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Endoscopic Treatment of Primary Vesicoureteral Reflux

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

From the Department of Urology, Childrens Hospital Boston, Boston (D.A.D.); and the Division of Pediatric Nephrology, Childrens Hospital of Michigan, Wayne State University School of Medicine, Detroit (T.K.M.). Address reprint requests to Dr. Diamond at the Department of Urology, Childrens Hospital Boston, 300 Longwood Ave., Boston, MA 02115, or at david.diamond@childrens.harvard.edu. 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-99labeled 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 recently 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 Cl inic a l Probl em

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 infection2,4,5 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 voiding dysfunction (the inability to release urine with a coordinated bladder contraction 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 vesicoureteral 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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Pathoph ysiol o gy a nd Effec t of Ther a py

The normal ureterovesical junction prevents retrograde flow of urine to the kidneys by means of a flap-valve mechanism. This mechanism does not include a typical anatomical valve but instead relies on the length of the ureter in the bladder wall and submucosa (the tunnel), its oblique insertion, and the support of the detrusor muscle behind the ureter (Fig. 1). A rise in intravesical pressure 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 vesicoureteral reflux, which is much less common, results 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 paraureteral 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 distribution 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 unknown and has been attributed to immunologic mechanisms, macromolecules that are released owing to cell injury and mesangial dysfunction, vascular alterations, hypertension, and hemodynamic alterations.22 Long-term antimicrobial prophylaxis and surgical correction of vesicoureteral reflux have both
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been used in an attempt to lower the risks of recurrent urinary tract infection and reflux nephropathy. 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 consists 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

Cl inic a l E v idence
Relatively few trials have compared endoscopic correction of vesicoureteral reflux with other therapeutic 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 treatment, 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 recurrences more common in girls than in boys. New parenchymal damage was detected by renal scintigraphy 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 receiving endoscopic treatment and 38% of those receiving antibiotic therapy.28
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Ureter

Intramural ureter

Reflux

Submucosal ureter

Possible reflux

No reflux

Figure 1. Anatomy of the Ureterovesical Junction. 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.

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 systematic 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

Cl inic 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 reduce the severity of reflux itself, the clinical trials do not provide convincing evidence that either surgery or antibiotic prophylaxis can reduce the incidence of recurrent urinary tract infection or, more important, the incidence of renal damage, as compared with surveillance alone. In addition, it is important to recognize that vesicoureteral reflux has
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a tendency to resolve in many patients with conservative management.7-9 However, the currently available data do not answer the question of whether more selective intervention may be helpful for the subgroup of patients at greatest risk for complications, 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 therapy), for those who cannot or do not consistently use antimicrobial therapy, and for those with progressive renal scarring.14 We also consider surgical repair in girls with vesicoureteral reflux that persists as puberty approaches. Voiding dysfunction is a relative contraindication to surgical correction of reflux because the likelihood of treatment failure and recurrent urinary tract infection is substantially increased.33-35 It is generally recommended that patients with bowel and bladder dysfunction undergo treatment

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Kidney Renal pelvis

Ureter

Bladder

Vesicoureteral reflux

Grade I
Reflux into a ureter without dilatation

Grade II
Reflux into the renal pelvis and calyces without dilatation

Grade III
Mild-to-moderate dilatation of the ureter, renal pelvis, and calyces with minimal blunting of the fornices

Grade IV
Moderate ureteral tortuosity and dilatation of the renal pelvis and calyces

Grade V
Gross dilatation of the ureter, pelvis, and calyces; loss of papillary impressions; and ureteral tortuosity

Figure 2. International Classification of Vesicoureteral Reflux. 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.

