Gluconeogenesis in the kidney: in health and in chronic kidney disease

Chronic kidney disease (CKD) is a global health issue with increasing prevalence. Despite large improvements in current therapies, slowing CKD progression remains a challenge. A better understanding of renal pathophysiology is needed to offer new therapeutic targets. The role of metabolism alterations and mitochondrial dysfunction in tubular cells is increasingly recognized in CKD progression. In proximal tubular cells, CKD progression is associated with a switch from fatty acid oxidation to glycolysis. Glucose synthesis through gluconeogenesis is one of the principal physiological functions of the kidney. Loss of tubular gluconeogenesis in a stage-dependent manner is a key feature of CKD and contributes to systemic and possibly local metabolic complications. The local consequences observed may be related to an accumulation of precursors, such as glycogen, but also to the various physiological functions of the gluconeogenesis enzymes. The basic features of metabolism in proximal tubular cells and their modifications during CKD will be reviewed. The metabolic modifications and their influence on kidney disease will be described, as well as the local and systemic consequences. Finally, therapeutic interventions will be discussed. Lay Summary We review the modifications of metabolism during chronic kidney disease with a special focus on glucose production through gluconeogenesis.