A combined epidemiologic and metabolomic approach improves CKD prediction

Eugene P. Rhee, Clary B. Clish, Anahita Ghorbani, Martin G. Larson, Sammy Elmariah, Elizabeth McCabe, Qiong Yang, Susan Cheng, Kerry Pierce, Amy Deik, Amanda L. Souza, Laurie Farrell, Carly Domos, Robert W. Yeh, Igor Palacios, Kenneth Rosenfield, Ramachandran S. Vasan, Jose C. Florez, Thomas J. Wang, Caroline S. FoxRobert E. Gerszten

Research output: Contribution to journalArticle

132 Scopus citations

Abstract

Metabolomic approaches have begun to catalog the metabolic disturbances that accompany CKD, but whether metabolite alterations can predict future CKD is unknown. We performed liquid chromatography/ mass spectrometry-based metabolite profiling on plasma from 1434 participants in the Framingham Heart Study (FHS) who did not have CKD at baseline. During the following 8 years, 123 individuals developed CKD, defined by an estimated GFR of <60 ml/min per 1.73 m 2. Numerous metabolites were associated with incident CKD, including 16 that achieved the Bonferroni-adjusted significance threshold of P≤0.00023. To explore how the human kidney modulates these metabolites, we profiled arterial and renal venous plasma from nine individuals. Nine metabolites that predicted CKD in the FHS cohort decreased more than creatinine across the renal circulation, suggesting that they may reflect non- GFR-dependent functions, such as renal metabolism and secretion. Urine isotope dilution studies identified citrulline and choline as markers of renal metabolism and kynurenic acid as a marker of renal secretion. In turn, these analytes remained associated with incident CKD in the FHS cohort, even after adjustment for eGFR, age, sex, diabetes, hypertension, and proteinuria at baseline. Addition of a multimarker metabolite panel to clinical variables significantly increased the c-statistic (0.77-0.83, P<0.0001); net reclassification improvement was 0.78 (95% confidence interval, 0.60 to 0.95; P<0.0001). Thus, the addition of metabolite profiling to clinical data may significantly improve the ability to predict whether an individual will develop CKD by identifying predictors of renal risk that are independent of estimated GFR.

Original languageEnglish (US)
Pages (from-to)1330-1338
Number of pages9
JournalJournal of the American Society of Nephrology
Volume24
Issue number8
DOIs
StatePublished - Jul 31 2013
Externally publishedYes

ASJC Scopus subject areas

  • Nephrology

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    Rhee, E. P., Clish, C. B., Ghorbani, A., Larson, M. G., Elmariah, S., McCabe, E., Yang, Q., Cheng, S., Pierce, K., Deik, A., Souza, A. L., Farrell, L., Domos, C., Yeh, R. W., Palacios, I., Rosenfield, K., Vasan, R. S., Florez, J. C., Wang, T. J., ... Gerszten, R. E. (2013). A combined epidemiologic and metabolomic approach improves CKD prediction. Journal of the American Society of Nephrology, 24(8), 1330-1338. https://doi.org/10.1681/ASN.2012101006