Hepcidin and Anemia in Children: Mechanisms and Modifiers

铁调素和儿童贫血：机制和调节因素

• 批准号: 8262155
• 负责人: Meredith Ann Atkinson
• 金额: $ 17.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262155
• 关键词: Achievement; Adult; Adverse effects; Affect; American; Anemia; Canada; Cessation of life; Child; Childhood; Chronic Kidney Failure; Clinical Research; Clinical Trials; Cohort Studies; Comorbidity; Cost of Illness; Data; Development; Dialysis procedure; Dose; Effectiveness; Enrollment; Ergocalciferols; Erythropoiesis; Erythropoietin; Funding; Future; Glomerular Filtration Rate; Goals; Health; Heart Diseases; Hemoglobin; Hemoglobin concentration result; High Prevalence; Immune system; Inflammation; Inflammatory; Interruption; Intervention; Iron; K-Series Research Career Programs; Kidney; Left Ventricular Hypertrophy; Literature; Liver; Measures; Mediating; Metabolism; Methods; Nutritional; Oral; Outcome; Pathway interactions; Patients; Peptides; Population; Production; Quality of life; Randomized Controlled Clinical Trials; Recruitment Activity; Relative (related person); Renal clearance function; Research; Resistance; Review Literature; Risk Factors; Serum; Staging; Stimulus; Supplementation; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Training; United States National Institutes of Health; Vitamin D; Vitamin D Deficiency; Vitamin D2; adaptive immunity; antimicrobial; base; clinical practice; cohort; cytokine; defined contribution; design; follow-up; hepcidin; immunoregulation; improved; innovation; iron deficiency; iron supplementation; mortality; novel; pilot trial; prospective; public health relevance

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.

描述（由申请人提供）：在1000万美国透析前慢性肾病（CKD）患者中，有一半以上的人患有贫血，贫血与多种不良反应有关，包括死亡率和生活质量下降。对红细胞生成刺激剂（ESA）治疗无反应的贫血在临床实践中很常见。许多证据表明，在患有难治性贫血的CKD患者中，ESA治疗的递增与不良健康影响相关。然而，在确定导致CKD贫血的其他机制以确定安全有效的预防性治疗方面几乎没有取得进展。铁调素是一种由肝脏产生的抗微生物肽，其产生受炎症刺激，干扰红细胞生成对铁储存的利用。铁调素对CKD儿童贫血发生的具体作用尚未进行前瞻性研究。此外，新出现的证据表明，25-羟基维生素D（25 D）缺乏是CKD贫血的一个新的风险因素，这可能是由于25 D依赖性免疫调节。中断增加铁调素产生的炎症刺激可以使补铁和ESA更有效地管理CKD相关性贫血。拟议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。本项目的具体目的是（1）在已建立的NIH资助的儿童慢性肾病（CKiD）前瞻性队列研究中，确定血清铁调素水平升高与血红蛋白和ESA低反应性的相关性，以及（2）评价麦角钙化醇的作用在透析前CKD儿童的一项前瞻性干预性试验中，补充维生素D2对血清铁调素、血红蛋白和ESA剂量水平的影响。我们的中心假设是，在轻度至中度CKD，血清铁调素升高与贫血（定义为低血红蛋白）。此外，我们假设在CKD的情况下，补充麦角钙化醇将与血清铁调素的降低和血红蛋白的增加相关。我们的假设已经制定的基础上广泛审查的文献维生素D，hepcidin和贫血，我们自己的初步数据，通过测量血清hepcidin值在124名儿童参加CKiD，其中较高的hepcidin水平与贫血，和正常儿童的初步研究显示低25 D水平与贫血。提出的观察性和干预性方法相结合的基本原理是加速我们对导致CKD贫血的生物学机制的理解，同时开发新的创新干预措施来治疗儿童CKD中的这种常见合并症。 公共卫生相关性：贫血影响着超过1000万美国慢性肾脏疾病（CKD）患者中的一半以上，并与心脏病和死亡等不良健康结果相关。CKD贫血通常对目前的治疗有抵抗力，这表明CKD贫血可能有其他原因尚未确定。确定CKD贫血的特定途径的相对贡献将确定这种贫血的未来治疗方法，长期目标是改善生活质量，降低CKD人群的总体疾病和贫血治疗费用。