A injúria renal aguda representa um estado de senescência precoce induzida por estresse, e as células-tronco mesenquimais podem ser uma alternativa para seu tratamento. Células-tronco jovens reduzem o fenótipo de envelhecimento em rins quando comparadas a células idosas. O objetivo deste estudo foi avaliar se o tratamento com jovens células-tronco mesenquimais derivadas de cordão umbilical humano podem interferir na senescência renal induzida por lesão de isquemia-reperfusão em ratos. Ratos machos foram submetidos ao modelo de isquemia de artérias renais bilateralmente por 45 minutos, com reperfusão após, e alguns animais receberam 1 X 106 células por via intraperitoneal após 6 horas da indução da lesão. Os animais foram eutanasiados no segundo ou no sétimo dia pós-isquêmico. No segundo dia após a lesão de isquemia-reperfusão, o tratamento com as células melhorou a filtração glomerular e a função tubular, melhorou a expressão renal de aquaporina-2 e reduziu a infiltração de macrófagos nos rins. Proteínas relacionadas à senescência (-galactosidase, p21, p16 e fator de transformação do crescimento ) e microRNAs (mir-29a e miR-34a) estiveram com a expressão aumentada após a isquemia-reperfusão, e houve redução nesses parâmetros com o tratamento. A redução na expressão de Klotho e o estado pró-oxidativo gerados pela isquemia-reperfusão também foram revertidos pelo tratamento. A senescência induzida pela injúria renal aguda é um processo independente de telômeros. Ao sétimo dia pós-lesão, os ratos isquêmicos mantinham defeito de concentração urinária, que foi revertido nos animais tratados. Além disso, o tratamento reduziu o índice de necrose tubular aguda em tecido renal e reduziu o infiltrado macrofágico túbulo-intersticial. O marcador pró-senescência p16 foi completamente restabelecido nos animais tratados. Nossos dados demonstram que o tratamento com jovens células-tronco mesenquimais derivadas de cordão umbilical humano atenua a resposta inflamatória e de estresse oxidativo que ocorre na injúria renal aguda, e reduz a expressão de proteínas e microRNAs relacionados à senescência. Nossos achados expandem as perspecivas para o tratamento da injúria renal aguda / Acute kidney injury represents a status of premature stress-induced senescence, and mesenchymal stem cells are an alternative for treatment. Young stem cells reduce aging phenotype in kidneys when compared to old cells. The objective of this study was to evaluate if treatment with young human umbilical cord mesenchymal stem cells could interfere in kidney senescence induced by renal ischemia-reperfusion in rats. Male rats were induced to ischemia-reperfusion injury by 45-minutes clamping of both renal arteries; some rats received 1X106 cells intraperitonally six hours later. Rats were euthanatized on post-renal ischemia reperfusion days two and seven. At day 2 after ischemia-reperfusion injury, treatment with cells improved glomerular filtration, tubular function, improved renal expression of aquaporin 2 and decreased macrophage kidney infiltration. Senescence-related proteins (?-galactosidase, p21, p16 and transforming growth factor ?) and microRNAs (miR-29a and miRNA-34a) were overexpressed after ischemia-reperfusion, and reversed by the treatment. The Klotho reduced expression and the pro-oxidative status induced by ischemia-reperfusion were reversed by the treatment. Senescence induced acute kidney injury is a telomere-independent process. At day 7, ischemic rats maintained urinary concentrating defect, which is reversed in treated animals. Moreover, treatment decreased the index of acute tubular necrosis in kidney tissue and decreased macrophage kidney infiltration. Senescence marker p16 was completely restored in treated animals. Our data demonstrate that young human umbilical mesenchymal stem cells treatment attenuates the inflammatory and oxidative stress response occurring in acute kidney injury, and reduces the protein and microRNA expression related to senescence. Our findings broaden the perspectives for the treatment of AKI

