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Late Ureteral Obstruction After Endoscopic Treatment of Vesicoureteral Reflux With Polyacrylate Polyalcohol Copolymer
Pediatric Urology Late Ureteral Obstruction After Endoscopic Treatment of Vesicoureteral Reflux With Polyacrylate Polyalcohol Copolymer € ur Ozkan, €lya Yıldırım, Keramettin Ug Arzu S¸encan, Hu Bas¸ak Uc¸an, Aytac¸ Karkıner, and €r €nevver Hos¸go Mu OBJECTIVE
PATIENTS AND METHODS
RESULTS
CONCLUSION
To investigate the incidence and presentation of ureteral obstruction after endoscopic injection of polyacrylate polyalcohol copolymer (PPC) for the treatment of vesicoureteral reflux, and to analyze its possible causes, together with histopathologic assessment. The data of 189 patients who underwent endoscopic injection of PPC between May 2011 and December 2013 were retrospectively reviewed. After the injection, patients were followed up by urinalysis and ultrasonography monthly for 3 months. Control voiding cystouretrography was performed in the third postoperative month. Patients were then followed up by ultrasound every 3 months. If a new-onset hydroureteronephrosis (HUN) was observed, control ultrasound was performed monthly to follow the change in the degree of HUN. If a moderate or severe HUN was observed, technetium-99m mercaptoacetyltriglycine or dimercaptosuccinic acid scintigraphy was performed. For patients who needed open surgery, Cohen ureteroneocystostomy was performed. The distal 1 cm of the ureters was resected and examined histopathologically. One hundred eighty-nine patients with 268 refluxing ureters underwent endoscopic injection of PPC. Ureteral obstruction was observed in 3 ureters (1.1%), in 3 female patients of whom the degrees of reflux were grade 4, 5, and 5, respectively. Obstruction showed late onset in all 3 patients. Manifestations of obstruction included pain in 2 patients and recurrent febrile urinary tract infection with loss of function in scintigraphy in 1. All 3 patients underwent open ureteroneocystostomy. PPC may cause ureteral obstruction several months or even years after injection. Patients who undergo endoscopic treatment of PPC need long-term follow-up, despite reflux showing complete resolution. UROLOGY 84: 1188e1193, 2014. 2014 Elsevier Inc.
E
ndoscopic injection has proved to be a highly successful minimally invasive treatment for the correction of vesicoureteral reflux (VUR). With the development of new substances, subureteral injection of bulking agents has become a very popular alternative to ureteral reimplantation. Polyacrylate polyalcohol copolymer (PPC) (Vantris, Promedon, Cordoba, Argentina) is the newest injection material used in the endoscopic treatment. It is a nonbiodegradable substance of synthetic origin belonging to the acrylic family. It leads to the formation of a fibrotic capsule that can result in better
Financial Disclosure: The authors declare that they have no relevant financial interests. _ From the Department of Pediatric Surgery, Dr. Behc¸et Uz Children’s Hospital, Izmir, _ Turkey; and the Department of Pathology, Dr. Behc¸et Uz Children’s Hospital, Izmir, Turkey Address correspondence to: Arzu S¸encan, M.D., Department of Pediatric Surgery, _ Dr. Behc¸et Uz Children’s Hospital, Ismet Kaptan Mah. Sezer Dog an Sok. No: 11, _ 35210, Alsancak, Konak, Izmir 35350, Turkey. E-mail: [email protected] Submitted: May 21, 2014, accepted (with revisions): July 15, 2014
1188
ª 2014 Elsevier Inc. All Rights Reserved
stability and long-term durability in treating VUR. PPC particles have an average diameter of 300 mm. Therefore, the expected risk of migration is low.1 Very few studies about ureteral obstruction after endoscopic treatment of VUR with PPC have been reported in the literature before.2,3 Therefore, in this study, we aimed to report our cases of ureteral obstruction after injection of PPC, together with presenting patterns and histopathologic assessments.
PATIENTS AND METHODS The data of 189 patients who underwent endoscopic injection of PPC at our institution between May 2011 and December 2013 were retrospectively reviewed. All the patients who were included in this study had VUR determined by voiding cystouretrography (VCUG) and renal scarring in radionuclide scintigraphy. The reflux grade in VCUG was based according to the International Classification System (International Reflux Study Committee). Renal scarring in dimercaptosuccinic acid http://dx.doi.org/10.1016/j.urology.2014.07.030 0090-4295/14
Table 1. Characteristics of patients with ureteral obstruction after injection of polyacrylate polyalcohol copolymer Characteristic Age, y Sex Side and grade of VUR Side of obstruction Renal scarring Injected volume, mL Injection technique Number of injections Ureteral orifice configuration Associated condition Presentation Time of obstruction after injection, mo Treatment Follow-up period, mo
Patient 1
Patient 2
Patient 3
5 F Left, 4 Left Moderate 0.5 STING 1 Golf hole None Abdominal pain 6 Ureteral stent placement þ UNC 18
5 F Right, 5 Right Moderate 0.6 STING 1 Golf hole None Abdominal pain 24 UNC 32
3 F Left, 5 Left Mild 0.4 STING 2 Golf hole None Recurrent febrile UTI 6 UNC 8
F, female; STING, subureteric transurethral injection; UNC, ureteroneocystostomy; UTI, urinary tract infection; VUR, vesicoureteral reflux.
(DMSA) scintigraphy was classified in 3 groups: mild (focal defects with uptake between 40% and 45%), moderate (uptake of renal radionuclide between 20% and 40%), and severe (shrunken kidney with relative uptake <20%).4 Indications for surgical intervention were breakthrough urinary tract infection (UTI), progressive renal scarring, and nonresolution of VUR. Endoscopic treatment was performed under general anesthesia with a pediatric cystoscope (KARL STORZ GmbH & Co KG) using a technique similar to that described in the literature.5,6 The usual technique of subureteric transurethral injection, with the needle introduced submucosally under the ureteral orifice at the 6-o’clock position was used except for 6 patients with grade 4 and grade 5 VUR and a widely open orifice, in whom the injection was performed with the hydrodistention implantation technique. The agent was continued to be injected until the “volcanic” bulge was observed, raising the ureteral meatus onto the dome of the mound. Patients were discharged from the hospital the next day after the surgery. They were observed with urinalysis, renal and bladder ultrasound monthly for 3 months, and VCUG in the third postoperative month. Patients were maintained under antibiotic prophylaxis until the reflux was documented to resolve on postoperative cystogram. Patients were then followed up by ultrasound every 3 months. If a new-onset hydroureteronephrosis (HUN) was observed, control ultrasound was performed monthly to follow the degree of HUN. If a moderate or severe HUN was observed, technetium-99m mercaptoacetyltriglycine scintigraphy was added to the follow-up protocol. For patients who needed open surgery, open Cohen transtrigonal ureteroneocystostomy was performed. The distal 1 cm of the ureters was resected during surgery and assessed histopathologically. The specimens were stained with hematoxylin eosin and trichrome to assess for fibrosis. The ureteral mucosa, submucosa, the presence of chronic inflammation and granuloma, and the presence and localization of the injected material were assessed by a single pathologist.
