Acute Adipose Inflammation as a Contributor to Acute Kidney Injury After Trauma

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The broad objectives of the proposed project are to: 1) test the hypothesis that a systemic inflammatory response potentiated by adipose tissue underlies the association of obesity with acute kidney injury (AKI) after major trauma, 2) determine if adipose distribution (visceral versus subcutaneous) affects this association, 3) train the applicant in patient-oriented translational AKI research, and 4) provide the applicant with individualized mentoring to ensure his transition to the role of an independent investigator. AKI is common in critical illness. AKI makes ICU care more complex, is associated with a substantial mortality increase, and increases the risk of end stage renal disease in survivors. Over 2 million people are hospitalized for injury each year in the United States, and over one-third of critically ill trauma patients develop AKI. AKI pathophysiology, however, remains incompletely understood. We published a study showing a strong association of body mass index (BMI) with AKI after major trauma. Our additional preliminary studies suggest that excess adipose tissue, not lean mass, explains this association. The evolving understanding of the key role of inflammation in AKI pathogenesis, coupled with recent studies from our institution suggesting adipose tissue is a significant source of inflammatory mediators in response to acute stimuli, point toward adipose potentiation of the systemic inflammatory response to trauma as a potential mechanism underlying the obesity-AKI relationship. This proposal outlines a plan to study this mechanism in an existing cohort of critically ill trauma patients. Leveraging the near-uniform clinical use of computed tomography (CT) unique to this population, the association with AKI of precise CT-based adiposity measures will be determined to confirm the adiposity-AKI association. The association of admission plasma inflammatory mediator levels with both obesity and subsequent AKI will be tested in these subjects. Expression of these mediators will be compared in adipose tissue of trauma patients and healthy controls to test the contribution of adipose to the systemic inflammatory response to trauma and the associated AKI risk. The applicant will engage in a rigorous training program of didactic course work and mentoring by senior epidemiologists, biostatisticians, radiologists, and lab experts. He will gain skills in cohrt study conduct, molecular laboratory techniques, novel obesity measures, advanced statistical methodologies, and renal epidemiology. The applicant's attainment of benchmarks in research, publication, and career development will be regularly reviewed by his mentors and advisory committee. Facilitating the proposed aims is an environment which provides clinical research expertise in a collaborative setting, database and statistical support, and core research labs for plasma and tissue study. Through the conduct of the proposed study and training plan, the applicant will make significant contributions to the understanding of AKI pathophysiology, mature as an investigator, and prepare to compete successfully for R01 funding of future projects aimed at finding novel therapeutic targets tailored to populations at high risk for AKI.