endoscopic treatment of primary vesicoureteral reflux

clinical therapeutics

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 366;13 nejm.org march 29, 20121218

This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies,

the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the authors’ clinical recommendations.

Endoscopic Treatment of Primary Vesicoureteral Reflux

David A. Diamond, M.D., and Tej K. Mattoo, M.D., D.C.H.

From the Department of Urology, Chil-dren’s Hospital Boston, Boston (D.A.D.); and the Division of Pediatric Nephrology, Children’s Hospital of Michigan, Wayne State University School of Medicine, De-troit (T.K.M.). Address reprint requests to Dr. Diamond at the Department of Urology, Children’s Hospital Boston, 300 Longwood Ave., Boston, MA 02115, or at [email protected].

N Engl J Med 2012;366:1218-26.Copyright © 2012 Massachusetts Medical Society.

A 7-year-old girl with a history of recurrent urinary tract infection since the age of 3 years is known to have bilateral, moderately severe (grade III) vesicoureteral reflux. Renal scintigraphy with technetium-99–labeled dimercaptosuccinic acid has revealed bilateral scarring in the upper poles of her kidneys, with more severe scarring on the left kidney than on the right. Despite ongoing antimicrobial prophylaxis, she has re-cently had another febrile urinary tract infection, which responded well to antibiotic treatment. Radionuclide cystography reveals persistent bilateral, moderately severe vesicoureteral reflux. The patient has no history of constipation or dysfunctional voiding. She is referred to a pediatric urologist, who discusses with the patient and her parents the various treatment options, including endoscopic correction.

The Clinic a l Problem

Primary vesicoureteral reflux is one of the most common urologic abnormalities in children. The overall prevalence of the disorder is typically estimated to be about 1%.1 However, it has been suggested that the actual prevalence may be substantially higher.2,3 The frequency with which it is detected depends on the indication for testing that leads to the diagnosis. For example, vesicoureteral reflux is diagnosed in about one third of children (mostly girls) who are evaluated after urinary tract infec-tion2,4,5 and in about 10% of infants (mostly boys) with antenatal hydronephrosis. Vesicoureteral reflux is much less common in black children than in whites.5,6 The natural course of the disorder is spontaneous resolution, which has been reported to occur in anywhere from 25 to 80% of patients.7-9 Resolution may be delayed by void-ing dysfunction (the inability to release urine with a coordinated bladder contrac-tion and sphincter relaxation), which increases the risk of recurrent urinary tract infection.10-12

Vesicoureteral reflux in a child with urinary tract infection may predispose that child to pyelonephritis and renal scarring, termed reflux nephropathy.13 The renal scarring may be congenital or acquired in origin. The former appears to be a result of segmental renal dysplasia and is seen mostly in boys with high-grade vesicoure-teral reflux with no history of urinary tract infection. The latter is a result of renal injury caused by acute pyelonephritis and is seen mostly in girls. Patients with reflux nephropathy may be completely asymptomatic. The known complications of reflux nephropathy include hypertension and proteinuria.14 In addition, pregnancy-related complications and chronic kidney disease with end-stage renal failure may occur in some patients.14

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clinical Ther apeutics

n engl j med 366;13 nejm.org march 29, 2012 1219

Pathoph ysiol o gy a nd Effec t of Ther a py

The normal ureterovesical junction prevents retro-grade flow of urine to the kidneys by means of a flap-valve mechanism. This mechanism does not include a typical anatomical valve but instead re-lies on the length of the ureter in the bladder wall and submucosa (the “tunnel”), its oblique inser-tion, and the support of the detrusor muscle be-hind the ureter (Fig. 1). A rise in intravesical pres-sure causes compression of the ureter with no backflow of urine.

Primary vesicoureteral reflux results from failed development of the ureterovesical junction, which produces an abnormally short tunnel. Normally, the ratio of the intramural tunnel length to the ureteral diameter is 5:1,15,16 whereas the ratio is 1.4:1 in refluxing ureters.16,17 Secondary vesico-ureteral reflux, which is much less common, re-sults from urinary tract disease associated with increased intravesical pressure, which may occur with neurogenic bladder, posterior urethral valves, or dysfunctional voiding.18 Congenital anomalies involving the ureterovesical junction, such as para-ureteral bladder diverticula or complete ureteral duplication, also predispose to reflux.

