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Mechanisms of Failure of Endoscopic Treatment of Vesicoureteral Reflux Based on Endoscopic Anatomy
0022-5347/03/1704-1556/0 THE JOURNAL OF UROLOGY® Copyright © 2003 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 170, 1556 –1559, October 2003 Printed in U.S.A.
DOI: 10.1097/01.ju.0000084303.21983.26
MECHANISMS OF FAILURE OF ENDOSCOPIC TREATMENT OF VESICOURETERAL REFLUX BASED ON ENDOSCOPIC ANATOMY DAVID A. DIAMOND,* ANTHONY A. CALDAMONE, STUART B. BAUER
AND
ALAN B. RETIK
From the Department of Urology, Children’s Hospital, Harvard Medical School, Boston, Massachusetts, and Department of Urology, Hasbro Children’s Hospital, Providence, Rhode Island (AAC)
ABSTRACT
Purpose: We examined the mechanisms responsible for technical failure of the endoscopic technique for correcting vesicoureteral reflux based on endoscopic anatomy. Materials and Methods: The study included 25 patients, 2 to 15 years old (mean age 8) who received 57 ureteral injections on 1 or more occasions which failed to correct reflux. Each endoscopic procedure for every patient was videotaped and endoscopic photographs were taken to document pretreatment and posttreatment anatomy. Based on the comparative endoscopic anatomical findings, failures were categorized as secondary to volume loss, mound displacement, mound extrusion or indeterminate etiology. Results: Of the 57 ureters the cause of failure was believed to be due to mound displacement in 35%, volume loss in 23%, displacement and volume loss in 29%, mound extrusion in 2% and indeterminate in 11%. The direction of mound displacement was toward the bladder neck (medial, distal) in 76% of those cases. Conclusions: Endoscopic anatomical findings can account for failure of the injection technique to correct reflux in the majority of failed cases (90%). Mound displacement and volume loss account comparably for treatment failure. One incidence of mound extrusion, previously hypothesized as a mechanism for treatment failure, was documented in our study. KEY WORDS: vesico-ureteral reflux, endoscopy, chondrocytes
Since the STING technique was first described in 1984 by Puri and O’Donnell, endoscopic correction of vesicoureteral reflux using a variety of substances has been studied.1 The majority of series have focused on success rate as a function of reflux severity and number of procedures required.2 Few studies have analyzed reasons for failure of an endoscopic approach. We examined the mechanisms responsible for technical failure of the endoscopic technique based on endoscopic anatomy. MATERIALS AND METHODS
Between 1997 and 2002 a clinical study of the safety and efficacy of the use of autologous chondrocytes for endoscopic correction of vesicoureteral reflux was performed at Children’s Hospital, Boston and Hasbro Children’s Hospital, Providence, Rhode Island.3 The study included 22 girls and 3 boys 2 to 15 years old (mean age 8) with a total of 57 ureters in whom endoscopic treatment failed on 1 or more occasions. At the outset of treatment reflux was grade III in half of the ureters, grade II in a quarter, and equally divided between grades I and IV in a quarter. The endoscopic technique used has been described previously. A mean volume of 0.91 cc of chondrocytes in alginate was injected endoscopically, with a maximum volume of 3 cc. The desired anatomical end point was a volcano shape to the ureteral orifice, such that the orifice was elevated to sit squarely atop the implanted mound. Our protocol dictated that a voiding cystourethrogram be performed at 3 months and 12 months after endoscopic treatment to confirm the initial and intermediate success of surgery. In the event of failure to correct reflux noted on either postoperative study, patients were allowed the option of endoscopic re-treatment
to correct the reflux, and 43 received 1 reinjection and 14 received 2. Each endoscopic procedure for every patient was videotaped and endoscopic photographs were taken to document pretreatment and posttreatment anatomy. Each patient opted for at least 1 reinjection attempt at endoscopic cure. Preoperative endoscopic photographs documented the endoscopic anatomy of those cases that ultimately failed endoscopic treatment altogether and were treated with open ureteral reimplantation. All procedures were performed by 1 investigator at each center (DAD, AAC). Based on the comparative endoscopic anatomical findings, failures were categorized as secondary to volume loss (in excess of the anticipated 50% loss of volume), mound displacement, mound extrusion or indeterminate etiology.
