Novel biomarker validation and dosing algorithms for anemia management in ESRD

用于 ESRD 贫血管理的新型生物标志物验证和剂量算法

• 批准号: 8239234
• 负责人: MICHAEL E BRIER
• 金额: $ 59.07万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239234
• 关键词: Address; Algorithms; Anemia; Biological Markers; C-reactive protein; Chronic Kidney Failure; Clinical; Computer Assisted; Computers; Data; Decision Support Systems; Development; Dialysis procedure; Dose; End stage renal failure; Enrollment; Enzyme-Linked Immunosorbent Assay; Erythropoiesis; Erythropoietin; Goals; Grant; Hemodialysis; Hemoglobin; Hemoglobin concentration result; Inflammatory; Investigation; Iron; Kidney Diseases; Kidney Failure; Knowledge; Laboratories; Methods; Modeling; Monitor; Morbidity - disease rate; Nutritional status; Outcome; Overdose; Patients; Peptides; Pharmaceutical Preparations; Plasma; Population; Process; Protein Fragment; Proteins; Proteome; Protocols documentation; Publishing; Randomized Controlled Clinical Trials; Randomized Controlled Trials; Research; Resistance; Risk; Sensitivity and Specificity; Serum; Serum Proteins; Surrogate Markers; Techniques; Testing; Treatment outcome; Validation; base; cardiovascular risk factor; cost; cytokine; design; dosage; hepcidin; improved; indexing; mortality; novel; predictive modeling; prevent; response; tool; trend

DESCRIPTION (provided by applicant): Erythropoietin (EPO) and erythropoiesis-stimulating agents (ESAs) are used to treat the anemia of chronic renal disease in greater than 90% of all in-center hemodialysis patients at a cost of approximately 2 billion dollars per year. Despite protocols for anemia management in the end stage renal disease (ESRD) population, a large proportion of patients do not respond predictably to typical doses of EPO. Several recent randomized controlled trials looking to increase hemoglobin (Hb) in patients with the anemia of renal disease have uncovered many questions about the treatment of anemia with ESAs not previously addressed in new drug applications or in subsequent research. A call has been made for the establishment of the optimal Hb target, dosing algorithm, and monitoring approach for patients with anemia from chronic renal disease. We suggest that our poor understanding of the mechanisms leading to EPO resistance prevents the ability to objectively predict and design dosing algorithms for anemia management. We propose that this problem is best addressed with a semi-empirical method which uses surrogate markers of EPO responsiveness and computer-directed algorithms to achieve a specific Hb target range and to exaggerated oscillations in Hb levels. The broad-based long term goals of our research are to address a critical barrier to the progress with personalization of anemia management by developing more objective, patient specific approaches to EPO dosing in ESRD populations. Data developed in our labs suggests that the abundances of specific serum proteins and protein fragments correlate with EPO responsiveness in ESRD patients receiving dialysis therapy. These data suggest these proteins and protein fragments classify EPO response with more sensitivity and specificity than C-reactive protein and hepcidin. We hypothesize that specific serum proteins and peptides are candidate surrogate biomarkers for EPO responsiveness and can be used to improve existing algorithms for predictive EPO response indexing. We propose 2 aims. Aim 1 - We propose to validate selected candidate surrogate biomarkers in a larger population of ESRD patients enrolled from three geographically distinct centers. Within this aim we will address the null hypothesis that EPO resistance is characterized by altered expression of Th1- and Th2-cytokines, and address the hypothesis that serum peptides and proteins can predict EPO responsiveness. In Aim 2 - We propose to investigate the contribution of our surrogate biomarkers to dosage prediction in long-term administration of EPO and compare models base on these new biomarkers to established models. Using a novel Model Predictive Control (MPC) tool that we have previously published and demonstrated to be superior to standard EPO dosing techniques, we will access and incorporate the validated surrogate biomarkers to develop a refined clinical tool for dosing of ESAs. PUBLIC HEALTH RELEVANCE: The empirical treatment of anemia with erythropoiesis stimulating agents does not achieve optimal results in a significant number of end-stage renal disease patients receiving hemodialysis. Our laboratories have independently identified candidate surrogate serum biomarkers of erythropoiesis in end-stage renal disease hemodialysis patients that are associated with treatment outcome and have led the development and testing of computation methods for dosing of erythropoiesis stimulating agents. We propose to merge these two novel advances and determine their combined utility to improve erythropoiesis stimulating agent dosing in end-stage renal disease.

描述（由申请人提供）：促红细胞生成素（EPO）和促红细胞生成剂（ESA）用于治疗超过90%的中心血液透析患者的慢性肾病贫血，每年的费用约为20亿美元。尽管在终末期肾病（ESRD）人群中有贫血管理方案，但大部分患者对典型剂量的EPO没有可预测的反应。最近几项旨在增加肾病贫血患者血红蛋白（Hb）的随机对照试验发现了许多关于ESA治疗贫血的问题，这些问题以前在新药申请或后续研究中没有得到解决。人们呼吁为慢性肾病贫血患者建立最佳的血红蛋白目标、给药算法和监测方法。我们认为，我们对EPO耐药机制的认识不足，阻碍了客观预测和设计贫血管理的给药算法的能力。我们建议，这个问题是最好的解决与半经验的方法，使用替代标记的EPO的反应性和计算机指导的算法，以实现特定的Hb目标范围和夸张的Hb水平的振荡。我们研究的广泛的长期目标是通过开发更客观，患者特异性的ESRD人群EPO给药方法来解决贫血管理个性化进展的关键障碍。 我们实验室的数据表明，接受透析治疗的ESRD患者中特异性血清蛋白和蛋白片段的丰度与EPO反应性相关。这些数据表明，这些蛋白质和蛋白质片段分类EPO反应具有比C-反应蛋白和铁调素更高的灵敏度和特异性。我们假设特定的血清蛋白和肽是EPO反应性的候选替代生物标志物，并可用于改善现有的预测EPO反应指数的算法。我们提出两个目标。目的1 -我们建议在从三个地理位置不同的中心招募的更大的ESRD患者人群中验证选定的候选替代生物标志物。在这个目标，我们将解决的零假设，EPO抗性的特点是改变表达的Th 1和Th 2细胞因子，并解决假设，血清肽和蛋白质可以预测EPO的反应。在目标2中，我们提出研究我们的替代生物标志物对EPO长期给药中剂量预测的贡献，并将基于这些新生物标志物的模型与已建立的模型进行比较。使用一种新的模型预测控制（MPC）工具，我们以前已经发表，并证明是上级标准EPO给药技术，我们将访问和纳入验证的替代生物标志物，开发一个完善的临床工具，ESA的剂量。 公共卫生相关性：在大量接受血液透析的终末期肾病患者中，使用红细胞生成刺激剂经验性治疗贫血并未达到最佳效果。我们的实验室已经独立鉴定了终末期肾病血液透析患者红细胞生成的候选替代血清生物标志物，这些生物标志物与治疗结果相关，并领导了红细胞生成刺激剂给药计算方法的开发和测试。我们建议合并这两个新的进展，并确定其联合效用，以提高终末期肾病红细胞生成刺激剂的剂量。