Chronic Kidney Disease and Exposure to Nephrotoxic Metals

Abstract

Chronic kidney disease (CKD) is a common progressive disease that is typically characterized by the permanent loss of functional nephrons. As injured nephrons become sclerotic and die, the remaining healthy nephrons undergo numerous structural, molecular, and functional changes in an attempt to compensate for the loss of diseased nephrons. These compensatory changes enable the kidney to maintain fluid and solute homeostasis until approximately 75% of nephrons are lost. As CKD continues to progress, glomerular filtration rate decreases, and remaining nephrons are unable to effectively eliminate metabolic wastes and environmental toxicants from the body. This inability may enhance mortality and/or morbidity of an individual. Environmental toxicants of particular concern are arsenic, cadmium, lead, and mercury. Since these metals are present throughout the environment and exposure to one or more of these metals is unavoidable, it is important that the way in which these metals are handled by target organs in normal and disease states is understood completely.

Oxidative Stress and Vanadium

“…Finally, most of them are eliminated by the kidney, reason why this organ is one of the most affected structures by metals [38]. Also, there are reports that in CKD when there is a problem to eliminate pollutant metals, these can concentrate into kidney cells and the damage worsened when it occurs in humans, both in children and adults [39]. Oxidative stress and inflammation are the principal mechanisms of renal injury; in addition, arsenic, cadmium, mercury, and lead are associated to hyperglycemia that may aggravate the oxidative stress and the renal damage.…”

Pharmacokinetics and Toxicokinetics Roles of Membrane Transporters at Kidney Level

“…Exposure to As is associated with the development of tumors in various organs, like the skin, lung, bladder, liver and kidney, as well as cardiovascular diseases, hypertension, peripheral artery disease and diabetes mellitus (86). Arsenic is excreted in the urine through the kidney, where it accumulates, inducing tubulointerstitial nephritis and acute tubular necrosis characterized by hypercalciuria, albuminuria, nephrocalcinosis, and necrosis of the renal papillae (Orr and Bridges, 2017). After being absorbed into the kidney, iAs is methylated and the transport of iAs as well as its methylated forms play a key role in the accumulation of metal in proximal tubular cells and consequently in nephrotoxicity.…”

“…Hg binds to one or more thiol-containing biomolecules, such as GSH, Cys, N-acetylcysteine (NAC) and albumin. Its binding to GSH, by itself, already decreases the cellular antioxidant capacity against oxidative stress and inflammation (87,89). OATs uptake Hg 2+ and MeHg from the blood to proximal tubular cells, whereas the efflux to the urine is done by MRP2 and BCRP, which are responsible for their accumulation.…”

Benchmark dose estimation of urinary and blood cadmium as biomarkers of renal dysfunction among 40‐75‐year‐old non‐smoking women in rural areas of southwest China

“…Renal damage is the most sensitive and critical adverse effect of long-term Cd intake, which occurs initially as tubular damage, followed by glomerular damage, and is characterized by increased urinary excretion of low-molecular-weight proteins (LMWPs) or intracellular tubular enzymes (Jarup & Akesson, 2009;Orr & Bridges, 2017;Prozialeck & Edwards, 2012). LMWPs, such as urinary α 1 -microglobulin (α 1 -MG), β 2 -microglobulin (β 2 -MG), metallothionein (MT) and retinol-binding protein (RBP), are filtered freely in the glomerulus and then are absorbed normally along the proximal tubules (Åkerström, Lögdberg, Berggård, Osmark, & Lindqvist, 2000;Johri et al, 2010;Murakami, Cain, & Webb, 1983;Rehman, Fatima, Waheed, & Akash, 2018).…”

“…LMWPs, such as urinary α 1 -microglobulin (α 1 -MG), β 2 -microglobulin (β 2 -MG), metallothionein (MT) and retinol-binding protein (RBP), are filtered freely in the glomerulus and then are absorbed normally along the proximal tubules (Åkerström, Lögdberg, Berggård, Osmark, & Lindqvist, 2000;Johri et al, 2010;Murakami, Cain, & Webb, 1983;Rehman, Fatima, Waheed, & Akash, 2018). Alternatively, N-acetyl-β-D-glucosaminidase (NAG), an enzyme localized in the lysosomes of the tubular cells, is derived from the mitochondria within the proximal tubular epithelial cells and released into the tubular fluid after cells are injured (Matović, Buha, Ðukić-Ćosić, & Bulat, 2015;Orr & Bridges, 2017). Therefore, MT, α 1 -MG, β 2 -MG, RBP and NAG are valid biomarkers of tubular reabsorption.…”