Submitted by Fabíola Silva (fabiola.silva@famerp.br) on 2016-09-15T18:30:05Z No. of bitstreams: 1 mauriciodenassaumachado_tese.pdf: 15169790 bytes, checksum: 44c4bba3d0bddeb188ec239527b863f1 (MD5) / Made available in DSpace on 2016-09-15T18:30:05Z (GMT). No. of bitstreams: 1 mauriciodenassaumachado_tese.pdf: 15169790 bytes, checksum: 44c4bba3d0bddeb188ec239527b863f1 (MD5) Previous issue date: 2014-05-07 / Introduction: Acute kidney injury is a complex syndrome characterized by rapid (hours or days) reduction in renal excretion that occurs in a wide variety of situations. It has wide variability of epidemiology and is a common complication in critically ill and intensive care patients. Acute kidney injury generate increased hospital costs and is associated with high mortality rates being independent predictor of death. Currently, three diagnostic criteria for acute kidney injury has been highlighted: RIFLE (Risk, Injury, Failure, Loss, and End-stage kidney disease), AKIN (Acute Kidney Injury Network) and KDIGO (Kidney Disease: Improving Global Outcomes). Objectives: To evaluate the incidence, morbidity and mortality associated with acute kidney injury (and its value as a predictor of 30-day mortality) in patients undergoing on-pump coronary artery bypass grafting (article 1), patients undergoing cardiac valve surgery (article 2), patients with elevated preoperative baseline creatinine (article 3) and, in general, in patients undergoing cardiac surgery (coronary artery bypass grafting or cardiac valve surgery) (article 4). Methods: (Article 1) Patients undergoing on-pump CABG from January 2003 to January 2008 (817 patients) were divided according to the AKIN classification in AKI (+) and AKI (-) patients. Multivariable logistic regression was used to determine independent predictors of 30-day mortality. (Article 2) Patients undergoing cardiac valve surgery from January 2003 to May 2010 (837 patients) were divided according to the presence of infective endocarditis. Cox regression analysis was used to determine independent predictors of 30-day mortality. (Article 3) Patients with elevated baseline serum creatinine underwent cardiac surgery (CABG or CVS) from January 2003 to June 2013 (918 patients) were evaluated to determine whether the development of post-operative acute kidney injury based on KDIGO criteria was an independent predictor of 30-day mortality. (Article 4) Patients undergoing cardiac surgery (CABG or CVS) between January 2003 and June 2013 (2804 patients) were evaluated to determine if acute kidney injury based on KDIGO criteria was an independent predictor of 30-day mortality. Results: (all articles) Patients who developed AKI postoperatively had more clinical complications. The 30-day mortality increased progressively in all stages of acute kidney injury. Based on AKIN and KDIGO criteria, AKI was an independent predictor of 30-day mortality. Conclusions: (all articles) In this population, acute kidney injury after cardiac surgery was an independent predictor of 30-day mortality. / Introdução: Disfunção renal aguda é uma síndrome complexa caracterizada pela rápida (horas ou dias) redução da excreção renal que ocorre em uma grande variedade de situações. Ela tem ampla variabilidade epidemiológica e é complicação comum em pacientes gravemente enfermos e de terapia intensiva gerando aumento dos custos hospitalares e associando-se a altas taxas mortalidade sendo preditor independente do risco de morte. Atualmente, três critérios diagnósticos para lesão renal aguda tem se destacado: RIFLE (Risk, Injury, Failure, Loss, and End-stage kidney disease), AKIN (Acute Kidney Injury Network) e KDIGO (Kidney Disease: Improving Global Outcomes). Objetivos: Avaliar a incidência, morbidade e mortalidade associada a lesão renal aguda (e seu valor como preditor de óbito em 30 dias) em pacientes submetidos a cirurgia de revascularização do miocárdio com CEC, pacientes submetidos a cirurgia valvar, pacientes com creatinina basal elevada no pré-operatório e, de maneira global, em pacientes submetidos a cirurgia cardíaca (revascularização do miocárdio ou cirurgia valvar). Métodos: (artigo 1) Pacientes submetidos a RM com CEC no período de janeiro de 2003 a janeiro de 2008 (817 pacientes) foram divididos de acordo com a classificação AKIN em LRA (+) e LRA (-). Regressão logística multivariada foi utilizada para determinação de preditores independentes para óbito em 30 dias; (artigo 2) Pacientes submetidos a cirurgia valvar no período de janeiro de 2003 a maio de 2010 (837 pacientes) foram divididos de acordo com a presença de endocardite infecciosa. Regressão de Cox foi usada para determinar preditores independentes para óbito em 30 