RESULTS
Technical failure due to displacement of the chondrocyte mound from its original location beneath the ureteral orifice to an adjacent location no longer providing uniform backing and elevation of the orifice occurred as an isolated phenomenon in 20 ureters (35%). In an additional 17 ureters (29%) displacement and volume loss as combined phenomena were believed responsible for technical failures (fig. 1). When displacement of a mound was recognized, it was categorized in terms of direction away from its original position beneath the ureteral orifice (see table). Distal and medial displacement, toward the bladder neck, was most frequently recognized, accounting for 28 of the 37 migrations (76%). Technical failure due to isolated volume loss was believed to have occurred in 13 ureters (23%). As a 50% loss of volume was anticipated due to absorption of the alginate vehicle, an observed loss in excess of this volume was required for this phenomenon to be considered a primary cause of failure. Early in the study low volumes (less than 0.5 cc) of material
Supported by Curis, Inc. * Corresponding author: Children’s Hospital, 300 Longwood Ave., Boston, Massachusetts 02115 (e-mail: [email protected]). 1556
FAILURE OF ENDOSCOPIC TREATMENT OF VESICOURETERAL REFLUX
1557
FIG. 1. Endoscopic appearances of ureteral orifices following initial chondrocyte injection for bilateral grade III vesicoureteral reflux. A, right orifice. B, left orifice. C, successful right treatment 6 months postoperatively. D, failed left treatment secondary to distal mound migration and volume loss.
Direction of mound displacement No. Pts (%) Medial Distal ⫹ medial Distal Distal ⫹ lateral Lateral
9 (24) 12 (32) 7 (18) 1 (3) 8 (22)
were injected which correlated with failure due to volume loss. Once we increased the injected volumes to greater than 0.5 cc consistently we found no correlation between the volume of material injected and the perceived mechanism for failure. Two potential explanations are that volume loss was always relative to the initial injection, and that the technical complexity of re-treatments entailed injecting around established mounds, often in more than 1 location. In 1 patient (2%) evidence of mound extrusion was noted, and the endoscopic appearance resembled that of an incised ureterocele (fig. 2). In 6 cases, 3 from each center, no specific technical problem could be recognized as the etiology for failure. DISCUSSION
The endoscopic technique of correcting vesicoureteral reflux has considerable appeal because of its minimal invasive-
FIG. 2. A, successful right treatment of grade II vesicoureteral reflux. B, failed left treatment of grade III reflux secondary to mound extrusion (note incised ureterocele appearance).
ness, short duration and rapid recovery. Now that a bulking agent has been approved for this purpose by the Food and Drug Administration, this approach provides a viable alternative in the United States to traditional antireflux surgery. In comparing these approaches for families, the tradeoff for the minimal invasiveness of an endoscopic approach is its lower success rates compared to those of open surgery (65% to 70% versus 98%). Therefore, it would seem that any method to improve the success rates achieved with endoscopic correction would be valuable in making it comparable to or even more desirable than conventional surgery. With this in mind, we evaluated our failures with endoscopic treatment of vesicoureteral reflux to look for technical deficiencies, based on endoscopic anatomical findings. The precise mechanism by which endoscopic injection corrects reflux remains indeterminate. Proposed mechanisms have included improved fixation of the ureter to the trigonal musculature, improved backing of the ureterovesical junction by the bulking agent and decreased ureteral luminal caliber by the mound.2 We found it particularly enlightening to review cases of bilateral vesicoureteral reflux in which endoscopy was a success on 1 side and failed on the other side, and to make comparisons based on anatomical findings. We found a recurring pattern of mound displacement (in which the ureteral orifice appeared to have “fallen off of the mound”) or marked volume loss on the side that failed. Given the large number of series reported using a variety of injectable substances to correct reflux endoscopically, it is surprising that so few have evaluated anatomical causes of failure, even as many of these patients have undergone 2 or 3 endoscopic procedures as well as a subsequent open operation to resolve the reflux. There have been 3 reports on anatomical causes of failure on endoscopic therapy using polytetrafluoroethylene paste or polydimethylsiloxane. Bhatti et al evaluated unsuccessfully treated ureters at 3 months postoperatively and found that 48% had no evidence of a mound and the mound appeared misplaced in 35%.4 They proposed that the failures were due to leakage of polytetrafluoroethylene paste following injection or subsequent
