The Source and Pathophysiologic Significance of Excreted Cadmium

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) (E_Cd/C_cr, E_NAG/C_cr, and E_β2MG/C_cr). To link the loss of intact nephrons to Cd-induced tubular injury, we examined linear and quadratic regressions of estimated GFR (eGFR) on E_Cd/C_cr, eGFR on E_NAG/C_cr, and E_NAG/C_cr on E_Cd/C_cr. Estimated GFR varied inversely with both ratios, and E_NAG/C_cr varied directly with E_Cd/C_cr. Linear and quadratic regressions of E_β2MG/C_cr on E_Cd/C_cr and E_NAG/C_cr were significant in moderate and high Cd-exposure groups. The association of E_NAG/C_cr with E_Cd/C_cr 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 E_Cd/C_cr, E_NAG/C_cr, and eGFR were associated with one another because each parameter was determined by the tubular burden of Cd.