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 anticholinergic medications or alpha-blockers, and treatment of constipation.12 Open ureteral reimplantation has a 98% success rate in the definitive elimination of vesicoureteral 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 contraindications to its use. These include anatomic variants of the ureterovesical junction and severe vesicoureteral 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 nonfunctioning kidneys, paraureteral bladder diverticula, duplicated ureters, active voiding dysfunction,
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and ongoing urinary tract infection as contraindications for the endoscopic procedure. Endoscopic correction of vesicoureteral reflux was first described in 1984.36 The first procedures involved cystoscopic injection of polytetrafluoroethylene (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 injection 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 systemic circulation, alternative substances were developed. In 1995, the use of dextranomerhyalVersion 4 03/13/12 uronic acid (Deflux) was first described.24 Deflux Author Diamond obtained FDA approval in 2001 and remains the Fig # 2 Title Vesicoureteral Reflux only approved substance for endoscopic correction ME MP of grade II, III, or IV vesicoureteral reflux. There Jarcho DE Artist LAM was insufficient evidence for the FDA to approve AUTHOR PLEASE NOTE: Figure has been redrawn and type has been reset its use in grade V reflux. Please check carefully
COLOR FIGURE

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STING Technique
A C

HIT Technique

Figure 3. Endoscopic Correction of Vesicoureteral Reflux. 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 ureterovesical 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 hydrodistend 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 recent 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; urinalysis; 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 general anesthesia in an operating room with the pa1222
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tient in the lithotomy position. Prophylactic intravenous 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 dextranomerhyaluronic acid copolymer 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 orifice at the 6 oclock 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
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6 oclock position. In some cases, the HIT technique requires hydrodistention of the ureter with cystoscopic irrigation. With injection, the ureteral mucosa protrudes toward the ureteral orifice, producing a moundlike elevation with ureteral 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 dextranomerhyaluronic acid (available in 1-ml vials) that is injected varies according to the procedure, the severity of reflux, and the surgeons 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 injection volume and procedural success.37,40 After the procedure, patients are maintained on antibiotic prophylaxis (trimethoprimsulfamethoxazole or nitrofurantoin) until correction of the reflux has been confirmed on follow-up radionuclide cystography or voiding cystourethrography 3 months after the procedure. Some centers recommend confirmatory radionuclide cystography 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 approximately 30% and is therefore not advised.41 In a U.S. analysis conducted in 2002, the average cost of endoscopic correction of vesicoureteral reflux with dextranomerhyaluronic acid was estimated at $6,530 per patient, with the assumption that 40% of procedures were bilateral and that postinjection follow-up was included.42 In another U.S. study of data from 2002 to 2007, the average actual reimbursement for endoscopic treatment 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 procedures that were performed between 2003 and 2008 noted a 33% increase in the number of vials of dextranomerhyaluronic acid used per patient, from 1.67 to 2.22.44

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 ureterovesical junction. Such obstruction may cause severe 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 reoperation after ureteral reimplantation. For endoscopic correction with dextranomerhyaluronic acid, the incidence of significant postoperative obstruction is reported to be 0.7%.47 Such obstruction may require either ureteral stenting for up to 6 weeks or open reoperation.48 An unexpected outcome of subureteric injection with dextranomerhyaluronic acid is calcification of the submucosal mound, which has been observed as early as 3 years after injection.49 Because of its location at the ureterovesical junction, the calcified mound can mimic a distal ureteral calculus in some patients and require diagnostic clarification to avoid unnecessary intervention.49-51

A r e a s of Uncer ta 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 children.25-27 Selecting the right patient for the procedure 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 antibiotic prophylaxis is an indication for corrective surgery even though the frequency of urinary infections may not decrease after the procedure.35 Coexisting voiding dysfunction is not uncommon with vesicoureteral reflux but is a predictor of treatment failure and recurrent infection.33-35 Parental preferences can influence the decision to perform corrective surgery, but such preferences are substantially affected by the guidance and information that the parents receive.54 The long-term durability of the endoscopic procedure has not been well studied. Most series have reported success rates at 3 months, with few premarch 29, 2012

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 comn engl j med 366;13

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senting more long-term data. Reported rates of recurrence of vesicoureteral reflux range from 11 to 26% at 1 year after negative 3-month postoperative 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 represent clinical outcomes to patients and their families. Approximately half of failures are attributed 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 durable success, although very limited long-term follow-up data are available regarding this procedure.57

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 breakthrough 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.

