Pediatric Vesicoureteral Reflux Treatment & Management

Controversy persists over the optimal management of vesicoureteral reflux (VUR), specifically with respect to the timing, technique, and benefits of surgical correction. Guidelines have been published by the American Urological Association (AUA). ^[5] (See Guidelines.) Guidelines have also been developed by the European Association of Urology (EAU) and the European Association of Paediatric Urology (ESPU). ^[6] ​

Febrile urinary tract infection (UTI) with signs of pyelonephritis in children with VUR requires admission and also treatment with parenteral antibiotics to prevent renal damage. This is particularly true in children who are dehydrated, unable to retain oral intake, or in a toxic state.

The need for inpatient admission should be based on the clinical assessment at the time of presentation. Many patients with febrile UTI can be managed as outpatients. Children who are severely dehydrated or in a septic state, as well as those for whom there are social concerns regarding whether home caregivers can be relied on to care for the ill child properly and completely, should be admitted.

Hospitalization after open antireflux surgery typically lasts 24-72 hours. It is increasingly common for children to be discharged home the morning after surgery, and some centers are performing these procedures on an outpatient basis. Generally, children are discharged once they tolerate a regular age-appropriate diet, their pain is managed with oral pain medication, and they are active at an age-appropriate level. Endoscopic antireflux surgery is generally performed as an outpatient procedure.

The treatment of children with VUR aims to prevent kidney infection, kidney damage, and the complications of kidney damage. Treatment options include surveillance, medical therapy, and surgical therapy. ^{[5, 6]} (See Guidelines.) Walker summarized the general principles of management in children with known VUR as follows ^[7] :

• Spontaneous resolution of VUR is common in young children but is less common as puberty approaches
• Severe reflux is unlikely to resolve spontaneously
• Sterile reflux, in general, does not result in reflux nephropathy
• Long-term antibiotic prophylaxis in children is safe
• Surgery to correct VUR is highly successful in experienced hands

Resolution of reflux is dependent on numerous factors, including age, sex, grade of reflux, laterality, history of UTI, and other factors. Several centers have developed calculators or nomograms to help clinicians predict the probability of resolution within a given time frame (eg, 5 y), though these calculators may yield different results for similar inputs. In general, however, low-grade VUR (grades I-II) has high rates of spontaneous resolution (usually >80%). High-grade VUR, especially grade V, is much less likely to resolve at despite many years of observation.

Surveillance is infrequently used among those with high-grade VUR, for numerous reasons. Although the efficacy of prophylactic antibiotics for preventing either UTI or renal scarring has not been established in large randomized trials, several decades of clinical practice have demonstrated that antibiotic prophylaxis is usually well tolerated, and clinicians typically would rather provide at least some treatment than offer none at all. Medicolegal concerns about the risk of kidney damage while a patient is under surveillance have likewise limited the use of this approach.

Surveillance is still frequently employed among older children with VUR, especially boys who have never had a UTI. Children with low-grade VUR, especially those who have never had a UTI, are sometimes followed on surveillance without antibiotic prophylaxis.

Initial treatment of the child with a UTI involves supportive care and prompt administration of appropriate antibiotics. Timely institution of antibiotic therapy has been shown to be critical in preventing scar formation in kidneys with pyelonephritis.

Animal studies have demonstrated that permanent renal damage occurs if antibiotics are not started within 72 hours, though other studies indicate an even shorter window of opportunity. For this reason, clinicians must maintain a high index of suspicion for UTI in children.

Medical treatment with prophylactic antibiotics remains the mainstay of initial management of VUR (see Medication). Because VUR spontaneously resolves in most children, medical management allows this natural history to take its course while providing some measure of protection against recurrent UTI and renal injury.

Prophylaxis should be started once a child has completed treatment of the initial UTI (see Medication) and continued at least until imaging reveals VUR. If no VUR is seen, prophylaxis is discontinued. If VUR is present, prophylactic antibiotics are continued until one of the following occurs:

• VUR resolves
• VUR is surgically corrected
• The child grows old enough that prophylaxis is deemed no longer necessary

Virtually all children with a new diagnosis of grade I-IV reflux, as well as some with grade V, are given a trial of medical treatment. This consists of antibiotics administered at one fourth of the therapeutic dosage and regular follow-up care and imaging. A typical routine includes renal ultrasonography (US) and voiding cystourethrography (VCUG) or radionuclide cystography (RNC) every 12-18 months.

