Dataset Information

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

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.

SUBMITTER: Sekula P

PROVIDER: S-EPMC4814172 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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

Sekula Peggy P Goek Oemer-Necmi ON Quaye Lydia L Barrios Clara C Levey Andrew S AS Römisch-Margl Werner W Menni Cristina C Yet Idil I Gieger Christian C Inker Lesley A LA Adamski Jerzy J Gronwald Wolfram W Illig Thomas T Dettmer Katja K Krumsiek Jan J Oefner Peter J PJ Valdes Ana M AM Meisinger Christa C Coresh Josef J Spector Tim D TD Mohney Robert P RP Suhre Karsten K Kastenmüller Gabi G Köttgen Anna A

Journal of the American Society of Nephrology : JASN 20151008 4

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 ...[more]

PMID: 26449609

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Project description:ObjectiveTo determine the association between baseline kidney function and subsequent all-cause mortality.Design and settingA general population-based cohort study from rural Uganda.ParticipantsPeople aged 18 years and above with measured baseline estimated glomerular filtration rate (eGFR), recruited from survey rounds in 2011-2012 or 2014-2015 and followed up to March 2019.Outcome measureThe primary outcome was all-cause mortality, identified through reports from community health workers and verified by verbal autopsy. The association between baseline eGFR category and mortality was determined using multivariable Cox regression.ResultsOf 5812 participants in both rounds, we included 5678 (97.7%) participants with kidney function and mortality data; the median age was 36 years (IQR 24-50), 60.7% were female, 10.3% were hypertensive, 9.8% were HIV-positive and 1.5% were diabetic. During a median follow-up of 5.0 years (IQR 3.7-6.0) there were 140 deaths. In age-adjusted and sex-adjusted analyses, eGFR <45 mL/min/1.73 m2 at baseline was associated with a 5.97 (95% CI 2.55 to 13.98) increased risk of mortality compared with those with baseline eGFR >90 mL/min/1.73 m2. After inclusion of additional confounders (HIV, body mass index, diabetes, hypertension, alcohol and smoking status) into the model, eGFR <45 mL/min/1.73 m2 at baseline remained strongly associated with mortality (HR 6.12, 95% CI 2.27 to 16.45), although the sample size fell to 3102. Test for trend showed strong evidence (p<0.001) that the rate of mortality increased progressively as the category of baseline kidney function decreased. When very high eGFR was included as a separate category in age-adjusted and sex-adjusted analyses, baseline eGFR ≥120 mL/min/1.73 m2 was associated with increased risk of mortality (HR 2.68, 95% CI 1.47 to 4.87) compared with the reference category of 90-119 mL/min/1.73 m2.ConclusionIn a prospective cohort in rural Uganda we found that impaired baseline kidney function was associated with subsequently increased total mortality. Improved understanding of the determinants of kidney disease and its progression is needed in order to inform interventions for prevention and treatment.

Dataset Information

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

Publications

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

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