- Email: [email protected]
Endoscopic Subureteral Urocol Injection for the Treatment of Vesicoureteral Reflux
Endoscopic Subureteral Urocol Injection for the Treatment of Vesicoureteral Reflux Abdol-Mohammad Kajbafzadeh,* Zohreh Habibi and Parvin Tajik From the Department of Pediatric Urology, Children’s Hospital Medical Center, and Department of Epidemiology and Biostatistics, School of Public Health (PT), Tehran University of Medical Sciences, Tehran, Iran
Purpose: We evaluated the effect of Urocol injection for the endoscopic treatment of VUR in children. Materials and Methods: A total of 208 children (62 boys and 146 girls, mean age 4.78 years) with 346 refluxing ureters underwent subureteral injection of Urocol between January 2000 and February 2002. VCUG was performed at 6 months, and ultrasound was performed at 1 week and 3 months postoperatively. Results: Followup VCUG showed no evidence of reflux in 240 ureters (69%), significant decrease in reflux grade in 62 (18%) and no change in 44 (13%). Ultrasound revealed no obstruction or hydronephrosis. Conclusions: The results of this study demonstrate that subureteral injection of Urocol was effective for the treatment of VUR. We conclude that Urocol represents a new, safe, simple, less expensive and repeatable technique in treating VUR. Key Words: vesico-ureteral reflux, endoscopy, prostheses and implants, ureter, tricalcium phosphate
UR is one of the most common urinary tract anomalies in childhood. Persistent VUR can result in progressive renal damage and can ultimately lead to renal failure. The goal of treating children with VUR is prevention of recurrent pyelonephritis and subsequent renal scarring. The main treatment options are administration of prophylactic antibiotics, open surgery and endoscopic submucosal biomaterial injection. The long-term requirement of prophylactic antibiotic therapy and the occasional complications of surgical techniques led to the development of endoscopic treatment of VUR in the early 1980s.1 Since then, many foreign materials such as polytetrafluoroethylene, polydimethylsiloxane and bovine collagen have been used for subureteral injections, with cure rates ranging from 60% to 80%.2– 4 However, several studies have documented disadvantages of these materials. Polytetrafluoroethylene exhibits a risk of granuloma formation and migration to distant organs.5,6 Silicone has been associated with autoimmune reactions, and migration has also been reported.7 Injection of bovine collagen has the additional drawback of being a foreign protein, which may elicit an anaphylactic reaction, and because of autodigestion, early recurrence is reported.4 Consequently, new alternative substances have been proposed, including dextranomer,8 chondrocyte,9 calcium hydroxylaptite10 and Urocol.11 Dextranomer, which is now widely used, has been shown to be safe and highly successful for endoscopic treatment of VUR, with an 82% total cure rate.8 However, it is expensive and its transportation has special temperature limitations. The main component of Urocol is hy-
V
Submitted for publication August 26, 2005. * Correspondence and requests for reprints: No. 36, 2nd floor, 7th St., Saadat-Abad Ave., Tehran 19987, Iran (telephone: 98-21-22089946; FAX: 98-21-2206-9451; e-mail: [email protected]).
0022-5347/06/1754-1480/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
droxylapatite, which has been discussed extensively in the literature with regard to biochemical composition and in vivo predictability, as well as potential concerns and advantages.12 However, clinical data are lacking on the use of Urocol as an injectable substance for the endoscopic correction of VUR. Therefore, the objective of this study was to report our experience with subureteral Urocol injection in children with VUR. PATIENTS AND METHODS A total of 208 patients with 346 refluxing ureters underwent endoscopic subureteral injection of Urocol between January 2000 and February 2002. There were 146 girls and 62 boys. VUR was bilateral in 146 patients (70.2%) and unilateral in 62 (29.8%). Patient age ranged from 1 month to 18 years (mean 4.8 years). Vesicoureteral reflux was grade I in 9 ureters, grade II in 138, grade III in 96, grade IV in 73 and grade V in 30. Inclusion criteria were proved grade III to V vesicoureteral reflux on voiding VCUG, and low grade (I to II) VUR accompanied by urinary tract infection despite adequate antibiotic treatment or high grade reflux in the contralateral ureter. Exclusion criteria were secondary VUR due to neuropathic voiding dysfunction, posterior urethral valves, anterior urethral valves, the bladder exstrophy complex, classic epispadias, duplex system and failed ureteral reimplantation. Nondegradable urological implant. Urocol paste contains polyethylene glycol 400 and polyglucosamine ester in Ringer solution. Procedure. With the patient under general anesthesia routine cystoscopy is performed, and the ureteral orifice shape and location, and trigone and bladder wall trabeculation are observed. A Storz cystoscopic injection needle consisting of a
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Vol. 175, 1480-1484, April 2006 Printed in U.S.A. DOI:10.1016/S0022-5347(05)00675-0
UROCOL INJECTION FOR VESICOURETERAL REFLUX
FIG. 1. A, VCUG demonstrates bilateral VUR. B, VCUG of same patient 6 months after subureteral Urocol injection shows resolution of reflux.
