Renal abnormalities in rat fetuses exposed to doxorubicin.
OBJECTIVE
A rat model of the VATER (vertebral defects, anal atresia, tracheo-esophageal fistula with esophageal atresia, renal defects and radial limb dysplasia) association was created by exposing fetuses to doxorubicin early in gestation. Most fetuses had an absent bladder with ureters that were grossly dilated. We determined the effect of this absent bladder on kidneys development, particularly whether dysplasia was evident.


METHODS
Nine timed pregnant rats were injected intraperitoneally with doxorubicin at a dose of 2 mg/kg body weight on days 6 to 9 of gestation. The control group of 3 rats received saline. Fetuses were recovered on day 21 and examined macroscopically. Quantitative measurements were taken of renal wet and dry weights, renal length and ureteral diameter. Serial sections were then taken and stained alternately with hematoxylin and eosin or trichrome. The kidneys were compared under light microscopy. Comparisons between control and treated groups were made with the Student t test.


RESULTS
An absent bladder was confirmed in 50 of the 55 fetuses (91%). In most fetuses the kidneys were correctly located, although they were hydronephrotic and poorly developed. This finding was confirmed quantitatively with significant differences in treated and control fetuses in renal length (5.24 vs 4.13 mm, p <<0.01) and in the ratio of wet renal weight to body weight and dry weight (2.7 vs 3.4 mg, p <<0.01). Dilated, tortuous ureters were found bilaterally in most cases. Microscopically the kidneys had abnormal architecture and were less mature than in controls. Nephron induction was poor with abnormal configurations. Tubular differentiation was decreased and the medulla was thin and less cellular than in controls. Dilatation occurred mainly in the collecting system and ducts/tubules. There was no collagen deposition/fibrosis or aberrant tissue.


CONCLUSIONS
In this rat model the kidneys are exposed to obstruction early in development since the bladder does not form. The resulting kidneys are hydronephrotic with decreased parenchyma and poor differentiation. However, there is no fibrosis or aberrant tissue.
Temelcos
Catherine
C
F. Douglas Stephens Surgical Research Laboratory, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
Hutson
John M
JM
D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000818:Animals; D004317:Doxorubicin / Q000633:toxicity*; D007668:Kidney / Q000002:abnormalities* / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000002:abnormalities* / Q000187:drug effects*
D004317:Doxorubicin