Technical Report:Pediatrics

Intraureteral Injection of NASHA/Dx Gel UnderDirect Ureteroscopic Visualization for the Treatment

of Primary High-Grade Vesicoureteral Reflux

Girolamo Mattioli, PhD,1 Edoardo Guida, MD,1 Valentina Rossi, MD,1 Emilio Podesta, MD,1

Vincenzo Jasonni, PhD,1 and Gian Marco Ghiggeri, MD2

Abstract

Objective: To present a preliminary experience with the modified technique of extravesical intraureteral injectionof non–animal-stabilized hyaluronic acid/dextranomer (NASHA/Dx) gel under direct ureteroscopic visuali-zation for the treatment of primary high-grade vesicoureteral reflux (VUR).Patients and Methods: The medical records of all pediatric patients (age range, 0–14 years) who underwentintraureteral injection of NASHA/Dx gel under direct ureteroscopic visualization for the treatment of primaryhigh-grade VUR during the period June 2006–June 2010 were reviewed.Results: Eighty-nine children (61 boys, 28 girls; M:F ratio, 2.1) underwent intraureteral injection of NASHA/Dxgel under direct ureteroscopic visualization for the treatment of primary high-grade VUR during the studyperiod. VUR completely disappeared after the injection of NASHA/Dx gel into 105 (73%) of 144 ureters, with nofurther treatment required. Thirty-five (24.3%) required a second injection, and 2 (1.4%) required a third injectionfor resolution of their VUR. No intraoperative complications were observed. No ureteral obstruction duringfollow-up was observed using ultrasound or micturition studies.Conclusions: Intraureteral injection of NASHA/Dx gel under direct ureteroscopic visualization is safe andeffective in the treatment of primary high-grade VUR, including cases with ureteral duplication, if the ureteralmeatus is easy to pass through without mechanical dilation. This approach represents an effective and safealternative to antibiotic prophylaxis alone and open surgery.

Introduction

Vesicoureteral reflux (VUR) is the most commonurological abnormality seen in children, with an inci-

dence of about 1%–2%.1,2 Approximately 30%–40% of infantsand children with VUR present with urinary tract infections,secondary to VUR. The end result can be reflux nephropathy,a major cause of chronic renal failure.3

Non–animal-stabilized hyaluronic acid/dextranomer(NASHA/Dx) gel has been used successfully in Europe forover a decade for the endoscopic treatment of VUR. No long-term complications have been associated with its use.4,5 It is abiocompatible injectable agent that has been shown in animalmodels not to migrate from the injection site thanks to the sizeof the dextranomer microspheres.6,7

The procedure itself is well tolerated with a low risk ofassociated complications.4,8 The low morbidity associatedwith the endoscopic injection of these types of bulking agents

has encouraged many centers to recommend this approach asthe initial treatment for primary high-grade VUR instead ofantibiotic prophylaxis or re-implantation of the ureter.9–11

While biocompatible NASHA/Dx gel has become a popularsubureteral and intraureteral injectable agent for the endo-scopic treatment of VUR,5,12–15 its use for high-grade refluxhas not been standardized yet.

The purpose of this study is to present our preliminaryexperience with a modified technique of intraureteral extra-vesical injection of NASHA/Dx gel under direct uretero-scopic visualization for the treatment of primary high-gradeVUR in children.

Patients and Methods

The medical records of all pediatric patients (age range, 0–14 years) who underwent intraureteral injection of NASHA/Dx gel under direct ureteroscopic visualization in order to

1Paediatric Surgery and 2Paediatric Nephrology Departments, Giannina Gaslini Institute, University of Genoa, Genoa, Italy.

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treat primary high-grade VUR (grade 4–5) during the periodJune 2006–June 2010 at Gaslini Children’s Hospital andResearch Institute (Genoa, Italy) were reviewed. SymptomaticVUR was diagnosed by voiding cystourethrogram (VCUG)or ultrasound and classified according to the internationalclassification for VUR.10

Either a 99m-technetium-dimercaptosuccinic acid or amagnetic uroresonance was performed to evaluate the pres-ence of renal parenchymal scarring 4–6 months after a urinarytract infection. Patients with secondary VUR, including pos-terior urethral valve and neurogenic bladder, were excludedfrom the study because they first needed treatment for theprimary cause of VUR.

