Sepsis is the most common cause of death in the intensive care units worldwide. Despite the undeniable progress in pre- and clinical research, the effective causal therapeutic strategy still does not exist. Given to extremely complex and heterogenic host response to presence of infection, the paradigm "one disease, one drug" is obviously flawed and combination of multiple targets that involves early immunomodulation and cellular protection are needed. Cellular therapy using mesenchymal stem cells represents strategy that brought positive results in experiments with rodent septic models. Part of this thesis is dedicated to evaluation of safety and efficacy of stem cells intravenous administration to well-established large animal model of progressive peritoneal sepsis. Affecting of the neuroinflammatory reflex through the vagus nerve stimulation showed potential to attenuate sepsis in rodents. Rest of the text is dedicated to evaluation of vagus nerve stimulation effectivity in our model. KEYWORDS Sepsis, sepsis-associated acute kidney injury, mesenchymal stem cells, vagus nerve stimulation

Introduction: The high transmissibility and lethality of the novel coronavirus SARS-CoV-2 (COVID-19) have been catastrophic. Acute kidney injury (AKI) is one of the frequent complications in patients with respiratory insufficiency caused by the virus. The pathogenic mechanism is based on the binding of its S-proteins to the angiotensin-converting enzyme (ACE) receptors, which will trigger a cellular damage. A podocyte and tubular compromise are found in the kidneys which can lead to tubular necrosis and the consequent AKI. Objectives: The objective of this report is to identify the main risk factor to develop AKI in patients infected with SARS-CoV-2 with critical acute respiratory distress. Patients and Methods: We performed this report study, collecting data from 48 ICU patients. Data from 13 of them who developed AKI and needed renal replacement therapy (RRT)were analyzed. Clinical characteristics and laboratory findings were reported using STATA 10.0. Results: AKI was present in 27.08% of patients, mostly male (92.3%) with a mean age of 63.8 years old. Hypertension, diabetes and obesity were the main comorbidities in those patients. Additionally, the meantime between admission and AKI diagnosis was 2.69 days. All patients showed fibrinogen, D-dimer, ALT and values above normal range. Mortality was seen in 61.5% of patients. Conclusion: This report tries to show AKI as an important clinical manifestation in critically ill patients infected with SARS-CoV-2, with high mortality. Further studies are needed to demonstrate if there are independent risk factors. / Revisión por pares

Hintergrund: Die regionale Citrat-Antikoagulation im Rahmen der Nierenersatztherapie hat bei interdisziplinären Intensivpatienten in den letzten Jahren zunehmend an Bedeutung gewonnen. Für Schwerbrandverletzte existieren bislang kaum Untersuchungen zu diesem Verfahren. Ziel dieser Arbeit war es, die kontinuierliche Nierenersatztherapie mit Citrat-Antikoagulation bei Intensivpatienten mit akutem Nierenversagen nach schwerem Verbrennungstrauma im Hinblick auf Praktikabilität, Effektivität und Komplikationshäufigkeit sowie die Stabilität von Elektrolyt- und Säure-Basen-Haushalt und Gerinnung zu untersuchen. Daneben sollten Aussagen zur Prävalenz des akuten Nierenversagens in dieser Patientengruppe und zu dessen Einfluss auf die Letalität getroffen werden. Methode: Im Rahmen