃdia de idade de 36,8Â15,6 anos, sendo 80,8% do sexo masculino. Os principais sinais e sintomas apresentados foram febre (96,2%), mialgia (90,6%), icterÃcia (85,7%), cefaleia (74,2%), vÃmitos (70,7%), desidrataÃÃo (54%) e calafrios (53,7%). LRA foi observada em 237 pacientes (82%) pelo critÃrio RIFLE e 242 (84%) pelo AKIN. A mortalidade geral foi de 13%. A mortalidade foi semelhante nos pacientes que usaram e que nÃo usaram penicilina (11,6% vs. 13,7%, p=0,60). Aumento da mortalidade foi observado de acordo com as piores classificaÃÃes: RIFLE-R (2%), RIFLE-I (8%) e RIFLE-F (23%), assim como AKIN 1 (2%), AKIN 2 (8%) e AKIN 3 (23%), p < 0,0001. Os pacientes com oligÃria tiveram maior mortalidade (20%), em comparaÃÃo com os pacientes sem oligÃria (5%), p=0,02. Os fatores de risco independentes para Ãbito foram: RIFLE-F (OR=10,5, IC 95%=1,3-80,8, p<0,001), AKIN 3 (OR=7,5, IC 95%=2,2-25,2 p<0,001) e necessidade de diÃlise (OR=3,5, IC 95%=1,1-11,01, p=0,01). ConclusÃes. A LRA à uma complicaÃÃo frequente na leptospirose, com mortalidade significativa. Houve associaÃÃo entre as classificaÃÃes RIFLE e AKIN com a mortalidade na leptospirose. Os fatores de risco independentes para Ãbito sÃo classificaÃÃo RIFLE-F, AKIN 3 e necessidade de diÃlise. / Introduction. Leptospirosis is en endemic disease in Northeast of Brazil, which is characterized by potential fatal complications such as acute kidney injury (AKI). The aim of this study was to evaluate the clinical manifestations, the AKI classification and the risk factors for death in patients with the severe form of leptospirosis. Methods. A retrospective study was conducted in patients with severe form of leptospirosis admitted to tertiary hospitals in Fortaleza city, Northeast of Brazil. The clinical manifestations, laboratory tests at admission and during hospital stay, as well as treatment, were evaluated. AKI was defined according to the RIFLE and AKIN classifications, and the patients in each category were compared. Patients who used and who did not use penicillin, as well as survivors and non-survivors, were compared. Univariate and multivariate analysis were performed to investigate the risk factors for death. Statistical analysis was done with SPSS program version 10.0. Results. A total of 287 patients were included, with a mean age of 36.8Â15.6 years, and 80.8% were male. The main signs and symptoms at admission were fever (96.2%), myalgia (90.6%), jaundice (85.7%), headache (74.2%), vomiting (70.7%), dehydration (54%) and chills (53.7%). AKI was observed in 237 patients (82%) according to the RIFLE criteria and 242 (84%) according to AKIN. General mortality was 13%. Mortality was similar in patients who used and who did not use penicillin (11.6% vs. 13.7%, p=0.60). An increase in mortality was observed according to the worst classifications of RIFLE and AKIN: RIFLE-R (2%), RIFLE-I (8%) e RIFLE-F (23%), AKIN 1 (2%), AKIN 2 (8%) e AKIN 3 (23%), p<0.0001. Patients with oliguria had a higher mortality (20%), when compared to those without oliguria (5%), p=0.02. Independent risk factors for death were: RIFLE-F (OR=10.5, 95% CI=1.3-80.8, p<0.001), AKIN 3 (OR=7.5, 95% CI=2.2-25.2 p<0.001) and need of dialysis (OR=3.5, 95% CI=1.1-11.01, p=0.01). Conclusions. AKI is a frequent complication in leptospirosis, with significant mortality. There was association between RIFLE and AKIN classifications with mortality. Independent risk factors for death were RIFLE-F, AKIN 3 and need of dialysis.

