Hepcidin and Anemia in Children: Mechanisms and Modifiers

描述（由申请人提供）：在1000万患有透析前慢性肾脏疾病（CKD）的美国患者中，贫血影响了一半以上，并与各种不良反应相关，包括死亡率和生活质量下降。在临床实践中，贫血对促红细胞生成素（ESA）治疗无效是很常见的。许多证据表明，慢性肾病伴治疗难治性贫血患者的ESA治疗升级会对健康产生不良影响。然而，在确定CKD中导致贫血的其他机制以确定安全有效的辅助治疗方面进展甚微。Hepcidin是一种由肝脏产生的抗微生物肽，它的产生是由炎症刺激的，它会干扰铁储存对红细胞生成的利用。hepcidin在CKD患儿贫血发展中的具体作用尚未有前瞻性研究。此外，新的证据表明，25-羟基维生素D （25D）缺乏是CKD贫血的一个新的危险因素，这可能是由于25D依赖性免疫调节所致。阻断可增加hepcidin生成的炎症刺激，可以通过铁补充和esa更有效地管理ckd相关性贫血。该研究的长期目标是确定hepcidin介导的机制对早期CKD贫血的贡献，并了解hepcidin的产生是否可以通过治疗干预来改变。该项目的具体目的是：(1)在美国国立卫生研究院资助的儿童慢性肾病（CKiD）前瞻性队列研究中确定血清hepcidin水平升高与血红蛋白和ESA低反应性之间的关系；(2)在透析前CKD儿童的前瞻性介入试验中评估麦角钙化醇（维生素D2）补充对血清hepcidin、血红蛋白和ESA剂量的影响。我们的中心假设是，在轻度至中度CKD中，血清hepcidin升高与贫血（由低血红蛋白定义）有关。此外，我们假设在CKD的情况下，补充麦角钙化醇将与血清hepcidin的降低和血红蛋白的增加有关。我们的假设是基于对维生素D， hepcidin和贫血的文献的广泛回顾，以及我们自己的初步数据，通过测量124名参加CKiD的儿童的血清hepcidin值，其中较高的hepcidin水平与贫血相关，以及对正常儿童的初步研究，显示低25D水平与贫血相关。提出观察和干预相结合的基本原理是加速我们对CKD贫血的生物学机制的理解，同时开发新的和创新的干预措施来治疗儿童CKD中常见的合并症。

DESCRIPTION (provided by applicant): Anemia affects over half of the 10 million Americans with pre-dialysis chronic kidney disease (CKD) and is associated with a variety of adverse effects including mortality and decreased quality of life. Anemia which does not respond to treatment with erythropoiesis stimulating agents (ESA) is common in clinical practice. Much evidence points to adverse health effects associated with escalation of ESA therapy in CKD patients with treatment resistant anemia. However, little progress has been made toward identifying other mechanisms which contribute to anemia in CKD in order to identify safe and effective adjunctive treatments. Hepcidin, an anti-microbial peptide produced by the liver, whose production is stimulated by inflammation, interferes with the utilization of iron stores for erythropoiesis. The specific contribution of hepcidin to the development of anemia in children with CKD has not been explored in a prospective manner. In addition, emerging evidence suggests that 25-hydroxy vitamin D (25D) deficiency is a novel risk factor for anemia in CKD, which may be due to 25D-dependent immunomodulation. Interruption of the inflammatory stimuli which increase hepcidin production could make the management of CKD-associated anemia with iron supplementation and ESAs more effective. The long-term goal of the proposed research is to define the contribution of hepcidin mediated mechanisms to the anemia of early CKD, and to understand whether hepcidin production may be modified by a therapeutic intervention. The Specific Aims of this project are to (1) define how elevated serum levels of hepcidin are associated with hemoglobin and ESA hypo-responsiveness within the established NIH funded Chronic Kidney Disease in Children (CKiD) prospective cohort study, and (2) to evaluate the effects of ergocalciferol (vitamin D2) supplementation on serum levels of hepcidin, hemoglobin, and ESA dose in a prospective interventional trial in children with pre-dialysis CKD. Our central hypothesis is that in mild to moderate CKD, elevated serum hepcidin is associated with anemia (as defined by low hemoglobin). Furthermore, we hypothesize that in the setting of CKD, supplementation with ergocalciferol will be associated with a decrease in serum hepcidin and increase in hemoglobin. Our hypotheses have been formulated on the basis of an extensive review of the literature on vitamin D, hepcidin and anemia, and our own preliminary data produced by measuring serum hepcidin values in 124 children enrolled in CKiD, in whom higher hepdidin levels are associated with anemia, and preliminary study of normal children showing low 25D levels associated with anemia. The rationale for the combination of observational and interventional approaches proposed is to accelerate our understanding of the biologic mechanisms contributing to the anemia of CKD and simultaneously to develop new and innovative interventions to treat this common co-morbidity in childhood CKD. PUBLIC HEALTH RELEVANCE: Anemia affects more than half of the over 10 million Americans with chronic kidney disease (CKD), and is associated with poor health outcomes including heart disease and death. Anemia in CKD is often resistant to current treatments, suggesting that there may be other causes of anemia in CKD that have yet to be identified. Definition of the relative contributions of specific pathways to anemia in CKD will identify future treatments for this anemia, with the long term goal of improving quality of life, and decreasing both overall illness and the cost of anemia treatment in the CKD population.