Metabolomics- and proteomics-based multi-omics integration reveals early metabolite alterations in sepsis-associated acute kidney injury.

Abstract

Background: Sepsis-associated acute kidney injury (SA-AKI) is a frequent complication in patients with sepsis and is associated with high mortality. Therefore, early recognition of SA-AKI is essential for administering supportive treatment and preventing further damage. This study aimed to identify and validate metabolite biomarkers of SA-AKI to assist in early clinical diagnosis.

Methods: Untargeted renal proteomic and metabolomic analyses were performed on the renal tissues of LPS-induced SA-AKI and sepsis mice. Glomerular filtration rate (GFR) monitoring technology was used to evaluate real-time renal function in mice. To elucidate the distinctive characteristics of SA-AKI, a multi-omics Spearman correlation network was constructed integrating core metabolites, proteins, and renal function. Subsequently, metabolomics analysis was used to explore the dynamic changes of core metabolites in the serum of SA-AKI mice at 0, 8, and 24 h. Finally, a clinical cohort (28 patients with SA-AKI vs. 28 patients with sepsis) serum quantitative metabolomic analysis was carried out to build a diagnostic model for SA-AKI via logistic regression (LR).

Results: Thirteen differential renal metabolites and 112 differential renal proteins were identified through a multi-omics study of SA-AKI mice. Subsequently, a multi-omics correlation network was constructed to highlight five core metabolites, i.e., 3-hydroxybutyric acid, 3-hydroxymethylglutaric acid, creatine, myristic acid, and inosine, the early changes of which were then observed via serum time series experiments of SA-AKI mice. The levels of 3-hydroxybutyric acid, 3-hydroxymethylglutaric acid, and creatine increased significantly at 24 h, myristic acid increased at 8 h, while inosine decreased at 8 h. Ultimately, based on the identified core metabolites, we recruited 56 patients and constructed a diagnostic model named IC3, using inosine, creatine, and 3-hydroxybutyric acid, to early identify SA-AKI (AUC = 0.90).

Conclusions: We proposed a blood metabolite model consisting of inosine, creatine, and 3-hydroxybutyric acid for the early screening of SA-AKI. Future studies will observe the performance of these metabolites in other clinical populations to evaluate their diagnostic role.