Chronic kidney disease (CKD) is common and associated with a wide range of adverse outcomes. Two biomarkers, serum creatinine and albuminuria, provide the mainstay for staging and risk assessment for the majority of CKD patients. Both clinical trials and clinical care are hampered by the limitations of these markers and could benefit substantially from discovery and validation of additional markers. In reponse to the RFA, """"""""CKD Biomarker Discovery and Validation Consortium"""""""", we propose an innovative project that combines breakthrough methods for biomarker discovery with rigorous epidemiological, statistical and clinical chemistry expertise applied with a deep knowledge of four extremely well characterized cohorts.
Aim 1 : Biomarker Discovery. 1 .A. De novo discovery of serum filtration markers for CKD staging. State of the art proteomic discovery methods will identify proteins with >2x elevation from baseline to follow-up in stored serum of AASK participants whose measured GFR declined from >60 to <30 ml/min/1.73m2 or 2x their serum creatinine. 1 .B. Targeted discovery of urine and serum markers of damage for CKD progression. Absolute quantiation mass spectrometry methods will tests 15 of the most promising urine and serum markers in their ability to distinguish 100 cases with rapid CKD progression to EBRD from 100 controls with similar baseline measured GFR which remained stable from the AASK and MDRD Studies. 1 .C. Verification of the most promising markers from 1 .A. and 1 .B in a larger sample size Aim 2: Biomarker Validation: We will test the most promosing biomarkers identified in aim 1 and through by the consortium in their ability to estimate kidney function and risk of CKD progression in the entire AASK and MDRD Study population and case-control studies of progressive CKD in ARIC and a sample of NHANES. Our studies are guided by extensive experience in nephrology, biostatistics, epidemiology, proteomics, clinical chemistry, collaborative studies, recent pilot studies of novel markers for GFR estimation and genomic discoveries of relevant pathways for AKI and CKD.
Chronic kidney disease is common and usually stages by blood and urine markers. Currently serum creatinine and urinary albumin at the most widely used biomarkers for staging and prognosis of patients with chronic kidney disease. We propose to join a consortium whose goal is to discover and validate additional markers which will improve patient care and faciliate research in chronic kidney disease.
|Hoofnagle, Andrew N; Whiteaker, Jeffrey R; Carr, Steven A et al. (2016) Recommendations for the Generation, Quantification, Storage, and Handling of Peptides Used for Mass Spectrometry-Based Assays. Clin Chem 62:48-69|
|Inker, Lesley A; Tighiouart, Hocine; Coresh, Josef et al. (2016) GFR Estimation Using Î²-Trace Protein and Î²2-Microglobulin inÂ CKD. Am J Kidney Dis 67:40-8|
|Fu, Qin; Chen, Zhaohui; Zhang, Shenyan et al. (2016) Multiple and Selective Reaction Monitoring Using Triple Quadrupole Mass Spectrometer: Preclinical Large Cohort Analysis. Methods Mol Biol 1410:249-64|
|Foster, Meredith C; Coresh, Josef; Hsu, Chi-Yuan et al. (2016) Serum Î²-Trace Protein and Î²2-Microglobulin as Predictors of ESRD, Mortality, and Cardiovascular Disease in Adults With CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study. Am J Kidney Dis 68:68-76|
|Fu, Qin; Grote, Eric; Zhu, Jie et al. (2016) An Empirical Approach to Signature Peptide Choice for Selected Reaction Monitoring: Quantification of Uromodulin in Urine. Clin Chem 62:198-207|
|Waikar, Sushrut S; Sabbisetti, Venkata; Ã„rnlÃ¶v, Johan et al. (2016) Relationship of proximal tubular injury to chronic kidney disease as assessed by urinary kidney injury molecule-1 in five cohort studies. Nephrol Dial Transplant 31:1460-70|
|Rebholz, Casey M; Grams, Morgan E; Lutsey, Pamela L et al. (2016) Biomarkers of Vitamin D Status and Risk of ESRD. Am J Kidney Dis 67:235-42|
|Fufaa, Gudeta D; Weil, E Jennifer; Nelson, Robert G et al. (2015) Urinary monocyte chemoattractant protein-1 and hepcidin and early diabetic nephropathy lesions in type 1 diabetes mellitus. Nephrol Dial Transplant 30:599-606|
|Fufaa, Gudeta D; Weil, E Jennifer; Nelson, Robert G et al. (2015) Association of urinary KIM-1, L-FABP, NAG and NGAL with incident end-stage renal disease and mortality in American Indians with type 2 diabetes mellitus. Diabetologia 58:188-98|
|Rebholz, Casey M; Grams, Morgan E; Matsushita, Kunihiro et al. (2015) Change in novel filtration markers and risk of ESRD. Am J Kidney Dis 66:47-54|
Showing the most recent 10 out of 18 publications