Department of Medicine and Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
Service of Nephrology, Department of Medicine, Geneva University Hospitals, Geneva, Switzerland.
J Am Soc Nephrol. 2022 Apr;33(4):810-827. doi: 10.1681/ASN.2021050680. Epub 2022 Mar 10.
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.
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.
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.
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.
慢性肾脏病（CKD）与肾小管功能改变有关。在禁食期间，肾脏糖异生负责全身糖异生的 40%，但 CKD 如何以及为何影响这一过程，以及这种调节的后果尚不清楚。
我们使用了超过 200 例 CKD 患者和 43 例肾移植患者的肾脏糖异生途径数据，并研究了三种小鼠模型，即蛋白尿性 CKD（POD-ATTAC）、缺血性 CKD 和单侧尿路梗阻。我们分析了受益于肾脏导管插入术的患者队列和住院重症监护病房的患者回顾性队列。
CKD 和肾移植患者的肾脏活检显示，肾脏糖异生途径呈阶段性下降。两种 CKD 动物模型和一种肾脏纤维化模型证实了受损近端肾小管细胞中的糖异生下调。这种转变导致在外源乳酸负荷下，肾脏葡萄糖生成和乳酸清除发生改变。动物模型中的离体灌注肾脏技术和 CKD 患者的肾静脉导管插入术证实了肾脏葡萄糖生成和乳酸清除的减少。在重症监护病房住院的 CKD 患者中，系统葡萄糖和乳酸水平的改变更为普遍，与死亡率增加和随访时肾功能预后恶化相关。糖异生途径及其调节剂的表达减少预测了肾移植活检中肾脏疾病的组织学进展更快。
CKD 患者的肾脏糖异生功能受损。肾脏糖异生的改变导致系统代谢变化，葡萄糖减少，乳酸水平增加，并与肾脏预后恶化相关。
