Influence of Obstructive Uropathy on Cyst Formation and Nephrogenesis: Insights from a Fetal Lamb Model.

Abstract

Obstructive uropathy (OU) during fetal development induces a fetal cystic dysplastic kidney. The mechanisms of cyst formation and the onset of renal dysfunction remain unclear. Determining whether nephrogenic potential persists during fetal life may suggest whether early intervention could preserve renal development. We aimed to evaluate residual nephrogenic activity in fetal cystic dysplastic kidneys using β-catenin and CD10 immunostaining, and to assess whether the site of obstruction influences cystogenesis. After appropriate approval, 20 timed-gestation fetal lambs had OU created at 60 days. Males underwent urethral and urachal ligation (n = 8, 3 lost), and females underwent unilateral ureteric ligation (n = 8, 1 lost). Fetuses were sacrificed at 80 days (n = 6) and 140 days (term, n = 10), comparing kidneys with normal controls of the same gestational age using immunohistochemical staining for β-catenin and CD10. Developing fetal cystic dysplastic kidneys were identified at 80 days. β-catenin staining showed the absence of granular cytoplasmic expression in cystic regions, indicating arrested nephrogenesis. In male models, cysts originated exclusively from proximal tubules. Female models exhibited mixed proximal and distal tubular involvement. CD10 staining confirmed the loss of proximal tubular markers. Renal development remained arrested at term. Cyst formation disrupts renal development early in gestation, which persists until term. Differences in cystogenesis between the models suggest that the site of obstruction influences pathogenic mechanisms.