Systems biology approach to the management of chronic kidney disease-mineral bone disorder

与非退伍军人相比，退伍军人患肾脏疾病的风险更高。 心血管疾病和骨病是终末期肾病退伍军人死亡的两大原因 (ESRD)由矿物质代谢异常引起。特别是，矿物质和骨骼疾病(MBD)是一种 慢性肾脏病(CKD)和终末期肾病(ESRD)的常见并发症。这个 退伍军人ESRD人群中MBD的多因素特性使得对其进行有效的管理 情况复杂。适当的管理需要维持血清钙、磷和完好无损 甲状旁腺激素水平在国际工作组通过饮食咨询制定和完善的指导方针内， 磷酸盐结合剂、活性维生素D类似物、钙感受器激动剂和甲状旁腺切除术。 每个患者每个参数的目标目标的实现都是难以实现的，尽管研究已经 证明了实现所有三个参数的预期指导目标与较低的 心血管风险。需要检验的假设是，实现指导方针的成功率 通过对矿物质代谢的系统生物学建模，可以改进和更好地了解MMD管理 以及开发一种个性化的算法，用于当前每种疗法的处方。基础广泛的 这项研究的长期目标是解决取得进展的关键技术障碍 个性化的MBD管理，从而改善退伍军人患者的心血管和骨骼预后。 这方面的初步工作已经证明了系统生物学建模方法在 达到既定的临床指南。目前对这些退伍军人患者的护理是基于一项试验和 错误进场。理想情况下，MDB的多个药物的剂量应该根据对每个药物的个别反应来指导 这些特工。为了应对上述挑战，一种系统生物学方法来模拟复杂的 无序，MBD有利用价值。假设先进的计算技术可以 用于指导MBD中使用的试剂的最佳剂量。实现这一目标计划是 在这五个具体目标中概述： 1.代谢性骨病QSP-SB模型的建立 2.药物配药和血液透析模型的建立 3.开发从CPRS获得的临床数据数据库。 4.用于CKD-MBD的剂量算法和临床工具的开发 管理层。 5.开发的MBD-CKD配药算法和工具在中心进行测试 血液透析患者。 将对广泛的、包容的退伍军人群体进行研究，以开发这些新的剂量算法。改进 个体化控制钙、磷和甲状旁腺素可提高心血管死亡率 当达到推荐浓度时。这些工具将导致药物剂量的提高 对于慢性疾病，将适用于骨骼疾病以外的领域，并在 每一位患有肾病的退伍军人的健康状况。

Veterans are at an increased risk of kidney disease compared to the non-Veteran US population. Cardiovascular and bone disease are two major causes of death in Veterans with end stage renal disease (ESRD) resulting from abnormal mineral metabolism. Specifically, Mineral and Bone Disorder (MBD) is a universal complication of Chronic Kidney Disease (CKD) and End-Stage Renal Disease (ESRD). The multifactorial nature of MBD in the Veteran ESRD population makes the effective management of this condition complex. Proper management entails the maintenance of serum calcium, phosphorus, and intact PTH levels within guidelines established and refined by international working groups using dietary counseling, phosphate binders, active vitamin D analogues, calcium sensing receptor agonists, and parathyroidectomy. Achievement of the target goals for each parameter in every patient has been elusive, though studies have demonstrated that attainment of the desired guideline goals for all three parameters is associated with lower cardiovascular risk. The hypothesis to be tested is that the success rate in achievement of the guidelines for MBD management can be improved and better informed by systems biology modeling of mineral metabolism and development of a personalized algorithm for prescription of each of the current therapies. The broad-based long term goal of this research endeavor is to address critical technological barriers to the progress of personalized MBD management thus improving cardiovascular and bone outcomes in Veteran patients. Preliminary work in this area has demonstrated the feasibility of the systems biology modeling approach to the achievement of established clinical guidelines. Current care of these Veteran Patients is based in a trial and error approach. Ideally, dosing of multiple agents for MDB should be guided by individual response to each of these agents. To address the challenges outlined above, a systems biology approach to modeling the complex disorder, MBD with be utilized. The hypothesis is that advanced computational techniques can be used to optimally guide dosing of the agents used in MBD. The plan to accomplish this objective are outlined in these five specific aims: 1. Development of a QSP-SB model for metabolic bone disorder. 2. Development of a drug dosing and hemodialysis model 3. Development of a database of clinically derived data obtained from CPRS. 4. Development of a dosing algorithm and a clinical tool used for CKD-MBD management. 5. Testing of the developed MBD-CKD dosing algorithm and tool in in-center hemodialysis patients. A broad, inclusive, population of Veterans will be studied to develop these novel dosing algorithms. Improved individualized control of calcium, phosphorus, and PTH has been shown to improve cardiovascular mortality when recommended concentrations are achieved. These tools will result in an advance in the dosing of drugs for chronic conditions that will be applicable to areas other than bone disease and an improvement in the health of each individual Veteran with kidney disease.