Week_10_Pathophysiological_Responses_of_

Week_10_Pathophysiological_Responses_of_ - Week 10 -...

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Week 10 - Pathophysiological Responses of the Kidney Toxicant-induced damage to the kidney may be mild or severe, reversible or irreversible, depending upon the toxic agent and the dose. A wide variety of xenobiotics (drugs, environmental chemicals and metals) can cause nephrotoxicity. Nephrotoxicity is recognized side-effect of certain classes of drugs, most notably, antibiotics. The unusual susceptibility of the kidney to toxic insult can be attributed to the unique physiology of the organ. Although the kidneys only constitute about 0.5% of the total body mass, they receive 20-25% of the resting cardiac output. This means that any drug or chemical in the bloodstream will be delivered to the kidneys in relatively large amounts. The processes involved in concentrating urine also serve to concentrate xenobiotics in the tubular fluid. Therefore, nontoxic concentrations of a chemical in the plasma may become toxic concentrations within the kidney. Progressive concentration of toxicants along the nephron may result in precipitation of relatively insoluble compounds, leading to acute renal failure due to tubular obstruction. Addtionally, there is a great deal of xenobiotic metabolism that occurs within the kidney, increasing the probability of xenobiotic bioactivation within the kidney itself. Many nephrotoxicants have their primary effects on discrete segments of the nephron. For example: Glomerulus: immune complexes Proximal tubule: nephrotoxic antibiotics, antineoplastics, halogenated hydrocarbons, mycotoxins and heavy metals loop of Henle: fluoride ions medulla/papilla: analgesics The reasons underlying these specificities are complex but are most likely due to the differences in blood flow, transport and accumulation of the compounds, physiochemical properties of the epithelium, reactivity of cellular/molecular targets, bioactivation/detoxification, cellular energetics and or regenerative/repair mechanisms. Pathophysiological Responses of the Kidney Acute Renal Failure One of the most common manifestations of nephrotoxicity is acute renal failure (ARF). ARF is characterized by an abrupt decline in glomerular filtration rate (GFR) with resulting azotemia (elevated levels of nitrogen-containing compounds, such as urea and creatinine, in the blood). Any decline in GFR could be due to any number of prerenal, intrarenal or postrenal factors. Prerenal factors may include afferent arteriolar constriction, hypovolemia (decreased blood volume), insufficient cardiac output or obstruction of renal arteries. Intrarenal factors may include tubular epithelial cell death or loss, tubular obstruction, glomerular nephritis or tubulointerstitial nephritis. Postrenal factors may include such things as ureteral or bladder obstruction. There are many ways in which xenobiotics may induce ARF. If a chemical causes tubular
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Week_10_Pathophysiological_Responses_of_ - Week 10 -...

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