Given that a substantial number of children experience spontaneous resolution of VUR (50-85% of cases with grade I-III), medical treatment spares this group the morbidity of surgery while protecting the kidneys from further damage.

Once follow-up imaging demonstrates resolution of VUR, antibiotics are discontinued. The importance of conscientious follow-up care during medical management cannot be overemphasized. Lack of compliance with medications or surveillance imaging may result in progression of reflux nephropathy and renal failure in children who are susceptible.

In boys with persistent VUR who have not had recurrent UTIs, antibiotics are often discontinued as the boys approach puberty. However, because of concerns about future pregnancies, surgery may be recommended in girls approaching puberty who have persistent VUR.

The role of antibiotic prophylaxis in this setting has been challenged. Several studies failed to find any decrease in the incidence of UTIs in children with VUR who take antibiotics. However, these studies had significant flaws that made it difficult to state with certainty that antibiotic prophylaxis is ineffective. Accordingly, the National Institutes of Health (NIH) sponsored a large prospective clinical trial of prophylaxis in an effort to answer this key question.

In 2014, the results of the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) study were published. ^[8] This large 2-year trial showed that antibiotic prophylaxis with trimethoprim-sulfamethoxazole was associated with a decrease of approximately 50% in the incidence of recurrent UTI among children with VUR, in comparison with placebo. No difference in renal scarring was observed between groups (though the RIVUR study was not powered to detect such a difference). The frequency of resistant organisms was significantly higher in the treatment group than in the placebo group, though this finding did not seem to impact outcomes.

According to a study by Su et al, risk factors for the development of breakthrough UTI in children with VUR who receive continuous antibiotic prophylaxis include younger age at the initial diagnosis of UTI (≤ 12 mo), bilateral VUR, and bladder and bowel dysfunction. ^[22]

Some authors have suggested that continuous low-dose antibiotic prophylaxis may have an adverse effect on growth in children with VUR. ^[23] However, other large series have found no evidence that prophylaxis impacts weight gain or obesity. ^[24]

Controversies surrounding antibiotic prophylaxis for UTI notwithstanding, the role of antibiotics in the treatment of acute UTI is not debatable, and failure to institute appropriate therapeutic antibiotics in the setting of pyelonephritis (kidney infection) is associated with permanent renal injury and scarring. Children at risk for such infection, such as those with VUR, need prompt and timely evaluation of possible UTI to prevent such outcomes.

The importance of aggressive bladder and bowel management for dysfunctional elimination cannot be overemphasized. In toilet-trained children with recurrent UTI, voiding postponement behaviors, incomplete emptying, and constipation are extremely common and may be much more important etiologic factors than the reflux itself.

Anticholinergic medication, in conjunction with timed voiding, may improve symptoms of dysfunctional voiding and reduces the risk of infection. Anticholinergic agents should be used in select patients so as not to compound the problems of incomplete bladder emptying or worsening constipation.

Many of these patients benefit from some form of bladder training to achieve balanced, low-pressure voiding with coordinated relaxation of the external sphincter and pelvic floor. Such training may range from simple timed voiding regimens to get the children emptying regularly all the way to formal biofeedback programs to teach and improve pelvic muscle coordination. In children with primary bowel elimination problem, treatment with enemas, dietary changes, and stool bulking agents, in coordination with a pediatric gastroenterologist, is critical for success.

The most dramatic change in the management of VUR has been the rapid growth of endoscopic treatment. Although endoscopic techniques had been used in Europe for many years, it was only after the introduction (and approval by the US Food and Drug Administration [FDA]) of injectable dextranomer/hyaluronic acid copolymer (DHA) that endoscopic antireflux therapy became widespread in the United States. ^[25]  The perceived benefits of endoscopic treatment include short procedural time, low morbidity, comparable success rates, and preservation of the option for subsequent open surgical repair.

