Toll-like Receptor 4 in Acute Kidney Injury.

Acute kidney injury (AKI) is a common and devastating pathologic condition, associated with considerable high morbidity and mortality. Although significant breakthroughs have been made in recent years, to this day no effective pharmacological therapies for its treatment exist. AKI is known to be connected with intrarenal and systemic inflammation. The innate immune system plays an important role as the first defense response mechanism to tissue injury. Toll-like receptor 4 (TLR4) is a well-characterized pattern recognition receptor, and increasing evidence has shown that TLR4 mediated inflammatory response, plays a pivotal role in the pathogenesis of acute kidney injury. Pathogen-associated molecular patterns (PAMPS), which are the conserved microbial motifs, are sensed by these receptors. Endogenous molecules generated during tissue injury, and labeled as damage-associated molecular pattern molecules (DAMPs), also activate pattern recognition receptors, thereby offering an understanding of sterile types of inflammation. Excessive, uncontrolled and/or sustained activation of TLR4, may lead to a chronic inflammatory state. In this review we describe the role of TLR4, its endogenous ligands and activation in the inflammatory response to ischemic/reperfusion-induced AKI and sepsis-associated AKI. The potential regeneration signaling patterns of TLR4 in acute kidney injury, are also discussed.

Detección rápida de antígenos de Streptococcus pyogenes en pacientes de 0 a 14 años asistidos en dos servicios de urgencia pediátrica (14/2/2018-13/4/2018) / Rapid detection of Streptococcus pyogenes' antigens in patients of 0 to 14 years of age, assisted in two pediatric emergency wards (2/14/2018-4/13/2018) / Detecção rápida de antígenos de Streptococcus pyogenes em pacientes de 0 a 14 anos de idade assistidos por emergência pediátrica (14/2/2018-13/4/2018)

Introducción: las infecciones estreptocócicas pueden presentarse con fiebre, inflamación faringoamigdalina con o sin exudados, petequias en el paladar, adenitis cervical, exantema escarlatiniforme y / o dolor abdominal. Resulta útil en área de urgencia disponer de pruebas de detección rápida de antígenos de S. pyogenes (DRASP) de alta especificidad y sensibilidad algo menor. Objetivos: conocer la utilidad de un test de DRASP en 2 servicios de Urgencia Pediátrica, describiendo las características clínicas y epidemiológicas de los pacientes estudiados durante el período de la investigación y su correlación con el cultivo de exudado faríngeo mediante el cálculo de sensibilidad (S), especificidad (E), valor predictivo positivo (VPP) y valor predictivo negativo (VPN). Material y métodos: estudio prospectivo, observacional, transversal en dos servicios de emergencia pediátrica. Se incluyeron niños a los que se les realizó DRASP y exudado faríngeo (EF) entre el 14 de febrero y el 13 de abril de 2018. Se registró: sexo, edad, motivo de consulta, diagnóstico, tratamiento, destino, resultado del test y de cultivo faríngeo. Se calcularon S, E, VPP y VPN. Resultados: n=241 niños. Rango 8 meses - 14 años, media 6 años. Consultaron por fiebre 103 niños (42,7%); por odinofagia 48, por erupción 11 y 47 por otros síntomas. Al 95% de los niños se le otorgó el alta. DRASP negativos 87,6% (N: 211) y positivos 12,9% (N: 31). EF negativos 80,1% (n: 193) y positivos para SßHGA en 13,7% (n: 33). La sensibilidad de la prueba fue del 52% y su especificidad del 93%. El VPP 55% y el negativo 92%. El diagnóstico más frecuente fue faringitis viral 132 (54,7%). Conclusiones: el test se aplicó fundamentalmente a escolares febriles, algunos con odinofagia. Contribuye a diferenciar en forma rápida la etiología y habilita a no usar antibióticos en caso de resultado negativo. Estos resultados avalan el uso de DRASP en la urgencia pediátrica.

Introduction: streptococcal infections can show fever, pharyngotonsillar inflammation with or without swabs, palatal petechiae, cervical adenitis, scarlatiniform rash and/or abdominal pain. Rapid detection tests for S. pyogenes antigens (DRASP) with high specificity and somewhat lower sensitivity are a useful at the Emergency Ward. Objectives: know the usefulness of a DRASP test in 2 Pediatric Emergency, describe the clinical and epidemiological characteristics of the patients studied during the research period and its correlation with the culture of pharyngeal exudates by calculating sensitivity (S) , specificity (S), positive predictive value (PPV), and negative predictive value (NPV). Material and Methods: prospective, observational, cross-sectional study carried out in two pediatric emergency wards. We included children who underwent DRASP and pharyngeal swab (PS) between February 14 and April 13, 2018. The following data were recorded: sex, age, reason for consultation, diagnosis, treatment, destination, test results and throat cultures. S, S, PPV and NPV were calculated. Results: n=241 children. Range 8 months - 14 years, average 6 years. 103 children (42.7%) consulted due to fever; 48 due to sore throat, 11 due to rash and 47 due to other symptoms. 95% of children were discharged. DRASP negative 87.6% (N: 211) and positive 12.9% (N: 31). Negative EP 80.1% (n: 193) and positive for SßHGA in 13.7% (n: 33). The test sensitivity was 52% and specificity 93%. The PPV 55% and the negative 92%. The most frequent diagnosis was viral pharyngitis 132 (54.7%). Conclusions: the test was applied mainly to febrile schoolchildren, some with odynophagia. A quick etiology differentiation is helpful, since it prevents antibiotics from being used in the event of a negative result. These results support the use of DRASP in pediatric emergency wards.

