The clinical controversy regarding the timing of surgery for asymptomatic newborns with obstructed hydronephrosis was addressed using a model of reversible partial ureteral obstruction in the newborn rabbit. The histomorphometric changes in the ureteropelvic junction complex (for example, pelvis, ureteropelvic junction and upper ureter) and kidney in 44 normal cases were determined and compared with the effects of 47 cases of ongoing partial obstruction and timed reversal of partial obstruction at 1 week in 9 cases, at 2 weeks in 10 or at 4 weeks in 10 (end of the study at age 8 weeks). After partial obstruction hydronephrosis appeared by 1 week postoperatively. There were progressive increases in the thickness of the lamina muscularis and mass index of smooth muscle and collagen (all p < 0.001). However, since the per cent surface area of smooth muscle did not change significantly in comparison to normal, there was disproportionately more collagen. For reversals at 1 week the muscle and collagen in the lamina muscularis were not significantly different from normal. For reversals at 2 weeks the mass index of collagen was greater than normal (p < 0.05) and reversal at 1 week (p < 0.05). For reversals at 4 weeks the lamina muscularis was thicker, and the mass index of collagen and muscle was greater than the earlier reversal groups and normal (all p < 0.05). In conclusion, partial ureteral obstruction causes progressive thickening of the lamina muscularis by collagen and muscle with a disproportionately greater increase in collagen than muscle. The earlier the obstruction can be reversed, the more normal is the ureteropelvic junction complex histology. The functional significance of these changes needs to be determined.

Urothelium synthesizes a group of integral membrane proteins called uroplakins, which form two-dimensional crystals (urothelial plaques) covering >90% of the apical urothelial surface. We show that the ablation of the mouse uroplakin III (UPIII) gene leads to overexpression, defective glycosylation, and abnormal targeting of uroplakin Ib, the presumed partner of UPIII. The UPIII-depleted urothelium features small plaques, becomes leaky, and has enlarged ureteral orifices resulting in the back flow of urine, hydronephrosis, and altered renal function indicators. Thus, UPIII is an integral subunit of the urothelial plaque and contributes to the permeability barrier function of the urothelium, and UPIII deficiency can lead to global anomalies in the urinary tract. The ablation of a single urothelial-specific gene can therefore cause primary vesicoureteral reflux (VUR), a hereditary disease affecting approximately 1% of pregnancies and representing a leading cause of renal failure in infants. The fact that VUR caused by UPIII deletion seems distinct from that caused by the deletion of angiotensin receptor II gene suggests the existence of VUR subtypes. Mutations in multiple gene, including some that are urothelial specific, may therefore cause different subtypes of primary reflux. Studies of VUR in animal models caused by well-defined genetic defects should lead to improved molecular classification, prenatal diagnosis, and therapy of this important hereditary problem.