The standard diagnostic test for vesicoureteral reflux is voiding cystourethrography. This study is typically performed by filling the bladder with a radiocontrast agent through a urethral catheter and then using fluoroscopy to observe the distri-bution of the dye. Retrograde filling of the upper urinary tract is diagnostic of vesicoureteral reflux, which is graded from I to V, with grade V being the most severe (Fig. 2).19

The presence of vesicoureteral reflux provides a mechanism by which bacteria in the bladder can reach the kidney and produce pyelonephritis and reflux nephropathy. The scarring may occur after a single episode of pyelonephritis, especially in young children.20 There is a significant correlation between the grade of reflux and the development of abnormalities on renal scintigraphy 1 to 2 years later.21 The mechanism for renal scarring is un-known and has been attributed to immunologic mechanisms, macromolecules that are released owing to cell injury and mesangial dysfunction, vascular alterations, hypertension, and hemody-namic alterations.22

Long-term antimicrobial prophylaxis and sur-gical correction of vesicoureteral reflux have both

been used in an attempt to lower the risks of re-current urinary tract infection and reflux nephrop-athy. The standard surgical correction is ureteral reimplantation through an open or laparoscopic procedure. In this procedure, a long submucosal tunnel is created for the ureter to achieve a ratio of tunnel length to ureteral diameter of 4:1 or 5:1.23

An alternative to reimplantation is endoscopic injection of a biocompatible bulking agent at the ureterovesical junction (Fig. 3). This procedure is believed to prevent reflux by buttressing the distal ureter and narrowing the ureterovesical junction without impeding the normal flow of urine from kidneys to bladder. The bulking agent in current use for this purpose is a copolymer gel that con-sists of dextranomer microspheres suspended in hyaluronic acid (Deflux, Salix Pharmaceuticals). After injection, the hyaluronic acid undergoes gradual absorption over time and is replaced by a collagen matrix, resulting in the formation of a persistent tissue implant at the site of injection.24

Clinic a l E v idence

Relatively few trials have compared endoscopic cor-rection of vesicoureteral reflux with other therapeu-tic options. The largest such trial, the Swedish Reflux Trial in Children, enrolled 128 girls and 75 boys who were between the ages of 1 and 2 years and who had grade III or IV vesicoureteral reflux. Study subjects were randomly assigned to receive antibiotic prophylaxis, endoscopic treat-ment, or surveillance alone. At 2 years, on the basis of repeat voiding cystourethrography, reflux had resolved or diminished to grade I or II in 39% of subjects receiving antibiotic prophylaxis, 71% of those receiving endoscopic treatment, and 47% of those undergoing surveillance alone25; recurrent febrile urinary tract infection occurred in 14%, 21%, and 37%, respectively,26 with recur-rences more common in girls than in boys. New parenchymal damage was detected by renal scin-tigraphy in 0%, 9%, and 13%, respectively, and was again more frequent in girls than in boys.27 In another smaller randomized trial, 61 children who were older than 1 year of age and had grade II to IV vesicoureteral reflux were assigned in a 2:1 ratio to receive either endoscopic treatment or antibiotic therapy. At 1 year, reflux had resolved or diminished to grade I in 69% of subjects re-ceiving endoscopic treatment and 38% of those receiving antibiotic therapy.28





No randomized clinical trials have compared endoscopic correction of vesicoureteral reflux with ureteral reimplantation. However, resolution of reflux is expected to be nearly 100% with open reimplantation. In comparison, a recent system-atic review of the endoscopic procedure with the use of dextranomer and hyaluronic acid copolymer gel showed a success rate of 77% at 3 months after a single injection. Efficacy ranged from 81% for grade I reflux to 62% for grade V reflux.29

Clinic a l Use

The optimal management of vesicoureteral reflux remains a subject of debate.14,30-32 Although it is clear that surgical intervention can eliminate or re-duce the severity of reflux itself, the clinical trials do not provide convincing evidence that either sur-gery or antibiotic prophylaxis can reduce the in-cidence of recurrent urinary tract infection or, more important, the incidence of renal damage, as com-pared with surveillance alone. In addition, it is im-portant to recognize that vesicoureteral reflux has

a tendency to resolve in many patients with con-servative management.7-9 However, the currently available data do not answer the question of wheth-er more selective intervention may be helpful for the subgroup of patients at greatest risk for com-plications, and enrollment in clinical trials has typically not been restricted to such patients. We recommend consideration of surgical treatment for patients with higher-grade reflux (grade III, IV, or V), for those in whom antimicrobial prophylaxis has proved to be ineffective (as shown by recurrent urinary tract infections while receiving such ther-apy), for those who cannot or do not consistently use antimicrobial therapy, and for those with pro-gressive renal scarring.14 We also consider surgical repair in girls with vesicoureteral reflux that per-sists as puberty approaches.

