A systematic survey of the plasma metabolome is a promising approach for CKD biomarker research because CKD lies at the intersection of various metabolic disorders, because of the broad impact renal function has on circulating metabolites, and because circulating metabolites may themselves participate in disease pathogenesis. We propose to perform liquid chromatography, mass spectrometry based metabolite profiling on plasma obtained at study entry from 1800 individuals in the Chronic Renal Insufficiency Cohort (CRIC) Study with the goal to discover novel blood-based biomarkers of CKD progression; to understand the cross- sectional association of these metabolites with estimated glomerular filtration rate (eGFR), level of proteinuria, and other CKD phenotypes; and to integrate the metabolite data with genotyping that has already been performed.
Aim 1 will use multivariable Cox regression to examine the relation between baseline metabolite levels and a composite time-to-event outcome of end-stage renal disease or halving of eGFR. We will test the hypothesis that decreased tryptophan and arginine levels and increased cAMP levels are markers of CKD progression, as well as conduct an agnostic examination of all measured metabolite levels.
Aim 2 will assess how plasma metabolites vary across levels of CKD severity (eGFR and level of proteinuria) and in relation to existing markers of disordered metabolism in CKD (albumin, clinical lipids, insulin, advanced glycation end- products, PTH, FGF-23, phosphate, hsCRP, and IL-6).
Aim 3 will perform a genome wide association study (GWAS) to identify causal determinants of metabolite biomarkers of CKD and CKD progression highlighted in Aims 1 and 2, and to assess whether these markers are modulated by genetic loci that have previously been associated with CKD. These studies will permit assessment of whether novel markers belong to causal pathways, and unlike prior metabolomics GWAS would examine a racially diverse population enriched for CKD and its metabolic antecedents. In addition to these scientific objectives, in Aim 4 we seek to establish CRIC as a platform for the validation of novel biomarkers discovered as part of the wider CKD Biomarker Consortium efforts. With extensive study data and an explicit focus on CKD and its complications, the CRIC Study is uniquely positioned to catalyze each component of the proposal, and the CRIC Steering Committee is strongly committed to enriching the broader consortium activities. Importantly, preliminary studies across a spectrum of renal disease demonstrate feasibility for all of the stated Aims. Further, the proposal incorporates technological improvements that have dramatically increased the breadth of our metabolomics platform to now include ~350 known metabolites and >5000 unknown metabolite peaks, thus expanding the scope of metabolites surveyed beyond our prior studies. Finally, all data will be made public via dbGAP as with prior metabolomics and GWAS data generated by our group, providing a powerful resource for the research community.

Public Health Relevance

The rate of chronic kidney disease continues to grow worldwide, but available treatment options are of only limited benefit. The goal of this proposal i to identify new blood markers of chronic kidney disease and to identify the genes that affect these blood markers. These efforts have the potential to improve our ability to identify which individuals with kidney disease will subsequently progress to end-stage renal disease and to improve our understanding of underlying disease mechanisms.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZDK1)
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Gossett, Daniel Robert
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Massachusetts General Hospital
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Grams, Morgan E; Shafi, Tariq; Rhee, Eugene P (2018) Metabolomics Research in Chronic Kidney Disease. J Am Soc Nephrol 29:1588-1590
Rhee, Eugene P (2018) A Systems-Level View of Renal Metabolomics. Semin Nephrol 38:142-150
Rhee, Eugene P (2018) How Omics Data Can Be Used in Nephrology. Am J Kidney Dis 72:129-135