RESULTS One hundred fourteen female (60%) and 75 male (40%) patients, a total of 189 patients with a median age of 5.5 years (4 months-15 years) underwent subureteric injection of PPC in our clinic. VUR was unilateral in 110 patients (58.2%) and bilateral in 79 patients (41.8%). Median observation time on antibiotic prophylaxis before UROLOGY 84 (5), 2014
proceeding with endoscopic treatment was 7 months (3-36 months). One hundred eighteen right (44%) and 150 left (56%), a total of 268 ureters were injected. The overall mean injected volume was 0.6 mL (0.1-1.6 mL). There were 16 (5.9%) grade-1, 32 (11.9%) grade-2, 103 (38.4%) grade-3, 85 (31.7%) grade-4, and 32 (11.9%) grade-5 VURs. Ureters with grade 1 reflux were injected as the contralateral DMSA scan revealed renal scarring in 105 (39.2%) renal units. Renal scarring was mild in 40 (38%), moderate in 47 (44.8%), and severe in 18 (17.2%) patients. Median follow-up time was 18.6 months (6-31 months). Ureteral obstruction was observed in 3 of the 268 ureters (1.1%) in 3 female patients. Obstruction showed late onset in all 3 patients (Table 1). The first patient was a 5-year-old girl with a left-sided grade-4 reflux. She had recurrent febrile UTI and moderate renal scarring on the left. Preoperative ultrasonography (USG) showed bilateral mild pelvicaliectasis. She underwent an endoscopic injection of 0.5-mL PPC for left VUR. Left ureteral orifice was golf-hole shaped, and the bladder mucosa was normal. USG in the first month after the injection of Vantris showed grade-2 HUN, and there was no reflux in the VCUG performed in the third month after the injection. She had intermittent abdominal pain during follow-up. HUN upgraded to grade 4 on USG in the sixth month. Cystoscopy was performed with suspicion of obstruction. During cystoscopy, stenosis of the left ureteral orifice was observed, and a Double-J catheter was placed in the left ureter. Ultrasonography performed 1 month after the Double-J catheter insertion showed that HUN had resolved. The ureteral catheter was left in place for 2 months. One month after the removal of the catheter, grade-4 HUN developed again, and open left ureteroneocystostomy was performed to correct the obstruction that developed as a result of injection. Control VCUG in the sixth postoperative month showed that reflux had resolved. Histopathologic examination of the distal ureter of the patient showed normal uroepithelium with edema, hemorrhage, and chronic mononuclear inflammation in the submucosal layer. There was significant fibrosis in the muscular layer. The 1189
injected material was seen in the adventitia, together with chronic granulomatous foreign body reaction. The second patient was a 5-year-old girl with rightsided grade-5 VUR. She had the history of recurrent febrile UTI, day-time incontinence, and constipation. Preoperative USG showed right mild pelvicaliectasis, and she had moderate renal scarring on the right kidney. Preoperative urodynamic evaluation was normal. PPC (0.6 mL) was injected to the golf-hole shaped right ureteral orifice. The bladder mucosa was normal. She had anticholinergic treatment postoperatively, and her urinary symptoms regressed. Control VCUG in the third month was normal. She had intermittent abdominal pain during follow-up. Ultrasonography showed right grade-2 HUN until 18th postoperative month. HUN progressed to grade 4 in the 24th postoperative month. Lasix renogram by technetium-99m mercaptoacetyltriglycine showed obstruction on the right. As grade-4 HUN persisted on the 25th postoperative month, cystoscopy was performed. During cystoscopy, bladder mucosa appeared normal, and the right ureteral orifice was observed stenotic. A 3F ureteral catheter could not be passed through the right ureter. Open right ureteroneocystostomy was performed to correct the obstruction. She was in the fourth postoperative month. Histopathologic examination of the distal ureter showed normal uroepithelium, but edema, hemorrhage, and chronic mononuclear inflammation in the submucosal layer. There was significant fibrosis in both the submucosal and the muscular layers (Fig. 1). The injected material was seen in the adventitia, together with chronic granulomatous foreign body reaction (Fig. 2). The ureteral lumen was significantly obliterated. The last patient was a 3-year-old girl with a left-sided grade-5 reflux. She had the history of antenatal hydronephrosis and also having an endoscopic injection of calcium hydroxyapatite for grade-5 left VUR at another institution 2 years before admission to our hospital. Preoperative USG showed mild left pelvicaliectasis. She had mild renal scarring on the left. She underwent an endoscopic injection of 0.4-mL PPC. The left ureteral orifice was golf-hole shaped, and the bladder mucosa was normal. The first month USG after the injection of Vantris showed left grade-2 HUN. Control VCUG in the third month showed grade-3 reflux on the contralateral side and no reflux on the left. She developed 3 febrile UTIs during the follow-up. USG in the sixth month after the injection showed grade-4 HUN. Control DMSA scintigraphy revealed that split renal function on the left decreased to 4%, whereas it was 42% preoperatively. Then, bilateral open ureteroneocystostomy with left ureteral tapering was performed. At operation, the left ureteral orifice was observed to be severely obstructed. She was in the second postoperative month. Histopathologic examination of the left distal ureter of the patient showed normal uroepithelium. However, there was edema and minimal hemorrhage together with chronic mononuclear inflammation in the submucosal layer. 1190
Figure 1. The obliterated lumen of the ureter and significant fibrosis in the submucosa and muscularis propria in Trichrome stain (40). (Color version available online.)
