Thomas Verissimo1, Anna Faivre1,2, Anna Rinaldi3, Maja Lindenmeyer4, Vasiliki Delitsikou1, Christelle Veyrat-Durebex1,5, Carolyn Heckenmeyer1, Marylise Fernandez1, Lena Berchtold1,2, Delal Dalga1, Clemens Cohen6, Maarten Naesens7, Sven-Erik Ricksten8, Pierre-Yves Martin2, Jérôme Pugin9, Franck Merlier10, Karsten Haupt10, Joseph M Rutkowski11, Solange Moll12, Pietro E Cippà3, David Legouis1,9, Sophie de Seigneux13,2. 1. Department of Medicine and Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland. 2. Service of Nephrology, Department of Medicine, Geneva University Hospitals, Geneva, Switzerland. 3. Division of Nephrology, Ente Ospedaliero Cantonale, Lugano, Switzerland. 4. III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 5. Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 6. Nephrological Center, Medical Clinic and Polyclinic IV, University of Munich, Munich, Germany. 7. Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium. 8. Department of Anesthesiology and Intensive Care, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden. 9. Division of Intensive Care, Department of Acute Medicine, Geneva University Hospitals, Geneva, Switzerland. 10. Université de Technologie de Compiègne, CNRS Laboratory for Enzyme and Cell Engineering, Compiègne, France. 11. Department of Medical Physiology, Texas A&M University Health Science Center, Bryan, Texas. 12. Service of Clinical Pathology, Department of Pathology and Immunology, University Hospitals and University of Geneva, Geneva, Switzerland. 13. Department of Medicine and Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland sophie.deseigneux@hcuge.ch.
Abstract
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.
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.
Authors: Joseph M Rutkowski; Zhao V Wang; Ae Seo Deok Park; Jianning Zhang; Dihua Zhang; Ming Chang Hu; Orson W Moe; Katalin Susztak; Philipp E Scherer Journal: J Am Soc Nephrol Date: 2013-01-18 Impact factor: 10.121
Authors: Li Li; Pierre Galichon; Xiaoyan Xiao; Ana C Figueroa-Ramirez; Diana Tamayo; Jake J-K Lee; Marian Kalocsay; David Gonzalez-Sanchez; Maria S Chancay; Kyle W McCracken; Nathan N Lee; Takaharu Ichimura; Yutaro Mori; M Todd Valerius; Julia Wilflingseder; Dario R Lemos; Elazer R Edelman; Joseph V Bonventre Journal: EMBO Rep Date: 2021-05-25 Impact factor: 9.071