Increased gentamicin nephrotoxicity in normal and diseased dogs administered identical serum drug concentration profiles: increased sensitivity in subclinical renal dysfunction.

Attempts to avoid gentamicin-induced nephrotoxicity in the presence of renal dysfunction assume that the nephrotoxicity threshold is unchanged from that of the normal patient. The purpose of the present study was to compare the response of the subclinically diseased kidney to the normal kidney when exposed to identical serum concentrations of gentamicin. This study used exponentially declining infusions based on preinfusion pharmacokinetics to achieve identical serum gentamicin concentration profiles in intact (intact-gentamicin) and subtotally nephrectomized (nephrectomized-gentamicin) beagle dogs. After 10 daily 12-hr infusions, relative nephrotoxicity was compared using serum chemistries and histopathologic analysis in intact- and nephrectomized-control (untreated) dogs. For intact-gentamicin and nephrectomized-gentamicin dogs, respectively, infusion steady-state serum concentrations were 5.3 +/- 0.3 vs. 5.5 +/- 0.5 (microgram/ml) and elimination rates were 0.19 +/- 0.02 vs. 0.20 +/- 0.01(hr-1) (mean +/- S.E.M.). Postinfusion histopath scoring of renal lesions (0-30, with 30 being most severe) were 11 +/- 5 (nephrectomized-gentamicin), 4 +/- 2 (nephrectomized-control), 2 +/- 2 (intact-gentamicin) and 0 +/- 0 (intact-control). Gentamicin-induced renal dysfunction in nephrectomized dogs was characterized further by administering nonindividualized multiple dosage regimens. Toxicity in the subclinical disease state was marked by oliguria and acute renal failure in contrast to the mild polyuria seen in intact animals. These findings support increased sensitivity to gentamicin nephrotoxicity in dogs with mild renal dysfunction secondary to subtotal surgical nephrectomy.