Figure 2. The obliterated lumen of the ureter and foreign body in the adventitia (Hematoxylin stain, 100). (Color version available online.)
There was significant fibrosis in both the submucosal and the muscular layers. The injected material was seen in the adventitia, together with chronic granulomatous foreign body reaction (Fig. 3).
COMMENT Since the introduction of the endoscopic treatment of VUR in 1981 by Matouschek5 and with the development of new bulking agents, endoscopic subureteral injection has become increasingly popular and has been widely accepted as the first-line surgical treatment in the management of VUR. Few publications on ureteral obstruction after endoscopic injection have been reported, and most of them are the result of dextranomer/ hyaluronic acid (Dx/HA) injection.7-9 In this study, we aimed to report our cases of ureteral obstruction after injection with PPC. We also histopathologically assessed the distal ureters that were resected during open ureteroneocystostomy. UROLOGY 84 (5), 2014
Figure 3. Chronic granulomatous foreign body response as the result of ingestion of the polyacrylate polyalcohol copolymer particles by phagocytic giant cells (Hematoxylin stain, 100). (Color version available online.)
Two hundred sixty-eight ureters of 189 patients with VUR underwent an endoscopic injection of PPC at our institution in a period of 2.5 years. There were 3 ureteral obstructions among these ureters (1.1%). This obstruction rate was similar to or lower than the obstruction rates reported in other studies. Alizadeh et al,2 in their study about postoperative ureteral obstruction after endoscopic treatment with PPC, reported that obstruction was observed in 8 of the 131 ureters. They described 2 patterns of obstruction: early onset, during the first 3-4 days after the operation and late onset, which appeared 3 months-1 year after the surgery. In our study group, all 3 obstructions showed late onset. Ormaechea et al3 reported 1 ureteral obstruction among 88 ureters that were treated with PPC. The patient underwent ureteral reimplantation 6 months after the injection. However, their final diagnosis of the ureter was a primary obstructive megaureter with associated VUR. It is important to rule out primary obstructive megaureter, because ureters with obstructive component may deteriorate after endoscopic injection, and obstruction may worsen. Histopathologically, there is an increased collagen deposition in the juxtavesical segment of the obstructed megaureter.10,11 However, in our 3 cases, there was significant fibrosis in the submucosal and muscular layers and chronic inflammatory cell infiltration secondary to the injected material, but no increased collagen matrix was observed. Depending on these histopathologic findings, these 3 ureters were consistent with obstruction as the result of injected material. Moreover, films that we routinely obtained after voiding, right after VCUG showed that the upper tracts were completely drained in these 3 patients. Poor drainage of the upper tracts might suggest associatedevesicoureteral junction obstruction. However, VCUG findings were not consistent with primary obstructive megaureter. There might be some potential factors that are assumed to be responsible for the development of obstruction after injection. The first one is associated anomalies together UROLOGY 84 (5), 2014
with VUR. Vandersteen et al7 reported the incidence of ureteral obstruction after the injection of Dx/HA as 0.7% and 80% of the patients had severe dysfunctional voiding or myelomeningocele. One patient had unilateral ureteral duplication and another had a unilateral reflux into a solitary functioning kidney. In another study performed by Misra et al,12 it was reported that 1 among 51 neurogenic bladder patients (2%) developed ureteral obstruction after injection of Teflon (Polytef; Codman & Shurteff, Randolph, MA). Alizadeh et al reported bilateral obstruction after injection of PPC in a patient with bladder outlet obstruction and an inflamed bladder mucosa.2 They suggested that abnormal bladder mucosa could be a risk factor for postinjection ureteral obstruction. Mazzone et al9 reported that among 5 ureters that developed obstruction after Dx/HA injection, 1 had a crossed ectopic solitary left kidney with a diverticulum adjacent to the ureteric orifice. Two patients had a ureteropelvic junction obstruction that was corrected previously. However, asymptomatic chronic partial obstruction has also been reported after the injection of Dx/HA in a normal ureter.12 Similarly, our 3 patients who developed ureteral obstruction did not have associated anomalies at all. One of them had intermittent daytime incontinence, but her urodynamic evaluation was normal. Moreover, all 3 patients had normalappearing bladder mucosa on cystoscopy. The other risk factor for obstruction might be repeated injections. Mazzone et al suggested that giant cell inflammatory reaction may account for decreased tissue compliance as the result of repeated injections.9 Similarly, the histopathologic assessment of the ureters in our study demonstrated chronic granulomatous foreign body reaction. On the other hand, Puri et al,13 in their series of 149 reinjections and 19 third injections, reported no case of obstruction. However, among our 3 patients, only 1, of whom the first injection material was different from PPC, had 2 injections. Therefore, this factor cannot be considered as predisposing in our complicated 3 patients. Injection technique is also considered to be influencing the risk of obstruction. Arlen et al8 reported a case of chronic partial obstruction of a normal ureter after injection of Dx/HA via hydrodistension implantation technique. Alizadeh et al2 observed obstruction with all techniques and a combination of them. In our patient group, the injection technique was a subureteric transurethral injection in all 3 patients. Further evaluation is needed to clarify the possible influence of injection techniques. Injection volume may be considered as another risk factor for ureteral obstruction after injection. Al-Hunayan et al,14 in their study of a symptomatic obstruction after injection of polydimethylsiloxane, attributed the obstruction to excess amount of injected material. McMann et al,15 in a series of 986 ureters in which the injected volume of Dx/HA ranged from 0.74 to 1.59 mL, reported no case of obstruction. In our cases, the injected volumes were low (0.4-0.6 mL). We think that it is not possible to make a correlation between the injected 1191
