Arsenic and Chronic Kidney Disease in the Strong Heart Study
Zheng, Laura Y.
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Arsenic is a worldwide public health problem that affects tens of millions of people. Arsenic has several well-known adverse health effects, but less is known about the role of arsenic in the development of chronic kidney disease (CKD). Most research on arsenic and kidney disease outcomes is cross-sectional in nature and prospective evidence is lacking. The objective of this dissertation was to investigate the association of arsenic exposure and CKD outcomes (albuminuria and reduced eGFR) in a population-based study of American Indians exposed to low-moderate levels of arsenic in drinking water. First, we conducted a systematic review of the epidemiological evidence on arsenic and chronic kidney disease outcomes. We identified 27 epidemiological studies (6 on albuminuria, 8 on CKD, 11 on other kidney disease markers, and 5 on kidney disease mortality). There was a positive association between arsenic and albuminuria and kidney disease mortality, but the associations were inconclusive regarding CKD and other kidney disease markers. Many studies were of poor quality and lacked adjustment for confounders and dose-response modeling. Second, we conducted a cross-sectional analysis in adults aged 45-74 years old from American Indian communities from the Strong Heart Study to evaluate the association between urine arsenic and baseline albuminuria. The multivariable-adjusted prevalence ratios (95% confidence interval) of albuminuria ≥30 mg/g comparing the three highest to the lowest quartile of the sum of inorganic and methylated arsenic species (ƩAs) were 1.16 (1.00, 1.34), 1.24 (1.07, 1.43), and 1.55 (1.35, 1.78), respectively (P trend <0.001). The association between urine arsenic and albuminuria was observed across all participant subgroups and for varying levels of albuminuria. Third, we conducted a prospective study of arsenic and incident albuminuria following the participants who were free of albuminuria at baseline. The hazard ratio (95% confidence interval) for incident albuminuria comparing the three highest to the lowest quartile of ƩAs were 1.03 (0.79, 1.33), 1.10 (0.84, 1.45), and 1.13 (0.85, 1.50), respectively. The nonsignificant association was consistent across most participant characteristics. Fourth, we conducted a cross-sectional and prospective study of arsenic with prevalent and incident CKD status in adults aged 45-74 years old from American Indian communities. We found that adjusted odds ratio (95%CI) of prevalent CKD for an interquartile range in ƩAs was 0.68 (0.56, 0.82). This was mostly due to a strong inverse association with inorganic arsenic (odds ratio 0.35 (0.29, 0.43)). MMA and DMA were positively associated with prevalent CKD after adjustment for inorganic arsenic species in urine (odds ratios 3.75 and 1.77, respectively). The CKD incidence rate was 23.5 per 1,000 person-years. The multi-adjusted hazard ratio of incident CKD for an interquartile range in ƩAs was 1.20 (1.03, 1.41). The corresponding hazard ratios for inorganic arsenic, MMA and DMA were 1.00 (0.86, 1.17), 1.15 (0.99, 1.34) and 1.21 (1.04, 1.42), respectively. In conclusion, at low to moderate levels of arsenic exposure, arsenic may be a risk factor for the development of chronic kidney disease. Reduced inorganic arsenic excretion by reduced glomerular function may explain our inverse association between inorganic arsenic and prevalent CKD. Individuals with CKD may thus be at risk of higher inorganic arsenic internal dose at similar exposure levels than those without CKD. Our findings may influence arsenic risk assessment. First, because current arsenic risk assessment has only considered non-cancer endpoints qualitatively. Second, by identifying CKD as a condition that might increase susceptibility to arsenic exposure and related health effects.