Introdução: as infecções estreptocócicas manifestam-se com febre, inflamação faringotonsilar com ou sem exsudado, petéquias palatinas, adenite cervical, erupção cutânea escarlatiniforme e/ou dor abdominal. Nos serviços de emergência é útil realizar testes de detecção rápida para antígenos de S. pyogenes (DRASP) com alta especificidade e sensibilidade um pouco mais baixa Objetivos: conhecer a utilidade do teste DRASP em 2 Emergências Pediátricas, descrever as características clínicas e epidemiológicas dos pacientes estudados durante o período da pesquisa e sua correlação com a cultura de exsudatos faríngeos por meio do cálculo de sensibilidade (S) , especificidade (S), positivo valor preditivo (VPP) e valor preditivo negativo (VPN). Material e métodos: estudo prospectivo, observacional, transversal, realizado em duas unidades de emergência pediátrica. Foram incluídas crianças que realizaram DRASP e swab faríngeo (PS) entre 14 de fevereiro e 13 de abril de 2018. Foram registrados os seguintes dados: sexo, idade, motivo da consulta, diagnóstico, tratamento, destino, resultados de exames e culturas de garganta. S, S, VPP e VPN foram calculados. Resultados: n=241 crianças. Faixa 8 meses - 14 anos, média 6 anos. 103 crianças (42,7%) consultadas por febre; 48 por dor de garganta, 11 por erupção cutânea e 47 por outros sintomas. 95% das crianças receberam alta. DRASP negativo 87,6% (N: 211) e positivo 12,9% (N: 31). EP negativo 80,1% (n: 193) e positivo para SßHGA em 13,7% (n: 33). A sensibilidade do teste foi de 52% e a especificidade de 93%. O PPV 55% e o negativo 92%. O diagnóstico mais frequente foi faringite viral 132 (54,7%). Conclusões: o teste foi aplicado principalmente em escolares febris, alguns com odinofagia. A rápida diferenciação etiológica é útil, pois evita o uso de antibióticos em caso de resultado negativo. Esses resultados apoiam o uso do DRASP em enfermarias de emergência pediátrica.

Lactantes febriles menores de tres meses sin foco aparente: ¿es necesario cambiar la estrategia de evaluación?: probamos el step by step / Febrile infants of under three months of age without apparent focus: is it necessary to change the assessment strategy?: we tested the step-by-step approach / Lactentes febris com menos de três meses de idade e sem foco aparente: é necessário alterar a estratégia de avaliação?: tentamos o "passo a passo"

Introducción: la fiebre es un motivo muy frecuente de consulta y hasta en un 20% de los pacientes no se encuentra la causa. En el ámbito de la emergentología pediátrica clásicamente ha existido interés en homogeneizar la forma de evaluar los lactantes febriles menores de tres meses. Contar con un protocolo que permita detectar precozmente el niño que cursa una infección bacteriana invasiva (IBI) sin realizar conductas desproporcionadas es todo un desafío. Objetivo: evaluar y comparar la capacidad para identificar IBI en la pauta actual de fiebre sin foco (FSF) como en la estrategia step by step, en lactantes con FSF valorados en el DEP-CHPR. Material y métodos: estudio observacional, descriptivo, retrospectivo y de pruebas diagnósticas. Criterios de inclusión: lactantes menores de 90 días de vida que consultaron en 2017 y 2018 en DEP-CHPR con diagnóstico de FSF. Resultados: se incluyeron 261 lactantes evaluados con la pauta de FSF actual, en ellos se aplicó la estrategia step by step. El rango de edad fue de 84 días (4-88 días) con una media de 41 días. Sexo masculino 148 niños (56,7%). Se registraron 37 infecciones bacterianas (14,2%) de las cuales 3 fueron IBI (1,1%) y 34 fueron no-IBI (13,1%). La sensibilidad para step by step fue de 0,94% y de 0,89 para la pauta actual, con un VPN de 0,98 para ambas estrategias. Discusión: los lactantes menores de 3 meses son más susceptibles por características fisiológicas a infecciones bacterianas invasivas y cuanto más pequeño aumenta aún más la frecuencia. El step by step discrimina a menores de 1 mes en menores de 21 días y otro grupo de más de 21 días. Nuestra pauta no hace esta discriminación y realiza por igual laboratorio en sangre, orina y líquido cefalorraquídeo; realizando en ocasiones estudios cruentos no necesarios. Conclusiones: ambas estrategias aplicadas en esta población resultaron altamente sensibles para identificar infección bacteriana con un VPN elevado. La aplicación de step by step presenta como beneficio adicional evitar con seguridad la punción lumbar en recién nacidos entre los 21 y 28 días.

Introduction: fever is a very frequent reason for consultation and in up to 20% of patients the cause has not been found. In the field of pediatric emergentology, there has been a traditional interest in homogenizing the way of assessing febrile infants under three months of age. Having a protocol that enables early detection of children with IBIs without engaging in disproportionate procedures is a challenge. Objective: to evaluate and compare the ability to identify IBIs in the present FSF regimen as in the Step-by-Step strategy, in infants with FSF assessed at the Pereira Rossell Pediatric Hospital Center. Material and methods: observational, descriptive, retrospective study and diagnostic tests. Inclusion criteria: Infants under 90 days of age who consulted in 2017 and 2018 at the DEP-CHPR with a diagnosis of FSF. Results: 261 infants diagnosed with FSF regimen were included and they all received a Step-by-Step approach. The age range was 84 days (4 - 88) days with a mean of 41 days. Males 148 children (56.7%). There were 37 bacterial infections (14.2%), of which 3 were IBI (1.1%) and 34 were Non-IBI (13.1%). The sensitivity for the Step-by-Step approach was 0.94% and 0.89 for the current regimen, with a NPV of 0.98 for both strategies. Discussion: infants younger than 3 months-old are more susceptible due to physiological characteristics to invasive bacterial infections, and the younger they are, the higher the frequency. The Step-by-Step Approach splits children of under 1 month of age into those under or over 21 days of age. Our guideline does not make this discrimination and performs the same blood, urine and cerebrospinal fluid laboratory tests sometimes carrying out blood tests is not necessary. Conclusions: both approaches used in this population were highly sensitive to the identification of bacterial infections with a high NPV. The application of the "Step-by-Step" approach has the additional benefit of avoiding lumbar puncture to newborns of between 21 and 28 days of age.

