Nephrotoxicity exposure

Bimer G, Vamvakas S, Dekant W, et al. 1993. Nephrotoxic and genotoxic N-acetyl-S-dichlorovinyl-L-cysteine is a urinary metabolite after occupational 1,1,2-trichloroethene exposure in humans Implications for the risk of trichloroethene exposure. Environ Health Perspect 99 281-284. 

One of the major drawbacks of calcineurin inhibitors is their ability to cause acute and chronic nephrotoxicity. Acute nephrotoxicity has been correlated with high calcineurin inhibitor doses and usually is reversible. Chronic toxicity, however, typically is irreversible and is linked to chronic drug exposure. Table 52—4 expands on the more common calcineurin inhibitor-induced adverse events. 

Response to antifungal therapy in invasive candidiasis is often more rapid than for endemic fungal infections. Resolution of fever and sterilization of blood cultures are indications of response to antifungal therapy. Toxicity associated with antifungal therapy is similar in these patients as described earlier with the caveat that some toxicities maybe more pronounced in crit-ically-ill patients with invasive candidiasis. Nephrotoxicity and electrolyte disturbances, with amphotericin B in particular, are problematic and may not be avoidable even with lipid amphotericin B formulations. Fluconazole and echinocandins are generally safer options, and are generally well tolerated. Decisions to use one class of agents over the other is principally driven by concerns of non-albicans species, patient tolerability, or history of prior fluconazole exposure (risk factor for non-albicans species.). 

Chia KS, Jeyaratnam J, Lee J, et al. 1995b. Lead-induced nephropathy Relationship between various biological exposure indices and early markers of nephrotoxicity. Am J Ind Med 27 883 895. 

GoyerR. 1992. Nephrotoxicity and carcinogenicity of lead. In Beck, BD. Symposium overview an update on exposure and effects of lead. Fundam Appl Toxicol 18 1-16. 

In studies of acute effects on humans caused by exposure to Pb, nephrotoxic effects as well as gastrointestinal effects have been observed [40], Encephalopathy can affect both children and adults. Acute encephalopathy has been shown to increase the incidence of neurological and cognitive impairments. 

Chronic exposure to Pb has been shown to cause anaemia, neurotoxic effects, such as reduced cognitive performance and reduced peripheral nerve conduction velocity, and nephrotoxicity. Children are more sensitive to exposure to Pb than adults, especially during the first 2 years of life [41], For children, exposure to lead can cause growth retardation, affect the neuropsychological development and cause encephalopathy [39]. Adverse reproductive effects due to lead exposure have been observed for both men and women. Exposure of pregnant women to low concentrations of lead is associated with miscarriages and low birth weights [40],... 

Comparative Toxicokinetics. There are differences in the effects of hexachloroethane on different species and between sexes. Male rats are particularly susceptible to kidney damage following hexachloroethane exposure because of the binding of hexachloroethane to 2p-globulin (NTP 1989). However, nephrotoxicity is also seen in female rats and in mice and rabbits (Gorzinski et al. 1985 NTP 1977, 1989 Weeks et al. 

The kidney is a frequent site of toxic insult due to drug and chemical exposure in experimental animals and man. Broad classes of drugs and industrial chemicals are implicated in nephrotoxic reactions (Cohen and Barac Neito, 1973 Smith et al.,... 

Isepamicin Population PK and Bayesian estimates of individual PK parameters were used to calculate various surrogate markers of isepamicin exposure to be tentatively correlated with clinical outcome and nephrotoxicity. No correlation was found between peak, AUC, or their ratio with MIC and clinical efficacy suggesting the drug should not be monitored using PK parameters... 

Several animal studies indicate that chloroform interacts with other chemicals within the organism. The lethal and hepatotoxic effects of chloroform were increased by dicophane (DDT) (McLean 1970) and phenobarbital (a long-acting barbiturate) in rats (Ekstrom et al. 1988 McLean 1970 Scholler 1970). Increased hepatotoxic and nephrotoxic effects were observed after interaction with ketonic solvents and ketonic chemicals in rats (Hewitt and Brown 1984 Hewitt et al. 1990) and in mice (Cianflone et al. 1980 Hewitt et al. 1979). The hepatotoxicity of chloroform was also enhanced by co-exposure to carbon tetrachloride in rats (Harris et al. 1982) and by co-exposure to ethanol in mice (Kutob and Plaa 1962). Furthermore, ethanol pretreatment in rats enhanced chloroform-induced hepatotoxicity (Wang et al. 1994) and increased the in vitro metabolism of chloroform (Sato et al. 1981). 

