A Metabolome-Wide Association Study of Kidney Function and Disease in the General Population - PubMed (original) (raw)

. 2016 Apr;27(4):1175-88.

doi: 10.1681/ASN.2014111099. Epub 2015 Oct 8.

Oemer-Necmi Goek 2, Lydia Quaye 3, Clara Barrios 4, Andrew S Levey 5, Werner Römisch-Margl 6, Cristina Menni 3, Idil Yet 3, Christian Gieger 7, Lesley A Inker 5, Jerzy Adamski 8, Wolfram Gronwald 9, Thomas Illig 10, Katja Dettmer 9, Jan Krumsiek 11, Peter J Oefner 9, Ana M Valdes 12, Christa Meisinger 13, Josef Coresh 14, Tim D Spector 3, Robert P Mohney 15, Karsten Suhre 16, Gabi Kastenmüller 17, Anna Köttgen 18

Affiliations

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

Peggy Sekula et al. J Am Soc Nephrol. 2016 Apr.

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.

Keywords: CKD; GFR; epidemiology; metabolism; outcomes.

Copyright © 2016 by the American Society of Nephrology.

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Figures

Figure 1.

Figure 1.

Distribution of eGFR-associated markers across strata of CKD and its major risk factors. (A) Creatinine (MS-quantified). (B) N-acetylalanine. (C) Myo-inositol. (D) C-mannosyltryptophan. (E) O-sulfo-L-tyrosine. (F) Pseudouridine. (G) Erythronate. (H) N-acetylcarnosine. The two box plots on the right of each panel represent strata of cystatin-C based CKD and show that especially concentrations of erythronate, pseudouridine, and C-mannosyltryptophan differ more strongly by CKD status than does serum creatinine. Differences in the dependencies on sex and age can be observed for different metabolites.

Figure 2.

Figure 2.

Comparison of serum C-mannosyltryptophan and pseudouridine with serum creatinine and cystatin C over age by sex. (A) C-mannosyltryptophan. (B) Pseudouridine. (C) Serum creatinine (standard method). (D) Serum cystatin C. Results are shown with solid lines for men and dashed lines for women. The three lines correspond to the median and 25th and 75th percentiles. Creatinine and cystatin C are transformed (median-scaled, log10 transformed) similarly to the MS-quantified metabolites to facilitate comparison. In contrast to other markers, serum creatinine concentrations are clearly higher in men than in women. They increase less with advanced age, when muscle mass typically declines.

References

    1. Eckardt KU, Coresh J, Devuyst O, Johnson RJ, Köttgen A, Levey AS, Levin A: Evolving importance of kidney disease: From subspecialty to global health burden. Lancet 382: 158–169, 2013 - PubMed
    1. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, Jafar TH, Heerspink HJ, Mann JF, Matsushita K, Wen CP: Chronic kidney disease and cardiovascular risk: Epidemiology, mechanisms, and prevention. Lancet 382: 339–352, 2013 - PubMed
    1. Stevens LA, Coresh J, Greene T, Levey AS: Assessing kidney function--measured and estimated glomerular filtration rate. N Engl J Med 354: 2473–2483, 2006 - PubMed
    1. Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, Kusek JW, Manzi J, Van Lente F, Zhang YL, Coresh J, Levey AS, CKD-EPI Investigators : Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 367: 20–29, 2012 - PMC - PubMed
    1. Shlipak MG, Matsushita K, Ärnlöv J, Inker LA, Katz R, Polkinghorne KR, Rothenbacher D, Sarnak MJ, Astor BC, Coresh J, Levey AS, Gansevoort RT, CKD Prognosis Consortium : Cystatin C versus creatinine in determining risk based on kidney function. N Engl J Med 369: 932–943, 2013 - PMC - PubMed

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