Experimental fetal vesicoureteral reflux induces renal tubular and glomerular damage, and is associated with persistent bladder instability

Purpose: We assessed renal function and urodynamic status in animals with experimental congenital vesicoureteral reflux. Materials and Methods: Vesicoureteral reflux was surgically induced in male sheep fetuses at 95 days of gestation. After birth the animals were maintained on antibiotic prophylaxis. At ages 1 week and 6 months reflux was assessed by fluoroscopic voiding cystography. Cystometrography was performed with the animals awake. Serum creatinine, inulin clearance and the excretion of urinary N-acetyl-β- D-glucosaminidase were measured at ages 1 week, 1 month and 6 months by surveillance urine cultures. Urinary concentrating capacity was assessed by desmopressin testing at ages 1 and 6 months. Results: Nine animals (18 renal units) were born after the induction of reflux. There was no reflux in 2 renal units, while reflux was mild in 2, moderate in 5 and severe in 9. In the 6 animals available for followup at age 6 months only severe reflux persisted. Reflux resolution was associated with normalization of bladder urodynamics. Surveillance urine cultures were negative until age 6 months, when infection developed in 3 of the 6 lambs. In all animals serum creatinine was normal during followup. Glomerular filtration rate in the lambs with reflux was no different from normal at age 1 week but it was significantly less than normal independent of infection at age 6 months (2.7 versus 3.9 ml./kg. per minute, p = 0.002). As an indicator of renal tubular injury the ratio of N-acetyl-β-D-glucosaminidase-to-creatinine remained significantly higher in animals with reflux than in normal animals from ages 1 week to 6 months (51.0 versus 10.2 IU/mg., p = 0.03). Maximal concentrating ability after desmopressin testing was already less than normal by age 1 month with a maximal increase of 98 versus 435 mOsm./1, in lambs with reflux versus normal lambs (p <0.0001). It was further impaired by age 6 months. Urodynamic evaluation of the animals with reflux revealed decreased bladder compliance at age 1 week with normal voiding pressure. In addition, in those with reflux there was a more pronounced immature voiding pattern with multiple phasic contractions due to sphincteric activity as well as a post-void bladder contraction. Conclusions: Our model of fetal vesicoureteral reflux induces alterations in renal function that are consistent with clinical observations and marked by altered tubular function but a relatively mild decrease in glomerular filtration. Bladder dynamics are altered, consistent with observations in human neonates with high grade reflux and bladder instability. Whether this represents cause or effect remains unclear. Our model permits focused study of the interaction of these factors in neonatal reflux and may allow the application of more specific therapies, particularly those directed toward mechanisms of renal and bladder dysfunction.