Nephrotoxicity tubule injury

Serum creatinine and BUN, the most common indicators of renal function used in both clinical and preclinical safety laboratory panels, are relatively insensitive markers of injury, particularly for the renal tubules. Urinary measurements of alanine aminopeptidase and A-acetyl-beta-D-glucosaminidase and kidney injury molecule-1 (KIM-1) can provide much more sensitivity when nephrotoxicity is a potential safety concern [28,29], These are also suitable for safety monitoring in early-phase human trials if preclinical studies validate such use to monitor product nephrotoxicity. 

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]. 

Because NADPH-cytochrome P-450 reductase activity is highest in the cortex [77,121] and medullary microsomes lack cytochrome P450 [121], renal cortical tissue was used to investigate peroxidative injury caused by p-lactam accumulation in the kidney. Renal cortical microsomes, slices, tubule and cell suspensions, primary cultured renal cells and established kidney cell lines were exposed to -lactams with the aim to investigate the subcellular mechanism of the nephrotoxic injury. 

Cases of anuria have been reported when EDTA was administered to treat lead poisoning. Such kidney injury is reversible and is probably not due to the chelate directly, but to the reabsorption of the metal in the tubules. Of 130 children that received dime-rcaprol and EDTA, 3% developed acute renal failure and 13% had biochemical evidence of nephrotoxicity. However, lead poisoning can cause kidney injury without EDTA therapy. In another study, 122 patients were given EDTA and none showed posttreatment increases in plasma creatinine. 

Chronic kidney disease develops as the result of injury to involved glomerular and tubular units while others remain relatively intact. The remaining functional nephron units develop hyperfiltering glomeruli and hyperfunctioning tubules to compensate for the damaged nephrons. These residual nephrons are more susceptible to nephrotoxic injury due to their increased energy requirements and... 

The nature of tubular injury in acute renal failure (ARF) includes reversible sublethal injury (swelling, loss of apical brush border) and lethal injury (necrosis and apoptosis) [1, 2]. Proximal tubular cell death due to ischemic ARF in vivo and hypoxia in vitro results predominantly in necrosis, hence the term acute tubular necrosis or ATM. Apoptotic cell death in ischemic renal injury has been inconsistently demonstrated [3]. When apoptosis has been demonstrated in early ischemic ARF, it is present in the distal tubule [4, 5]. Apoptosis in proximal tubules may play a role in tubular regeneration and was demonstrated to occur at 3 days after ischemic injury in regenerating FT [6]. Thus, the nature of nephrotoxic injury, whether it is tubular dysfunction necrosis or apoptosis is also an important consideration. 

Proximal tubular injury due to nephrotoxicants occurs more frequently than other nephrotoxic effects, and this probably reflects a combination of the proportion of the total renal blood supply received by the renal cortex and the number of xenobiotics reabsorbed and excreted within the proximal tubule. Xenobiotics can alter or inhibit the transport processes of passive diffusion and/or carrier transporters for both anionic/base and cationic molecules. 

De SK, McMaster MT, Dey SK, Andrews GK (1989) Cell-specific metallothionein gene expression mouse decidua and placentae. Development 107 611-621 De SK, Enders GC, Andrews GK (1991) High levels of metallothionein mRNAs in male germ cells of the adult mouse. Mol Endocrinol 5 628-636 Dorian C, Gattone II VH, Klaassen CD (1992) Renal cadmium deposition and injury as a result of accumulation of cadmium-metallothionein (Cd-MT) by the proximal convoluter tubules. Toxicol Appl Pharmacol 114 173-181 Dudley RE, Gammal LM, Klaassen CD (1985) Cadmium-induced hepatic and renal injury in chronically exposed rats likely role of hepatic cadmium-metallothionein in nephrotoxicity. Toxicol Appl Pharmacol 77 414-426 Ershoff BH (1948) Conditioning factors in nutritional disease. Physiol Rev 28 107-137... 

The sequestration of cadmium by MT is a double-edged sword, i.e., although Cd-MT is relatively inert when stored as an intracellular complex, it becomes a potent nephrotoxicant after reaching the systemic circulation (Cherian et al. 1976 Squibb et al. 1984). Human cadmium nephrotoxicity may be related to Cd-MT exposure, because this may be a major form of cadmium in diet (Maitani et al. 1984). Cadmium salts absorbed from the GI tract or lungs are initially transported to liver, where synthesis of MT is induced. Continual exposure to cadmium results in liver injury with leakage of Cd-MT into the systemic circulation (Dudley et al. 1985). The complex is transported to kidney, filtered, and reabsorbed by the proximal tubule, possibly via a mechanism involving receptor mediated endocytosis (Foulkes... 

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