Timing of morphologic and apoptotic changes in the sheep fetal kidney in response to bladder outflow obstruction

Purpose: Posterior urethral valves are the main cause of bladder outflowobstruction in human fetuses. Thirty per cent of boys with valves develop end-stagerenal disease, despite intervention in the postnatal period. The timing and mechanismsof renal damage in bladder outflow obstruction are unknown. We investigatedthe timing of changes in morphology and apoptosis in the fetal sheep kidney inresponse to obstruction.Materials and methods: Thirty-three fetal lambs at day 70 of gestation underwentsurgical creation of bladder outflow obstruction. Twenty-nine fetal lambs had shamsurgery. Fetal kidneys were collected 2, 5, 10, 20 and 30 days after surgery. Renalhistology was examined. Real-time PCR was used to quantify the renal cortical expressionof the pro-apoptotic gene Bax and anti-apoptotic gene Bcl-X. The TUNELtechnique was used to assess regional renal apoptosis in response to obstruction.Results: Changes in renal morphology were evident as early as 2 days after surgeryin fetuses with bladder outflow obstruction, and progressed over 20e30 days to cysticrenal dysplasia. Bladder outflow obstruction increased the renal cortical expressionof Bax relative to Bcl-X. Tubular apoptosis peaked after 2 days of obstruction.Blastemal apoptosis peaked after 5 days of obstruction.