Classification

Reflux severity is graded using the International Reflux Study Classification of I to V and is based on the appearance of the urinary tract on a contrast voiding cystourethrogram (VCUG) (Figs. 533-2 and 533-3). The higher the reflux grade, the greater the likelihood of renal injury. Reflux severity is an indirect indication of the degree of abnormality of the ureterovesical junction.

Figure 533-2 Grading of vesicoureteral reflux. Grade I: reflux into a nondilated ureter. Grade II: reflux into the upper collecting system without dilatation. Grade III: reflux into dilated ureter and/or blunting of calyceal fornices. Grade IV: reflux into a grossly dilated ureter. Grade V: massive reflux, with significant ureteral dilatation and tortuosity and loss of the papillary impression.

Figure 533-3 Voiding cystourethrogram showing grade IV right vesicoureteral reflux.

Reflux may be primary or secondary (Table 533-1). Bladder and bowel dysfunction instability can worsen pre-existing reflux if there is a marginally competent ureterovesical junction. In the most severe cases, there is such massive reflux into the upper tracts that the bladder becomes overdistended. This condition, the megacystis-megaureter syndrome, occurs primarily in boys and may be unilateral or bilateral (Fig. 533-4). Reimplantation of the ureters into the bladder to correct reflux resolves the condition.

Table 533-1 CLASSIFICATION OF VESICOURETERAL REFLUX

Figure 533-4 Voiding cystourethrogram in newborn boy with megacystis-megaureter syndrome. Note the massive ureteral dilatation due to high-grade vesicoureteral reflux. The bladder is very distended. There was no urethral obstruction or neuropathic dysfunction.

Approximately 1/125 children have a duplication of the upper urinary tract in which 2 ureters rather than 1 drain the kidney. Duplication may be partial or complete. In partial duplication, the ureters join above the bladder and there is 1 ureteral orifice. In complete duplication, the attachment of the lower pole ureter to the bladder is superior and lateral to the upper pole ureter. The valve-like mechanism for the lower pole ureter often is marginal, and reflux into the lower ureter occurs in as many as 50% of cases. Reflux occurs into both the lower and upper systems in some persons (Fig. 533-5). With a duplication anomaly, some patients have an ectopic ureter, in which the upper pole ureter drains outside the bladder (Chapters 534 and 537 and see Figs. 537-6 and 537-7). If the ectopic ureter drains into the bladder neck, typically it is obstructed and refluxes. Duplication anomalies also are common in children with a ureterocele, which is a cystic swelling of the intramural portion of the distal ureter. These patients often have reflux into the associated lower pole ureter or the contralateral ureter. Generally reflux is present when the ureter enters a bladder diverticulum (Fig. 533-6).

Figure 533-5 Various anatomic defects of the ureterovesical junction associated with vesicoureteral reflux.

Figure 533-6 Reflux and bladder diverticulum. The voiding cystourethrogram demonstrates left vesicoureteral reflux and a paraureteral diverticulum.

Reflux is present at birth in 25% of children with neuropathic bladder, as occurs in myelomeningocele, sacral agenesis, and many cases of high imperforate anus. Reflux is seen in 50% of boys with posterior urethral valves. Reflux with increased intravesical pressure (as in detrusor-sphincter dyssynergia or bladder outlet obstruction) can result in renal injury, even in the absence of infection.

Primary reflux occurs in association with several congenital urinary tract abnormalities. Of children with a multicystic dysplastic kidney or renal agenesis (Chapter 531), 15% have reflux into the contralateral kidney, and 10-15% of children with a ureteropelvic junction obstruction have reflux into either the hydronephrotic kidney or the contralateral kidney.

Reflux (idiopathic) appears to be an autosomal dominant inherited trait with variable penetrance. Approximately 35% of siblings of children with reflux also have reflux, and reflux is found in nearly half of newborn siblings. The likelihood of a sibling having reflux is independent of the grade of reflux or sex of the index child. Approximately 12% of asymptomatic siblings with reflux have evidence of renal scarring. In addition, 50% of children born to women with a history of reflux also have reflux. In 2010 the American Urological Association Vesicoureteral Reflux Guidelines Panel stated that, in siblings of individuals with reflux, a VCUG or radionuclide cystogram is recommended if there is evidence of renal cortical abnormalities or renal size asymmetry on sonography, or if the sibling has a history of UTI. Otherwise, screening is optional. Reflux may be suggested on a prenatal ultrasound, which demonstrates dilated renal calyces. Primary reflux is less common in African-Americans.

Clinical Manifestations

Reflux usually is discovered during evaluation for a UTI (Chapter 532). Among these children, 80% are female, and the average age at diagnosis is 2-3 yr. In other children, a VCUG is performed during evaluation of voiding dysfunction, renal insufficiency, hypertension, or other suspected pathologic process of the urinary tract. Primary reflux also may be discovered during evaluation for prenatal hydronephrosis. In this select population, 80% of affected children are male, and the reflux grade usually is higher than in girls whose reflux is diagnosed following a UTI.

