Environment-Wide Association Study of CKD

Abstract

Background and objectives: Exposure to environmental chemicals has been recognized as one of the possible contributors to CKD. We aimed to identify environmental chemicals that are associated with CKD.

Design, setting, participants, & measurements: We analyzed the data obtained from a total of 46,748 adults who participated in the National Health and Nutrition Examination Survey (1999-2016). Associations of chemicals measured in urine or blood (n=262) with albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g), reduced eGFR (<60 ml/min per 1.73 m²), and a composite of albuminuria or reduced eGFR were tested and validated using the environment-wide association study approach.

Results: Among 262 environmental chemicals, seven (3%) chemicals showed significant associations with increased risk of albuminuria, reduced eGFR, or the composite outcome. These chemicals included metals and other chemicals that have not previously been associated with CKD. Serum and urine cotinines, blood 2,5-dimethylfuran (a volatile organic compound), and blood cadmium were associated with albuminuria. Blood lead and cadmium were associated with reduced eGFR. Blood cadmium and lead and three volatile compounds (blood 2,5-dimethylfuran, blood furan, and urinary phenylglyoxylic acid) were associated with the composite outcome. A total of 23 chemicals, including serum perfluorooctanoic acid, seven urinary metals, three urinary arsenics, urinary nitrate and thiocyanate, three urinary polycyclic aromatic hydrocarbons, and seven volatile organic compounds, were associated with lower risks of one or more manifestations of CKD.

Conclusions: A number of chemicals were identified as potential risk factors for CKD among the general population.

Keywords: Caprylates; Cotinine; Fluorocarbons; Polycyclic Aromatic Hydrocarbons; Renal Insufficiency, Chronic; Thiocyanates; Volatile Organic Compounds; albuminuria; cadmium; chronic kidney disease; creatinine; environmental chemicals; glomerular filtration rate; lead; perfluorooctanoic acid; phenylglyoxylic acid; risk factors; volatile organic compounds.

Graphical abstract

Figure 1.

Schematic flow chart for the association analysis of environmental chemicals with CKD. BMI, body mass index; DM, diabetes mellitus; HTN, hypertension.

Figure 2.

Manhattan plot of EWAS of environmental chemicals for CKD. (A) Manhattan plot of EWAS for albuminuria. (B) Manhattan plot of EWAS for reduced eGFR. (C) Manhattan plot of EWAS for composite CKD outcome. The associations between environmental chemicals and CKD in the discovery set are presented with Manhattan plot of EWAS. y axis represent the −log₁₀(P value) of the meta-analysis in the discovery set. x axis represents the categorized environmental chemicals. Dashed line represents the cut-off value of significance corresponding to FDR 1%. Different colors were assigned to different environmental chemical groups. Circle indicates environmental chemical tested in the discovery set. Large square indicates validated discovered (false discovery rate <1%) and validated chemicals (meta-analysis P<0.05) both in the discovery set and validation set. PCB, polychlorinated biphenyls.