NATURAL-HISTORY OF AMINOGLYCOSIDE NEPHROTOXICITY IN THE DOG

  • 1 January 1980
    • journal article
    • research article
    • Vol. 95  (3) , 463-474
Abstract
The natural history of aminoglycoside nephrotoxicity is not well described. This study investigated in the dog renal functional and electrolyte abnormalities during and for 20 days following a 10-day course of low-dose gentamicin (7 mg/kg per day), high-dose gentamicin (30 mg/kg per day) and netilmicin (30 mg/kg per day) [antineoplastic drugs]. Renal histology was examined at the end of the study. Renal functional abnormalities occurred only in animals receiving high-dose gentamicin. A fall in maximal urinary osmolality (1579 .+-. 347 milliosmoles/kg per H2O to 450 .+-. 118, P < 0.05) was followed by renal glycosuria and a fall in GFR [glomerular filtration rate] (66.9 .+-. 11.9 ml/min to 21.3 .+-. 8.6, P < 0.05). These 3 functional indices had recovered by day 30 in the survivors. Plasma potassium fell in animals receiving high-dose gentamicin (3.8 .+-. 0.02 meq/l to 3.3 .+-. 0.4, P < 0.05) and reached the lowest values (2.7 and 2.9 meq/l) just prior to death in two animals dying of uremia. Netilmicin also caused a significant fall in plasma potassium (4.3 .+-. 0.1 meq/l to 3.9 .+-. 0.1, P < 0.05). Hypocalcemia (10.0 .+-. 1.3 mg/dl to 7.8 .+-. 1.4, P < 0.05) but not hypomagnesemia developed following high-dose gentamicin. Peak serum aminoglycoside levels after high-dose gentamicin and netilmicin were comparable, but trough levels rose only in high-dose gentamicin animals and paralleled the fall in GFR. Light microscopy of the kidney 3 wk after high-dose gentamicin demonstrated no proximal tubular necrosis but extensive focal tubulointerstitial nephritis, especially in the juxtamedullary cortex. Similar but less extensive derangements were noted in animals receiving low-dose gentamicin, despite the absence of functional abnormalities. Minor histological abnormalities were noted in animals receiving netilmicin. Major renal functional and electrolyte abnormalities developed only following high-dose gentamicin and included impaired urinary concentration, glycosuria, reduced GFR, hypokalemia and hypocalcemia; except for a fall in plasma potassium, similar doses of netilmicin were not nephrotoxic. Tubulointerstitial nephritis, particularly in the juxtamedullary cortex, occurred with low-dose gentamicin and high-dose gentamicin and may be a factor in delayed or incomplete recovery from gentamicin nephrotoxicity. In this model, netilmicin at comparable doses was substantially less nephrotoxic than gentamicin. Renal potassium wasting may be a heretofore unrecognized consequence of aminoglycoside administration.