Os rins desempenham um papel fundamental no sistema urinário e sua principal função é a filtração do sangue. Uma das causas que podem comprometer o funcionamento dos rins é a Insuficiência Renal Aguda (IRA) que é definida como a diminuição da taxa de filtração glomerular (TFG) de forma rápida e inesperada, causando a perda da função renal. Essa doença apresenta um número significativo de internações e também óbitos. O marcador padrão usado nos exames laboratoriais é a creatinina sérica, no entanto, a concentração da creatinina sérica pode variar dependendo de vários fatores, como idade, sexo, nutrição, entre outros. Além disso, sua concentração não varia consideravelmente nas primeiras indicações da lesão renal. Dessa forma, o diagnóstico é tardio e a função renal já pode estar comprometida. A proteína cistatina C (CST3) vem sendo indicada como um novo marcador para a doença, mostrando superioridade especialmente para detectar pequenas variações da TFG. A concentração da cistatina C não varia significativamente com a idade, sexo e massa muscular. Assim, foi desenvolvido um imunossensor para detectar a cistatina C, usando a configuração de transistor de efeito de campo de porta estendida e separada (SEGFET). Os eletrodos foram caracterizados por várias técnicas como MEV, microscopia de força atômica, técnicas eletroquímicas e também foi analisada a sensibilidade do ouro. As etapas de construção do imunossensor, e a interação do anticorpo com concentrações crescentes da proteína foram verificadas através de técnicas eletroquímicas, na faixa de concentração de 3 a 100 ng.mL-1. Nas medidas no SEGFET observou-se uma mudança significativa da corrente após a adição da cistatina C e para as substâncias interferentes não. O imunossensor apresentou alta sensibilidade detectando concentrações bem baixas da proteína alvo. A curva analítica &#916;IDS% x [CST3] obteve-se L.D. = 0,75 ng.mL-1, L.Q. = 2,27 ng.mL-1 e r = 0,98122. A curva analítica &#916;VGS% x [CST3] obteve-se L.D. = 0,28 ng.mL-1, L.Q. = 0,87 ng.mL-1 e r = 0,99846. Embora tenha algumas limitações o imunossensor é inovador e apresenta muitas vantagens podendo ser aplicado futuramente para o diagnóstico da doença. / The kidneys play a key role in the urinary system and its main function is the filtration of blood. One of the causes that can compromise the functioning of the kidneys is the Acute Kidney Injury (AKI), which is defined as the quickly and unexpected decrease in Glomerular Filtration Rate (GFR), causing the loss of kidney function. This disease presents a significant number of hospitalizations and also deaths. The standard marker used in laboratory tests is serum creatinine, however, serum creatinine concentration may vary depending on a number of factors, such as age, sex, nutrition, and so on. In addition, its concentration does not vary considerably in the first indications of renal injury. Thus, the diagnosis is delayed and renal function may already be compromised. The cystatin C protein (CST3) has been indicated as a new marker for the disease, showing superiority especially for detecting small variations in GFR. The concentration of cystatin C does not vary significantly with age, sex and muscle mass. Thus, an immunosensor was developed to detect cystatin C using the extended and a separate gate field effect transistor (SEGFET) configuration. The electrodes were characterized by several techniques such as SEM, atomic force microscopy, electrochemical techniques and also the sensitivity of gold was analyzed. The construction of the immunosensor, and the interaction of the antibody with increasing concentrations of the protein were verified by electrochemical techniques, in the concentration range of 3 to 100 ng.mL-1. In the measurements in the SEGFET a significant change of the current was observed after the addition of cystatin C and for the interfering substances there was no difference. The immunosensor showed high sensitivity detecting very low concentrations of the target protein. The analytical curve &#916;IDS% x [CST3] was obtained L.D. = 0,75 ng.mL-1, L.Q. = 2,27 ng.mL-1 and r = 0,98122. The analytical curve &#916;VGS% x [CST3] was obtained L.D. = 0,28 ng.mL-1, L.Q. = 0,87 ng.mL-1 and r = 0,99846. Although it has some limitations the immunosensor is innovative and presents many advantages and can be applied in the future to diagnose the disease.

