Animal models of acute tubular necrosis do not correlate well with human acute renal failure (Lieberthal et al., 2000; Rosen and Heyman, 2001; Heyman et al., 2002; Bonventre and Weinberg, 2003). Human acute renal failure may follow transient mild hypotension with blood pressure between 80 and 100 mmHg, but rat kidneys survive a blood pressure of less than 50 mmHg for 2-3 hours (Lieberthal et al., 2000). Blood pressure must be less than 20 mmHg to induce renal failure in rats. In contrast, total renal ischemia for 30-60 minutes is often used to produce acute tubular necrosis in rats, but human kidneys tolerate up to 75 minutes of warm ischemia without acute renal failure after transplantation. Structural and functional changes similar to those observed in human acute renal failure have been produced by the combined effect of high-output heart failure with indomethacin and L-NAME to inhibit prostaglandin and nitric oxide production (Goldfarb et al., 2001), or by combining endo-toxin infusions with inhibition of nitric oxide synthase (Heyman et al., 2000). HBOCs have not been tested in models such as these. Instead, several studies have used 30 minutes of ischemia with reperfusion and found that aa-crosslinked hemoglobin and raffinose-crosslinked hemoglobin given immediately after 30 minutes of ischemia did not exacerbate the effects on GFR (Paller, 1988; Lieberthal et al., 2000).
Pig kidneys are anatomically more similar to human kidneys than are rat or dog kidneys. Experiments with swine may provide the best picture of human responses to HBOCs. Hess and MacDonald (Hess et al., 1992) used SFH to resuscitate dehydrated swine after they were hemorrhaged to a blood pressure of 44 mmHg. Creatinine rose to 3mg and returned to control levels after 5 days, which indicates a transient decrease in GFR. Lactated Ringer's solution resuscitated swine without an increase in creatinine. Other studies with swine (McNeil et al., 2001; Knudson et al., 2003) were of short duration, and did not examine renal function or pathology.
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