dias; (artigo 3) Pacientes portadores de creatinina basal elevada (pré-operatório) submetidos a cirurgia cardíaca (RM ou CV) entre janeiro de 2003 a junho de 2013 (918 pacientes) foram avaliados para determinar se o desenvolvimento de lesão renal aguda pós-operatória baseada nos critérios KDIGO foi preditor independente de óbito em 30 dias; (artigo 4) Pacientes submetidos a cirurgia cardíaca (RM ou CV) entre janeiro de 2003 a junho de 2013 (2804 pacientes) foram avaliados para determinar se o desenvolvimento de lesão renal aguda pós-operatória baseada nos critérios KDIGO foi preditor independente de óbito em 30 dias. Resultados: (todos artigos) Pacientes que evoluíram com LRA tiveram mais complicações no pós-operatório. A mortalidade em 30 dias aumentou progressivamente em todos os estágios de lesão renal aguda. Baseado nos critérios AKIN e KDIGO, LRA foi preditor independente de óbito em 30 dias. Conclusões: (todos artigos) Na população estudada, alteração aguda da função renal no pós-operatório foi preditor independente de óbito em 30 dias.

A epidemiologia da injúria renal aguda (IRA) nos países desenvolvidos e em desenvolvimento ainda não foi sistematicamente examinada. Estudos epidemiológicos da incidência de IRA nos países em desenvolvimento são escassos e mais raros são estudos populacionais prospectivos na Amazônia brasileira. No capítulo I descreveu-se uma revisão sistemática de estudos sobre a epidemiologia da IRA em pacientes internados em unidades de terapia intensiva (UTI) publicados (2005-2015) nas bases de dados PUBMED, CENTRAL, LILACS e IBECs. Foram examinadas as diferenças na incidência de IRA, a severidade e a mortalidade; seguindo a divisão dos países de acordo com os critérios da Organização das Nações Unidas. Identificaram-se 92 estudos: 59 de países desenvolvidos, 32 de países em desenvolvimento e um estudo com dados de ambos os grupos de países. Dos estudos avaliados, 78 por cento usaram critérios padrão para definição da IRA (RIFLE, AKIN ou KDIGO). Entretanto, encontramos 11 diferentes definições para oligúria e 23 diferentes definições para a creatinina basal. Ambos os grupos relataram ocorrência de IRA na UTI de até 40 por cento . No entanto, a necessidade de diálise, tempo de permanência na UTI e as taxas de mortalidade foram maiores nos países em desenvolvimento, o que pode refletir diferenças nas condições sociais e na infraestrutura hospitalar nesses países. No capítulo II foi realizado um estudo prospectivo em todas as UTIs da cidade de Rio Branco, que atendem a cerca de 75 por cento da população do estado do Acre. Os dados foram coletados durante 18 meses nos anos 2014 e 2016. Pacientes com menos de 18 anos, doença renal crônica dialítica, transplante renal ou internação na UTI < 48 horas foram excluídos. A IRA foi diagnosticada pelo KDIGO e a mortalidade foi avaliada durante a internação na UTI, 30 e 180 dias após a alta da UTI. Dos 1494 pacientes admitidos, 1073 preencheram os critérios de inclusão. A incidência de IRA foi de 52,8 por cento , e a prevalência foi de 67,3. A diálise foi oferecida a 8,2 por cento dos pacientes que fizeram IRA na UTI. Apenas 2,2 por cento das internações foram devidas às doenças tropicais. Os fatores de risco para IRA foram: balanço hídrico positivo maior que 1500 ml / 24h (OR 2,98, p <0,001), pacientes não cirúrgicos (OR 1,69; p = 0,001), aumento de idade (OR 1,16 para aumento de 10 anos; p <0,001) e aumento do escore APACHE II (OR 1,06 para aumento de uma unidade; p <0,001). Em comparação com pacientes que não tiveram IRA, o tempo de permanência na UTI (7 vs 5 dias, p <0,001), assim como as mortalidades na UTI e no hospital (43,4 por cento vs 14 por cento , p <0,001 e 52 por cento vs 18,5 por cento , p <0,001, respectivamente) foram maiores nos pacientes que fizeram IRA na UTI. Foram fatores de risco para mortalidade nos pacientes com IRA na UTI: aumento da idade, sepse, KDIGO estágio 3, uso de ventilação mecânica, de drogas vasoativas e choque. A mortalidade precoce e tardia (até 30 ou 180 dias após a alta na UTI, respectivamente) se associou à presença de IRA. Portanto a IRA é comum em pacientes de UTI nessa região, com poucas internações por doenças tropicais e similares etiologias e fatores de risco com os países desenvolvidos; contudo, com taxas de mortalidade mais altas, o que pode representar as condições econômicas e a dificuldade no acesso aos