einer retrospektiven Untersuchung wurden unter Verwendung von Patientenakten und Patientendatenmanagementsystem (PDMS) Daten von 27 Schwerbrandverletzten (VKOF ≥ 20% oder ABSI ≥ 8) mit akutem Nierenversagen ausgewertet, die zwischen Januar 2004 und Dezember 2009 im Verbrennungszentrum des Klinikums Sankt Georg Leipzig mit einer kontinuierlichen Nierenersatztherapie behandelt wurden. Bei allen Patienten kam ein Dialysegerät Prisma CFM (Gambro Hospal GmbH, Deutschland) mit einer Polyacrylnitril-Filtermembran (AN 69, Filterset M 100) der gleichen Firma zum Einsatz. Standardverfahren war eine kontinuierliche veno-venöse Hämodiafiltration (CVVHDF) im Prädilutionsmodus. Bei 18 Patienten wurde eine regionale Citrat-Antikoagulation als Antikoagulationsverfahren eingesetzt, bei 7 Patienten eine systemische Heparin-Antikoagulation, bei 2 Patienten kamen alternierend beide Verfahren zum Einsatz. Für die 18 Patienten unter regionaler Citrat-Antikoagulation erfolgte eine detaillierte Analyse des akuten Nierenversagens unter Einbeziehung des klinischen Verlaufes, der Laborparameter und der Behandlungsdaten des Nierenersatzverfahrens. Ergebnisse: Die Prävalenz eines akuten Nierenversagens mit Notwendigkeit zur Nierenersatztherapie bei Schwerbrandverletzten betrug 15,5%. Die Sterblichkeitsrate war in der Patientengruppe mit Nierenversagen etwa fünffach erhöht (25,9 vs. 4,8%). Die Letalitätsrate bei den Patienten unter systemischer Heparin-Antikoagulation war bei vergleichbarem Verbrennungsausmaß etwa fünfmal höher als unter regionaler Citrat-Antikoagulation (57,1 vs. 11.1%). Die Nierenersatztherapie wurde im Median nach 6 Tagen begonnen, die mediane Behandlungsdauer pro Patient betrug 7 Tage. Bei Start der CVVHDF wiesen 94,4% der Patienten einen Schockzustand mit Notwendigkeit einer Vasopressortherapie auf, 83,3% zeigten schwere Dysfunktionen in mindestens 3 Organsystemen, der SOFA-score lag im Median bei 14. Bei einer mittleren Citratkonzentration von 3,6 mmol/l Blut im Extrakorporalkreiskauf konnte eine mediane effektive Filterlaufzeit von 67 Stunden erreicht werden. Hypocalcämien (<0,9 mmol/l) fanden sich in 1,1%, Hypercalcämien (>1,3 mmol/l) in 0,4%. Hypernatriämien (<150 mmol) waren mit 0,4% ebenso selten wie metabolische Alkalosen (pH >7,50 und BE >4) mit 0,2%. Im Gesamtdialysezeitraum von 3790 Stunden gab es nur ein Blutungsereignis, die Gerinnungsparameter zeigten bis auf einen passageren Abfall der Thrombozytenzahl keine signifikanten Veränderungen. Die erzielte mittlere Dialysedosis war mit 35,1 ml/kg Körpergewicht/h ausreichend hoch. Neben einer Reduktion der Nierenretentionsparameter Serum-Creatinin und Serum-Harnstoff fanden sich unter dem Nierenersatzverfahren verbesserte Oxygenierungsindices und sinkende SOFA-scores. Keiner der überlebenden Patienten war zum Zeitpunkt der Entlassung dialysepflichtig. Zusammenfassung: Die CVVHDF unter regionaler Citrat-Antikoagulation ist bei Schwerbrandverletzten ein effektives und in Bezug auf Säure-Basen-Haushalt, Elektrolyte und Gerinnung sicheres Verfahren. Neben einer effektiven Elimination harnpflichtiger Substanzen konnten eine exzellente Stabilität von Elektrolyten und metabolischen Parametern sowie eine suffiziente Antikoagulation im Extrakorporalkreislauf mit niedrigem Blutungsrisiko und konstant langen Filterlaufzeiten nachgewiesen werden. Die Prävalenz des akuten Nierenversagens bei Schwerbrandverletzten ist hoch, die Letalität bei Vorliegen des Organversagens vier-bis fünffach erhöht.