Background. There are few studies of renal function evaluation in visceral leishmaniasis (Kala-azar). The aim of this study was to investigate the clinical manifest and the risk factors associated with acute kidney injury (AKI) based on RIFLE criteria in patients with visceral leishmaniasis (VL). Methods. A retrospective study of medical records from patients over 14 years old, without previous kidney disease, with VL, treated at SÃo Josà Infectious Diseases Hospital, from 2002 to 2008. Clinical manifestations and risk factors for AKI (defined by using RIFLE criteria) were studied. A multivariate analysis was performed to analyze the risk factors for AKI. Results. A total of 224 patients were included. The mean age was 36Â15 years and 76.8% were males. AKI was observed in 76 patients (33.9% of cases) and % 52.6 (40) were class F on RIFLE criteria. The main clinical symptoms were dyspnea, edema and jaundice in patients with VL and AKI (p<0.05). Oliguria was observed in 6.5% of patients with AKI. Risk factors associated with AKI were male gender (OR=2.2, 95% CI= 1.0-4.7, p=0.03), age > 40 years (OR = 1.05, 95% CI= 1.02-1.08, p < 0.001) and jaundice (OR=2.9, 95% CI= 1.5-5.8 p=0.002). There was an strong association between amphotericin B use and AKI (OR=18.4, 95% CI=7.9-42.8, p<0.0001), whereas glucantime use was associated with a lower incidence of AKI when compared to amphotericin B users (OR=0.05, 95% CI=0.02-0.12, p<0.0001). Mortality was 13.3% and it was higher in AKI patients (30.2% vs. 4.7%, p<0.0001). RIFLE criteria presented mortality 40%, 20.8% e 35% in R, I and F respective class. Conclusions. The risk factors associated with AKI in patients with VL were male gender, advanced age, jaundice and amphotericin B. The last one was the most important factor of AKI in VL. / IntroduÃÃo. Hà poucos dados na literatura que relacionam a Leishmaniose visceral (LV) à lesÃo renal aguda (LRA). O objetivo deste estudo à avaliar as manifestaÃÃes clÃnicas e fatores de risco associados à LRA em pacientes com LV e aplicar o critÃrio RIFLE. MÃtodo. Estudo retrospectivo, incluindo pacientes acima de 14 anos, sem doenÃa renal prÃvia, com diagnÃstico de LV, internados no HSJ entre 2002 e 2008. Foram avaliadas manifestaÃÃes clÃnicas e os fatores de risco relacionados à LRA (avaliada atravÃs do critÃrio RIFLE) nesses pacientes, aplicando regressÃo logÃstica multivariada. Resultados. Foram incluÃdos 224 pacientes com idade mÃdia de 36Â15 anos sendo 76,8% do gÃnero masculino. LRA foi observada em 76 pacientes (33,9%) sendo que 52,6% (40) estavam na classe F do critÃrio RIFLE. Dispneia, edema e icterÃcia foram os principais sinais e sintomas associados à LRA (p<0,05). OligÃria foi observada em 6,5% dos pacientes com LRA. Os fatores de risco associados à LRA foram gÃnero masculino (OR=2,2, 95% IC=1,0-4,7, p=0,03), idade acima de 40 anos (OR = 1,05, 95% IC = 1,02-1,08, p<0,001) e icterÃcia (OR=2,9, 95% IC=1,5-5,8, p=0,002). Foi verificada considerÃvel associaÃÃo entre o emprego de anfotericina B e LRA (OR=18,4, 95% IC=7,9-42,8, p<0,0001), contudo o uso de glucantime foi associado a menor ocorrÃncia de LRA (OR=0,05, 95% IC=0,02-0,12, p<0,0001). A mortalidade geral foi 13,3% e foi mais alta nos pacientes que desenvolveram LRA (30,2% vs. 4,7%, p<0,0001). Os percentuais de mortalidade nas classes R, I e F foram respectivamente 40%, 20,8% e 35%. ConclusÃes. Os fatores de risco preditores de LRA em pacientes com LV foram sexo masculino, anfotericina B, idade acima de 40 anos e icterÃcia. Anfotericina B foi o fator mais importante de LRA na LV.