sistemas de saúde / The epidemiology of Acute Kidney Injury (AKI) in the developed and developing world has not been systematically examined. Epidemiological studies of AKI incidence in developing countries are still scantier and scarcer are prospective population-based studies in Brazilian Amazon, a peculiar region, epidemiologically different from the others. On chapter I we describe a systematic review of published studies (20052015) identified in PUBMED, CENTRAL, LILACS, and IBECs databases using the search terms defining acute kidney injury (AKI) and intensive care unit (ICU). We examined the differences in ICUAKI incidence, severity, associated mortality and describe geographic variations based on the gross national income. We identified 92 studies: 59 from developed countries and 32 from developing countries. One study had data from both group of countries. Of these, 78 per cent used standard criteria (RIFLE, AKIN, KDIGO); however, we found 11 different definitions for oliguria and 23 different definitions for baseline creatinine. Both groups related ICUAKI incidence up to 40 per cent . However, the need for RRT, ICU length of stay and mortality rates were higher in developing countries. Despite the attempt to standardize the criteria for defining AKI, there is still no uniformity in the settings for baseline creatinine, oliguria and timeframe for AKI assessment. Differences in ICU length of stay need for RRT and mortality rates may reflect differences in the entry criteria and the social conditions, access to health care and hospital infrastructure. On chapter II, we did a prospective study on all adult patients admitted in all ICUs of Rio Branco, a western amazon region (600 square kilometers and 800,000 inhabitants). Data were collected for 18 months during the years 2014 and 2016. Patients with age under 18, chronic kidney disease stage 5, kidney transplant or ICU stay < 48 hours were excluded. AKI was diagnosed by KDIGO and mortality was assessed 30 and 180 days after ICU discharge. Of 1494 patients admitted, 1073 fulfilled selection criteria. AKI incidence was 52.8 per cent , and the prevalence was 67.3 per cent . Only 2.2 per cent had tropical diseases. Risk factors for AKI were positive fluid balance over 1500 ml/24h (OR 2.98; p <0,001), nonsurgical patients (OR 1.69; p =0,001), increased age for 10 years interval (OR 1,16; p <0,001) and increased APACHE II score (OR 1,06; p <0,001). ICU length of stay was higher in ICUAKI patients (7 vs 5 days, p <0,001), as well as ICU and hospital mortality (43.4 per cent vs 14 per cent , p <0,001 and 52 per cent vs 18.5 per cent , p <0,001, respectively) compared with no AKI patients. Risk factors for mortality in patients with AKI during ICU stay were: age, presence of sepsis, KDIGO stage 3, use of mechanical ventilation, vasoactive drugs and shock. In conclusion, we observed that AKI is common in ICU patients in the western Brazilian Amazon with few hospitalizations for tropical diseases and similar etiologies, risk factors and outcomes as in developed countries; however, with higher mortality rate that may be due to the local economic conditions and poor access to health care

The U.S. Department of Veterans Affairs (VA) studies on acute kidney injury (AKI) have focused on defined procedures and outcomes but not on gender differences. The purpose of this study was to investigate differences in health services utilization by gender and other predisposing factors (age and race) among hospitalized veterans with AKI during a 5-year period from 2008 to 2013. The study included a retrospective cohort design and the behavioral model of health services utilization as the underlying theoretical framework. Secondary data were collected from an existing VA cohort. Data from 1,636 hospitalized AKI veterans were subjected to t tests to assess gender differences in VA health services use and short-term outcomes. ANOVAs were conducted on data from 6,102 veterans to assess the effect of age and race on VA health services utilization. Results indicated no significant gender differences in VA health services use and short-term outcomes. However, significant differences were found in some VA health services utilization for age and race. Results may be used by VA policymakers and administrators to identify and reduce gender inequalities in VA health services use and outcomes.

