Reduced glomerular filtration rate (GFR) in chronic kidney disease (CKD) results in an accumulation of a large number of metabolites, a subset of which likely mediate risk of end-stage renal disease (ESRD). In this proposal, we will discover and validate blood metabolites whose levels predict ESRD risk beyond that marked by low GFR in 5 CKD studies. Highest emphasis will be placed on metabolomic abnormalities which are promising therapeutics targets and/or outcomes for CKD clinical trials.
Study aim summary:
Aim 1 : To discover metabolic risk factors for CKD progression through global metabolomic profiling. Unbiased global metabolomic profiling now allows reliable quantification of ~1,000 named metabolites from a large compound library. We will apply these methods to samples from AASK (n=804, 296 incident ESRD), MDRD Study (n=697, 546 incident ESRD) and CRIC (case-cohort design, n=500 with 250 incident ESRD cases). We hypothesize that a subset of metabolites with altered levels in CKD will remain risk factors for ESRD after rigorously adjusting for baseline GFR. These metabolites will also hold great promise for risk stratification and as therapeutic targets (e.g., to diet and microbiome manipulation).
Aim 2 : To validate findings from Aim 1 in an independent sample and extend analyses to other CKD etiologies (polycystic kidney disease, PKD; kidney transplantation, KT). Validation will focus on four methodological aspects: 1) longitudinal stability in follow-up samples (n =50 per study); 2) risk associations of total vs. free metabolite levels, with the latter determined by removal of protein- bound metabolites; 3) external replication in additional samples in a general CKD cohort, CRIC (N=400); and 4) replication in 2 CKD cohorts with distinct etiologies (HALT-PKD and FAVORIT (KT); N=400 each).
Aim 3 : To characterize the effect of randomized dietary interventions on the metabolome in CKD Using samples at baseline and after randomization we will test the hypothesis that randomized interventions in MDRD Study (low protein diets and essential keto-acids) and FAVORIT (folate and B-vitamin) dramatically alter the metabolome; and that metabolite alterations will relate to subsequent outcomes and may explain subgroups where the intervention was effective, although the trials were negative overall.
Aim 4 : To develop, evaluate, and apply clinical assays for validated metabolites Targeted assays provide the absolute quantification and greater precision needed for clinical application. We will develop clinical laboratory tests to CAP (College of American Pathologists) standards for the top hits from Aim 2, re-measure a subsample from each cohort and test in a new clinical cohort (n=800). The proposal benefits from our extensive history of innovation and collaboration in CKD-Biocon as well as CKD clinical guideline development, CKD Epidemiology Collaboration, CKD Prognosis Consortium, CKD genetics, and FDA workshops and can result in great advances in the understanding and treatment of CKD progression.
This proposal will extent work on biomarkers for chronic kidney disease and focus on small molecules (metabolites) whose levels predict higher risk of progression to dialysis or kidney transplantation. The area is particularly promising new technologies (metabolomics) are available, the kidneys filter all small molecules and toxic ones can often be changed by diet or other treatments.
| Hu, Jiun-Ruey; Coresh, Josef; Inker, Lesley A et al. (2018) Serum metabolites are associated with all-cause mortality in chronic kidney disease. Kidney Int 94:381-389 |
| Rebholz, Casey M; Yu, Bing; Zheng, Zihe et al. (2018) Serum metabolomic profile of incident diabetes. Diabetologia 61:1046-1054 |
| Rebholz, Casey M; Selvin, Elizabeth; Liang, Menglu et al. (2018) Plasma galectin-3 levels are associated with the risk of incident chronic kidney disease. Kidney Int 93:252-259 |
| Luo, Shengyuan; Coresh, Josef; Tin, Adrienne et al. (2018) Soluble Urokinase-Type Plasminogen Activator Receptor in Black Americans with CKD. Clin J Am Soc Nephrol 13:1013-1021 |
| Grams, Morgan E; Shafi, Tariq; Rhee, Eugene P (2018) Metabolomics Research in Chronic Kidney Disease. J Am Soc Nephrol 29:1588-1590 |
| Park, Meyeon; Hsu, Chi-Yuan; Go, Alan S et al. (2017) Urine Kidney Injury Biomarkers and Risks of Cardiovascular Disease Events and All-Cause Death: The CRIC Study. Clin J Am Soc Nephrol 12:761-771 |
| Tuttle, Katherine R (2017) Back to the Future: Glomerular Hyperfiltration and the Diabetic Kidney. Diabetes 66:14-16 |
| Rebholz, Casey M; Inker, Lesley A; Chen, Yuan et al. (2017) Risk of ESRD and Mortality Associated With Change in Filtration Markers. Am J Kidney Dis 70:551-560 |
| Inker, Lesley A; Coresh, Josef; Sang, Yingying et al. (2017) Filtration Markers as Predictors of ESRD and Mortality: Individual Participant Data Meta-Analysis. Clin J Am Soc Nephrol 12:69-78 |
| Wheelock, Kevin M; Cai, Jian; Looker, Helen C et al. (2017) Plasma bradykinin and early diabetic nephropathy lesions in type 1 diabetes mellitus. PLoS One 12:e0180964 |
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