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Metabolite Profiling Identifies Markers of Uremia

Eugene P. Rhee^*,, Amanda Souza, Laurie Farrell, Martin R. Pollak, Gregory D. Lewis, David J.R. Steele^*, Ravi Thadhani^*, Clary B. Clish, Anna Greka^* and Robert E. Gerszten^,,||

*Nephrology Division, Massachusetts General Hospital, Boston, Massachusetts;
Broad Institute, Cambridge, Massachusetts;
Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts;
Nephrology Division, Brigham and Women's Hospital, Boston, Massachusetts; and
^||Center for Immunology & Inflammatory Diseases, Massachusetts General Hospital, Boston, Massachusetts

Correspondence: Dr. Robert Gerszten, Massachusetts General Hospital, 149 13th Street, 8th Floor, Charlestown, MA 02129. Phone: 617-724-8322; Fax: 617-726-5651; E-mail: rgerszten{at}partners.org

Received for publication November 30, 2009. Accepted for publication February 3, 2010.

ESRD is a state of small-molecule disarray. We applied liquid chromatography/tandem mass spectrometry-based metabolite profiling to survey >350 small molecules in 44 fasting subjects with ESRD, before and after hemodialysis, and in 10 age-matched, at-risk fasting control subjects. At baseline, increased levels of polar analytes and decreased levels of lipid analytes characterized uremic plasma. In addition to confirming the elevation of numerous previously identified uremic toxins, we identified several additional markers of ESRD, including dicarboxylic acids (adipate, malonate, methylmalonate, and maleate), biogenic amines, nucleotide derivatives, phenols, and sphingomyelins. The pattern of lipids was notable for a universal decrease in lower-molecular-weight triacylglycerols, and an increase in several intermediate-molecular-weight triacylglycerols in ESRD compared with controls; standard measurement of total triglycerides obscured this heterogeneity. These observations suggest disturbed triglyceride catabolism and/or β-oxidation in ESRD. As expected, the hemodialysis procedure was associated with significant decreases in most polar analytes. Unexpected increases in several metabolites, however, indicated activation of a broad catabolic program, including glycolysis, lipolysis, ketosis, and nucleotide breakdown. In summary, this study demonstrates the application of metabolite profiling to identify markers of ESRD, provide perspective on uremic dyslipidemia, and broaden our understanding of the biochemical effects of hemodialysis.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673