Renal toxins

The proximal tubule and descending limb of Henle s loop are freely permeable to water (Table 15-1). Any osmotically active agent that is filtered by the glomerulus but not reabsorbed causes water to be retained in these segments and promotes a water diuresis. Such agents can be used to reduce intracranial pressure and to promote prompt removal of renal toxins. The prototypic osmotic diuretic is mannitol. 

The renal toxins of A. smithiana are identified as allenic norleucine and chlorocrotylglycine [102]. Poisoning with A. smithiana which were mistaken for the edible Tricholoma magnivelare (edible pine mushroom or matsutake) was reported in three Asian patients in the Pacific Northwest and two patients in Taiwan [103,104]. Nausea, vomiting, water diarrhea and abdominal discomfort without liver injury developed 4-11 hours post ingestion. Renal failure occurred 2 to 4 days later and temporary required hemodialysis. After several weeks, renal function recovered to the basehne level [104]. 

Many of the same chemicals that are hepatotoxic are also nephrotoxic. A partial list of renal toxins is contained in Table 31.1. This list is drawn from the Scorecard kidney toxicant lists, which contains references to original sources... 

As seen from Table 31.1, and associated references, many single chemicals are renal toxins. Several have been studied in detail. The following are illustrative examples ... 

Table 31.1 Partial List of Renal Toxins (Continued)...

Given the almost constant exposure of humans to toxic chemicals (via air pollution, water pollution, or food contamination) and the filtration function of the kidneys, one could easily argue that the kidneys are almost constantly exposed to mixtures of toxic chemicals and that the uptake of additional xenobiotic chemicals creates new mixtures. As we have already seen earlier, many single chemicals have been shown to be renal toxins. Whether the observed nephrotoxic effects of any of these chemicals are because of its interactions with endogenous or other exogenous chemicals is unknown. What is known is that exposures to some chemical mixtures are toxic to the kidneys of test animals and humans. Examples of studies demonstrating mixture effects follow ... 

Carbon tetrachloride, which has been used in fire extinguishers as a fire suppressant, is a known renal toxin. In a study of people exposed to carbon tetrachloride vapors during fire fighting activities, it was found that those individuals with histories of alcohol abuse experience greater nephrotoxic effects (including renal failure) than those who do not abuse alcohol. The authors of the study conclude that ethanol potentiates the nephrotoxic effects of carbon tetrachloride. 11 This is an example of a potentiated effect being observed when exposure is to a mixture of a lipophile (carbon tetrachloride Kow = 2.83) and a hydrophile (ethanol Kow = -0.32). 

Although both ethanol and tobacco smoke are renal toxins, a laboratory animal study demonstrated that the combination of the two produced nephrotoxic effects different from either one alone. P9]... 

In the case of ifosfamide, the mechanism ofifosfamide-induced nephrotoxicity has been the topic of intense study which has yielded important clues as pathophysiology [54, 76-82], As noted above, ifosfamide is a prodrug that must undergo activation to ifosfamide mustard to exert its anticancer effects (Fig. 6). Ifosfamide metabolism can produce either ifosfamide mustard by ring hydrox-ylation or chloracetaldehyde by side chain oxidation [71, 77, 79], It has been demonstrated that chloracetaldehyde produced by intrarenal metabolism can act as a potent renal toxin, both in vitro and in vivo [76, 77, 80], It has also been clearly demonstrated that the use of concurrent antioxidant therapy—in the case of ifosfamide with 27-acetylcysteine—can prevent ifosfamide-induced renal injury, again both in vitro and in vivo [79-81], This approach has been shown in a small number of case reports to be effective in children with cancer [82],... 

In order to test the NMR-PR approach further, the time course of metabolic urinary changes induced by two renal toxins has been investigated in detail. In this case, toxic lesions were induced in Fisher 344 rats by a single acute dose of the renal cortical toxin mercury(II) chloride and the medullary toxin 2-bromoethanamine. The rat urine was collected for up to 9 days after dosing and was analysed using NMR spectroscopy. The onset, progression and recovery of the lesions were also followed using histopath-... 

I. Mechanism of toxicity. Carbon tetrachloride and chloroform are CNS depressants and potent hepatic and renal toxins. They may also increase the sensitivity of the myocardium to arrhythmogenic effects of catecholamines. The mechanism of hepatic and renal toxicity is thought to be a result of a toxic free-radical intermediate of cytochrome P-450 metabolism. (Bioactivation of CCI4 has become a model for chemical toxicity induced by free radicals.) Chronic use of metabolic enzyme inducers such as phenobarbital and ethanol increases the toxicity of carbon tetrachloride. Carbon tetrachloride is a known animal and suspected human carcinogen. Chloroform is embryotoxic and an animal carcincogen. 

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