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Hyaluronic Acid Injection for Vesicoureteral Reflux
Multivariate Analysis of Factors Predicting Success With Dextranomer/Hyaluronic Acid Injection for Vesicoureteral Reflux Selcuk Yucel, Amit Gupta and Warren Snodgrass* From the Department of Urology, Pediatric Urology Section, University of Texas Southwestern Medical Center at Dallas and Children’s Medical Center Dallas, Dallas, Texas
Purpose: Factors influencing outcomes of dextranomer/hyaluronic acid injection for vesicoureteral reflux remain poorly defined. We performed multivariate analysis of the experience of 1 surgeon (WS). Materials and Methods: The study group contained 168 patients and 259 refluxing units. Goal of injection was coaptation of the orifice with creation of a volcanic mound. Outcomes were determined by cystography obtained 12 weeks following injection. Intraoperative photographs of mounds were independently reviewed by 2 authors (WS, SY) without knowledge of results, and classified as “satisfactory” or “other.” Univariate and multivariate logistic regression analysis was done evaluating influence of gender, age, voiding dysfunction, reflux grade, unilateral vs bilateral reflux, ureteral duplication, orifice laterality, subureteral vs intraureteral injection, volume injected and mound appearance. Results: A single injection resolved reflux in 70% of patients and 78% of ureters. Additional injection resulted in overall success in 82% of patients and 86% of ureters. Multivariate analysis demonstrated that reflux grade, volume of dextranomer/ hyaluronic acid injected and mound appearance correlated with outcomes. A satisfactory mound was achieved in 81% of ureters, of which 87% no longer refluxed. Conclusions: The ability to create a satisfactory mound was the most important factor determining success of dextranomer/ hyaluronic acid injection. Increasing reflux grade was associated with a decreased likelihood of achieving a volcanic mound, and increasing volume injected suggested difficulty in creating a mound. Key Words: vesico-ureteral reflux, dextranomer-hyaluronic acid copolymer
espite increasing use of Dx/HA injection to resolve vesicoureteral reflux, there is uncertainty regarding factors influencing success, with few published reports of outcomes. In the original clinical trials Lackgren et al emphasized therapy for children with dilating reflux.1 Accordingly, only 5% of patients had grade II reflux, while 26% had grade IV reflux. Consequently, their series is not representative of cases referred in the United States for management, the majority of which are grades I to III reflux. Subsequently, Kirsch et al published their observations following Dx/HA injection in children with grades I to IV reflux, and examined factors potentially predicting outcomes.2 They noted a learning curve with improvement after their initial 20 cases but otherwise found no difference in success vs failure on the basis of reflux grade or injected volume. However, in a subsequent article these authors reported increased success after modifying the injection technique and using greater injection volumes.3 Lavelle et al analyzed outcomes and similarly found no difference in success by reflux grade or injected volume, noting creation of a desired mound was the only factor identified correlating with outcome.4 In contrast, Elder et al performed meta-
D
Submitted for publication September 1, 2006. * Correspondence: Department of Urology, Pediatric Urology Section, Children’s Medical Center and University of Texas Southwestern Medical Center, 6300 Harry Hines Blvd., Suite 1401, Dallas, Texas 75235 (telephone: 214-456-2481; FAX: 214-456-8803; e-mail: [email protected]).
For another article on a related topic see page 1546.
