Non-invasive Imaging Biomarkers to Identify a High-risk Chronic Kidney Disease Phenotype

项目总结 慢性肾脏疾病(CKD)患者患心血管疾病的风险增加， 进展到终末期肾病，并过早死亡。将科学突破转化为 临床试验受到我们识别正确研究人群的能力的限制。通过评估间质的程度 纤维化/肾小管萎缩(IFTA)、球性肾小球硬化(GS)和微血管疾病(MVD)、肾脏 组织病理学提示CKD进展的风险，独立于估计的肾小球滤过率(EGFR)和 蛋白尿。先前的研究表明，肾微血管灌注减少和由此导致的慢性缺氧 肾纤维化的发病机制。由于肾活检有风险，一种新的成像生物标志物的研究 肾微血管血流灌注检查可提供一种非侵入性工具来识别高危CKD表型。通过 评估血管内微泡造影剂的运动，对比增强超声(CEUS)可以 检测肾脏微血管灌注量。在令人兴奋的初步数据中，斯里瓦斯塔瓦博士发现了一个很低的微泡 晚期CKD患者和重度CKD患者的洗净率，提示肾脏微血管灌注率低 慢性组织病理学损害。在拟议的研究中，他将全面评估微气泡 健康和疾病中的洗牌率。在目标1中，他将测试微泡洗入率与 用对氨基马尿酸盐和碘海醇测量肾血流和肾功能的金标准评估 分别为净空。在目标2中，他将使用微泡洗入率来区分慢性肾脏病患者。 来自健康的志愿者。在目标3中，他将测试微泡洗入率与MVD、IFTA、 GS，以及接受天然肾脏活检的个体中EGFR随时间的变化。结果将通知 新型非侵入性影像生物标志物在慢性肾脏病中的应用。作为高度临床相关研究的补充， 斯里瓦斯塔瓦博士将实施一项着眼于战略的职业发展计划，以获取图像数据方面的技能 影像生物标记物的分析和发展，2)将影像生物标记物纳入患者导向 研究性研究，3)学习进行成像生物标记物验证的方法，4)发展科学 管理技能，并与生物标记物和成像专家建立合作关系，以及5)增加研究 投资组合和提高授勋技能。为了实现这些目标，斯里瓦斯塔瓦博士组建了多个 CKD中以患者为导向的研究和临床试验专家的学科指导团队(主要导师， 塔玛拉·伊萨科娃博士)、CEU(共同导师，托马斯·格兰特博士)、生物标记物开发和验证(Dr。 Sushrut Waikar)、CEUS图像分析(Jason Streeter博士)、血流成像(Michael Markl博士)和患者 以成像终点为导向的研究(詹姆斯·卡尔博士)执行拟议的研究、购置 西北大学的培养目标和在健全的科学环境中的杰出导师将 职位斯里瓦斯塔瓦博士过渡到一名独立的调查员，在使用新的非 CKD患者以患者为中心的研究和临床试验中的侵入性成像生物标记物。

PROJECT SUMMARY Patients with chronic kidney disease (CKD) are at increased risks of developing cardiovascular disease, progressing to end stage renal disease, and dying prematurely. Translation of scientific breakthroughs into clinical trials is limited by our ability to identify the right study population. By assessing the degree of interstitial fibrosis/tubular atrophy (IFTA), global glomerulosclerosis (GS), and microvascular disease (MVD), kidney histopathology informs risk of CKD progression, independent of estimated glomerular filtration rate (eGFR) and proteinuria. Prior studies implicate decreased renal microvascular perfusion and resultant chronic hypoxia in the pathogenesis of renal fibrosis. Since kidney biopsy carries risks, investigation of a novel imaging biomarker of renal microvascular perfusion may provide a non-invasive tool to identify a high-risk CKD phenotype. By assessing the motion of intravascular microbubble contrast agents, contrast enhanced ultrasound (CEUS) may detect renal microvascular perfusion. In exciting preliminary data, Dr. Srivastava found a low microbubble wash-in rate, suggestive of low renal microvascular perfusion, in patients with advanced CKD and with severe chronic histopathologic lesions. In the proposed studies, he will comprehensively evaluate the microbubble wash-in rate in health and disease. In Aim 1, he will test the association of the microbubble wash-in rate with gold standard assessments of renal blood flow and function, measured by para-aminohippurate and iohexol clearances, respectively. In Aim 2, he will use the microbubble wash-in rate to differentiate patients with CKD from healthy volunteers. In Aim 3, he will test the association of the microbubble wash-in rate with MVD, IFTA, GS, and change in eGFR over time in individuals undergoing a native kidney biopsy. The results will inform the field of novel non-invasive imaging biomarkers in CKD. Complementary to the highly clinically relevant studies, Dr. Srivastava will implement a strategically focused career development plan 1) to acquire skills in image data analysis and development of imaging biomarkers, 2) to incorporate imaging biomarkers into patient oriented research studies, 3) to learn methods to perform imaging biomarker validation, 4) to develop scientific management skills and build collaborations with biomarker and imaging experts, and 5) to increase research portfolio and improve grantsmanship skills. To accomplish these goals, Dr. Srivastava assembled a multi- disciplinary mentoring team of experts in patient oriented research and clinical trials in CKD (Primary mentor, Dr. Tamara Isakova), CEUS (Co-mentor, Dr. Thomas Grant), biomarker development and validation (Dr. Sushrut Waikar), CEUS image analysis (Dr. Jason Streeter), flow imaging (Dr. Michael Markl), and patient oriented research with imaging endpoints (Dr. James Carr). Execution of the proposed studies, acquisition of the training goals, and outstanding mentorship in a robust scientific environment at Northwestern University will position Dr. Srivastava to transition to an independent investigator with unique expertise in use of novel non- invasive imaging biomarkers in patient oriented research studies and clinical trials in patients with CKD.