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Schnellman_Kelly - Pathophysiology of Nephrotoxic Acute...

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15 Pathophysiology of Nephrotoxic Acute Renal Failure H umans are exposed intentionally and unintentionally to a variety of diverse chemicals that harm the kidney. As the list of drugs, natural products, industrial chemicals and environ- mental pollutants that cause nephrotoxicity has increased, it has become clear that chemicals with very diverse chemical structures pro- duce nephrotoxicity. For example, the heavy metal HgCl 2 , the myco- toxin fumonisin B 1 , the immunosuppresant cyclosporin A, and the aminoglycoside antibiotics all produce acute renal failure but are not structurally related. Thus, it is not surprising that the cellular targets within the kidney and the mechanisms of cellular injury vary with dif- ferent toxicants. Nevertheless, there are similarities between chemical- induced acute tubular injury and ischemia/reperfusion injury. The tubular cells of the kidney are particularly vulnerable to toxi- cant-mediated injury due to their disproportionate exposure to circu- lating chemicals and transport processes that result in high intracellu- lar concentrations. It is generally thought that the parent chemical or a metabolite initiates toxicity through its covalent or noncovalent binding to cellular macromolecules or through their ability to produce reactive oxygen species. In either case the activity of the macromole- cule(s) is altered resulting in cell injury. For example, proteins and lipids in the plasma membrane, nucleus, lysosome, mitochondrion and cytosol are all targets of toxicants. If the toxicant causes oxidative stress both lipid peroxidation and protein oxidation have been shown to contribute to cell injury. In many cases mitochondria are a critical target and the lack of adenosine triphosphate (ATP) leads to cell injury due to the depen- dence of renal function on aerobic metabolism. The loss of ATP leads Rick G. Schnellmann Katrina J. Kelly C H A P T E R
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15.2 Acute Renal Failure to disruption of cellular ion homeostasis with decreased cellular K + content, increased Na + content and membrane depolariza- tion. Increased cytosolic free Ca 2+ concentrations can occur in the early or late phase of cell injury and plays a critical role lead- ing to cell death. The increase in Ca 2+ can activate calcium acti- vated neutral proteases (calpains) that appear to contribute to the cell injury that occurs by a variety of toxicants. During the late phase of cell injury, there is an increase in Cl - influx, fol- lowed by the influx of increasing larger molecules that leads to cell lysis. Two additional enzymes appear to play an important role in cell injury, particularly oxidative injury. Phospholipase A 2 consists of a family of enzymes in which the activity of the cytosolic form increases during oxidative injury and contributes to cell death. Caspases are a family of cysteine proteases that are activated following oxidative injury and contribute to cell death.
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