Introdução: a febre é um motivo muito comum de consulta e em até 20% dos pacientes a causa não é encontrada. No campo da emergência pediátrica, tradicionalmente tem havido interesse em homogeneizar a forma de avaliação de lactentes febris menores de três meses de idade. Ter um protocolo que permita a detecção precoce de uma criança com IBI sem realizar procedimentos desproporcionais é um desafio. Objetivo: avaliar e comparar a capacidade de identificação de IBI na atual Diretriz da FSF e na estratégia Passo a Passo, em lactentes com FSF avaliados no DEP-CHPR. Material e métodos: estudo observacional, descritivo, retrospectivo e de testes diagnósticos. Critérios de inclusão: Lactentes com menos de 90 dias de idade que consultaram em 2017 e 2018 no Hospital Pediátrico Pereira Rossell do Uruguai com diagnóstico de FSF. Resultados: Foram incluídos 261 lactentes avaliados com a atual diretriz da FSF, nos quais foi aplicada a estratégia Passo a Passo. A faixa etária foi de 84 dias (4 - 88) dias com média de 41 dias. Sexo masculino 148 crianças (56,7%). Foram registradas 37 infecções bacterianas (14,2%), sendo 3 IBI (1,1%) e 34 Não IBI (13,1%). A sensibilidade para Passo a Passo foi de 0,94% e 0,89 para o esquema atual, com VPN de 0,98 para ambas estratégias. Discussão: crianças menores de 3 meses de idade são mais suscetíveis a infecções bacterianas invasivas devido às características fisiológicas e quanto menores, mais frequentes. O Passo a Passo separa crianças menores de 1 mês em dois grupos: menores de 21 dias e acima de 21 dias. Nossa diretriz não faz essa discriminação e realiza exames laboratoriais de sangue, urina e líquido cefalorraquidiano da mesma forma; às vezes realizando estudos de sangue que não são necessários. Conclusões: ambas as estratégias aplicadas nesta população foram altamente sensíveis para identificar infecção bacteriana com alto VPN. A aplicação do "Passo a Passo" apresenta como benefício adicional evitar a punção lombar em recém-nascidos entre 21 e 28 dias.

Repercusión de la pandemia por SARS-COV-2 sobre las consultas en los Servicios de Emergencia Pediátrica en Uruguay / Consequences of the SARS-COV-2 pandemic on Pediatric Emergency Services in Uruguay / Repercussão da pandemia de SARS-COV-2 nas consultas nos Serviços de Emergência Pediátrica do Uruguai

En marzo de 2020 se confirma el primer caso de enfermedad por coronavirus en Uruguay, recomendándose un confinamiento social. La atención sanitaria se redujo a servicios de urgencia y emergencia (SE). Objetivo: analizar las características de las consultas pediátricas en los SE del subsector público y privado en Uruguay, durante los primeros 4 meses de la pandemia por SARS-CoV-2. Metodología: estudio descriptivo, retrospectivo, multicéntrico. Resultados: participaron 23 SE de todas las regiones del país. Período 1 prepandemia: 14/03/19-29.07.19, período 2: 14/03/20-29/07/20 Consultas: período 1 n=121.116, período 2 n=33.099 (desciende 73%). Hospitalizaciones desde el SE: período 1 n= .6649 (tasa 5,5%). Período 2: n=2.948 (tasa 9,5%). Diagnósticos período 1: infección respiratoria aguda (IRA) alta 39.892 (33%), IRA baja 86.56 (7%), trauma menor 8.651 (7%), gastroenteritis 8.044 (6,6%), crisis asmática/CBO 7.974 (6,5%), lesiones 4.389 (3,6%), dolor abdominal 3.528 (3%), problemas de salud mental 859 (0,7%), convulsiones 758 (0,7%), patología social 678 (0,5%). Diagnósticos 2020: IRA alta 5.168 (16%), trauma menor 2.759 (8%), lesiones 2.652 (8%), dolor abdominal 1.494 (4,5%), gastroenteritis 1.296 (4%), asma/CBO 1.095 (3,3%), IRA baja 700 (2,1%), patología social 522 (1,6%), problemas de salud mental 471 (1,4%), convulsiones 408 (1,2%). Conclusiones: en los primeros meses de la pandemia hubo una reducción sostenida y significativo de consultas pediátricas en los SE. No hubo aumento en frecuencia absoluta de ninguno de los diagnósticos. Se registró un descenso histórico de las IRA bajas y las hospitalizaciones por esta causa en todo el país. Mantener una vigilancia de las consultas en los SE permitiría identificar e intervenir oportunamente si se produjeran cambios o situaciones de riesgo hasta el momento no detectadas.

In March 2020 the first case of coronavirus disease was confirmed in Uruguay, and lockdown was recommended. Health care services were reduced to Urgency and Emergency Services (ES). Objectives: to analyze the epidemiological characteristics of pediatric visits to the ES of the public and private subsector in Uruguay, during the first 4 months of the SARS-CoV-2 pandemic. Methods: descriptive, retrospective. Results: 23 institutions participated. 2 periods were considered: 1) pre-pandemic, 03/14/19 to 07/29/19, 2) 03/14/20 to 07/29/20. Visits: period 1: n=121,116 (< 15 years), period 2: n=33.099 (73% decrease). Hospital admissions: period 1: n=6,649 (rate 5.5). Period 2: n=2.948 (rate 9,5). Diagnoses period 1: High acute respiratory infection 39,892 (33%), low acute respiratory infection 8,656 (7%), minor trauma 8,651 (7%), gastroenteritis 8,044 (6,6%), asthmatic crisis/CBO 7.974 (6,5%), injuries 4,389 (3,6%), abdominal pain (3,528) 3%, mental health problems 859 (0.7%), seizures 758 (0.7%), social pathology 678 (0.5% ). 2020 diagnoses: high acute respiratory infection 5.168 (16%), minor trauma 2,759 (8%), injuries 2,652 (8%), abdominal pain 1,494 (4.5%), gastroenteritis 1,296 (4%), asthma/CBO 1,095 (3,3%), low acute respiratory infection 700 (2,1%), social pathology 522 (1,6%), mental health problems 471 (1,4%), seizures 408 (1,2%). Conclusions: in the first months of the pandemic there was a sustained and significant reduction in pediatric consultations in ES. There was no increase in absolute frequency of any of the diagnoses. There was a historical decrease in low respiratory infections and hospitalizations due to this cause in the whole country. Maintaining a surveillance of the visits in the ES would enable practitioners to identify and take action in case of changes or previously undetected risk situations.