Submitted by Rosangela Silva (rosangela.silva3@unioeste.br) on 2018-05-22T20:11:58Z No. of bitstreams: 2 Luis César Bredt.pdf: 2819596 bytes, checksum: e18996972cd3e27519b13782d1d376bc (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-05-22T20:11:58Z (GMT). No. of bitstreams: 2 Luis César Bredt.pdf: 2819596 bytes, checksum: e18996972cd3e27519b13782d1d376bc (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-03-03 / This research aims to identify risk factors for the occurrence of acute kidney injury (AKI) in the postoperative period of partial hepatectomies. Methods: Retrospective analysis of 446 consecutive resections in 405 patients, analyzing clinical characteristics, preoperative laboratory data, intraoperative data, and postoperative laboratory data and clinical evolution. Adopting the International Club of Ascites (ICA) criteria for the definition of AKI, potential predictors of AKI by logistic regression were identified. Results: Of the total 446 partial liver resections, postoperative AKI occurred in 80 cases (17.9%). Identified predictors of AKI were: non-dialytic chronic kidney injury (CKI), biliary obstruction, the Model for End-Stage Liver Disease (MELD) score, the extent of hepatic resection, the occurrence of intraoperative hemodynamic instability, post-hepatectomy haemorrhage (PHH), and postoperative sepsis. Conclusion: The MELD score, the presence of non-dialytic CKI and biliary obstruction in the preoperative period, and perioperative hemodynamics instability, bleeding, and sepsis are risk factors for the occurrence of AKI in patients that underwent partial hepatectomy. / Atualmente, a hepatectomia parcial é o tratamento de escolha para uma grande variedade de patologias hepatobiliares. Dentre as possíveis complicações das hepatectomias parciais, a injúria renal aguda (IRA) deve ser considerada como uma importante causa de aumento da morbidade e mortalidade pós-operatória. Contudo, existem dados limitados na literatura médica quanto à sua real incidência e relevância clínica. Além disto, não existe uma padronização da definição de IRA no pós-operatório de hepatectomias parcias, com vários critérios diagnósticos propostos nas publicações sobre o assunto. Objetivo: Esta pesquisa tem o objetivo de identificar fatores de risco para a ocorrência de IRA no pós-operatório de hepatectomias parciais. Métodos: Por análise retrospectiva de 446 ressecções consecutivas em 405 pacientes, foram analisadas características clínicas, dados laboratoriais pré-operatórios, dados intra- operatórios e evolução clínico-laboratorial pós-operatória, e adotando os critérios do “International Club of Ascites” (ICA) para definição de IRA, foram analisados os potenciais preditores de IRA por regressão logística. Resultados: Do total de 446 ressecções hepáticas, a IRA pós-operatória ocorreu em 80 casos (17,9%). Foram fatores preditores de IRA: a IRC não-dialítica, obstrução biliar, o índice do “Model for End-Stage Liver Disease” (MELD), a ocorrência de instabilidade hemodinâmica intra- operatória, o porte da ressecção hepática, a hemorragia pós-hepatectomia, e a sepsis pós-operatória. Conclusão: O índice de MELD, a presença de IRC não-dialítica, obstrução biliar pré-operatória, o sangramento excessivo peri-operatório e a instalação de sepsis no período pós- operatório foram fatores de risco para a ocorrência de IRA em pacientes submetidos à hepatectomia parcial.

A gravidade da síndrome isquemia/reperfusão determina o prognóstico da lesão renal aguda (LRA). Agentes como o citrato de sildenafil (Sil) e a N-acetilcisteína (NAC) tem demonstrado efeito renoprotetor na LRA isquêmica com resultados ainda inconclusivos. Esse estudo investigou o efeito do Sil e da NAC na LRA com diferentes tempos de isquemia. Foram utilizados grupos de ratos Wistar, adultos e machos: SHAM; Isquemia 30 min (clampeamento dos pedículos renais por 30 min); Isquemia 30 + Sil (Sil 0,25 mg/kg 60 min antes da isquemia renal); Isquemia 30 + NAC (NAC 150 mg/kg antes e após a isquemia renal); Isquemia 45 (clampeamento dos pedículos renais por 45 min); Isquemia 45 + Sil e Isquemia 45 + NAC. Foram avaliadas a função renal (clearance de creatinina e fração de excreção de sódio-FENa); a lesão oxidativa (peróxidos urinários; substâncias reativas ao ácido tiobarbitúrico - TBARS; óxido nítrico - NO e tióis no tecido renal); a síntese protéica da óxido nítrico sintase induzível iNOS e da heme oxigenase-1 HO-1 (western blotting) e análise histológica renal (área intersticial relativa - AIR e lesão tubulointersticial). Os grupos 30 min tratados com Sil e NAC demonstraram