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.

Public Health Relevance

Severe trauma results in 2 million hospitalizations per year in the United States and may set in motion a dysfunctional response from the body that results in damage to vital organs, including the kidneys (known as acute kidney injury or AKI). AKI occurs in 30-40% of patients with severe trauma and is more common in obese patients, but the reasons for this elevated risk are unknown. The research outlined in this proposal will shed light on the possibility that excess inflammation, stemming from excess fat tissue, contributes to AKI after trauma and may ultimately provide a novel target for AKI prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23DK097307-01
Application #
8425800
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2013-01-15
Project End
2016-11-30
Budget Start
2013-01-15
Budget End
2013-11-30
Support Year
1
Fiscal Year
2013
Total Cost
$156,619
Indirect Cost
$11,601
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Shashaty, Michael G S; Reilly, John P; Sims, Carrie A et al. (2016) Plasma Levels of Receptor Interacting Protein Kinase-3 (RIP3), an Essential Mediator of Necroptosis, are Associated with Acute Kidney Injury in Critically Ill Trauma Patients. Shock 46:139-43
Anderson, Brian J; Reilly, John P; Shashaty, Michael G S et al. (2016) Admission plasma levels of the neuronal injury marker neuron-specific enolase are associated with mortality and delirium in sepsis. J Crit Care 36:18-23
Palakshappa, Jessica A; Anderson, Brian J; Reilly, John P et al. (2016) Low Plasma Levels of Adiponectin Do Not Explain Acute Respiratory Distress Syndrome Risk: a Prospective Cohort Study of Patients with Severe Sepsis. Crit Care 20:71
Lin, Jennie; Zhang, Xuan; Xue, Chenyi et al. (2015) The long noncoding RNA landscape in hypoxic and inflammatory renal epithelial injury. Am J Physiol Renal Physiol 309:F901-13
Hopkins, S E; Austin, M A; Metzger, J S et al. (2015) Sex differences in obesity prevalence and cardiometabolic factors among Western Alaska Native people. Nutr Metab Cardiovasc Dis 25:312-8
Jolly, Stacey E; Koller, Kathryn R; Metzger, Jesse S et al. (2015) Prevalence of Hypertension and Associated Risk Factors in Western Alaska Native People: The Western Alaska Tribal Collaborative for Health (WATCH) Study. J Clin Hypertens (Greenwich) 17:812-8
Koller, Kathryn R; Metzger, Jesse S; Jolly, Stacey E et al. (2015) Cardiometabolic correlates of low type 2 diabetes incidence in western Alaska Native people - The WATCH study. Diabetes Res Clin Pract 108:423-31
Reilly, John P; Anderson, Brian J; Mangalmurti, Nilam S et al. (2015) The ABO Histo-Blood Group and AKI in Critically Ill Patients with Trauma or Sepsis. Clin J Am Soc Nephrol 10:1911-20
Lin, Jennie; Fernandez, Hilda; Shashaty, Michael G S et al. (2015) False-Positive Rate of AKI Using Consensus Creatinine-Based Criteria. Clin J Am Soc Nephrol 10:1723-31
Semler, Matthew W; Shashaty, Michael G S (2015) Walking on Water: Volume Overload and Ambulation in Survivors of Septic Shock. Ann Am Thorac Soc 12:1745-6

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