Diagnosis

Diagnosis of reflux requires catheterization of the bladder, instillation of a solution containing iodinated contrast or a radiopharmaceutical, and radiologic imaging of the lower and upper urinary tract: a contrast VCUG or radionuclide cystogram (RNC), respectively. The bladder and upper urinary tracts are imaged during bladder filling and voiding. Reflux occurring during bladder filling is termed low-pressure or passive reflux; reflux during voiding is termed high-pressure or active reflux. Reflux in children with passive reflux is less likely to resolve spontaneously than in children who exhibit only active reflux. Radiation exposure during an RNC is significantly less than that from a contrast VCUG. The contrast study provides more anatomic information, such as demonstration of a duplex collecting system, ectopic ureter, paraureteral (bladder) diverticulum, bladder outlet obstruction in boys, upper urinary tract stasis, and signs of voiding dysfunction, such as a “spinning top” urethra in girls. The reflux grading system is based on the appearance on VCUG. Consequently, the VCUG is used as the initial study. For follow-up evaluation, the RNC often is preferred because of the lower radiation exposure (Fig. 533-7), although it may be difficult to determine whether the reflux severity has changed.

Figure 533-7 Radionuclide cystogram shows bilateral reflux.

Children undergoing cystography may be psychologically traumatized by the catheterization. Careful preparation by caregivers or administration of oral or nasal midazolam (for sedation and amnesia) or propofol before the study can result in a less-distressing experience.

Indirect cystography is a technique of detecting reflux without catheterization that involves injecting an intravenous radiopharmaceutical that is excreted by the kidneys, waiting for it to be excreted into the bladder, and imaging the lower urinary tract while the patient voids. This technique detects only 75% of reflux cases. Another technique, which avoids radiation exposure, involves instilling sonographic contrast medium through a urethral catheter. The kidneys are imaged sonographically. This technique is investigational.

After reflux is diagnosed, assessment of the upper urinary tract is important. The goal of upper tract imaging is to assess whether renal scarring and associated urinary tract anomalies are present. Renal imaging typically is performed with a renal sonogram or renal scintigraphy (Fig. 533-8; Chapter 532).

The child should be evaluated for bladder and bowel dysfunction, including urgency, frequency, diurnal incontinence, infrequent voiding, or a combination of these (Chapter 537). Children with an overactive bladder often undergo a regimen of behavioral modification with timed voiding, and, on occasion, anticholinergic therapy.

After diagnosis, the child’s height, weight, and blood pressure should be measured and monitored. If upper tract imaging shows renal scarring, a serum creatinine measurement should be obtained. The urine should be assessed for infection and proteinuria.

Natural History

The incidence of renal scarring or reflux nephropathy increases with the grade of reflux. With bladder growth and maturation, the reflux grade can resolve or improve over time. Lower grades of reflux are much more likely to resolve than are higher grades. For grades I and II reflux, the likelihood of resolution is similar regardless of age at diagnosis and whether it is unilateral or bilateral. For grade III, a younger age at diagnosis and unilateral reflux usually are associated with a higher rate of spontaneous resolution (Fig. 533-9). Bilateral grade IV reflux is much less likely to resolve than is unilateral grade IV reflux. Grade V reflux rarely resolves. The mean age at reflux resolution is 6 yr.

Reflux does not usually cause renal injury in the absence of infection, but in situations with high-pressure reflux, as in children with posterior urethral valves, neuropathic bladder, and non-neurogenic neurogenic bladder (i.e., Hinman syndrome), sterile reflux can cause significant renal damage. Children with high-grade reflux who acquire a UTI are at significant risk for pyelonephritis and new renal scarring (see Fig. 533-8).

Figure 533-8 A, Voiding cystourethrogram (VCUG) in a 3 yr old girl with 2 febrile urinary tract infections shows bilateral grade III reflux. B, At 5 yr, repeat VCUG shows worsening reflux and calyceal clubbing, indicating renal scarring. C, At 11 yr, she has developed rennin-mediated hypertension. DMSA renal scan shows significant reflux-related renal scarring.

Figure 533-9 A, Percentage chance of reflux persistence, grades I, II, and IV, for 1-5 yr after presentation. B, Percentage chance of reflux persistence by age at presentation, grade III, for 1-5 yr after presentation.

(From Elder JS, Peters CA, Arant BS Jr, et al: Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children, J Urol 157:1846–1851, 1997.)

Treatment

The goals of treatment are to prevent pyelonephritis, reflux-related renal injury, and other complications of reflux. Medical therapy is based on the principle that reflux often resolves over time and that if UTI can be prevented, the morbidity or complications of reflux may be avoided without surgery. The basis for surgical therapy is that in selected children, ongoing reflux has caused or has significant potential for causing renal injury or other reflux-related complications and that elimination of reflux minimizes the likelihood of these problems.

