Correlation between prenatal urinary matrix metalloproteinase activity and the degree of kidney damage in a large animal model of congenital obstructive uropathy.
OBJECTIVE
We aimed to determine whether the profile of matrix metalloproteinase (MMP) activity in fetal urine correlates with the degree of kidney damage in the setting of congenital obstructive uropathy.


METHODS
Fetal lambs underwent either a sham operation or creation of a complete urinary tract obstruction. Necropsies were performed before term, when urinary MMP profiling was performed by zymography; and kidney damage was assessed histologically by multiple semiquantitative analyses and histomorphometric measurements.


RESULTS
There was a significant correlation between inner medullary thickness and MMP-9 (P = .005) and 63-kd MMP-2 (P = .019) activities. In like manner, the only MMPs associated with kidney fibrosis were MMP-9 and 63-kd MMP-2. Matrix metalloproteinase-9 activity was a highly significant independent predictor of the total combined kidney fibrosis score (P < .001) as well as of higher fibrosis grades in each of 6 kidney areas analyzed (all with P < .01). The activity of 63-kd MMP-2 correlated significantly with higher fibrosis in select areas.


CONCLUSIONS
In a fetal ovine model, urinary MMP activity correlates with the degree of kidney damage. The presence of MMP-9 (in particular) and that of 63-kd MMP-2 are independent predictors of severity. Prenatal urinary MMP profiling may enhance patient stratification and counseling in the setting of congenital obstructive uropathy.
Nicksa
Grace A
GA
Department of Surgery, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
O'Neil
Edward
E
Yu
David C
DC
Curatolo
Adam S
AS
McNeish
Brendan L
BL
Barnewolt
Carol E
CE
Zurakowski
David
D
Buchmiller
Terry L
TL
Moses
Marsha A
MA
Rosen
Seymour
S
Fauza
Dario O
DO
D000818:Animals; D015415:Biomarkers / Q000652:urine; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005315:Fetal Diseases / Q000201:enzymology* / Q000473:pathology; D005355:Fibrosis; D007668:Kidney / Q000196:embryology*; D007674:Kidney Diseases / Q000151:congenital / Q000473:pathology* / Q000652:urine; D020778:Matrix Metalloproteinase 2 / Q000652:urine*; D020780:Matrix Metalloproteinase 9 / Q000652:urine*; D011247:Pregnancy; D011270:Pregnancy, Animal; D011296:Prenatal Diagnosis; D012720:Severity of Illness Index; D012756:Sheep; D014517:Ureteral Obstruction / Q000151:congenital / Q000196:embryology / Q000201:enzymology*
D015415:Biomarkers; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9