Developing personalized immunosuppression for older kidney transplant recipients

摘要 超过400，000名老年人（年龄≥55岁）患有终末期肾病（ESRD）。已经有5倍的 这个年龄组的肾移植（KT）数量增加。老年收件人是一个独特的群体， 体内平衡受损、合并症负担增加和免疫系统衰减。这些生理因素 影响老年KT接受者对免疫抑制（IS）药物的反应，这是一种终身治疗。 在老年人中，IS的短期获益和长期不良结局之间的平衡可能具有挑战性。 KT接收者。良好的短期结果（1年移植物存活率>95%，急性排斥反应[AR]<15%） 但我们的初步研究结果表明，年龄较大的KT接受者 IS耐受性差的风险增加1.5倍。年龄较大的KT接受者也更容易受到长期不良反应的影响。 与现代IS方案相关的结局，如感染、恶性肿瘤和新发糖尿病， 在某些实施方案中，免疫抑制剂是部分由减弱的免疫应答引起的NODAT移植。我们的初步研究结果 提示使用钙调磷酸酶抑制剂的IS方案增加了老年接受者痴呆的风险。但我们的 初步数据表明IS不是个性化的;中心实践占IS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总成本受累积的影响 IS在该人群中的长期不良结局。IS不是在不考虑成本的环境中选择的;如果风险 且获益相似，则成本效益是IS方案选择的重要辅助因素。风险， 老年KT接受者的益处和成本效益不能简单地从年轻人的研究中推断出来。 接受者或临床试验，在很大程度上排除了老年接受者。包含所有关键字的综合数据集 需要数据元素来为年长的KT接受者开发个性化的IS。 为了为老年KT接受者开发个性化的IS方法，我们将整合3个新的数据集， > 78，800名年长的KT接受者KT接受者（2005-2019年）：（1）来自科学登记处的国家数据 移植受者（SRTR）;（2）医疗保险索赔，以确定KT后的结果和成本;（3）药房 声称不仅确定了所使用的IS药物，而且还确定了代谢IS水平的新实验室数据（对于14，000名老年人， 收件人）。利用这些综合数据，我们将：1）比较IS方案对疗效、发病率、 2）建立马尔可夫模型并计算IS的成本-效果 老年KT接受者的治疗方案; 3）生成预测疗效、发病率和 死亡率沿着IS方案的费用，从业者用于老年KT接受者的临床咨询。 我们的目标是提供证据和沟通工具，以帮助移植领域远离 从基于中心的IS协议到针对老年KT接受者的个性化IS。在AR中预测权衡的能力 在年龄较大的KT受者中，针对特定IS方案的长期不良结局的移植物存活将允许 患者和医生以具有成本效益和更知情的方式定制IS选择。 !

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. !