The pathogenesis of albuminuria in cadmium nephropathy

[Display omitted] •Cadmium readily enters the body and preferentially accumulates in renal proximal tubular cells (PTCs).•PTCs reabsorb all filtered β2-microglobulin (β2M) and a minority of filtered albumin by megalin-mediated endocytosis.•In Cd-exposed subjects, excretion rates of albumin and β2M correlated closely with each other and with the rate of Cd excretion.•It appears that Cd adversely affects a single phenomenon involved in reabsorption of both albumin and β2M.•The affected phenomenon is probably receptor-mediated endocytosis involving megalin. Urinary cadmium excretion (ECd) 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 (Eβ2M) is an established marker of proximal tubular dysfunction, we hypothesized that a comparison of albuminuria (Ealb) to Eβ2M in Cd-exposed subjects would provide evidence of similar mishandling of both proteins. To depict excretion rates per functional nephron, ECd, Ealb, and Eβ2M were normalized to creatinine clearance (Ccr), 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 Ealb/Ccr, Eβ2M/Ccr, and eGFR to several independent variables. Simple linear regressions of eGFR, Ealb/Ccr, and Eβ2M/Ccr on ECd/Ccr 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 Ealb/Ccr and Eβ2M/Ccr and decrements in eGFR were quantified through four quartiles of ECd/Ccr. As age or ECd/Ccr rose, Ealb/Ccr and Eβ2M/Ccr also rose, and eGFR fell. In linear regressions, slopes relating Ealb/Ccr and Eβ2M/Ccr to ECd/Ccr were similar. After adjustment of dependent variables for age, coefficients of determination (R2) for all regressions rose by a multiple, and slopes approached unity. Ealb/Ccr and Eβ2M/Ccr were similarly associated with each other. Mean Ealb/Ccr and Eβ2M/Ccr rose and mean eGFR fell in stepwise fashion through quartiles of ECd/Ccr. Whereas Eβ2M/Ccr did not vary with blood pressure, Ealb/Ccr 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