The role of functional iron deficiency in systemic complications of CKD

退伍军人患心血管疾病（CV）、糖尿病和慢性肾病的风险不成比例地增加 与普通人群相比，CKD的发病率更高。最近有人提出， 在各种代谢和CV疾病的发病机制中发挥关键作用。铁代谢紊乱是 在CKD中高度流行，但其系统性造血外后果，包括糖尿病、肾脏和CV 风险，尚未调查。在CKD中，炎症信号的诱导增加了铁调素，这是一个关键因素。 防止口服铁吸收和铁从网状内皮动员的肝铁调节剂 店铁调素可能通过减少循环中的铁来介导功能性铁的形成 铁缺乏症（FID），其中红系前体细胞和其他细胞类型中的铁掺入不足 尽管体内有足够的铁储备因此，FID的特征在于低血清转铁蛋白饱和度（Tsat）， 反映了用于细胞摄取的可用血浆铁减少，以及铁蛋白增加，反映了足够的总铁 体内铁储存。鉴于铁不仅对红细胞生成至关重要，而且对线粒体能量也至关重要， 在高代谢器官中，铁供应不足可能导致广泛的全身不良反应。 方面的影响.虽然贫血是FID最公认的临床后果，但其对其他器官的影响从未被发现。 在CKD人群中进行评估。 我们假设铁调素诱导的FID导致（1）组织水平的铁缺乏， 最依赖于线粒体氧化能力的高代谢器官衰竭的风险增加， 心脏和肾脏，以及（2）由于与胰岛素抵抗相关的新发糖尿病风险增加 肌肉线粒体呼吸不足。缺乏对造血外后果的认识， 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。 机关因此，当前标准CKD管理在缺乏明显的铁缺乏的情况下不能评估铁状态。 贫血然而，不存在贫血的铁缺乏与老年人显著的死亡风险有关。 心衰此外，Tsat和铁蛋白定义FID的联合阈值尚未开发以预测 CKD中的造血外临床事件，削弱了临床医生准确诊断 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系统性并发症中作用的认识对于开发一种更有效的治疗方法至关重要。 风险分层和确定创新治疗靶点的综合策略。 我们建议通过两项观察性研究来解决上述知识差距，涉及（1）a 使用退伍军人事务信息学和计算基础设施（VINCI）的数据的历史队列和（2） 来自正在进行的NIDDK申办的慢性肾功能不全队列的补充前瞻性队列 （CRIC），这是一项自2003年以来对3，939例具有可用生物标本的CKD患者进行的纵向观察性研究。我们 建议从CRIC获取生物样本，以测量血清铁调素和铁指数。使用这些分析 结合CRIC和VINCI的纵向数据，我们将评估FID的关系 和铁调素在两个队列中与肾脏、糖尿病和CV结局的关系。VINCI提供了很大的统计功效， 探索Tsat和铁蛋白定义FID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允许将VINCI结果应用于 独立的队列，以确定FID和探讨hepcidin的作用，这是不能通过VINCI。 这是第一项研究，以检查（i）铁阈值定义FID最相关的心力衰竭风险， (ii)FID和铁调素在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，有可能影响目前的 CKD实践，在没有明显贫血的情况下不评估铁状态。

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.