title: Natural history of aminoglycoside nephrotoxicity in the dog.
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/day), high-dose gentamicin (30 mg/kg/day), and netilmicin (30 mg/kg/day). 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 mOsm/kg/H2O to 450 +/- 118, p less than 0.05) was followed by renal glycosuria and a fall in GFR (66.9 +/- 11.9 ml/min to 21.3 +/- 8.6, p less than 0.05). These three 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 less than 0.05) and reached the lowest values (2.7 and 2.9 mEq/L) just prior to death in two animals dying in uremia. Netilmicin also caused a significant fall in plasma potassium (4.3 +/- 0.1 mEq/L to 3.9 +/- 0.1, p less than 0.05). Hypocalcemia (10.0 +/- 1.3 mg/dl to 7.8 +/- 1.4, p less than 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 weeks 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. To summarize: 1) 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); (2) tubulointerstitial nephritis, particularly in the juxtamedullary cortex, occurred with low-dose gentamicin as well as high-dose gentamicin and may be a factor in delayed or incomplete recovery from gentamicin nephrotoxicity; (3) in this model, netilmicin at comparable doses was substantially less nephrotoxic than gentamicin; (4) renal postassium wasting may be a heretofore unrecognized consequence of aminoglycoside administration.
mesh_terms: D000818:Animals; D004285:Dogs; D004573:Electrolytes / Q000097:blood; D005839:Gentamicins / Q000633:toxicity*; D005919:Glomerular Filtration Rate; D005947:Glucose; D006029:Glycosuria; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D009395:Nephritis, Interstitial / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D009428:Netilmicin / Q000633:toxicity*; D009994:Osmolar Concentration
chemical_list: D004573:Electrolytes; D005839:Gentamicins; D009428:Netilmicin; D005947:Glucose