Searching for mechanisms that matter in early septic acute kidney injury: an experimental study

Abstract

IntroductionIn 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.MethodsThirty-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.ResultsIn 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).ConclusionsThe 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.

Renal Hemodynamics in AKI

“…However, studies in large mammals, including humans, suggest that global renal hypoperfusion cannot be invoked as the sole etiology of AKI. [2][3][4][5] The causative contribution of renal blood flow (RBF) to kidney dysfunction is particularly puzzling in sepsis, and there is widespread disagreement as to whether RBF is reduced, normal, or even increased. 2,3,[6][7][8] In the few large animal and clinical studies, the patterns of RBF in AKI and its relation with systemic hemodynamics are highly variable.…”

“…[2][3][4][5] The causative contribution of renal blood flow (RBF) to kidney dysfunction is particularly puzzling in sepsis, and there is widespread disagreement as to whether RBF is reduced, normal, or even increased. 2,3,[6][7][8] In the few large animal and clinical studies, the patterns of RBF in AKI and its relation with systemic hemodynamics are highly variable. 3,6 Absence of benefit of vasodilator therapy in human sepsis-associated AKI 9 may be explained by variability in blood flow.…”

“…2,3,[6][7][8] In the few large animal and clinical studies, the patterns of RBF in AKI and its relation with systemic hemodynamics are highly variable. 3,6 Absence of benefit of vasodilator therapy in human sepsis-associated AKI 9 may be explained by variability in blood flow. Unfortunately, more specific knowledge about the relationship between RBF and AKI in sepsis is limited by the lack of reliable methods to monitor continuous RBF in human AKI.…”

“…First, renal circulatory changes might behave differently in sepsis with AKI as opposed to sepsis alone. 3 Second, renal hemodynamics in subjects with sepsis and AKI cannot be predicted reliably from systemic hemodynamics. 3 Third, sepsis-associated AKI may be accompanied by dissociation between systemic and renal vascular resistance.…”

“…3 Second, renal hemodynamics in subjects with sepsis and AKI cannot be predicted reliably from systemic hemodynamics. 3 Third, sepsis-associated AKI may be accompanied by dissociation between systemic and renal vascular resistance. These differences in systemic and renal vascular resistances may relate to both species differences and most importantly, the time periods of observations after the induction of sepsis.…”