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

治疗慢性肾病-矿物质性骨病的系统生物学方法

• 批准号: 10310403
• 负责人: ELEANOR D LEDERER
• 金额: --
• 依托单位: VA NORTH TEXAS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310403
• 关键词: Achievement; Address; Adult; Agonist; Algorithmic Software; Algorithms; Anemia; Area; Biological Models; Bone Diseases; Calcium; Calcium-Sensing Receptors; Cardiovascular Diseases; Cardiovascular system; Caring; Cause of Death; Cessation of life; Chronic; Chronic Kidney Failure; Clinical; Clinical Decision Support Systems; Clinical Practice Guideline; Complex; Complication; Computational Technique; Computerized Medical Record; Computers; Consensus; Counseling; Data; Development; Dialysis procedure; Disease; Disease Management; Dose; Drug usage; End stage renal failure; Equation; Evaluation; Funding; Goals; Guidelines; Health; Hemodialysis; Hypertension; Immunosuppression; Individual; International; Kidney Diseases; Literature; Maintenance; Medical; Metabolic Bone Diseases; Metabolic Pathway; Metabolism; Minerals; Minority; Modeling; Monitor; Morbidity - disease rate; Nature; Osteoporosis; Outcome; Parathyroidectomy; Patients; Pharmaceutical Preparations; Pharmacology; Phosphorus; Plant Roots; Population; Publishing; Regulation; Renal function; Research; Risk; Series; Serum; Special Population; System; Systems Biology; Techniques; Testing; Therapeutic; Translating; United States Department of Veterans Affairs; United States National Institutes of Health; Veterans; Vitamin D; Vitamin D Analog; Work; base; bone; bone turnover; calcification; cardiovascular risk factor; clinical database; clinical practice; comorbidity; computerized tools; cost; cost effective; dietary; dose information; first-in-human; glycemic control; improved; individual response; individualized medicine; inorganic phosphate; military veteran; mimetics; mortality; novel; novel strategies; patient response; personalized approach; personalized medicine; pharmacometrics; success; tool; working group

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.

与非退伍军人美国人口相比，退伍军人患肾脏疾病的风险增加。 心血管和骨骼疾病是终末期肾病退伍军人死亡的两个主要原因 （ESRD）由异常的矿物质代谢引起。矿物质和骨骼疾病（MBD）是一种 慢性肾病（CKD）和终末期肾病（ESRD）的普遍并发症。的 退伍军人ESRD人群中MBD的多因素性质使得有效管理这一点 条件复杂。适当的管理需要维持血清钙，磷， PTH水平在国际工作组使用饮食咨询建立和完善的指南范围内， 磷酸盐结合剂、活性维生素D类似物、钙敏感受体激动剂和甲状旁腺切除术。 尽管研究表明，在每个患者中实现每个参数的目标是难以捉摸的， 表明，实现所有三个参数的预期指导方针目标与较低的 心血管风险有待检验的假设是， MBD管理可以通过矿物质代谢的系统生物学建模来改进和更好地了解 以及开发用于当前每种疗法的处方的个性化算法。基础广泛的 这项研究奋进的长期目标是解决关键的技术障碍， 个性化MBD管理，从而改善退伍军人患者的心血管和骨骼结局。 在这方面的初步工作已经证明了系统生物学建模方法的可行性， 实现既定的临床指南。目前对这些退伍军人患者的护理是基于一项试验， 误差逼近理想地，用于MDB的多种药剂的给药应当由对以下各项的个体响应来指导： 这些代理人。为了解决上述挑战，系统生物学方法来模拟复杂的 疾病，MBD可以使用。假设是先进的计算技术可以 用于最佳地指导MBD中使用的药剂的剂量。实现这一目标的计划是 这五个具体目标概述如下： 1.代谢性骨疾病QSP-SB模型的建立 2.药物给药和血液透析模型的开发 3.开发从CPRS获得的临床衍生数据的数据库。 4.用于CKD-MBD的给药算法和临床工具的开发 管理 5.在中心测试开发的MBD-CKD给药算法和工具 血液透析患者 将研究一个广泛的、包容性的退伍军人群体，以开发这些新的给药算法。改进 钙、磷和PTH的个体化控制已被证明可改善心血管死亡率 达到推荐浓度时。这些工具将导致药物剂量的进步 对于慢性疾病，将适用于骨疾病以外的领域，并改善 每一位患有肾病的退伍军人的健康状况。