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Urine metabolomics insight into acute kidney injury point to oxidative stress disruptions in energy generation and H2S availability

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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 (LC-MS/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 N-acetylneuraminic 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-β-synthase, and ethanolamine-phosphate cytidylyltransferase, and increased N-acetylneuraminate synthase as the potentially underlying cause of changes in urinary metabolites. A urinary metabolite panel identified AKI 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.

Key messages

  • The urinary metabolome reflects AKI evolution and severity of injury.

  • Kidney transcriptomics revealed enzymatic expression changes.

  • Enzymatic expression changes may be the potentially underlying cause of changes in urine metabolites.

  • Identified metabolite changes link oxidative stress, energy generation, and H2S availability to AKI.

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Acknowledgements

The authors thank Dolores Molero from CAI-RMN, UCM, Consuelo Agüeros from Nephrology Investigation Unit, and Servicio de Nefrología del Hospital Valdecilla. This work was supported by the Instituto de Salud Carlos III cosupported by FEDER grants [PI10/00624, PI13/01873, PI14/01650, PI15/00298, PI016/02057, PI16/01334, IF08/3667-1, CP09/00229, CPII15/00027, CP14/00133, PT13/0001/0013, intensificacion to AO, and REDinREN (RD12/0021/0001 and RD16/0009)], Fundación SENEFRO, and Fundación Conchita Rábago de Jiménez Díaz.

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Author notes

  1. Marta Martin-Lorenzo and Laura Gonzalez-Calero contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, IIS-Fundacion Jimenez Diaz-UAM, REDinREN, Madrid, Spain

    Marta Martin-Lorenzo, Laura Gonzalez-Calero, Fernando Vivanco & Gloria Alvarez-Llamas

  2. Nephrology Department, Hospital Valdecilla, Universidad de Cantabria, Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Cantabria, Spain

    Angeles Ramos-Barron, Carlos Gomez-Alamillo & Manuel Arias

  3. Department of Nephrology/IRSIN, IIS-Fundación Jiménez Díaz-UAM, REDinREN, Madrid, Spain

    Maria D. Sanchez-Niño & Alberto Ortiz

  4. CAI-RMN, Universidad Complutense, Madrid, Spain

    Juan Manuel García-Segura

  5. Department of Biochemistry and Molecular Biology I, Universidad Complutense, Madrid, Spain

    Juan Manuel García-Segura & Fernando Vivanco

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  1. Marta Martin-Lorenzo
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  2. Laura Gonzalez-Calero
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  3. Angeles Ramos-Barron
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  4. Maria D. Sanchez-Niño
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  6. Juan Manuel García-Segura
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  7. Alberto Ortiz
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  8. Manuel Arias
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  9. Fernando Vivanco
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  10. Gloria Alvarez-Llamas
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Correspondence to Gloria Alvarez-Llamas.

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Martin-Lorenzo, M., Gonzalez-Calero, L., Ramos-Barron, A. et al. Urine metabolomics insight into acute kidney injury point to oxidative stress disruptions in energy generation and H2S availability. J Mol Med 95, 1399–1409 (2017). https://doi.org/10.1007/s00109-017-1594-5

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  • DOI: https://doi.org/10.1007/s00109-017-1594-5

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