Differences in urine cadmium associations with kidney outcomes based on serum creatinine and cystatin C

Abstract

Cadmium is a well known nephrotoxicant; chronic exposure increases risk for chronic kidney disease. Recently, however, associations between urine cadmium and higher creatinine-based estimated glomerular filtration rate (eGFR) have been reported. Analyses utilizing alternate biomarkers of kidney function allow evaluation of potential mechanisms for these observations. We compared associations of urine cadmium with kidney function measures based on serum cystatin C to those with serum creatinine in 712 lead workers. Mean (standard deviation) molybdenum-corrected urine cadmium, Modification of Diet in Renal Disease (MDRD) eGFR and multi-variable cystatin C eGFR were 1.02 (0.65) μg/g creatinine, and 97.4 (19.2) and 112.0 (17.7) mL/min/1.73 m2, respectively. The eGFR measures were moderately correlated (rs = 0.5; p less than 0.001). After adjustment, ln(urine cadmium) was not associated with serum cystatin-C-based measures. However, higher ln(urine cadmium) was associated with higher creatinine-based eGFRs including the MDRD and an equation incorporating serum cystatin C and creatinine (beta-coefficient = 4.1 ml/min/1.73 m2; 95% confidence interval =1.6, 6.6). Urine creatinine was associated with serum creatinine-based but not cystatin-C-based eGFRs. These results support a biomarker-specific, rather than a kidney function, effect underlying the associations observed between higher urine cadmium and creatinine-based kidney function measures. Given the routine use of serum and urine creatinine in kidney and biomarker research, additional research to elucidate the mechanism(s) for these associations is essential.

Associations of multiple metals with kidney outcomes in lead workers

“…As previously published, a statistical mechanism related to the use of creatinine in both exposure and outcome metrics is a consideration for these associations. 9 The striking change in urine creatinine associations when a statistically significant metal is in the model, as evidenced by models 1 and 2 (tables 3 and 4), lends support for this mechanism. However, given the differences in associations between metals, unique metal-specific mechanisms, such as metaleprotein binding affecting excretion 48 must also be considered.…”

Impact of urine concentration adjustment method on associations between urine metals and estimated glomerular filtration rates (eGFR) in adolescents

“…Furthermore, these metals are potential or known nephrotoxicants (Shelley et al, 2012, 2014; Weaver et al, 2011a, 2011b). However, no consistent evidence of nephrotoxicity was observed in this analysis.…”

“…Positive associations between urine nephrotoxicant levels and measures of estimated glomerular filtration rate (eGFR) have been reported recently in a range of populations (de Burbure et al, 2006; Ferraro et al, 2010; Shelley et al, 2012; Weaver et al, 2011b; You et al, 2011). The direction of these associations is contrary to what is expected in nephrotoxicity, despite the fact that some of these toxicants, such as lead and cadmium, have well established nephrotoxic effects.…”

“…The direction of these associations is contrary to what is expected in nephrotoxicity, despite the fact that some of these toxicants, such as lead and cadmium, have well established nephrotoxic effects. The underlying cause of these associations is currently unknown although variation by biomarker (serum creatinine- versus cystatin C-based eGFR) (Weaver et al, 2011b) and/or estimating equation (You et al, 2011) have been observed. Unexpected associations by urine concentration adjustment method have also been reported.…”

Effects of environmental levels of cadmium, lead and mercury on human renal function evaluated by structural equation modeling

“…In that study, the ratio of urine cadmium to urine creatinine was used to adjust for urine dilution. Additional investigations using cystatin C based eGFR measures strongly suggested that the positive association of urine cadmium with kidney function may be a statistical effect related to the use of urine creatinine adjustments and serum creatinine based measures of kidney function (Weaver et al 2011b). …”