0022-5347/07/1774-1505/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION
analysis of injection therapy for reflux and found outcomes depended on reflux grade.5 Given these conflicting observations, we performed multivariate analysis of the experience of 1 surgeon (WS) with Dx/HA injection for reflux resolution. MATERIALS AND METHODS A total of 213 children (32 males, 181 females) underwent Dx/HA injection for vesicoureteral reflux by 1 surgeon (WS) between March 2002 and June 2005. For this analysis patients with neurogenic bladder (12) and those without postoperative cystography (33) were excluded from further consideration, resulting in a study group of 168 patients (26 males, 142 females) and 259 refluxing renal units. Mean patient age was 4.2 years (range 7 months to 15 years). Indications for injection included breakthrough febrile urinary tract infection despite antibiotic prophylaxis, persistent reflux and/or parental preference for injection over antibiotic prophylaxis. Preoperative evaluation included renal ultrasonography and voiding cystourethrography. Detailed questioning was used to diagnose the urge syndrome, infrequent voiding and/or constipation with therapy, including timed voiding, anticholinergics and/or laxatives as indicated, initiated before injection. Grade I reflux was treated when associated with contralateral reflux of higher grade, and in 4 patients following febrile urinary tract infection whose parents preferred injection over antibiotic prophylaxis. Cystoscopy was performed with the bladder nearly empty, with the orifice location visually categorized as “A” to “D,” following the description of Mackie and Stephens.6
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Vol. 177, 1505-1509, April 2007 Printed in U.S.A. DOI:10.1016/j.juro.2006.11.077
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FACTORS PREDICTING DEXTRANOMER/HYALURONIC ACID INJECTION SUCCESS
A, example of volcano-like mound morphology designated “satisfactory.” B, example of mound morphology designated “other”
Two different injection techniques were used. In the first 80 patients subureteral injection was performed as popularized by O’Donnell and Puri,7 which involves inserting the needle 2 to 3 mm below the orifice and advancing the tip under the distal ureter. For the subsequent 88 patients the needle was placed directly into the orifice and advanced into the subureteral space. In both procedures Dx/HA was injected with the intention to create a mound elevating and coapting the orifice. When initial puncture did not result in a symmetrical bulge coapting the orifice additional sites were injected to achieve the desired appearance. Satisfactory coaptation was confirmed visually by directing the irrigating stream toward the orifice after treatment was completed. Pre-injection and post-injection photographs were taken in all cases. Antibiotic prophylaxis continued after injection until reflux resolution was confirmed by postoperative cystography at 12 weeks. Followup renal ultrasonography was also obtained. Success was defined as complete reflux resolution. Cases with reflux resolution were released from followup, while those with persistent reflux were recommended for a 2nd injection. Cystography and renal ultrasonography were again performed at 12 weeks after repeat injections. Photographs were independently reviewed by 2 of the authors (SY, WS) to categorize posttreatment orifice configuration after first injection as a “satisfactory mound” or “other morphology” while blinded to results of subsequent cystography (see figure). Outcomes were determined for patients and ureters. In instances of bilateral reflux the higher grade was used for analysis of patient results. Reflux grade and volume of Dx/HA injected were analyzed as continuous and categorical variables. Continuous variables were compared using the t test. Categorical variables were compared by Chisquare or Fisher’s exact test. Univariate and multivariate logistic regression analysis was performed to identify factors predicting outcomes. Statistical significance was considered p ⱕ0.05, and all p values were 2-sided. Analyses were done with commercially available computer software (SAS® version 8.02).
