Abstract
Sepsis-induced acute kidney injury (SI-AKI) is a serious condition in critically ill patients. Currently, the diagnosis is based on either elevated serum creatinine levels or oliguria, which partially contribute to delayed recognition of AKI. Metabolomics is a potential approach for identifying small molecule biomarkers of kidney diseases. Here, we studied serum metabolomics alterations in rats with sepsis to identify early biomarkers of sepsis and SI-AKI. A rat model of SI-AKI was established by intraperitoneal injection of lipopolysaccharide (LPS). Thirty Sprague-Dawley (SD) rats were randomly divided into the control (CT) group and groups treated for 2 hours (LPS2) and 6 hours (LPS6) with LPS (10 rats per group). Nontargeted metabolomics screening was performed on the serum samples from the control and SI-AKI groups. Combined multivariate and univariate analysis was used for pairwise comparison of all groups to identify significantly altered serum metabolite levels in early-stage AKI in rats with sepsis. Orthogonal partial least squares discriminant analysis (OPLS-DA) showed obvious separation between the CT and LPS2 groups, CT and LPS6 groups, and LPS2 and LPS6 groups. All comparisons of the groups identified a series of differential metabolites according to the threshold defined for potential biomarkers. Intersections and summaries of these differential metabolites were used for pathway enrichment analysis. The results suggested that sepsis can cause an increase in systemic aerobic and anaerobic metabolism, an impairment of the oxygen supply, and uptake and abnormal fatty acid metabolism. Changes in the levels of malic acid, methionine sulfoxide, and petroselinic acid were consistently measured during the progression of sepsis. The development of sepsis was accompanied by the development of AKI, and these metabolic disorders are directly or indirectly related to the development of SI-AKI.
Highlights
The clinical mortality rate from sepsis is approximately 20% to 50% and can exceed 70% if sepsis is combined with acute kidney injury [1]
Thirty SD rats were randomly divided into the control (CT), LPS 2 h (LPS2), and LPS 6 h (LPS6) groups (10 rats per group)
Malic acid is an important organic acid produced during metabolic processes in the body and an important metabolic intermediate in the tricarboxylic acid (TCA) cycle that directly participates in mitochondrial energy metabolism [19]
Summary
The clinical mortality rate from sepsis is approximately 20% to 50% and can exceed 70% if sepsis is combined with acute kidney injury [1]. Sepsis-induced acute kidney injury (SIAKI) is defined as AKI occurring simultaneously with or subsequent to sepsis without other aetiologies [2] and is characterized by high mortality and poor prognosis mainly due to the lack of early and reliable diagnostic markers of AKI, which results in delayed initiation of effective interventions [3]. Identifying new and early markers of kidney injury is required for timely treatment [5]. New biomarkers have been identified in the past few years, including cystatin-C, neutrophil gelatinase-associated lipocalin (NGAL), and interleukin (IL)-18; these markers are not sensitive enough to diagnose AKI in the intensive care unit [6]
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