Associations of Plasma Amino Acid and Acylcarnitine Profiles with Incident Reduced Glomerular Filtration Rate

Abstract

Background and objectives: Metabolomics is instrumental in identifying novel biomarkers of kidney function to aid in the prevention and management of CKD. However, data linking the metabolome to incident eGFR are sparse, particularly in Asian populations with different genetic backgrounds and environmental exposures. Therefore, we aimed to investigate the associations of amino acid and acylcarnitine profiles with change in eGFR in a Chinese cohort.

Design, setting, participants, & measurements: This study included 1765 community-living Chinese adults aged 50-70 years with baseline eGFR≥60 ml/min per 1.73 m2. At baseline, 22 amino acids and 34 acylcarnitines in plasma were quantified by gas or liquid chromatography coupled with mass spectrometry. Annual rate of change in eGFR was calculated, and incident eGFR decline was defined as eGFR<60 ml/min per 1.73 m2 by the end of 6 years of follow-up.

Results: The mean (SD) unadjusted annual change in eGFR was 2.2±2.0 ml/min per 1.73 m2 and the incidence of reduced eGFR was 16%. After Bonferroni correction, 13 of 56 metabolites were significantly associated with annual eGFR change. After multivariable adjustment of baseline covariates, including baseline eGFR, seven of the 13 metabolites, including cysteine, long-chain acylcarnitines (C14:1OH, C18, C18:2, and C20:4), and other acylcarnitines (C3DC and C10), were significantly associated with incident reduced eGFR (relative risks ranged from 1.16 to 1.25 per SD increment of metabolites; P<3.8E-03 after Bonferroni correction of multiple testing of the 13 metabolites). Moreover, principal component analysis identified two factors, consisting of cysteine and long-chain acylcarnitines, respectively, that were associated with incident reduced eGFR.

Conclusions: Elevated plasma levels of cysteine and a panel of acylcarnitines were associated with a higher incidence of reduced eGFR in Chinese adults, independent of baseline eGFR and other conventional risk factors.

Keywords: Adult; Amino Acids; Biomarkers; Carnitine; Chromatography, Liquid; Cysteine; Environmental Exposure; Follow-Up Studies; Genetic Background; Humans; Incidence; Mass Spectrometry; Metabolome; Metabolomics; Principal Component Analysis; Renal Insufficiency, Chronic; acylcarnitine; glomerular filtration rate; risk factors.

Copyright © 2018 by the American Society of Nephrology.

Figures

Graphical abstract

Figure 1.

Associations of plasma amino acids and their ratios with baseline eGFR (eight amino acids significantly associated) and annual change in eGFR (three significantly associated) in the Nutrition and Health of Aging Population in China study. (A) Difference in eGFR per SD increment in metabolite (ml/min per 1.73 m2). (B) Difference in change in eGFR per SD increment in metabolite (ml/min per 1.73 m2 per year). Effect sizes (β) (left y axis), with corresponding P values (right y axis), for the amino acids arranged by ascending β (model 3) for annual eGFR change along the x axis are shown. The dotted horizontal line shows the cutoff for P=8.9E-04 after Bonferroni correction for multiple testing of the 56 metabolites. Model 2 was adjusted for age, sex, region, residence, educational attainment, physical activity, current smoking, current drinking, body mass index, lipid-lowering medication use, HDL, LDL, cardiovascular disease, hypertension, and type 2 diabetes. Model 3 was further adjusted for baseline eGFR only for outcome of annual eGFR change.

Figure 2.

Associations of plasma acylcarnitines (acylCNs) with baseline eGFR (seven acylCNs significantly associated) and annual change in eGFR (10 significantly associated) in the Nutrition and Health of Aging Population in China study. (A) Difference in eGFR per SD increment in metabolite (ml/min per 1.73 m2). (B) Difference in change in eGFR per SD increment in metabolite (ml/min per 1.73 m2 per year). Effect sizes (β) (left y axis), with corresponding P values (right y axis), for the acylCNs arranged by ascending acyl chain length along the x axis are shown. The dotted horizontal line shows the cutoff for P=8.9E-04 after Bonferroni correction for multiple testing of the 56 metabolites. Short-, medium-, and long-chain acylCN categories were calculated as Z scores of log-transformed acylCNs of carbon chains ≤6, 7–12, and ≥14, respectively. Model 2 was adjusted for age, sex, region, residence, educational attainment, physical activity, current smoking, current drinking, body mass index, lipid-lowering medication use, HDL, LDL, cardiovascular disease, hypertension, and type 2 diabetes. Model 3 was further adjusted for baseline eGFR only for outcome of annual eGFR change.