Endoscopic Treatment of Vesicoureteral Reflux

ANGELA M. ARLEN

ANDREW J. KIRSCH

Vesicoureteral reflux (VUR) is the retrograde flow of urine from the bladder to the upper urinary tract and is one of the most common urologic diagnoses affecting children, with an estimated prevalence of 0.4% to 1.8% in the general pediatric population and 30% in those with a history of febrile urinary tract infection (UTI) (1,2). VUR is a risk factor for pyelonephritis, which can lead to renal scarring and subsequent complications such as hypertension, proteinuria, and even chronic kidney disease (3). VUR is one of several modifiable risk factors in the development of UTI. The goal of VUR treatment is to prevent pyelonephritis and preserve renal function. Management options include observation with or without continuous antibiotic prophylaxis and surgical correction via endoscopic, open, or laparoscopic/robotic approaches. Surgical intervention may be necessary in children with persistent reflux, renal scarring, or recurrent febrile UTIs. An individualized risk-based approach that takes into consideration a multitude of demographic, radiographic, and clinical factors should guide management (4).

Endoscopic treatment of VUR is an outpatient procedure associated with decreased morbidity compared to ureteral reimplantation. Endoscopic injection for VUR was introduced in 1981 as an investigational method with the first clinical experience published in 1984 (5,6). Over the past three decades, both injection techniques and bulking agents have significantly improved, which has resulted in higher treatment success rates (7,8). The success rate of outpatient endoscopic treatment of VUR approaches that of open ureteral reimplantation and offers considerable advantages to patients including limited morbidity, fewer complications, and reduced cost. Endoscopic injection has become an increasingly common method of correcting VUR because of its minimal invasiveness and high success rates (9).

DIAGNOSIS

Contrast voiding cystourethrogram (VCUG) has long been a mainstay of VUR diagnosis. Advantages include the ability to grade the severity of reflux based on a standardized international scale, visualization of bladder anatomy, and assessment of the urethra during voiding (10). VUR can also be diagnosed via radionuclide cystography (RNC), which has comparable sensitivity to VCUG (11). VUR grading system conveys clinical significance not only for spontaneous resolution but also for treatment method and outcome (4,12). VCUGs performed with a single cycle of filling and voiding show false negatives up to 15% to 20%; for improved sensitivity, cyclic VCUGs consisting of three voiding cycles are recommended (13,14).

Approximately 30% to 40% of children with febrile UTIs are subsequently diagnosed with VUR. Children who experience recurrent febrile UTIs without evidence of VUR by VCUG may suffer from occult VUR. It is conceivable that despite negative conventional VCUG, occult VUR is clinically significant. One method to diagnose occult VUR is the positional instillation of contrast cystography (PICC). The tip of the cystoscope is positioned at the ureteral orifice and contrast instilled at full flow with a pressure of 80 cm of water. A patient is designated PICC-positive if contrast is seen in the ureter (15). An alternative approach for the diagnosis of occult VUR is hydrodistention of the distal ureter, thus avoiding the use of contrast and ionizing radiation. The degree of hydrodistention has been shown to correlate with the presence of occult reflux. VUR may be incidentally discovered by a VCUG obtained for reasons other than febrile UTIs, such as posterior urethral valves, patent urachus, or suspected bladder rupture.

The obligation to diagnose VUR in asymptomatic patients (no history of febrile UTIs, prenatally diagnosed hydronephrosis, sibling screening) has been questioned because the natural history of asymptomatic VUR may be benign and treatment unnecessary. The “top-down approach” in the management of UTI attempts to distinguish clinically significant from insignificant VUR by evaluating kidneys for pyelonephritis and/or scarring with dimercaptosuccinic acid (DMSA) scans performed within weeks of the onset of acute pyelonephritis. A positive DMSA scan is an indication for VCUG, and consequently, 50% of “unnecessary” VCUGs can be avoided. The 2010 American Urological Association (AUA) Summary Guidelines recommend DMSA imaging in children with primary VUR in whom ultrasound is abnormal or there is greater concern for scarring due to breakthrough UTI, high-grade VUR, or elevated creatinine (16).

INDICATIONS FOR SURGERY

Spontaneous resolution of primary reflux is common secondary to remodeling of the ureterovesical junction (UVJ), elongation of the intravesical ureter, and stabilization of bladder voiding dynamics. Reflux resolution depends on multiple factors including initial grade of reflux, gender, age, voiding dysfunction, presence of renal scarring, and timing of VUR on VCUG (4,12). Management should therefore be individualized and based on patient age, health, VUR grade, clinical course, presence of renal scarring, and parental preference. Surgical intervention may be necessary in children with persistent reflux, renal scarring, or recurrent febrile UTIs.

