A Metabolome-Wide Association Study of Kidney Function and Disease in the General Population

Peggy Sekula, Oemer Necmi Goek, Lydia Quaye, Clara Barrios, Andrew S. Levey, Werner Römisch-Margl, Cristina Menni, Idil Yet, Christian Gieger, Lesley A. Inker, Jerzy Adamski, Wolfram Gronwald, Thomas Illig, Katja Dettmer, Jan Krumsiek, Peter J. Oefner, Ana M. Valdes, Christa Meisinger, Josef Coresh, Tim D. SpectorRobert P. Mohney, Karsten Suhre, Gabi Kastenmüller, Anna Köttgen

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76 Citations (Scopus)

Abstract

Small molecules are extensively metabolized and cleared by the kidney. Changes in serum metabolite concentrations may result from impaired kidney function and can be used to estimate filtration (e.g., the established marker creatinine) or may precede and potentially contribute to CKD development. Here, we applied a nontargeted metabolomics approach using gas and liquid chromatography coupled to mass spectrometry to quantify 493 small molecules in human serum. The associations of these molecules with GFR estimated on the basis of creatinine (eGFRcr) and cystatin C levels were assessed in ≤1735 participants in the KORA F4 study, followed by replication in 1164 individuals in the TwinsUK registry. After correction for multiple testing, 54 replicated metabolites significantly associated with eGFRcr, and six of these showed pairwise correlation (r≥0.50) with established kidney function measures: C-mannosyltryptophan, pseudouridine, N-acetylalanine, erythronate, myo-inositol, and N-acetylcarnosine. Higher C-mannosyltryptophan, pseudouridine, and O-sulfo-L-tyrosine concentrations associated with incident CKD (eGFRcr <60 ml/min per 1.73 m(2)) in the KORA F4 study. In contrast with serum creatinine, C-mannosyltryptophan and pseudouridine concentrations showed little dependence on sex. Furthermore, correlation with measured GFR in 200 participants in the AASK study was 0.78 for both C-mannosyltryptophan and pseudouridine concentration, and highly significant associations of both metabolites with incident ESRD disappeared upon adjustment for measured GFR. Thus, these molecules may be alternative or complementary markers of kidney function. In conclusion, our study provides a comprehensive list of kidney function-associated metabolites and highlights potential novel filtration markers that may help to improve the estimation of GFR.

Original languageEnglish
Pages (from-to)1175-1188
Number of pages14
JournalJournal of the American Society of Nephrology : JASN
Volume27
Issue number4
DOIs
Publication statusPublished - 1 Apr 2016
Externally publishedYes

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Keywords

  • CKD
  • epidemiology
  • GFR
  • metabolism
  • outcomes

ASJC Scopus subject areas

  • Nephrology

Cite this

Sekula, P., Goek, O. N., Quaye, L., Barrios, C., Levey, A. S., Römisch-Margl, W., Menni, C., Yet, I., Gieger, C., Inker, L. A., Adamski, J., Gronwald, W., Illig, T., Dettmer, K., Krumsiek, J., Oefner, P. J., Valdes, A. M., Meisinger, C., Coresh, J., ... Köttgen, A. (2016). A Metabolome-Wide Association Study of Kidney Function and Disease in the General Population. Journal of the American Society of Nephrology : JASN, 27(4), 1175-1188. https://doi.org/10.1681/ASN.2014111099