In 1997, the American Urological Association (AUA) released treatment guidelines for vesicoureteral reflux.

Surgery

In children who fail medical management (breakthrough UTI, persistent reflux), or those with high reflux grades that are unlikely to resolve, the AUA recommended surgical therapy. The purpose of surgical therapy is to minimize the risks of ongoing reflux and nonsurgical therapy (prophylaxis and follow-up testing). Reflux can be corrected through a lower abdominal or inguinal incision, laparoscopically, or cystoscopically.

Open surgical management involves modifying the abnormal ureterovesical attachment to create a 4 : 1 to 5 : 1 ratio of intramural ureter length:ureteral diameter. The operation can be performed from either outside or inside the bladder. When reflux is associated with severe ureteral dilatation (i.e., megaureter) is corrected, the ureter must be tailored or narrowed to a more normal size to allow a normal length:width ratio for the intramural tunnel, and a corner of the bladder is attached to the psoas tendon, forming a psoas hitch. Most children can be discharged the day following surgery. If the refluxing kidney is poorly functioning, nephrectomy or nephroureterectomy is indicated. Laparoscopic reflux correction either through the bladder (termed vesicoscopic) or with an extravesical approach is being investigated.

The success rate in children with primary reflux is >95-98% for grades I-IV, with 2% experiencing persistent reflux and 1% having ureteral obstruction that requires correction. The success rate is so high that many pediatric urologists do not perform a postoperative VCUG unless the child develops clinical pyelonephritis. For grade V reflux, the success rate is approximately 80%. In lower grades of reflux, a failed reimplantation is most likely to occur in children with undiagnosed voiding dysfunction. In children with secondary reflux (posterior urethral valves, neuropathic bladder), the success rate is slightly lower than with primary reflux. The risk of pyelonephritis in children with grades III and IV reflux is significantly lower following open surgical correction. Surgical repair will not reverse renal scarring or cause improvement in renal function.

Endoscopic repair of reflux involves injection of a bulking agent through a cystoscope just beneath the ureteral orifice, creating an artificial flap-valve (Figs. 533-10 and 11). The advantage of subureteral injection is that it is a noninvasive outpatient procedure (performed under general anesthesia) with no recovery time. The success rate is 70-80% and is highest for lower grades of reflux. If the first injection is unsuccessful, one or two repeat injections can be performed. In October 2001, the U.S. Food and Drug Administration (FDA) approved the use of a biodegradable material, dextran microspheres suspended in hyaluronic acid (Deflux), for subureteral injection. The reflux recurrence rate is approximately 10%. In the USA, currently >40% of antireflux surgery is performed with this procedure.

Figure 533-10 Endoscopic correction of reflux. Through a cystoscope, a needle is inserted into the submucosal plane deep to the ureteral orifice and bulking agent is injected, creating a flap-valve to prevent reflux.

(Adapted from Ortenberg J: Endoscopic treatment of vesicoureteral reflux in children, Urol Clin North Am 25:151–156, 1998.)

Figure 533-11 A, Endoscopic view of right refluxing ureter. B, The same ureter after subureteral injection of dextranomer microspheres.

The dogma regarding antibiotic prophylaxis has been questioned. Three randomized controlled prospective trials have suggested that the risk of UTI in children with reflux is not reduced by prophylaxis. Most of the children in these trials had grades I-III reflux, and few <1 yr old were studied. In contrast, the PRIVENT trial from Australia showed benefit to prophylaxis in children with reflux. The Swedish Reflux Trial in Children studied children <2 yr of age with grades III and IV reflux; they compared antibiotic prophylaxis to observation. In the surveillance group, there was a significantly higher incidence of febrile UTI and new renal scarring compared to the other treatment groups. In this series, trimethoprim was used for prophylaxis, whereas in the other trials TMP-SMX was the prophylactic medication. Consequently, further research is necessary. The National Institutes of Health (NIH) have instituted the Randomized Intervention for Vesicoureteral Reflux (RIVUR) trial to study the issue of prophylaxis. In children with persistent low-grade reflux and normal bladder function, several retrospective studies with short follow-up have demonstrated that discontinuing prophylaxis generally is safe, with approximately 15% developing UTI, but longitudinal studies into adulthood, particularly in women, have not been performed.

Prophylaxis is recommended by the AUA in children at greatest risk for reflux-related renal injury (i.e., those <1 yr of age). In addition, evaluation for bladder and bowel dysfunction (BBD) is considered a standard part of initial and ongoing patient evaluation in children with reflux. Because children with BBD and reflux are much more likely to have recurrent UTIs and renal scarring, prophylaxis is recommended for these children. In children with reflux who are being managed by surveillance, if a febrile UTI occurs, prophylaxis is recommended. The decision whether to recommend observation, medical therapy, or surgery is based on the risk of reflux to the patient, the likelihood of spontaneous resolution, and the parents’ and patient’s preferences, and the family should understand the risks and benefits of each treatment approach.