Acute kidney injury (AKI) after cardiac surgery requiring cardiopulmonary bypass (CS-AKI) occurs in up to one- third of patients. Currently, there are no pharmacologic or biologic treatments to either prevent or treat AKI. The pathogenesis of AKI involves ischemia-reperfusion injury (IRI), endothelial cell dysfunction and activation of immune cells in the cardiopulmonary bypass circuit. In experimental AKI models, two complementary, intrinsic systems have been identified that A) promote native resistance to kidney injury and B) can be targeted pharmacologically to inhibit the development of AKI. The sphingosine 1-phosphate (S1P) vascular gradient is an important determinant of susceptibility to AKI in the mouse kidney IRI model. Similarly, a deficit of Tregs predisposes mice to kidney IRI. For both protective mediators (S1P and Tregs): therapies that increase their intra-vascular abundance are efficacious at preventing renal injury and dysfunction in the mouse AKI model. S1P acts directly on the endothelium to strengthen the endothelial barrier, while Tregs act on the innate immune cells that infiltrate the injured kidney and exacerbate the damage. We propose to measure Treg number and whole blood and plasma S1P levels in 200 adult cardiac surgery patients that undergo cardiopulmonary bypass; blood will be obtained both just before and 24 hr after surgery. Our main research question is whether relatively low levels of either mediator prior to surgery correlates with increased incidence of post-surgical AKI. If either variable correlates negatively with AKI, we be motivated to investigate the potential therapeutic use/targeting of Tregs and/or S1P-modulating agents for prevention of AKI in this clinical setting. These could be breakthrough therapies for protecting future patients from CS-AKI. We have established a multidisciplinary collaboration to investigate these kidney-protective mediators in patients undergoing cardiac surgery that requires cardiopulmonary bypass. As Co-PIs, Drs. Rosner, Lynch and Kinsey bring complementary expertise in clinical AKI, S1P and Treg biology, respectively. Dr. Kern (Division Chief of Cardiothoracic Surgery) will provide input from the surgeon's perspective and ensure access to potential study subjects and Sandra Burks, RN, CCRC (Associate Director of the Surgical Therapeutic Advancement Center) will manage the study, obtain informed consent from the patients and collect the specimens. Dr. Ma (Professor of Biostatistics) has extensive experience with clinical studies in multiple types of kidney disease and will offer support in study design and perform statistical analyses. Our overall hypotheses are 1) that high circulating Tregs and S1P correlates with reduced AKI, 2) measuring their levels prior to surgery can help predict those patients at higher risk for AKI and 3) therapeutic strategies based on Tregs and/or S1P might be useful to reduce the incidence of CS-AKI.

Project Narrative After heart surgery, the endothelial cells lining blood vessels become leaky and immune cells are activated; these events contribute to post-surgical acute kidney injury (AKI). Sphingosine 1-phosphate (S1P) is a signaling molecule that circulates in blood where it functions to maintain endothelial barrier integrity and regulatory T lymphocytes (Tregs) are cells inhibit the immune cell activation. Strategies to raise the levels of either of these mediators are efficacious in models of AKI (ischemia-reperfusion injury in mice) and this project will test the hypothesis that low blood S1P or Treg levels just before heart surgeries using cardiopulmonary bypass correlate with an increased incidence of AKI in these patients.