melhora da função renal, redução dos índices oxidantes e NO, ausência de iNOS e presença de HO-1. Nos grupos 45 min, o Sil manteve a função renal, porém demonstrou proteção tubular e oxidante; a NAC não demonstrou efeito protetor em nenhum dos parâmetros avaliados. Quanto à histologia, apenas o Sil induziu redução da AIR e da lesão tubulointersticial nos tempos 30 e 45 min. O estudo confirmou que as características funcionais e histológicas induzidas pelo tempo de isquemia na LRA determinam as respostas às manobras farmacológicas de prevenção. A expressão HO-1 pode ser considerada um mediador de proteção renal. / Severity of ischemic/reperfusion injury syndrome determines the prognosis of acute kidney injury (AKI). Agents such as sildenafil citrate (Sil) and N-acetylcysteine (NAC) have demonstrated renoprotective effect on ischemic AKI which data is still inconclusive. This study investigated the protective action of Sil and NAC in the AKI with different time of ischemia. Adult, male, Wistar rats were divided: SHAM, Ischemia 30 min (renal pedicles clamping for 30 min), Ischemia 30 + Sil (Sil 0,25 mg/kg 60 min before renal ischemia), Ischemia 30 + NAC (NAC 150 mg/kg before and after renal ischemia), Ischemia 45 min (renal pedicles clamping for 45 min), Ischemia 45 + Sil, Ischemia 45 + NAC. Renal function (creatinine clearance and urine sodium fractional excretion - FENa); oxidative injury (urinary peroxides, thiobarbituric acid reactive substances - TBARS, nitric oxide - NO and thiols in renal tissue); expression of inducible nitric oxide synthase - iNOS and heme oxygenase-1 HO-1 (western blotting) and kidney histological analysis (fractional interstitial area - FIA and tubuleinterstitial injury) were evaluated. Sil and NAC treatment in 30 min renal ischemia induced increase in renal function, decrease in the rate of oxidation and NO levels, iNOS absence and HO-1 expression. In the Ischemia 45 groups, Sil it maintained renal function, however demonstrated tubular and oxidative protection; NAC produced no renoprotective effect on any of the parameters evaluated. Histology studies showed that, only Sil induced reduction in FIA and tubuleinterstitial injury at 30 and 45 min ischemic time. The study confirmed that the functional and histological characteristics induced by time of ischemia determine the renoprotective pharmacological agent action in the AKI. HO-1 expression can be a renal protection mediator.

L’insuffisance rénale aiguë (IRA) est une pathologie fréquente en réanimation. Elle est associée à une mortalité et une morbidité importante. Le sepsis en est la cause la plus fréquente. La compréhension de la physiopathologie du sepsis et de ses complications a beaucoup progressé ces dernières années mais ne s’est pas encore traduite par des avancées thérapeutiques significatives en pratique clinique. Le paradigme d’une altération de la perfusion sanguine comme paramètre clé de la constitution des lésions rénales a ainsi été remis en question, plusieurs travaux révélant que le débit sanguin rénal n’est pas toujours altéré en cas de sepsis, et qu’une IRA peut se développer en cas de débit sanguin rénal préservé, voire augmenté. Le sepsis est caractérisé par de profondes perturbations de la réponse immunitaire et une réaction inflammatoire disproportionnée. A l’origine de l’atteinte rénale, l’inflammation et les altérations de la microcirculation sont maintenant considérés comme des mécanismes physiopathologiques fondamentaux. Au-delà de leur rôle dans l’hémostase, la contribution des plaquettes sanguines à la réponse inflammatoire, au maintien de l’intégrité tissulaire et à la défense contre les infections a considérablement élargi le spectre de leurs compétences et en a fait des acteurs physiopathologiques potentiels dans le sepsis. Les plaquettes sanguines exercent la plupart de ces fonctions grâce à l’expression de nombreux médiateurs membranaires ou solubles. Parmi eux, le CD154 tient une place particulière : les plaquettes sont une source essentielle de CD154 dans l’organisme et il joue un rôle central dans la réponse inflammatoire. Nous proposons dans ce travail un aperçu de ces avancées physiopathologiques récentes et nous discutons de la contribution des plaquettes et du CD154 dans les atteintes microcirculatoires et les défaillances multi-viscérales dans le sepsis. Nous nous sommes intéressés au rôle pro-inflammatoire du CD154 en conditions d’hypoxie au niveau de l’épithélium tubulaire rénal. Des données récentes soulignent en effet l’importance de l’hypoxie dans la réaction inflammatoire. Le contrôle de la production