Metabolite profiling of CKD progression in the chronic renal insufficiency cohort (CRIC) study.

BACKGROUND: Metabolomic profiling in individuals with chronic kidney disease (CKD) has the potential to identify novel biomarkers and provide insight into disease pathogenesis.

METHODS: We examined the association between blood metabolites and CKD progression, defined as the subsequent development of end-stage renal disease (ESRD) or estimated glomerular filtrate rate (eGFR) halving, in 1773 participants of the Chronic Renal Insufficiency Cohort (CRIC) study, 962 participants of the African American Study of Kidney Disease and Hypertension (AASK), and 5305 participants of the Atherosclerosis Risk in Communities (ARIC) study.

RESULTS: In CRIC, more than half of measured metabolites were associated with CKD progression in minimally adjusted Cox proportional hazards models, but the number and strength of associations were markedly attenuated by serial adjustment for covariates, particularly eGFR. Ten metabolites were significantly associated with CKD progression in fully-adjusted models in CRIC; three of these metabolites were also significant in fully-adjusted models in AASK and ARIC, highlighting potential markers of glomerular filtration (pseudouridine), histamine metabolism (methylimidazoleacetate), and azotemia (homocitrulline). Our findings also nominate N-acetylserine as a potential marker of kidney tubular function, with significant associations with CKD progression observed in CRIC and ARIC.

CONCLUSION: Together, our findings demonstrate the application of metabolomics to identify potential biomarkers and causal pathways in CKD progression.

TRIAL REGISTRATION: Not applicableFUNDING. This study was supported by the NIH (U01 DK106981, U01 DK106982, U01 DK085689, R01 DK108803, R01 DK124399).