Pathophysiologic evidence of gentamicin nephrotoxicity in neonatal puppies

Abstract

Newborn puppies were paired (it = 21 pairs) at birth, given gentamicin (5 mg/kg/day for 7 days and then 7.5 mg/kg/day) or saline intramuscularly (IM) and studied at 10, 20, or 30 days of age. Peak gentamicin concentrations correlated neither with total body water nor extracellular fluid volume. The ratio of outer/inner cortical gentamicin concentrations increased with therapy (n = 579; P < 0.01). Pathologic changes in proximal tubular cells of superficial and juxtamedullary cortices corresponded to tissue accumulation of gentamicin. Inulin clearance was lower but not statistically different in gentamicin puppies at 20 and 30 days, but tubular reabsorption of phosphate was lower at 30 days (P < 0.02). Plasma creatinine decreased during the first month of life in both control and gentamicin puppies (n = -0.370; P < 0.02) and was not different between puppies even at 20 and 30 days when tubular damage was marked. No differences in urine sediment, osmolarity, glucose, and protein concentrations were noted between paired animals. Mean values of gentamicin half-life in gentamicin (control) puppies decreased from 80.3 (84.0) min at 10 days to 45.3 (50.3) min at 20 days, but increased to 61.0 (40.0; P < 0.05) min at 30 days. Similar studies in older puppies and adult animals given gentamicin resulted in an increase in plasma creatinine and gentamicin half-life within 10 days. Results of these studies confirmed that gentamicin nephrotoxicity occurred within 10 days in puppies treated from birth. The relative tolerance of the neonatal puppy to the toxic effects of gentamicin was attributed to the distribution of renal blood flow predominantly to juxtamedullar nephrons at birth which spared superficial nephrons from gentamicin accumulation and toxicity until renal blood flow was redistributed to the outer cortex and filtration in superficial nephrons began after the first wk of life. Speculation: The relative tolerance of the neonate to the nephrotoxic effects of gentamicin and perhaps other aminoglycosides can be explained by the distribution of renal blood flow during development. Nephrons in the juxtamedullary cortex of the neonate receive a major fraction of renal blood flow initially and manifest gentamicin toxicity earlier than do nephrons in the outer cortex. Any impairment to nephron function in the inner cortex of the neonatal kidney during 7 to 10 days of gentamicin therapy would be offset by the successive contribution of more superficial nephrons to overall renal function. Once filtration has begun in all nephrons, gentamicin nephrotoxicity in the infant is comparable to the adult. © 1980 International Pediatric Research Foundation, Inc.