d’interleukine (IL)-6, une cytokine centrale de la réponse inflammatoire, par le CD154 a été étudié dans un modèle de culture de cellules épithéliales tubulaires (CET) rénales. Un modèle murin d’IRA par ischémie/reperfusion rénale a également été mis au point et appliqué à des souris déficientes en CD154 et CD40. Nos travaux révèlent que le CD154 induit fortement la sécrétion d’IL-6 par les CET en conditions d’hypoxie et que les souris déficientes en CD154 régénèrent plus rapidement leur épithélium tubulaire après ischémie/reperfusion rénale. Ces résultats pourraient ouvrir la voie à de potentielles pistes thérapeutiques pour la prise en charge des IRA d’origine septique. / Acute kidney injury (AKI) is a common complication in critically ill patients and is associated with increased morbidity and mortality. Sepsis is the most common cause of AKI. The understanding of sepsis pathophysiology and its complications has progressed significantly in recent years but has not yet been translated into significant therapeutic advances in clinical practice. The traditional paradigm that sepsis-induced AKI is linked to renal hypoperfusion has been challenged by recent evidences showing that renal blood flow is not universally impaired during sepsis,and that AKI can develop in the presence of normal or even increased renal bloodflow. Sepsis is characterized by profound alterations of the immune response and adisproportionate inflammatory response. Inflammation and microcirculatorydysfunction are now considered as fundamental pathophysiological mechanisms atthe origin of renal injuries. Beyond haemostasis, the contribution of platelets ininflammation, tissue integrity and defence against infections has considerablywidened the spectrum of their role and made them potential physiopathologicalactors in sepsis. Platelets fulfil most of these functions through the expression ofmembrane-bound or soluble mediators. Among them, CD154 holds a peculiarposition, as platelets represent a major source of CD154 and as CD154 is a centralregulator of inflammation. Here, we provide an overview of these recentpathophysiological advances and discuss the platelets and CD154 contribution tomicrocirculatory alterations in multi-organ dysfunction in sepsis. We investigated thepro-inflammatory role of CD154 under hypoxic conditions in the renal tubularepithelium as recent data highlight the importance of hypoxia in the inflammatoryreaction. We studied the control of interleukin (IL)-6 production, a key cytokineinvolved in inflammation, by CD154 in oxygen deprivation conditions using a kidneytubular epithelial (TEC) cell line model. We also studied a murine model of kidneyinjury after ischemia/reperfusion, a model that was applied in CD154 and CD40deficient mice. We found that CD154 is a potent inducer of IL-6 secretion by TEC inhypoxia and that CD154-deficient mice regenerate earlier the tubular epithelium afterischemia/reperfusion injury. These findings may provide potential avenues for septicAKI management and therapy.

Ischemia and reperfusion are natural steps during kidney transplantation, and IRI is considered one of the most important nonspecific factors affecting allograft dysfunction. Transplanted organs experience several episodes of ischemia, in which cold ischemia occurs during allograft storage in preservation solutions. Even though cold ischemia has been studied extensively, all of the studies have been carried out in vitro and ex vivo models. There is no in vivo model available to examine renal IRI induced solely by cold ischemia. In the present study, we developed an in vivo mouse model to study renal IRI induced exclusively by cold ischemia through clamping the renal pedicle for 1 to 5 hours. During the ischemic phase, blood was flushed from the kidney with cold saline through a small opening on the renal vein. The kidney was kept cold in a kidney cup with circulating cooled saline, while the body temperature was maintained at 37℃ during the experiment. The level of kidney injury was evaluated by plasma creatinine, KIM-1, NAGL, GFR, and histology. Plasma creatinine was significantly increased from 0.15±0.04 mg/dl in the sham group to 1.14±0.21 and 2.65±0.14 mg/dl in 4 and 5-hours ischemia groups at 24 hours after cold IRI. The plasma creatinine in mice with ischemic time <3 hours demonstrated no significant increase compared with sham mice. Changes in KIM-1, NAGL, GFR and histology were similar to plasma creatinine. 65 In summary, we developed and characterized a novel in vivo IRI-induced AKI mouse model exclusively produced by cold ischemia.

