Vancomycin-induced nephrotoxicity in rats: is enzyme elevation a consistent finding in tubular injury?

Measurement of urinary enzymes facilitates early detection of acute renal impairment. Since in the case of vancomycin-induced nephrotoxicity, there are different findings for the enzyme N-acetyl-beta-D-glucosaminidase (NAG) in various studies, we decided to measure 3 other important urinary enzymes -- gamma-glutamyl-transferase (GGT), alanine aminopeptidase (AAP) and lactate dehydrogenase (LDH) -- in nephrotoxic rats.

Male rats were given intraperitoneal injections of vancomycin (VAN) in doses of 50, 100, 200 and 400 mg/kg or normal saline every 12 hours for 7 days. After the 14th injection, the animals were placed in metabolic cages to collect urine samples.

All animals receiving 400 mg/kg VAN died before completion of treatment course. The nephrotoxicity was completely dose-dependent according to pathologic findings. The major insults were in tubules, resembling acute tubular necrosis. GGT, AAP and LDH activity was measured in urine and corrected by dividing it by urinary creatinine (Cr) concentration. LDH activity showed a dose-dependent increase, while GGT and AAP activity decreased in the 200 mg/kg treated group, but only GGT showed a significant difference with controls. Serum urea and Cr and kidney weights were increased and animals' weights were decreased significantly in the 200 mg/kg VAN group compared with other groups.

It seems that pathologic assessment remains the most accurate way to diagnose VAN nephrotoxicity. Changes in urinary enzymes could be not detected in minor tubular injuries; however, LDH appears to be the most sensitive factor. In multiple-dose studies, activity of AAP and GGT seems not to be a reliable index of nephrotoxicity.