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: 10337261
• 负责人: Anand Srivastava
• 金额: $ 19.09万
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337261
• 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; 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; ultrasound

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.

项目总结