volume and the obstruction rate in the present study. On the other hand, however, the possible obstructing effect of the injected volume may vary among different bulking agents. In our previous study about the early results of endoscopic treatment of VUR with PPC, we reported that lower amount of PPC, compared with that of other bulking agents, was enough to correct VUR (mean injected volume, 0.75 mL).16 Elder et al,17 in a metaanalysis pertaining to endoscopic treatment of VUR, reported that mean injected volumes were different, with the highest amount in collagen being 1.69 mL, whereas the lowest amount in polytetrafluoroethylene with 0.75 mL. PPC, because of its high molecular mass and large particle size, can provide adequate bulkiness at the ureteral orifice in lower volumes. Therefore, a volume which might cause no ureteral obstruction with a different bulking agent may lead to obstruction with PPC. Alizadeh et al reported that there was a female dominancy in their series of ureteral obstruction and suggested that UTI was more common in girls.2 However, they concluded that this was probably a reflection of their patient population. Similarly, all 3 patients in our series who developed ureteral obstruction were girls. Three of them had recurrent episodes of febrile UTI before injection. Frequent UTI might have affected the bladder mucosa adversely. However, the bladder mucosa of these 3 patients appeared smooth and normal during injection. Nevertheless, there might be chronic inflammation on the bladder mucosa, which can only be detected microscopically. Therefore, it is not possible to conclude that it was the frequent UTI that predisposed to obstruction. Histopathologic assessment of the ureters showed significant fibrosis in both the submucosal and the muscular layers. PPC was proved to develop edema, hemorrhage, chronic mononuclear inflammation, and foreign body reaction after injection. All 3 patients in this study had late-onset obstruction. Chronic inflammation that is generated by the continuing tissue stimulus of PPC and formation of significant fibrosis in the submucosal and muscular layers are the factors that may contribute to the development of late-onset obstruction. For the ureteral obstruction that develops early after infection, however, transient periureteral edema, incorrect placement, or high volumes of the bulking agent may be the factors that cause obstruction. We do not think that surgeon inexperience was a contributing factor for obstruction in our series. The injections were performed by 4 senior pediatric surgeons, and the obstructions were not encountered at the beginning of their learning curve. All 3 patients with obstruction were symptomatic. Other patients who had no obstruction, however, were symptom free. They did not have significant abdominal pain or UTI during the follow-up. Nevertheless, depending on the results of a limited number of patients with obstruction, it is not possible to make a conclusion that ultrasound examinations should be limited in those without UTI or pain. As the obstructions showed late 1192
onset, we recommend that all patients should be followed up with ultrasound for long periods (for at least 2 years) after endoscopic injection with Vantris. We performed open ureteral reimplantation for the treatment of obstruction in 3 ureters. In 1 patient, we placed a retrograde Double-J stent before open surgery. However, stenting did not provide a permanent solution for ureteral obstruction. Open ureteral reimplantation is a very effective procedure, and it can safely be performed after complicated endoscopic treatment of VUR. PPC is a new bulking agent used as an injection material, and there are only a limited number of reports in the literature regarding ureteral obstruction after its injection. We concluded that no identifiable cause has been established by this or the other studies. This most likely relates to the relative rarity of this complication. To our knowledge, this study is the third reporting ureteral obstruction after endoscopic treatment of VUR with PPC. However, a limitation of this study is that it was not possible to make a comparison between PPC and other bulking agents in terms of obstruction. Another limitation is that it was not obvious which factor was the real etiologic factor in the development of ureteral obstruction.
CONCLUSION As a result, ureteral obstruction may develop several months or even years after injection. Patients who undergo endoscopic treatment of PPC for the treatment of VUR need long-term follow-up, despite reflux showing complete resolution after injection. References 1. Ferrer FA, McKenna PH, Hochman HI, et al. Results of a vesicoureteral reflux practice pattern survey among American Academy of Pediatrics, Section on Pediatric Urology members. J Urol. 1998; 160:1031-1037. 2. Alizadeh F, Mazdak H, Khorrami MH, et al. Postoperative ureteral obstruction after endoscopic treatment of vesicoureteral reflux with polyacrylate polyalcohol copolymer (Vantris). J Pediatr Urol. 2013; 9:488-492. 3. Ormaechea M, Ruiz E, Denes E, et al. New tissue bulking agent (polyacrylate polyalcohol) for treating vesicoureteral reflux: preliminary results in children. J Urol. 2010;183:714-717. 4. Report of the International Reflux Study Committee. Medical versus surgical treatment of primary vesicoureteral reflux: a prospective international reflux study in children. J Urol. 1981;125: 277-283. 5. Matouschek E. Treatment of vesicorenal reflux by transurethral teflon-injection. Urologe A. 1981;20:263-264. 6. O’Donnell B, Puri P. Treatment of vesicoureteric reflux by endoscopic injection of Teflon. 1984. J Urol. 2002;167:1808-1809. 7. Vandersteen DR, Routh JC, Kirsch AJ, et al. Postoperative ureteral obstruction after subureteral injection of dextranomer/hyaluronic acid copolymer. J Urol. 2006;176:1593-1595. 8. Arlen AM, Pakalniskis BL, Cooper CS. Asymptomatic chronic partial obstruction of a normal ureter following dextranomer/hyaluronic acid copolymer (Deflux) injection for grade I vesicoureteral reflux. J Pediatr Urol. 2012;8:27-30. 9. Mazzone L, Gobet R, Gonzalez R, et al. Ureteral obstruction following injection of dextranomer/hyaluronic acid copolymer: an
UROLOGY 84 (5), 2014
10.
11. 12.
13.
infrequent but relevant complication. J Pediatr Urol. 2012;8: 514-519. Gosling JA, Dixon JS. Functional obstruction of the ureter and renal pelvis. A histological and electron microscopic study. Br J Urol. 1978;50:145-152. Escala JM, Keating MA, Boyd G, et al. Development of elastic fibres in the upper urinary tract. J Urol. 1989;141:969-973. Misra D, Potts SR, Brown S, et al. Endoscopic treatment of vesicoureteric reflux in neurogenic bladdere8 years’ experience. J Pediatr Surg. 1996;31:1262-1264. Puri P, Pirker M, Mohanan N, et al. Subureteral dextranomer/hyaluronic acid injection as first line treatment in the management of high grade vesicoureteral reflux. J Urol. 2006;176:1856-1859.
UROLOGY 84 (5), 2014
14. Al-Hunayan AA, Kehinde EO, Elsalam MA, et al. Outcome of endoscopic treatment for vesicoureteral reflux in children using polydimethylsiloxane. J Urol. 2002;168:2181-2183. 15. McMann LP, Scherz HC, Kirsch AJ. Long-term preservation of dextranomer/hyaluronic acid copolymer implants after endoscopic treatment of vesicoureteral reflux in children: a sonographic volumetric analysis. J Urol. 2007;177:316-320. 16. Sencan A, Uc¸an B, Evciler H, et al. Early results of endoscopic treatment of vesicoureteral reflux with polyacrylate polyalcohol copolymer. Urol Int. 2014;92:219-222. 17. 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;175:716-722.
