The Pathogenesis of Albuminuria in Cadmium Nephropathy

Background: Urinary cadmium excretion (E) 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 β-microglobulinuria (E) is an established marker of proximal tubular dysfunction, we hypothesized that a comparison of albuminuria (E) to E in Cd-exposed subjects would provide evidence of similar mishandling of both proteins.

Methods: To depict excretion rates per functional nephron, E, E, and E were normalized to creatinine clearance (C), 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/C, E/C, and eGFR to several independent variables. Simple linear regressions of eGFR, E/C, and E/C on E/C 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/C and E/C and decrements in eGFR were quantified through four quartiles of E/C.

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

Conclusions: Our data indicate that Cd in renal tissue affected tubular reabsorption of albumin and βM 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.