RESULTS Patients A single Dx/HA injection resolved reflux in 117 of the 168 patients (70%). Of the 51 patients with treatment failure 33 consented to a 2nd injection, with 20 (61%) achieving complete reflux resolution. One child received a 3rd injection, which was successful. Therefore, overall success was achieved in 138 patients (82%, table 1). Table 2 provides descriptive statistics and comparison between patients successfully and unsuccessfully treated. Of analyzed factors, including gender, age, unilateral vs bilateral reflux, ureteral duplication, maximum reflux grade and dysfunctional voiding, only reflux grade differed significantly. On univariate logistic regression analysis higher reflux grade (OR 0.56, 95% CI 0.37– 0.83, p ⫽ 0.004) and bilateral reflux (OR 0.51, 95% CI 0.26 –1.01, p ⫽ 0.053) correlated with decreased reflux resolution. However, on multivariate logistic regression analysis only reflux grade significantly predicted outcomes. We did not observe a learning curve in this study, since the success rate was 70%, 70%, 66% and 73% for successive patient quartiles. Ureters A single Dx/HA injection resolved reflux in 201 of 259 ureters (78%, table 3). Of the remaining 58 refluxing ureters reflux grade diminished in 30, remained unchanged in 27 and increased in 1 (table 4). Second injections were performed in 34 ureters, with reflux resolution in 20 (59%), and a third injection
TABLE 1. Reflux resolution in patients treated with Dx/HA injection No. Successes/No. Pts (%) Reflux Grade I II III IV V Totals
First Injection 4/4 69/93 36/52 6/12 2/7
(100) (74) (69) (50) (29)
117/168 (70)
Second Injection 12/17 (71) 5/10 (50) 2/4 (50) 1/2 (50) 20/33 (61)
Third Injection
1/1 (100)
1/1 (100)
FACTORS PREDICTING DEXTRANOMER/HYALURONIC ACID INJECTION SUCCESS TABLE 2. Reflux resolution in patients and related factors No. Success (%)* Gender: M F Reflux laterality: Unilat Bilat Max reflux grade: I II III IV V Dysfunctional voiding: Yes No Not toilet trained Ureteral duplication: No Unilat Bilat
No. Failure (%)†
p Value (chi-square test)
11 (42.3) 40 (28.2)
59 (76.6) 58 (63.7)
18 (23.4) 33 (36.3)
4 (3.4) 69 (59) 36 (30.8) 6 (5.1) 2 (1.7)
0 (0) 24 (47.1) 16 (31.4) 6 (11.8) 5 (9.8) 0.41
32 (27.4) 36 (30.8) 49 (41.9)
11 (21.6) 13 (25.5) 27 (52.9)
104 (88.9) 13 (11.1) 0 (0)
43 (84.3) 6 (11.8) 2 (3.9)
0.1
TABLE 3. Reflux resolution in ureters treated with Dx/HA injection No. Successes/No. Ureters Injected (%)
Totals
I
II
III
IV
V
0 I II III IV V
11 11 0 0 0 0 0
147 122 4 20 1 0 0
79 58 2 13 6 0 0
15 8 0 4 3 0 0
7 2 1 0 3 0 1
0.03
was successful in 1 ureter. Therefore, overall success was 222 of 259 ureters (86%). Of the 259 ureters treated 27 (10%) were duplicated (table 5). Because univariate analysis showed no difference in outcomes for single vs duplicated ureters with reflux, these rates were combined in all calculations. Table 6 provides descriptive statistics and comparison between successful and failed injections for ureters. Reflux grade, orifice location, volume injected and mound morphology were significantly different between patients with resolved vs persistent reflux. Increasing reflux grade and laterality of orifices were associated with decreased success. Mean volume injected was 0.54 cc (SD 0.27), and volumes less than 0.5 cc were more likely to be successful than those greater than 0.5 cc. A “satisfactory” mound was achieved in 196 of 243 ureters (81%), of which 170 (87%) no longer refluxed and 26 (13%) persistently refluxed. “Other” morphology was seen in 47 ureters (19%), of which 17 (36%) nevertheless had reflux resolution, while 30 (64%) continued to reflux. There was no significant difference in subureteral vs intraureteral injection outcomes. Table 7 shows results of univariate and multivariate logistic regression analyses. Multivariate analysis of these factors by ureters treated indicated reflux grade (OR 0.46, p ⫽ 0.0008, 95% CI 0.29 – 0.72), injected volume (OR 0.3, p ⫽ 0.046, 95% CI 0.09 – 0.98) and mound appearance (OR 11.5, p ⬍0.0001, 95% CI 5.3–25) predicted outcomes. Achievement of a satisfactory mound was the strongest determinant of results. One patient had asymptomatic ob-
I II III IV V
Preop Reflux Grade Postop Reflux Grade
0.07
* Mean age 4.3 years (SD 3.1). † Mean age 3.9 years (SD 2.8).
Reflux Grade
TABLE 4. Results in ureters following single Dx/HA injection
0.15 15 (57.7) 102 (71.8)
First Injection
Second Injection
11/11 (100) 122/147 (83) 58/79 (73) 8/15 (53) 2/7 (29)
9/16 (56) 7/12 (58) 3/4 (75) 1/2 (50)
201/259 (78)
20/34 (59)
struction of 1 ureter following Dx/HA injection, which required surgical correction. This case has been described previously.8 DISCUSSION A single Dx/HA injection was successful in 70% of our patients and 78% of refluxing ureters. These results are similar to those reported in a meta-analysis of endoscopic therapy by Elder et al, which showed 67% of patients and 76% of ureters were successfully treated with 1 injection.5 Although Kirsch et al2 excluded patients with grade V reflux, outcomes from 1 Dx/HA injection were nearly identical to ours, with 72% of patients and 77% of ureters successfully treated.2 Similarly, Lavelle et al noted success in 71% of patients and 80% of ureters with grades I to IV reflux after 1 Dx/HA injection.4 Additional injection was successful in another 64% of our patients and 