Decreased Renal Gluconeogenesis Is a Hallmark of Chronic Kidney Disease

医学 肾脏疾病 糖异生 内科学 肾功能 内分泌学 泌尿系统 肾病科 泌尿科
作者
Thomas Verissimo,Anna Faivre,Anna Rinaldi,Maja Lindenmeyer,Vasiliki Delitsikou,Christelle Veyrat-Durebex,Carolyn Heckenmeyer,Marylise Fernandez,Lena Berchtold,Delal Dalga,Clemens Cohen,Maarten Naesens,Sven-Erik Ricksten,Pierre-Yves Martin,Jérôme Pugin,Franck Merlier,Karsten Haupt,Joseph M. Rutkowski,Solange Moll,Pietro E. Cippà,David Legouis,Sophie de Seigneux
出处
期刊:Journal of the American Society of Nephrology [American Society of Nephrology]
卷期号:: ASN.2021050680-ASN.2021050680
标识
DOI:10.1681/asn.2021050680
摘要

Introduction CKD 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. Methods We 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. Results Renal 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. Conclusion Renal 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.
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