1193
PATIENTS AND METHODS
RESULTS
CONCLUSION
To investigate the incidence and presentation of ureteral obstruction after endoscopic injection of polyacrylate polyalcohol copolymer (PPC) for the treatment of vesicoureteral reflux, and to analyze its possible causes, together with histopathologic assessment. The data of 189 patients who underwent endoscopic injection of PPC between May 2011 and December 2013 were retrospectively reviewed. After the injection, patients were followed up by urinalysis and ultrasonography monthly for 3 months. Control voiding cystouretrography was performed in the third postoperative month. Patients were then followed up by ultrasound every 3 months. If a new-onset hydroureteronephrosis (HUN) was observed, control ultrasound was performed monthly to follow the change in the degree of HUN. If a moderate or severe HUN was observed, technetium-99m mercaptoacetyltriglycine or dimercaptosuccinic acid scintigraphy was performed. For patients who needed open surgery, Cohen ureteroneocystostomy was performed. The distal 1 cm of the ureters was resected and examined histopathologically. One hundred eighty-nine patients with 268 refluxing ureters underwent endoscopic injection of PPC. Ureteral obstruction was observed in 3 ureters (1.1%), in 3 female patients of whom the degrees of reflux were grade 4, 5, and 5, respectively. Obstruction showed late onset in all 3 patients. Manifestations of obstruction included pain in 2 patients and recurrent febrile urinary tract infection with loss of function in scintigraphy in 1. All 3 patients underwent open ureteroneocystostomy. PPC may cause ureteral obstruction several months or even years after injection. Patients who undergo endoscopic treatment of PPC need long-term follow-up, despite reflux showing complete resolution. UROLOGY 84: 1188e1193, 2014. 2014 Elsevier Inc.
E
ndoscopic injection has proved to be a highly successful minimally invasive treatment for the correction of vesicoureteral reflux (VUR). With the development of new substances, subureteral injection of bulking agents has become a very popular alternative to ureteral reimplantation. Polyacrylate polyalcohol copolymer (PPC) (Vantris, Promedon, Cordoba, Argentina) is the newest injection material used in the endoscopic treatment. It is a nonbiodegradable substance of synthetic origin belonging to the acrylic family. It leads to the formation of a fibrotic capsule that can result in better
Financial Disclosure: The authors declare that they have no relevant financial interests. _ From the Department of Pediatric Surgery, Dr. Behc¸et Uz Children’s Hospital, Izmir, _ Turkey; and the Department of Pathology, Dr. Behc¸et Uz Children’s Hospital, Izmir, Turkey Address correspondence to: Arzu S¸encan, M.D., Department of Pediatric Surgery, _ Dr. Behc¸et Uz Children’s Hospital, Ismet Kaptan Mah. Sezer Dog an Sok. No: 11, _ 35210, Alsancak, Konak, Izmir 35350, Turkey. E-mail: [email protected] Submitted: May 21, 2014, accepted (with revisions): July 15, 2014
1188
ª 2014 Elsevier Inc. All Rights Reserved
stability and long-term durability in treating VUR. PPC particles have an average diameter of 300 mm. Therefore, the expected risk of migration is low.1 Very few studies about ureteral obstruction after endoscopic treatment of VUR with PPC have been reported in the literature before.2,3 Therefore, in this study, we aimed to report our cases of ureteral obstruction after injection of PPC, together with presenting patterns and histopathologic assessments.
PATIENTS AND METHODS The data of 189 patients who underwent endoscopic injection of PPC at our institution between May 2011 and December 2013 were retrospectively reviewed. All the patients who were included in this study had VUR determined by voiding cystouretrography (VCUG) and renal scarring in radionuclide scintigraphy. The reflux grade in VCUG was based according to the International Classification System (International Reflux Study Committee). Renal scarring in dimercaptosuccinic acid http://dx.doi.org/10.1016/j.urology.2014.07.030 0090-4295/14
Table 1. Characteristics of patients with ureteral obstruction after injection of polyacrylate polyalcohol copolymer Characteristic Age, y Sex Side and grade of VUR Side of obstruction Renal scarring Injected volume, mL Injection technique Number of injections Ureteral orifice configuration Associated condition Presentation Time of obstruction after injection, mo Treatment Follow-up period, mo
Patient 1
Patient 2
Patient 3
5 F Left, 4 Left Moderate 0.5 STING 1 Golf hole None Abdominal pain 6 Ureteral stent placement þ UNC 18
5 F Right, 5 Right Moderate 0.6 STING 1 Golf hole None Abdominal pain 24 UNC 32
3 F Left, 5 Left Mild 0.4 STING 2 Golf hole None Recurrent febrile UTI 6 UNC 8
F, female; STING, subureteric transurethral injection; UNC, ureteroneocystostomy; UTI, urinary tract infection; VUR, vesicoureteral reflux.
(DMSA) scintigraphy was classified in 3 groups: mild (focal defects with uptake between 40% and 45%), moderate (uptake of renal radionuclide between 20% and 40%), and severe (shrunken kidney with relative uptake <20%).4 Indications for surgical intervention were breakthrough urinary tract infection (UTI), progressive renal scarring, and nonresolution of VUR. Endoscopic treatment was performed under general anesthesia with a pediatric cystoscope (KARL STORZ GmbH & Co KG) using a technique similar to that described in the literature.5,6 The usual technique of subureteric transurethral injection, with the needle introduced submucosally under the ureteral orifice at the 6-o’clock position was used except for 6 patients with grade 4 and grade 5 VUR and a widely open orifice, in whom the injection was performed with the hydrodistention implantation technique. The agent was continued to be injected until the “volcanic” bulge was observed, raising the ureteral meatus onto the dome of the mound. Patients were discharged from the hospital the next day after the surgery. They were observed with urinalysis, renal and bladder ultrasound monthly for 3 months, and VCUG in the third postoperative month. Patients were maintained under antibiotic prophylaxis until the reflux was documented to resolve on postoperative cystogram. Patients were then followed up by ultrasound every 3 months. If a new-onset hydroureteronephrosis (HUN) was observed, control ultrasound was performed monthly to follow the degree of HUN. If a moderate or severe HUN was observed, technetium-99m mercaptoacetyltriglycine scintigraphy was added to the follow-up protocol. For patients who needed open surgery, open Cohen transtrigonal ureteroneocystostomy was performed. The distal 1 cm of the ureters was resected during surgery and assessed histopathologically. The specimens were stained with hematoxylin eosin and trichrome to assess for fibrosis. The ureteral mucosa, submucosa, the presence of chronic inflammation and granuloma, and the presence and localization of the injected material were assessed by a single pathologist.
