Serum Metabolomic Profiling and Incident CKD among African Americans

Abstract

Background and objectives Novel biomarkers that more accurately reflect kidney function and predict future CKD are needed. The human metabolome is the product of multiple physiologic or pathophysiologic processes and may provide novel insight into disease etiology and progression. This study investigated whether estimated kidney function would be associated with multiple metabolites and whether selected metabolomic factors would be independent risk factors for incident CKD.Design, setting, participants, & measurements In total, 1921 African Americans free of CKD with a median of 19.6 years follow-up among the Atherosclerosis Risk in Communities Study were included. A total of 204 serum metabolites quantified by untargeted gas chromatography-mass spectrometry and liquid chromatographymass spectrometry was analyzed by both linear regression for the cross-sectional associations with eGFR (specified by the Chronic Kidney Disease Epidemiology Collaboration equation) and Cox proportional hazards model for the longitudinal associations with incident CKD.Results Forty named and 34 unnamed metabolites were found to be associated with eGFR specified by the Chronic Kidney Disease Epidemiology Collaboration equation with creatine and 3-indoxyl sulfate showing the strongest positive (2.8 ml/min per 1.73 m 2 per +1 SD; 95% confidence interval, 2.1 to 3.5) and negative association (214.2 ml/min per 1.73 m 2 per +1 SD; 95% confidence interval, 217.0 to 211.3), respectively. Two hundred four incident CKD events with a median follow-up time of 19.6 years were included in the survival analyses. Higher levels of 5-oxoproline (hazard ratio, 0.70; 95% confidence interval, 0.60 to 0.82) and 1,5-anhydroglucitol (hazard ratio, 0.68; 95% confidence interval, 0.58 to 0.80) were significantly related to lower risk of incident CKD, and the associations did not appreciably change when mutually adjusted.Conclusions These data identify a large number of metabolites associated with kidney function as well as two metabolites that are candidate risk factors for CKD and may provide new insights into CKD biomarker identification.

Metabolite Markers of Incident CKD Risk

“…In this study, the authors first examined the cross-sectional association of serum metabolite levels with eGFR calculated using the CKD-EPI study equation (eGFR CKD-EPI ). Consistent with several prior reports (9-12), Yu et al found that the levels of many metabolites are higher among individuals with lower eGFR (8). Extending these cross-sectional observations, Yu et al linked metabolite profiles at the beginning of follow-up to the future occurrence of CKD, defined as an eGFR CKD-EPI ,60 ml/min per 1.73 m 2 and ,75% of baseline, or a CKD-related hospitalization or death during a median follow-up of 19.6 years.…”

“…Extending these cross-sectional observations, Yu et al linked metabolite profiles at the beginning of follow-up to the future occurrence of CKD, defined as an eGFR CKD-EPI ,60 ml/min per 1.73 m 2 and ,75% of baseline, or a CKD-related hospitalization or death during a median follow-up of 19.6 years. Using Cox proportional hazards models to analyze the 1921 study participants (204 of whom developed CKD), the authors highlight 5-oxoproline (hazard ratio , 0.70 per 11 SD; P,0.001; 95% CI, 0.60 to 0.82; [8]) and 1,5-anhydroglucitol (hazard ratio, 0.68 per 11 SD; P,0.001; 95% CI, 0.58 to 0.80; [8]) as significant markers whose higher levels were associated with a decreased risk of future CKD, after adjusting for baseline eGFR, age, sex, systolic BP, antihypertensive medication use, diabetes status, smoking status, coronary heart disease, as well as HDL and LDL cholesterol.The explanation for why higher levels of these markers were associated with lower disease risk is unclear. The authors speculate that elevated 5-oxoproline levels may be salutary by contributing to the biosynthesis of glutathione, an antioxidant that could attenuate the oxidative…”

“…In this issue of CJASN, Yu et al (8) extend the existing literature on metabolomics and incident CKD, examining 204 metabolites measured in 1921 African-American participants in the Atherosclerosis Risk in Communities (ARIC) study. In this study, the authors first examined the cross-sectional association of serum metabolite levels with eGFR calculated using the CKD-EPI study equation (eGFR CKD-EPI ).…”

Estudo do efeito da nefropatia crônica experimental induzida pelos 5/6 de nefrectomia nas glândulas salivares de ratos

“…As alterações incluem desequilíbrios ácido-base, homeostase (Goek et al, 2013;Rhee et al, 2013;Yu et al, 2014).…”

“…Análises dos perfis metabólicos plasmáticos de pacientes renais crônicos identificaram modificações em diversos metabólitos, entre eles: moléculas relacionadas ao metabolismo do triptofano, como indoxil sulfato, ácido quinurênico, quinurenina e outros como intermediários do ciclo de Krebs, aconitato e isocitrato (Goek et al, 2013;Rhee et al, 2013;Yu et al, 2014).…”