Project Summary of Parent Grant Cardiac surgery-associated acute kidney injury (CSA-AKI) is a major public health burden. Over 500,000 cardiac surgeries are performed annually in the U.S. alone, with as many as 64% complicated by CSA-AKI. Those who develop CSA-AKI have a 6- to 18-fold higher acute mortality compared to those without CSA-AKI. No pharmacologic therapy reliably prevents or treats CSA-AKI. Based on a strong pathophysiologic rationale from both animal models and human studies, we propose that hepcidin and other heme/iron regulatory proteins play a key role in CSA-AKI. In Aims 1 and 2, we will leverage the CABG Genomics Project, a large prospective cohort study of adult patients who underwent cardiac surgery. CABG Genomics collected detailed clinical data and biospecimens, including plasma/serum samples pre- and postoperatively at multiple time points. In Aim 1, we will measure plasma hepcidin preoperatively in 2,000 patients to test its association with CSA-AKI. We will use multivariable models to adjust for potential confounders, including plasma IL-6. We will externally validate our findings using samples from the TRIBE-AKI study, which enrolled 1219 high-risk adults who underwent cardiac surgery at 6 sites in North America. In Aim 2, we will measure plasma hepcidin, free hemoglobin, haptoglobin, hemopexin, transferrin saturation, and ferritin longitudinally in a nested 1:1 case-control study (n=600) to test whether early changes in these markers are independently associated with CSA-AKI. In Aim 3, we will enroll 250 high-risk adult patients undergoing cardiac surgery at three major hospitals in Boston. We will isolate peripheral blood mononuclear cells pre- and postoperatively to investigate the relationship between monocyte expression of ferroportin and other heme/iron regulatory proteins, examined by flow cytometry, with CSA-AKI. We will also assess whether early postoperative changes in monocyte expression of ferroportin and other heme/iron regulatory proteins are associated with CSA-AKI. Investigating the hepcidin-ferroportin-iron axis and other heme/iron regulatory proteins in the setting of CSA-AKI could have actionable implications for the design of future trials to prevent CSA-AKI. Unlike many other markers previously examined in CSA-AKI, those proposed here are directly involved in the pathogenesis of CSA-AKI and are targetable. This proposal will help determine the therapeutic strategy targeting disordered iron homeostasis that has the highest likelihood of success. If low preoperative hepcidin is confirmed as an independent risk factor for CSA-AKI, prophylactic administration of hepcidin agonists, which are currently in development, could be tested in future studies of CSA-AKI prevention. Alternatively, if the proposed studies reveal that other heme/iron regulatory proteins (e.g., haptoglobin, CD163, HO-1) have a greater influence on CSA-AKI than hepcidin/ferroportin, therapeutic strategies targeting these proteins c...