Assessing the Effects of Metal Mixtures in Urine and Blood on Kidney Function

BACKGROUND AND AIM: Exposure to metal(oid)s including lead (Pb), cadmium (Cd), and arsenic (As) may impair kidney function individually and in mixtures. However, each metal has unique toxicokinetics reflected in respective biological media (e.g., blood, urine), implying that no single medium is ideal to study multiple metals simultaneously. We hypothesized that multi-media biomarkers (MMBs), integrated exposure indices that combine information across biomarkers into a common metric are informative of adverse kidney function. METHODS: Levels of Pb, Cd, and As were quantified in blood and urine in 300 4-6 year-old Mexican children in the PROGRESS longitudinal cohort study. MMBs were constructed for the metals using weighted quantile sum regression (WQS) and the two media. We estimated the joint effects of the Pb-Cd-As metal mixture on cystatin C-based estimated glomerular filtration rate (eGFR) and serum creatinine (SCR) assessed at 8-10 years of age, adjusted for covariates. RESULTS:Quartile increases in the WQS urine metal index and the WQS index across urine and blood (MMBs) were associated with increased eGFR (2.5%, 95%CI [0.1, 5.0]) and (3.0%, 95%CI [0.2, 5.7]), respectively. Additionally, all three—blood, urine, and MMBs—indices predicted decreased SCR: blood (-0.18 mg/L, 95%CI [-0.33, -0.04]), urine (-0.12 mg/L, 95%CI [-0.23, -0.01]), and MMBs (-0.20 mg/L, 95%CI [-0.35, -0.06]). Regardless of medium, weights indicate that Cd contributed most to the associations with eGFR, while Pb contributed most to the associations with SCR. CONCLUSIONS:We observed associations between metal mixtures, in two media, and hyperfiltration, an early indicator of potential kidney function decline. KEYWORDS: Exposure assessment-biomarkers of exposure, Mixtures, Mixtures analysis, Heavy metals