Fetal Ovine Congenital Obstructive Uropathy: Morphological Observations and Correlation with Metalloproteinase Activity
EB O'Neill, GA Nicksa, DC Yu, AS Curatolo, BL McNeish, CE Barnewolt, TL Buchmiller, D Zurakowski, MA Moses, S Rosen, D Fauza. Beth Israel Deaconess Medical Center, Boston, MA; Children's Hospital Boston, Boston, MA
Background: Congenital obstructive uropathy is the most common cause of renal failure in early childhood. Developing predictive tests for its occurrence and severity is important. The fetal lamb is an appropriate large animal model for these studies. Urinary metalloproteinase activity (MMP) has been found to be abnormal in these animal models. The aim of this study is to see if the profiles of MMP correlate with the degree of renal damage.
Design: Fetal lambs (N=32) were divided into 2 groups at 90-100 days gestation. Group 1 (N=15) underwent sham operation. Group 2 (N=17) underwent creation of complete urinary tract obstruction. Urinary MMP profiling was performed by gelatin zymography for 4 MMP species of 10 different molecular weights. Fibrotic change and degree of disorganization was assessed by semi-quantitative grading scale (0-4+) in subcapsular zone, labyrinth, medullary ray, outer medulla/inner stripe, inner medulla and pelvis. Medullary ray number per 10 mm was assessed. Statistical analysis was by Student t-test, Mann-Whitney U-test and multiple regression.
Results: No dysplastic changes were seen. Medullary ray number was reduced (6.2+/-0.9 vs 8.1+/-0.8) (P<0.001). The inner medulla was markedly fibrotic and attenuated with disorganization of remaining tubular structures in the obstructed animals. The most conspicuous fibrosis occurred in the inner medulla, subcapsular zone and pelvis. MMP-9 activity was a significant independent predictor of the total combined fibrosis score (P<0.001) and the fibrosis score in each of the individual areas analyzed (P<0.01). The activity of MMP-2 correlated only with inner medullary changes (P=0.03), inner stripe (P=0.01) and subcapsular fibrosis (P=0.01).
Conclusions: Urethral obstruction in the fetal lamb produces an altered renal cortical organization (reduction of medullary rays), fibrotic changes throughout the kidney and marked thinning and fibrosis of the inner medulla, without frank dysplastic changes. Urinary metalloproteinase activity closely correlated with these alterations and may be useful in assessing injury related to human fetal urinary obstruction.
Category: Kidney (does not include tumors)
Wednesday, March 24, 2010 1:00 PM
Poster Session VI # 252, Wednesday Afternoon