Background In the event of an acute coronary syndrome (ACS), the risk of death and complications such as stroke and re-infarction is high during the first month. Diabetes, impaired kidney function, elevated markers of systemic inflammation and high level of platelet reactivity have all been associated with worsened prognosis in ACS patients. Impaired kidney function is a condition with high cardiovascular morbidity and there is an established association between level of kidney function and outcome in the event of an ACS. Aims We sought to investigate the level of platelet reactivity during the first days of an ACS and specifically the level of platelet reactivity in patients with different conditions associated with worsened prognosis in the event of an ACS. We also wanted to investigate the prognostic impact of baseline levels of cystatin C as well as the importance of decreasing kidney function during the first days of an ACS. Methods We included 1028 unselected patients with ACS or suspected ACS during the years 2002 and 2003, of which 534 were diagnosed with an acute myocardial infarction (AMI). Blood samples for measuring platelet aggregation, cystatin C levels and other clinically important biomarkers were collected day 1, 2, 3 and 5 following admission. Platelet reactivity was measured using 2 different methods. Platelet aggregation was measured using Pa-200, a particle count method, based on scattering of laser light. PFA 100 is a method of measuring primary hemostasis in whole blood. Results Platelet aggregation and comorbidities. We found an increase in platelet aggregation when an ACS was complicated by an infection and there was an increased frequency of aspirin non-responsiveness in patients suffering from pneumonia during the first days of an ACS. Furthermore, we found an independent association between levels of C-reactive protein and platelet aggregation. During the first 3 days following an acute myocardial infarction, platelet aggregation increased despite treatment with anti-platelet agents. Platelet aggregation was found to be more pronounced in patients with diabetes. Patients with impaired kidney function, showed increased platelet aggregation compared to patients with normal renal function, however, this difference was explained by older age, higher prevalence of DM and levels of inflammatory biomarkers. We found no independent association between chronic kidney disease (CKD) and levels of platelet aggregation. Kidney function and outcome Serum levels of cystatin C on admission had an independent association with outcome following an acute myocardial infarction. With a mean follow-up time of 2.9 years, the adjusted HR for death was 1.62 (95% CI 1.28-2.03; p&lt;0.001) for each unit of increase in cystatin C on admission. The level of dynamic changes in cystatin C during admission for an acute myocardial infarction was independently associated with prognosis in patients with normal or mild impairment of renal function. The adjusted HR for death was 10.1 (95% CI 3.4-29.9; p&lt;0.001). Conclusion In patients suffering from an AMI platelet aggregation increases during the first days, despite anti-platelet treatment. Diabetes, age and biomarkers of inflammation are independently associated with platelet aggregation. Admission levels of cystatin C as well as changes in cystatin C levels during hospitalisation are independently associated with outcome.

