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

项目摘要 这是Alison波托克博士在Dena Rifkin博士的指导下首次提交的K23申请， 在加州圣地亚哥大学（UCSD）。这项提案将使波托克博士成为一名独立的 研究者，并将通过以下方式评价肾小球滤过率估计值差异的临床应用： 胱抑素C（eGFRCys）与肌酐（eGFRCr），用于长期预后和短期药物给药。 候选人：波托克博士的培训目标和职业目标，通过这一建议包括：1）成为一个 老年肾病学专家，精通老年药理学和药物给药; 2）培养技能 在先进的统计方法，流行病学，手稿和赠款写作; 3）学习必要的技能， 设计和开展临床研究，并建立研究团队。她组织了一个多学科的 导师团队由主要导师Rifkin博士组成，他是老年肾病学的公认领导者， 以下额外的共同导师和合作者：肾病临床试验专家Ix博士;摩尔博士， 古铁雷斯博士是老年医学和衰老研究的权威，他是一位肾病专家， 卒中地理和种族差异原因（REGARDS）研究的经验和见解 Katz博士，华盛顿大学生物统计学主任， 与Rifkin、Ix和波托克博士以及在决策曲线方面具有专长的医学教授Hallan博士进行了广泛的交流 目标1所使用的挪威Nord-Trondelag健康研究（HUNT）的分析和丰富经验。 研究：大多数慢性肾病（CKD）患者不会进展为终末期肾病 （ESKD）由于竞争性死亡风险。与ESKD风险相比，虚弱可能会增加死亡风险。的 目前的肾衰竭风险方程（KFRE）和肾脏疾病死亡风险方程（MREK）不 解释脆弱在初步工作中，波托克博士已经表明，半胱氨酸蛋白酶抑制剂C与 肌酸酐（eGFRDiff定义为eGFRCys-eGFRCr）与偶发虚弱和死亡的风险相关。 此外，波托克博士的初步结果表明，在eGFRDiff谱中， 半胱氨酸蛋白酶抑制剂C与肌酸酐之间的哪种标记物是真实肾功能的最佳替代物。整体 假设eGFRDiff可用于指导临床医生是否开始为患者进行肾移植做准备， 替代疗法和药物剂量。在目标1中，她将决定是否将 eGFRDiff作为KFRE和MREK内的虚弱标志物，将改善对以下竞争风险的评估： ESKD与老年人死亡该目标将在年龄> 65岁的CKD受试者中进行， HUNT研究，仅白色欧洲人群。在目标2中，她将探讨ESKD的竞争风险 vs.在一个双胞胎美国人的死亡率方面。在目标3中，波托克博士将检查eGFRDiff是否 可用于确定不应信任eGFRCr进行药物给药的患者，而eGFRCys应 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.