Some clinicians advocate endoscopic treatment as initial management for newly diagnosed VUR, arguing that immediate antireflux treatment obviates the need for long-term antibiotics and repeated imaging studies. However, such a strategy inevitably results in the overtreatment of a large number of children. VUR spontaneously resolves in most children, and even those with persistent VUR may not have a clinical indication for antireflux procedures. In addition, the true long-term success rates for endoscopic treatment with DHA are still to be determined.

Endoscopic techniques involve injection of a bulking substance into the muscular posterior wall of the ureterovesical junction (UVJ). The resulting bulking effect compresses the ureteral lumen and provides a substitute for the normal muscular backing of the transmural ureter.

Some authors emphasize the importance of creating a large mound or "volcanic" appearance of the bulking agent under the orifice, compressing the orifice into a slit. Other authors have described an intramural injection, in which the distal ureter is distended with a jet of saline from the cystoscope, allowing the injection needle to be advanced into the submucosa of the intramural ureter at the 6 o'clock position.

In general, the rates of success (defined as resolution of VUR on postprocedural imaging) reported for endoscopic treatment have been significantly lower than those reported for open antireflux surgery. A meta-analysis of over 5000 patients undergoing endoscopic treatment with various bulking agents found a success rate of 74% after one injection and 85% after one or more injections. ^[26]  The success rate among the DHA studies was 69% after one injection.

Most studies of endoscopic treatment have found success rates to be lower in patients with higher grades of VUR (ie, the very patients most likely to need antireflux surgery). The meta-analysis previously mentioned found a success rate of 63% after one injection for grade IV VUR. ^[26]

Single-center reports have noted significantly higher success rates with DHA, with resolution rates of over 90% with one or more injections at some centers.

Additional bulking agents have been used extensively in Europe, particularly polytetrafluoroethylene (PTFE). Although thousands of patients have undergone treatment with PTFE over the past 30 years, persistent concerns over the safety of this bulking agent have limited its use in the United States.

Other bulking agents that have been reported include autologous fat, blood, and chondrocytes; bovine collagen; and polydimethylsiloxane. Although all have certain advantages, concerns over particle migration, carcinogenesis, and technical handling problems have limited their use.

Polyacrylate polyalcohol copolymer (PPC) has been studied as an alternative bulking agent in Europe and South America. ^{[27, 28, 29]} Findings suggest that PPC is associated with higher success rates than DHA, at the cost of a higher risk of UVJ obstruction.

Children who undergo endoscopic antireflux treatment need continued follow-up. They require postprocedural imaging, including VCUG at 3-4 months. Patients should be maintained on antibiotic prophylaxis until resolution of VUR is confirmed.

Studies of endoscopic injection of DHA have found that as many as 25% of children whose VUR was cured on the initial VCUG (at 3-4 mo) subsequently had recurrence of VUR on a delayed VCUG (12 mo). The reasons for late failure of endoscopic therapy are uncertain but may include reabsorption of the injected material, migration of the injected material, or secondary patient factors such as dysfunctional voiding. Some clinicians recommend additional VCUG at 12-18 months after endoscopic treatment because of concerns over the durability of the DHA implant.

Delayed adverse effects of DHA antireflux therapy appear to be uncommon. However, some studies have observed that the DHA implants can strongly resemble a kidney stone in the distal ureter on computed tomography (CT), apparently because of calcification of the DHA implant. Because many children who undergo DHA injection for treatment of VUR eventually undergo CT for numerous reasons, treating physicians and radiologists must recognize that DHA implants may produce a misleading appearance on CT.

