Proximal tubular necrosis

Trichloroethylene is metabolized similarly and gives rise to dichlorovinyl cysteine. It has been found that S-(l,2-dichlorovinyl)-L-cysteine (DCVC) and S-(2-chloroethyl)-DL-cysteine (CEC) (Fig. 7.30) are both nephrotoxic when administered to animals causing renal proximal tubular necrosis. CEC does not require 3-lyase activation to be nephrotoxic, but can rearrange, possibly to a reactive episulfonium ion, by nucleophilic displacement of the chlorine atom. These compounds decrease the activity of the renal tubular anion and cation transport system. 

Chloroform is an anesthetic and solvent, which may be nephrotoxic and hepato toxic. It requires metabolic activation by cytochrome P-450, and male mice are more susceptible to the nephrotoxicity than females, which are more likely to suffer hepatic damage. The renal damage, proximal tubular necrosis, is accompanied by fatty infiltration. The metabolic activation, which may take place in the kidney, produces phosgene, which is reactive and can bind to critical proteins. 

These drugs (e.g., cephaloridine) may be nephrotoxic causing proximal tubular necrosis. Cephaloridine is actively taken up from blood into proximal tubular cells by OAT 1. The drug therefore accumulates in the kidney. Metabolic activation via cytochrome P-450 may be involved. GSH is oxidized, and as NADPH is also depleted, the GSSG cannot be reduced back to GSH. As vitamin E-depleted animals are more susceptible, it has been suggested that lipid peroxidation may be involved. Damage to mitochondria also occurs. 

Chloroform causes kidney damage (proximal tubular necrosis) and liver damage (hepatic necrosis). The mechanism is believed to involve metabolic activation of the chloroform in the kidney to produce phosgene, which is probably responsible for the toxicity. Both liver and kidney damage may be modulated by treating animals with enzyme inducers and therefore it seems likely that the liver damage is also mediated by a reactive metabolite. 

Phospholipidosis is an early cellular alteration induced by gentamicin (Table 29.3) and is characterized by an increase in total phospholipid content with no change in relative amounts of individual phospholipids. Both in vivo and in vitro, gentamicin inhibits a variety of enzymes involved with phospholipid metabolism, including lysosomal phospholipases A and C and extra-lysosomal phosphatidylino-sitol-specihc phospholipase C. However, cultured rat hbroblasts incubated with gentamicin display phospholipidosis with no loss in cell viability. The exact role of phospholipidosis in gentamicin-induced proximal tubular necrosis, therefore, is not clear. 

Large doses of acetaminophen can cause renal and hepatic toxicity in rats and mice. Toxicity is characterized by renal tubular necrosis in the proximal tubules (Schnellmann, 2001). Acetaminophen toxicity has also been reported in humans. Generally, toxicosis is a result of large overdoses which result in proximal tubular necrosis. Aspirin, ibuprofen, and acetaminophen are the important analgesics, which are reported to cause toxicosis in veterinary medicine. Renal lesions including renal tubular necrosis and papillary necrosis have been reported in dogs. 

Beta-lactam nephrotoxicity has been reviewed, particularly considering structure-activity relations (112). Acute proximal tubular necrosis as a consequence of beta-lactam toxicity develops in proportion to ... 

Cytochrome P-450 and cysteine conjugate p-lyse are primarily localized in the proximal tubules, and these enzymes also contribute to the susceptibility of the proximal tubule to toxicant injury. Specifically, widely used industrial solvents such as chloroform produce tubular nephrotoxicity via cytochrome P-450 activation, and haloaUcanes and haloalkenes (e.g. trichloroethylene) are rendered toxic by cysteine conjugate (3-lyse activation [24,24a]. In addition, overdoses of acetaminophen (APAP) cause nephrotoxicity that is characterized by proximal tubular necrosis [25]. APAP undergoes cytochrome P-450-mediated activation to produce a toxic electrophile, N-acetyl-p-benzoquinon-eimine (NAPQI) [25a]. Although NAPQI is extremely reactive, it is detoxified by conjugation with reduced GSH unless NAPQI is formed in excess of the cellular capacity for GSH conjugation. The excess NAPQI is available to bind to critical cellular proteins and to induce oxidative stress, resulting in disruption of cellular homeostasis and tubular injury [26]. 

Shanley PE, Rosen MD, Brezis M, Silva P, Epstein EEI, Rosen S Topography of focal proximal tubular necrosis after ischemia with reflow in the rat kidney. Am.J.Pathol. 122 462-468,1986... 

Chronic analgesic nephrotoxicity is characterized by renal papillary necrosis and interstitial nephritis rather than the proximal tubular necrosis observed in acute nephrotoxicity. In most cases, chronic... 

Tacrolimus nephrotoxicity can occur as proximal tubular vacuolization, proximal tubular necrosis, or glomerular capillary/arteriolar thrombi. Although there are reports that tacrolimus may be less potent as a nephrotoxicant than cyclosporine, tacrolimus potentiates cyclosporine nephrotoxicity in humans. 

Verstrepen WA, Nouwen EJ, Yue XS, De Broe ME. Altered growth factor expression during toxic proximal tubular necrosis and regeneration. Kidney Int 1993 43 1267-1279. 

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