PROJECT ABSTRACT For over 4 decades, studies identify Contrast-Induced Nephropathy (CIN) as a leading cause of acute kidney injury (AKI). Following exponential increases in CT imaging, exposures to contrast media are a major public health problem, especially in the emergency care setting: >10% of patients with chest symptoms undergo CT of the pulmonary arteries (CTPA) for suspected pulmonary embolism (PE). However, recent studies question whether contrast media exposure actually contributes to overall AKI-risk, even in patients with renal dysfunction. Without prospective validation of either conclusion, physicians are unable to accurately identify high risk patients and are left with current practices that delay or forgo contrast-enhanced imaging, but may not actually reduce AKI-risk. Preliminary data from the PI underscores the significance of the problem perpetuated by this knowledge gap: 1) >15% of patients develop AKI after CTPA; 2) AKI is associated with a 2-fold increase in the risk of subsequent death, renal failure and major cardiovascular events; and 3) Serum creatinine screening (and GFR estimation) has unacceptable sensitivity (13%) in the heterogeneous emergency care setting. In response, the applicant derived a clinical decision rule, the AKIrisk Score. The long-term goal is to identify causes of (such as CIN), and, ultimately, prevent AKI in the emergency care setting. The immediate objectives are to 1) Validate risk-stratification methods in the emergency care setting and 2) Test if contrast media exposure, as a result of CTPA for PE, increases the risk of AKI and subsequent severe outcomes. The central hypothesis is that while a clinical decision rule more accurately risk-stratifies patients for AKI than serum creatinine screening, subsequent avoidance of exposure to contemporary contrast media agents does NOT alter overall AKI-risk, and will be tested by three specific aims: 1) Determine if an AKIrisk score <2 points predicts <10% AKI; 2) Test if cystatin-C and/or NGAL improve AKIrisk score accuracy; and 3) Compare the incidence of AKI and long-term outcomes in 600 patients with an AKIrisk score ≥2 points, randomized to CTPA (contrast media exposure) or ventilation scintigraphy (VQ, unexposed control). The first aim will validate the AKIrisk score, which has previously demonstrated improved accuracy over serum creatinine screening in a large prospective cohort (633 patients). The second aim will also validate the applicant’s prior work demonstrating the additional benefit of acute-phase biomarkers of renal dysfunction. In the third aim, patients will be randomized to contrast media exposure with one of two standard-of-care PE imaging studies and followed for AKI and long-term outcomes. This innovative approach departs from serum creatinine screening, which is outdated and ineffective in the undifferentiated, acutely ill population characteristic of the emergency care setting, and is the first truly feasible trial of AKI-risk that addresses the challenge of prospectively randomizing contrast media exposure. The proposed work will significantly impact real-world imaging practices.

PROJECT NARRATIVE While Contrast-Induced Nephropathy (CIN) has been consistently identified as leading source of acute kidney injury (AKI) for patients exposed to the iodinated contrast media used for contrast-enhanced CT imaging, recent evidence suggests that contrast media exposure does not actually increase the risk of clinically significant AKI, even in patients with renal dysfunction. The proposed research is relevant to public health because it will address a long-standing, unmet need for knowledge guiding physicians in accurately identifying patients at increased risk of AKI and will determine if limiting contrast-exposure reduces the risk of AKI in patients who undergo CT imaging of the pulmonary arteries (CTPA) for chest symptoms and suspected pulmonary embolism (PE) the emergency care setting. Thus, the proposed research is relevant to the NIH’s mission that pertains to discoveries that will directly impact current clinical practice, across medical specialties, and reduce the burden of AKI subsequent severe health outcomes.