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

用于识别高风险慢性肾脏病表型的非侵入性成像生物标志物

• 批准号: 9891319
• 负责人: Anand Srivastava
• 金额: $ 19.24万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9891319
• 关键词: Affect; Age; Animals; Atrophic; Back; Biological Markers; Blood flow; Cardiovascular Diseases; Chronic; Chronic Kidney Failure; Clinical; Clinical Trials; Collaborations; Contrast Media; Data; Data Analyses; Development; Development Plans; Disease; Disease Progression; End stage renal failure; Enrollment; Environment; Erythrocytes; Evaluation; Fibrosis; Functional Imaging; Future; Gases; Glomerular Filtration Rate; Goals; Gold; Grant; Health; Histopathology; Hypoxia; Image; Image Analysis; Individual; Injury; Investigation; Iohexol; Japanese Population; Kidney; Lead; Lesion; Link; Longevity; Measures; Mentors; Mentorship; Microbubbles; Microcirculation; Microvascular Dysfunction; Motion; Multicenter Studies; Outcome; Pathogenesis; Patients; Performance; Perfusion; Population; Positioning Attribute; Property; Proteinuria; Protocols documentation; Renal Blood Flow; Renal function; Reporting; Research; Research Personnel; Risk; Suggestion; Testing; Time; Training; Translations; Tubular formation; Ultrasonography; Universities; base; biomarker development; biomarker evaluation; biomarker selection; biomarker validation; cardiovascular disorder risk; career development; clinically relevant; contrast enhanced; disease phenotype; experience; glomerulosclerosis; health data; healthy volunteer; high risk; human data; imaging biomarker; imaging modality; improved; interstitial; kidney biopsy; kidney fibrosis; learning strategy; mortality; multidisciplinary; non-invasive imaging; novel; novel therapeutics; patient oriented research; premature; prognostic value; prospective; recruit; renal damage; research study; skills; study population; tool

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.

项目概要 慢性肾病（CKD）患者患心血管疾病的风险增加， 进展为终末期肾病并过早死亡。将科学突破转化为 临床试验受到我们确定正确研究人群的能力的限制。通过评估间隙程度 纤维化/肾小管萎缩 (IFTA)、整体性肾小球硬化 (GS) 和微血管疾病 (MVD)、肾脏 组织病理学可告知 CKD 进展的风险，与估计的肾小球滤过率 (eGFR) 无关，并且 蛋白尿。先前的研究表明肾微血管灌注减少并导致慢性缺氧 肾纤维化的发病机制。由于肾活检存在风险，因此研究一种新型成像生物标志物 肾微血管灌注的监测可能提供一种非侵入性工具来识别高风险 CKD 表型。经过 评估血管内微泡造影剂的运动，超声造影（CEUS）可以 检测肾微血管灌注情况。在令人兴奋的初步数据中，Srivastava 博士发现了低微泡 晚期 CKD 和严重肾病患者的洗入率表明肾微血管灌注较低 慢性组织病理学病变。在拟议的研究中，他将全面评估微泡 健康和疾病的洗入率。在目标 1 中，他将测试微泡冲入率与 通过对氨基马尿酸和碘海醇测量肾血流量和功能的金标准评估 间隙，分别。在目标 2 中，他将使用微泡洗入率来区分 CKD 患者 来自健康的志愿者。在目标 3 中，他将测试微泡冲入率与 MVD、IFTA、 GS，以及接受天然肾活检个体的 eGFR 随着时间的变化。结果将告知 CKD 新型非侵入性成像生物标志物领域。对高度临床相关研究的补充， Srivastava 博士将实施战略性的职业发展计划 1) 获取图像数据技能 成像生物标志物的分析和开发，2）将成像生物标志物纳入以患者为导向的 研究，3) 学习执行成像生物标志物验证的方法，4) 开发科学 管理技能并与生物标志物和成像专家建立合作，5) 加强研究 投资组合并提高资助技能。为了实现这些目标，斯里瓦斯塔瓦博士组建了一个多 以患者为中心的 CKD 研究和临床试验专家学科指导团队（主要导师、 Tamara Isakova 博士），CEUS（联合导师 Thomas Grant 博士），生物标志物开发和验证（Dr. Tamara Isakova） 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，获取 西北大学强大的科学环境中的培训目标和出色的指导将 使 Srivastava 博士转型为一名独立研究者，在使用新型非药物方面拥有独特的专业知识 以患者为导向的 CKD 患者研究和临床试验中的侵入性成像生物标志物。