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

Abstract

Acute Kidney Injury (AKI) is strongly associated with adverse outcome and mortality independently of the cause of renal damage [1][2][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][5][6][7][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][10][11][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 AKIassociated 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.To study the impact of AKI on renal glucose and lactate metabolism, we performed renal vein catheterization in patients undergoing cardiac surgery with cardiopulmonary bypass and experiencing (n=18) or not (n=87) post-operative AKI (Supplementary Table 1). We found a switch from net renal lactate uptake to net renal lactate release in patients experiencing AKI (-0.01±0.03 mmol/min to 0.02±0.02 mmol/min, p<0.001). Moreover, AKI patients showed a decrease in the renal net glucose release (0.06±0.07 mmol/min to 0.01±0.04 mmol/min, p=0.016) compared to the control group (Fig. 1 a,b). This suggested a simultaneous reduction of gluconeogenesis and activation of glycolysis in the kidney in response to AKI. Glycosuria was unlikely to be involved since all patients had arterial glucose levels below the glycosuria threshold (5.4 ± 0.94 mmol/L). To further characterize this process, we compared kidney allograft biopsies obtained during transplantation shortly (49±16 minutes) after

Metabolic Alterations in SARS-CoV-2 Infection and Its Implication in Kidney Dysfunction

“…However, even regenerating tubules present increased glycolytic enzyme expression, and this irreversibility of metabolic profile led the cell to hypoxia and induced the profibrotic signaling (Lan et al, 2016), which can contribute to the progression from AKI to chronic pathology. In line with this, it was observed an increase in glycolytic profile in experimental and clinical AKI, in contrast with the reduction of gluconeogenesis (Legouis et al, 2020). It was observed that rate-limiting gluconeogenesis enzymes were decreased during the early phase following ischemia-reperfusion injury, but the expression of glycolytic enzymes was increased.…”

“…The reduction of renal gluconeogenesis can contribute to hypoglycemia in stress conditions, compromising the systemic metabolism and contributing to worsening patient condition. Metabolic reprogramming of glucose metabolism during AKI was associated with mortality, as reported by Legouis et al (2020). COVID-19 patients with metabolic disorders have a worsening of the clinical condition associated with acute kidney disease, which suggests that dysfunction in systemic metabolism may contribute to renal injury in COVID-19.…”

“…Conversely, the progressive decline of the kidney function, dependent or independent of metabolic etiology, causes changes in the systemic metabolism (de Boer and Utzschneider, 2017). In physiological conditions, kidneys are responsible for up to 40% of the glucose production by gluconeogenesis, and perturbation in the metabolism of the renal cells, such as proximal tubular epithelial cells (PTECS), profoundly impacts on glucose metabolism, affecting glycolytic and gluconeogenic pathways (Legouis et al, 2020). Besides, other metabolic routes can be affected in renal injury, such as lipid and mitochondrial metabolism, starting in renal cortex, followed by medulla and plasma (Wei et al, 2014), demonstrating that altered renal energy metabolism, specifically in renal cell, is correlated with kidney injury development and it can affect systemic metabolism.…”

“…However, the exact cause of hypoglycemia in these patients is unknown (Klonoff et al, 2020). Legouis et al (2020) observed that gluconeogenesis is impaired in renal PTECs in clinical and experimental AKI. In this study, the author verified the increase of glycolytic enzymes and reduction of gluconeogenesis, demonstrating that the glucose metabolism reprogramming in renal PTECs had an effect on systemic levels of glucose and was correlated with patient mortality.…”

The dysregulation of metabolic pathways and induction of the pentose phosphate pathway in renal ischaemia–reperfusion injury

“…Legouis et al have recently shown that AKI leads to increased glycolysis and reduced gluconeogenesis in the kidney, which together lead to lactate accumulation and a decrease in systemic glucose levels. AKI‐associated mortality was reduced when glucose metabolism was restored by thiamine supplementation, thereby demonstrating the need to explore metabolic disturbances in AKI as new areas for therapeutic intervention [48].…”