Open antireflux surgery

The decision to proceed to antireflux surgery is based on many factors, and the medical, social, and emotional needs of the patient and the family must be considered. Accepted indications for surgical treatment include the following:

• Breakthrough febrile UTIs despite adequate antibiotic prophylaxis
• Severe reflux (grade V or bilateral grade IV) that is unlikely to resolve spontaneously, especially if renal scarring is present
• Mild or moderate reflux in females that persists as the patient approaches puberty, despite several years of observation
• Poor compliance with medications or surveillance programs
• Poor renal growth or function or appearance of new scars

Virtually all open antireflux operations involve reconstruction of the UVJ to create a lengthened submucosal tunnel for the ureter, which functions as a one-way valve as the bladder fills. Dozens of procedures have been described. Surgery for VUR should be performed by a qualified pediatric urologist who is experienced in multiple techniques, so that the surgical procedure can be tailored to the unique anatomic circumstances of the individual patient.

Although several studies have shown that antireflux surgery decreases the incidence of pyelonephritis, randomized trials of antibiotic prophylaxis versus surgical therapy plus antibiotic prophylaxis have not shown differences in the development of nonfebrile UTI, renal scarring, or renal failure. However, most of these studies were statistically underpowered, and the true benefit of antireflux surgery remains to be fully defined.

Intravesical repair

In the intravesical approach, the bladder is opened anteriorly via a low abdominal incision. The ureters are separated from their attachments to the bladder muscle and connective tissue and repositioned under a submucosal tunnel to create the necessary 5:1 length-to-diameter ratio.

The Politano-Leadbetter procedure, developed in the 1950s, is the prototypical intravesical operation. The ureter is dissected completely free of its attachments and passed through a new muscular hiatus created higher on the bladder wall. The ureter is then passed down through a submucosal tunnel, and the orifice is sutured to the mucosa at its original meatal position. This procedure has a reported success rate of 97-99%.

An evolution of the Politano-Leadbetter procedure is the Cohen cross-trigonal technique, which is probably the most popular intravesical repair performed today. In this repair, the original muscular hiatus is used, but the ureter is dissected from its attachments and pulled across the trigone through a submucosal tunnel, and the meatus is sutured into a new position at the end of the tunnel. Reported success rates with this technique are also in the range of 97-99%.

A retrospective review by Lin et al (N = 46) compared the Politano-Leadbetter procedure (P) with the Cohen procedure (C) in children with VUR (n = 24) or primary obstructive megaureter (n = 22). ^[30]  Reflux was clinically resolved for all 24 VUR patients; however, the resolution rate was 75% for the C group (in which three patients experienced persistent low-grade, clinically insignificant reflux), whereas it was 100% for the P group. 

Extravesical repair

The extravesical approach was developed in an effort to avoid the time and morbidity associated with the cystotomy and ureteral anastomosis required for intravesical repair. It is particularly useful in patients with unilateral reflux.

Developed concurrently in Europe and the United States, the Lich-Gregoire repair approaches the bladder via the retroperitoneum. The ureter is dissected from the detrusor, but the orifice is left intact. A narrow furrow in the detrusor then is created, down to but not disrupting the mucosa, and extended cephalad from the ureteral orifice. The distal ureter is then laid into this furrow and the detrusor closed over it. Although early American results were disappointing, further experience and modifications have demonstrated success rates comparable to those of the standard intravesical techniques.

One complication of the extravesical approach is postoperative urinary retention, which generally resolves spontaneously. Judicious use of a bipolar electrocautery during the posterior bladder dissection can reduce incidence of this complication to less than 5%. Rare reports of permanent voiding dysfunction and retention in patients undergoing bilateral extravesical procedures have led some surgeons to use this technique only for unilateral cases.

Robotic-assisted laparoscopic ureteral implantation

Although open ureteral reimplantation is still the surgical gold standard in the treatment of VUR, there is increasing interest in robotic-assisted laparoscopic ureteral reimplantation (RALUR) as an option. ^{[31, 32, 33]}  Hydronephrosis has been noted to occur de novo after RALUR; Mittal et al reported an incidence of 13.5% in their cohort but found that the majority of such occurrences were transient and resolved spontaneously within 1 year of surgery, with very little need for reintervention. ^[34]

Children with frequent UTIs often have concurrent problems with constipation and poor bowel habits. Institution of a bowel program in these children can reduce the frequency of infection. High-fiber diets combined with a stool softener, such as docusate, can improve bowel function and reduce colonic and rectal dilation. For severe cases, daily polyethylene glycol is often used.

