Developing personalized immunosuppression for older kidney transplant recipients

为老年肾移植受者开发个性化免疫抑制

• 批准号: 10063523
• 负责人: Mara A. McAdams DeMarco
• 金额: $ 65.48万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-18 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063523
• 关键词: Accounting; Acute; Age; Allografting; Attenuated; Benefits and Risks; Calcineurin inhibitor; Car Phone; Characteristics; Clinical; Clinical Trials; Communication Tools; Cost Savings; Counseling; Custom; Data; Data Element; Data Set; Databases; Dementia; Diabetes Mellitus; Dose; Elderly; End stage renal failure; Environment; Equilibrium; Fracture; Goals; Graft Survival; Guidelines; Homeostasis; Immune response; Immune system; Immunosuppression; Impairment; Infection; Inpatients; Internet; Kidney Transplantation; Link; Malignant Neoplasms; Measures; Medicare; Medicare claim; Metabolism; Methods; Modernization; Morbidity - disease rate; Outcome; Outpatients; Patients; Pharmaceutical Preparations; Pharmacy facility; Physicians; Physiological; Pneumonia; Population; Probability; Protocols documentation; Records; Regimen; Registries; Reporting; Risk; Sepsis; Serum; Survival Analysis; Testing; Time; Transplant Recipients; Transplantation; Update; Variant; Work; adverse outcome; age group; attenuation; base; blind; comorbidity; comparative cost effectiveness; cost; cost effective; cost effectiveness; data registry; dementia risk; frailty; markov model; mortality; novel; personalized approach; personalized medicine; prevent; response; transplant registry

ABSTRACT >400,000 older adults (age ≥55) suffer from end-stage renal disease (ESRD). There has been a 5-fold increase in the number of kidney transplants (KT) in this age group. Older recipients are a distinct group due to impaired homeostasis, higher comorbidity burden, and immune system attenuation. These physiologic factors influence older KT recipients’ response to immunosuppression (IS) medications, a lifelong treatment. The balance between short-term benefits and long-term adverse outcomes of IS can be challenging in older KT recipients. Excellent short-term outcomes (1-year allograft survival>95% and acute rejection [AR]<15%) are achieved in younger patients with modern IS, but our preliminary findings suggest that older KT recipients are at 1.5x increased risk of poor IS tolerance. Older KT recipients are also more susceptible to long-term adverse outcomes associated with the modern IS regimens like infections, malignancy, and new-onset diabetes after transplantation (NODAT) resulting in part from an attenuated immune response. Our preliminary findings suggest that IS regimens with calcineurin inhibitors increase an older recipient’s dementia risk. Yet, our preliminary data suggest that IS is not personalized; center practices account for 46% of IS regimen variation. While KT has been found to be cost saving for ESRD patients, the total KT cost is influenced by accumulating long-term adverse outcomes of IS in this population. IS is not chosen in a cost-blind environment; if the risks and benefits are similar, then cost-effectiveness is an important adjunct to IS regimen choice. The risks, benefits, and cost-effectiveness for an older KT recipient cannot simply be inferred from studies of younger recipients or from clinical trials that largely excluded older recipients. A comprehensive dataset with all key data elements is needed to develop personalized IS for older KT recipients. To develop a personalized approach to IS for older KT recipients, we will integrate 3 novel datasets with >78,800 older KT recipients KT recipients (2005-2019): (1) national data from the Scientific Registry of Transplant Recipients (SRTR); (2) Medicare claims to identify post-KT outcomes and costs; (3) pharmacy claims to identify not only IS agents used but also novel lab data of metabolized IS levels (for 14,000 older recipients). Using this integrated data, we will: 1) compare the effects of IS regimens on efficacy, morbidity, and mortality for older KT recipients; 2) develop Markov models and calculate cost-effectiveness for IS regimens for older KT recipients; and 3) generate individualized reports of predicted efficacy, morbidity, and mortality along with IS regimen cost for practitioners to use for the clinical counseling of older KT recipients. Our goal is to provide evidence and communication tools to help move the field of transplantation away from center-based protocols for IS to personalized IS for older KT recipients. The ability to predict trade-offs in AR and graft survival against long-term adverse outcomes for specific IS regimens in older KT recipients will allow patients and physicians to customize IS choices in a cost-effective and more informed manner. !

抽象的 >400,000 名老年人（年龄≥55 岁）患有终末期肾病（ESRD），增加了 5 倍。 该年龄组的肾移植（KT）数量增加是一个独特的群体。 体内平衡受损、合并症负担较高和免疫系统减弱这些生理因素。 影响老年 KT 接受者对免疫抑制 (IS) 药物（一种终生治疗）的反应。 对于老年人来说，IS 的短期益处和长期不良后果之间的平衡可能具有挑战性。 KT 接受者具有出色的短期结果（1 年同种异体移植存活率 >95% 且急性排斥反应 [AR]<15%）。 在患有现代 IS 的年轻患者中取得了成功，但我们的初步研究结果表明老年 KT 接受者 老年 KT 接受者的 IS 耐受性差的风险增加 1.5 倍，也更容易受到长期不良影响。 与现代 IS 治疗方案相关的结果，如感染、恶性肿瘤和新发糖尿病 移植（NODAT）的部分原因是免疫反应减弱。 表明含有钙调神经磷酸酶抑制剂的 IS 方案会增加老年接受者患痴呆症的风险。 初步数据表明 IS 不是个性化的；中心实践占 IS 治疗方案变化的 46%。 虽然 KT 已被发现可以为 ESRD 患者节省成本，但 KT 总成本受到累积的影响 如果存在风险，则不会在成本盲目的环境中选择 IS 的长期不良后果； 且获益相似，那么成本效益是 IS 方案选择的重要辅助因素。 老年 KT 接受者的益处和成本效益不能简单地从对年轻人的研究中推断出来 接受者或来自很大程度上排除老年接受者的临床试验的数据集，包含所有关键信息。 需要数据元素来为老年 KT 接受者开发个性化 IS。 为了为老年 KT 接受者开发个性化的 IS 方法，我们将集成 3 个新颖的数据集 >78,800 名老年 KT 接受者 KT 接受者（2005-2019 年）：(1) 来自科学登记处的国家数据 移植接受者 (SRTR)；(2) 医疗保险索赔，以确定 KT 后的结果和费用；(3) 药房 声称不仅可以识别所使用的 IS 制剂，还可以识别代谢 IS 水平的新实验室数据（针对 14,000 名老年人） 使用这些综合数据，我们将：1) 比较 IS 方案对疗效、发病率的影响， 和老年 KT 接受者的死亡率；2) 开发马尔可夫模型并计算 IS 的成本效益 老年 KT 接受者的治疗方案；3) 生成预测疗效、发病率的个性化报告 死亡率以及从业者用于老年 KT 接受者临床咨询的 IS 方案成本。 我们的目标是提供证据和交流工具，帮助移植领域远离 基于中心的 IS 协议到老年 KT 接受者的个性化 IS 预测 AR 权衡的能力。 老年 KT 受者的特定 IS 方案的长期不良后果的移植物存活率将允许 患者和医生以经济有效且更明智的方式定制 IS 选择。 ！