62% of ureters. Therefore, reflux resolution was achieved with 1 to 3 injections in 82% of our patients and 86% of refluxing ureters. In the meta-analysis by Elder et al5 second treatments were successful in 54% of patients and 68% of ureters, while Elmore et al9 reported on 39 patients and 53 ureters undergoing second injections with Dx/HA, noting success in 90% and 89%, respectively. The apparent difference in our results and those of Elmore et al9 probably relate to differences in reflux grade, since their mean grade was 2.2, with 15% of ureters grade I and none greater than grade III, vs our mean grade of 2.7, with no grade I and 18% grades IV and V. In our series reflux grade correlated with success of Dx/HA injection, with 100% of grade I, 83% of grade II, 73% of grade III, 53% of grade IV and 29% of grade V cases successfully managed by a single injection (p ⫽ 0.0003). When additional injections are considered success was 100%, 89%, 84%, 73% and 43% for grades I to V, respectively. Neither Kirsch2 nor Lavelle4 et al reported correlation of reflux grade with outcome. Additionally, Lavelle et al did not provide the number of ureters with each grade in their series.4 Since results by ureter in our patients and those of Kirsch et al2 appear similar, it is not clear why their analysis failed to achieve statistical significance for reflux
TABLE 5. Reflux resolution in duplicated ureters treated with Dx/HA injection No. Successes/No. Ureters Injected (%)
Third Injection Reflux Grade 1/1 (100)
1/1 (100)
1507
II III IV V Totals
First Injection
Second Injection
8/13 (62) 5/9 (56) 2/3 (67) 0/2 (0)
0/1 (0) 4/4 (100) 0/1 (0) 0/1 (0)
15/27 (56)
4/7 (57)
1508
FACTORS PREDICTING DEXTRANOMER/HYALURONIC ACID INJECTION SUCCESS
TABLE 6. Reflux resolution in ureters after 1 Dx/HA injection by univariate analysis
Reflux grade: I II III IV V Orifice location (257 ureters): A B C D Vol injected (257 ureters): Less than 0.5 cc More than 0.5 cc Mound morphology: Satisfactory Other Injection technique: Subureteral Intraureteral
No. Ureters (%)
No. Success (%)
No. Failure (%)
11 (4) 147 (57) 79 (31) 15 (6) 7 (3)
11 (100) 122 (83) 58 (73) 8 (53) 2 (29)
0 25 (17) 21 (27) 7 (47) 5 (71)
p Value 0.0003*
0.01† 3 (1) 93 (36) 147 (57) 14 (5)
2 (67) 76 (82) 116 (79) 6 (43)
1 (33) 17 (18) 31 (21) 8 (57)
156 (61) 101 (39)
130 (83) 70 (69)
26 (17) 31 (31)
196 (81) 47 (19)
170 (87) 17 (36)
26 (13) 30 (64)
122 137
94 (77) 107 (78)
28 (23) 30 (22)
0.008* ⬍0.0001* 0.84*
* Chi-square test. † Fisher’s exact test.
grade, although our inclusion of grade V ureters may contribute to the disparity. The goal of injection was to create a subureteral mound that would elevate and coapt the ureteral orifice. Diminishing success with increasing reflux grade and lateral position of the orifice as determined cystoscopically with the bladder nearly empty most likely indicates increasing difficulty in achieving the desired implant. Similarly, increasing volume of injected Dx/HA meant difficulty achieving the desired appearance and so correlated with failure. Our mean injected volume of 0.54 cc compares to 0.6 cc and 0.83 cc reported by Lackgren1 and Kirsch2 et al, respectively. We found no difference in outcomes based on subureteral vs intraureteral injection, demonstrating either technique may be useful to achieve a satisfactory mound. Nevertheless, we subjectively considered intraureteral injection superior for visualizing changes in orifice configuration during injection. From the earliest descriptions of endoscopic injection therapy for reflux resolution creation of a subureteral mound has been the stated goal.7 We found satisfactory mound morphology most strongly correlated with outcomes. When the implant elevated and coapted the orifice, as achieved in 81% of ureters at first treatment, reflux resolved in 87%. Conversely, failure to achieve elevation and coaptation corresponded to success in only 36% of ureters. Although there were too few cases to
demonstrate statistical significance, we noted a trend for lower reflux grades to have a greater likelihood of resolution when suboptimal mound morphology occurred with injection. Lavelle et al also found mound morphology predicted outcomes of Dx/HA injection.4 In their smaller series of 80 ureters a subureteral mound with coapted orifice correlated with reflux resolution in 87%. The importance of the mound is further suggested by analysis of treatment failures, in which volume loss of the implant and/or shifting of the mound from under the orifice is noted in 90% of cases.10 Given the results of our series and similar outcomes reported in the literature, it appears that the ability to achieve a mound with ureteral coaptation and then to have it maintained for at least 3 months after implantation provides reflux resolution