Elsevier

Seminars in Nephrology

Volume 23, Issue 5, September 2003, Pages 500-508
Seminars in Nephrology

Toxic nephropathy: environmental chemicals

https://doi.org/10.1016/S0270-9295(03)00094-9Get rights and content

Abstract

The kidney is the target of numerous xenobiotic toxicants, including environmental chemicals. Anatomical, physiological, and biochemical features of the kidney make it particularly sensitive to many environmental compounds. Factors contributing to the sensitivity of the kidney include: large blood flow, the presence of a variety of xenobiotic transporters and metabolizing enzymes, and concentration of solutes during urine production. In many cases, the conjugation of environmental chemicals to glutathione and/or cysteine targets these chemicals to the kidney where inhibition of renal function occurs through a variety of mechanisms. For example, heavy metals such as mercury and cadmium target the kidney after glutathione/cysteine conjugation. Trichloroethlene and bromobenzene are metabolized and conjugated to glutathione in the liver before renal uptake and toxicity. In contrast, renal injury produced by chloroform and aristolochic acids is dependent on renal cytochrome P450 metabolism to toxic metabolites. Other compounds, such as paraquat or diquat, damage the kidney via the production of reactive oxygen species. Finally, the low solubility of ethylene glycol metabolites causes crystal formation within the tubular lumen and nephrotoxicity. This chapter explores mechanisms of nephrotoxicity by environmental chemicals, using these example compounds. What remains to be accomplished and by far the most difficult process is the elucidation of the detailed mechanisms of tubular cell injury after toxicant uptake and metabolism. The large number of individuals experiencing a decline in renal function with age makes the search for these mechanisms very compelling.

Section snippets

Mercury

Mercury, like cadmium, gold, lead, nickel, chromium, and uranium, is a nephrotoxic metal.1 Mercury can exist in 3 oxidation states: elemental mercury (Hg0), mercurous mercury (Hg1+), and mercuric mercury (Hg2+). Hg0 is a ubiquitous environmental pollutant introduced primarily by degassing of the earth’s crust and is oxidized to Hg2+ in mammalian cells.2 Organomercurials, such as methyl mercury, are produced by microbial metabolism of both Hg0 and Hg2+.3 Organomercurials are hydrophobic and

Trichloroethylene

Trichloroethylene (TCE) is a widely used industrial solvent and a common environmental contaminant. Although TCE exposures may come from contaminated drinking water, higher-level exposures are more likely to originate from occupational exposures. Although the kidney is not a selective target of TCE directly, S-(1,2-dichlorovinyl)-L-cysteine (DCVC), a biotransformation product of TCE, is a nephrotoxicant in several mammalian species. DCVC offers an additional example of how GSH and cysteine

Paraquat/diquat

Paraquat and diquat are structurally similar nonselective herbicides. When used properly these compounds offer no significant risk to humans, partly because the intact skin provides a significant barrier against penetration. However, most poisonings occur from accidental ingestion or in cases of attempted suicide. Interestingly, diquat solutions as low as 1% have resulted in human toxicity.27 When ingested, these compounds cause multisystem toxicity to the lung, kidney, heart, and central

Ethylene glycol

Ethylene glycol (EG) is an antifreeze in cooling systems, a component of hydraulic brake fluid, an ingredient in chemical synthesis, and a solvent. Further, EG also has been used to de-ice airplanes and runways. Life-threatening human exposures to EG generally occur from ingestion of large quantities in attempted suicides. Dogs and cats, 2 species prone to accidental EG poisonings,31 have shown signs of nephrotoxicity after ingestion of mishandled EG sources.

EG-mediated renal toxicity requires

Herbal remedies

Aristolochic acids, plant alkaloid products of the Chinese herb Aristolochia fangchi, are nephrotoxic. Between 1990 and 1992, renal failure developed in young Belgian woman who were on a slimming regimen containing Chinese herbs. The rapidly fibrosing nephropathy is now described as Chinese herbs nephropathy (CHN). About 100 cases of CHN have been identified in Belgium, with approximately half of them requiring renal transplantation.34 In 1994, the presence of aristolochic acids in diet pills,

Summary

Because of the unique anatomy, biochemistry, and physiology of the kidney, it is the target of numerous environmental chemicals. The toxicants discussed in this article show several mechanisms by which the kidney is targeted by xenobiotics. The ability of the kidneys to selectively accumulate GSH-conjugate species of chemicals such as TCE, bromobenzene, and mercury make it the target of these toxicants and various drugs. What remains to be accomplished and by far the most difficult process is

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