Chronic Renal Tubular Effects in Relation to Urine Cadmium Levels

Abstract

In this study the urine activities of two brush border membrane enzymes, alanine aminopeptidase (AAP) and γ-glutamyltranspeptidase (GGT), and the lysosomal enzyme N-acetyl-β-D-glucosaminidase (NAG) were measured in men exposed to cadmium to investigate chronic renal toxicity. The subjects consist of a group with urine cadmium levels < 2.0 μg/l and a group with higher cadmium levels (urine cadmium > 2.0 μg/l) with past or present occupational exposure to cadmium. The mean NAG value corrected for creatinine in the higher cadmium group (2.95 U/g creatinine) is significantly different from the mean low cadmium group value (0.92 U/g creatinine, p = 0.0083). Likewise, AAP in the higher group (13.83 U/g creatinine) is significantly different from that of the low group (6.58 U/g creatinine; p = 0.0018). NAG and AAP also give significant correlations with cadmium levels in urine (NAG: r = 0.51; p = 0.0001; AAP: r = 0.56; p = 0.0001). There is no similar statistically significant difference in GGT means in the two groups. In contrast to cadmium correlations, blood lead does not correlate with NAG, AAP, or GGT. A dose-response relationship was found between NAG and cadmium and between AAP and cadmium. The analysis of this relationship gives estimates of a 10% chance of observing an elevated NAG value at a cadmium level of 6.3 μg/g creatinine (8.0 μg/l) and a 10% chance of observing an elevated AAP at a cadmium level of 5.0 μg/g creatinine (3.4 μg/l). These data indicate elevations of NAG and AAP at urine cadmium levels below the level of 10 μg/g creatinine recommended as an upper limit by the 1980 World Health Organization Study Group. Since elevated levels of NAG and AAP in cadmium-exposed workers may reflect chronic renal tubular nephrotoxicity, these findings indicate that cadmium levels below 10 μg/g creatinine may be accompanied by subclinical tubular dysfunction, and that WHO guidelines should be interpreted cautiously, particularly with reference to workers who are no longer exposed and may have had higher cadmium body burdens in the past.

Health effects of cadmium exposure in the general environment in Japan with special reference to the lower limit of the benchmark dose as the threshold level of urinary cadmium

“…In studies of health effects caused by exposure to cadmium, the urinary cadmium concentration is often used as an indicator of internal dose. Reports on cadmium levels of workers and animals have shown a close relationship between urinary cadmium excretion and the total body burden of cadmium (23)(24)(25)(26)(27). We found that urinary cadmium increased with the increasing lifetime cadmium intake among inhabitants of the general environment (10).…”

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

“…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).…”

“…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.…”

Health hazard evaluation report: HETA-88-199-2071, Gates Energy Products, Inc., Gainesville, Florida.

“…[33][34][35] In either of our surveys, abnormal levels of NAGA or AAP (defined by the arithmetic mean in the unexposed plus two standard deviations) were associated only with urine cadmium levels greater than 10 ug/g creatinine.…”