1558
FAILURE OF ENDOSCOPIC TREATMENT OF VESICOURETERAL REFLUX
shrinkage of the mound. In a small number of failed cases Dewan and Higgs noted polytetrafluoroethylene mounds abnormally positioned relative to the ureteral orifice.5 In their study of 15 failures following polydimethylsiloxane injection, Herz et al noted on cystoscopy that the mound in 7 cases was abnormally located medial or lateral to the longitudinal axis of the ureter.6 They authors hypothesized that if a mound was not visualized on ultrasound, it could represent erosion of the overlying mucosa and expulsion of the implant material during voiding. Vereecken and Proesmans proposed a similar hypothesis to account for some of their failures following polytetrafluoroethylene injection.7 Collagen injections were studied by Trsinar8 and Frey9 et al, all of whom concluded that failures were associated with improper positioning of the collagen mound relative to the ureteral orifice. Frey et al did not distinguish between faulty injection technique and subsequent displacement medially or laterally, whereas Trsinar et al proposed that displacement related to voiding dysfunction. However, no urodynamic studies or voiding diaries were completed on their patients to corroborate this hypothesis. Capozza et al also proposed bladder instability as an etiology for the medial and distal displacement of the collagen and, subsequently, dextranomer/ hyaluronic acid copolymer mounds for failure in patients following injection therapy.10 Based on analysis of videotape images of the ureteral orifice before, after and at subsequent endoscopy (as in our series) the authors concluded that of the 45 failures 60% were due to mound displacement and 33% to mound absence in the Deflux series. These clinicians found displacement to have occurred typically toward the bladder neck, and they proposed high intravesical pressures as the culprit, although no urodynamic data were presented. No reason for loss of the dextranomer/hyaluronic acid copolymer in 33% of cases was hypothesized.11 To our knowledge our report is the first related to the endoscopic appearance of autologous chondrocytes in alginate. While differing biological behaviors of each bulking agent may account for different etiologies of technical failure, the potential mechanisms responsible seem common to all. We noted mound displacement and volume loss to occur with relatively equal frequency in our series. Because a 50% volume loss is expected, due to alginate absorption, it was anticipated that some failures would result from lack of a critical volume of bulking agent beneath the ureteral orifice. Although the operators would inject enough chondrocytes in alginate to afford adequate bulking despite absorption of the vehicle, this determination was imprecise. Displacement of the mound, which occurred with slightly greater frequency (64% versus 52%), had not been anticipated in our series. We attempted to categorize the position of the displaced mound relative to the ureteral orifice. We expected that bladder contractions had a significant role, and found that in roughly three-fourths of the patients there appeared to be a distinctly distal component to the displacement. In contrast to the series of Capozza et al,10 we could not document a higher incidence of voiding dysfunction based on clinical history in our endoscopic failures related to mound displacement. It is noteworthy that 2 cases reported by Capozza et al and a number of our unilateral failures seemed to be caused by mound displacement on the ipsilateral side with the cured, contralateral side having a normal location for the mound. This finding suggests technical and biological factors above and beyond increased bladder contractility. Admit-
tedly, a shortcoming of our study was that assessment of the endoscopic appearance of corrected reflux was limited to those few cases with unilateral failure. Finally, mound extrusion has been postulated by other authors but not yet reported to occur. Our case in which the extrusion site resembled an incised ureterocele represents the first documented occurrence of this adverse outcome to our knowledge. Its etiology is unclear, as similar volumes were injected bilaterally (left 1 cc, right 0.8 cc) using identical technique. CONCLUSIONS
