5.1.1. U.S. Population

An increment of [Pb]b to 10 μg/dL was associated with a decrease in creatinine clearance of 10.4 mL/min in an early study of U.S. men participating in the Normative Aging Study between 1988 and 1991 [288]. Subsequently, an increased risk of CKD was associated with Pb and Cd exposures in participants of various NHANES cycles. In NHANES 1999–2006, adults with [Cd]u levels ≥ 1 μg/<sup>L</sup> had 1.48- and 1.41-fold increases in the risk of low eGFR and albuminuria [44], while those with [Cd]b ≥0.6 μg/<sup>L</sup> had 1.53-, 1.92-, and 2.91-fold increases in the risk of low eGFR, albuminuria and low eGFR plus albuminuria, respectively [289]. In addition, [Pb]b ≥ 2.4 μg/dL, which is 12% of the exposure limit in occupational exposure settings of 20 μg/dL, was associated with a 1.56-fold increase in the risk of low eGFR [289]. Of interest, the risk of CKD was increased further when subjects were exposed to both metals: the odds ratios for low eGFR, albuminuria, low eGFR plus albuminuria rose to 1.98, 2.34, and 4.10 in participants who had both [Cd]b and [Pb]b in the highest quartiles, compared with those who had [Cd]b and [Pb]b in the lowest quartiles [289]. Likewise, in adults enrolled in NHANES 2007–2012, [Cd]b > 0.61 μg/<sup>L</sup> was associated, respectively, with 1.80- and 1.60-fold higher risk of having low eGFR and albuminuria, compared with [Cd]b ≤ 0.11 μg/<sup>L</sup> [45]. A pronounced e ffect of Cd on eGFR was seen in women who had diabetes and/or hypertension. On average, women with diabetes, hypertension and [Cd]b in the highest quartile (0.61−9.3 μg/L) had 4.9 mL/min/1.73 m<sup>2</sup> lower eGFR than nondiabetic, normotensive women who had the lowest [Cd]b (0.11−0.21 μg/L) [46]. In those women with hypertension and the highest [Cd]b quartile, the mean eGFR was 5.77 mL/min/1.73 m<sup>2</sup> lower than the normotensive with the same lowest [Cd]b quartile [46].

In another analysis of data from adult participants in NHANES 2011–2012, [Cd]b > 0.53 μg/<sup>L</sup> was associated with 2.21- and 2.04-fold increases in the risk of low eGFR and albuminuria, respectively. [Cd]u as low as 0.22 μg/<sup>L</sup> was associated with higher urinary albumin excretion, compared with [Cd]u < 0.126 μg/L, but neither Pb nor Hg was associated with elevated albumin excretion [290].

### 5.1.2. Swedish Population

In a study of Swedish women, 53–64 years of age, [Cd]u ≥ 0.6 μg/g creatinine was associated with a significant increase in tubular injury and decrease in eGFR [227]. In a longitudinal study (*n* = 4341), [Pb]b ≥ 3.3 μg/dL was associated with a 1.49-fold increase in the incidence of CKD, and the mean eGFR of subjects with this range of [Pb]b fell by 24 mL/min/1.73 m<sup>2</sup> during a 16-year follow-up period [291]. In a prospective, nested case–control study, 118 cohort participants developed ESKD during a 7-year period [292]. The mean values for erythrocyte Cd and Pb of these cases were 1.3 and 7.6 μg/dL, respectively. After adjusting for potential confounders, including Cd and Hg, smoking, body mass index, diabetes, and hypertension, only erythrocyte Pb was associated with an increase in the risk of developing ESKD [292].
