Purpose: When prenatal ultrasound reveals urinary tract dilatation, fetal reflux is suspected. Postnatal voiding cystourethrography confirms the diagnosis. The origin of reflux nephropathy is controversial, and the roles of urinary tract infection and pressure effects of sterile reflux on the developing kidneys are debatable. We evaluate the relationship between sterile reflux and renal scarring..

Materials and Methods: We reviewed the records of 100 infants and children seen during a 15-year period in whom fetal reflux had been diagnosed, including 81 with bilateral and 19 with unilateral vesicoureteral reflux. In 12 of the 19 patients voiding cystourethrography revealed unilateral grade IV or V reflux, and they comprise the study group. Split renal function was measured in all 12 patients by radionuclide renal scan shortly after birth and before urinary tract infection developed.

Results: Individual renal function was 0 to 40% in all refluxing renal units. Split renal function was less than 10% in 3 kidneys, 10 to 30% in 5 and 30 to 40% in 4. There were 2 nonfunctioning kidneys. In the remaining 10 kidneys isotope distribution on the nuclear scan indicated de-creased renal length and mass. Subsequently 7 patients had breakthrough urinary tract infections while on antibiotic chemoprophylaxis. Nephrectomy, and nephroureterectomy and ureteral reimplantation with or without tapering were performed in 3 and 9 refluxing ureters, respectively. Pathological examination of the 3 nephrectomy specimens revealed severe renal dysplasia consisting of persistent primitive ducts and nests of metaplastic cartilage.

Conclusions: Our study supports the notion that renal impairment associated with severe fetal reflux is present at birth, and it is likely due to congenital dysplasia

The origin of reflux nephropathy is controversial, and the roles of urinary tract infection and pressure effects of sterile reflux on the developing kidneys are debatable. Our under-standing of the relationship among vesicoureteral reflux, pyelonephritis and renal scarring continues to evolve. In the last 10 years the widespread use of maternal ultrasound has resulted in the detection of vesicoureteral reflux in some newborns. The ability to identify reflux in the newborn has provided a clinical model to study the effect of vesicoureteral reflux in the absence of infection. By studying patients in whom unilateral high grade reflux without obstruction, coexisting urological anomalies or urinary tract infection was diagnosed prenatally we evaluated the relationship between sterile reflux and renal scarring.

We reviewed the records of 100 infants and children seen during a 15-year period in whom fetal reflux had been diagnosed. Positive prenatal ultrasound was defined as fetal renal pelvic diameter greater than 0.8 cm. Renal ultrasound, urine culture and voiding cystourethrography were per-formed after birth. The degree of reflux was classified according to the international classification system.¹ Bilateral and unilateral vesicoureteral reflux was present in 81 and 19 patients, respectively. Of those with unilateral reflux 9 boys and 3 girls with grade IV or V reflux comprise the study group (see table).

The 12 study patients were placed on 25 mg./kg. amoxicillin daily on day 1 of life. Urine cultures were repeated every 1017 I 3 months. Split renal function was measured by ^99mtechnetium glucoheptonate radionuclide renal scan at 4 to 6 weeks of life before urinary tract infection developed. Patients with evidence of renal obstruction or an abnormal contralateral kidney were excluded from study. No patient had coexisting urological anomalies.

Individual renal function was 0 to 40% in all refluxing renal units. Split renal function was less than 10% in 3 kidneys, 10 to 30% in 5 and 30 to 40% in 4. There were 2 nonfunctioning kidneys. In the remaining 10 kidneys isotope distribution on the nuclear scan indicated decreased renal length with generally decreased isotope uptake. Subsequently 7 of the 12 patients had a breakthrough urinary tract infection while on antibiotic chemoprophylaxis. Nephrectomy, and nephroureterectomy and ureteral reimplantation with or without tapering were performed in 3 and 9 refluxing ureters, respectively. Pathological examination of the 3 nephrectomy specimens revealed severe renal dysplasia, consisting of persistent primitive ducts and nests of metaplastic cartilage.

We performed cystoscopy before ureteral reimplantation or nephrectomy, and recorded the location and shape of the ureteral orifice. An orifice was considered normal when its distance from the midline of the trigone was similar to that of the contralateral nonrefluxing orifice. The shape of the orifice was classified as normal or gaping.