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Of 18 patients who experienced 1 failed Urocol implantation 17 underwent an additional injection. VCUG performed 6 months later showed no evidence of reflux in 11 patients (64.7%), a significant grade reduction in 3 (17.6%) and no improvement in 3 (17.6%). There was no significant difference between the overall success rates of the first and second Urocol implantations. Among 56 patients with reduced reflux 45 (80.4%) had postoperative bilateral or unilateral low grade VUR (grade I or II) and underwent noninvasive treatment. A total of 11 patients (19.6%) with grade III or IV reflux were offered a repeat injection. Reinjection was performed in 9 patients, and the complete success rate was 66.7%. Our treatment algorithm and patient outcomes are illustrated in figure 2. No patient experienced complications such as dysuria or gross hematuria after the procedure, and followup ultrasound revealed no evidence of hydronephrosis in any of the treated patients. DISCUSSION
10 mm long, 21 gauge, 3Fr needle connected to a 30 cm length plastic tube is advanced through the working channel of a miniature (6.75Fr) Wolf neonatal cystourethroscope. The needle tip is inserted at the 6 o’clock position into the subureteral space approximately 1 to 2 mm distal to the ureteral orifice and is advanced proximally. An average of 0.4 to 0.6 cc bulking material is injected slowly until a volcano bulge obliterates the ureteral orifice. The needle is kept in position for 2 to 3 minutes before it is withdrawn to minimize extravasation of injected material through the needle track. Renal and bladder ultrasound was obtained at 1 week and 3 months postoperatively to monitor the appearance of the upper urinary tract and the presence of hydronephrosis. To assess outcome, followup VCUG was performed 6 months after injection. All patients were carefully followed by regular clinical visits and urinary bacteriology tests, and subjects in whom the first endoscopic treatment failed were offered a second injection. Statistical methods. The data were evaluated by chisquare test and Wilcoxon signed rank test, and p value ⬍0.05 was considered statistically significant. RESULTS All patients were followed for at least 6 months, and the evaluation is still ongoing. After 6 months of followup VCUG revealed that 134 cases (64.4%) were cured completely, 56 (26.9%) were improved (downgraded at least 1 grade, or 1 ureter was cured in cases of bilateral reflux), and 18 (8.7%) remained unchanged and were considered treatment failures (fig. 1). The response to treatment in all 346 ureters and the distribution of responses according to reflux grade are summarized in the table. Comparison of reflux grades before and after treatment demonstrated a significant improvement in the treated ureters (Wilcoxon signed rank test, p ⬍0.001). However, there was no statistically significant association between reflux grade and failure rate (chisquare, p ⫽ 0.79). Subureteral Urocol injection resulted in failure rates of 10.3% and 4.8% in patients suffering from bilateral and unilateral reflux, respectively.
Endoscopic treatment of VUR has proved to be a safe and minimally invasive technique with few complications. Subureteral injections of different foreign materials (ie polytetrafluoroethylene, silicone, collagen and dextranomer) have been used to correct VUR.1– 4,8 However, there have been concerns about the side effects of treatment with some of these materials. Experimental and clinical studies have demonstrated the presence of migratory polytetrafluoroethylene particles in distant organs such as the brain and lungs following injection into the bladder.5,6 In addition, migration of silicone particles has been reported.7 It has also been shown that polytetrafluoroethylene and silicone injections may result in calcification and granuloma formation.13,14 Moreover, questions have been raised concerning the possible carcinogenicity of these materials.15,16 Finally, it is well known that foreign proteins such as silicone and bovine collagen are associated with autoimmune reactions.5,8 In experimental studies using collagen eosinophilic reactions around the injected implant have been reported.4 New biocompatible, safe and efficacious materials for the endoscopic treatment of VUR have been sought out, and new materials have been introduced for this purpose. Dextranomer has proved to be an effective implant that is well tolerated for an extended period, and may even change the management of VUR in pediatric cases.17 Initially, we started our experience with dextranomer. However, because of its difficult handling conditions (ie 8C temperature limitations) and its high cost, we decided to try another biocompatible material.
Results of endoscopic treatment with Urocol in refluxing ureters by reflux grade Reflux Grade
No. Cured (%)
No. Improved (%)
No. Failed (%)
Total No.