Long-term alterations in the anatomy of the ureteral orifice following endoscopic treatment for reflux likely explain treatment failure and are recognizable endoscopically. Based on our experience, it is likely that a minimum critical volume for each injectable substance will be necessary for success. Positioning the mound slightly more superolateral relative to the ureteral orifice, rather than inferomedial, may accommodate displacement and contribute to success. It is possible that certain injectable agents will prove more adherent to adjacent tissue and, therefore, less likely to be displaced. It is also possible that urodynamic studies may prove useful in patient selection for open versus endoscopic techniques to correct reflux. These issues will require further study. REFERENCES
1. Puri, P. and O’Donnell, B.: Correction of experimentally produced vesicoureteric reflux in the piglet by intravesical injection of Teflon. Br Med J, 289: 5, 1984 2. Joyner, B. D. and Atala, A.: Endoscopic substances for the treatment of vesico-ureteral reflux. Urology, 50: 489, 1997 3. 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 4. Bhatti, H. A., Khattak, H. and Boston, V. E.: Efficacy and causes of failure of endoscopic subureteric injection of Teflon in the treatment of primary vesicoureteral reflux. Br J Urol, 71: 221, 1993 5. Dewan, P. A. and Higgs, M. J.: Correlation of the endoscopic appearance with clinical outcome for submucous polytef paste injection in vesicoureteral reflux. Aust N Z J Surg, 65: 642, 1995 6. Herz, D., Hafez, A., Bagli, D., Capolicchio, G., McLorie, G. and Khoury, A.: Efficacy of endoscopic subureteral polydimethylsiloxane injection for the treatment of vesicoureteral reflux in children: a North American clinical report. J Urol, 166: 1880, 2001 7. Vereecken, R. L. and Proesmans, W.: Results of endoscopic treatment of vesicoureteral reflux. J Urol, 27: 76, 1995 8. Trsinar, E., Cotic, D. and Oblak, C.: Possible causes of unsuccessful endoscopic collagen treatment of vesicoureteral reflux in children. Eur Urol, 36: 635, 1999 9. Frey, P., Berger, D., Jenny, P. and Herzog, B.: Subureteral collagen injection for endoscopic treatment of vesicoureteral reflux in children. Followup study of 97 treated ureters and histological analysis of collagen implants. J Urol, 148: 718, 1992 10. Capozza, N., Caione, P., DeGennaro, N., Nappo, S. and Patricolo, M.: Endoscopic treatment of vesicoureteral reflux and urinary incontinence: technical problems in the paediatric patient. Br J Urol, 75: 538, 1995 11. Capozza, N., Lais, A., Matarazzo, E., Nappo, S., Patricolo, M. and Caione, P.: Influence of voiding dysfunction on the outcome of endoscopic treatment for vesicoureteral reflux. J Urol, 168: 1695, 2002
FAILURE OF ENDOSCOPIC TREATMENT OF VESICOURETERAL REFLUX
1559
DISCUSSION Dr. Mark Adams. Do you ever see anything on the preoperative pictures in this retrospective study, which suggests that it is the anatomy that might increase the risk of failure or the need for a second injection. Also, as a corollary, do you ever look in and decide this is not a patient for an injection? Dr. David Diamond. We had a couple of children with grade IV reflux in whom the ureteral orifice was extremely lateral and I thought it was going to be extremely tough to correct. But we gave it a try and we were successful in some. Therefore, I found that there was no way that I could predict preoperatively which patients would do well. What was most interesting to me was to study those cases that were successes on 1 side and failures on the other. By and large, these patients had relatively symmetric anatomy preoperatively, and either for technical or other physiological reasons, had enough migration or shrinkage of the mound which resulted in failure. Dr. Antoine Khoury. Can you identify a subureteral mound by ultrasound postoperatively and correlate that with the voiding cystourethrogram, because that may itself be a marker of success. Doctor Diamond. That has been studied by our radiologists and what they found was that with time, at least with the chondrocyte and alginate material, the mounds would become more calcific by ultrasound. The absence of a mound correlated closely with failure. However, if they saw a mound it was of no predictive value, presumably because the mound may not be in the right place.