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A terapia renal substitutiva contínua (TRSC) é amplamente utilizada em pacientes criticamente enfermos com insuficiência renal aguda (IRA). O meropenem é um carbapenêmico usado em pacientes críticos que tem uma atividade antibacteriana dependente do tempo. O objetivo do estudo foi avaliar a farmacocinética do meropenem infundido em três horas em pacientes submetidos à TRSC. Estudamos as concentrações plasmáticas e de efluente em cinco pacientes submetidos à TRSC. As amostras foram coletadas em momentos 0, 30 min, e 1, 2, 4, 6 e 8 horas após o início de uma infusão de 3 horas. As determinações de meropenem foram feitas por cromatografia líquida de alta eficiência. Quatro pacientes do sexo masculino e um feminino, idade de 53,0 ± 19,7 (23 a 80 anos), 62,1 ± 10,6 kg, foram estudados. Parâmetros farmacocinéticos apresentados em mediana (amplitude): concentrações plasmáticas, 34.86mg / L (10,08-139,27); tempo de meia vida (t ½), 1,8 h (1,4-3,0); volume de distribuição (Vd), 8,29 L (5,8-15,3); depuração total (Dept ) 3,98 L / h (2,51-4,35); concentração máxima (Cmax) 48,5 mg/L (37,0-105,8); concentração mínima (Cmin) 20,1 mg / L (14,0-16,6); constante de eliminação (Kel), 0,38 (0,34-0,43); área sob a curva de concentração versus tempo (AUC 0 a 8 h), 251,1 mg / Lh (229,7-398,4); (AUC de 0a∞), 275,1 mg /Lh (263,8-453,6).A depuração total pela TRSC variou de 8,46 a 18,33 ml/min. No efluente as concentrações máximas foram 24,35 e 74,81 mg /L. A eliminação de meropenem por TRSC é semelhante ao que é relatado pelo rim normal, quando é infundido por 3 horas a cada 8 h. Os níveis plasmáticos foram sempre acima do MIC necessário. Podemos concluir que não houve necessidade de ajuste de dose do meropenem com a dose de TRSC prescrita. / Continuous renal replacement therapy (CRRT) is widely used in critically ill patients with acute kidney injury (AKI). Meropenem is a carbapenem used in critically ill patients, which has a time dependent antibacterial activity. The aim of the study was to assess the pharmacokinetics of meropenem on a 3-hour infusion in patients undergoing CRRT due to AKI. We studied the plasmatic and effluent concentrations in five patients undergoing CRRT. The samples were collected at moments 0, 30 minutes, and 1, 2, 4, 6 and 8 hours after the beginning of the 3-hour infusion. The meropenem determinations were made through high performace efficiency liquid chromatography (HPLC). Four male patients and one female patient, with a mean age of 53,0 ± 19,7 (23 to 80 years), weighing 62,1 ± 10,6 kgs were studied. Pharmacokinetic parameters presented in medians (range): plasmatic concentrations, 34.86mg / L (10,08-139,27); half-life (t ½), 1,8 h (1,4-3,0); volume of distribution (Vd), 8,29 L (5,8-15,3); total clearance (CLT) 3,98 L / h (2,51-4,35); (Cmax) (maximum plasma concentration), 48,5 mg / L (37,0-105,8); Cmin (minimum plasma concentration)20,1 mg / L (14,0-16,6); elimination constant (Kel), 0,38 (0,34-0,43); area under the concentration versus time curve (AUC 0 a 8 h), 251,1 mg / Lh (229,7-398,4); (AUC 0 a ∞) 275,1 mg / Lh (263,8-453,6). In the effluent, the maximum concentrations varied from 24,35 to 74,81 mg/L, and the clearance from the therapy varied from 8,46 to 18,33 ml/min. The elimination of meropenem through CRRT is similar to that of a normal kidney, given a 3-hour infusion every 8 hours. Plasmatic levels were always above the necessary MICs. We can conclude there was no need for dose adjustment of meropenem with the prescribed CRRT dose.