Altered proximal tubular cell glucose metabolism during acute kidney injury is associated with mortality

Creators: Legouis, David¹; Ricksten, Sven-Erick^{2, 3}; Faivre, Anna¹; Verissimo, Thomas¹; Gariani, Karim¹; Verney, Charles⁴; Galichon, Pierre⁴; Berchtold, Lena^{1, 5}; Feraille, Eric⁶; Fernandez, Marylise¹; Placier, Sandrine⁴; Koppitch, Kari⁷; Hertig, Alexandre⁴; Martin, Pierre-Yves¹; Naesens, Maarten^{5, 8}; Pugin, Jérôme¹; McMahon, Andrew P.⁷; Cippà, Pietro E.^{7, 9}; de Seigneux, Sophie¹

1. University Hospital of Geneva
2. Sahlgrenska University Hospital
3. University of Gothenburg
4. Tenon Hospital
5. Universitair Ziekenhuis Leuven
6. University of Geneva
7. University of Southern California
8. Naesens-Maarten
9. Ente Ospedaliero Cantonale

Abstract

Acute kidney injury (AKI) is strongly associated with mortality, independently of its cause. The kidney contributes to up to 40% of systemic glucose production by gluconeogenesis during fasting and under stress conditions. Whether kidney gluconeogenesis is impaired during AKI and how this might influence systemic metabolism remain unknown. Here we show that glucose production and lactate clearance are impaired during human and experimental AKI by using renal arteriovenous catheterization in patients, lactate tolerance testing in mice and glucose isotope labelling in rats. Single-cell transcriptomics reveal that gluconeogenesis is impaired in proximal tubule cells during AKI. In a retrospective cohort of critically ill patients, we demonstrate that altered glucose metabolism during AKI is a major determinant of systemic glucose and lactate levels and is strongly associated with mortality. Thiamine supplementation increases lactate clearance without modifying renal function in mice with AKI, enhances glucose production by renal tubular cells ex vivo and is associated with reduced mortality and improvement of the metabolic pattern in a retrospective cohort of critically ill patients with AKI. This study highlights an unappreciated systemic role of renal glucose and lactate metabolism under stress conditions, delineates general mechanisms of AKI-associated mortality and introduces a potential intervention targeting metabolism for a highly prevalent clinical condition with limited therapeutic options.

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Funding

This study was funded by the Swiss National Science Foundation (grant nos. PP00P3 157454 to S.S. and 167773 to P.E.C.), by a STARTER grant (no. RS03-25) to S.S. and D.L. from the HUG private foundation (the foundation of Geneva University Hospitals and the University of Geneva’s Faculty of Medicine) and by The Eli and Edythe Broad Foundation (to P.C. and A.P.M.). P.G. was supported by the ATIP Avenir programme. We thank G. Alvarado, A. Ransick and A. Kim for technical support.

Acknowledgement

We thank G. Alvarado, A. Ransick and A. Kim for technical support.

Contributions

D.L. and S.S. conceived and designed the project. S.-E.R. performed human renal catheterization. D.L., A.F., S.P., C.V., K.G., L.B., M.F., T.V. and K.K. performed experiments. D.L., P.-Y.M. and J.P. generated and analysed ICU datasets. P.E.C. and A.P.M conducted snRNA-seq experiments and analysis. M.N. and P.E.C. provided RNA-seq data from kidney allograft recipients and D.L. performed analyses. S.S., D.L. and P.E.C. performed data interpretation. P.G., A.H. and E.F. validated data interpretation.

Data Availability

RNAseq data for human kidney biopsies are respectively available at GEO GSE126805.

Mouse RNAseq data are available on GEO, PMID: 24569379 [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE52004] and as supplementary table at https://doi.org/10.1172/jci.insight.94716. NucSeq data will be made available upon publication. Clinical are available from the corresponding authors upon reasonable request. All data analyzed during this study are included in this published article (and its supplementary information files).

Errata

17 February 2021: An Author Correction to this article was published on 01 September 2020. (https://doi.org/10.1038/s42255-020-00283-6)

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