Gender Differences in the Severity of Cadmium Nephropathy

Abstract

The excretion of β₂-microglobulin (β₂M) above 300 µg/g creatinine, termed tubulopathy, was regarded as the critical effect of chronic exposure to the metal pollutant cadmium (Cd). However, current evidence suggests that Cd may induce nephron atrophy, resulting in a reduction in the estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m². Herein, these pathologies were investigated in relation to Cd exposure, smoking, diabetes, and hypertension. The data were collected from 448 residents of Cd-polluted and non-polluted regions of Thailand. The body burden of Cd, indicated by the mean Cd excretion (E_Cd), normalized to creatinine clearance (C_cr) as (E_Cd/C_cr) × 100 in women and men did not differ (3.21 vs. 3.12 µg/L filtrate). After adjustment of the confounding factors, the prevalence odds ratio (POR) for tubulopathy and a reduced eGFR were increased by 1.9-fold and 3.2-fold for every 10-fold rise in the Cd body burden. In women only, a dose-effect relationship was seen between β₂M excretion (E_β2M/C_cr) and E_Cd/C_cr (F = 3.431, η² 0.021). In men, E_β2M/C_cr was associated with diabetes (β = 0.279). In both genders, the eGFR was inversely associated with E_β2M/C_cr. The respective covariate-adjusted mean eGFR values were 16.5 and 12.3 mL/min/1.73 m² lower in women and men who had severe tubulopathy ((E_β2M/C_cr) × 100 ≥ 1000 µg/L filtrate). These findings indicate that women were particularly susceptible to the nephrotoxicity of Cd, and that the increment of E_β2M/C_cr could be attributable mostly to Cd-induced impairment in the tubular reabsorption of the protein together with Cd-induced nephron loss, which is evident from an inverse relationship between E_β2M/C_cr and the eGFR.

Keywords: GFR; cadmium; diabetes; hypertension; smoking; tubular proteinuria; β2-microglobulin.

Figure 1

Blood cadmium and urinary cadmium excretion relationship. Scatterplots relating log([Cd]_b × 10³] to log[(E_Cd/C_cr) × 10⁵] in women and men (a). Coefficients of determination (R²) and p-values are provided for all scatterplots. Bar graph (b) depicts mean log([Cd]_b × 10³] values in women and men across E_Cd/C_cr tertiles. Letters a and c refer to groups of women whose E_Cd/C_cr values were in low and middle E_Cd/C_cr tertiles, respectively. Letters b and d refer to groups of men whose E_Cd/C_cr values were in low and middle E_Cd/C_cr tertiles, respectively. All means were obtained via univariate analysis with adjustment for covariates and interactions. For women, respective arithmetic means and standard deviations (SD) for (E_Cd/C_cr) × 100 tertiles 1, 2, and 3 are 0.37 (0.47), 2.34 (0.52), and 6.84 (4.46) µg/L of filtrate. For men, respective arithmetic means and standard deviations (SD) for (E_Cd/C_cr) × 100 tertiles quartiles 1, 2, and 3 are 0.36 (0.42), 2.14 (0.63), and 6.81 (3.78) µg/L of filtrate. For all tests, p-values ≤ 0.05 indicate statistically significant differences.

Figure 2

Dose–effect relationship of β₂-microgloubulin and cadmium excretion. Scatterplots relate log[(E_βM/C_cr) × 10³] to log[(E_Cd/C_cr) × 10⁵] in all subjects (a), and in women and men (c). Coefficients of determination (R²) and p-values are provided for all scatterplots. The color-coded area graph (b) depicts means of log[(E_β2M/C_cr) × 10³] across E_Cd/C_cr tertiles. Shaded areas indicate variability of means. Bar graph (d) depicts mean log[(E_β2M/C_cr) × 10³] in women and men in each E_Cd/C_cr tertile. The respective numbers of subjects in E_Cd/C_cr tertiles 1, 2, and 3 are 149, 149, and 150. In Figure 2d, a letter a refers to a group of women whose ECd/C_cr values were in low E_Cd/C_cr tertile. All means were obtained via univariate analysis with adjustment for covariates and interaction. For women, respective arithmetic means and standard deviations (SD) for (E_Cd/C_cr) × 100 tertiles 1, 2, and 3 are 0.37 (0.47), 2.34 (0.52), and 6.84 (4.46) µg/L of filtrate. For men, respective arithmetic means and standard deviations (SD) for (E_Cd/C_cr) × 100 tertiles 1, 2, and 3 are 0.36 (0.42), 2.14 (0.63), and 6.81 (3.78) µg/L of filtrate. For all tests, p-values ≤ 0.05 indicate statistically significant differences.

Figure 3

An inverse relationship of eGFR with β₂-microgloubulin excretion. Scatterplots relate eGFR to log[(E_βM/C_cr) × 10³] in all subjects (a), and in women and men (c). Coefficients of determination (R²) and p-values are provided for all scatterplots. The color-coded area graph (b) depicts means of eGFR across three E_β2M/C_cr ranges. Shaded areas indicate variability of means. Bar graph (d) depicts means of eGFR in women and men in each E_β2M/C_cr range. The respective numbers of subjects in (E_β2M/C_cr) × 100 < 300, 300−999 and ≥1000 µg/L of filtrate are 184, 156, and 109. In Figure 3d, letters a and c refer to groups of women whose (E_β2M/C_cr) × 100 < 300 and 300–999 µg/L filtrate, respectively. The letter b refers to a group of men whose (E_β2M/C_cr) × 100 < 300 µg/L filtrate, respectively. All means were obtained via univariate analysis with adjustment for covariates and interaction. For all tests, p-values ≤ 0.05 indicate statistically significant differences.

Figure 3

An inverse relationship of eGFR with β₂-microgloubulin excretion. Scatterplots relate eGFR to log[(E_βM/C_cr) × 10³] in all subjects (a), and in women and men (c). Coefficients of determination (R²) and p-values are provided for all scatterplots. The color-coded area graph (b) depicts means of eGFR across three E_β2M/C_cr ranges. Shaded areas indicate variability of means. Bar graph (d) depicts means of eGFR in women and men in each E_β2M/C_cr range. The respective numbers of subjects in (E_β2M/C_cr) × 100 < 300, 300−999 and ≥1000 µg/L of filtrate are 184, 156, and 109. In Figure 3d, letters a and c refer to groups of women whose (E_β2M/C_cr) × 100 < 300 and 300–999 µg/L filtrate, respectively. The letter b refers to a group of men whose (E_β2M/C_cr) × 100 < 300 µg/L filtrate, respectively. All means were obtained via univariate analysis with adjustment for covariates and interaction. For all tests, p-values ≤ 0.05 indicate statistically significant differences.