A metabolome-wide association study of kidney function and disease in the general population
Open accessAbstract
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.
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C-mannosyl tryptophan and pseudouridine were identified as excellent renal functional surrogates in a recent untargeted metabolomics study.
“In a recent untargeted metabolomics study examining nearly 500 analytes to identify those that most closely correlate with renal function, C-mannosyl tryptophan and pseudouridine were identified as excellent renal functional surrogates.24”
From Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women (2019) · cites this paper as [24]
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- Authors
- 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., Spector, T. D., Mohney, R. P., Suhre, K., Kastenmüller, G., & Köttgen, A.
- Affiliations
- University of Freiburg (DE)
- King's College London (GB)
- Tufts Medical Center (US)
- Medizinische Hochschule Hannover (DE)
- University of Nottingham (GB)
- Helmholtz Munich (DE)
- Institute of Bioinformatics and Systems Biology (DE)
- Corresponding author
- Sekula, Peggy
- Goek, Oemer-Necmi
- Gieger, Christian
- Illig, Thomas
- Suhre, Karsten
- Köttgen, Anna
- ORCID
- Sekula, Peggy
- Barrios, Clara
- Levey, Andrew S.
- Menni, Cristina
- Gieger, Christian
- Inker, Lesley A.
- Adamski, Jerzy
- Gronwald, Wolfram
- Illig, Thomas
- Dettmer, Katja
- Krumsiek, Jan
- Oefner, Peter J.
- Valdes, Ana M.
- Meisinger, Christa
- Coresh, Josef
- Spector, Tim D.
- Mohney, Robert P.
- Suhre, Karsten
- Kastenmüller, Gabi
- Köttgen, Anna
- Venue
- Journal of the American Society of Nephrology
- Published
- 2016-04
- Volume
- 27
- Issue
- 4
- Pages
- 1175-1188
- ISSN
- 1046-6673 (ISSN-L)
- PMC
- PMC4814172
- OpenAlex
- W2180331025
- Cited by
- 203
- References
- 61
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 19 · 2023: 16 · 2022: 18 · 2021: 28 · 2020: 21 · 2019: 25 · 2018: 24 · 2017: 20 · 2016: 7 · 2014: 1
- FWCI
- 7.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of the American Society of Nephrology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion)
- Site cant be reached (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- OPUS (Augsburg University) (submittedVersion)
- Funders
- Wellcome Trust
- National Institute for Health and Care Research (NF-SI-0514-10027)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK097020)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Keywords
- renal function, chronic kidney disease, estimated glomerular filtration rate, cystatin C, serum metabolites, untargeted metabolomics, pseudouridine, end-stage renal disease, creatinine, TwinsUK
- MeSH terms
- Cross-Sectional Studies, Female, Glomerular Filtration Rate, Humans, Male, Middle Aged, Renal Insufficiency, Chronic, Genome-Wide Association Study, Metabolome
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