Nephrotoxicity metals

Oskarsson, A., and Fowler, B. A. 1987. Alterations in renal heme biosynthesis during metal nephrotoxicity. Annals of the New York Academy of Sciences 514(1) 268-277. 

Vacca C. Heavy metal nephrotoxicity lead differentiated from cadmium and mercury. Am J Clin Pathol 1980 73 308. 

Kidney Metal ion-mediated nephrotoxicity Protoporphyrin photo-oxidation... 

In mammals, cadmium inhibits copper absorption across the intestinal mucosa (Aaseth and Norseth 1986). Intercorrelations of copper with cadmium and zinc in livers of polar bears (Ursus maritimus) are probably mediated by metallothioneins, which may contain all three metals (Braune etal. 1991). In rats, copper protects against nephrotoxicity induced by cadmium, provided that copper is administered 24 h prior to cadmium insult. Specifically, rats given 12.5 mg Cu/kg BW by way of subcutaneous injection 24 h before receiving 0.4 mg Cd/kg BW — when compared to a group receiving Cd alone — did not have excessive calcium in urine and renal cortex or excessive protein in urine. Thus, 2.8 mg Cu/kg BW protects against 0.25 mg Cd/kg BW (Liu et al. 1992). 

Mithra mycin 25 mcg/kg IV over 4-6 hours 12 hours Decreased liver function renal insufficiency diarrhea metallic taste Nausea/vomiting stomatitis thrombocytopenia nephrotox-... 

Isolated proximal tubules have been utilized to study the mechanisms of nephrotoxicity induced by antibiotics (Sina et al., 1985, 1986), radiocontrast dyes (Humes et al., 1987), metals (Rylander et al., 1985), anoxia (Weinberg, 1985 Weinberg et al., 1987), cellular oxidants (Messana et al., 1988), cysteine conjugates (Rylander et al., 1985 Schnellman et al., 1987 Zhang and Stevens, 1989), and a variety of nephrotoxic bromobenzene metabolites (Schnellman and Mandel, 1986 Schnellman et al., 1987). 

Most contrast agents elicit nephrotoxicity because they are primarily excreted by the kidneys. However, when administered in small doses, they constitute a rich source of GFR markers. The two major classes of contrast agents that are finding clinical utility as GFR markers are iodinated aromatic compounds and metal complexes. lodinated aromatics such as iohexol and iothalamate (Fig. 13) are commonly used as contrast agents for computed tomography (GT). They also have pharmacokinetics similar to inulin and hence are useful indicators of renal status [215]. The iodinated molecules used for GFR measurements consist of a triiodo-benzene core and hydrophilic groups to enhance solubility in aqueous medium. 

Because the drug and the mobilized metals are excreted via the urine, the drug is relatively contraindicated in anuric patients. In such instances, the use of low doses of EDTA in combination with hemodialysis or hemofiltration has been described. Nephrotoxicity from EDTA has been reported, but in most cases can be prevented by maintenance of adequate urine flow, avoidance of excessive doses, and limitation of a treatment course to 5 or fewer consecutive days. EDTA may result in temporary zinc depletion that is of uncertain clinical significance. Analogs of EDTA, the calcium and zinc disodium... 

Thus, sulfate conjugation and acetylation may be involved in the metabolic activation of N-hydroxy aromatic amines, glutathione conjugation may be important in the nephrotoxicity of compounds, methylation in metal toxicity, glucuronidation in the carcinogenicity of p-naphthylamine and 3, 2 -dimethyl-4-aminobiphenyl. 

These proteins are important for binding potentially toxic metals such as cadmium, mercury, and lead, which all bind to sulfydryl groups. Consequently, the binding and removal of these metals are protective functions. Metallothioneins are markedly induced by cadmium exposure and the small protein, rich in SH groups, can then sequester the metal. They also may have a protective role in oxidative stress and protect redox-sensitive processes. The protein also has a role in cadmium nephrotoxicity (see chap. 7). 

The binding of cadmium to metallothionein decreases toxicity to the testes but increases the nephrotoxicity, possibly because the complex is preferentially, and more easily, taken up by the kidney than the free metal. Dosing animals with the cadmium-metallothionein complex leads to acute kidney damage, whereas exposure to single doses of cadmium itself does not. 

Renal Effects. Occupational exposure to silver metal dust has been associated with increased excretion of a particular renal enzyme (N-acetyl-p-D glucosaminidase), and with decreased creatinine clearance (Rosenman et al. 1987). Both of these effects are diagnostic of marginally impaired renal function. However, the workers in this study were also exposed to cadmium, which was detected in the urine of 5 of the 27 workers studied. Cadmium is known to be nephrotoxic differentiation of the effects of the two metals in the kidney is not possible with the data presented. Therefore, no conclusion can be drawn regarding renal effects of silver based on this study. 

Nitrilotriacetic acid (NTA) is a constituent of various domestic and hospital detergents and is a common water contaminant. NTA forms water-soluble chelate complexes with various metal ions, including iron, at neutral pH. Its iron complex, Fe-NTA, is a known potent nephrotoxic agent. The renal toxicity is assumed to be caused by the elevation of serum free-iron concentration following the reduction of Fe-NTA at the luminal side of the proximal tubule, which generates reactive oxygen species and leads to enhancement of lipid peroxidation. 

Liu JX, Nordberg GF. 1995. Nephrotoxicities of aluminum and/or cadmium-metallothionein in rats Creatinine excretion and metabolism of selected essential metals. Pharmacol Toxicol 77 155-160. 

Tetracycline Tetracycline injections have an acid pH. Incompatibility may reasonably be expected with alkaline preparations or with drugs unstable at low pH. Care should be taken when administering tetracyclines, since chelation takes place with metal ions. Tetracyclines interact with inorganic metal ions. They should not be used with drugs that cause hepatotoxicity and nephrotoxicity (e.g., digoxin, theophylline, ergot alkaloids, methotrexate, oral contraceptives, and penicillins). 

Simultaneous administration of gold compounds with other nephrotoxic, hep-atotoxic, or myelosuppressive and penicillamine drugs must be avoided because of associated toxicities. Metal toxicity can be treated with dimercaprol, and drugs must be withdrawn. 

Triebig G, Zschiesche W, Schaller KH, et al. 1987. Studies on the nephrotoxicity of heavy metals in iron and steel industries. J Biochem Toxicol 1 29-39. 

A classic example of essential metal deficiency resulting from nonessential metal exposure is Itai itai disease. Cadmium pollution in the Jinzu River basin in Japan resulted in severe nephrotoxicity in approximately 184 people. Renal tubule damage caused excessive loss of electrolytes and small proteins from the urine. In severe cases, urinary Ca loss was so severe that bone Ca was mobilized, resulting in osteomalacia. Renal tubular defects persisted for life and induced hypophosphatemia, hyperuricemia, and hyperchloremia, which are characteristic biochemical features of Itai-itai disease (see Section 21.6.1). 

Exposures to chemical substances such as carbon tetrachloride, 1,1-dichloroeth-ylene, paradichlorobenzene, ethylbenzene, monochlorobenzene, tetrachloroethyl-ene, toluene, 1,1,2-trichloroethane, xylenes, cadmium, and lead are known to canse adverse effects on the kidney. The kidney is unusually susceptible because of its role in filtering harmful substances from the blood. Some of these toxicants canse acnte injury to the kidney, while others produce chronic changes that can lead to end-stage renal failure or cancer. Furthermore, evaluation of the nephrotoxicity of complex industrial waste mixtures with organic chemicals and metals reqnires more stndies. 

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