Abstract: Acute kidney injury (AKI) is one of the main complications in acute care medicine and a risk factor for chronic kidney disease (CKD). AKI incidence has increased; however, its diagnosis has limitations and physiopathological mechanisms are underexplored. We investigated urine samples, aiming to identify major metabolite changes during human AKI evolution. Metabolic signatures found were further explored for a potential link to severity of injury. Twenty-four control subjects and 38 hospitalized patients with AKI were recruited and urine samples were collected at the time of diagnosis, during follow-up and at discharge. Nuclear magnetic resonance (NMR) was used in a first discovery phase for identifying potential metabolic differences. Target metabolites of interest were confirmed by liquid chromatography-mass spectrometry (LCMS/ MS) in an independent group. Underlying metabolic defects were further explored by kidney transcriptomics of murine toxic AKI. Urinary 2-hydroxybutyric acid, pantothenic acid, and hippuric acid were significantly downregulated and urinary Nacetylneuraminic acid, phosphoethanolamine, and serine were upregulated during AKI. Hippuric acid, phosphoethanolamine, and serine showed further downregulation/upregulation depending on the metabolite in acute tubular necrosis (ATN) AKI compared to prerenal AKI. Kidney transcriptomics disclosed decreased expression of cystathionase, cystathionine-?-synthase, and ethanolamine-phosphate cytidylyltransferase, and increased N-acetylneuraminate synthase as the potentially underlying cause of changes in urinary metabolites. A urinary metabolite panel identifiedAKI patients and provided insight into intrarenal events. A urine fingerprint made up of six metabolites may be related to pathophysiological changes in oxidative stress, energy generation, and H2S availability associated with AKI.

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