The role of functional iron deficiency in systemic complications of CKD

功能性缺铁在 CKD 全身并发症中的作用

• 批准号: 10292417
• 负责人: MONIQUE Eun Hee CHO
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292417
• 关键词: Address; Anemia; Anemia due to Chronic Disorder; Biological Assay; Cardiovascular Diseases; Cardiovascular system; Cell physiology; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Clinical Trials; DNA; Data; Development; Diabetes Mellitus; Dialysis procedure; Disease; Disease Management; End stage renal failure; Energy Metabolism; Erythroid; Erythropoiesis; Event; Failure; Ferritin; Future; General Population; Goals; Health; Heart; Heart failure; Hematopoietic; Hemoglobin; Hepatic; Homeostasis; Inflammatory; Informatics; Infrastructure; Insulin Resistance; Intravenous; Iron; Iron Metabolism Disorders; Joints; Kidney; Knowledge; Lead; Longitudinal observational study; Measures; Mediating; Metabolic; Metabolic Diseases; Mitochondria; Muscle Mitochondria; Myocardium; National Institute of Diabetes and Digestive and Kidney Diseases; Observational Study; Oral; Organ; Organ failure; Outcome; Pathogenesis; Pathway interactions; Patients; Physiological; Plasma; Play; Population; Prospective cohort; Respiration; Risk; Risk Factors; Role; Safety; Serum; Signal Transduction; Therapeutic; Tissues; Transferrin; United States Department of Veterans Affairs; Veterans; accurate diagnosis; base; cardiovascular effects; cardiovascular risk factor; cell type; clinical development; clinical investigation; clinical risk; cofactor; cohort; diabetes risk; diabetic; hepcidin; improved; indexing; innovation; iron absorption; iron deficiency; modifiable risk; mortality; mortality risk; novel; oxidation; prevent; risk stratification; therapeutic target; therapy development; uptake

Veterans have disproportionately increased risks for cardiovascular (CV), diabetic, and chronic kidney diseases (CKD) compared to the general population. Abnormal iron homeostasis has recently been suggested to play a critical role in the pathogenesis of various metabolic and CV disorders. Iron metabolism disorder is highly prevalent in CKD, but its systemic extra-hematopoietic consequences, including diabetic, renal, and CV risks, have not been investigated. In CKD, induction of inflammatory signaling increases hepcidin, a key hepatic iron regulator which prevents oral iron absorption and mobilization of iron from reticuloendothelial stores. By reducing available circulating iron, hepcidin likely mediates the development of functional iron deficiency (FID), in which insufficient iron incorporation into erythroid precursors and other cell types occurs despite adequate body iron stores. Thus, FID is characterized by low serum transferrin saturation (Tsat), reflecting reduced available plasma iron for cellular uptake, and increased ferritin, reflecting adequate total body iron stores. Given that iron is essential not only for erythropoiesis but also for mitochondrial energy metabolism, inadequate iron supply to highly metabolic organs could lead to a wide range of adverse systemic effects. While anemia is the most recognized clinical consequence of FID, its effect on other organs has never been assessed in the CKD population. We hypothesize that hepcidin-induced FID in CKD leads to (1) iron deficiency at the tissue level, with increased risk for failure of highly metabolic organs most dependent on mitochondrial oxidative capacity, such as heart and kidney, and (2) enhanced new-onset diabetes risk due to insulin resistance associated with inadequate muscle mitochondrial respiration. The lack of knowledge on extra-hematopoietic consequences of FID in CKD has led to a singular focus on anemia management without regard to its potential harm to other organs. The current standard CKD management thus does not evaluate iron status in the absence of obvious anemia. Yet, iron deficiency without the presence of anemia has been associated with marked mortality risk in heart failure. Moreover, the joint thresholds of Tsat and ferritin defining FID have not been developed to predict extra-hematopoietic clinical events in CKD, undermining the ability of clinicians to accurately diagnose the problem. In addition, the relationship of hepcidin with FID has not been characterized in a large CKD cohort. Improved knowledge of the role of iron in systemic complications of CKD is critical to developing a more integrated strategy for risk stratification and identifying innovative therapeutic targets. We propose to address the above knowledge gap using two observational studies involving (1) a historical cohort using data from the Veterans Affairs Informatics and Computing Infrastructure (VINCI) and (2) a complementary prospective cohort from the ongoing NIDDK-sponsored Chronic Renal Insufficiency Cohort (CRIC), a longitudinal observational study of 3,939 CKD patients with available biospecimens since 2003. We propose to access biospecimens from CRIC to measure serum hepcidin and iron indices. Using these assay results from CRIC and longitudinal data from both CRIC and VINCI, we will evaluate the relationship of FID and hepcidin with renal, diabetic, and CV outcomes in both cohorts. VINCI provides large statistical power to explore the joint thresholds of Tsat and ferritin defining FID and to evaluate the association between FID and clinical risks, with direct relevance to Veteran health. CRIC allows the ability to apply the VINCI results in an independent cohort to identify FID and to explore the role of hepcidin, which is not available through VINCI. This is the first study to examine (i) the iron thresholds defining FID most associated with heart failure risk and (ii) the role of FID and hepcidin in the renal, diabetic and CV complications of CKD. Positive findings from our study will identify iron status and hepcidin as novel modifiable risk factors with the potential to impact current CKD practice, which does not assess iron status in the absence of obvious anemia.