I II III IV V Totals
8 (89) 105 (76) 66 (69) 42 (58) 19 (63) 240 (69)
0 (0) 13 (9) 17 (18) 23 (32) 9 (30) 62 (18)
1 (11) 20 (14) 13 (14) 8 (11) 2 (7) 44 (13)
9 138 96 73 30 346
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UROCOL INJECTION FOR VESICOURETERAL REFLUX
FIG. 2. Flow chart of patients, treatment and outcomes. Urocol, Urocol
Urocol, a paste of hydroxylapatite, also seems to fulfill all treatment criteria. Urocol is an ideal material that is not allergenic and does not induce granuloma formation or migrate in the body.11 The properties of hydroxylapatite are well documented with regard to toxicity, mutagenicity and biocompatibility, and it has been observed to be a highly biocompatible material that is safe for application in humans.18 Furthermore, because hydroxylapatite is biocompatible and the particle size is between 100 and 400 m, no migration or granuloma formation has been seen.11 This material has been used in the form of coated endosseous implants in the treatment of dental patients,12 prostheses in orthopedic surgery and orbital implants in anophthalmos.19 In addition, studies suggest that ossicular replacement prostheses made of dense hydroxylapatite are suitable for reconstructive ear surgery.20 In recent years calcium hydroxylapatite gel has been used for the endoscopic treatment of VUR. An American multicenter experience reported by Mevorach et al revealed calcium hydroxylapatite gel to be a safe and effective treatment for VUR, with a 74% cure rate.10 This implant received the first limited Food and Drug Administration approval for the endoscopic treatment of VUR.10 In this study we investigated the effect of subureteral injection of Urocol in 208 children suffering from VUR. At 6-month followup reflux was cured or reduced to a lower grade in most of the injected ureters, with the results being comparable to those of Mevorach et al.10 Based on our investigation, the failure rate was not associated with reflux grade. Additionally, the success rate was higher in patients with unilateral reflux. Moreover, repeat injection resulted in an acceptable success rate. Therefore, if Urocol is not effective following an initial injection, it can be tried an additional time.
CONCLUSIONS Our results confirm that endoscopic injection of Urocol can correct reflux in a large number of patients. Because of the simplicity of the technique, rare complications, short hospitalization and high success rate, it can be considered as an alternative to other treatments for VUR. The procedure is repeatable in failed cases, without any signs of fibrosis or adhesions at previous injection sites. However, there is limited clinical experience with the use of Urocol as a biocompatible material in correcting VUR. Consequently, longterm followup of patients treated with this injectable substance is required and is ongoing at our center.
ACKNOWLEDGMENTS Mr. Behrad Kajbafzadeh reviewed the manuscript.
Abbreviations and Acronyms VCUG ⫽ voiding cystourethrography VUR ⫽ vesicoureteral reflux
REFERENCES 1. Matouschek, E.: Die behandlung des vesilorenalen refluxes durch transurethrale einspritzung von Teflon paste. Urologe A, 20: 263, 1981 2. Chertin, B., Colhoun, E., Velayudham, M. and Puri, P.: Endoscopic treatment of vesicoureteral reflux: 11 to 17 years of followup. J Urol, 167: 1443, 2002 3. Smith, D. P., Kaplan, W. E. and Oyasu, R.: Evaluation of polydimethylsiloxane as an alternative in the endoscopic treatment of vesicoureteral reflux. J Urol, 152: 1221, 1994
UROCOL INJECTION FOR VESICOURETERAL REFLUX 4. Lipsky, H. and Wurnschimmel, E.: Endoscopic treatment of vesicoureteric reflux with collagen. Five years’ experience. Br J Urol, 72: 965, 1993 5. Aaronson, I. A., Rames, R. A., Greene, W. B., Walsh, L. G., Hassal, U. and Garen, P. D.: Endoscopic treatment of reflux: migration of Teflon to the lungs and brain. Eur Urol, 23: 394, 1993 6. Malizia, A. A., Jr., Reiman, H. M., Myers, R. P., Sande, J. R., Barham, S. S., Benson, R. C., Jr. et al: Migration of granulomatous reaction after periurethral injection of polytef (Teflon). JAMA, 251: 3277, 1984 7. Biesang, A. A., 3rd and Ersek, R. A.: Mammalian response to subdermal implantation of textured microimplants. Aesthetic Plast Surg, 16: 83, 1992 8. Capozza, N., Lais, A., Nappo, S. and Caione, P.: The role of endoscopic treatment of vesicoureteral reflux: a 17-year experience. J Urol, 172: 1626, 2004 9. Caldamone, A. A. and Diamond, D. A.: Long-term results of the endoscopic correction of vesicoureteral reflux in children using autologous chondrocytes. J Urol, 165: 2224, 2001 10. Mevorach, R., Rabinowitz, R., Beck, C. and Hulbert, W.: Endoscopic treatment of vesicoureteral reflux with Coaptite™: the first 50 patients. J Urol, suppl., 167: 107, abstract 429, 2002 11. Bos, S. D., Ypma, A. F. and Timmermans, C. J.: Subureteric Urocol injection in the treatment of vesico-ureteric reflux. Br J Urol, 76: 275, 1995 12. Biesbrock, A. R. and Edgerton, M.: Evaluation of the clinical predictability of hydroxyapatite-coated endosseous dental implants: a review of the literature. Int J Oral Maxillofac Implants, 10: 712, 1995 13. Claes, H., Stroobants, D., Van Meerbeek, J., Verbeken, E., Knockaert, D. and Baert, L.: Pulmonary migration following periurethral