Dose-Response Analysis of the Tubular and Glomerular Effects of Chronic Exposure to Environmental Cadmium.

We retrospectively analyzed data on the excretion of cadmium (E Cd ), β 2 -microglobulin (E β2M ) and N-acetyl-β-D-glucosaminidase (E NAG ), which were recorded for 734 participants in a study conducted in low- and high-exposure areas of Thailand. Increased E β2M and E NAG were used to assess tubular integrity, while a reduction in the estimated glomerular filtration rate (eGFR) was a criterion for glomerular dysfunction. E Cd , E β2M and E NAG were normalized to creatinine clearance (C cr ) as E Cd /C cr , E β2M /C cr and E NAG /C cr to correct for interindividual variation in the number of surviving nephrons and to eliminate the variation in the excretion of creatinine (E cr ). For a comparison, these parameters were also normalized to E cr as E Cd /E cr , E β2M /E cr and E NAG /E cr . According to the covariance analysis, a Cd-dose-dependent reduction in eGFR was statistically significant only when E cd was normalized to C cr as E Cd /C cr ( F = 11.2, p < 0.001). There was a 23-fold increase in the risk of eGFR ≤ 60 mL/min/1.73 m 2 in those with the highest E Cd /C cr range ( p = 0.002). In addition, doubling of E Cd /C cr was associated with lower eGFR (β = -0.300, p < 0.001), and higher E NAG /C cr (β = 0.455, p < 0.001) and E β2M /C cr (β = 0.540, p < 0.001). In contrast, a covariance analysis showed a non-statistically significant relationship between E Cd /E cr and eGFR ( F = 1.08, p = 0.165), while the risk of low eGFR was increased by 6.9-fold only among those with the highest E Cd /E cr range. Doubling of E Cd /E cr was associated with lower eGFR and higher E NAG /E cr and E β2M /E cr , with the β coefficients being smaller than in the C cr -normalized dataset. Thus, normalization of Cd excretion to C cr unravels the adverse effect of Cd on GFR and provides a more accurate evaluation of the severity of the tubulo-glomerular effect of Cd.