Non Invasive Assessment of Microcirculation Function and Kidney Disease

PROJECT SUMMARY This is a submission of a K23 application by Dr. Rakesh Malhotra, MD, MPH, a nephrologist at University of California San Diego (UCSD). Through this proposal Dr. Malhotra intends to establish himself as an independent investigator studying non-invasive microvascular measurements in chronic kidney disease (CKD). Candidate: Dr. Malhotra’s training objectives include; 1) to become proficient in the measurement of non- invasive microvascular techniques and translation to patient-oriented research; 2) to gain expertise in advanced statistical methods relevant to clinical trials; and 3) to learn the necessary skills to develop an independent research program and to design and lead clinical trials. Dr. Malhotra will accomplish these objectives through mentorship, coursework, and participation in workshops. He has assembled a multidisciplinary team of scientists including Dr. Joachim Ix, an expert clinical trialist (primary mentor), Dr. Boy Houben, a leader in the field of microcirculation (co-mentor); Dr. Matthew Allison, a leader in the field of vascular health and assessment (co-mentor) and Dr. Florin Vaida, a PhD level biostatistician (statistical co- mentor). In addition, Dr. Haiyan Zhang a renal pathologist with experience in nephropathology and Dr. Ithaar Derweesh a urologist with expertise in minimally invasive surgery will participate as a consultant without pay. Research: Renal microcirculation plays an important role in the pathogenesis of CKD. The kidney biopsy is the standard technique to assess abnormalities in renal microvasculature, but is invasive and rarely done. Dr. Malhotra’s overall hypothesis is that the non-invasive microvascular measurements may improve our understanding of the renal microcirculation, and improve our ability to identify those at risk of kidney disease progression. In Aim 1, Dr. Malhotra will evaluate the relationship between non-invasive microvascular measurements (skin capillary density and % recruitment (by capillaroscopy) and heat-induced skin %- hyperemia (by laser Doppler)) with glomerular sclerosis among 100 individuals with CKD undergoing kidney biopsy and 50 persons with CKD undergoing nephrectomy for suspected kidney cancer. In Aim 2a, Dr. Malhotra will evaluate the association of clinical risk factors with microvascular dysfunction as assessed with capillaroscopy and laser Doppler among 200 CKD subjects. In Aim 2b, Dr. Malhotra will determine the associations between skin microvascular function and longitudinal changes in kidney function in the 200 CKD subjects. Lastly, in Aim 3, Dr. Malhotra will evaluate whether acute changes in % capillary recruitment in response to a dietary protein load is correlated with concurrent changes in eGFR, as measure of RFR in 20 CKD subjects. Both the training and research plans will lay the groundwork for use of non-invasive microvascular techniques in clinical trials to allow assessment of renal hemodynamics and monitor responses to therapies and clinical outcomes in the next and independent phase of Dr. Malhotra’s career.