Nephrotoxicity thresholds

Higher nephrotoxic threshold in animals (10- to 60-fold) than in humans... 

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."... 

Methoxyflurane (Penthmne) is the most potent inhala-tional agent available, but its high solubility in tissues limits its use as an induction anesthetic. Its pharmacological properties are similar to those of halothane with some notable exceptions. For example, since methoxyflurane does not depress cardiovascular reflexes, its direct myocardial depressant effect is partially offset by reflex tachycardia, so arterial blood pressure is better maintained. Also, the oxidative metabolism of methoxyflurane results in the production of oxalic acid and fluoride concentrations that approach the threshold of causing renal tubular dysfunction. Concern for nephrotoxicity has greatly restricted the use of methoxyflurane. 

Nephrotoxicity has been found with methoxyflurane when serum fluoride ion concentrations exceeded 50 pmol/l (SEDA-20,106). Although this safety threshold has been applied to other volatile anesthetics as well, renal toxicity has not been reported for the other three anesthetics, even though the threshold can be exceeded during prolonged anesthesia. 

Compound A is nephrotoxic in rats at thresholds estimated at 180 ppm/hour [67]. Renal toxicity is characterized histologically by proximal tubular cell degeneration and necrosis in the corticomedullar region of die kidney and biochemically by proteinuria, glucosuria, and enzymuria (NAG and a-GST) with increased serum creatinine and BUN concentrations occurring with severe toxicity [67-70]. 

When injnry scores are dichotomized into positive and nonpositive, sensitivity and specificity are usually estimated and displayed in an ROC curve (Pepe, 2003). The area under the ROC curve (AUROC) is a common summary performance metric. Some advantages of this approach are that ROC curve estimation generally requires few assumptions, a plot of the ROC curve gives an easily interpreted visual display of results, and the AUROC is a global metric that does not require the specification of a threshold. Since both sensitivity and specificity can be greatly influenced by characteristics that are study specific such as severity or type of injury, it is advisable to compare candidate marker performance to that of standard markers. In rodent nephrotoxicity studies, candidate markers are commonly compared to sCr and BUN. 

Finally, sections of this chapter demonstrate that clinical and scientific research on Pb nephropathy has produced parallels with other adverse effects in humans. That is, continued research produces continued declines in accepted thresholds for nephrotoxic effects of Pb over time. The scientific record now makes it clear that nephrotoxicity in terms of both tubular and glomerular... 

The literature on Pb nephrotoxicity in human populations exposed to relatively low, ambient levels of Pb has made up not only an extensive new literature but also a literature which has markedly improved our understanding of thresholds in Pb nephropathy, the prevalence and incidence of Pb nephrotoxic effects at low exposures, mechanisms of toxic action, etc. Furthermore, sampling and statistical issues are less problematic with general populations. 

The very low mean PbBs in these women and those men and women in the Muntner et al. (2003) U.S. NHANES III provided good evidence that the relative threshold for Pb nephrotoxic effects with environmental exposures in the general population is an order of magnitude less than was observed in the older occupational Pb literature, 60 pg/dl. Low body lead burdens indexed as chelatable Pb amounts of <80 pg/dl were also found to be a predictor of decreased kidney function (Lin et al., 2006). Taiwanese chronic kidney disease patients (N = 108) without diabetes were assigned to chelation and nonchelation groups. Those patients who were not periodically chelated over a 24-month testing period sustained a mean reduction in GFR of 4.6 ml/min/1.732 m and showed increased serum creatinine. 

Table 22.3 presents the full-spectrum of dose—toxic response relationships for lead toxicity in adults in terms of lowest reported adverse effect level thresholds. As with the earlier tables, only the lowest values for PbB in the associations specific for the indicated range are identified. It is also understood with these adult tabulations that as PbB values rise above lowest levels of determined associations, those toxic effects increase in severity and multiplicity. Toxicity criteria for reliability and validity parallel those enumerated for the earlier childhood tables. A number of dose-responses scaled to dose/exposure are identified in the table. In many cases, including hematotoxicity, peripheral neurotoxicity, and nephrotoxicity, effects are qualitatively similar but occur at higher empirically measured thresholds. 

Hirata M, Tanaka A, Hisanaga A, Ishinishi N (1990) Effects of glutathione depletion on the acute nephrotoxic potential of arsenite and on arsenic metabolism in hamsters. Toxicol Appl Pharmacol 106 469-481 Hoffman JL (1980) The rate of transmethylation in mouse liver as measured by trapping S-adenosylhomocysteine. Arch Biochem Biophys 205 132-135 Hopenhayn-Rich C, Smith AH, Goeden HM (1993) Human studies do not support the methylation threshold hypothesis for the toxicity of inorganic arsenic. Environ Res 60 161-177... 

Ubiquity of Cd make it a serious environmental health problem that needs to be assessed because, besides being a well-known occupational hazard, CLCE is a health problem for 10% of the general population that increases organ toxicity, especially nephrotoxicity, without a known threshold, implying that there is currently no safe limit for CLCE. 

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