polytetrafluoroethylene injection for urinary incontinence. J Urol, 142: 821, 1989 14. Travis, W. D., Balogh, K. and Abraham, J. L.: Silicone granulomas: report of three cases and review of the literature. Hum Pathol, 16: 19, 1985 15. Dewan, P. A.: Is injected polytetrafluoroethylene (Polytef) carcinogenic? Br J Urol, 69: 29, 1992 16. Hatanaka, S., Oneda, S., Okazaki, K., Shong, L. J., Yoshida, A., Isaka, H. et al: Induction of malignant fibrous histiocytoma in female Fisher rats by implantation of cyanoacrylate, zirconia, polyvinyl chloride or silicone. In Vivo, 7: 111, 1993 17. Aaronson, I. A.: Does Deflux alter the paradigm for the management of children with vesicoureteral reflux? Curr Urol Rep, 6: 152, 2005 18. Liu, C., Wang, W., Shen, W., Chen, T., Hu, L. and Chen, Z.: Evaluation of the biocompatibility of a nonceramic hydroxyapatite. J Endod, 23: 490, 1997 19. Jordan, D. R., Gilberg, S., Mawn, L., Brownstein, S. and Grahovac, S. Z.: The synthetic hydroxyapatite implant: a report on 65 patients. Ophthal Plast Reconstr Surg, 14: 250, 1998 20. Ye, Q., Ohsaki, K., Li, K., Li, D. J., Zhu, C. S., Ogawa, T. et al: Histological reaction to hydroxyapatite in the middle ear of rats. Auris Nasus Larynx, 28: 131, 2001
EDITORIAL COMMENTS The use of injectable bulking agents in the treatment of VUR is widely accepted in pediatric urology. It has rapidly grown in popularity in the United States since the introduction of agents that maintain a more durable implant and minimize migration or degradation of material. It is valuable to support studies that evaluate new bulking agents and will continue to foster the evolution of this therapy. However, this article raises several concerns. To begin with, one must caution against propaganda that “Persistent
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VUR can result in progressive renal damage and can ultimately lead to renal failure.” Long-term clinical studies support the premise that sterile reflux does not cause progressive renal damage. This is one of the major tenets in the medical management of VUR. Another concern involves the conclusion that “Urochol represents a new, safe, simple, less expensive” technique. This article does not present any data regarding cost of treatment or comparison of costs to other injectable materials. Therefore, this study does not support that conclusion. Furthermore, to call it “simple” is not completely accurate. There is a significant learning curve among practitioners, there are significant differences in success rates between different institutions and there are variations in technique that may alter success. The assessment of outcomes is dependent on the voiding cystourethrogram. The VCUG is certainly a skilled study of the pediatric radiologist dependent on several variables, including the quality of the voiding films, the impact of sedation and the timing of the study following surgery. These authors wait an appropriate length of time after injection to allow for resolution of swelling and contraction of the bolus. However, future studies should also strive to document specifics of the VCUG protocol (ie type and size of catheter, whether or not sedation was used, etc), and document the performance of voiding images (which is important to ensure standardization and optimal sensitivity). Last, the reduction to lower grade of reflux is an overstated benefit. It is not clear that simply reducing the grade of reflux is clinically beneficial to the patient. Reflux techniques should be judged on the cure rate alone. The success rate of alternative surgical techniques to treat reflux, such as ureteral reimplantation, are judged by cure rate alone, not improvement. Therefore, ongoing comparison should be based on that criterion. John V. Kryger Division of Pediatric Urology Department of Surgery University of Wisconsin Children’s Hospital Madison, Wisconsin The authors report a substantial series that warrants consideration that extends well beyond the confines of the 67% anatomical cure rate in patients and 69% for ureters, which compares reasonably to current series for dextranomer/hyaluronic acid, particularly given the 6-month delay to VCUG.1,2 The authors chose tricalcium phosphate ceramic due to logistic needs but the cost savings of this equally biocompatible material should be attractive to all urologists and could enhance the savings achieved by curtailed diagnostic followup. As the durable efficacy of endoscopic injection regresses toward a mean of two thirds, efforts redouble to focus on “clinical” outcome and ignore “anatomical” results, under the guise of patient preference. The clinical well-being experienced by nearly all of the patients in this series and the clinical equivalence observed in the 146 “anatomical cures” and 54 “anatomical failures” suggest that it may be presumptive to treat the majority of children (particularly when
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UROCOL INJECTION FOR VESICOURETERAL REFLUX
30% are male) with endoscopic or even open surgery except when medical treatment fails. Robert Mevorach Department of Urology University of Rochester School of Medicine Rochester, New York
