A Combined Epidemiologic and Metabolomic Approach Improves... : Journal of the American Society of Nephrology (original) (raw)

Clinical Research

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

*Nephrology Division,

‡Cardiology Division,

‡‡Diabetes Unit,

§§Center for Human Genetic Research, and

‖‖‖Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts;

†Broad Institute, Cambridge, Massachusetts;

§Framingham Heart Study of the National Heart, Lung, and Blood Institute and Boston University School of Medicine, Framingham, Massachusetts;

‖Department of Mathematics and Statistics, Boston University, Boston, Massachusetts;

¶Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts;

**Cardiovascular Division and

¶¶Endocrinology Division, Brigham & Women’s Hospital, Boston, Massachusetts;

††Preventive Medicine and Epidemiology and Cardiology Sections, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts;

‖‖Division of Cardiovascular Medicine, Vanderbilt University Medical Center, and Vanderbilt Heart and Vascular Institute, Nashville, Tennessee; and

***Division of Intra-mural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland

C.S.F. and R.E.G. contributed equally to this work.

Correspondence: Dr. Eugene P. Rhee, Nephrology Division, Department of Medicine, Massachusetts General Hospital, 149 13th Street, 8th Floor, 8401, Charlestown, MA 02129, or Dr. Robert E. Gerszten, Cardiology Division, Department of Medicine, Massachusetts General Hospital, 185 Cambridge Street, Simches Research Center, Room 3412, Boston, MA 02114. Email: [email protected] or [email protected]

Received October 19, 2012

Accepted February 27, 2013

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 m2. 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.