BACKGROUND: The pathophysiology of sepsis-induced acute kidney injury remains elusive. Although mitochondrial dysfunction is often perceived as the main culprit, data from preclinical models yielded conflicting results so far. The aim of this study was to assess the immune-metabolic background of sepsis-associated renal dysfunction using sequential biopsy approach with mitochondria function evaluation in a large clinically relevant porcine models mimicking two different paces and severity of sepsis and couple this approach with traditional parameters of renal physiology. METHODS: In this randomized, open-label study, 15 anaesthetized, mechanically ventilated and instrumented (renal artery flow probe and renal vein catheter) pigs were randomized in two disease severity groups-low severity (LS) sepsis (0.5 g/kg of autologous faeces intraperitoneally) and high severity (HS) sepsis (1 g/kg of autologous faeces intraperitoneally). Sequential cortical biopsies of the left kidney were performed and a pyramid-shaped kidney specimen with cortex, medulla and renal papilla was resected and processed at the end of the experiment. Oxygraphic data and western blot analysis of proteins involved in mitochondrial biogenesis and degradation were obtained. RESULTS: In contrast to increased mitochondrial activity observed in LS sepsis, a significant decrease in the oxidative phosphorylation capacity together with an increase in the respiratory system uncoupling was observed during the first 24 h after sepsis induction in the HS group. Those changes preceded alterations of renal haemodynamics. Furthermore, serum creatinine rose significantly during the first 24 h, indicating that renal dysfunction is not primarily driven by haemodynamic changes. Compared to cortex, renal medulla had significantly lower oxidative phosphorylation capacity and electron-transport system activity. PGC-1-alfa, a marker of mitochondrial biogenesis, was significantly decreased in HS group. CONCLUSIONS: In this experimental model, unique sequential tissue data show that the nature and dynamics of renal mitochondrial responses to sepsis are profoundly determined by the severity of infectious challenge and resulting magnitude of inflammatory insult. High disease severity is associated with early and stepwise progression of mitochondria dysfunction and acute kidney injury, both occurring independently from later renal macro-haemodynamic alterations. Our data may help explain the conflicting results of preclinical studies and suggest that sepsis encompasses a very broad spectrum of sepsis-induced acute kidney injury endotypes.

• Klíčová slova
• Acute kidney injury, Mitochondrial dysfunction, Renal biopsy, Sepsis, Septic shock,
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: In almost half of all sepsis patients, acute kidney injury (AKI) develops. However, the pathobiologic differences between sepsis patients with and without AKI are only poorly understood. We used a unique opportunity to examine dynamic inflammatory, renal hemodynamic, and microvascular changes in two clinically relevant large-animal models of sepsis. Our aim was to assess variability in renal responses to sepsis and to identify both hemodynamic and nonhemodynamic mechanisms discriminating individuals with AKI from those in whom AKI did not develop. METHODS: Thirty-six pigs were anesthetized, mechanically ventilated, and instrumented. After a recovery period, progressive sepsis was induced either by peritonitis (n = 13) or by continuous intravenous infusion of live Pseudomonas aeruginosa (n = 15). Eight sham operated-on animals served as time-matched controls. All animals received standard intensive care unit (ICU) care, including goal-directed hemodynamic management. Before, and at 12, 18, and 22 hours of sepsis, systemic and renal (ultrasound flow probe) hemodynamics, renal cortex microcirculation (laser Doppler), inflammation (interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), oxidative stress (thiobarbituric acid reactive species (TBARS), nitrite/nitrate concentrations (NOx), and renal oxygen kinetics and energy metabolism were measured. RESULTS: In 14 (50%) pigs, AKI developed (62% in peritonitis, 40% in bacteria infusion model). Fecal peritonitis resulted in hyperdynamic circulation, whereas continuous bacteria infusion was associated with normodynamic hemodynamics. Despite insults of equal magnitude, comparable systemic hemodynamic response, and uniform supportive treatment, only those pigs with AKI exhibited a progressive increase in renal vascular resistance. This intrarenal vasoconstriction occurred predominantly in the live-bacteria infusion model. In contrast to AKI-free animals, the development of septic AKI was preceded by early and remarkable inflammatory response (TNF-α, IL-6) and oxidative stress (TBARS). CONCLUSIONS: The observed variability in susceptibility to septic AKI in our models replicates that of human disease. Early abnormal host response accompanied by subsequent uncoupling between systemic and renal vascular resistance appear to be major determinants in the early phase of porcine septic AKI. Nonuniform and model-related renal hemodynamic responses that are unpredictable from systemic changes should be taken into consideration when evaluating hemodynamic therapeutic interventions in septic AKI.

• MeSH
• akutní poškození ledvin krev   etiologie   patofyziologie   MeSH
• biologické markery krev   MeSH
• časové faktory MeSH
• hemodynamika fyziologie   MeSH
• interleukin-6 krev   MeSH
• modely nemocí na zvířatech MeSH
• oxidační stres fyziologie   MeSH
• prasata MeSH
• sepse komplikace   MeSH
• TNF-alfa krev   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• interleukin-6 MeSH
• TNF-alfa MeSH