1. Perez-Brayfield, M., Kirsch, A. J., Hensle, T. W., Koyle, M. A., Furness, P. and Scherz, H. C.: Endoscopic treatment with dextranomer/hyaluronic acid for complex cases of vesicoureteral reflux. J Urol, 172: 1614, 2004 2. Kirsch, A. J., Perez-Brayfield, M., Smith, E. A. and Scherz, H. C.: The modified sting procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol, 171: 2413, 2004
Purpose: We evaluated the effect of Urocol injection for the endoscopic treatment of VUR in children. Materials and Methods: A total of 208 children (62 boys and 146 girls, mean age 4.78 years) with 346 refluxing ureters underwent subureteral injection of Urocol between January 2000 and February 2002. VCUG was performed at 6 months, and ultrasound was performed at 1 week and 3 months postoperatively. Results: Followup VCUG showed no evidence of reflux in 240 ureters (69%), significant decrease in reflux grade in 62 (18%) and no change in 44 (13%). Ultrasound revealed no obstruction or hydronephrosis. Conclusions: The results of this study demonstrate that subureteral injection of Urocol was effective for the treatment of VUR. We conclude that Urocol represents a new, safe, simple, less expensive and repeatable technique in treating VUR. Key Words: vesico-ureteral reflux, endoscopy, prostheses and implants, ureter, tricalcium phosphate
UR is one of the most common urinary tract anomalies in childhood. Persistent VUR can result in progressive renal damage and can ultimately lead to renal failure. The goal of treating children with VUR is prevention of recurrent pyelonephritis and subsequent renal scarring. The main treatment options are administration of prophylactic antibiotics, open surgery and endoscopic submucosal biomaterial injection. The long-term requirement of prophylactic antibiotic therapy and the occasional complications of surgical techniques led to the development of endoscopic treatment of VUR in the early 1980s.1 Since then, many foreign materials such as polytetrafluoroethylene, polydimethylsiloxane and bovine collagen have been used for subureteral injections, with cure rates ranging from 60% to 80%.2– 4 However, several studies have documented disadvantages of these materials. Polytetrafluoroethylene exhibits a risk of granuloma formation and migration to distant organs.5,6 Silicone has been associated with autoimmune reactions, and migration has also been reported.7 Injection of bovine collagen has the additional drawback of being a foreign protein, which may elicit an anaphylactic reaction, and because of autodigestion, early recurrence is reported.4 Consequently, new alternative substances have been proposed, including dextranomer,8 chondrocyte,9 calcium hydroxylaptite10 and Urocol.11 Dextranomer, which is now widely used, has been shown to be safe and highly successful for endoscopic treatment of VUR, with an 82% total cure rate.8 However, it is expensive and its transportation has special temperature limitations. The main component of Urocol is hy-
V
Submitted for publication August 26, 2005. * Correspondence and requests for reprints: No. 36, 2nd floor, 7th St., Saadat-Abad Ave., Tehran 19987, Iran (telephone: 98-21-22089946; FAX: 98-21-2206-9451; e-mail: [email protected]).
0022-5347/06/1754-1480/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
droxylapatite, which has been discussed extensively in the literature with regard to biochemical composition and in vivo predictability, as well as potential concerns and advantages.12 However, clinical data are lacking on the use of Urocol as an injectable substance for the endoscopic correction of VUR. Therefore, the objective of this study was to report our experience with subureteral Urocol injection in children with VUR. PATIENTS AND METHODS A total of 208 patients with 346 refluxing ureters underwent endoscopic subureteral injection of Urocol between January 2000 and February 2002. There were 146 girls and 62 boys. VUR was bilateral in 146 patients (70.2%) and unilateral in 62 (29.8%). Patient age ranged from 1 month to 18 years (mean 4.8 years). Vesicoureteral reflux was grade I in 9 ureters, grade II in 138, grade III in 96, grade IV in 73 and grade V in 30. Inclusion criteria were proved grade III to V vesicoureteral reflux on voiding VCUG, and low grade (I to II) VUR accompanied by urinary tract infection despite adequate antibiotic treatment or high grade reflux in the contralateral ureter. Exclusion criteria were secondary VUR due to neuropathic voiding dysfunction, posterior urethral valves, anterior urethral valves, the bladder exstrophy complex, classic epispadias, duplex system and failed ureteral reimplantation. Nondegradable urological implant. Urocol paste contains polyethylene glycol 400 and polyglucosamine ester in Ringer solution. Procedure. With the patient under general anesthesia routine cystoscopy is performed, and the ureteral orifice shape and location, and trigone and bladder wall trabeculation are observed. A Storz cystoscopic injection needle consisting of a
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Vol. 175, 1480-1484, April 2006 Printed in U.S.A. DOI:10.1016/S0022-5347(05)00675-0
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FIG. 1. A, VCUG demonstrates bilateral VUR. B, VCUG of same patient 6 months after subureteral Urocol injection shows resolution of reflux.