Nephrotoxicity is a dose-limiting side effect of gentamicin that accounts for a significant portion of clinical acute kidney injury (AKI). The mechanism of gentamicin-induced nephrotoxicity is uncertain and effective therapy for gentamicin-induced renal cell injury is limited by incomplete mechanistic insight. To address this challenge, we hypothesized that RNAi signal pathway screening can identify both a unifying mechanism of gentamicin-induced cell injury and a therapeutic that ameliorates its toxicity. Dual shRNA screens of 5,000 individually barcoded signal pathway genes were performed in gentamicin-exposed human proximal tubule cell lines and differentially expressed shRNAs were analyzed by Ingenuity Pathways Analysis (IPA) software. Computational analysis of RNAi signal screens identified the Cross-Organelle Stress Response (CORE), the Unfolded Protein Response (UPR), and cell chaperones as key injury targets of gentamicin-induced proteotoxicity. To validate these injury mechanisms, we assessed the effect of gentamicin on the CORE, UPR and cell chaperone function, and tested the therapeutic efficacy of enhancing cell chaperone content. Early gentamicin exposure disrupted the CORE, evidenced by a rise in the ATP:ADP ratio, mitochondrial-specific H2O2 accumulation, Drp-1 associated mitochondrial fragmentation, and endoplasmic reticulum-mitochondrial dissociation. CORE disruption preceded measurable increases in whole cell oxidative stress, misfolded protein content, transcriptional UPR activation and its untoward downstream effects: CHOP expression, PARP cleavage and cell death. Geranylgeranylacetone, a therapeutic that increases cell chaperone content, prevented mitochondrial H2O2 accumulation, preserved the CORE, reduced the burden of misfolded proteins and CHOP expression, and significantly improved survival in gentamicin-exposed cells. We identify CORE disruption as an early and remediable cause of gentamicin proteotoxicity that precedes downstream cytosolic UPR activation and cell death. Preserving the CORE is associated with improved renal cell survival likely by reducing organelle-specific proteotoxicity during gentamicin exposure.

Orientador: Paulo do Nascimento Junior / Resumo: Introdução: Reduzir o fluxo de gases frescos (FGF) para menos de 1 L.min-1 durante a anestesia resulta no aquecimento e umidificação dos gases inalados, redução de custos e menor exposição ocupacional. O Composto A é formado pelo sevoflurano quando reage com absorvedores de dióxido de carbono contendo bases fortes em FGF mínimo, sendo nefrotóxico em animais. Até o momento, nenhum dado conclusivo mostrou aumento do risco em seres humanos para anestesia com sevoflurano em FGF mínimo. Objetivos: avaliar a função renal pós-operatória de pacientes submetidos a cirurgia cardíaca com circulação extracorpórea (CEC), quando anestesiados com sevoflurano FGF de 0,5 mL.min-1, em comparação ao FGF de 2 L.min-1. Método: duzentos e quatro pacientes adultos de ambos os sexos agendados para cirurgia cardíaca com CEC anestesiados com sevoflurano foram randomizados em dois grupos diferenciados pelo FGF: FGF mínimo (0,5 L.min-1) ou FGF alto (2,0 L.min-1). A medida da creatinina basal pré-operatória foi comparada diariamente aos valores obtidos nos primeiros cinco dias de pós-operatório, e o débito urinário de 24 horas foi monitorado, de acordo com os guidelines KDIGO para definir lesão renal aguda (LRA). As medidas da creatinina sérica também foram obtidas 20 e 120 dias após a alta hospitalar. Resultados: A análise por protocolo envolveu 88 e 92 pacientes no grupo FGF mínimo e FGF alto, respectivamente. A LRA pós-operatória ocorreu em 55 pacientes, 26 pacientes (29,5%) no grupo FGF mínimo e 29 p... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Reducing fresh gas flow (FGF) to less than 1 L.min-1 during anesthesia results in warming and humidification of inhaled gases, cost reduction and less occupational exposure. Compound A is generated by sevoflurane when it reacts with carbon dioxide absorbers with strong bases at minimal FGF and is nephrotoxic in animals. To date, no conclusive data has shown increased risk for minimal FGF sevoflurane anesthesia in humans. Objectives: To evaluate the postoperative renal function of patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) when anesthetized with sevoflurane at 0.5 mL.min-1 FGF compared to 2 L.min-1 FGF. Method: Two hundred and four adult patients of both sexes scheduled for on-pump cardiac surgery under sevoflurane anesthesia were randomly allocated to two groups differentiated by FGF: minimal FGF anesthesia (0.5 L.min-1) or high FGF anesthesia (2.0 L.min-1). Baseline creatinine measured before surgery was compared daily to values assayed on the first five postoperative days, and 24-hour urinary output was monitored, according to the KDIGO guideline to define acute kidney injury (AKI). Creatinine measurements were also obtained 20 and 120 days after hospital discharge. Results: Per protocol analyses involved 88 and 92 patients in the minimal and high FGF groups, respectively. Postoperative AKI occurred in 55 patients, 26 patients (29.5%) in the minimal FGF group and 29 patients (31.5%) in the high FGF group (P = 0.774). Patients with AK... (Complete abstract click electronic access below) / Doutor