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: 10701057
• 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 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10701057
• 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; Longitudinal, observational study; Measures; Mediating; Metabolic; Metabolic Diseases; Mitochondria; Muscle; Muscle Mitochondria; National Institute of Diabetes and Digestive and Kidney Diseases; Observational Study; Oral; Organ; Organ failure; Outcome; Pathogenesis; Pathway interactions; Patients; Persons; 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; 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.

退伍军人的心血管（CV），糖尿病和慢性肾脏的风险不成比例 与普通人群相比，疾病（CKD）。最近提出了异常铁稳态 在各种代谢和简历疾病的发病机理中发挥关键作用。铁代谢障碍是 在CKD中极为普遍，但其系统性的超大型造成后果，包括糖尿病，肾脏和CV 风险，尚未调查。在CKD中，炎症信号传导的诱导增加了肝素，这是钥匙 肝铁调节剂可防止口服铁的吸收和动员铁网状内皮 商店。通过减少可用的循环铁，肝素可能介导功能铁的发展 缺陷（FID），其中不足的铁掺入红细胞前体和其他细胞类型发生 尽管有足够的人体铁储存。因此，FID的特征是低血清转铁蛋白饱和（TSAT）， 反映可减少可用的血浆铁可用于细胞摄取，并增加铁蛋白，反映出足够的总 人体铁储存。鉴于铁不仅对红细胞生成至关重要，而且对线粒体能量也是必不可少的 代谢，对高度代谢器官的铁供应不足可能导致广泛的不良系统性 效果。尽管贫血是FID最公认的临床后果，但其对其他器官的影响从未 在CKD人群中进行了评估。 我们假设Hepcidin诱导的CKD中的FID导致（1）在组织水平上的铁缺乏症，并且 高度代谢器官失败的风险最大，最依赖于线粒体氧化能力，这样 作为心脏和肾脏，以及（2）由于与 肌肉线粒体呼吸不足。缺乏对额外细胞质的后果的知识 CKD中的FID导致了对贫血管理的奇异关注，而无需考虑其对其他人的潜在伤害 器官。因此，当前的标准CKD管理不会在没有明显的情况下评估铁状态 贫血。然而，没有贫血而没有贫血的铁缺乏症与死亡率的显着风险有关 心脏衰竭。此外，尚未开发出TSAT和铁蛋白定义FID的联合阈值以预测 CKD中的细胞质外临床事件，破坏了临床医生准确诊断的能力 问题。此外，在大型CKD队列中尚未表征肝素与FID的关系。 提高了对铁在CKD系统并发症中的作用的了解对于开发更多 风险分层的综合策略并确定创新的治疗靶标。 我们建议使用涉及（1）A的两项观察性研究来解决上述知识差距 使用退伍军人事务信息学和计算基础设施（VINCI）和（2）的历史群体 来自正在进行的NIDDK赞助的慢性肾功能不全队列的互补前瞻性队列 （CRIC），一项自2003年以来的3,939例CKD患者的纵向观察研究。 提议从CRIC中获取生物测量，以测量血清肝素和铁指数。使用这些测定 来自CRIC和VINCI的CRIC和纵向数据的结果，我们将评估FID的关系 在两个队列中，都有肾脏，糖尿病和CV结果的肝素。 Vinci为 探索定义FID的TSAT和铁蛋白的联合阈值，并评估FID与 临床风险，与退伍军人健康直接相关。 CRIC允许使用Vinci的能力导致 独立的队列识别FID并探索肝素的作用，这是通过Vinci获得的。 这是第一项研究（i）定义与心力衰竭风险最相关的FID的铁阈值和 （ii）FID和肝素在CKD的肾脏，糖尿病和CV并发症中的作用。我们的积极发现 研究将识别铁状态和肝素素是新的可修改风险因素，并可能影响电流 CKD实践，在没有明显的贫血的情况下无法评估铁地位。