RESULTS One hundred fourteen female (60%) and 75 male (40%) patients, a total of 189 patients with a median age of 5.5 years (4 months-15 years) underwent subureteric injection of PPC in our clinic. VUR was unilateral in 110 patients (58.2%) and bilateral in 79 patients (41.8%). Median observation time on antibiotic prophylaxis before UROLOGY 84 (5), 2014
proceeding with endoscopic treatment was 7 months (3-36 months). One hundred eighteen right (44%) and 150 left (56%), a total of 268 ureters were injected. The overall mean injected volume was 0.6 mL (0.1-1.6 mL). There were 16 (5.9%) grade-1, 32 (11.9%) grade-2, 103 (38.4%) grade-3, 85 (31.7%) grade-4, and 32 (11.9%) grade-5 VURs. Ureters with grade 1 reflux were injected as the contralateral DMSA scan revealed renal scarring in 105 (39.2%) renal units. Renal scarring was mild in 40 (38%), moderate in 47 (44.8%), and severe in 18 (17.2%) patients. Median follow-up time was 18.6 months (6-31 months). Ureteral obstruction was observed in 3 of the 268 ureters (1.1%) in 3 female patients. Obstruction showed late onset in all 3 patients (Table 1). The first patient was a 5-year-old girl with a left-sided grade-4 reflux. She had recurrent febrile UTI and moderate renal scarring on the left. Preoperative ultrasonography (USG) showed bilateral mild pelvicaliectasis. She underwent an endoscopic injection of 0.5-mL PPC for left VUR. Left ureteral orifice was golf-hole shaped, and the bladder mucosa was normal. USG in the first month after the injection of Vantris showed grade-2 HUN, and there was no reflux in the VCUG performed in the third month after the injection. She had intermittent abdominal pain during follow-up. HUN upgraded to grade 4 on USG in the sixth month. Cystoscopy was performed with suspicion of obstruction. During cystoscopy, stenosis of the left ureteral orifice was observed, and a Double-J catheter was placed in the left ureter. Ultrasonography performed 1 month after the Double-J catheter insertion showed that HUN had resolved. The ureteral catheter was left in place for 2 months. One month after the removal of the catheter, grade-4 HUN developed again, and open left ureteroneocystostomy was performed to correct the obstruction that developed as a result of injection. Control VCUG in the sixth postoperative month showed that reflux had resolved. Histopathologic examination of the distal ureter of the patient showed normal uroepithelium with edema, hemorrhage, and chronic mononuclear inflammation in the submucosal layer. There was significant fibrosis in the muscular layer. The 1189
injected material was seen in the adventitia, together with chronic granulomatous foreign body reaction. The second patient was a 5-year-old girl with rightsided grade-5 VUR. She had the history of recurrent febrile UTI, day-time incontinence, and constipation. Preoperative USG showed right mild pelvicaliectasis, and she had moderate renal scarring on the right kidney. Preoperative urodynamic evaluation was normal. PPC (0.6 mL) was injected to the golf-hole shaped right ureteral orifice. The bladder mucosa was normal. She had anticholinergic treatment postoperatively, and her urinary symptoms regressed. Control VCUG in the third month was normal. She had intermittent abdominal pain during follow-up. Ultrasonography showed right grade-2 HUN until 18th postoperative month. HUN progressed to grade 4 in the 24th postoperative month. Lasix renogram by technetium-99m mercaptoacetyltriglycine showed obstruction on the right. As grade-4 HUN persisted on the 25th postoperative month, cystoscopy was performed. During cystoscopy, bladder mucosa appeared normal, and the right ureteral orifice was observed stenotic. A 3F ureteral catheter could not be passed through the right ureter. Open right ureteroneocystostomy was performed to correct the obstruction. She was in the fourth postoperative month. Histopathologic examination of the distal ureter showed normal uroepithelium, but edema, hemorrhage, and chronic mononuclear inflammation in the submucosal layer. There was significant fibrosis in both the submucosal and the muscular layers (Fig. 1). The injected material was seen in the adventitia, together with chronic granulomatous foreign body reaction (Fig. 2). The ureteral lumen was significantly obliterated. The last patient was a 3-year-old girl with a left-sided grade-5 reflux. She had the history of antenatal hydronephrosis and also having an endoscopic injection of calcium hydroxyapatite for grade-5 left VUR at another institution 2 years before admission to our hospital. Preoperative USG showed mild left pelvicaliectasis. She had mild renal scarring on the left. She underwent an endoscopic injection of 0.4-mL PPC. The left ureteral orifice was golf-hole shaped, and the bladder mucosa was normal. The first month USG after the injection of Vantris showed left grade-2 HUN. Control VCUG in the third month showed grade-3 reflux on the contralateral side and no reflux on the left. She developed 3 febrile UTIs during the follow-up. USG in the sixth month after the injection showed grade-4 HUN. Control DMSA scintigraphy revealed that split renal function on the left decreased to 4%, whereas it was 42% preoperatively. Then, bilateral open ureteroneocystostomy with left ureteral tapering was performed. At operation, the left ureteral orifice was observed to be severely obstructed. She was in the second postoperative month. Histopathologic examination of the left distal ureter of the patient showed normal uroepithelium. However, there was edema and minimal hemorrhage together with chronic mononuclear inflammation in the submucosal layer. 1190
Figure 1. The obliterated lumen of the ureter and significant fibrosis in the submucosa and muscularis propria in Trichrome stain (40). (Color version available online.)
Figure 2. The obliterated lumen of the ureter and foreign body in the adventitia (Hematoxylin stain, 100). (Color version available online.)
