Plasma metabolomics analysis in murine prerenal azotemia reveals changes in energy substrates, amino acid metabolism, and uremic toxins

Pre-renal azotemia (PRA) accounts for 10-30% of hospitalized cases of acute kidney injury (AKI). In contrast to AKI from acute tubular injury (ATI), PRA is considered a benign condition, despite evidence that it is associated with adverse clinical consequences. In this study, we used untargeted metabolomics to study the potential systemic consequences of PRA as compared to ATI. We hypothesized that the PRA and ATI plasma metabolomes would share certain features, since both are marked by a decline in glomerular filtration rate (GFR), but that a unique PRA signature would be identified. Wildtype male C57BL/6 mice were used in established models of ischemic acute kidney injury (iAKI) or PRA induced by intraperitoneal furosemide followed by GFR restoration with normal saline resuscitation. Plasma from iAKI and PRA cohorts were analyzed by mass spectrometry metabolomics. The PRA plasma metabolome was defined by 40 significantly changed metabolites, including 7 uremic toxins, with significant enrichment of tryptophan and fatty acid oxidation metabolites. When comparing models, the PRA and iAKI metabolomes overlap at the individual metabolite level (50% of the PRA metabolome represented in the iAKI metabolome) and share three significantly enriched pathways involved in energy substrate and amino acid metabolism. Further analysis identified cystathionine, kynurenine, and indolepyruvate as possible PRA plasma biomarkers. Our results demonstrate that PRA causes systemic metabolic changes, some of which mirror changes found in ATI. Our results challenge the notion that PRA is inconsequential, and the metabolic pathways and uremic toxins identified herein warrant further study.