Guidel ine s
In 2007, the National Institute for Health and Clinical Excellence (NICE) of Great Britain published guidelines for the management of urinary tract infection 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 renal 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 Swedish 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 primary vesicoureteral reflux in children.12 The recommendations are stratified into three categories (standard, recommendation, and option) on the basis of the current available evidence, with standard being the most rigid statement policy. Accordingly, in these guidelines, among patients with breakthrough febrile urinary tract infections while
References
1. Lebowitz RL. The detection and char-

R ec om mendat ions
The patient described in the vignette is a good candidate 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 because reflux nephropathy will place this patient at higher risk for pregnancy-related complications in adult life. We would therefore recommend intervention at this stage. It is important that the pediatric 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.

acterization of vesicoureteral reflux in the child. J Urol 1992;148:1640-2. 2. Sargent MA. What is the normal prevalence of vesicoureteral reflux? Pediatr Radiol 2000;30:587-93. 3. Venhola M, Hannula A, Huttunen NP, et al. Occurrence of vesicoureteral reflux in children. Acta Paediatr 2010;99:1875-8.

4. Wu CY, Chiu PC, Hsieh KS, Chiu CL,

Shih CH, Chiou YH. Childhood urinary tract infection: a clinical analysis of 597 cases. Acta Paediatr Taiwan 2004;45:328-33. 5. Chand DH, Rhoades T, Poe SA, Kraus S, Strife CF. Incidence and severity of vesicoureteral reflux in children related to age, gender, race and diagnosis. J Urol 2003; 170:1548-50.

6. Skoog SJ, Belman AB. Primary vesico-

ureteral reflux in the black child. Pediatrics 1991;87:538-43. 7. Schwab CW Jr, Wu HY, Selman H, Smith GH, Snyder HM 3rd, Canning DA. Spontaneous resolution of vesicoureteral reflux: a 15-year perspective. J Urol 2002; 168:2594-9. 8. Birmingham Reflux Study Group.

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Prospective trial of operative versus nonoperative treatment of severe vesicoureteric reflux in children: five years observation. Br Med J (Clin Res Ed) 1987;295: 237-41. 9. Tamminen-Mbius T, Brunier E, Ebel KD, et al. Cessation of vesicoureteral reflux for 5 years in infants and children allocated to medical treatment: the International Reflux Study in Children. J Urol 1992;148:1662-6. 10. Cooper CS. Diagnosis and management of vesicoureteral reflux in children. Nat Rev Urol 2009;6:481-9. 11. Schwentner C, Oswald J, Lunacek A, et al. Health-related quality of life in children with vesicoureteral reflux impact of successful endoscopic therapy. J Pediatr Urol 2008;4:20-6. 12. Peters CA, Skoog SJ, Arant BS Jr, et al. Summary of the AUA Guideline on Management of Primary Vesicoureteral Reflux in Children. J Urol 2010;184:1134-44. 13. Shaikh N, Ewing AL, Bhatnagar S, Hoberman A. Risk of renal scarring in children with a first urinary tract infection: a systematic review. Pediatrics 2010; 126:1084-91. 14. Mattoo TK. Vesicoureteral reflux and reflux nephropathy. Adv Chronic Kidney Dis 2011;5:348-54. 15. Paquin AJ Jr. Ureterovesical anastomosis: the description and evaluation of a technique. J Urol 1959;82:573-83. 16. Radmayr C, Schwentner C, Lunacek A, Karatzas A, Oswald J. Embryology and anatomy of the vesicoureteric junction with special reference to the etiology of vesicoureteral reflux. Ther Adv Urol 2009; 1:243-50. 17. Tanagho EA, Guthrie TH, Lyon RP. The intravesical ureter in primary reflux. J Urol 1969;101:824-32. 18. Khoury A, Bagli DG. Reflux and megaureter. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA, eds. CampbellWalsh urology. 9th ed. Philadelphia: Saunders, 2007:3423-81. 19. Lebowitz RL, Olbing H, Parkkulainen KV, Smellie JM, Tamminen-Mbius TE. International system of radiographic grading of vesicoureteric reflux: International Reflux Study in Children. Pediatr Radiol 1985;15:105-9. 20. Ransley PG, Risdon RA. Reflux nephropathy: effects of antimicrobial therapy on the evolution of the early pyelonephritic scar. Kidney Int 1981;20:733-42. 21. Swerkersson S, Jodal U, Sixt R, Stokland E, Hansson S. Relationship among vesicoureteral reflux, urinary tract infection and renal damage in children. J Urol 2007;178:647-51. 22. Cotran RS. Glomerulosclerosis in reflux nephropathy. Kidney Int 1982;21:52834. 23. Politano VA, Leadbetter WF. An operative technique for the correction of vesicoureteral reflux. J Urol 1958;79:932-41.
24. Stenberg A, Lckgren G. A new bioim39. Dave S, Lorenzo AJ, Khoury AE, et al.

