This award will support a prospective clinical study and the career development of Loren E. Smith, MD, PhD. 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 AKI in cardiac surgery patients. In her proposed study, Dr. Smith will test the hypotheses that higher perioperative concentrations of apolipoprotein (apo) A-I and specific HDL-microRNAs (miRNAs) are associated with less postoperative AKI (Aim 1), that a higher HDL functional capacity to suppress endothelial cell intercellular adhesion molecule 1 (ICAM-1) and renal proximal tubule cell toll-like receptor (TLR) 2 and TLR4 expression is associated with less AKI (Aim 2), and that exogenous HDL administration to mice before renal ischemia and reperfusion (IR) reduces renal ICAM-1, TLR2, and TLR4 expression and AKI (Aim 3).
Aims 1 and 2 will be tested in a 150-subject prospective study of patients undergoing cardiac or vascular surgery. Blood, urine, and clinical data will be collected longitudinally throughout the perioperative period. ApoA-I concentration will be determined with an ELISA; HDL-miRNAs will be isolated, sequenced and quantified with RT-PCR; and HDL functional capacity to suppress ICAM-1, TLR2, and TLR4 will be measured in vitro using human endothelial and renal proximal tubule cells stimulated with TNF-? and hypoxia respectively. Study subjects? HDL characteristics will be compared to their severity of renal tubule stress and damage, quantified by urinary concentrations of tissue inhibitor of metalloproteinase 2, insulin-like growth factor- binding protein 7, and kidney injury molecule 1 and to their severity of AKI, quantified with 48-hour serum creatinine change from baseline using latent variable regression modeling. During Aim 3 studies, threedifferent doses of HDL particles will be administered to mice before renal IR injury or sham surgery, and the effects of HDL dose on renal damage will be quantified. In a second experiment, HDL containing different miRNAs will be administered before renal IR injury to determine the effect of specific HDL-miRNAs on AKI. By completing this study, Dr. Smith will obtain training in the management of a translational research team and in vivo experimental design from Dr. Linton; perioperative clinical study execution and AKI phenotyping from Dr. Billings; and HDL-associated microRNA (miRNA) sequencing and bioinformatics analysis from Dr. Vickers. In this manner, with the support of this career development award, her mentorship team, and her institutional environment, Dr. Smith will obtain the necessary skills to establish an independent translational research program focused on developing novel lipoprotein-based therapies to reduce postoperative AKI.
Postoperative acute kidney injury (AKI) occurs in 20% of patients following cardiac and vascular surgery and increases the risk of developing chronic kidney disease and death. We have demonstrated that a higher preoperative high-density lipoprotein (HDL) cholesterol concentration is associated with a reduced risk of AKI after cardiac surgery, and now proposed studies to test the hypothesis that apolipoprotein A-I and specific miRNAs on HDL suppress endothelial intercellular adhesion molecule 1, renal tubule toll-like receptor (TLR) 2 and TLR4 expression, and reduce AKI. These studies will provide the candidate with experience in prospective clinical research, miRNA sequencing, and preclinical murine models of AKI, preparing her to establish an independent translational research career focused on developing novel methods of reducing postoperative AKI.
