Hepcidin and Anemia in Children: Mechanisms and Modifiers

描述(申请人提供)：贫血影响超过一半的1000万美国透析前慢性肾脏疾病(CKD)患者，并与包括死亡率和生活质量下降在内的各种不良反应有关。贫血是一种对促红细胞生成剂(ESA)治疗无效的疾病，在临床上很常见。许多证据表明，对患有难治性贫血的CKD患者，升级ESA治疗会对健康产生不利影响。然而，为了确定安全有效的辅助治疗，在确定其他导致慢性肾脏病贫血的机制方面进展甚微。海普西丁是一种由肝脏产生的抗菌肽，其产生受到炎症的刺激，干扰了铁储存用于红细胞生成的利用。海普西丁在CKD儿童贫血发生中的具体作用尚未有前瞻性的探讨。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依赖的免疫调节所致。阻断增加海普西丁产生的炎性刺激可以使补铁和ESA更有效地治疗CKD相关性贫血。这项拟议研究的长期目标是确定海普西丁介导的机制在早期CKD贫血中的作用，并了解是否可以通过治疗干预来改变海普西丁的产生。该项目的具体目标是：(1)在已建立的国立卫生研究院资助的儿童慢性肾脏病(CKiD)前瞻性队列研究中，明确血清中升高的海普西丁水平与血红蛋白和ESA低反应性之间的关系，以及(2)在一项前瞻性干预试验中，评估补充麦角钙醇(维生素D2)对透析前慢性肾脏病儿童血清中海普西丁、血红蛋白和ESA剂量的影响。我们的中心假设是，在轻到中度的CKD中，血清海普西丁升高与贫血(定义为低血红蛋白)有关。此外，我们假设在慢性肾脏病的情况下，补充麦角钙化醇将与血清海普西丁的降低和血红蛋白的增加相关。我们的假设是基于对维生素D、海普西丁和贫血文献的广泛回顾，以及我们自己的初步数据，这些数据是通过测量124名登记在CKiD中的儿童的血清海普西丁值而产生的，在这些儿童中，较高的海普丁水平与贫血有关，而对正常儿童的初步研究显示，25D水平较低与贫血相关。提出观察性和干预性方法相结合的基本原理是为了促进我们对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中的这种常见的共病。

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.