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Of 18 patients who experienced 1 failed Urocol implantation 17 underwent an additional injection. VCUG performed 6 months later showed no evidence of reflux in 11 patients (64.7%), a significant grade reduction in 3 (17.6%) and no improvement in 3 (17.6%). There was no significant difference between the overall success rates of the first and second Urocol implantations. Among 56 patients with reduced reflux 45 (80.4%) had postoperative bilateral or unilateral low grade VUR (grade I or II) and underwent noninvasive treatment. A total of 11 patients (19.6%) with grade III or IV reflux were offered a repeat injection. Reinjection was performed in 9 patients, and the complete success rate was 66.7%. Our treatment algorithm and patient outcomes are illustrated in figure 2. No patient experienced complications such as dysuria or gross hematuria after the procedure, and followup ultrasound revealed no evidence of hydronephrosis in any of the treated patients. DISCUSSION
10 mm long, 21 gauge, 3Fr needle connected to a 30 cm length plastic tube is advanced through the working channel of a miniature (6.75Fr) Wolf neonatal cystourethroscope. The needle tip is inserted at the 6 o’clock position into the subureteral space approximately 1 to 2 mm distal to the ureteral orifice and is advanced proximally. An average of 0.4 to 0.6 cc bulking material is injected slowly until a volcano bulge obliterates the ureteral orifice. The needle is kept in position for 2 to 3 minutes before it is withdrawn to minimize extravasation of injected material through the needle track. Renal and bladder ultrasound was obtained at 1 week and 3 months postoperatively to monitor the appearance of the upper urinary tract and the presence of hydronephrosis. To assess outcome, followup VCUG was performed 6 months after injection. All patients were carefully followed by regular clinical visits and urinary bacteriology tests, and subjects in whom the first endoscopic treatment failed were offered a second injection. Statistical methods. The data were evaluated by chisquare test and Wilcoxon signed rank test, and p value ⬍0.05 was considered statistically significant. RESULTS All patients were followed for at least 6 months, and the evaluation is still ongoing. After 6 months of followup VCUG revealed that 134 cases (64.4%) were cured completely, 56 (26.9%) were improved (downgraded at least 1 grade, or 1 ureter was cured in cases of bilateral reflux), and 18 (8.7%) remained unchanged and were considered treatment failures (fig. 1). The response to treatment in all 346 ureters and the distribution of responses according to reflux grade are summarized in the table. Comparison of reflux grades before and after treatment demonstrated a significant improvement in the treated ureters (Wilcoxon signed rank test, p ⬍0.001). However, there was no statistically significant association between reflux grade and failure rate (chisquare, p ⫽ 0.79). Subureteral Urocol injection resulted in failure rates of 10.3% and 4.8% in patients suffering from bilateral and unilateral reflux, respectively.
Endoscopic treatment of VUR has proved to be a safe and minimally invasive technique with few complications. Subureteral injections of different foreign materials (ie polytetrafluoroethylene, silicone, collagen and dextranomer) have been used to correct VUR.1– 4,8 However, there have been concerns about the side effects of treatment with some of these materials. Experimental and clinical studies have demonstrated the presence of migratory polytetrafluoroethylene particles in distant organs such as the brain and lungs following injection into the bladder.5,6 In addition, migration of silicone particles has been reported.7 It has also been shown that polytetrafluoroethylene and silicone injections may result in calcification and granuloma formation.13,14 Moreover, questions have been raised concerning the possible carcinogenicity of these materials.15,16 Finally, it is well known that foreign proteins such as silicone and bovine collagen are associated with autoimmune reactions.5,8 In experimental studies using collagen eosinophilic reactions around the injected implant have been reported.4 New biocompatible, safe and efficacious materials for the endoscopic treatment of VUR have been sought out, and new materials have been introduced for this purpose. Dextranomer has proved to be an effective implant that is well tolerated for an extended period, and may even change the management of VUR in pediatric cases.17 Initially, we started our experience with dextranomer. However, because of its difficult handling conditions (ie 8C temperature limitations) and its high cost, we decided to try another biocompatible material.
Results of endoscopic treatment with Urocol in refluxing ureters by reflux grade Reflux Grade
No. Cured (%)
No. Improved (%)
No. Failed (%)
Total No.