Em março de 2020, foi confirmado o primeiro caso de doença por coronavírus no Uruguai, recomendando o confinamento. A assistência à saúde foi reduzida a serviços de urgência e emergência (SE). Objetivo: analisar as características das consultas pediátricas no SE do subsetor público e privado no Uruguai, durante os primeiros 4 meses da pandemia de SARS-CoV-2. Metodologia: estudo descritivo, retrospectivo, multicêntrico. Resultados: participaram 23 SEs de todas as regiões do país. Período pré-pandemia 1: 14/03/19-29/07/19, período 2: 14/03/20-29/07/20 Consultas: período 1 n=121.116, período 2 n=33.099 (redução de 73%) . Internações da SE: período 1 n= 0,6649 (taxa 5,5%). Período 2: n=2.948 (taxa de 9,5%). Diagnósticos do período 1: infecção respiratória aguda alta (IRA) 39.892 (33%), LRA baixa 86,56 (7%), trauma menor 8.651 (7%), gastroenterite 8.044 (6,6%), crise asmática/CBO 7.974 (6, 5% ), lesões 4.389 (3,6%), dor abdominal 3.528 (3%), problemas de saúde mental 859 (0,7%), convulsões 758 (0,7%), patologia social 678 (0,5%). Diagnósticos 2020: IRA alta 5.168 (16%), trauma leve 2.759 (8%), lesões 2.652 (8%), dor abdominal 1.494 (4,5%), gastroenterite 1.296 (4%), asma/CBO 1.095 (3, 3%), IRA baixa 700 (2,1%), patologia social 522 (1,6%), problemas de saúde mental 471 (1,4%), convulsões 408 (1,2%). Conclusões: nos primeiros meses da pandemia houve uma redução sustentada e significativa das consultas pediátricas no SE. Não houve aumento na frequência absoluta de nenhum dos diagnósticos. Foi registrado um decréscimo histórico de IRAs baixas e internações por essa causa em todo o país. A manutenção de uma vigilância das consultas no SE permitiria identificar e intervir atempadamente nos casos de alterações ou situações de risco que até agora não tinham sido detectadas.

Simulación in situ y "madre" simulada, nuevas estrategias pedagógicas en pediatría / Simulação in situ e simulação "mãe", novas estratégias pedagógicas em pediatria / In situ simulation and simulated "mother", new pedagogical strategies in pediatrics

El proceso de docencia-aprendizaje de las disciplinas clínicas tiene entre sus desafíos la adquisición de habilidades del estudiante con el paciente. Las oportunidades de prácticas clínicas se han reducido. La menor cantidad de consultas pediátricas en el año 2020 durante la pandemia por Coronoavirus exacerbó este hecho. Objetivo: Comunicar la experiencia de simulación in situ y madre simulada realizada por docentes del Departamento de Emergencia Pediátrica del Centro Hospitalario Pereira Rossell, dirigida al entrenamiento de estudiantes de la Unidad Curricular Pediatría (Facultad de Medicina-UdelaR), en la realización de la anamnesis de un paciente con patología respiratoria. Metodología: estudio descriptivo. Madre simulada: docentes/residentes. Simulador: lactante-tecnología intermedia. Participantes del escenario: 2 estudiantes. Lugar: DEP-CHPR. Período: setiembre-diciembre 2020. Resultados: Participaron de la simulación 327 estudiantes, 255 contestaron el censo. Utilidad de la simulación: 53,2% muy útil/excelente, poco o nada útil 24,8%, no contesta 22%. Credibilidad: aceptable 38%, muy creíble/excelente 27,5%, 12,5% poco o nada creíble, 22% no contesta. Participación grupal en el debriefing 64,5%, participación parcial 11,4%, sin debriefing 2,1%, no contesta 22%.Discusión: De los 327 estudiantes que realizaron la simulación al menos 24,% la percibió como poco o nada útil. La falta de información previa, la participación en el escenario de 2 estudiantes por grupo y la poca interacción en el debriefing en algunos grupos pudo haber influído. Conclusiones: La experiencia comunicada generó nuevas oportunidades de docencia aprendizaje. Se identificaron aspectos metodológicos que pueden mejorarse.

The teaching-learning process in clinical disciplines includes amongst its challenges the acquisition of the student's skills with the patient. Opportunities for clinical practice have diminished. A smaller number of pediatric visits in 2020 during the Coronavirus pandemic increased this fact. Objective: to communicate the experience of in situ simulation and simulated mother carried out by the faculty of the Pediatric Emergency Department of the Pereira Rossell Hospital Center, address to students in the Pediatrics Curricular Unit (School of Medicine- UdelaR), in the case of an infant patient with respiratory pathology. Methods: Descriptive study. Simulated mother: faculty members/residents. Simulator: intermediate technology infant. Participants in the scenario: 2 students. Location: DPE.PRHC. Period: September- December 2020.Results: 327 students participated in the simulation, 255 answered the census. Usefulness of the simulation: 53.2% very useful / excellent, little or not at all useful 24.8%, no answer 22%. Credibility: acceptable 38%, very credible / excellent 27.5%, 12.5% ​​little or not at all credible, 22% do not answer. Group participation in the debriefing 64.5%, partial participation 11.4%, without debriefing 2.1%, no answer 22%. Discussion: Of the 327 students who carried out the simulation at least 24,8 % perceived it as little or not useful. The lack of previous information, the participation in the scenario of 2 students per group and the little interaction in the debriefing in some groups could have influenced. Conclusions: The communicated experience generated new teaching-learning opportunities. Methodological aspects that can be improved were identified.