Vol. 170, 1556 –1559, October 2003 Printed in U.S.A.
DOI: 10.1097/01.ju.0000084303.21983.26
MECHANISMS OF FAILURE OF ENDOSCOPIC TREATMENT OF VESICOURETERAL REFLUX BASED ON ENDOSCOPIC ANATOMY DAVID A. DIAMOND,* ANTHONY A. CALDAMONE, STUART B. BAUER
AND
ALAN B. RETIK
From the Department of Urology, Children’s Hospital, Harvard Medical School, Boston, Massachusetts, and Department of Urology, Hasbro Children’s Hospital, Providence, Rhode Island (AAC)
ABSTRACT
Purpose: We examined the mechanisms responsible for technical failure of the endoscopic technique for correcting vesicoureteral reflux based on endoscopic anatomy. Materials and Methods: The study included 25 patients, 2 to 15 years old (mean age 8) who received 57 ureteral injections on 1 or more occasions which failed to correct reflux. Each endoscopic procedure for every patient was videotaped and endoscopic photographs were taken to document pretreatment and posttreatment anatomy. Based on the comparative endoscopic anatomical findings, failures were categorized as secondary to volume loss, mound displacement, mound extrusion or indeterminate etiology. Results: Of the 57 ureters the cause of failure was believed to be due to mound displacement in 35%, volume loss in 23%, displacement and volume loss in 29%, mound extrusion in 2% and indeterminate in 11%. The direction of mound displacement was toward the bladder neck (medial, distal) in 76% of those cases. Conclusions: Endoscopic anatomical findings can account for failure of the injection technique to correct reflux in the majority of failed cases (90%). Mound displacement and volume loss account comparably for treatment failure. One incidence of mound extrusion, previously hypothesized as a mechanism for treatment failure, was documented in our study. KEY WORDS: vesico-ureteral reflux, endoscopy, chondrocytes
Since the STING technique was first described in 1984 by Puri and O’Donnell, endoscopic correction of vesicoureteral reflux using a variety of substances has been studied.1 The majority of series have focused on success rate as a function of reflux severity and number of procedures required.2 Few studies have analyzed reasons for failure of an endoscopic approach. We examined the mechanisms responsible for technical failure of the endoscopic technique based on endoscopic anatomy. MATERIALS AND METHODS
Between 1997 and 2002 a clinical study of the safety and efficacy of the use of autologous chondrocytes for endoscopic correction of vesicoureteral reflux was performed at Children’s Hospital, Boston and Hasbro Children’s Hospital, Providence, Rhode Island.3 The study included 22 girls and 3 boys 2 to 15 years old (mean age 8) with a total of 57 ureters in whom endoscopic treatment failed on 1 or more occasions. At the outset of treatment reflux was grade III in half of the ureters, grade II in a quarter, and equally divided between grades I and IV in a quarter. The endoscopic technique used has been described previously. A mean volume of 0.91 cc of chondrocytes in alginate was injected endoscopically, with a maximum volume of 3 cc. The desired anatomical end point was a volcano shape to the ureteral orifice, such that the orifice was elevated to sit squarely atop the implanted mound. Our protocol dictated that a voiding cystourethrogram be performed at 3 months and 12 months after endoscopic treatment to confirm the initial and intermediate success of surgery. In the event of failure to correct reflux noted on either postoperative study, patients were allowed the option of endoscopic re-treatment
to correct the reflux, and 43 received 1 reinjection and 14 received 2. Each endoscopic procedure for every patient was videotaped and endoscopic photographs were taken to document pretreatment and posttreatment anatomy. Each patient opted for at least 1 reinjection attempt at endoscopic cure. Preoperative endoscopic photographs documented the endoscopic anatomy of those cases that ultimately failed endoscopic treatment altogether and were treated with open ureteral reimplantation. All procedures were performed by 1 investigator at each center (DAD, AAC). Based on the comparative endoscopic anatomical findings, failures were categorized as secondary to volume loss (in excess of the anticipated 50% loss of volume), mound displacement, mound extrusion or indeterminate etiology.