I II III IV V Totals
8 (89) 105 (76) 66 (69) 42 (58) 19 (63) 240 (69)
0 (0) 13 (9) 17 (18) 23 (32) 9 (30) 62 (18)
1 (11) 20 (14) 13 (14) 8 (11) 2 (7) 44 (13)
9 138 96 73 30 346
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UROCOL INJECTION FOR VESICOURETERAL REFLUX
FIG. 2. Flow chart of patients, treatment and outcomes. Urocol, Urocol
Urocol, a paste of hydroxylapatite, also seems to fulfill all treatment criteria. Urocol is an ideal material that is not allergenic and does not induce granuloma formation or migrate in the body.11 The properties of hydroxylapatite are well documented with regard to toxicity, mutagenicity and biocompatibility, and it has been observed to be a highly biocompatible material that is safe for application in humans.18 Furthermore, because hydroxylapatite is biocompatible and the particle size is between 100 and 400 m, no migration or granuloma formation has been seen.11 This material has been used in the form of coated endosseous implants in the treatment of dental patients,12 prostheses in orthopedic surgery and orbital implants in anophthalmos.19 In addition, studies suggest that ossicular replacement prostheses made of dense hydroxylapatite are suitable for reconstructive ear surgery.20 In recent years calcium hydroxylapatite gel has been used for the endoscopic treatment of VUR. An American multicenter experience reported by Mevorach et al revealed calcium hydroxylapatite gel to be a safe and effective treatment for VUR, with a 74% cure rate.10 This implant received the first limited Food and Drug Administration approval for the endoscopic treatment of VUR.10 In this study we investigated the effect of subureteral injection of Urocol in 208 children suffering from VUR. At 6-month followup reflux was cured or reduced to a lower grade in most of the injected ureters, with the results being comparable to those of Mevorach et al.10 Based on our investigation, the failure rate was not associated with reflux grade. Additionally, the success rate was higher in patients with unilateral reflux. Moreover, repeat injection resulted in an acceptable success rate. Therefore, if Urocol is not effective following an initial injection, it can be tried an additional time.
CONCLUSIONS Our results confirm that endoscopic injection of Urocol can correct reflux in a large number of patients. Because of the simplicity of the technique, rare complications, short hospitalization and high success rate, it can be considered as an alternative to other treatments for VUR. The procedure is repeatable in failed cases, without any signs of fibrosis or adhesions at previous injection sites. However, there is limited clinical experience with the use of Urocol as a biocompatible material in correcting VUR. Consequently, longterm followup of patients treated with this injectable substance is required and is ongoing at our center.
ACKNOWLEDGMENTS Mr. Behrad Kajbafzadeh reviewed the manuscript.
Abbreviations and Acronyms VCUG ⫽ voiding cystourethrography VUR ⫽ vesicoureteral reflux
REFERENCES 1. Matouschek, E.: Die behandlung des vesilorenalen refluxes durch transurethrale einspritzung von Teflon paste. Urologe A, 20: 263, 1981 2. Chertin, B., Colhoun, E., Velayudham, M. and Puri, P.: Endoscopic treatment of vesicoureteral reflux: 11 to 17 years of followup. J Urol, 167: 1443, 2002 3. Smith, D. P., Kaplan, W. E. and Oyasu, R.: Evaluation of polydimethylsiloxane as an alternative in the endoscopic treatment of vesicoureteral reflux. J Urol, 152: 1221, 1994
UROCOL INJECTION FOR VESICOURETERAL REFLUX 4. Lipsky, H. and Wurnschimmel, E.: Endoscopic treatment of vesicoureteric reflux with collagen. Five years’ experience. Br J Urol, 72: 965, 1993 5. Aaronson, I. A., Rames, R. A., Greene, W. B., Walsh, L. G., Hassal, U. and Garen, P. D.: Endoscopic treatment of reflux: migration of Teflon to the lungs and brain. Eur Urol, 23: 394, 1993 6. Malizia, A. A., Jr., Reiman, H. M., Myers, R. P., Sande, J. R., Barham, S. S., Benson, R. C., Jr. et al: Migration of granulomatous reaction after periurethral injection of polytef (Teflon). JAMA, 251: 3277, 1984 7. Biesang, A. A., 3rd and Ersek, R. A.: Mammalian response to subdermal implantation of textured microimplants. Aesthetic Plast Surg, 16: 83, 1992 8. Capozza, N., Lais, A., Nappo, S. and Caione, P.: The role of endoscopic treatment of vesicoureteral reflux: a 17-year experience. J Urol, 172: 1626, 2004 9. Caldamone, A. A. and Diamond, D. A.: Long-term results of the endoscopic correction of vesicoureteral reflux in children using autologous chondrocytes. J Urol, 165: 2224, 2001 10. Mevorach, R., Rabinowitz, R., Beck, C. and Hulbert, W.: Endoscopic treatment of vesicoureteral reflux with Coaptite™: the first 50 patients. J Urol, suppl., 167: 107, abstract 429, 2002 11. Bos, S. D., Ypma, A. F. and Timmermans, C. J.: Subureteric Urocol injection in the treatment of vesico-ureteric reflux. Br J Urol, 76: 275, 1995 12. Biesbrock, A. R. and Edgerton, M.: Evaluation of the clinical predictability of hydroxyapatite-coated endosseous dental implants: a review of the literature. Int J Oral Maxillofac Implants, 10: 712, 1995 13. Claes, H., Stroobants, D., Van Meerbeek, J., Verbeken, E., Knockaert, D. and Baert, L.: Pulmonary migration following periurethral polytetrafluoroethylene injection for urinary incontinence. J Urol, 142: 821, 1989 14. Travis, W. D., Balogh, K. and Abraham, J. L.: