Experimental vesicoureteral reflux in the fetus depends on bladder function and causes renal fibrosis

Purpose: Prenatal diagnosis allows the early detection of vesicoureteral reflux in an increasing number of newborns, some of whom are born with impaired kidney function. This situation challenges our current understanding of the pathophysiology, natural history and, therefore, treatment of reflux. We created a fetal sheep model of vesicoureteral reflux to study the mechanisms of fetal reflux nephropathy. Materials and Methods: Vesicoureteral reflux was induced in fetal sheep at 95 days of gestation (term 140 days) by open bladder incision of the intravesical ureteral tunnel. All animals underwent urachal ligation and in female 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 subjects there was no change in renal weight. Renal histology revealed a thin, structurally normal cortex with small subcortical cysts and a hypoplastic medulla with mesenchymal tissue replacing normal ducts. Total mean renal collagen content was significantly increased to 51.7 mg. (range 35 to 81) in the refluxing kidneys of male animals, while it was 23.8 mg. (range 12.1 to 38.4) in normal male animals (p = 0.03). The fractional excretion of sodium was elevated in refluxing kidneys based on sodium-to-creatinine ratios in bladder urine. Conclusions: In a novel model of fetal vesicoureteral reflux we showed that prenatal reflux nephropathy is characterized by altered renal growth regulation, structural maldevelopment without overt dysplasia, excess matrix deposition and impaired excretory function.