Novel biomarker validation and dosing algorithms for anemia management in ESRD

描述（由申请人提供）：促红细胞生成素（EPO）和促红细胞生成素刺激剂（esa）用于治疗90%以上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。尽管在终末期肾病（ESRD）人群中有贫血管理方案，但很大一部分患者对典型剂量的EPO没有可预测的反应。最近的几项随机对照试验旨在增加肾病贫血患者的血红蛋白（Hb），这些试验揭示了许多关于用esa治疗贫血的问题，这些问题以前在新药应用或后续研究中没有得到解决。呼吁建立慢性肾脏疾病贫血患者的最佳血红蛋白靶点、给药算法和监测方法。我们认为，我们对导致EPO耐药机制的理解不足，妨碍了客观预测和设计贫血管理的给药算法的能力。我们建议最好使用半经验方法来解决这个问题，该方法使用EPO响应性的替代标记和计算机定向算法来实现特定的Hb目标范围和Hb水平的夸张振荡。我们研究的广泛的长期目标是通过开发更客观的、针对ESRD人群的EPO给药方法来解决个性化贫血管理进展的关键障碍。我们实验室开发的数据表明，在接受透析治疗的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，与c反应蛋白和hepcidin相比，这些蛋白和蛋白片段对EPO反应的分类具有更高的敏感性和特异性。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，可用于改进现有的EPO反应预测索引算法。我们提出了两个目标。目的1：我们建议在三个地理位置不同的中心招募的ESRD患者中验证选定的候选替代生物标志物。在这一目标中，我们将解决EPO耐药以Th1-和th2细胞因子表达改变为特征的零假设，并解决血清肽和蛋白质可以预测EPO反应性的假设。在目标2中，我们建议研究替代生物标志物对EPO长期给药剂量预测的贡献，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。使用我们之前发表并证明优于标准EPO给药技术的新型模型预测控制（MPC）工具，我们将访问并合并经过验证的替代生物标志物，以开发一种精细的esa给药临床工具。

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.