O processo de ensino-aprendizagem de disciplinas clínicas tem entre seus desafios a aquisição de habilidades do aluno com o paciente. As oportunidades de estágio clínico foram reduzidas. O menor número de consultas pediátricas em 2020 durante a pandemia de Coronoavirus exacerbou esse fato. Objetivo: Comunicar a experiência de simulação in situ e simulação materna realizada pela docentes do Serviço de Urgência Pediátrica do Centro Hospitalar Pereira Rossell, com alunos da Unidade Curricular Pediatria (Faculdade de Medicina-UdelaR), na anamnese de paciente com doença respiratória. Metodologia: estudo descritivo. Mãe simulada: professores / residentes. Simulador: lactente de tecnologia intermédia. Participantes do cenário: 2 alunos. Local: DEP-CHPR. Período: setembro a dezembro de 2020. Resultados: 327 alunos participaram da simulação, 255 responderam a pesquisa. Utilidade da simulação: 53,2% muito útil / excelente, pouco ou nada útil 24,8%, sem resposta 22%. Credibilidade: aceitável 38%, muito credível / excelente 27,5%, 12,5% pouco ou nada credível, 22% não respondem. Participação do grupo no debriefing 64,5%, participação parcial 11,4%, sem debriefing 2,1%, sem resposta 22%. Discussão: Dos 327 alunos que realizaram a simulação, pelo menos 24,% a perceberam como pouco ou nada útil. A falta de informação prévia, a participação no cenário de 2 alunos por grupo e a pouca interação no debriefing em alguns grupos podem ter influenciado. Conclusões: A experiência comunicada gerou novas oportunidades de ensino-aprendizagem. Aspectos metodológicos que podem ser melhorados foram identificados.

Molecular Mechanisms of Hypertensive Nephropathy: Renoprotective Effect of Losartan through Hsp70.

Hypertensive nephrosclerosis is the second most common cause of end-stage renal disease after diabetes. For years, hypertensive kidney disease has been focused on the afferent arterioles and glomeruli damage and the involvement of the renin angiotensin system (RAS). Nonetheless, in recent years, novel evidence has demonstrated that persistent high blood pressure injures tubular cells, leading to epithelial-mesenchymal transition (EMT) and tubulointerstitial fibrosis. Injury primarily determined at the glomerular level by hypertension causes changes in post-glomerular peritubular capillaries that in turn induce endothelial damage and hypoxia. Microvasculature dysfunction, by inducing hypoxic environment, triggers inflammation, EMT with epithelial cells dedifferentiation and fibrosis. Hypertensive kidney disease also includes podocyte effacement and loss, leading to disruption of the filtration barrier. This review highlights the molecular mechanisms and histologic aspects involved in the pathophysiology of hypertensive kidney disease incorporating knowledge about EMT and tubulointerstitial fibrosis. The role of the Hsp70 chaperone on the angiotensin II-induced EMT after angiotensin II type 1 receptor (AT1R) blockage, as a possible molecular target for therapeutic strategy against hypertensive renal damage is discussed.

Severely ill pediatric patients with Shiga toxin-associated hemolytic uremic syndrome (STEC-HUS) who suffered from multiple organ involvement in the early stage.

BACKGROUND: Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) is the main cause of pediatric acute kidney injury (AKI) in Argentina. Endothelial injury is the trigger event in the microangiopathic process. The host inflammatory response to toxin and E. coli lipopolysaccharide (LPS) is involved in disease pathophysiology. METHODS: This retrospective study describes pediatric STEC-HUS patients with multiorgan involvement at the initial phase of disease. A retrospective study of critically ill HUS patients with evidence of E. coli infection was conducted through a period of 15 years. RESULTS: Forty-four patients 35.4 ± 4.1 months were admitted to the intensive care unit for 21 ± 2 days. Mechanical ventilation was required in 41 patients, early inotropic support in 37, and 28 developed septic shock. Forty-one patients required kidney replacement therapy for 12 ± 1 days. Forty-one patients showed neurological dysfunction. Dilated cardiomyopathy was demonstrated in 3 patients, left ventricular systolic dysfunction in 4, and hypertension in 17. Four patients had pulmonary hemorrhage, and acute respiratory distress syndrome in 2. Colectomy for transmural colonic necrosis was performed in 3 patients. Thirty-seven patients were treated with therapeutic plasma exchange, and 28 patients received methylprednisolone (10 mg/kg for 3 days). Of the surviving 32 patients, neurological sequelae were seen in 11 and chronic kidney failure in 5. CONCLUSIONS: Severe clinical outcome at onset suggests an amplified inflammatory response after exposure to Shiga toxin and/or E. coli LPS. STEC-HUS associated with severe neurological involvement, hemodynamic instability, and AKI requires intensive care and focused therapy.

The renal antioxidative effect of losartan involves heat shock protein 70 in proximal tubule cells.

Angiotensin II exerts a cardinal role in the pathogenesis of hypertension and renal injury via action of angiotensin II type 1 (AT1) receptors. Local renin-angiotensin system (RAS) activity is essential for the mechanisms mediating pathophysiological functions. Proximal tubular angiotensinogen and tubular AT1 receptors are augmented by intrarenal angiotensin II. Caveolin 1 plays an important role as a regulatory molecule for the compartmentalization of redox signaling events through angiotensin II-induced NADPH oxidase activation in the kidney. A role for the renin-angiotensin system in the development and/or maintenance of hypertension has been demonstrated in spontaneously hypertensive rats (SHRs). Many effects of angiotensin II are dependent on the AT1 stimulation of reactive oxygen species (ROS) production by NADPH oxidase. Angiotensin II upregulation stimulates oxidative stress in proximal tubules from SHR. The NADPH oxidase 4 (Nox4) is abundantly expressed in kidney proximal tubule cells. Induction of the stress response includes synthesis of heat shock protein 70, a molecular chaperone that has a critical role in the recovery of cells from stress and in cytoprotection, guarding cells from subsequent insults. HSP70 chaperones function in part by driving the molecular triage decision, which determines whether proteins enter the productive folding pathway or result in client substrate ubiquitination and proteasomal degradation. This review examines regulation of losartan-mediated antioxidative stress responses by the chaperone HSP70 in proximal tubule cells of spontaneously hypertensive rats.

