Gentamicin Nephrotoxicity in the Dog: Sequential Light and Electron Microscopy

Sequential percutaneous renal biopsies in six dogs given gentamicin at 10 mg/kg every 8 hours (intramuscular) were examined before treatment and 5, 9 and 12 days after treatment. Renal function tests (blood urea nitrogen and serum creatinine) and urinary enzyme excretion (β glucuronidase, N acetyl-glucosaminidase, galactosidase and muramidase) were measured daily. Periodic acid Schiff (PAS)-stained, 3-μm sections of renal biopsies taken before drug treatment showed pale and swollen proximal tubular epithelium that occluded the tubular lumen. The apical surface of all proximal tubules (brush border) stained intensely. On day 5, brush border staining was decreased or absent and many proximal tubules had open lumina and hyaline globules in the cytoplasm. Ultrastructurally, the numbers of cytoplasmic lysosomes were increased and most contained large lamellar inclusions (myelin figures). Biopsies on day 9 were characterized by an increase in the size and number of cytoplasmic hyaline globules and an absence of brush border staining. Scattered proximal tubule cells were necrotic. Intact proximal tubules and other parts of the nephron frequently contained amorphous granular casts or necrotic debris. Ultrastructurally, proximal tubules had intact brush borders and showed a remarkable increase in the number and size of lysosomes of all types. On day 12 the severity of these changes progressed, and cytosegrosomes became numerous. Urinary enzyme levels (β glucuronidase and N acetyl-glucosaminidase) were elevated by day 2, galactosidase elevated by day 4 and muramidase elevated by day 5. Clinically significant elevations in serum creatinine (day 6) and blood urea nitrogen (day 12) were preceded by elevations in urinary enzyme excretion and by severe alterations in renal tubular morphology.