Nephrotoxic Biomarkers with Specific Indications for Metallic Pollutants: Implications for Environmental Health

Abstract

Environmental and occupational exposure to heavy metals and metalloids is a major global health risk. The kidney is often a site of early damage. Nephrotoxicity is both a major consequence of heavy metal exposure and potentially an early warning of greater damage. A paradigm shift occurred at the beginning of the 21st century in the field of renal medicine. The medical model of kidney failure and treatment began to give way to a social model of risk factors and prevention with important implications for environmental health. This development threw into focus the need for better biomarkers: markers of exposure to known nephrotoxins; markers of early damage for diagnosis and prevention; markers of disease development for intervention and choice of therapy. Constituents of electronic waste, e-waste or e-pollution, such as cadmium (Cd), lead (Pb), mercury (HG), arsenic (As) and silica (SiO₂) are all potential nephrotoxins; they target the renal proximal tubules through distinct pathways. Different nephrotoxic biomarkers offer the possibility of identifying exposure to individual pollutants. In this review, a selection of prominent urinary markers of tubule damage is considered as potential tools for identifying environmental exposure to some key metallic pollutants.

Keywords: Heavy metals; environmental and occupational exposure; kidney injury; nephrotoxicity; urinary biomarkers.

Figure 1.

Biomarker Publications 2004 to 2019. The number of publications retrieved by year 2004 to 2019 in a search using the terms ‘biomarker’ and ‘nephrotoxicity’, brown columns, ‘biomarker’ and ‘Acute Kidney Injury, AKI’, green columns. The blue shaded area is the number of publications in 100 seconds retrieved by year 2004 to 2019 in a search using the term ‘biomarker’.

Figure 2.

The molecular mechanisms involved in the release of NAG, NGAL and KIM-1 from the tubular epithelial cells in the s1, s2 and s3 segments of the proximal renal tubule (Right hand side), schematic representation of the renal tubule indicating the segmental origin of NAG, NGAL and KIM-1 (Left hand side).

Figure 3.

Mechanisms of Cd and Hg uptake by proximal tubule epithelial cells in s1/s2. Cd-metallothionein complexes are also taken up on the apical membrane, but it is endocytosed by megalin. Cd²⁺ ions have a strong affinity for sulphur groups and form complexes with select sulphydryl (thiol)-containing biomolecules. Cd²⁺-thiol complexes are taken up by the basal organic cation transporter OCT2. Divalent Metal Transporter 1 (DMT1) allows transmembrane movement of a number of metals including Cd and Hg. Insert identifies section of proximal tubule illustrated in main figure.

Figure 4.

Mechanisms of Pb and As uptake by proximal tubule epithelial cells in s1/s2. Pb acetate is taken up by nonreceptor-mediated endocytosis. At least 4 DMT1 isoforms are expressed, IVS4+44C/A may play a particular role in the uptake of Pb in the kidney. The phosphate transporters PiT1 and PiT2 have a similar affinity for the Arsenate form of As as they do for Pi. Arsenate competes with Pi and reduces Pi transport in both PiT1 and PiT2, inducing inward currents similar to Pi. The insert identifies a section of the proximal tubules illustrated in the main figure.