Cadmium-Induced Proteinuria: Mechanistic Insights from Dose-Effect Analyses

Cadmium (Cd) is a toxic metal that accumulates in kidneys, especially in the proximal tubular epithelial cells, where virtually all proteins in the glomerular ultrafiltrate are reabsorbed. Here, we analyzed archived data on the estimated glomerular filtration rate (eGFR) and excretion rates of Cd (E-Cd), total protein (E-Prot), albumin (E-alb), beta(2)-microglobulin (E-beta 2M), and alpha 1-microglobulin (E-alpha 1M), which were recorded for residents of a Cd contamination area and a low-exposure control area of Thailand. Excretion of Cd and all proteins were normalized to creatinine clearance (C-cr) as E-Cd/C-cr and E-Prot/C-cr to correct for differences among subjects in the number of surviving nephrons. Low eGFR was defined as eGFR <= 60 mL/min/1.73 m(2), while proteinuria was indicted by E-Pro/C-cr >= 20 mg/L of filtrate. E-Prot/C-cr varied directly with E-Cd/C-cr (beta = 0.263, p < 0.001) and age (beta = 0.252, p < 0.001). In contrast, eGFR values were inversely associated with E-Cd/C-cr (beta = -0.266, p < 0.001) and age (beta = -0.558, p < 0.001). At E-Cd/C-cr > 8.28 ng/L of filtrate, the prevalence odds ratios for proteinuria and low eGFR were increased 4.6- and 5.1-fold, respectively (p < 0.001 for both parameters). Thus, the eGFR and tubular protein retrieval were both simultaneously diminished by Cd exposure. Of interest, E-Cd/C-cr was more closely correlated with E-Prot/C-cr (r = 0.507), E-beta 2M (r = 0.430), and E-alpha 1M/C-cr (r = 0.364) than with E-Alb/C-cr (r = 0.152). These data suggest that Cd may differentially reduce the ability of tubular epithelial cells to reclaim proteins, resulting in preferential reabsorption of albumin.

Automated summary

Cadmium is a toxic metal that accumulates in kidneys, particularly in proximal tubular epithelial cells, affecting the reabsorption of proteins in the glomerular ultrafiltrate. This study analyzed data on estimated glomerular filtration rate (eGFR) and excretion rates of various proteins, finding a positive correlation between Cd excretion and proteinuria, while eGFR was negatively associated with Cd excretion. Higher Cd excretion rates were linked to increased odds of proteinuria and low eGFR. These findings suggest that Cd exposure diminishes both eGFR and tubular protein retrieval, with a preferential reabsorption of albumin in the kidneys.