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• W2980928502 abstract "Nature letter Acute Kidney Injury (AKI) is strongly associated with adverse outcome and mortality independently of the cause of renal damage 1-3 . The mechanisms determining the deleterious systemic effects of AKI are poorly understood and specific interventions, including optimization of renal replacement therapy, had a marginal effect on AKI-associated mortality in clinical trials 4-8 . The kidney contributes to up to 40% of systemic glucose production by gluconeogenesis during fasting and stress conditions, mainly synthesized from lactate in the proximal tubule 9-12 , rendering this organ a major systemic lactate disposal 13 . Whether kidney gluconeogenesis is impaired during AKI and how this might influence systemic metabolism remains unknown. Here we demonstrate that glucose production and lactate clearance are impaired during human AKI using renal arteriovenous catheterization in patients. Using single cell transcriptomics in mice and RNA sequencing in human biopsies, we show that glycolytic and gluconeogenetic pathways are modified during AKI in the proximal tubule specifically, explaining the metabolic alterations. We further demonstrate that impaired renal gluconeogenesis and lactate clearance during AKI are major determinants of systemic glucose and lactate levels in critically ill patients. Most importantly, altered glucose metabolism in AKI emerged as a major determinant of AKI-associated mortality. Thiamine supplementation restored renal glucose metabolism and substantially reduced AKI-associated mortality in intensive care patients. This study highlights an unappreciated systemic role of renal glucose and lactate metabolism in stress conditions, delineates general mechanisms explaining AKI-associated mortality and introduces a potential therapeutic intervention for a highly prevalent clinical condition with limited therapeutic options." @default.
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• W2980928502 date "2019-10-16" @default.
• W2980928502 modified "2023-09-27" @default.
• W2980928502 title "Impaired renal gluconeogenesis is a major determinant of acute kidney injury associated mortality" @default.
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• W2980928502 doi "https://doi.org/10.1101/804997" @default.
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