The Source and Pathophysiologic Significance of Excreted Cadmium.

Soisungwan Satarug,Glenda C Gobe,Werawan Ruangyuttikarn,David A Vesey,Kenneth R Phelps,Muneko Nishijo

doi:10.3390/toxics7040055

Abstract

In theory, the identification of the source of excreted cadmium (Cd) might elucidate the pathogenesis of Cd-induced chronic kidney disease (CKD). With that possibility in mind, we studied Thai subjects with low, moderate, and high Cd exposure. We measured urine concentrations of Cd, ([Cd]u); N-acetyl-β-d-glucosaminidase, a marker of cellular damage ([NAG]u); and β2-microglobulin, an indicator of reabsorptive dysfunction ([β2MG]u). To relate excretion rates of these substances to existing nephron mass, we normalized the rates to creatinine clearance, an approximation of the glomerular filtration rate (GFR) (ECd/Ccr, ENAG/Ccr, and Eβ2MG/Ccr). To link the loss of intact nephrons to Cd-induced tubular injury, we examined linear and quadratic regressions of estimated GFR (eGFR) on ECd/Ccr, eGFR on ENAG/Ccr, and ENAG/Ccr on ECd/Ccr. Estimated GFR varied inversely with both ratios, and ENAG/Ccr varied directly with ECd/Ccr. Linear and quadratic regressions of Eβ2MG/Ccr on ECd/Ccr and ENAG/Ccr were significant in moderate and high Cd-exposure groups. The association of ENAG/Ccr with ECd/Ccr implies that both ratios depicted cellular damage per surviving nephron. Consequently, we infer that excreted Cd emanated from injured tubular cells, and we attribute the reduction of eGFR to the injury. We suggest that ECd/Ccr, ENAG/Ccr, and eGFR were associated with one another because each parameter was determined by the tubular burden of Cd.

Highlights

Cadmium (Cd), a divalent metal used for industrial purposes, is an important environmental pollutant in some regions of the world [1,2,3,4,5]
Hepatocytes take up Cd not bound to MT [10], synthesize MT in response to the metal, and store complexes of CdMT
These complexes are subsequently released from hepatocytes and transported to the kidneys [8,11,12]

Summary

Introduction

Cadmium (Cd), a divalent metal used for industrial purposes, is an important environmental pollutant in some regions of the world [1,2,3,4,5]. Cd is bound to red blood cells, albumin, glutathione (GSH), sulfur-containing amino acids, MT, and PC [6,7,8,9,10]. Hepatocytes take up Cd not bound to MT [10], synthesize MT in response to the metal, and store complexes of CdMT. These complexes are subsequently released from hepatocytes and transported to the kidneys [8,11,12]. Cd in plasma is filterable by glomeruli if it is bound to GSH, amino acids, MT, or PC [8,9], but the fraction of circulating Cd that enters the filtrate is unknown. Basolateral uptake may add to the cellular content of Cd in the proximal tubule [16,17,18]

Methods

Results

Conclusion