Association and mediation analyses among multiple metals exposure, plasma folate, and community-based impaired estimated glomerular filtration rate in central Taiwan

Abstract

Background Chronic kidney disease (CKD) is increasing, with heavy metal exposure an important risk factor. Additionally, the antioxidant folic acid has been studied for reducing blood arsenic levels and related tissue damage. Therefore, we explored the association and mediation effects among various heavy metal levels in blood, plasma folate, other CKD risk factors, and impaired estimated glomerular filtration rate (eGFR). Methods We constructed a community-based cross-sectional study from the Human Biomonitoring and Environmental Health Program in central Taiwan. A total of 1643 participants had lived locally for > 5 years, > 40 years old, and completely received health examinations and biospecimen collections. Impaired eGFR was defined as one single eGFR < 60 mL/min/1.73 m2. Plasma folate and metal levels in blood were determined, as well as urinary 8-hydroxy-2′-deoxyguanosine as an oxidative stress marker. Generalized weighted quantile sum (WQS) regression analysis was used to calculate a WQS score, reflecting overall body-burden of multiple metals (arsenic, cadmium, chromium, nickel, and lead) in blood. Results Impaired eGFR was identified in 225 participants. Participants with high WQS scores had increased risk of impaired eGFR (odds ratio = 1.67; 95% confidence interval [CI]: 1.34, 2.07). Of five metals, arsenic, lead, and cadmium were weighted highly in impaired eGFR. Participants with high WQS and folate insufficiency (< 6 ng/mL) had 2.38-fold risk of impaired eGFR compared to those with low WQS and high folate (≥6 ng/mL) (95% CI: 1.55, 5.17). Similar increased 4.16-fold risk of impaired eGFR was shown in participants with high WQS and uric acid levels (95% CI: 2.63, 6.58). However, there were no significant WQS–folate (p = 0.87) or WQS–uric acid (p = 0.38) interactions on impaired eGFR risk. As a mediator, uric acid contributed 24% of the association between WQS score and impaired eGFR risk (p < 0.0001). However, no mediation effect of plasma folate was observed. Conclusion WQS analysis could be applied to evaluate the joint effects of multiple metals exposure. High WQS scores may influence impaired eGFR risk through increased uric acid levels. A large-scale and prospective cohort study is necessary to validate these results and demonstrate any causal relationship.

Human Health Effects of Oral Exposure to Chromium: A Systematic Review of the Epidemiological Evidence

“…The reviewed studies included healthy adult populations who served either as controls in case control studies or unexposed in cross-sectional and cohort studies. Blood chromium measured in these populations ranged from non-detectable levels to 0.92 µg/L, with median values from 0.15 µg/L to 0.42 µg/L [29,61,79], consistent with reference values reported to range from 0.01 to 1.2 µg/L [99,100]. It should be noted that a Chinese study involved a relatively large sample of 11,037 adults, representative of the general Chinese population [61].…”

“…In contrast, higher odds of developing CKD, defined as eGFR < 60 mL/min/1.73 m 2 , were not evident in two other cross-sectional studies, in which subjects with impaired renal function comprised 2.5% [82] and 14% [79] of the total study population. Similarly, no higher hazard ratio for end-stage renal disease was observed in response to Cr concentration in residential soil [81].…”

“…Cr and renal system Chronic kidney disease (CKD) is another health problem that has been studied in relation to Cr exposure [79][80][81][82]. A strong negative association between urinary Cr levels and estimated glomerular filtration rate (eGFR), which is derived through linear regression models, has been reported in a population with normal ranges of eGFR values [80].…”

“…Possible mechanisms involved in impaired renal function have been suggested to include the reduction of Cr(VI) to Cr(III) in the stomach and gastrointestinal tract, leading to an increase in renal Cr excretion. In addition, simultaneous exposure to Cr, Pb, and Cd might cause a further decrease in glomerular filtration rate, possibly mediated by oxidative stress in the kidney and thus increasing the risk of renal damage [79,80,83]. Motor neuron disease SMR = 1.12 (95% CI: 1.08, 1.17) for exposed municipalities 15.5% higher risk of MND [87] (+): positive association, (−): negative association, ALT: alanine transaminase, AST: aspartate aminotransferase, BKMR: Bayesian kernel machine regression, BMI: body mass index, CAT: catalase, CHD: coronary heart disease, CI: confidence interval, CKD: chromic kidney disease, Cr-B: Cr in blood.…”

Iron Deficiency and Nephrotoxic Heavy Metals: A Dangerous Interplay?

“…Multiple epidemiological studies have linked exposure to cadmium [ 19 , 20 , 21 , 22 ], lead [ 19 , 22 ], nickel [ 23 , 24 ], manganese [ 25 ], and the metalloid arsenic [ 19 , 22 ] to an increased risk of developing CKD in the general population. CKD is a clinical diagnosis often defined as an (estimated) glomerular filtration rate ((e)GFR) below 60 mL/min per 1.73 m 2 or markers of kidney damage (e.g., proteinuria) for more than three months [ 26 ].…”