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

Abstract

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 (ECd), total protein (EProt), albumin (Ealb), β2-microglobulin (Eβ2M), and α1-microglobulin (Eα1M), 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 (Ccr) as ECd/Ccr and EProt/Ccr to correct for differences among subjects in the number of surviving nephrons. Low eGFR was defined as eGFR ≤ 60 mL/min/1.73 m2, while proteinuria was indicted by EPro/Ccr ≥ 20 mg/L of filtrate. EProt/Ccr varied directly with ECd/Ccr (β = 0.263, p < 0.001) and age (β = 0.252, p < 0.001). In contrast, eGFR values were inversely associated with ECd/Ccr (β = −0.266, p < 0.001) and age (β = −0.558, p < 0.001). At ECd/Ccr > 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, ECd/Ccr was more closely correlated with EProt/Ccr (r = 0.507), Eβ2M (r = 0.430), and Eα1M/Ccr (r = 0.364) than with EAlb/Ccr (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.

Current Levels of Environmental Exposure to Cadmium in Industrialized Countries as a Risk Factor for Kidney Damage in the General Population: A Comprehensive Review of Available Data

“…Cd has been shown to impair the ability of the kidney to conduct proper glomerular filtration (evaluated according to the eGFR) at concentrations in the blood of 0.18 µg/L or higher, and the risk of a reduced eGFR correlates positively with the blood Cd concentration [66,84]. A similar relationship has been shown in other studies [124,164,165,167]. Ferraro et al [167] reported that the OR of a reduced eGFR reached 1.48 at a Cd concentration > 1 µg/L in the blood and urine.…”

“…When assessing the impact of Cd on the function of the renal glomeruli, albuminuria and parameters describing glomerular filtration, such as the GFR and eGFR, are commonly evaluated [30,37,84,164,165]. Albuminuria is the occurrence of an increased amount of albumin in the urine, presenting an albumin concentration (mg/g urine) to creatinine concentration (mg/g urine) ratio over 30.…”

Cadmium-Induced Tubular Dysfunction in Type 2 Diabetes: A Population-Based Cross-Sectional Study

“…Similar observations were then made in studies from Sweden [8,9], Australia [10], the U.S. [11], and Korea [12]. The defective tubular reabsorption of proteins, indicated by an increase in the excretion of proteins of low molecular weight, such as β 2 -microglobulin (β 2 M), is the most frequently reported sign of Cd nephrotoxicity [13,14]. In early studies, the effect of Cd on the glomerular filtration rate (GFR) involved workplace exposure, where workers were exposed mainly through the inhalation of relatively high levels of Cd in fumes and dust [15,16].…”

Is Chronic Kidney Disease Due to Cadmium Exposure Inevitable and Can It Be Reversed?

“…To show the effects of normalisation methods on dose-effect relationship evaluation, data on urinary excretion of Cd and various proteins recorded for residents of a Cdcontaminated area of Thailand [47] are recapitulated (Table 2). 2).…”

“…E x , excretion of x; cr, creatinine; C cr , creatinine clearance; Cd, cadmium; β 2 M, β 2 -microglobulin; α1M, α1microglobulin; alb, albumin; Prot, protein. Numbers are the arithmetic means ± standard deviation (SD)[47]. eGFR was based on the CKD-Epidemiology Collaboration equations[48].…”