Pathophysiologic Evidence of Gentamicin Nephrotoxicity in Neonatal Puppies

Cowan, Richard H; Jukkola, Alina F.; Arant, Billy S.

doi:10.1203/00006450-198011000-00011

Cited by 87 publications

(39 citation statements)

References 39 publications

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“…Although the youngest group of puppies sustained some degree of renal structural damage and functional loss as a consequence of UN administration, these alterations were not as severe as in the oldest puppies and (by indirect comparison from other studies) in the adult dog (1 1,24). In accordance with our observations is the recent finding by Cowan et al (9) that chronologic age, and therefore the degree of development, plays a significant role in determining the final response of the renal toxic effects of gentamicin in developing puppies.…”

Section: General Resziltssupporting

confidence: 81%

“…Recently, experimental studies in neonatal dogs have substantiated a relative tolerance of immature kidney to the nephrotoxic effects of gentamicin (9). This protective effect appeared to be afforded by the pattern of renal blood flow distribution seen during normal development.…”

Section: General Resziltsmentioning

confidence: 95%

“…These studies have examined the mechanisms by which antibiotics and heavy metals induce ARF (4,7,10,11,24); however, little attention has been given to the pattern and pathogenesis of nephrotoxic ARF in the developing mammal. There is some clinical and experimental evidence suggesting that the immature kidney is more tolerant to the nephrotoxic effects of aminoglycosides than its adult counterpart (9,19).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

The Influence of Age on Acute Renal Toxicity of Uranyl Nitrate in the Dog

et al. 1983

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Section: General Resziltssupporting

confidence: 81%

Section: General Resziltsmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The Influence of Age on Acute Renal Toxicity of Uranyl Nitrate in the Dog

et al. 1983

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“…Cowan et al (7) found smaller amounts of gentamicin in puppies than in the adult dog. The same has been found in the rat (19,21).…”

Section: Discussionmentioning

confidence: 99%

Influence of Intrauterine Maturation on the Pharmacokinetics of Amikacin in the Neonatal Period

et al. 1982

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SummaryThe effect of intrauterine maturation on amikacin disposition was studied in 29 preterm and term neonates. Mean gestational age (weeks) of the patients was 34.5 f 3.3 S.D. and their birth weight 1.980 f 920 g.After the last administration of the drug, amikacin decay was measured in plasma and urine for 100-250 h. The serum concentration versus time profiles were fitted by nonlinear regression analysis. The parameters of a 2-or 3-compartment model with elimination from the central compartment were calculated. Initial elimination T %, voll~me of the central compartment, and steady state volunle of distribution were significantly related to intrauterine maturation (respectively r = -0.76; -0.63; -0.57) whereas no significant linear correlation was found between clearance and gestational age (r = 0.19).Patients with gestational age less than 34 wk had a significantly reduced clearance when compared with the neonates with gestational age greater than 36 wk (0.78 f 0.17 versus 1.0 f 0.4 ml/h/ kg, P < 0.05). The ratio between the volumes of distribution showed that a higher amount of amikacin penetrates the peripheral compartments with increased gestational age. The renal clearance calculated in six patients averaged 66% of the total body clearance, suggesting that elimination of the drug can occur in the neonate via nonrenal routes. Analysis of the long term urinary elimination of amikacin showed that about 5% of the total amount of the drug administered in 5-8 days of treatment is retained in the organism. Although quantitatively small, this amount is relevant for the potential nephrotoxicity of the drug.The current recommendations for aminoglycoside antibiotic dosages in children and adults are based upon the recognition that the clinical toxicity of these compounds is associated with elevated serum concentrations but that efficacy too is related to the achievement of concentrations higher than the minimal inhibitory concentrations on the causal bacteria (5). Pharmacokinetic models have been developed in adults and children to improve predictions of serum aminoglycoside concentrations and permit early recognition of patients in whom excessive accumulation is occurring (6, 9, 27). Several risk factors have been recognized and some of them, such as kidney failure have pharmacokinetic implications.Clearly, the neonate shows a peculiar situation because rapid changes in body composition and renal function occur early after birth. The different degree of maturation at birth is another influencing factor. Improved intensive care has raised the survival rate of very low birth weight neonates. Hence there is increasing importance in obtaining data on the factors that influence drug disposition in this age group.The present study was designed to further investigate the pharmacokinetics of amikacin in the neonate. This drug is currently recommended for treatment of infections with gram negative bacteria resistant to other aminoglycosides. Its use in the neonate is still limited. Pharmacokinetic studies on amikacin in t...

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“…In view of the developmental pattern of proximal tubule length in this species (12), it is clear that any effect of gentamicin on tubular growth would be more easily detectable in the late stages of development, when the growth rate is fast, than in the early stages, when it is slower. The more pronounced impairment of the juxtamedullary than of the superficial nephrons observed here was probably a result of the centrifugal pattern of renal cortex maturation which, as already suggested, might for a while preserve the superficial nephrons from the delivery, accumulation, and, hence, toxicity of gentamicin (4,9). In addition, as previously demonstrated in fetal guinea pigs (12), the maturation of the superficial nephrons is accompanied by a morphologic imbalance between glomerular and tubular growth and also by a phase of functional glomerular preponderance which may exist for the handling of gentamicin as for other substances.…”

Section: Discussionmentioning

confidence: 52%

Effect of fetal exposure to gentamicin on kidneys of young guinea pigs

Lelièvre-Pégorier¹,

Gilbert²,

Sakly³

et al. 1987

Antimicrob Agents Chemother

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Clearance experiments were performed with young pups born of guinea pigs given a daily injection of 4 mg of gentamicin per kg (body weight) from days 48 to 54 of gestation (term, 68 days). For 3-day-old animals, the glomerular filtration rate was similar to that measured in control guinea pigs of the same age whose mothers were given saline during the same period of gestation. The same applied to fractional excretion of water, urea, total solutes, Na, K, Ca, and Mg but not to fractional phosphate excretion, which increased significantly in the gentamicin group when compared with the controls (mean ± standard error, 21.7 ± 4.9 versus 7.3 ± 1.8%; P < 0.05; n = 6 for both). The glomerular volume of the juxtamedullary nephrons diminished by about 40%, and their proximal tubule length decreased by about 20%. The glomerular volume of the superficial nephrons also diminished, by about 30%, but their proximal tubule length did not change. The gentamicin concentration was higher in the renal cortex than in the medulla (13.1 ± 2.6 versus 5.7 ± 2.2 ,ug/g [dry wt]; P < 0.01; n = 6 for each). It decreased significantly from days 3 to 20 in both tissues. No functional impairment of the kidney was found in 10-day-old animals, and normal or even supranormal morphometry of the nephrons was observed in the 20-day-old animals. It is concluded that fetal exposure to gentamicin impairs proximal tubular function in the developing animal and might also adversely affect glomerular and tubular growth. However, both the functional and morphometric impairments of nephrons are transitory.

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Pathophysiologic Evidence of Gentamicin Nephrotoxicity in Neonatal Puppies

Cited by 87 publications

References 39 publications

The Influence of Age on Acute Renal Toxicity of Uranyl Nitrate in the Dog

The Influence of Age on Acute Renal Toxicity of Uranyl Nitrate in the Dog

Influence of Intrauterine Maturation on the Pharmacokinetics of Amikacin in the Neonatal Period

Effect of fetal exposure to gentamicin on kidneys of young guinea pigs

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