Perioperative high-density lipoprotein and postoperative AKI

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PROJECT SUMMARY- NO CHANGE This award will support a prospective clinical study and the career development of Loren E. Smith, MD, PhD, and provide her with the skills and experience in prospective clinical research needed to advance her towards her long-term goal of becoming an independent translational physician-scientist who discovers novel methods of perioperative renal protection to decrease acute kidney injury (AKI). Dr. Smith completed a PhD in high-density lipoprotein (HDL) molecular biology with Dr. Sean Davidson at the University of Cincinnati and residency training in Anesthesiology at Vanderbilt University Medical Center (VUMC), where she was appointed faculty in 2017. VUMC is a tertiary academic hospital renowned for its highly collaborative research environment, exceptional career development programs, and extensive core facilities. During her T32 fellowship Dr. Smith and her mentors, Drs. Linton, Billings, and Vickers, discovered an association between higher preoperative HDL and reduced postoperative AKI. Dr. Smith is exploring this association in order to design lipoprotein-based treatments for AKI. By completing this study, she will obtain training in the management of a translational research team and HDL functional analysis from Dr. Linton, perioperative clinical study execution and AKI phenotyping from Dr. Billings, and cutting-edge HDL-associated microRNA (miRNA) sequencing and quantification from Dr. Vickers. Dr. Smith will test the hypotheses that specific HDL proteins and miRNA are associated with postoperative AKI (Aim 1), and that increased HDL anti-inflammatory and anti-oxidant functional capacities are associated with decreased AKI (Aim 2). She will test these hypotheses in a 150-subject prospective study of patients undergoing cardiac or vascular surgery. Blood, urine, and clinical data will be collected prior to, during, and following surgery. Study subject's HDL composition will be characterized by measuring apolipoprotein A-I and serum amyloid A (SAA) protein content and by sequencing HDL-associated miRNAs. HDL anti-inflammatory capacity will be quantified as HDL particles' in vitro capacity to suppress SAA-stimulated macrophage IL-6 and TNF-α expression and to suppress renal proximal tubule cell TLR2 and 4 expression during hypoxia. HDL paraoxonase-1 activity will be used to estimate anti-oxidant capacity. These HDL characteristics will be compared to severity of renal tubule stress and damage, quantified by urinary levels of tissue inhibitor of metalloproteinase 2, insulin-like growth factor-binding protein 7, and kidney injury molecule 1 and to severity of AKI, quantified with 48-hour serum creatinine change from baseline using multivariate regression modeling, adjusted for potential confounders. Associations identified between HDL properties and AKI will then be evaluated as mediators of the association between preoperative HDL concentration and AKI. With the support of this career development award, her mentorship team, and her institutional environment, Dr. Smith will gain the skills required to establish a translational research program to reduce postoperative AKI.