退伍军人患心血管疾病、糖尿病和慢性肾脏疾病的风险增加得不成比例 与普通人群相比，疾病(CKD)的发病率更高。最近有人提出了铁稳态异常的说法 在各种代谢和心血管疾病的发病机制中发挥关键作用。铁代谢紊乱是 在慢性肾脏病中非常常见，但它的全身性造血外后果，包括糖尿病、肾脏和心血管疾病 风险，还没有被调查。在CKD中，炎症信号的诱导增加了海普西丁，这是一个关键 肝铁调节剂阻止口服铁吸收和网状内皮铁动员 商店。通过减少有效循环铁，海普西丁可能调节功能铁的发展。 缺乏(FID)，即红系前体细胞和其他细胞类型的铁结合不足 尽管体内有足够的铁储备。因此，FID的特点是血清转铁蛋白饱和度(TSAT)低， 反映可用于细胞摄取的血浆铁减少，以及铁蛋白增加，反映足够的总 身体铁储藏室。鉴于铁不仅对红细胞生成是必需的，而且对线粒体能量也是必不可少的 新陈代谢，高代谢器官的铁供应不足可能导致广泛的不良全身性 效果。虽然贫血是FID最公认的临床后果，但它对其他器官的影响从未 在慢性肾脏病人群中进行了评估。 我们假设，海普西丁诱导的慢性肾脏病的FID导致(1)组织水平的铁缺乏， 主要依赖线粒体氧化能力的高代谢器官衰竭的风险增加，如 如心脏和肾脏，以及(2)由于与以下因素相关的胰岛素抵抗而增加的新发糖尿病风险 肌肉线粒体呼吸不足。对血液病的超外造血后果缺乏了解 CKD的FID导致了对贫血管理的单一关注，而没有考虑它对其他人的潜在危害 器官。因此，当前标准的CKD管理在缺乏明显的情况下不评估铁的状态 贫血。然而，缺铁而不伴有贫血与显著的死亡风险有关。 心力衰竭。此外，还没有建立TSAT和铁蛋白定义FID的联合阈值来预测 CKD中的造血外临床事件，破坏了临床医生准确诊断 有问题。此外，海普西丁与FID的关系还没有在一个大的CKD队列中得到表征。 提高对铁在慢性肾脏病全身并发症中的作用的认识对于开发更多的 风险分层和确定创新治疗靶点的综合战略。 我们建议通过两项观察性研究来解决上述知识差距，这些研究涉及(1)a 使用退伍军人事务部信息学和计算基础设施(Vinci)和(2)数据的历史队列 正在进行的NIDDK赞助的慢性肾功能不全队列的补充性前瞻性队列 (CRIC)，这是一项自2003年以来对3939名使用生物显微镜的CKD患者进行的纵向观察研究。我们 建议从CRIC获取生物检验品，以测量血清中的肝素和铁指数。使用这些化验 来自CRIC的结果以及CRIC和Vinci的纵向数据，我们将评估FID的关系 在两个队列中，海普西丁与肾脏、糖尿病和心血管疾病的结局有关。芬奇提供了强大的统计能力 探讨TSAT和铁蛋白定义FID的联合阈值，并评估FID和FID之间的关联 临床风险，与退伍军人健康直接相关。CRIC允许将芬奇结果应用于 确定FID并探索海普西丁的作用的独立队列，这是芬奇无法获得的。 这是第一项研究：(I)定义FID的铁阈值与心力衰竭风险和 (Ii)FID和海普西丁在CKD的肾脏、糖尿病和心血管并发症中的作用。来自我们的积极调查结果 研究将确定铁状态和海普西丁是潜在影响电流的新的可改变的危险因素 CKD实践，在没有明显贫血的情况下不评估铁的状况。