Metabolomics of CKD and CKD Progression

CKD 和 CKD 进展的代谢组学

• 批准号: 8976919
• 负责人: EUGENE P. RHEE
• 金额: $ 44.71万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-14 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8976919
• 关键词: Advanced Glycosylation End Products; Affect; Albumins; Arginine; Biological; Biological Markers; Biology; Blood; Cardiovascular system; Cessation of life; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Clinical Data; Cohort Studies; Communities; Cyclic AMP; Data; Diabetes Mellitus; Dialysis patients; Disease; Disease Progression; End stage renal failure; Epidemiology; Event; Fibroblast Growth Factor; Genes; Genetic; Genetic Determinism; Genotype; Glomerular Filtration Rate; Goals; Heterogeneity; Human Genetics; Individual; Insulin; Interleukin-6; Investigation; Kidney; Kidney Diseases; Kidney Failure; Link; Lipids; Measures; Metabolic; Metabolic Diseases; Methods; Obesity; Outcome; Pathogenesis; Pathway interactions; Phenotype; Pilot Projects; Plasma; Population Heterogeneity; Population Study; Positioning Attribute; Proteinuria; Renal function; Research; Resolution; Resource Allocation; Resources; Risk; Sampling; Severity of illness; Surveys; Testing; Time; Tryptophan; Urine; Validation; base; clinical care; cohort; disease diagnosis; disease phenotype; drug development; genome wide association study; improved; inorganic phosphate; insight; interest; liquid chromatography mass spectrometry; metabolomics; novel; novel marker; outcome forecast; public health relevance; small molecule

 DESCRIPTION (provided by applicant): 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.