RESULTS
Technical failure due to displacement of the chondrocyte mound from its original location beneath the ureteral orifice to an adjacent location no longer providing uniform backing and elevation of the orifice occurred as an isolated phenomenon in 20 ureters (35%). In an additional 17 ureters (29%) displacement and volume loss as combined phenomena were believed responsible for technical failures (fig. 1). When displacement of a mound was recognized, it was categorized in terms of direction away from its original position beneath the ureteral orifice (see table). Distal and medial displacement, toward the bladder neck, was most frequently recognized, accounting for 28 of the 37 migrations (76%). Technical failure due to isolated volume loss was believed to have occurred in 13 ureters (23%). As a 50% loss of volume was anticipated due to absorption of the alginate vehicle, an observed loss in excess of this volume was required for this phenomenon to be considered a primary cause of failure. Early in the study low volumes (less than 0.5 cc) of material
Supported by Curis, Inc. * Corresponding author: Children’s Hospital, 300 Longwood Ave., Boston, Massachusetts 02115 (e-mail: [email protected]). 1556
FAILURE OF ENDOSCOPIC TREATMENT OF VESICOURETERAL REFLUX
1557
FIG. 1. Endoscopic appearances of ureteral orifices following initial chondrocyte injection for bilateral grade III vesicoureteral reflux. A, right orifice. B, left orifice. C, successful right treatment 6 months postoperatively. D, failed left treatment secondary to distal mound migration and volume loss.
Direction of mound displacement No. Pts (%) Medial Distal ⫹ medial Distal Distal ⫹ lateral Lateral
9 (24) 12 (32) 7 (18) 1 (3) 8 (22)
were injected which correlated with failure due to volume loss. Once we increased the injected volumes to greater than 0.5 cc consistently we found no correlation between the volume of material injected and the perceived mechanism for failure. Two potential explanations are that volume loss was always relative to the initial injection, and that the technical complexity of re-treatments entailed injecting around established mounds, often in more than 1 location. In 1 patient (2%) evidence of mound extrusion was noted, and the endoscopic appearance resembled that of an incised ureterocele (fig. 2). In 6 cases, 3 from each center, no specific technical problem could be recognized as the etiology for failure. DISCUSSION
The endoscopic technique of correcting vesicoureteral reflux has considerable appeal because of its minimal invasive-
FIG. 2. A, successful right treatment of grade II vesicoureteral reflux. B, failed left treatment of grade III reflux secondary to mound extrusion (note incised ureterocele appearance).
ness, short duration and rapid recovery. Now that a bulking agent has been approved for this purpose by the Food and Drug Administration, this approach provides a viable alternative in the United States to traditional antireflux surgery. In comparing these approaches for families, the tradeoff for the minimal invasiveness of an endoscopic approach is its lower success rates compared to those of open surgery (65% to 70% versus 98%). Therefore, it would seem that any method to improve the success rates achieved with endoscopic correction would be valuable in making it comparable to or even more desirable than conventional surgery. With this in mind, we evaluated our failures with endoscopic treatment of vesicoureteral reflux to look for technical deficiencies, based on endoscopic anatomical findings. The precise mechanism by which endoscopic injection corrects reflux remains indeterminate. Proposed mechanisms have included improved fixation of the ureter to the trigonal musculature, improved backing of the ureterovesical junction by the bulking agent and decreased ureteral luminal caliber by the mound.2 We found it particularly enlightening to review cases of bilateral vesicoureteral reflux in which endoscopy was a success on 1 side and failed on the other side, and to make comparisons based on anatomical findings. We found a recurring pattern of mound displacement (in which the ureteral orifice appeared to have “fallen off of the mound”) or marked volume loss on the side that failed. Given the large number of series reported using a variety of injectable substances to correct reflux endoscopically, it is surprising that so few have evaluated anatomical causes of failure, even as many of these patients have undergone 2 or 3 endoscopic procedures as well as a subsequent open operation to resolve the reflux. There have been 3 reports on anatomical causes of failure on endoscopic therapy using polytetrafluoroethylene paste or polydimethylsiloxane. Bhatti et al evaluated unsuccessfully treated ureters at 3 months postoperatively and found that 48% had no evidence of a mound and the mound appeared misplaced in 35%.4 They proposed that the failures were due to leakage of polytetrafluoroethylene paste following injection or subsequent
