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Background: Exposure to heavy metals (cadmium, mercury, and lead) has been linked with adverse health outcomes, especially their nephrotoxic effects at high levels of exposure. We conducted a replication study to examine the association of low-level heavy metal exposure and chronic kidney disease (CKD) using a larger NHANES data set compared to previous studies. Methods: The large cross-sectional study comprised 5,175 CKD cases out of 55677 participants aged 20–85 years from the 1999–2020 National Health and Nutrition Examination Survey [NHANES]. Logistic regression analysis was applied to estimate the associations between CKD and heavy metals [Cd, Pb, Hg] measured as categorical variables after adjusting with age, race, gender, socioeconomic status, hypertension, diabetes mellitus and blood cotinine level as smoking status. Results: Compared to the lowest quartile of blood Cd, exposures to the 2nd, 3rd and 4th quartiles of blood Cd were statistically significantly associated with higher odds of CKD after adjustment for blood Pb and Hg, with OR = 1.79, [95% CI; 1.55–2.07, p<0.0001], OR = 2.17, [95% CI; 1.88–2.51, p<0.0001] and OR = 1.52, [95% CI; 1.30–1.76, p<0.0001] respectively. The 2nd, 3rd and 4th quartiles of blood Cd remained statistically significantly associated with higher odds of CKD after adjustment for blood cotinine level, with OR = 2.06, [95% CI; 1.80–2.36, p<0.0001], OR = 3.18, [95% CI; 2.79–3.63, p<0.0001] and OR = 5.54, [95% CI; 4.82–6.37, p<0.0001] respectively. Exposure to blood Pb was statistically significantly associated with higher odds of CKD in the 2nd, 3rd and 4th quartile groups, after adjustment for all co-variates (ag, gender, race, socio-economic status, hypertension, diabetes mellitus, blood cadmium, mercury, and cotinine levels) in all the four models. Blood Hg level was statistically significantly associated with lower odds of CKD in the 2nd quartile group in model 2, 3rd quartile group in model 1, 2 and 3, and the 4th quartile group in all the four models. Conclusions: Our findings showed that low blood levels of Cd and Pb were associated with higher odds of CKD while low blood levels of Hg were associated with lower odds of CKD in the US adult population. However, temporal association cannot be determined as it is a cross sectional study. [ABSTRACT FROM AUTHOR]