Does Intervention in Utero Preserve the Obstructed Kidneys of Fetal Lambs? A Histological, Cytological, and Molecular Study

Abstract

Ureteropelvic junction obstruction is a common cause of end-stage nephropathy in children. Our aim was to investigate whether relief of obstruction in utero can alleviate the development of nephropathy. A silastic tube was tied around the left superior segment ureter to induce unilateral partial ureteral obstruction in 22 fetal sheep at 75-85 d of gestation. Three weeks later, the tubes were removed to relieve the obstruction in 10 of the 22 lambs. A sham operation was performed on four fetuses (the control). At birth, the lambs were killed, and their kidneys were removed to study the changes in histology, podocytes, and expression of paired-box 2 (PAX2) and VEGF. In the obstructed kidneys, we observed cysts of various sizes in the cortex, fibrosis in the interstitial tissue, much decreased number of glomeruli, severe podocyte foot process fusion, and markedly increased PAX2 and decreased VEGF expressions. However, relief of obstruction preserved the number of glomeruli, significantly increased VEGF expression, reduced fusion of the podocyte foot processes, and restored expression of PAX2 to some extent. Thus, relief of obstruction in utero may prevent or attenuate the development of nephropathy in lambs. (1)]. At present, infants suffering from UPJO are either simply followed up or given surgical treatment based on hydronephrosis grade or renal function condition. However, Murer et al (2) found that the recovery from renal function injury even after the relief of UPJO was not assured in some children. Intervention in utero may help these patients. Chevalier et al (3) found that the relief of obstruction markedly reduced tubular atrophy and interstitial fibrosis in developing kidneys. However, Josephson et al (4) found that renal damage persisted despite very early efforts to remove obstruction. Because there is no consistent evidence linking recovery from renal damage to relief of UPJO in utero in humans, we decided to study this issue in fetal lambs.Podocytes are needed to maintain normal renal function; yet, they are easily injured by various abnormal situations. To our knowledge, changes in podocytes in obstructed kidneys have rarely been studied.Paired-box 2 (PAX2) is an important regulatory factor that functions early in the development of the kidney, and is restricted to the developing kidney. In damaged kidneys, PAX2 expression seems to be related to the proliferation of cystic renal epithelia, which is common in obstructed kidneys. VEGF is needed to maintain the renal blood vessel system. Decrease in VEGF will lead to fibrosis, another very common condition in obstructed kidneys.In this study, whether the relief of UPJO in utero in lambs would attenuate the development of nephropathy was investigated by observing changes in histology, podocytes, and expression of PAX2 and VEGF in kidneys after ureteral obstruction relief in utero. MATERIALS AND METHODSSevere unilateral partial ureteral obstruction was produced in 22 sheep fetuses at 75-85 d of gestation. In brief, open hysterotomy was perfo...

Mechanisms of renal injury and progression of renal disease in congenital obstructive nephropathy

“…This underscores the remarkably fine regulation in counterbalanced growth of the two kidneys. Release of an experimental UPJ obstruction in the fetal sheep restores podocyte architecture and prevents loss of glomeruli, suggesting that surgical intervention during nephrogenesis (as in the neonatal mouse and rat models) may provide an advantage over later intervention [93]. Studies of UPJ obstruction in the fetal primate indicate that the depletion of medullary progenitor cells in the obstructed kidney may limit future repair potential and could increase susceptibility to chronic kidney disease in later life [66].…”

Congenital ureteropelvic junction obstruction: human disease and animal models

“…2003a) which regulates metanephric development (Saifudeen et al. 2009) or Pax‐2 (Fenghua et al. 2009) and Wnt4 (Nguyen et al.…”

“…2000; Mure et al. 2006a), associated to podocyte foot processes fusion (Fenghua et al. 2009) and cystic‐like changes such as dilatation of Bowman’s space and collapsed capillary loops (Liapis et al.…”

“…While complete UUO induced a complete loss of renal VEGF expression in foetal lambs and neonatal rats (Burt et al. 2007; Fenghua et al. 2009), partial UUO in neonatal rats led to strong inter‐individual heterogeneity, with VEGF expression varying between down‐ to up‐regulation (Table 7) (Burt et al.…”

Environmental influences on renal tract development: a focus on maternal diet and the glucocorticoid hypothesis

“…█ dysplastic kidneys (organs containing immature and sometimes cystic structures), and █ aplastic or agenenetic kidneys (respectively, tiny kidneys and organs which never began to form). studies, the relief of anatomical obstruction tends to improve kidney histology and preserve glomerular numbers [27].…”