Voiding dysfunction is a relative contraindica-tion to surgical correction of reflux because the likelihood of treatment failure and recurrent uri-nary tract infection is substantially increased.33-35

It is generally recommended that patients with bowel and bladder dysfunction undergo treatment

Intramural ureter

Ureter

Reflux

Possible reflux

No refluxA

B

C

Submucosal ureter

Figure1.AnatomyoftheUreterovesicalJunction.

Primary vesicoureteral reflux results from the failure of development of the ureterovesical junction, producing a short, inadequate intramural tunnel. The likelihood of vesicoureteral reflux is related to the length of the ureteral tunnel in the bladder. In this figure, A denotes a tunnel of normal length, and no reflux is present; B, a shorter tunnel, which could be associated with reflux; C, a short tunnel, which could be associated with reflux. Normally, the ratio of the length of the intramural tunnel to the ureteral diameter is 5:1, whereas the ratio is 1.4:1 in patients with vesicoureteral reflux.





for this condition before surgical intervention. Although optimal treatment of bowel and bladder dysfunction is not well defined, options include behavioral therapy, biofeedback, the use of anti-cholinergic medications or alpha-blockers, and treatment of constipation.12

Open ureteral reimplantation has a 98% suc-cess rate in the definitive elimination of vesicoure-teral reflux and remains the standard procedure. However, the endoscopic procedure, in spite of a lower success rate (70 to 80%), has become a viable alternative because it is less invasive than ureteral reimplantation. The indications for endoscopic correction are similar to those for reimplantation, but there are a number of relative contraindi-cations to its use. These include anatomic variants of the ureterovesical junction and severe vesicoure-teral reflux (grade IV or V), for which endoscopic surgery is less successful. In addition, the Food and Drug Administration (FDA) has listed the association of vesicoureteral reflux with nonfunc-tioning kidneys, paraureteral bladder diverticula, duplicated ureters, active voiding dysfunction,

and ongoing urinary tract infection as contrain-dications for the endoscopic procedure.

Endoscopic correction of vesicoureteral reflux was first described in 1984.36 The first procedures involved cystoscopic injection of polytetrafluoro-ethylene (Teflon, DuPont) at the ureterovesical junction immediately beneath the ureteral orifice. The treatment was given the acronym STING (for subureteral Teflon injection). This approach was subsequently modified to include submucosal in-jection in the distal ureter, which may require distention of the ureter with irrigating fluid and is designated HIT (hydrodistention implantation technique).37 Because of safety concerns related to the migration of Teflon particles into the sys-temic circulation, alternative substances were de-veloped. In 1995, the use of dextranomer–hyal-uronic acid (Deflux) was first described.24 Deflux obtained FDA approval in 2001 and remains the only approved substance for endoscopic correction of grade II, III, or IV vesicoureteral reflux. There was insufficient evidence for the FDA to approve its use in grade V reflux.

Grade I Grade II Grade III Grade IV Grade V

Bladder

Ureter

Vesicoureteralreflux

Kidney

Renalpelvis

Reflux into a ureter without dilatation

Reflux into the renal pelvis and calyces without

dilatation

Mild-to-moderate dilatation of the

ureter, renal pelvis, and calyces with minimal blunting

of the fornices

Moderate ureteral tortuosity and

dilatation of the renal pelvis and

calyces

Gross dilatation of the ureter, pelvis,

and calyces; loss of papillary impres-

sions; and ureteral tortuosity

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Vesicoureteral Reflux

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Figure2.InternationalClassificationofVesicoureteralReflux.

During voiding cystourethrography, the bladder is filled with a radiocontrast agent through a urethral catheter and the distribution of the contrast material is observed on fluoroscopy. Retrograde filling of the upper urinary tract is diagnostic of vesicoureteral reflux, which is graded in severity from I to V as indicated.





STING Technique HIT Technique

A

B

C

D

Figure3.EndoscopicCorrectionofVesicoureteralReflux.

