Chronic kidney disease (CKD) affects more than one in ten Americans. CKD does progress to end stage kidney disease (ESKD) in some, but not all patients, despite 'optimal'management. Biomarkers that 'predict'the risk and/or rate of progression in individual CKD patients sufficiently to guide preventive interventions are currently not available. Thus, discovery of 'predictive'biomarkers for CKD progression is an important unmet need and the goal of the proposed New York CKD Biomarker Discovery Program. The Program will bring together an interdisciplinary team of nephrologists, laboratory medicine specialists, pathologists, and statisticians to achieve this goal, in collaboration and with guidance from the NIDDK CKD Biomarker Consortium. In preliminary discovery work by our groups, 78 candidate biomarkers, including neutrophil gelatinaseassociated lipocalin (LCN2 or NGAL), a urinary biomarker for acute kidney injury, were identified by genomewide transcriptional profiling and systems biology analysis in kidney tissue of a range of murine models with diabetic, immune-mediated, and glomemlar renal diseases.
In Aim 1 (Qualification Phase) we propose to examine the urinary excretion profiles of up to 20 top candidates, selected from the 78 candidate CKD biomarkers, and including NGAL, in few selected 'gold standard'cases of advanced CKD, and controls by systematic western blotting. Next, we will establish and characterize commercially available ELISA for candidates that passed the western blot screen.
In Aim 2 (Verification Phase), the top candidate biomarkers will be measured by ELISA in urine samples of patients with progressive or non-progressive CKD that have been followed in well-characterized, longterm cohorts, including the African-American Study of Kidney Disease in Hypertension (AASK), the Modification of Diet in Renal Disease (MDRD), and the Diabetes Control And Complications Trial/Epidemiology Of Diabetes Intervention And Complications (DCCT/EDIC), together with samples from patients without CKD. Statistical analysis will be applied to assess the candidate CKD biomarker as 'predictors'of progression of CKD. Intrarenal expression of highly credentialed candidates (anticipated 2 to 4) delivered in Aim 2, will be assessed by immunohistochemistry at the Renal Pathology Laboratory at Columbia University. The long-term goal of the proposed New York CKD Biomarker Program is to work collaboratively with the emerging NIDDK CKD Biomarker Consortium to discover and develop promising 'predictive'CKD biomarkers towards clinical application.

Public Health Relevance

Biomarkers that 'predict'the risk and/or rate of progression in individual CKD patients sufficiently to guide preventive interventions are currently not available. Thus, discovery of 'predictive'biomarkers for CKD progression is an important unmet need and the goal of the proposed New York CKD Biomarker Discovery Program.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK085688-04
Application #
8312652
Study Section
Special Emphasis Panel (ZDK1-GRB-S (O1))
Program Officer
Kimmel, Paul
Project Start
2009-09-30
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$588,763
Indirect Cost
$308,416
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Rebholz, Casey M; Grams, Morgan E; Coresh, Josef et al. (2015) Serum fibroblast growth factor-23 is associated with incident kidney disease. J Am Soc Nephrol 26:192-200
Foster, Meredith C; Inker, Lesley A; Levey, Andrew S et al. (2013) Novel filtration markers as predictors of all-cause and cardiovascular mortality in US adults. Am J Kidney Dis 62:42-51
Gottesman, O; Scott, S A; Ellis, S B et al. (2013) The CLIPMERGE PGx Program: clinical implementation of personalized medicine through electronic health records and genomics-pharmacogenomics. Clin Pharmacol Ther 94:214-7

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