Children with VUR can engage in normal activity. Toilet hygiene, especially proper wiping technique in girls, should be taught to children of appropriate age to reduce the frequency of UTI.

Obstruction after open antireflux surgery

Most cases of postoperative upper tract obstruction are mild, produce no symptoms, and spontaneously resolve. These cases are due to edema at the ureteroneocystostomy site, blood clots, or mucus causing mechanical obstruction. Cases of severe obstruction often have a delayed presentation (1-2 wk or longer) and may be associated with flank or abdominal pain, nausea, and vomiting.

US reveals dilation on the affected side, though this can be difficult to assess in patients who had significant dilation preoperatively.

High-grade obstruction is usually due to ischemia of the implanted ureteral segment with resulting fibrosis and stricture. This is a rare complication. Occasionally, patients may present with intermittent obstruction due to kinking of the reimplanted ureter with bladder filling.

Treatment for high-grade obstruction is surgical revision of the obstructed system. Percutaneous nephrostomy for temporary drainage may be required if the patient is symptomatic or in a toxic state.

Persistent vesicoureteral reflux after antireflux surgery

Open surgery

Modern series consistently report success rates greater than 95% for antireflux surgery. When VUR persists postoperatively, initial observation with continued antibiotic prophylaxis is indicated. Reoperation is generally reserved for patients with persisted febrile UTI despite prophylaxis.

A very high percentage of patients in whom surgery has failed have voiding dysfunction. Urodynamic evaluation should be considered in these patients, especially if reoperation is considered. Even so, a substantial majority of patients with reflux at the first postoperative study have complete resolution at the 1-year follow-up point.

Endoscopic surgery

Initial management is often repeat injection. Many investigators report routinely injecting as many as three separate times. Patients in whom multiple injections fail should be reevaluated and treated for causes of secondary VUR. Patients with persistent VUR and indications for surgical correction should proceed to open surgery.

New contralateral vesicoureteral reflux after unilateral antireflux surgery

New onset of VUR in a renal unit that had no VUR on preoperative imaging occurs in 10-32% of patients after open correction and 7-14% of patients after endoscopic correction. In general, the new VUR is thought to be of low grade and may be more likely to resolve spontaneously. ^[35]

Good communication between the urologist and the primary care physician is essential for the effective management of VUR. This is especially true for children being treated medically, in whom regular follow-up care and prompt evaluation and treatment of breakthrough UTI are critical in preventing renal damage.

Involvement of a pediatric nephrologist is indicated for children at risk for or manifesting evidence of reflux nephropathy.

Children whose VUR is being managed medically are regularly seen on an annual basis. Routine evaluation includes urinalysis and urine culture, appropriate imaging, and blood pressure measurement. Parents must understand the need for proper evaluation and urine culture if they suspect UTI. In some cases, parents are taught to perform urinalysis at home. Positive home urinalysis results should prompt formal testing at a physician's office.

After surgical correction of VUR, patients are seen in the clinic 2-6 weeks after discharge with renal US or renal scintigraphy to exclude upper-tract obstruction. Patients continue taking prophylactic antibiotics until a second return visit 3-6 months postoperatively, at which time VCUG or nuclear cystography is performed.

Some have abandoned the practice of a follow-up VCUG or RNC after open surgical treatment because success rates are high. Antibiotic therapy is usually stopped after normal postnatal US results are obtained. If VCUG or RNC is performed postoperatively and reveals resolution of reflux, antibiotics are discontinued, and no further invasive studies are necessary unless further febrile UTIs develop.

A study by Arlen et al suggested that routine VCUG is not necessary after endoscopic treatment of pediatric primary VUR with the double HIT (hydrodistention implantation technique) approach. ^[36] The authors recommended that postoperative VCUG be considered an option rather than a recommendation in this setting unless it is indicated on the basis of high grade, young age, clinical failure, or family or surgeon preference.

Some clinicians continue to observe children with VUR periodically with blood pressure checks and renal US.