Gentamicin nephrotoxicity. I. Degree and permanence of acquired insensitivity

Insensitivity to the nephrotoxic effects of gentamicin develops in F344 rats during the course of gentamicin-mediated acute renal failure. Functional and structural recovery occur thereafter in spite of continued gentamicin administration. To determine the degree of insensitivity, we compared structural and functional recovery of rats treated continuously with gentamicin to rats in which gentamicin was stopped after 14 days, at the height of dysfunction. Continued treatment did not reduce the rate or ultimate degree of recovery of structure, CIn, or in vitro renal cortical PAH uptake; however, both the rate and degree of recovery of NMN uptake were reduced in continuously treated animals. Furthermore, doubling the dose of gentamicin during the recovery period overcame insensitivity, causing a second episode of acute renal failure. The permanence of insensitivity was examined by re-treating rats 6 months after recovery from gentamicin-mediated acute renal failure. There was no evidence of residual resistance to gentamicin nephrotoxicity in these animals. These results indicate that although gentamicin insensitivity is substantial, it is not complete, as indicated by low-grade, ongoing tubular toxicity to the organic base transport system and sensitivity to higher doses of gentamicin. Furthermore, insensitivity is a transient phenomenon.