Chronic renal effects in three studies of men and women occupationally exposed to cadmium

Abstract

We measured sensitive indicators of renal damage in three different populations occupationally exposed to cadmium, and examined the degree of variation in damage and the relative sensitivity of different types of indicators. The three studies included (1) men exposed in a cadmium recovery plant, (2) men exposed in a nickel/cadmium battery plant, and (3) women exposed in the latter plant. The indicators of renal damage were urinary proteins in three categories: (1) the high molecular weight enzymes alanine aminopeptidase (AAP) and N-acetyl-beta-D-glucosaminidase (NAG), (2) the intermediate molecular weight protein albumin (ALB), and (3) the low molecular weight proteins retinol-binding protein (RBP) and beta 2-microglobulin (B2M). These tests indicate that exposed groups with higher urine cadmium levels had varying degrees of renal damage. All exposed groups showed evidence of renal damage when compared with their respective control groups. A higher percentage of elevated protein levels was noted in the exposed group of Study 1 than in the exposed groups of Studies 2 and 3. In Study 1, the means of all five protein levels and ALB, RBP, and B2M fractional clearances were significantly elevated in the group with higher urine cadmium concentrations when compared with the groups with lower urine cadmium concentrations. Highly significant dose-response relationships for all of the urinary protein tests, including fractional clearances, were found. All of the tests were more sensitive in detecting evidence of subclinical renal damage than serum creatinine, a commonly used indicator of renal function. The order of test sensitivity in men was determined by considering three factors: (1) the magnitude of the correlation coefficient between the test and the urine cadmium concentration in the study with the most advanced damage, (2) the relative cadmium level predicted by the dose-response model at which there is a 10% chance of observing an elevated test value, and (3) the ability of the tests to detect renal effects in the population with less advanced damage. The tests in order of decreasing sensitivity in men are ALB, AAP, NAG, RBP approximately B2M. The women with higher urine cadmium levels in Study 3 had a higher percentage of elevated AAP and NAG values when compared with the control group.

Effects of exposure to low levels of environmental cadmium on renal biomarkers.

“…Results from previous studies of high occupational cadmium exposures have suggested that urinary albumin may be a sensitive indicator of cadmium-induced renal effects (7). Cadmium levels in the high-exposure groups from these studies ranged from 6 µg to 16 µg cadmium/g creatinine (7), well above the levels observed in this study's environmentally exposed population.…”

“…An association between AAP and urinary cadmium was previously observed in studies of individuals with high occupational exposures (7,11), and NAG has been used as a marker of cadmium nephrotoxicity in several occupational and environmental studies (7,(10)(11)(12)33,34).…”

“…We determined urine cadmium levels using established procedures (7,24), and quality-control procedures included performing 10% replicates and 5-15% controls and using field blanks for urine cadmium tests. As described previously, AAP was measured by an automated Jung and Scholz method (25), and NAG was measured by the Leaback and Walker method (26) and automated for the centrifugal analyzer Cobas Fara II (Roche Diagnostic Systems, Basel, Switzerland) (27).…”

“…Low-molecular-weight proteinuria among exposed workers with > 10 µg urinary cadmium/g creatinine was irreversible and exacerbated the age-related decline in the glomerular filtration rate (4)(5)(6). Elevations in enzymes primarily of renal tubular origin, such as N-acetyl-β-Dglucosaminidase (NAG) and alanine aminopeptidase (AAP), have been observed at occupational cadmium exposures of 3.7-6.3 µg urinary cadmium/g creatinine (2,4,7). Increases in these enzymes have been associated with chemical-induced renal tubular damage (8,9) Most studies of cadmium-induced renal effects using these and other biomarkers have been conducted among individuals with occupational or high environmental exposures (4,7,(10)(11)(12)(13)(14)(15)(16).…”

“…Elevations in enzymes primarily of renal tubular origin, such as N-acetyl-β-Dglucosaminidase (NAG) and alanine aminopeptidase (AAP), have been observed at occupational cadmium exposures of 3.7-6.3 µg urinary cadmium/g creatinine (2,4,7). Increases in these enzymes have been associated with chemical-induced renal tubular damage (8,9) Most studies of cadmium-induced renal effects using these and other biomarkers have been conducted among individuals with occupational or high environmental exposures (4,7,(10)(11)(12)(13)(14)(15)(16). Results of a national health survey indicate that the geometric mean value (and 95th percentile) for urinary cadmium among the U.S. general population age 6 years or older is approximately 0.27 (1.48) µg/g creatinine (17), but little information is available on renal effects that may occur in people with urinary cadmium levels < 2 µg/g.…”