While open ureteral reimplantation may be a good treatment option after failed injection therapy, endoscopic treatment has also been successfully employed after failed ureteral reimplantation (Table 93.1). Current evidence suggests that either antireflux surgery or continuous antibiotic prophylaxis reduces the incidence of new renal scarring when compared to observation alone (17); however, no study has demonstrated a reduction in the incidence of end-stage renal disease. Valuable goals of VUR treatment are to prevent UTIs, particularly pyelonephritis, to avoid long-term antibiotic prophylaxis, and to reduce the need for distressing VCUGs and radiation exposure. Proponents of the endoscopic approach argue that decreasing the incidence of febrile UTIs is the main goal of therapy. Recurrence, while possible, may occur in the absence of symptoms and be viewed as subclinical, similar to an individual with VUR diagnosed after a sibling screen or for fetal hydronephrosis. Proponents of the open surgical approach comment that ureteral reimplantation provides a permanent cure and is worth the increased morbidity to achieve this goal.

In terms of reducing the risk of UTI, endoscopic treatment may achieve this goal as well as or better than open surgery (8,16,18). Indications for surgical correction of VUR via open, robot-assisted laparoscopic, or endoscopic approach include moderate- to high-grade reflux (grades III to V), low probability of spontaneous resolution, renal scarring, recurrent pyelonephritis, breakthrough febrile UTI while on continuous antibiotic prophylaxis, and parental preference (19,20). While endoscopic injection has focused on the treatment of primary VUR, it was initially largely avoided for cases of complex VUR (i.e., VUR associated with functional or anatomic abnormalities such as neurogenic bladder or megaureters). In general, endoscopic treatment is emerging at many centers as the firstline surgical treatment modality of choice for VUR, whereas ureteral reimplantation remains reserved for cases of failed injection therapy, significant anatomic abnormalities (i.e., large paraureteral diverticula, ectopic ureters, megaureters), and surgeon or parental preference.

TABLE 93.1 SUCCESS RATES OF ENDOSCOPIC TREATMENT FOR PRIMARY AND COMPLEX VESICOURETERAL REFLUX

Reference	Indication	Bulking agent	Volume (mL)	Ureters	Follow-up (months)	Success (%)
Elder JS et al., 2006	Various	Various	0.2-1.7	8,101	Variable	85
Capozza N et al., 2004	Various	Various	0.2-2.2	1,694	12-204	77
Kirsch AJ et al., 2004	Various	Dx/HA	0.5-1.5	119	3-12	92
Kirsch AJ et al., 2006	Various	Dx/HA	0.8-2.0	139	3-18	93
Van Capelle JW et al., 2004	Primary	PDMS	0.2-2.0	311	3-110	75
Kajbafzadeh AM et al., 2006	Primary	Ca hydroxylapatite	0.4-0.6	364	6	69
Yu RN et al., 2006	Primary	Dx/HA	1.0	162	2-26	93
Puri P et al., 2006	Various	Dx/HA	0.2-1.5	1101	3-46	96
Lorenzo AJ et al., 2006	Various	PDMS	—	351	72	72
Pinto KJ et al., 2006	Primary	Dx/HA	—	86	3	84
Perez-Brayfield M et al., 2004	Neurogenic bladder	Dx/HA	0.4-2.0	9	3	78
Läckgren G et al., 2007	Voiding dysfunction	Dx/HA	—	74	12	83
Elmore JM et al., 2006	Failed initial injection	Dx/HA	1.0-1.5	53	3	89
Perez-Brayfield M et al., 2004	Failed reimplantation	Dx/HA	0.4-2.0	19	3	88
Kitchens D et al., 2006	Failed reimplantation	Dx/HA	0.7-3.8	20	19	83
Campbell JB et al., 2006	Renal transplantation	Dx/HA	—	11	—	55
Molitierno JA et al., 2007	Duplicated ureter	Dx/HA	0.8-2.8	63	1.3	85
Cerwinka WH et al., 2007	Paraureteral diverticulum	Dx/HA	0.8-1.8	20	6.6	81
Chertin B et al., 2007	Ureterocele	Various	—	44	1-21	91
Routh JC et al., 2010	Various	Dx/HA	—	7303	Variable	77
Hacker FM et al., 2011	Various	Dx/HA	—	174	18-100	98
Kaye JD et al., 2011	Primary	Dx/HA	Mean 1.3	521	12-36	90
Kalisvaart et al., 2011	Primary	Dx/HA	0.8-2.7	82	13-27	93
Meta-analysis by Elder JS et al. (25) summarizes results until 2003. Routh et al. (28), 2010, is a meta-analysis of Dx/HA studies published through 2008.
Success after one or several treatments in some studies.
Dx/HA, dextranomer/hyaluronic acid; PDMS, polydimethylsiloxane.