Follow-up consisted of periodic urinalysis, renal bladderultrasound 1 month after treatment, and VCUG and ultra-sound 4–6 months after the procedure and then 1 year afterthe procedure. Further endoscopic treatment was consideredif VUR persisted. Antibiotic prophylaxis was continued untilthe radiological follow-up and was suspended if VUR wasdisappeared.

Surgical technique

The patient is placed in the lithotomy position, and cysto-ureteroscopy is performed with a nonflexible pediatric ur-eteroscope 8–15 French (according to the patient’s age), 15�lens, with the patient under general anesthesia. Hydrodisten-tion of the distal ureter is created through a pressured streamby placing the tip of the ureteroscope at the ureteral orifice.Hydrodistention is graded according to the classification sys-tem developed by Kirsch et al.15 If hydrodistention allows in-sertion of the ureteroscope without mechanical dilation, theinjection of NASHA/Dx gel under direct ureteroscopic visu-alization of the intraureteral injection site is performed.

A ureteral catheter is introduced before the injectionsthrough the meatus into the ureteral lumen in order to iden-tify the level of the detrusor muscle. A flexible needle (OceanaTherapeutics Ltd., Edison, NJ) is used in order to perform theinjection. About 0.1–0.2 mL of NASHA/Dx gel is used foreach submucosal injection. In total, six submucosal injectionsare performed at different levels and sites (Fig. 1): twointraureteral, extravesical injections proximal to ureteral in-sertion into the vesical wall and detrusor muscle; two in-traureteral, intravesical injections at the level of the detrusormuscle; and the last two intravesical, subureteral, 2–3 mmbelow the refluxing orifice as described by Puri et al.4,11

Results

Eighty-nine children (61 boys, 28 girls; M:F ratio, 2.1) under-went intraureteral injection of NASHA/Dx gel under directureteroscopic visualization for the treatment of primary high-grade VUR during the study period. Patients’ ages rangedfrom 4 months to 15 years (median age, 3 years). The medianoperative time was 15 minutes (range, 5–25 minutes).

VUR was unilateral and bilateral in 34 (38.2%) and 55(61.8%) patients, respectively, resulting in 144 high-grade re-fluxing ureters. Ureteral duplication was present in 23 of 89patients (25.8%). In 27 of 55 patients with bilateral VUR(49.1%), a lower grade of VUR (grade 1–3) in one of two sideswas observed. In 42 of 89 patients (47.2%), a scarred kidneywas identified through 99m-technetium-dimercaptosuccinicacid scans.

VUR completely disappeared after the first injection ofNASHA/Dx gel in 105 of the 144 ureters (72.9%), thus re-quiring no further treatment, whereas a second injectionwas required in 35 (24.3%) and a third injection in 2 (1.4%)(Table 1).

Two patients underwent re-implantation of the ureter aftera single injection because of parental preference. One patientpresented with a new contralateral VUR during follow-upafter correction of unilateral VUR by a single endoscopic in-jection of NASHA/Dx. No intraoperative complications werereported. No ureteral obstruction during follow-up was ob-served using ultrasound or through the evaluation of urinaryflow rate. No major hematuria, postoperative infections, orurinary retention were seen. After VUR resolution, urinarytract infections were no longer described in any patient.

FIG. 1. Two submucosal extravesical injections are per-formed proximal to ureteral insertion into the vesical walland detrusor muscle. Two more intravesical injections areperformed at the level of the detrusor muscle, always sub-mucosally, and another two inside the meatus and sub-ureterally as described by O’Donnell and Puri.22

Table 1. Results of Endoscopic Treatment

of High-Grade Vesicoureteral Reflux Using

the Intraureteral, Direct Ureteroscopic, Multiple

Submucosal Non–Animal-Stabilized Hyaluronic

Acid/Dextranomer Gel Injections

Total n (%)

High-grade VUR patients 89Male 61 61/89 (68.5)Female 28 28/89 (31.5)

Unilateral VUR 34 34/89 (38.2)Bilateral VUR 55 55/89 (61.8)Numbers of ureters treated 144

Resolution after 1 procedure 105 105/144 (72.9)Resolution after 2 procedures 35 35/144 (24.3)Resolution after 3 procedures 2 2/144 (1.4)

Resolution rate 87 87/89 (97.8)Open surgery patients (after 1 injection

due to parents’ preference)2 2/89 (2.24)

Percentages are based on the number of total ureters treated.VUR, vesicoureteral reflux.

