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.