There was significant fibrosis in both the submucosal and the muscular layers. The injected material was seen in the adventitia, together with chronic granulomatous foreign body reaction (Fig. 3).
COMMENT Since the introduction of the endoscopic treatment of VUR in 1981 by Matouschek5 and with the development of new bulking agents, endoscopic subureteral injection has become increasingly popular and has been widely accepted as the first-line surgical treatment in the management of VUR. Few publications on ureteral obstruction after endoscopic injection have been reported, and most of them are the result of dextranomer/ hyaluronic acid (Dx/HA) injection.7-9 In this study, we aimed to report our cases of ureteral obstruction after injection with PPC. We also histopathologically assessed the distal ureters that were resected during open ureteroneocystostomy. UROLOGY 84 (5), 2014
Figure 3. Chronic granulomatous foreign body response as the result of ingestion of the polyacrylate polyalcohol copolymer particles by phagocytic giant cells (Hematoxylin stain, 100). (Color version available online.)
Two hundred sixty-eight ureters of 189 patients with VUR underwent an endoscopic injection of PPC at our institution in a period of 2.5 years. There were 3 ureteral obstructions among these ureters (1.1%). This obstruction rate was similar to or lower than the obstruction rates reported in other studies. Alizadeh et al,2 in their study about postoperative ureteral obstruction after endoscopic treatment with PPC, reported that obstruction was observed in 8 of the 131 ureters. They described 2 patterns of obstruction: early onset, during the first 3-4 days after the operation and late onset, which appeared 3 months-1 year after the surgery. In our study group, all 3 obstructions showed late onset. Ormaechea et al3 reported 1 ureteral obstruction among 88 ureters that were treated with PPC. The patient underwent ureteral reimplantation 6 months after the injection. However, their final diagnosis of the ureter was a primary obstructive megaureter with associated VUR. It is important to rule out primary obstructive megaureter, because ureters with obstructive component may deteriorate after endoscopic injection, and obstruction may worsen. Histopathologically, there is an increased collagen deposition in the juxtavesical segment of the obstructed megaureter.10,11 However, in our 3 cases, there was significant fibrosis in the submucosal and muscular layers and chronic inflammatory cell infiltration secondary to the injected material, but no increased collagen matrix was observed. Depending on these histopathologic findings, these 3 ureters were consistent with obstruction as the result of injected material. Moreover, films that we routinely obtained after voiding, right after VCUG showed that the upper tracts were completely drained in these 3 patients. Poor drainage of the upper tracts might suggest associatedevesicoureteral junction obstruction. However, VCUG findings were not consistent with primary obstructive megaureter. There might be some potential factors that are assumed to be responsible for the development of obstruction after injection. The first one is associated anomalies together UROLOGY 84 (5), 2014
with VUR. Vandersteen et al7 reported the incidence of ureteral obstruction after the injection of Dx/HA as 0.7% and 80% of the patients had severe dysfunctional voiding or myelomeningocele. One patient had unilateral ureteral duplication and another had a unilateral reflux into a solitary functioning kidney. In another study performed by Misra et al,12 it was reported that 1 among 51 neurogenic bladder patients (2%) developed ureteral obstruction after injection of Teflon (Polytef; Codman & Shurteff, Randolph, MA). Alizadeh et al reported bilateral obstruction after injection of PPC in a patient with bladder outlet obstruction and an inflamed bladder mucosa.2 They suggested that abnormal bladder mucosa could be a risk factor for postinjection ureteral obstruction. Mazzone et al9 reported that among 5 ureters that developed obstruction after Dx/HA injection, 1 had a crossed ectopic solitary left kidney with a diverticulum adjacent to the ureteric orifice. Two patients had a ureteropelvic junction obstruction that was corrected previously. However, asymptomatic chronic partial obstruction has also been reported after the injection of Dx/HA in a normal ureter.12 Similarly, our 3 patients who developed ureteral obstruction did not have associated anomalies at all. One of them had intermittent daytime incontinence, but her urodynamic evaluation was normal. Moreover, all 3 patients had normalappearing bladder mucosa on cystoscopy. The other risk factor for obstruction might be repeated injections. Mazzone et al suggested that giant cell inflammatory reaction may account for decreased tissue compliance as the result of repeated injections.9 Similarly, the histopathologic assessment of the ureters in our study demonstrated chronic granulomatous foreign body reaction. On the other hand, Puri et al,13 in their series of 149 reinjections and 19 third injections, reported no case of obstruction. However, among our 3 patients, only 1, of whom the first injection material was different from PPC, had 2 injections. Therefore, this factor cannot be considered as predisposing in our complicated 3 patients. Injection technique is also considered to be influencing the risk of obstruction. Arlen et al8 reported a case of chronic partial obstruction of a normal ureter after injection of Dx/HA via hydrodistension implantation technique. Alizadeh et al2 observed obstruction with all techniques and a combination of them. In our patient group, the injection technique was a subureteric transurethral injection in all 3 patients. Further evaluation is needed to clarify the possible influence of injection techniques. Injection volume may be considered as another risk factor for ureteral obstruction after injection. Al-Hunayan et al,14 in their study of a symptomatic obstruction after injection of polydimethylsiloxane, attributed the obstruction to excess amount of injected material. McMann et al,15 in a series of 986 ureters in which the injected volume of Dx/HA ranged from 0.74 to 1.59 mL, reported no case of obstruction. In our cases, the injected volumes were low (0.4-0.6 mL). We think that it is not possible to make a correlation between the injected 1191
