PROTECTIVE EFFECT OF HUMAN ULINASTATIN AGAINST GENTAMICIN-INDUCED ACUTE-RENAL-FAILURE IN RATS

We investigated the protective effect of human ulinastatin against gen tamicin-induced acute renal failure in rats. Gentamicin sulfate war; s ubcutaneously injected at a dose of 100 mg/kg for 5 consecutive days. After 3 days administration of gentamicin, a slight decrease in renal function was observed, as well as granulovascular degeneration in the proximal tubular cells as a change in the renal histology. After 5 day s administration of gentamicin, a remarkable increase in plasma concen tration of creatinine (from 0.27 +/- 0.02 to 1.17 +/- 0.18 mg/dL) and urea nitrogen (from 17.8 +/- 0.6 to 48.8 +/- 5.1 mg/dL) and a signific ant decrease in creatinine clearance (from 0.64 +/- 0.08 to 0.20 +/- 0 .03 mL . 100 g(-1). min(-1)) were observed. In addition, an apparent i ncrease in urinary excretion of N-acetyl-beta-D-glucosaminidase and al bumin was detected. In the renal histology, proximal tubular necrosis and desquamation of the epithelial cells in the cortex were observed. Furthermore, hyaline cast formation was frequently observed in the out er stripe of the outer medulla. Ulinastatin at doses of 100 000 or 300 000 U/kg was coadministered intraperitoneally just after each gentami cin injection. Ulinastatin treatment showed a dose-dependent suppressi on of gentamicin-induced biochemical alterations and histological chan ges. After 5 days treatment with 300 000 U . kg(-1). day(-1) of ulinas tatin, the magnitude of gentamicin-induced changes in renal function w as significantly lessened, by 45-80%. The score for proximal tubular i njuries and the rate of hyaline cast formation were also significantly lower in the same group of animals than those in the group treated wi th gentamicin alone. In the in vitro study, ulinastatin at 10-300 U/mL showed a concentration-dependent suppression on the fragility of the lysosomal membrane isolated from rat kidney cortex during hypotonic tr eatment. These results indicate that human ulinastatin has a prominent protective effect on gentamicin-induced acute renal failure in rats, and the lysosomal membrane stabilizing effect is possibly involved as a mechanism of this action.