In Panel A, a gel consisting of dextranomer microspheres suspended in hyaluronic acid (Deflux) is injected at the ureterovesical junction just below the ureteral orifice, a procedure that was given the acronym STING (for subureteral Teflon injection, because of the material that was originally used). In Panel B, the injection of the gel results in the buttressing of the distal ureter and narrowing of the uretero-vesical junction. The ureteral orifice may have a volcano-like appearance after completion of the procedure. In Panel C, in a modification of the STING procedure that is termed HIT (hydrodistention implantation technique), cystoscopic irrigation is performed in order to hydro-distend the ureter so that the injection needle can enter the tunnel. In Panel D, the injection needle is positioned within the distal ureter, resulting in protrusion of the ureteral mucosa to create a mound. In a further elaboration of this approach, two injections are performed, one more proximally and one more distally within the ureter (the double-HIT technique).

Children undergoing endoscopic treatment for vesicoureteral reflux should have results from re-cent voiding cystourethrography for delineation of anatomy (e.g., paraureteral diverticulum, occult duplication) available for review. Depending on the clinical presentation and severity of renal scarring, preprocedural laboratory testing may include a complete blood count; measurement of electrolyte, blood urea nitrogen, and creatinine levels; urinaly-sis; and urine culture. Patients with fever or other signs of acute infection should not undergo the procedure until the infection has been treated and resolved.

Endoscopic treatment is carried out under gen-eral anesthesia in an operating room with the pa-

tient in the lithotomy position. Prophylactic in-travenous antibiotics (cefazolin at a dose of 50 mg per kilogram of body weight) are administered. The procedure is performed through a cystoscope under direct visualization of the ureterovesical junction. The dextranomer–hyaluronic acid copoly-mer gel is injected with the use of a 23-gauge needle attached to a syringe through an injection catheter. For the STING technique, the needle is positioned immediately beneath the ureteral ori-fice at the 6 o’clock position. With injection, a localized mound is created, causing the orifice to become volcano-shaped (Fig. 3A and 3B). In the HIT technique, the needle is placed within the ureteral orifice beneath the mucosa at the





6 o’clock position. In some cases, the HIT tech-nique requires hydrodistention of the ureter with cystoscopic irrigation. With injection, the ure-teral mucosa protrudes toward the ureteral ori-fice, producing a moundlike elevation with ure-teral narrowing (Fig. 3C). In a further elaboration of this approach, two injections are performed, one proximally and one more distally, within the ureter (the double-HIT technique). The volume of dextranomer–hyaluronic acid (available in 1-ml vials) that is injected varies according to the procedure, the severity of reflux, and the sur-geon’s preference but may range from 0.5 to 2.0 ml per ureter.37-39 Some, but not all, investigators have found a correlation between greater injec-tion volume and procedural success.37,40

After the procedure, patients are maintained on antibiotic prophylaxis (trimethoprim–sulfa-methoxazole or nitrofurantoin) until correction of the reflux has been confirmed on follow-up radionuclide cystography or voiding cystourethrog-raphy 3 months after the procedure. Some cen-ters recommend confirmatory radionuclide cys-tography at 1 year. In the event of a failed first injection, a second injection may be considered, but the success rate decreases to 50 to 60%. The success rate with a third injection is approxi-mately 30% and is therefore not advised.41

In a U.S. analysis conducted in 2002, the aver-age cost of endoscopic correction of vesicoureteral reflux with dextranomer–hyaluronic acid was esti-mated at $6,530 per patient, with the assumption that 40% of procedures were bilateral and that postinjection follow-up was included.42 In anoth-er U.S. study of data from 2002 to 2007, the aver-age actual reimbursement for endoscopic treat-ment of unilateral reflux was estimated at $4,259 per patient.43 An important variable in the cost of the procedure is the cost of the dextranomer–hyaluronic acid, which is currently approximately $1,900 per single-use vial. A study examining pro-cedures that were performed between 2003 and 2008 noted a 33% increase in the number of vials of dextranomer–hyaluronic acid used per patient, from 1.67 to 2.22.44

A dv er se Effec t s

The most common adverse effects of endoscopic treatment for vesicoureteral reflux include transient hydronephrosis, febrile urinary tract infection, hematuria, flank pain, and emesis. These com-

plications, which are typically short-lived and without long-term sequelae, have been reported in fewer than 10% of patients in several large series.25,34,37,45,46

The most serious complication of any antireflux procedure is persistent obstruction of the uretero-vesical junction. Such obstruction may cause se-vere hydronephrosis and irreversible damage to the kidney. Oliguria or anuria with renal failure may occur if bilateral obstruction occurs. The 1997 guidelines of the American Urological Association reported a 2% rate of obstruction requiring reop-eration after ureteral reimplantation. For endo-scopic correction with dextranomer–hyaluronic acid, the incidence of significant postoperative obstruction is reported to be 0.7%.47 Such obstruc-tion may require either ureteral stenting for up to 6 weeks or open reoperation.48