1558
FAILURE OF ENDOSCOPIC TREATMENT OF VESICOURETERAL REFLUX
shrinkage of the mound. In a small number of failed cases Dewan and Higgs noted polytetrafluoroethylene mounds abnormally positioned relative to the ureteral orifice.5 In their study of 15 failures following polydimethylsiloxane injection, Herz et al noted on cystoscopy that the mound in 7 cases was abnormally located medial or lateral to the longitudinal axis of the ureter.6 They authors hypothesized that if a mound was not visualized on ultrasound, it could represent erosion of the overlying mucosa and expulsion of the implant material during voiding. Vereecken and Proesmans proposed a similar hypothesis to account for some of their failures following polytetrafluoroethylene injection.7 Collagen injections were studied by Trsinar8 and Frey9 et al, all of whom concluded that failures were associated with improper positioning of the collagen mound relative to the ureteral orifice. Frey et al did not distinguish between faulty injection technique and subsequent displacement medially or laterally, whereas Trsinar et al proposed that displacement related to voiding dysfunction. However, no urodynamic studies or voiding diaries were completed on their patients to corroborate this hypothesis. Capozza et al also proposed bladder instability as an etiology for the medial and distal displacement of the collagen and, subsequently, dextranomer/ hyaluronic acid copolymer mounds for failure in patients following injection therapy.10 Based on analysis of videotape images of the ureteral orifice before, after and at subsequent endoscopy (as in our series) the authors concluded that of the 45 failures 60% were due to mound displacement and 33% to mound absence in the Deflux series. These clinicians found displacement to have occurred typically toward the bladder neck, and they proposed high intravesical pressures as the culprit, although no urodynamic data were presented. No reason for loss of the dextranomer/hyaluronic acid copolymer in 33% of cases was hypothesized.11 To our knowledge our report is the first related to the endoscopic appearance of autologous chondrocytes in alginate. While differing biological behaviors of each bulking agent may account for different etiologies of technical failure, the potential mechanisms responsible seem common to all. We noted mound displacement and volume loss to occur with relatively equal frequency in our series. Because a 50% volume loss is expected, due to alginate absorption, it was anticipated that some failures would result from lack of a critical volume of bulking agent beneath the ureteral orifice. Although the operators would inject enough chondrocytes in alginate to afford adequate bulking despite absorption of the vehicle, this determination was imprecise. Displacement of the mound, which occurred with slightly greater frequency (64% versus 52%), had not been anticipated in our series. We attempted to categorize the position of the displaced mound relative to the ureteral orifice. We expected that bladder contractions had a significant role, and found that in roughly three-fourths of the patients there appeared to be a distinctly distal component to the displacement. In contrast to the series of Capozza et al,10 we could not document a higher incidence of voiding dysfunction based on clinical history in our endoscopic failures related to mound displacement. It is noteworthy that 2 cases reported by Capozza et al and a number of our unilateral failures seemed to be caused by mound displacement on the ipsilateral side with the cured, contralateral side having a normal location for the mound. This finding suggests technical and biological factors above and beyond increased bladder contractility. Admit-
tedly, a shortcoming of our study was that assessment of the endoscopic appearance of corrected reflux was limited to those few cases with unilateral failure. Finally, mound extrusion has been postulated by other authors but not yet reported to occur. Our case in which the extrusion site resembled an incised ureterocele represents the first documented occurrence of this adverse outcome to our knowledge. Its etiology is unclear, as similar volumes were injected bilaterally (left 1 cc, right 0.8 cc) using identical technique. CONCLUSIONS
