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: 8721943
• 负责人: MICHAEL E BRIER
• 金额: $ 45.74万
• 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/8721943
• 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.

描述(申请人提供)：促红细胞生成素(EPO)和促红细胞生成素(ESA)用于治疗超过90%的中心血液透析患者的慢性肾脏疾病贫血，每年花费约20亿美元。尽管有终末期肾病(ESRD)人群的贫血治疗方案，但很大一部分患者对典型剂量的EPO没有可预测的反应。最近几项旨在提高肾病贫血患者的血红蛋白(Hb)的随机对照试验发现了许多关于ESA贫血的治疗问题，这些问题以前在新药应用或后续研究中没有解决。呼吁为慢性肾脏病贫血患者建立最佳的Hb目标、剂量算法和监测方法。我们认为，我们对导致EPO耐药性的机制缺乏了解，阻碍了客观预测和设计贫血治疗的剂量算法的能力。我们认为这个问题最好用半经验方法来解决，这种方法使用EPO反应的替代标记和计算机指导的算法来实现特定的Hb目标范围和Hb水平的夸大振荡。我们研究的广泛的长期目标是通过在ESRD人群中开发更客观的、患者特有的EPO剂量方法来解决贫血个性化管理进展的关键障碍。我们实验室开发的数据表明，接受透析治疗的终末期肾病患者的特定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对EPO反应的分类比C反应蛋白和海普西丁更敏感和特异。我们假设特定的血清蛋白和多肽是EPO反应的候选替代生物标志物，并可用于改进现有的预测EPO反应指数的算法。我们提出了两个目标。目的1-我们建议在来自三个不同地理位置的中心登记的更多ESRD患者中验证选定的候选替代生物标记物。在这一目标中，我们将解决EPO抵抗的特征是Th1和Th2细胞因子表达改变的零假设，并解决血清多肽和蛋白质可以预测EPO反应性的假设。在目标2中，我们建议调查我们的替代生物标记物对EPO长期给药剂量预测的贡献，并将基于这些新生物标记物的模型与已建立的模型进行比较。使用我们之前发布并证明优于标准EPO剂量技术的新型模型预测控制(MPC)工具，我们将访问并整合经过验证的替代生物标记物，以开发用于ESA剂量的改进临床工具。