Losartan through Hsp70 Avoids Angiotensin II Induced Mesenchymal Epithelial Transition in Proximal Tubule Cells from Spontaneously Hypertensive Rats.

BACKGROUND/AIMS: Renal injury related to hypertension is characterized by glomerular and tubulointerstitial damage. The overactivation of the renin-angiotensin system mainly by angiotensin II (AII) seems to be a main contributor to progressive renal fibrosis. Epithelial to mesenchymal transition (EMT) is a mechanism that promotes renal fibrosis. Owing to heat shock protein 70 (Hsp70) cytoprotective properties, the chaperone exhibits an important potential as a therapeutic target. We investigate the role of Hsp70 on Angiotensin II induced epithelial mesenchymal transition within the Losartan effect in proximal tubule cells (PTCs) from a genetic model of hypertension in rats (SHR). METHODS: Primary cell culture of PTCs from SHR and Wistar Kyoto (WKY) rats were stimulated with AII, treated with Losartan (L), (L+AII) or untreated (Cc). The functional Hsp70 role in Losartan effect, after silencing its expression by cell transfection, was determined by Immunofluorescence; Western blotting; Gelatin Zymography assays; Scratch wound assays; flow cytometry; and Live Cell Time-lapse microscopy. RESULTS: (L) and (L+AII) treatments induced highly organized actin filaments and increased cortical actin in SHR PTCs. However, SHR PTCs (Cc) and (AII) treated cells showed disorganized actin. After Hsp72 knockdown in SHR PTCs, (L) was unable to stabilize the actin cytoskeleton. We demonstrated that (L) and (L+AII) increased E-cadherin levels and decreased vinculin, α-SMA, vimentin, pERK, p38 and Smad2-3 activation compared to (AII) and (Cc) SHR PTCs. Moreover, (L) inhibited MMP-2 and MMP-9 secretion, reduced migration and cellular displacement, stabilizing intercellular junctions. Notably, (L) treatment in shHsp72 knockdown SHR PTCs showed results similar to SHR PTCs (Cc). CONCLUSION: Our results demonstrate that Losartan through Hsp70 inhibits the EMT induced by AII in proximal tubule cells derived from SHR.

Rab7b participation on the TLR4 (Toll-like receptor) endocytic pathway in Shiga toxin-associated Hemolytic Uremic Syndrome (HUS).

BACKGROUND: The inflammatory response of the host to Shiga toxin and/or lipopolysaccharide (LPS) of Escherichia coli (E. coli) is included in (HUS). The TLR4-LPS complex is internalized and TLR4 induced inflammatory signaling is stopped by targeting the complex for degradation. Rab7b, a small guanosine triphosphatase (GTPase) expressed in monocytes, regulates the later stages of the endocytic pathway. OBJECTIVE: we studied the Rab7b participation on the TLR4 endocytic pathway and its effect on monocyte cytokine production along the acute course of pediatric Shiga toxin-associated HUS. METHODS AND RESULTS: Monocytes were identified according to their positivity in CD14 expression. Surface TLR4 expression in monocytes from 18 HUS patients significantly increased by day 1 to 6, showing the highest increase on day 4 compared to monocytes of 10 healthy children. Significant higher surface TLR4 expression was accompanied by increased proinflammatory intracellular cytokines, tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). In contrast, after these time points, surface TLR4 expression and intracellular TNF-α levels, returned to near control levels after 10 days. Furthermore, confocal immunofluorescence microscopy proved colocalization of increased intracellular TLR4/Rab7b determined by Pearson's coefficient in monocytes from HUS patients from day 1 on the highest colocalization of both proteins by day 4. Decreased TLR4/Rab7b colocalization was shown 10 days after HUS onset. CONCLUSION: The colocalization of TLR4 and Rab7b allows us to suggest Rab7b participation in the control of the TLR4 endocytic pathway in HUS patient monocytes. A consequential fall in cytokine production throughout the early follow up of HUS is demonstrated.

Urinary Renin in Patients and Mice With Diabetic Kidney Disease.

In patients with diabetic kidney disease (DKD), plasma renin activity is usually decreased, but there is limited information on urinary renin and its origin. Urinary renin was evaluated in samples from patients with longstanding type I diabetes mellitus and mice with streptozotocin-induced diabetes mellitus. Renin-reporter mouse model (Ren1d-Cre;mT/mG) was made diabetic with streptozotocin to examine whether the distribution of cells of the renin lineage was altered in a chronic diabetic environment. Active renin was increased in urine samples from patients with DKD (n=36), compared with those without DKD (n=38; 3.2 versus 1.3 pg/mg creatinine; P<0.001). In mice with streptozotocin-induced diabetes mellitus, urine renin was also increased compared with nondiabetic controls. By immunohistochemistry, in mice with streptozotocin-induced diabetes mellitus, juxtaglomerular apparatus and proximal tubular renin staining were reduced, whereas collecting tubule staining, by contrast, was increased. To examine the role of filtration and tubular reabsorption on urinary renin, mice were either infused with either mouse or human recombinant renin and lysine (a blocker of proximal tubular protein reabsorption). Infusion of either form of renin together with lysine markedly increased urinary renin such that it was no longer different between nondiabetic and diabetic mice. Megalin mRNA was reduced in the kidney cortex of streptozotocin-treated mice (0.70±0.09 versus 1.01±0.04 in controls, P=0.01) consistent with impaired tubular reabsorption. In Ren1d-Cre;mT/mG with streptozotocin-induced diabetes mellitus, the distribution of renin lineage cells within the kidney was similar to nondiabetic renin-reporter mice. No evidence for migration of cells of renin linage to the collecting duct in diabetic mice could be found. Renin mRNA in microdissected collecting ducts from streptozotocin-treated mice, moreover, was not significantly different than in controls, whereas in kidney cortex, largely reflecting juxtaglomerular apparatus renin, it was significantly reduced. In conclusion, in urine from patients with type 1 diabetes mellitus and DKD and from mice with streptozotocin-induced diabetes mellitus, renin is elevated. This cannot be attributed to production from cells of the renin lineage migrating to the collecting duct in a chronic hyperglycemic environment. Rather, the elevated levels of urinary renin found in DKD are best attributed to altered glomerular filteration and impaired proximal tubular reabsorption.

