The pathogenesis of albuminuria in cadmium nephropathy

Urinary cadmium excretion (E_Cd) rises with renal tissue content of the metal. Whereas glomerulopathies are sometimes associated with massive albuminuria, tubular accumulation of Cd typically causes modest albuminuria. Since β₂-microglobulinuria (E_β2M) is an established marker of proximal tubular dysfunction, we hypothesized that a comparison of albuminuria (E_alb) to E_β2M in Cd-exposed subjects would provide evidence of similar mishandling of both proteins.

To depict excretion rates per functional nephron, E_Cd, E_alb, and E_β2M were normalized to creatinine clearance (C_cr), a surrogate for the glomerular filtration rate (GFR). Estimation of GFR itself (eGFR) was accomplished with CKD-EPI formulas (2009). Linear and logistic regression analyses were performed to relate E_alb/C_cr, E_β2M/C_cr, and eGFR to several independent variables. Simple linear regressions of eGFR, E_alb/C_cr, and E_β2M/C_cr on E_Cd/C_cr were examined before and after adjustment of dependent variables for age. All regressions were performed after log-transformation of ratios and standardization of all variables. Increments in E_alb/C_cr and E_β2M/C_cr and decrements in eGFR were quantified through four quartiles of E_Cd/C_cr.

As age or E_Cd/C_cr rose, E_alb/C_cr and E_β2M/C_cr also rose, and eGFR fell. In linear regressions, slopes relating E_alb/C_cr and E_β2M/C_cr to E_Cd/C_cr were similar. After adjustment of dependent variables for age, coefficients of determination (R²) for all regressions rose by a multiple, and slopes approached unity. E_alb/C_cr and E_β2M/C_cr were similarly associated with each other. Mean E_alb/C_cr and E_β2M/C_cr rose and mean eGFR fell in stepwise fashion through quartiles of E_Cd/C_cr. Whereas E_β2M/C_cr did not vary with blood pressure, E_alb/C_cr rose in association with hypertension in two of the four quartiles.

Our data indicate that Cd in renal tissue affected tubular reabsorption of albumin and β₂M similarly in a large cohort of exposed subjects. The results suggest that Cd reduced receptor-mediated endocytosis and subsequent lysosomal degradation of each protein by a shared mechanism.