Se describe la evidencia actual del efecto del SARS-CoV-2 a nivel de tejido renal. Se realizó una revisión narrativa de los artículos publicados en SCOPUS y PUBMED hasta septiembre de 2020. Los resultados se dividieron en las siguientes secciones: evidencia del efecto directo del virus en el riñón, mecanismos de invasión celular, mecanismos de injuria celular y las potenciales implicaciones terapéuticas de estos hallazgos. El SARS-CoV-2 invade las células del túbulo proximal y los podocitos, a través del receptor ECA-2. La invasión y replicación viral podrían producir daño mediante un efecto citopático directo aunado a un daño mediado por la respuesta inmune. Debido a la expresión celular de ECA-2, se ha propuesto a los Inhibidores del Sistema Renina–Angiotensina–Aldosterona como un potencial tratamiento contra la COVID-19. Sin embargo, a la fecha, la evidencia no apoya su uso. / We describe evidence on SARS-CoV-2 effect on the kidney. We carried a narrative review of articles published in SCOPUS and PUBMED until September 2020. The results were divided into six topics: evidence of direct effect of virus on the kidney, mechanisms of cellular invasion, mechanisms of kidney injury, and potential therapeutic implications. SARS-Cov-2 gains access to proximal tubule cells and podocytes via ACE-2 receptors. Viral invasion and replication may induce kidney damage through a direct cytopathic effect and immune-mediated damage. Due to ACE-2 cellular expression, Renin–Angiotensin–Aldosterone System Inhibitors have been proposed as potential treatment for COVID-19. However, current evidence does not support its therapeutic use. / Trabajo de investigación

Cytochrom P450 (CYP) Enzyme tragen zur Bioaktivierung von langkettigen mehrfach ungesättigten Fettsäuren bei. Die gebildeten Monoepoxy- und Monohydroxy-Metaboliten werden zusammenfassend als CYP-Eicosanoide bezeichnet und fungieren als Mediatoren bei der Regulation des Gefäßtonus, der Herz- und Nierenfunktion, sowie einer Vielzahl weiterer physiologischer Prozesse, wobei die biologische Aktivität oftmals abhängig von der Positions- und Stereoisomerie der Eicosanoide ist. Prominente Vertreter der CYP-Eicosanoid-Familie sind die aus der Arachidonsäure gebildeten Epoxyeicosatriensäuren (EETs) und 20-Hydroxyeicosatetraensäure (20-HETE). EETs und 20-HETE haben zum Teil gegensätzliche biologische Aktivitäten, die zur Aktivierung bzw. Inhibition antiinflammatorischer und weiterer Zell- und Organ-protektiver Signalwege beitragen. Ziel der vorliegenden Arbeit war es, durch Analyse endogener Metabolitenprofile zum besseren Verständnis der Rolle von CYP-Eicosanoiden bei der Entstehung von Ischämie/Reperfusions (I/R)-bedingten Organschäden beizutragen. Als Hauptergebnisse ergaben sich (i) die Entdeckung und Charakterisierung einer protektiven Rolle von EETs in Tiermodellen der Initiationsphase des akuten Nierenversagens, sowie des therapeutischen Potentials stabiler EET-Analoga; (ii) die Identifizierung von 8,9-EET und 20-HETE als mögliche prädiktive Biomarker für das post-operative Auftreten von akutem Nierenversagen nach offener Herzoperation; und (iii) die Entwicklung und Validierung eines analytischen Verfahrens der chiralen Lipidomik (chiral-LC-ESI-MS/MS), das eine Analyse endogener Enantiomere sowohl von Monoepoxy- als auch Monohydroxy-Eicosanoiden in komplexen biologischen Proben erstmalig ermöglichte und dafür genutzt werden konnte, die stereospezifische Regulation der EETs durch Epoxid-Hydrolasen in vitro wie auch in vivo zu beschreiben. / Cytochrome P450 (CYP) enzymes contribute to the bioactivation of long-chain polyunsaturated fatty acids. The monoepoxy- and monohydroxy-metabolites generated by CYP enzymes are collectively termed CYP-eicosanoids. CYP-eicosanoids act as mediators in the regulation of vascular tone, heart- and kidney function and several further physiological processes, mostly in a regio- and stereospecific manner. Arachidonic acid-derived epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE) are prominent members of the CYP-eicosanoid family. EETs and 20-HETE show partially opposing biological activities that contribute to the activation or inhibition of anti-inflammatory and other cell- and organ-protective mechanisms. The aim of the present work was to study the role of CYP-eicosanoids in ischemia/reperfusion (I/R) related organ damage by analyses of endogenous metabolite profiles. The main results were (i) discovery and characterization of the EETs protective role in animal models of the initiation phase of acute kidney injury (AKI) and the therapeutic potential of stable EET-analogs, (ii) identification of 8,9-EET and 20-HETE as potential predictive biomarkers for AKI in patients who underwent open heart surgery, (iii) the development and validation of a novel analytical method for chiral lipidomics (chiral LC-ESI-MS/MS) that allows to study endogenous enantiomers of monohydroxy- and monoepoxy-eicosanoids in complex matrices of biological and clinical samples. Furthermore, the approach was applied to describe the stereospecific regulation of EETs by epoxide hydrolases in vitro and in vivo.

