Acute Kidney Injury (AKI) is a common complication in hospitalized patients and is associated with increased morbidity and mortality. In order to improve patient outcomes in the setting of AKI we seek to 1) further define the role of Cystatin C (CyC) in 2 distinct settings of AKI 2) improve our understanding of the genetic factors that control CyC expression and separate factor which impact susceptibility to AKI. Compared to the current standard, plasma creatinine, plasma and urine CyC have shown promise as early biomarkers of AKI.
Specific aim #1 will validate urine CyC as an early biomarker of AKI following adult cardiothoracic surgery. All 1800 patients enrolled in the NIH funded Translational Research Investigating Biomarker Endpoints in AKI (TRIBE AKI) trial will be prospectively studied with pre-operative and post-operative blood and urine collection. Separately, specific aim #2 will seek to expand the role of both plasma and urine CyC in diagnosing AKI via the prospective study of subjects admitted to the medical intensive care unit with sepsis. In both trials we expect that in those with AKI, both plasma and urine concentrations of CyC will increase significantly earlier than plasma creatinine. We expect this effect to be more pronounced in those going on to require renal replacement therapy. Recent data point to a difference between the normative values of plasma CyC for persons of different racial background. Additionally, genetic polymorphisms in the region of the CyC gene (CST3) play a strong role in steady state plasma CyC concentration.
Aim #3 will delineate the genetic variability in the region of the CST3 gene using the DMAs collected from the 1800 subject TRIBE AKI cohort and seek to further define the relationship between these polymorphisms and plasma and urine CyC concentrations and other phenotypes. Thus refining what is known about the inter-racial differences in CyC levels and potentially glomerular filtration rate. Finally, this Aim will also seek to correlate a variety of phenotypes in the TRIBE AKI cohort with genetic variation in several genes known who's products are known to play a role in AKI. We hypothesize that by improving patient's pre-operative risk stratification, via improved understanding of the genetics of CST3 and AKI and providing an earlier diagnosis of AKI through CyC, we will reduce mortality, improve patient outcomes and advance our understanding of role of CyC in AKI.

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 #
5K23DK081616-05
Application #
8450910
Study Section
Special Emphasis Panel (ZDK1-GRB-S (J2))
Program Officer
Rankin, Tracy L
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$143,640
Indirect Cost
$10,640
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Koyner, Jay L; Garg, Amit X; Thiessen-Philbrook, Heather et al. (2014) Adjudication of etiology of acute kidney injury: experience from the TRIBE-AKI multi-center study. BMC Nephrol 15:105
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Huynh, Toan; Sun, Bing; Li, Liang et al. (2013) Chemical analog-to-digital signal conversion based on robust threshold chemistry and its evaluation in the context of microfluidics-based quantitative assays. J Am Chem Soc 135:14775-83
Koyner, Jay L; Parikh, Chirag R (2013) Clinical utility of biomarkers of AKI in cardiac surgery and critical illness. Clin J Am Soc Nephrol 8:1034-42
Koyner, Jay L; Garg, Amit X; Shlipak, Michael G et al. (2013) Urinary cystatin C and acute kidney injury after cardiac surgery. Am J Kidney Dis 61:730-8
Koyner, Jay L; Garg, Amit X; Coca, Steven G et al. (2012) Biomarkers predict progression of acute kidney injury after cardiac surgery. J Am Soc Nephrol 23:905-14
Eadon, Michael T; Koyner, Jay L (2012) Autologous creatinine clearance in a case of necrotizing fasciitis and anuria. Am J Nephrol 35:225-9
Murray, Patrick; Udani, Suneel; Koyner, Jay L (2011) Does renal replacement therapy improve outcome? Controversies in acute kidney injury. Contrib Nephrol 174:212-21
Hall, Isaac E; Koyner, Jay L; Doshi, Mona D et al. (2011) Urine cystatin C as a biomarker of proximal tubular function immediately after kidney transplantation. Am J Nephrol 33:407-13

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