EXPERIMENTAL VESICOURETERAL REFLUX IN THE FETUS DEPENDS ON BLADDER FUNCTION AND CAUSES RENAL FIBROSIS

Purpose: Prenatal diagnosis allows the early detection of vesicoureter al reflux in an increasing number of newborns, some of whom are born w ith impaired kidney function. This situation challenges our current un derstanding of the pathophysiology, natural history and, therefore, tr eatment of reflux. We created a fetal sheep model of vesicoureteral re flux to study the mechanisms of fetal reflux nephropathy. Materials an d Methods: Vesicoureteral reflux was induced in fetal sheep at 95 days of gestation (term 140 days) by open bladder incision of the intraves ical ureteral tunnel. All animals underwent urachal ligation and in fe male subjects mild bladder outlet obstruction was created with a gold ring. Results: At term reflux was detected in 18 of 28 renal units by filling cystography. Refluxing kidneys were hydronephrotic and larger than normal. At term mean kidney weight was 21.1 gm. (range 12.2 to 35 .0) in male subjects with reflux compared to 8.5 gm. (range 6.5 to 11. 3) in normal male subjects (p <0.001) and 11.5 gm. (range 8.5 to 15.8) in male subjects with urachal ligation only (p = 0.035). In female su bjects there was no change in renal weight. Renal histology revealed a thin, structurally normal cortex with small subcortical cysts and a h ypoplastic medulla with mesenchymal tissue replacing normal ducts. Tot al mean renal collagen content was significantly increased to 51.7 mg. (range 35 to 81) in the refluxing kidneys of male animals, while it w as 23.8 mg. (range 12.1 to 38.4) in normal male animals (p = 0.03). Th e fractional excretion of sodium was elevated in refluxing kidneys bas ed on sodium-to-creatinine ratios in bladder urine. Conclusions: In a novel model of fetal vesicoureteral reflux we showed that prenatal ref lux nephropathy is characterized by altered renal growth regulation, s tructural maldevelopment without overt dysplasia, excess matrix deposi tion and impaired excretory function.