plant for the endoscopic treatment of vesicoureteral reflux: experimental and shortterm clinical results. J Urol 1995;154:800-3. 25. Holmdahl G, Brandstrm P, Lckgren G, et al. The Swedish reflux trial in children: II. vesicoureteral reflux outcome. J Urol 2010;184:280-5. 26. Brandstrm P, Esbjrner E, Herthelius M, Swerkersson S, Jodal U, Hansson S. The Swedish reflux trial in children: III. Urinary tract infection pattern. J Urol 2010; 184:286-91. 27. Brandstrm P, Nevus T, Sixt R, Stokland E, Jodal U, Hansson S. The Swedish reflux trial in children: IV. Renal damage. J Urol 2010;184:292-7. 28. Capozza N, Caione P. Dextranomer/ hyaluronic acid copolymer implantation for vesico-ureteral reflux: a randomized comparison with antibiotic prophylaxis. J Pediatr 2002;140:230-4. 29. Routh JC, Inman BA, Reinberg Y. Dextranomer/hyaluronic acid for pediatric vesicoureteral reflux: systematic review. Pediatrics 2010;125:1010-9. 30. Alon US, Hoberman A, Dairiki Shortliffe LM. Treatment of a 6-year-old girl with vesicoureteral reflux. N Engl J Med 2011;365:266-70. 31. Lorenzo AJ. Medical versus surgical management for vesicoureteric reflux: the case for medical management. Can Urol Assoc J 2010;4:276-8. 32. Khalil BA, Goyal A, Dickson AP. Surgical intervention in children with vesicoureteric reflux: are we intervening too late? Pediatr Surg Int 2010;26:729-31. 33. Higham-Kessler J, Reinert SE, Snodgrass WT, et al. A review of failures of endoscopic treatment of vesicoureteral reflux with dextranomer microspheres. J Urol 2007;177:710-4. 34. Capozza N, Lais A, Matarazzo E, Nappo S, Patricolo M, Caione P. Influence of voiding dysfunction on the outcome of endoscopic treatment for vesicoureteral reflux. J Urol 2002;168:1695-8. 35. Traxel E, DeFoor W, Reddy P, Sheldon C, Minevich E. Risk factors for urinary tract infection after dextranomer/hyaluronic acid endoscopic injection. J Urol 2009;182: Suppl:1708-12. 36. Puri P, ODonnell B. Correction of experimentally produced vesicoureteric reflux in the piglet by intravesical injection of Teflon. Br Med J (Clin Res Ed) 1984; 289:5-7. 37. Kirsch AJ, Perez-Brayfield M, Smith EA, Scherz HC. The modified STING procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol 2004;171:2413-6. 38. Puri P, Chertin B, Velayudham M, Dass L, Colhoun E. Treatment of vesicoureteral reflux by endoscopic injection of dextranomer/hyaluronic acid copolymer: preliminary results. J Urol 2003;170:1541-4.

