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.

退伍军人患心血管 (CV)、糖尿病和慢性肾病的风险显着增加 疾病（CKD）与一般人群的比较。最近有人提出铁稳态异常 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 CKD 中非常普遍，但其系统性造血外后果，包括糖尿病、肾脏和心血管疾病 风险，尚未调查。在 CKD 中，炎症信号的诱导会增加铁调素（hepcidin），这是一个关键因素 肝铁调节剂，防止口服铁吸收和网状内皮细胞铁的动员 商店。通过减少可用的循环铁，铁调素可能介导功能性铁的发育 缺乏症（FID），其中铁与红系前体细胞和其他细胞类型的结合不足 尽管体内铁储备充足。因此，FID 的特点是血清转铁蛋白饱和度 (Tsat) 低， 反映细胞摄取的可用血浆铁减少，铁蛋白增加，反映总铁充足 身体铁商店。鉴于铁不仅对红细胞生成至关重要，而且对线粒体能量也至关重要 新陈代谢，高代谢器官铁供应不足可能导致一系列不良的全身性疾病 影响。虽然贫血是 FID 最常见的临床后果，但其对其他器官的影响却从未出现过。 在 CKD 人群中进行了评估。 我们假设 CKD 中铁调素诱导的 FID 导致 (1) 组织水平缺铁， 最依赖线粒体氧化能力的高代谢器官衰竭的风险增加，例如 如心脏和肾脏，以及（2）由于与以下疾病相关的胰岛素抵抗而增加新发糖尿病的风险 肌肉线粒体呼吸不足。缺乏对造血系统外后果的了解 CKD 中的 FID 导致了对贫血管理的单一关注，而不考虑其对其他疾病的潜在危害 器官。因此，当前标准的 CKD 管理在没有明显证据的情况下不会评估铁状态。 贫血。然而，在没有贫血的情况下缺铁与显着的死亡风险相关。 心脏衰竭。此外，尚未开发出定义 FID 的 Tsat 和铁蛋白联合阈值来预测 CKD 中的造血外临床事件，削弱了临床医生准确诊断的能力 问题。此外，铁调素与 FID 的关系尚未在大型 CKD 队列中得到表征。 提高对铁在 CKD 全身并发症中作用的认识对于开发更多铁剂至关重要。 风险分层和确定创新治疗目标的综合策略。 我们建议使用两项观察性研究来解决上述知识差距，其中涉及（1） 使用退伍军人事务信息学和计算基础设施 (VINCI) 数据的历史队列和 (2) 来自 NIDDK 资助的慢性肾功能不全队列的补充前瞻性队列 (CRIC)，一项自 2003 年以来对 3,939 名 CKD 患者进行的纵向观察研究，并提供了可用的生物样本。 建议使用 CRIC 的生物样本来测量血清铁调素和铁指数。使用这些检测 根据 CRIC 的结果以及 CRIC 和 VINCI 的纵向数据，我们将评估 FID 的关系 和铁调素对两个队列中肾脏、糖尿病和心血管结局的影响。 VINCI 提供强大的统计能力 探索 Tsat 和铁蛋白定义 FID 的联合阈值，并评估 FID 和铁蛋白之间的关联 临床风险，与退伍军人健康直接相关。 CRIC 允许将 VINCI 结果应用于 独立队列来识别 FID 并探索铁调素的作用，这是 VINCI 无法提供的。 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，以及 (ii) FID 和铁调素在 CKD 的肾脏、糖尿病和心血管并发症中的作用。我们的积极发现 研究将确定铁状态和铁调素作为新的可改变的风险因素，有可能影响当前的 CKD 实践，在没有明显贫血的情况下不评估铁状态。