Since the 1960s many clinical and experimental studies have evaluated the relationship among vesicoureteral reflux, pyelonephritis and renal scarring. In 1959 Hodson recognized the association of renal scars in children with recurrent urinary tract infection, including 97% with vesicoureteral reflux.² In a piglet model Hodson and Edwards unroofed the intramural ureter and created bladder outlet obstruction by placing a constricting ring around the urethra, which produced reflux.³ They proposed that sterile reflux may cause renal scarring. In a similar piglet model Ransley and Risdon created reflux by unroofing the intramural ureter, although they did not create bladder outlet obstruction.⁴ In contrast to the study of Hodson and Edwards,³ they did not observe scarring with sterile urine reflux. Others verified the importance of infection in the development of new scars only in patients with reflux who had recurrent infections.^5,6 Atala and Keating noted that most clinical and experimental studies underscore the important role of infection in the evolution of most renal scars.⁷

New imaging techniques have contributed to our current understanding of the relationship between infection and renal scarring. The introduction and refinement of renal cortical scintigraphy have provided a means to study the progression of renal parenchymal damage from the time of infection until the development of renal scarring.^8,9 In the last 10 years the widespread use of maternal ultrasound has resulted in the detection of vesicoureteral reflux in some newborns. Renal scintigraphy performed in this population of patients with fetal reflux shows unexpected renal functional abnormalities before any episodes of infection, which suggests fetal nephropathy in some with high grade fetal re-flux..^10,11

Wallin and Baje reported that patterns of dimercaptosuccinic acid distribution associated with vesicoureteral re-flux include polar defects (decreased uptake in the upper or lower pole), a medial defect (decreased uptake of the whole medial part of the kidney), and small renal size and de-creased renal length (global decreased uptake).¹² The latter type is more likely to be due to congenital dysplasia than urinary tract infection. In our patients function was de-creased in all refluxing units. Two kidneys were nonfunctioning, and in the remaining 10 the isotope distribution pattern indicated decreased renal length with global reduced uptake.

Before the development of renal scintigraphy Mackie and Stephens suggested that renal dysplasia closely correlated with an abnormal ureteral orifice location.¹³ A laterally positioned ureteral bud provides an embryological explanation for reflux. A mismatch between a laterally positioned ureteral bud and the renal blastema during early gestation results in dysplasia and an incompetent ureterovesical junction. This theory has been well demonstrated in a duplex kidney model. However, before the ability to detect fetal reflux it was difficult to prove that the dysplasia associated with reflux was in fact congenital and not secondary to infection. Our cystoscopy data show that the majority of refluxing orifices are gaping and lateral. We consider this finding to be further evidence in support of the Mackie and Stephens theory.

We evaluated the relationship between sterile reflux and renal scarring. By limiting our study group to patients with prenatally diagnosed unilateral high grade reflux without any evidence of obstruction, coexisting urological anomalies or urinary tract infection we believe that our data strongly support the notion that reflux nephropathy may develop in the absence of infection.

1. Medical versus surgical treatment of primary vesicoureteral re-flux. International Reflux Study Committee. Pediatrics, 67: 392, 1981.

2. Hodson, C. J.: The radiologic diagnosis of pyelonephritis. Proc. Roy. Soc. Med., 52: 669, 1959.

3. Hodson, C. J. and Edwards, D.: Chronic pyelonephritis and vesicoureteral reflux. Clin. Rad., 11: 219, 1960.

4. Ransley, P. G. and Risdon, R. A.: Reflux and renal scarring. Brit. J. Rad., suppl., 51: 1, 1978.

5. Smellie, J. M., Edwards, D. and Hunter, N.: Vesicoureteral re-flux and renal scarring. Kid. Int., suppl. 4, 8: 65, 1975.

6. Huland, H. and Busch, R.: Pyelonephritic scarring in patients with upper and lower urinary tract infections: long-term follow-up in 213 patients. J. Urol., 132: 936, 1984,

7. Atala, A. and Keating, M. A.: Vesicoureteral reflux and mega-ureter. In: Campbell's Urology, 7th ed. Edited by P. C. Walsh, A. B. Retik, E. D. Vaughan, Jr. and A. J. Wein. Philadelphia: W. B. Saunders Co., chapt. 61, pp. 1859-1916, 1997.

8. Rushton, H. G. and Majd, M.: Dimercaptosuccinic acid renal scintigraphy evaluation of pyelonephritis and renal scarring: a review of experimental and clinical studies. J. Urol., 148: 1726, 1992.

9. Rushton, H. G.: Reflux versus nonreflux pyelonephritis: is there a difference? Prob. Urol., 8: 473, 1994.

10. Anderson, P. A. M. and Rickwood, A. M. K.: Features of primary vesicoureteral reflux detected prenatal sonography. Brit. J. Urol., 67: 267, 1991.

11. Najmaldin, A., Burge, D. M. and Atwell, J. D.: Reflux nephropathy secondary to intrauterine vesicoureteral reflux. J. Ped. Surg., 25: 387, 1990.

12. Wallin, L. and Bajc, M.: The significance of vesicoureteral reflux on kidney development assessed by dimercaptosuccinate renal scintigraphy. Brit. J. Urol., 73: 607.

13. Mackie, G. G. and Stephens, F. D.: Duplex kidneys: a correlation of renal dysplasia with position of the ureteral orifice. J. Urol., 114:274, 1975.