Learning from the learning curve: factors associated with successful endoscopic correction of vesicoureteral reflux using dextranomer/hyaluronic acid copolymer. J Urol 2008;180:Suppl:1594-9. 40. Gupta A, Snodgrass W. Intra-orifice versus hydrodistention implantation technique in dextranomer/hyaluronic acid injection for vesicoureteral reflux. J Urol 2008;180:Suppl:1589-92. 41. Elder JS, Diaz M, Caldamone AA, et al. Endoscopic therapy for vesicoureteral reflux: a meta-analysis: I. Reflux resolution and urinary tract infection. J Urol 2006; 175:716-22. 42. Kobelt G, Canning DA, Hensle TW, Lckgren G. The cost-effectiveness of endoscopic injection of dextranomer/hyaluronic acid copolymer for vesicoureteral reflux. J Urol 2003;169:1480-4. 43. Saperston K, Smith J, Putman S, et al. Endoscopic subureteral injection is not less expensive than outpatient open reimplantation for unilateral vesicoureteral reflux. J Urol 2008;180:Suppl:1626-9. 44. Sorensen MD, Koyle MA, Cowan CA, Zamilpa I, Shnorhavorian M, Lendvay TS. Injection volumes of dextranomer/hyaluronic acid are increasing in the endoscopic management of vesicoureteral reflux. Pediatr Surg Int 2010;26:509-13. 45. Lckgren G, Whlin N, Skldenberg E, Stenberg A. Long-term followup of children treated with dextranomer/hyaluronic acid copolymer for vesicoureteral reflux. J Urol 2001;166:1887-92. 46. Capozza N, Lais A, Nappo S, Caione P. The role of endoscopic treatment of vesicoureteral reflux: a 17-year experience. J Urol 2004;172:1626-8. 47. Vandersteen DR, Routh JC, Kirsch AJ, et al. Postoperative ureteral obstruction after subureteral injection of dextranomer/ hyaluronic acid copolymer. J Urol 2006; 176:1593-5. 48. Snodgrass WT. Obstruction of a dysmorphic ureter following dextranomer/ hyaluronic acid copolymer. J Urol 2004; 171:395-6. 49. Cerwinka WH, Kaye JD, Scherz HC, Kirsch AJ, Grattan-Smith JD. Radiologic features of implants after endoscopic treatment of vesicoureteral reflux in children. AJR Am J Roentgenol 2010;195:234-40. 50. Nelson CP, Chow JS. Dextranomer/ hyaluronic acid copolymer (Deflux) implants mimicking distal ureteral calculi on CT. Pediatr Radiol 2008;38:104-6. 51. Noe HN. Calcification in a Deflux bleb thought to be a ureteral calculus in a child. J Pediatr Urol 2008;4:88-9. 52. Lorenzo AJ, Pippi Salle JL, Barroso U, et al. What are the most powerful determinants of endoscopic vesicoureteral reflux correction? Multivariate analysis of a single institution experience during 6 years. J Urol 2006;176:1851-5. 53. Yucel S, Gupta A, Snodgrass W. Multi-

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variate analysis of factors predicting success with dextranomer/hyaluronic acid injection for vesicoureteral reflux. J Urol 2007;177:1505-9. 54. Krill AJ, Pohl HG, Belman AB, et al. Parental preferences in the management of vesicoureteral reflux. J Urol 2011;186: 2040-4. 55. Lee EK, Gatti JM, Demarco RT, Murphy JP. Long-term followup of dextranomer/ hyaluronic acid injection for vesicoureteral reflux: late failure warrants continued followup. J Urol 2009;181:1869-74. 56. Diamond DA, Caldamone AA, Bauer SB, Retik AB. Mechanisms of failure of endoscopic treatment of vesicoureteral reflux based on endoscopic anatomy. J Urol 2003;170:1556-8. 57. Kalisvaart JF, Scherz HC, Cuda S, Kaye JD, Kirsch AJ. Intermediate to longterm follow-up indicates low risk of recurrence after Double HIT endoscopic treatment for primary vesico-ureteral reflux. J Pediatr Urol 2011 August 3 (Epub ahead of print). 58. National Institute for Health and Clinical Excellence. Urinary tract infection in children (CG54). August 2007 (http://www.nice.org.uk/CG54).
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