Silicone granulomas: report of three cases and review of the literature. Hum Pathol, 16: 19, 1985 15. Dewan, P. A.: Is injected polytetrafluoroethylene (Polytef) carcinogenic? Br J Urol, 69: 29, 1992 16. Hatanaka, S., Oneda, S., Okazaki, K., Shong, L. J., Yoshida, A., Isaka, H. et al: Induction of malignant fibrous histiocytoma in female Fisher rats by implantation of cyanoacrylate, zirconia, polyvinyl chloride or silicone. In Vivo, 7: 111, 1993 17. Aaronson, I. A.: Does Deflux alter the paradigm for the management of children with vesicoureteral reflux? Curr Urol Rep, 6: 152, 2005 18. Liu, C., Wang, W., Shen, W., Chen, T., Hu, L. and Chen, Z.: Evaluation of the biocompatibility of a nonceramic hydroxyapatite. J Endod, 23: 490, 1997 19. Jordan, D. R., Gilberg, S., Mawn, L., Brownstein, S. and Grahovac, S. Z.: The synthetic hydroxyapatite implant: a report on 65 patients. Ophthal Plast Reconstr Surg, 14: 250, 1998 20. Ye, Q., Ohsaki, K., Li, K., Li, D. J., Zhu, C. S., Ogawa, T. et al: Histological reaction to hydroxyapatite in the middle ear of rats. Auris Nasus Larynx, 28: 131, 2001
EDITORIAL COMMENTS The use of injectable bulking agents in the treatment of VUR is widely accepted in pediatric urology. It has rapidly grown in popularity in the United States since the introduction of agents that maintain a more durable implant and minimize migration or degradation of material. It is valuable to support studies that evaluate new bulking agents and will continue to foster the evolution of this therapy. However, this article raises several concerns. To begin with, one must caution against propaganda that “Persistent
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VUR can result in progressive renal damage and can ultimately lead to renal failure.” Long-term clinical studies support the premise that sterile reflux does not cause progressive renal damage. This is one of the major tenets in the medical management of VUR. Another concern involves the conclusion that “Urochol represents a new, safe, simple, less expensive” technique. This article does not present any data regarding cost of treatment or comparison of costs to other injectable materials. Therefore, this study does not support that conclusion. Furthermore, to call it “simple” is not completely accurate. There is a significant learning curve among practitioners, there are significant differences in success rates between different institutions and there are variations in technique that may alter success. The assessment of outcomes is dependent on the voiding cystourethrogram. The VCUG is certainly a skilled study of the pediatric radiologist dependent on several variables, including the quality of the voiding films, the impact of sedation and the timing of the study following surgery. These authors wait an appropriate length of time after injection to allow for resolution of swelling and contraction of the bolus. However, future studies should also strive to document specifics of the VCUG protocol (ie type and size of catheter, whether or not sedation was used, etc), and document the performance of voiding images (which is important to ensure standardization and optimal sensitivity). Last, the reduction to lower grade of reflux is an overstated benefit. It is not clear that simply reducing the grade of reflux is clinically beneficial to the patient. Reflux techniques should be judged on the cure rate alone. The success rate of alternative surgical techniques to treat reflux, such as ureteral reimplantation, are judged by cure rate alone, not improvement. Therefore, ongoing comparison should be based on that criterion. John V. Kryger Division of Pediatric Urology Department of Surgery University of Wisconsin Children’s Hospital Madison, Wisconsin The authors report a substantial series that warrants consideration that extends well beyond the confines of the 67% anatomical cure rate in patients and 69% for ureters, which compares reasonably to current series for dextranomer/hyaluronic acid, particularly given the 6-month delay to VCUG.1,2 The authors chose tricalcium phosphate ceramic due to logistic needs but the cost savings of this equally biocompatible material should be attractive to all urologists and could enhance the savings achieved by curtailed diagnostic followup. As the durable efficacy of endoscopic injection regresses toward a mean of two thirds, efforts redouble to focus on “clinical” outcome and ignore “anatomical” results, under the guise of patient preference. The clinical well-being experienced by nearly all of the patients in this series and the clinical equivalence observed in the 146 “anatomical cures” and 54 “anatomical failures” suggest that it may be presumptive to treat the majority of children (particularly when
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30% are male) with endoscopic or even open surgery except when medical treatment fails. Robert Mevorach Department of Urology University of Rochester School of Medicine Rochester, New York
1. Perez-Brayfield, M., Kirsch, A. J., Hensle, T. W., Koyle, M. A., Furness, P. and Scherz, H. C.: Endoscopic treatment with dextranomer/hyaluronic acid for complex cases of vesicoureteral reflux. J Urol, 172: 1614, 2004 2. Kirsch, A. J., Perez-Brayfield, M., Smith, E. A. and Scherz, H. C.: The modified sting procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol, 171: 2413, 2004