IntroductionCKD is associated with alterations of tubular function. Renal gluconeogenesis is responsible for 40% of systemic gluconeogenesis during fasting, but how and why CKD affects this process and the repercussions of such regulation are unknown.MethodsWe used data on the renal gluconeogenic pathway from more than 200 renal biopsies performed on CKD patients and from 43 kidney allograft patients, and studied three mouse models, of proteinuric CKD (POD-ATTAC), of ischemic CKD, and of unilateral urinary tract obstruction. We analyzed a cohort of patients who benefitted from renal catheterization and a retrospective cohort of patients hospitalized in the intensive care unit.ResultsRenal biopsies of CKD and kidney allograft patients revealed a stage-dependent decrease in the renal gluconeogenic pathway. Two animal models of CKD and one model of kidney fibrosis confirm gluconeogenic downregulation in injured proximal tubule cells. This shift resulted in an alteration of renal glucose production and lactate clearance during an exogenous lactate load. The isolated perfused kidney technique in animal models and renal venous catheterization in CKD patients confirmed decreased renal glucose production and lactate clearance. In CKD patients hospitalized in the intensive care unit, systemic alterations of glucose and lactate levels were more prevalent and associated with increased mortality and a worse renal prognosis at follow-up. Decreased expression of the gluconeogenesis pathway and its regulators predicted faster histologic progression of kidney disease in kidney allograft biopsies.ConclusionRenal gluconeogenic function is impaired in CKD. Altered renal gluconeogenesis leads to systemic metabolic changes with a decrease in glucose and increase in lactate level, and is associated with a worse renal prognosis.

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 chronic kidney disease will be reviewed. The metabolic modifications and their influence on kidney disease will be described, as well as the local and systemic consequences. Therapeutic interventions will finally be discussed.

Phosphoenolpyruvate Carboxykinase 1 (PCK1, PEPCK-C) is a cytosolic enzyme converting oxaloacetate to phosphoenolpyruvate, with a potential role in gluconeogenesis, ammoniagenesis and cataplerosis in the liver. Kidney proximal tubule cells display a high expression of this enzyme, which importance is currently not well defined. We generated PCK1 kidney specific knock-out and knock-in mice under the tubular cell specific PAX8 promoter. We studied the effect of PCK1 deletion and overexpression at the renal level on tubular physiology under normal condition and during metabolic acidosis and proteinuric renal disease. PCK1 deletion led to hyperchloremic metabolic acidosis characterized by reduced but not abolished ammoniagenesis. PCK1 deletion also resulted in glycosuria, lactaturia and altered systemic glucose and lactate metabolism at baseline and during metabolic acidosis. Metabolic acidosis resulted in kidney injury in PCK1 deficient animals with decreased creatinine clearance and albuminuria. PCK1 further regulated energy production by the proximal tubule and PCK1 deletion decreased ATP generation. In proteinuric chronic kidney disease, mitigating PCK1 downregulation led to better renal function preservation. PCK1 is essential for kidney tubular cell acid base control, mitochondrial function and glucose/lactate homeostasis. Loss of PCK1 increases tubular injury during acidosis. Mitigating kidney tubular PCK1 downregulation during proteinuric renal disease improves renal function.