Hypokalemic Distal Renal Tubular Acidosis.

Distal renal tubular acidosis (DRTA) is defined as hyperchloremic, non-anion gap metabolic acidosis with impaired urinary acid excretion in the presence of a normal or moderately reduced glomerular filtration rate. Failure in urinary acid excretion results from reduced H+ secretion by intercalated cells in the distal nephron. This results in decreased excretion of NH4+ and other acids collectively referred as titratable acids while urine pH is typically above 5.5 in the face of systemic acidosis. The clinical phenotype in patients with DRTA is characterized by stunted growth with bone abnormalities in children as well as nephrocalcinosis and nephrolithiasis that develop as the consequence of hypercalciuria, hypocitraturia, and relatively alkaline urine. Hypokalemia is a striking finding that accounts for muscle weakness and requires continued treatment together with alkali-based therapies. This review will focus on the mechanisms responsible for impaired acid excretion and urinary potassium wastage, the clinical features, and diagnostic approaches of hypokalemic DRTA, both inherited and acquired.

Heat Shock Protein 70 and CHIP Promote Nox4 Ubiquitination and Degradation within the Losartan Antioxidative Effect in Proximal Tubule Cells.

BACKGROUND: Angiotensin II/Angiotensin II type 1 receptor (AT1R) effects are dependent on ROS production stimulated by NADPH oxidase activation. Hsp70 regulates a diverse set of signaling pathways through their interactions with proteins. CHIP is a E3 ubiquitin ligase that targets proteins for polyubiquitination and degradation. AIM: We study whether Hsp70/CHIP contribute to the negative regulation of Nox4 after AT1R blockage. METHODS/RESULTS: Primary culture of proximal tubule epithelial cells (PTCs) from SHR and WKY were stimulated with Angiotensin II (AII) or treated with Losartan (L) or Losartan plus Angiotensin II (L+AII). Losartan decreased AT1R and Nox4 while enhancing caveolin-1 and Hsp70 protein expression in SHR PTCs. Immunoprecipitation and immunofluorescence proved interaction and colocalization of increased Hsp70/CHIP with decreased Nox4 in SHR PTCs (L) vs (All). Hsp72 knockdown resulted in enhanced Nox4 protein levels, NADPH oxidase activity and ROS generation in (L+AII) revealing that Losartan was unable to abrogate AII effects on Nox4 expression and oxidative activity. Moreover, MG132 exposed PTCs (L) demostrated blocked ubiquitinated Nox4 degradation and increased colocalization of Nox4/Ubiquitin by inmunofluorescence. Conversely, Hsp72 depletion reduced Nox4/Ubiquitin colocalization causing Nox4 upregulation due to proteosomal degradation inhibition, although Losartan treatment. CONCLUSION: Our study demonstrates that Hsp70 and CHIP mediates the ubiquitination and proteasomal degradation of Nox4 as part of the antioxidative effect of Losartan in SHR.

Physiological Functions and Regulation of the Na+/H+ Exchanger [NHE1] in Renal Tubule Epithelial Cells.

The sodium-hydrogen exchanger isoform-1 [NHE1] is a ubiquitously expressed plasma membrane protein that plays a central role in intracellular pH and cell volume homeostasis by catalyzing an electroneutral exchange of extracellular sodium and intracellular hydrogen. Outside of this important physiological function, the NHE1 cytosolic tail domain acts as a molecular scaffold regulating cell survival and actin cytoskeleton organization through NHE1-dependent signaling proteins. NHE1 plays main roles in response to physiological stress conditions which in addition to cell shrinkage and acidification, include hypoxia and mechanical stimuli, such as cell stretch. NHE1-mediated modulation of programmed cell death results from the exchanger-mediated changes in pHi, cell volume, and/or [Na+]I; and, it has recently become known that regulation of cellular signaling pathways are involved as well. This review focuses on NHE1 functions and regulations. We describe evidence showing how these structural actions integrate with ion translocation in regulating renal tubule epithelial cell survival.

RhoA and MAPK signal transduction pathways regulate NHE1-dependent proximal tubule cell apoptosis after mechanical stretch.

Mechanical deformation after congenital ureteral obstruction is traduced into biochemical signals leading to tubular atrophy due to epithelial cell apoptosis. We investigated whether Na(+)/H(+) exchanger 1 (NHE1) could be responsible for HK-2 cell apoptosis induction in response to mechanical stretch through its ability to function as a control point of RhoA and MAPK signaling pathways. When mechanical stretch was applied to HK-2 cells, cell apoptosis was associated with diminished NHE1 expression and RhoA activation. The RhoA signaling pathway was confirmed to be upstream from the MAPK cascade when HK-2 cells were transfected with the active RhoA-V14 mutant, showing higher ERK1/2 expression and decreased p38 activation associated with NHE1 downregulation. NHE1 participation in apoptosis induction was confirmed by specific small interfering RNA NHE1 showing caspase-3 activation and decreased Bcl-2 expression. The decreased NHE1 expression was correlated with abnormal NHE1 activity addressed by intracellular pH measurements. These results demonstrate that mitochondrial proximal tubule cell apoptosis in response to mechanical stretch is orchestrated by signaling pathways initiated by the small GTPase RhoA and followed by the opposing effects of ERK1/2 and p38 MAPK phosphorylation, regulating NHE1 decreased expression and activity.

