The Clinical Applications of the Difference in Estimated Glomerular Filtration Rate by Cystatin C vs. Creatinine (eGFRDiff)

项目总结 这是艾莉森·波托克博士在德娜·里夫金博士的指导下提交的K23申请的初步申请， 在加州大学圣地亚哥分校(UCSD)。这项提议将使波托克博士成为一名独立的 研究人员，并将评估估计的肾小球滤过率的差异的临床应用 半胱氨酸氨基转移酶C(EGFRCys)与肌酐(EGFRcr)对远期预后和短期用药的影响。 候选人：波托克博士通过这项提议的培训目标和职业目标包括：1)成为 精通老年肾脏病，精通老年药理和用药；2)培养技能 在高级统计方法、流行病学、手稿和赠款写作方面；3)学习必要的技能 设计并开展临床研究，组建研究团队。她已经组建了一个多学科的 导师团队由主要导师里夫金博士组成，里夫金博士是老年肾病领域的知名领导者，以及 以下其他共同导师和合作者：肾脏病临床试验专家IX博士；Moore博士， 古铁雷斯博士是老年医学和衰老研究的权威，也是肾脏疾病的专家，拥有广泛的 中风研究中地理和种族差异原因的经验与洞察 用于AIM 2；卡茨博士，华盛顿大学生物统计学主任，他曾 与Rifkin，IX和Potok博士广泛合作；Hallan博士，在决策曲线方面有专长的医学教授 挪威诺德-特隆德拉格健康研究(亨特)用于目标1的分析和丰富经验。 研究：大多数慢性肾病患者不会进展到终末期肾病 (ESKD)由于相互竞争的死亡风险。虚弱可能会增加死亡风险，而不是ESKD风险。这个 目前的肾功能衰竭风险方程(KFRE)和肾脏疾病死亡风险方程(MREK)没有 这是脆弱的原因。在前期工作中，波托克博士已经证明了胱抑素C和 肌酐(eGFRDiff定义为eGFRCys-eGFRcr)与事件脆弱和死亡的风险有关。 此外，Potok博士的初步结果显示，eGFRDiff在以下方面存在异质性 胱抑素C和肌酐之间的哪一个标志物是真实肾功能的最佳替代指标。整体而言 假设eGFRDiff可用于指导临床医生是否开始为患者准备肾脏 替代疗法和用药剂量。在目标1中，她将决定是否纳入 作为KFRE和MREK内部脆弱性的标志，eGFRDiff将改善对 老年人的ESKD与死亡。这一目标将在65岁的CKD的参与者中进行 亨特研究，一个完全由欧洲白人组成的群体。在目标2中，她将探讨ESKD的竞争风险 关于混血美国人的死亡。在目标3中，波托克博士将研究eGFRDiff 可以用来确定哪些人不应该信任eGFRCR来给药，而eGFRCys应该 取而代之的是使用万古霉素作为原型药物。

PROJECT SUMMARY This is an initial submission of a K23 application by Dr. Alison Potok, under the mentorship of Dr. Dena Rifkin, at the University of California San Diego (UCSD). This proposal will establish Dr. Potok as an independent investigator, and will evaluate the clinical applications of the difference in estimated glomerular filtration rate by cystatin C (eGFRCys) vs. creatinine (eGFRCr), for prognosis in the long-term and drug dosing in the short-term. Candidate: Dr. Potok’s training objectives and career goals through this proposal include: 1) to become an expert in geriatric nephrology and proficient in pharmacology and drug dosing in the elderly; 2) to develop skills in advanced statistical methods, epidemiology, manuscript and grant writing; 3) to learn the necessary skills to design and conduct a clinical study and develop a research team. She has assembled a multidisciplinary mentorship team comprised of a primary mentor, Dr. Rifkin, an established leader in geriatric nephrology, and the following additional co-mentors and collaborators: Dr. Ix, an expert in nephrology clinical trials; Dr. Moore, an authority in geriatric medicine and aging research, Dr. Gutierrez, an expert in kidney disease with extensive experience and insight to the REasons for Geographic and Racial Differences in Stroke (REGARDS) study utilized for Aim 2; Dr. Katz, the Director of Biostatistics at the University of Washington, who has worked extensively with Drs. Rifkin, Ix, and Potok; Dr. Hallan, Professor of Medicine with expertise in decision curve analysis and extensive experience in the Norwegian Nord-Trondelag Health Study (HUNT) utilized for Aim 1. Research: Most patients with chronic kidney disease (CKD) will not progress to end stage kidney disease (ESKD) due to the competing risk of death. Frailty may increase the risk of death vs. the risk of ESKD. The current kidney failure risk equation (KFRE) and mortality risk equation in kidney disease (MREK) do not account for frailty. In preliminary work, Dr. Potok has showed that the difference in eGFR by cystatin C vs. creatinine (eGFRDiff defined as eGFRCys – eGFRCr) is associated with risk of incident frailty and death. Moreover, Dr. Potok’s preliminary results show heterogeneity across the spectrum of eGFRDiff regarding which marker between cystatin C vs. creatinine is the best surrogate for true kidney function. The overall hypothesis is that eGFRDiff can be used to guide clinicians on whether to start preparing patients for renal replacement therapy and with medication dosing. In Aim 1, she will determine whether the inclusion of eGFRDiff, as a marker of frailty within the KFRE and MREK will improve assessment of the competing risk of ESKD vs. death in older adults. This Aim will be conducted in participants aged >65years with CKD of the HUNT study, an exclusively White European population. In Aim 2, she will explore the competing risk of ESKD vs. death in a biracial American population in REGARDS. In Aim 3, Dr. Potok will examine whether eGFRDiff could be used to determine those in whom eGFRCr should not be trusted for drug dosing, and eGFRCys should be used instead, with vancomycin as the prototype medication.