Long-term alterations in the anatomy of the ureteral orifice following endoscopic treatment for reflux likely explain treatment failure and are recognizable endoscopically. Based on our experience, it is likely that a minimum critical volume for each injectable substance will be necessary for success. Positioning the mound slightly more superolateral relative to the ureteral orifice, rather than inferomedial, may accommodate displacement and contribute to success. It is possible that certain injectable agents will prove more adherent to adjacent tissue and, therefore, less likely to be displaced. It is also possible that urodynamic studies may prove useful in patient selection for open versus endoscopic techniques to correct reflux. These issues will require further study. REFERENCES
1. Puri, P. and O’Donnell, B.: Correction of experimentally produced vesicoureteric reflux in the piglet by intravesical injection of Teflon. Br Med J, 289: 5, 1984 2. Joyner, B. D. and Atala, A.: Endoscopic substances for the treatment of vesico-ureteral reflux. Urology, 50: 489, 1997 3. 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 4. Bhatti, H. A., Khattak, H. and Boston, V. E.: Efficacy and causes of failure of endoscopic subureteric injection of Teflon in the treatment of primary vesicoureteral reflux. Br J Urol, 71: 221, 1993 5. Dewan, P. A. and Higgs, M. J.: Correlation of the endoscopic appearance with clinical outcome for submucous polytef paste injection in vesicoureteral reflux. Aust N Z J Surg, 65: 642, 1995 6. Herz, D., Hafez, A., Bagli, D., Capolicchio, G., McLorie, G. and Khoury, A.: Efficacy of endoscopic subureteral polydimethylsiloxane injection for the treatment of vesicoureteral reflux in children: a North American clinical report. J Urol, 166: 1880, 2001 7. Vereecken, R. L. and Proesmans, W.: Results of endoscopic treatment of vesicoureteral reflux. J Urol, 27: 76, 1995 8. Trsinar, E., Cotic, D. and Oblak, C.: Possible causes of unsuccessful endoscopic collagen treatment of vesicoureteral reflux in children. Eur Urol, 36: 635, 1999 9. Frey, P., Berger, D., Jenny, P. and Herzog, B.: Subureteral collagen injection for endoscopic treatment of vesicoureteral reflux in children. Followup study of 97 treated ureters and histological analysis of collagen implants. J Urol, 148: 718, 1992 10. Capozza, N., Caione, P., DeGennaro, N., Nappo, S. and Patricolo, M.: Endoscopic treatment of vesicoureteral reflux and urinary incontinence: technical problems in the paediatric patient. Br J Urol, 75: 538, 1995 11. Capozza, N., Lais, A., Matarazzo, E., Nappo, S., Patricolo, M. and Caione, P.: Influence of voiding dysfunction on the outcome of endoscopic treatment for vesicoureteral reflux. J Urol, 168: 1695, 2002
FAILURE OF ENDOSCOPIC TREATMENT OF VESICOURETERAL REFLUX
1559
DISCUSSION Dr. Mark Adams. Do you ever see anything on the preoperative pictures in this retrospective study, which suggests that it is the anatomy that might increase the risk of failure or the need for a second injection. Also, as a corollary, do you ever look in and decide this is not a patient for an injection? Dr. David Diamond. We had a couple of children with grade IV reflux in whom the ureteral orifice was extremely lateral and I thought it was going to be extremely tough to correct. But we gave it a try and we were successful in some. Therefore, I found that there was no way that I could predict preoperatively which patients would do well. What was most interesting to me was to study those cases that were successes on 1 side and failures on the other. By and large, these patients had relatively symmetric anatomy preoperatively, and either for technical or other physiological reasons, had enough migration or shrinkage of the mound which resulted in failure. Dr. Antoine Khoury. Can you identify a subureteral mound by ultrasound postoperatively and correlate that with the voiding cystourethrogram, because that may itself be a marker of success. Doctor Diamond. That has been studied by our radiologists and what they found was that with time, at least with the chondrocyte and alginate material, the mounds would become more calcific by ultrasound. The absence of a mound correlated closely with failure. However, if they saw a mound it was of no predictive value, presumably because the mound may not be in the right place.