An unexpected outcome of subureteric injection with dextranomer–hyaluronic acid is calcification of the submucosal mound, which has been ob-served as early as 3 years after injection.49 Because of its location at the ureterovesical junction, the calcified mound can mimic a distal ureteral calcu-lus in some patients and require diagnostic clari-fication to avoid unnecessary intervention.49-51

A r e a s of Uncerta in t y

As noted above, results of clinical trials suggest that endoscopic correction of vesicoureteral reflux is not appropriate for all patients with the disorder, since antimicrobial prophylaxis or even surveillance alone may have similar outcomes for many chil-dren.25-27 Selecting the right patient for the proce-dure remains an area of uncertainty. Intervention may not be necessary for children with milder grades of reflux, yet the procedure is typically more effective in such patients.39,52,53 Failure of anti-biotic prophylaxis is an indication for corrective surgery even though the frequency of urinary in-fections may not decrease after the procedure.35 Coexisting voiding dysfunction is not uncommon with vesicoureteral reflux but is a predictor of treat-ment failure and recurrent infection.33-35 Parental preferences can influence the decision to perform corrective surgery, but such preferences are sub-stantially affected by the guidance and informa-tion that the parents receive.54

The long-term durability of the endoscopic pro-cedure has not been well studied. Most series have reported success rates at 3 months, with few pre-





senting more long-term data. Reported rates of recurrence of vesicoureteral reflux range from 11 to 26% at 1 year after negative 3-month postopera-tive cystography24,55 to 13% at 2 to 5 years after negative cystography at both 3 and 12 months.45 These values suggest the need for adjustment of long-term success rates to more accurately rep-resent clinical outcomes to patients and their families. Approximately half of failures are at-tributed to anatomic shifting of the submucosal mound.33,56 It is possible that the HIT technique, by creating a larger mound that extends further into the ureteral orifice, might achieve more du-rable success, although very limited long-term follow-up data are available regarding this pro-cedure.57

Guidelines

In 2007, the National Institute for Health and Clin-ical Excellence (NICE) of Great Britain published guidelines for the management of urinary tract in-fection in children.58 These guidelines note that “current indications for surgery in the UK are symptomatic breakthrough urinary tract infections despite medical management and/or increased re-nal parenchymal defects,” but they conclude that “surgical management of vesicoureteral reflux is not routinely recommended.” The NICE guidelines were published before the completion of the Swed-ish Reflux Trial in Children, and they mention the need for randomized trials to evaluate the efficacy of endoscopic correction.

In 2010, the American Urological Association published its guidelines on management of pri-mary vesicoureteral reflux in children.12 The rec-ommendations are stratified into three categories (standard, recommendation, and option) on the basis of the current available evidence, with “stan-dard” being the most rigid statement policy. Ac-cordingly, in these guidelines, among patients with breakthrough febrile urinary tract infections while

receiving continuous antimicrobial prophylaxis, consideration of surgical intervention for curative therapy is a “recommendation,” whereas it is an “option” in patients with a single febrile break-through urinary tract infection and no evidence of preexisting or new renal cortical abnormalities; the other option in such cases is to change the prophylactic agent. The guidelines recommend treatment of bowel and bladder dysfunction, if present, before any surgical intervention. The panel acknowledges that the choice between open and endoscopic surgery reflects a balance between morbidity and efficacy, quoting a 98% success rate for open reimplantation versus 83% for endoscopic therapy after one injection.

R ecommendations

The patient described in the vignette is a good can-didate for surgical intervention because of her age, sex, breakthrough febrile urinary tract infection while receiving antimicrobial prophylaxis, grade of vesicoureteral reflux, and the presence of renal scarring. The age and sex are important because the vesicoureteral reflux has not improved during several years of conservative management and be-cause reflux nephropathy will place this patient at higher risk for pregnancy-related complications in adult life. We would therefore recommend inter-vention at this stage. It is important that the pe-diatric urologist have unbiased discussions with the patient and her family about the relative merits and risks of each surgical approach and the follow-up management, with a clear understanding that in selecting the endoscopic approach, morbidity is minimized at the cost of a reduced likelihood of success and indeterminate durability, as compared with the open surgical technique.

No potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

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