Early Sepsis Metabolic Changes in Kidney and Liver Precede Clinical Evidence of Organ Dysfunction.

Abstract

Organ-specific metabolic pathways, including those related to mitochondrial metabolism, could provide insight into mechanisms underlying sepsis-induced organ dysfunction. However, it remains unclear if metabolic changes result from or precede clinical organ dysfunction. To determine if blood concentrations of the mitochondrial metabolites acetylcarnitine and l-carnitine correlate with organ-specific signals of sepsis-induced dysfunction, we performed a series of translational analyses of two cohorts of human sepsis and experiments using a murine model of polymicrobial sepsis. We evaluated the association between mitochondrial metabolites and clinical indices of organ function. In the blood of patients with sepsis or septic shock, we found metabolic signals of dysfunctional mitochondrial β-oxidation that were correlated with clinical measures of renal and liver dysfunction. The relevance of these findings was corroborated in an experimental model that showed distinct patterns of change in organ metabolism that correlated with the blood acetylcarnitine to l-carnitine ratio. In addition, sepsis-induced changes in organ metabolism were distinct in the liver and kidney, highlighting the unique energy economies of each organ. Importantly, metabolic changes preceded changes in clinical indices of organ function and histological evidence of cellular apoptosis. On the basis of these findings, sepsis-induced disruption in blood concentrations of specific metabolites could serve as more physiologically relevant indicators of early organ dysfunction than those we presently use. These early metabolite signals provide mechanistic insights into altered metabolism that may hold the key to timely identification of impending organ dysfunction. This could lead to strategies directed at the interruption of sepsis-induced organ failure.