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Discussion

The current practice of low-dose, continuous antibioticprophylaxis for the treatment of VUR in children can resultin antibiotic resistance of common causative pathogensresponsible for urinary tract infections.16 Poor treatmentcompliance may also contribute to antibiotic resistance, asexposure to subtherapeutic levels of antibiotics encouragesthe development of resistant strains.17 Given the clinical andsocial ramifications of poor compliance with antibiotic treat-ments, there is a need for strategies to improve rates of com-pliance and/or for alternative therapies to deal with thisproblem.

Open surgery is costly, requires hospitalization, and resultsin postoperative pain as well as anxiety of both the child andthe caregiver. The two therapies for VUR (surgical ureteral re-implantation and endoscopic dextranomer–hyaluronic acidcopolymer injection) provide options that do not involvelong-term antibiotic prophylaxis. Compared with open sur-gery, endoscopic injection is minimally invasive, can be per-formed as an outpatient procedure, is cost-effective, andprovides VUR resolution rates are at least equivalent to sur-gery.18 These two options result in cure rates of 98% versus aspontaneous resolution rate of up to 50% over a year for pa-tients receiving prophylactic antibiotics.19

When given information on each of the two treatmentoptions, 80% of parents of patients with moderately severeVUR chose endoscopic injection.20 According to some stud-ies,10,12,21 the opinion of parents is important in the choice ofthe approach, and their clear preference for endoscopictreatment indicates a clear understanding of the minimallyinvasive nature of the procedure.

The rationale of our modified technique of injection can befound in the basic principles of treatment for primary high-grade VUR.12–15,21,22 Submeatal injection provides a solidsupport under the ureteral orifice, thus increasing the sub-mucosal length of the ureter, with resultant improvementof the anti-reflux valve mechanism.12,22 Intraureteral in-travesical injections at the level of the detrusor muscle allow areduction of the distal ureter lumen with a resultant lower riskof bolus dislodgement.12,23

The aim of our modified technique of submucosal in-traureteral extravesical injections proximal to ureteral in-sertion into the vesical wall and detrusor muscle on differentlevels, under direct visualization, is to obtain a lumen re-duction and remodeling of the ureteral wall as seen in theKalicinski ureteral folding technique for megaureter.24 In-jection on different axes allows the stacking-up of two bo-luses, thus reducing the risk of gel displacement or stricture.Direct ureteroscopic visualisation is mandatory to carefullyidentify intraureteral injection sites and to avoid ureteralobstruction.

Some reported studies do not recommend postoperativeVCUG if there are no clinical signs or symptoms.9,10,12 How-ever, we perform routine VCUG or ultrasound 4–6 monthsafter all procedures to confirm the surgical results.

This modified technique showed a high VUR resolutionrate (73%) after one injection of NASHA/Dx gel with asmaller complication rate compared with open surgery. Theprocedure can be easily repeated in case of persistence of re-flux.10 Moreover, open surgery following injection treatmentdid not represent a more difficult procedure in our experience.

In conclusion, thanks to the optimal results obtained over a4-year period, we have standardized our modified techniqueeven for high-grade primary VUR, including ureteral dupli-cation. Intraureteral injection of NASHA/Dx gel under directureteroscopic visualization is safe and effective if the meatusis easy to pass through without mechanical dilation, thus re-presenting an effective and safe alternative to antibiotic pro-phylaxis alone and open surgery.

Disclosure Statement

No competing financial interests exist.

References

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Address correspondence to:Girolamo Mattioli, MD

Paediatric Surgery DepartmentDINOGMI

Giannina Gaslini Children’s Hospital and Research InstituteLargo G. Gaslini 5, 16147

University of GenoaItaly

E-mail: girolamomattioli@ospedale-gaslini.ge.it

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