volume and the obstruction rate in the present study. On the other hand, however, the possible obstructing effect of the injected volume may vary among different bulking agents. In our previous study about the early results of endoscopic treatment of VUR with PPC, we reported that lower amount of PPC, compared with that of other bulking agents, was enough to correct VUR (mean injected volume, 0.75 mL).16 Elder et al,17 in a metaanalysis pertaining to endoscopic treatment of VUR, reported that mean injected volumes were different, with the highest amount in collagen being 1.69 mL, whereas the lowest amount in polytetrafluoroethylene with 0.75 mL. PPC, because of its high molecular mass and large particle size, can provide adequate bulkiness at the ureteral orifice in lower volumes. Therefore, a volume which might cause no ureteral obstruction with a different bulking agent may lead to obstruction with PPC. Alizadeh et al reported that there was a female dominancy in their series of ureteral obstruction and suggested that UTI was more common in girls.2 However, they concluded that this was probably a reflection of their patient population. Similarly, all 3 patients in our series who developed ureteral obstruction were girls. Three of them had recurrent episodes of febrile UTI before injection. Frequent UTI might have affected the bladder mucosa adversely. However, the bladder mucosa of these 3 patients appeared smooth and normal during injection. Nevertheless, there might be chronic inflammation on the bladder mucosa, which can only be detected microscopically. Therefore, it is not possible to conclude that it was the frequent UTI that predisposed to obstruction. Histopathologic assessment of the ureters showed significant fibrosis in both the submucosal and the muscular layers. PPC was proved to develop edema, hemorrhage, chronic mononuclear inflammation, and foreign body reaction after injection. All 3 patients in this study had late-onset obstruction. Chronic inflammation that is generated by the continuing tissue stimulus of PPC and formation of significant fibrosis in the submucosal and muscular layers are the factors that may contribute to the development of late-onset obstruction. For the ureteral obstruction that develops early after infection, however, transient periureteral edema, incorrect placement, or high volumes of the bulking agent may be the factors that cause obstruction. We do not think that surgeon inexperience was a contributing factor for obstruction in our series. The injections were performed by 4 senior pediatric surgeons, and the obstructions were not encountered at the beginning of their learning curve. All 3 patients with obstruction were symptomatic. Other patients who had no obstruction, however, were symptom free. They did not have significant abdominal pain or UTI during the follow-up. Nevertheless, depending on the results of a limited number of patients with obstruction, it is not possible to make a conclusion that ultrasound examinations should be limited in those without UTI or pain. As the obstructions showed late 1192
onset, we recommend that all patients should be followed up with ultrasound for long periods (for at least 2 years) after endoscopic injection with Vantris. We performed open ureteral reimplantation for the treatment of obstruction in 3 ureters. In 1 patient, we placed a retrograde Double-J stent before open surgery. However, stenting did not provide a permanent solution for ureteral obstruction. Open ureteral reimplantation is a very effective procedure, and it can safely be performed after complicated endoscopic treatment of VUR. PPC is a new bulking agent used as an injection material, and there are only a limited number of reports in the literature regarding ureteral obstruction after its injection. We concluded that no identifiable cause has been established by this or the other studies. This most likely relates to the relative rarity of this complication. To our knowledge, this study is the third reporting ureteral obstruction after endoscopic treatment of VUR with PPC. However, a limitation of this study is that it was not possible to make a comparison between PPC and other bulking agents in terms of obstruction. Another limitation is that it was not obvious which factor was the real etiologic factor in the development of ureteral obstruction.
CONCLUSION As a result, ureteral obstruction may develop several months or even years after injection. Patients who undergo endoscopic treatment of PPC for the treatment of VUR need long-term follow-up, despite reflux showing complete resolution after injection. References 1. Ferrer FA, McKenna PH, Hochman HI, et al. Results of a vesicoureteral reflux practice pattern survey among American Academy of Pediatrics, Section on Pediatric Urology members. J Urol. 1998; 160:1031-1037. 2. Alizadeh F, Mazdak H, Khorrami MH, et al. Postoperative ureteral obstruction after endoscopic treatment of vesicoureteral reflux with polyacrylate polyalcohol copolymer (Vantris). J Pediatr Urol. 2013; 9:488-492. 3. Ormaechea M, Ruiz E, Denes E, et al. New tissue bulking agent (polyacrylate polyalcohol) for treating vesicoureteral reflux: preliminary results in children. J Urol. 2010;183:714-717. 4. Report of the International Reflux Study Committee. Medical versus surgical treatment of primary vesicoureteral reflux: a prospective international reflux study in children. J Urol. 1981;125: 277-283. 5. Matouschek E. Treatment of vesicorenal reflux by transurethral teflon-injection. Urologe A. 1981;20:263-264. 6. O’Donnell B, Puri P. Treatment of vesicoureteric reflux by endoscopic injection of Teflon. 1984. J Urol. 2002;167:1808-1809. 7. Vandersteen DR, Routh JC, Kirsch AJ, et al. Postoperative ureteral obstruction after subureteral injection of dextranomer/hyaluronic acid copolymer. J Urol. 2006;176:1593-1595. 8. Arlen AM, Pakalniskis BL, Cooper CS. Asymptomatic chronic partial obstruction of a normal ureter following dextranomer/hyaluronic acid copolymer (Deflux) injection for grade I vesicoureteral reflux. J Pediatr Urol. 2012;8:27-30. 9. Mazzone L, Gobet R, Gonzalez R, et al. Ureteral obstruction following injection of dextranomer/hyaluronic acid copolymer: an
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10.
11. 12.
13.
infrequent but relevant complication. J Pediatr Urol. 2012;8: 514-519. Gosling JA, Dixon JS. Functional obstruction of the ureter and renal pelvis. A histological and electron microscopic study. Br J Urol. 1978;50:145-152. Escala JM, Keating MA, Boyd G, et al. Development of elastic fibres in the upper urinary tract. J Urol. 1989;141:969-973. Misra D, Potts SR, Brown S, et al. Endoscopic treatment of vesicoureteric reflux in neurogenic bladdere8 years’ experience. J Pediatr Surg. 1996;31:1262-1264. Puri P, Pirker M, Mohanan N, et al. Subureteral dextranomer/hyaluronic acid injection as first line treatment in the management of high grade vesicoureteral reflux. J Urol. 2006;176:1856-1859.
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14. Al-Hunayan AA, Kehinde EO, Elsalam MA, et al. Outcome of endoscopic treatment for vesicoureteral reflux in children using polydimethylsiloxane. J Urol. 2002;168:2181-2183. 15. McMann LP, Scherz HC, Kirsch AJ. Long-term preservation of dextranomer/hyaluronic acid copolymer implants after endoscopic treatment of vesicoureteral reflux in children: a sonographic volumetric analysis. J Urol. 2007;177:316-320. 16. Sencan A, Uc¸an B, Evciler H, et al. Early results of endoscopic treatment of vesicoureteral reflux with polyacrylate polyalcohol copolymer. Urol Int. 2014;92:219-222. 17. 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;175:716-722.
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