Indiana University-Purdue University Indianapolis (IUPUI) / Acute Kidney Injury (AKI) is a prevalent and significant problem whose primary treatment is supportive care. Ischemic preconditioning is a strategy used to protect organs from ischemic injury via a prior injury. Ischemic preconditioning in the kidneys has been shown to confer protection onto kidneys from subsequent ischemic insults with attenuated serum creatinine values in treated rats. In the preconditioned kidneys, the enzyme IDH2 was discovered to be upregulated in the mitochondria. Hydrodynamic fluid delivery to the kidney was found to be a viable technique for delivering this gene to the kidney, resulting in artificially upregulated expression of IDH2. Via a two-pronged effort to discern the functional significance of ischemic preconditioning and hydrodynamic IDH2 fluid injections, we performed mitochondrial oxygen respiration assays on both preconditioned and injected kidneys. We found that renal ischemic preconditioning resulted in no significant difference between sham and preconditioned, subsequently injured kidneys, which is similar to the results from the serum creatinine studies. Hydrodynamically IDH2-injected, and subsequently injured kidneys respire significantly better than vehicle injected, and subsequently injured kidneys, which shows that hydrodynamic injections of IDH2 protects kidneys against injury, and partially mimics the effects of preconditioning.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19599号 / 医博第4106号 / 新制||医||1014(附属図書館) / 32635 / 京都大学大学院医学研究科医学専攻 / (主査)教授 柳田 素子, 教授 妹尾 浩, 教授 浅野 雅秀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Introdução: Pacientes portadores de câncer estão sobrevivendo mais devido aos avanços no diagnóstico precoce e tratamento dos tumores. A diminuição da mortalidade relacionada ao câncer e o envelhecimento da população acarretaram um número crescente de pacientes oncológicos internados em UTI. Objetivos: Identificar a prevalência e os fatores de risco para IRA nos pacientes oncológicos críticos. Métodos: Foram avaliados, prospectivamente, 371 pacientes oncológicos internados nas UTIs do Instituto do Câncer do Estado de São Paulo e do Hospital AC Camargo, entre novembro de 2011 a março de 2013. Os pacientes foram avaliados na admissão, 24h e 48h da internação na UTI. Foram coletados os parâmetros demográficos, clínicos e laboratoriais os quais foram analisados para os desfechos IRA, conforme o critério AKIN (Cr > 0,3 mg/dl ou aumento de 50% sobre a Cr basal em 48h) e óbito na UTI. Os dados foram submetidos à análise bivariada e multivariada. Resultados: A incidência de IRA nos pacientes oncológicos foi de 45,1%, sendo que apenas 5,2% necessitaram de tratamento dialítico. Os pacientes com IRA apresentaram mais frequentemente admissão cirúrgica (49% IRA vs 34% sem IRA; p=0,022). Na admissão à UTI, os fatores associados ao desenvolvimento de IRA (IRA vs sem IRA) foram: ventilação mecânica (26,6% vs 16,0%; p=0,031), frequência cardíaca (88 bpm vs 82 bpm; p=0,029), balanço hídrico (575 ml vs 275 ml; p = 0,0002), lactato (19 mg/dL vs 17 mg/dL; p= 0,046) e fósforo (3,9 mg/dL vs 3,4 mg/dL; p < 0,0001). A taxa de óbito hospitalar foi de 37,3% sendo que 25,3% ocorreu na UTI. A mortalidade foi mais prevalente em pacientes com câncer hematológico (8,6% sobreviventes vs 19,5% óbitos; p = 0,008), procedentes do pronto atendimento (23,5% sobreviventes vs 34,1% óbitos; p = 0,002), admissão clínica (50,4% sobreviventes vs 84,1% óbitos; p < 0,0001) e internação