Uranium associations with kidney outcomes vary by urine concentration adjustment method

Uranium is a ubiquitous metal that is nephrotoxic at high doses. Few epidemiologic studies have examined the kidney filtration impact of chronic environmental exposure. In 684 lead workers environmentally exposed to uranium, multiple linear regression was used to examine associations of uranium measured in a 4-h urine collection with measured creatinine clearance, serum creatinine- and cystatin-C-based estimated glomerular filtration rates, and N-acetyl-beta-D-glucosaminidase (NAG). Three methods were utilized, in separate models, to adjust uranium levels for urine concentration-mu g uranium/g creatinine; mu g uranium/l and urine creatinine as separate covariates; and mu g uranium/4 h. Median urine uranium levels were 0.07 mu g/g creatinine and 0.02 mu g/4 h and were highly correlated (r(s) = 0.95). After adjustment, higher In-urine uranium was associated with lower measured creatinine clearance and higher NAG in models that used urine creatinine to adjust for urine concentration but not in models that used total uranium excreted (mu g/4 h). These results suggest that, in some instances, associations between urine toxicants and kidney outcomes may be statistical, due to the use of urine creatinine in both exposure and outcome metrics, rather than nephrotoxic. These findings support consideration of non-creatinine-based methods of adjustment for urine concentration in nephrotoxicant research.