The Source and Pathophysiologic Significance of Excreted Cadmium

Abstract

In theory, the identification of the source of excreted cadmium (Cd) might elucidate the pathogenesis of Cd-induced chronic kidney disease (CKD). With that possibility in mind, we studied Thai subjects with low, moderate, and high Cd exposure. We measured urine concentrations of Cd, ([Cd]u); N-acetyl-β-d-glucosaminidase, a marker of cellular damage ([NAG]u); and β2-microglobulin, an indicator of reabsorptive dysfunction ([β2MG]u). To relate excretion rates of these substances to existing nephron mass, we normalized the rates to creatinine clearance, an approximation of the glomerular filtration rate (GFR) (ECd/Ccr, ENAG/Ccr, and Eβ2MG/Ccr). To link the loss of intact nephrons to Cd-induced tubular injury, we examined linear and quadratic regressions of estimated GFR (eGFR) on ECd/Ccr, eGFR on ENAG/Ccr, and ENAG/Ccr on ECd/Ccr. Estimated GFR varied inversely with both ratios, and ENAG/Ccr varied directly with ECd/Ccr. Linear and quadratic regressions of Eβ2MG/Ccr on ECd/Ccr and ENAG/Ccr were significant in moderate and high Cd-exposure groups. The association of ENAG/Ccr with ECd/Ccr implies that both ratios depicted cellular damage per surviving nephron. Consequently, we infer that excreted Cd emanated from injured tubular cells, and we attribute the reduction of eGFR to the injury. We suggest that ECd/Ccr, ENAG/Ccr, and eGFR were associated with one another because each parameter was determined by the tubular burden of Cd.

A Comparison of the Nephrotoxicity of Low Doses of Cadmium and Lead

“…It is increasingly recognized that creatinine adjustment is problematic, and urine specific gravity has been used to correct for dilution effects [9,44,45,[50][51][52]. Herein, we have demonstrated the utility of normalizing excretion rate of metals to creatinine clearance that only required simultaneous urine and blood sampling together with the equations, given in Section 2.3 [33,35].…”

“…These data challenge a long-held view that tubular effects occur long before the glomerular effect becomes apparent. A recent quantitative analysis of excreted Cd in relation to levels of the eGFR, urinary NAG, and β 2 MG suggested a decrease in the GFR to be an early effect, given that excreted Cd emanates from injured tubular cells and that the injury leads to nephron atrophy, a decreased eGFR, and impaired reabsorption of filtered β 2 MG [35]. Accordingly, it can be hypothesized that sufficient tubular injury induced by Cd disables glomerular filtration, destroys nephrons, and causes glomerulosclerosis, interstitial inflammation, fibrosis and CKD [35,54].…”

“…Elevated dietary Cd intake has been associated with an increased risk of CKD in China [30]. A marked decrease in the GFR has also been observed in residents of an area with Cd pollution in Thailand [2,[31][32][33][34][35], as well as in Cd-exposed workers [36,37]. Likewise, marked GFR decreases have been noted in workers and residents of Pb-smelter communities [38].…”

“…However, a cross-sectional analysis of data from adolescents (n = 2709, aged 12-19 years) who were enrolled in NHANES 2009-2014 reported positive associations of urinary Cd and Pb with an increased eGFR and BUN in models that incorporated urinary creatinine as a covariate [42]. A common practice of normalizing urinary concentrations of Cd to urinary concentrations of creatinine may have caused these disparate findings [33,35,44,45].…”

Comparison of Methodologies to Estimate Dietary Cadmium Intake in an Italian Population

“…Dietary assessment of cadmium intake is considered prone to substantial measurement error of actual intake because of the large variation of cadmium content in food samples [13]. Biomonitoring of cadmium level is generally considered a valid method for assessment of exposure [14]. However, it captures exposure to cadmium from all sources, not just dietary; the specific contribution of dietary intake and inhalation to the overall exposure is not specified.…”