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

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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.