Actions Of Growth Factors In Acute Renal Failure

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Apoptosis

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Selected actions of growth factors in the setting of acute renal failure (ARF). After an acute renal injury, a spectrum of molecular responses occur involving the local expression of growth factors and their receptors. In addition, there is considerable variation in the mechanisms by which the growth factors are beneficial for ARF. After an

FIGURE 17-15

Rationale for the use of insulin-like growth factor IGF-I in the setting of acute renal failure (ARF). Of the growth factors that have been demonstrated to improve outcomes after acute renal injury, the most progress has been made with IGF-I. From this table, it is evident that IGF-I has a broad spectrum of activities, which makes it a logical choice for treatment of ARF. An agent that increased renal plasma flow and glomerular filtration rate and was mito-genic for proximal tubule cells and anabolic would address several features of ARF.

acute renal insult there is an initial decrease in both insulin-like growth factor (IGF-I) peptide and mRNA, which recovers over several days but only after the regenerative process is under way. The pattern with epidermal growth factor (EGF) is different in that a transient increase in available mature peptide from cleavage of preformed EGF is followed by a pronounced and prolonged decrease in both peptide and message. Both peptide and message for hepatocyte growth factor (HGF) are transiently increased in kidney after a toxic or an ischemic insult. The receptors for all three growth factors are increased after injury, which may be crucial to the response to exogenous administration.

The mechanism by which the different growth factors act in the setting of acute renal injury is quite variable. IGF-I is known to increase renal blood flow and glomerular filtration rate in both normal animals and those with acute renal injury. To the other extreme, EGF is a vasoconstrictor and HGF is vasoneutral. IGF-I has an additional advantage in that it has anabolic properties, and ARF is an extremely catabolic state. Neither EGF nor HGF seems to affect nutritional parameters. Finally, both EGF and HGF are potent mitogens for renal proximal tubule cells, the nephron segment is most often damaged by ischemic acute renal injury, whereas IGF-I is only a modest mitogen. Likewise, both EGF and HGF appear to be more effective than IGF-I at inhibiting apoptosis in the setting of acute renal injury, but it is not clear whether this is an advantage or a disadvantage.

Difference Between Arf And Crf
FIGURE 17-16

Serial serum creatinine values in rats with ischemic acute renal failure (ARF) treated with insulin-like growth factor (IGF-I) or vehicle. This is the original animal experiment that demonstrated a benefit from IGF-I in the setting of ARF. In this study, IGF-I was administered beginning 30 minutes after the ischemic insult (arrow). Data are expressed as mean ± standard error. Significant differences between groups are indicated by asterisks.

This experiment has been reproduced, with variations, by several groups, with similar findings. IGF-I has now been demonstrated to be beneficial when administered prophylactically before an ischemic injury and when started as late as 24 hours after reperfusion when injury is established. It has also been reported to improve outcomes for a variety of toxic injuries and is beneficial in a model of renal transplantation with delayed graft function and in cyclosporine-induced acute renal insufficiency. (From Miller et al. [2]; with permission.)

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