Persistent urothelial differentiation changes in the reconstructed exstrophic bladder: Congenital or acquired dysfunction of the epithelial barrier?

Abstract

We have previously characterised the urothelium from infants with classic bladder exstrophy (CBE) for the expression of urothelial differentiation-associated markers. We found abnormal expression patterns of uroplakin 3a, cytokeratin 13, cytokeratin 20 and claudin 4 in the majority of bladder biopsies taken at the time of primary bladder closure. Abnormal urothelial differentiation results in a compromised urothelial barrier with potential implications on bladder development and the success of reconstructive surgery. To investigate whether the urothelial differentiation changes observed in the unclosed exstrophic bladder persist after successful primary exstrophy repair. From 2005 to 2018 bladder biopsies from 115 children with CBE obtained at the time of primary bladder closure (n=67, median age: 8.1 weeks) and during secondary procedures aimed at achieving continence (n=48, median age: 6.8years) were prospectively collected. Following histological assessment immunohistochemistry was used to investigate the expression of uroplakin 3a, cytokeratin 13 and 20 and claudin 4, well-characterized markers associated with the terminally-differentiated, fully functional urothelial phenotype. The urothelium from 16 children with VUR and with non-refluxing disorders of the urinary tract served as controls. Tissue specimen from 100 children were included in the analysis. Only 32% of bladder specimens from children having undergone successful primary bladder closure in early infancy displayed a fully differentiated urothelial phenotype with regular expression of all 4 markers. The remaining bladders revealed irregular or absent marker expression suggesting abnormal urothelial differentiation. 86% of the samples had inflammatory, proliferative or metaplastic histological changes. Our results suggest persisting urothelial differentiation changes in two-thirds of exstrophic bladders following successful bladder closure in early infancy. Despite some limitations, the findings provide a platform for translational studies into the role of the urothelium for the developmental potential of the exstrophic bladder and the success of reconstructive surgery.