Acute kidney injury: what part do toll-like receptors play?

The innate immune system plays an important role as a first response to tissue injury. This first response is carried out via germline-encoded receptors. Toll-like receptors (TLRs) are the first identified and best studied family of pattern recognition receptors. TLRs are expressed on a variety of cell types, including epithelial cells, endothelia, dendritic cells, monocytes/macrophages, and B- and T-cells. TLRs initiate innate immune responses and concurrently shape the subsequent adaptive immune response. They are sensors of both pathogens, through the exogenous pathogen-associated molecular patterns (PAMPs), and tissue injury, through the endogenous danger-associated molecular patterns (DAMPs). TLR signaling is critical in defending against invading microorganisms; however, sustained receptor activation is also implicated in the pathogenesis of inflammatory diseases. Ischemic kidney injury involves early TLR-driven immunopathology, and the resolution of inflammation is needed for rapid regeneration of injured tubule cells. Notably, the activation of TLRs also has been implicated in epithelial repair. This review focuses on the role of TLRs and their endogenous ligands within the inflammatory response of acute kidney injury.

Granulomatosis with polyangiitis: rapidly progressive necrotizing glomerulonephritis in a pediatric patient.

Granulomatosis with polyangiitis (GPA) is associated with a broad range of clinical manifestations including renal disease. It is a systemic vasculitis that is rarely encountered in children. We present a 14-year-old girl who suffered from pharyngitis 1 week before admittance to hospital. She was admitted for macroscopic hematuria and oliguria, under the possibility of nephritic syndrome. Renal failure with rapidly progressive glomerulonephritis occurred within 24 hours. Immunologic tests showed the presence of type-C anti-neutrophil cytoplasmic antibodies (c-ANCA with antiproteinase 3 specificity) and renal biopsy revealed pauci-immune crescentic focal necrotizing glomerulonephritis. Treatment including methylprednisolone and cyclophosphamide intravenous pulses allowed renal recovery after 3 weeks. The clinical, hematological, and biochemical parameters improved substantially, achieving remission. Granulomatosis with polyangiitis, although rare in children, should be considered in the above clinical scenario. This case underlines that knowledge of renal histology diagnosis and early aggressive immunosuppressive therapy are essential for the management of these patients.

Hsp70 regulation on Nox4/p22phox and cytoskeletal integrity as an effect of losartan in vascular smooth muscle cells.

A series of signaling cascades are activated after angiotensin II binds to angiotensin II type I receptor (AT1R), a peptide that is an important mediator of oxidative stress. Hsp70 regulates a diverse set of signaling pathways through interactions with proteins. Here, we tested the hypothesis of angiotensin II AT1R inhibition effect on Hsp70 interaction with Nox4/p22phox complex and Hsp70 leading to actin cytoskeleton modulation in spontaneously hypertensive rats (SHR) vascular smooth muscle cells (VSMCs). SHR and Wistar-Kyotto rats (VSMCs from 8 to 10 weeks) were stimulated with angiotensin II (100 nmol/L) for 15 min (AII), treated with losartan (100 nmol/L) for 90 min (L), and with losartan for 90 min plus angiotensin in the last 15 min (L + AII). Whereas SHR VSMCs exposure to angiotensin II overexpressed AT1R and Nox4 nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase and slightly downregulated caveolin-1 expression, losartan decreased AT1R protein levels and increased caveolin-1 and Hsp70 expression in SHR VSMC membranes. Immunoprecipitation and immunofluorescence confocal microscopy proved interaction and colocalization of membrane translocated Hsp70 and Nox4/p22phox. Increased levels of Hsp70 contrast with the decreased immunoprecipitation of Nox4/p22phox and RhoA in membranes from SHR VSMCs (L) vs SHR VSMCs (AII). Hsp72 depletion resulted in higher Nox4 expression and increased NADPH oxidase activity in VSMCs (L + AII) from SHR when contrasted with nontransfected VSMCs (L + AII). After Hsp72 knockdown in SHR VSMCs, losartan could not impair angiotensin II-enhanced stress fiber formation and focal adhesion assembly. In conclusion, our data showing a negative regulation of Hsp70 on Nox4/p22phox demonstrates a possible mechanism in explaining the antioxidative function joined to cytoskeletal integrity modulation within the effects of losartan in VSMCs from SHR.

Abscesos profundos por Staphylococcus aureus meticilino resistente adquirido en la comunidad. Reporte de cuatro casos clínicos / Deep abscess methicillin resistant staphylococcus aureus community-acquired. Report of four cases

El Staphylococcus aureus meticilino resistente adquirido en la comunidad (SAMR-AC) emergió en Uruguay en el año 2001 y desde ese momento se ha establecido como agente de múltiples enfermedades infecciosas de la infancia. Algunas formas clínicas de presentación más frecuentes, como las infecciones superficiales, no ofrecen habitualmente dificultades diagnósticas. Otras menos frecuentes, como los abscesos de localización profunda, son formas menos conocidas donde el diagnóstico no es sencillo y existe riesgo de tratamiento tardío lo cual contribuye a una mayor carga de morbimortalidad por este agente. En este trabajo se comunican cuatro casos clínicos de abscesos profundos por SAMR-AC, en pacientes hospitalizados en los años 2009- 2011 en el Hospital Pediátrico del Centro Hospitalario Pereira Rossell. Se presentan tres casos de abscesos musculares, dos de ellos retroperitoneales, y un caso de abscesos hepáticos, forma de presentación infrecuente pero típica de este agente. Se destacan en esta serie las dificultades para el diagnóstico temprano por lo inespecífico de la presentación clínica, el apoyo fundamental de la imagenología en la confirmación diagnóstica, la necesidad de tratamiento antimicrobiano prolongado y del drenaje adecuado del material colectado importante en la identificación microbiológica del agente implicado...