WHO/IPCS have pubhshed Environmental Health Criteria Monographs on principles and methods for the assessment of toxicity associated with exposure to chemicals in relation to the following specific target organs and tissues immunotoxicity (WHO/IPCS 1996) (Section 4.7.6.3), nephrotoxicity (WHO/IPCS 1991), and neurotoxicity (WHO/IPCS 1986b, 2001) (Section 4.7.7.3). 

Toxicology. Cadmium oxide fume is a severe pulmonary irritant cadmium dust also is a pulmonary irritant, but it is less potent than cadmium fume because it has a larger particle size. Chronic exposure is associated with nephrotoxicity. Several inorganic cadmium compounds cause malignant tumors in animals. 

It does not appear that the nephrotoxicity attributable to a2u-globulin syndrome is relevant to humans. Most epidemiological studies have not shown an association between gasoline exposure and renal cancer risk. However, a recent case-control study from Finland reported a significant association between renal cell cancer and gasoline that was dose dependent."... 

Nephropathy has been associated with chronic lead poisoning. " A study of two large cohorts of heavily exposed lead workers followed through 1980 demonstrated a nearly threefold excess of deaths attributed to chronic nephritis or other hypertensive disease, primarily kidney disease. Most of the excess deaths occurred before 1970, among men who began work before 1946, suggesting that current lower levels of exposure may reduce the risk. Experimental animal studies suggest there may be a threshold for lead nephrotoxicity, and in workers, nephropathy occurred only in those with blood levels over 62p,g/dl for up to 12 years."... 

Exposure to tetralin-saturated vapor for 8 hours was lethal to rats. Nephrotoxicity, evidenced as increased cytoplasmic hyalin droplets in proximal convoluted tubular epithelial cells, occurred in male but not female rats exposed intragastrically for 2 weeks." ... 

Renal toxicity In a 1-year toxicity study, entacapone (plasma exposure 20 times that in humans receiving the MRDD of 1600 mg) caused an increased incidence of nephrotoxicity in male rats. 

Absorption, Distribution, Metabolism, and Excretion. Data are available on the pharmacokinetics of hexachlorobutadiene in animals by the oral route, but not in humans. There are no data in humans or animals on exposures to hexachlorobutadiene by the inhalation or dermal routes. Because of the key role of the liver in producing the metabolites which are responsible for the nephrotoxicity of this compound, knowledge of the pharmacokinetics of inhalation and dermal exposures would be valuable. Oral studies reported the presence of the enzymes responsible for the glutathione conjugation reaction and the subsequent formation of derivatives in the liver, intestines, and kidney. 

Idiosyncratic dmg reactions (IDRs) are most commonly characterized by a reaction involving fever or rash, with or without internal organ involvement. The spectrum of responses ranges from a minor rash, to potentially fatal toxic epidermal necrosis and Stevens-Johnson syndrome. Immunoglobulin E (IgE)-mediated anaphylactic shock, occasional joint pain, hepatotoxicity or nephrotoxicity are also well documented [24]. The frequency of such reactions are unknown but estimated to be between 1 1000 and 1 10000 exposures and may be enhanced on re-challenging susceptible individuals with the same dmg. 

Smialowicz RJ, Simmons JE, Luebke RW, et al. 1991. Immunotoxicologic assessment of subacute exposure of rats to carbon tetrachloride with comparison to hepatotoxicity and nephrotoxicity. Fund AppI Toxicol 17 186-196. 

The kidneys are susceptible to toxicity from xenobiotics (Fig. 7.1) because they too have a high blood flow. Cells of the tubular nephron face double-sided exposure, to agents in the blood on the basolateral side and in the Altered urine on the luminal side. Proximal tubule cells are generally the site of nephrotoxicity, since these cells have an abundance of cytochrome P450 and can transport organic anions and cations from the blood into the cells, thereby concentrating these chemicals manyfold. 

Two tetracyclines have sufficiently distinctive features to warrant separate mention. Doxycycline, with its longer half-hfe and lack of nephrotoxicity, is a popular choice for patients with preexisting renal disease or those who are at risk for developing renal insufficiency. The lack of nephrotoxicity is related mainly to biliary excretion, which is the primary route of doxycycline elimination. Doxycycline is the preferred parenteral tetracycline Doxycycline is a potential first-hne agent in the prophylaxis of anthrax after exposure. Doxycycline is the treatment of choice for the primary stage of Lyme disease in adults and children older than 8 years. 

---