não planejada (59,9% vs 86,6% óbitos; p < 0,0001). Outros fatores relacionados ao óbito foram: sinais de congestão, uso de drogas vasoativas, choque séptico e infecção respiratória (p < 0,0001). Os dias de internação prévios à admissão na UTI também se relacionaram ao óbito (6 dias óbitos vs 2 dias sobreviventes; p < 0,0001). Os exames laboratoriais que se relacionaram ao óbito foram (sobreviventes vs óbitos): hipoalbuminemia (2,7 g/dL vs 2,4 g/dL; p= 0,003), aumento do INR (1,3 vs 1,5; p < 0,0001); aumento do lactato (17 mg/dL vs 20,5 mg/dL; p = 0,037), PCR (41,8 mg/dL vs 148,4 mg/dL; p < 0,0001) e TP (69% vs 59,5%; p = 0,001). Conclusão: A IRA é frequente em pacientes oncológicos admitidos na UTI e apresenta alta mortalidade. As ocorrências de IRA e óbito encontram-se mais relacionados com a gravidade das disfunções orgânicas no momento da admissão à UTI, do que às características da neoplasia de base / Introduction: Cancer patients are currently presenting longer survival due to advances in diagnosis and treatment. Mortality reduction related to cancer and aging of population had led to an increased admission of cancer patients in the ICU. Objectives: Evaluation of the prevalence and risk factors for AKI in critically ill cancer patients. Methods: It was prospectively evaluated 371 cancer patients admitted to the ICU in Instituto do Câncer do Estado de São Paulo and Hospital AC Camargo, from November 2011 until March 2013. Patients were evaluated at admission, 24h and 48h in the ICU. Demographic, clinical and laboratory parameters were collected which were correlated with the outcome AKI (AKIN I - Cr > 0.3 mg/dL or 50% increase over baseline in 48h) and mortality in the ICU. Statistical analysis was performed using bivariate and multivariate analysis. Results: The incidence of AKI in cancer patients was 45.1% but only 5.2% were dialysed. AKI patients were more frequently admitted due to surgical admission (AKI 53% vs. 49% non-AKI, p=0.022). At ICU admission, factors associated with AKI development (AKI vs. non-AKI) were: mechanical ventilation (26.6% vs. 16%, p =0.031), heart beats (88 bpm vs. 82 bpm, p=0.029), fluid balance (575 ml vs. 275 ml, p=0.0002), lactate (19 mg/dLvs. 17 mg/dL, p=0.046) and phosphorus (3.9 mg/dL vs. 3.4 mg/dL, p < 0.0001). Hospital mortality rate was 37.3% whereas ICU mortality was 25.3%. Mortality was more prevalent in patients with hematological cancer (8.6% survivors vs. 19.5% non-survivors, p = 0.008), patients from emergency room (23.5% survivors vs. 34.1% non-survivors, p = 0.002), patients with clinical admission (50.4% survivors vs. 84.1% non-survivors, p < 0.0001) and non-elective admission (59.9% vs. 86.6% non-survivors, p < 0.0001). Other factors related to mortality were: volume overload, vasoactive drugs use, septic shock and pulmonary infection (p < 0.0001). Hospitalization period before ICU admission also correlated with mortality (6 days survivors vs. 2 days non-survivors, p 0.0001). The laboratory parameters that correlated to mortality were (survivors vs. non-survivors): hypoalbuminemia (2.7 g/dL vs. 2.4 g/dL, p=0.003), increased INR (1.3 vs. 1.5, p < 0.0001), increased lactate (17 mg/dL vs. 20.5 mg/dL, p=0.037), PCR (41.8 mg/dL vs 148.4 mg/dL, p < 0.0001) e PT (69% vs. 59.5%, p = 0.001). Conclusions: AKI is a frequent complication in cancer patients admitted to ICU, presenting high mortality rate. AKI and mortality outcomes are more related to the severity of organs dysfunction at ICU admission than the patient´s cancer disease