in 70% of patients with 1 injection, increasing to approximately 80% with an additional treatment for initial failures. This finding may represent the limits of success to be expected from injection therapy using current implant substances and injection techniques. Accordingly, we advise parents that the decision to pursue Dx/HA therapy for reflux resolution should take into account a 2-injection process before alternative treatments are considered. Recently, Kirsch et al modified the injection technique, emphasizing bulking the entire intravesical ureter (hydrodistention implantation technique) over creation of a mound under the orifice.3 This approach required increased injection volumes averaging 1 cc for successful cases, whereas this group previously reported mean volumes of 0.83 cc.2 Patient (89%) and ureteral (92%) reflux resolution success rates reportedly were significantly greater with the modified technique over the “standard subureteral transurethral injection” method they had used previously. However, there are several uncertainties arising from this report. For example it is not clear if “standard subureteral transurethral injection” refers to the intraureteral injection reported by Kirsch et al in 2003,2 or to the subureteral injection described by O’Donnell and Puri.7 Furthermore, of 181 patients with 3 months of followup the authors selected 52 to represent “standard subureteral transurethral injection” and 70 for the new method but did not state how these subgroups were chosen and why the remaining 59 patients were not evaluated. Finally, although outcomes by ureter reportedly were significantly improved with the modified technique, statistical significance was achieved only for grade III cases. Thus, it remains unclear if injection with the intention to coapt a greater length of ureter than the orifice yields better results than injection to create a mound coapting the orifice. We currently perform injection to bulk the intravesical ureter and obtain a mound under the orifice but do not yet have sufficient experience to state whether our results are im-
TABLE 7. Univariate and multivariate analyses of factors associated with reflux resolution in ureters after Dx/HA injection Univariate Analysis Parameter Mound morphology (243 ureters): Other Satisfactory Preop grade Vol injected (ml) Orifice location (257 ureters): A⫹B C D
OR
95% CI
Multivariate Analysis p Value
OR
95% CI
⬍0.0001 1 11.5 0.45 0.24
5.6–23.8 0.31–0.66 0.09–0.7
1 0.86 0.17
0.45–1.65 0.05–0.56
⬍0.0001 0.007 0.012 0.04 0.003
p Value ⬍0.0001
1 11.5 0.46 0.3
5.3–25 0.29–0.72 0.09–0.98
0.0008 0.046
FACTORS PREDICTING DEXTRANOMER/HYALURONIC ACID INJECTION SUCCESS proved. Even if the results we obtained in these patients represent the limits of Dx/HA injection success, the ability to resolve reflux in the majority of patients with 1 or 2 brief outpatient procedures is an advance that we believe should be discussed objectively along with expected outcomes of other treatment options for children with reflux. CONCLUSIONS Multivariate analysis demonstrated that reflux grade, volume of Dx/HA injected and creation of a volcanic mound coapting the orifice predicted outcomes of endoscopic Dx/HA injection in resolving reflux. The most important factor was the ability to achieve the desired mound, which was less likely as reflux grade increased. Similarly, smaller volumes of Dx/HA injected meant success in creating a mound and an increased likelihood of reflux resolution, in contrast to larger injected volumes, which indicated difficulty achieving the desired implant and a lower probability of resolving reflux. Reflux resolution in 70% of patients and 78% of ureters from a single injection correlates with reports in the literature, suggesting that this is the expected outcome using current implants and techniques.
2.
3.
4.
5.
6.
7.
8.
Abbreviations and Acronyms Dx/HA ⫽ dextranomer/hyaluronic acid REFERENCES 1.
Lackgren G, Wahlin N, Skoldenberg E and Stenberg A: Longterm followup of children treated with dextranomer/hyal-
9.
10.
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uronic acid copolymer for vesicoureteral reflux. J Urol 2001; 166: 1887. Kirsch AJ, Perez-Brayfield MR and Scherz HC: Minimally invasive treatment of vesicoureteral reflux with endoscopic injection of dextranomer/hyaluronic acid copolymer: the Children’s Hospitals of Atlanta experience. J Urol 2003; 170: 211. Kirsch AJ, Perez-Brayfield M, Smith EA and Scherz HC: The modified STING procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol 2004; 171: 2413. Lavelle MT, Conlin MJ and Skoog SJ: Subureteral injection of Deflux for correction of reflux: analysis of factors predicting success. Urology 2005; 65: 564. Elder JS, Diaz M, Caldamone AA, Cendron M, Greenfield S, Hurwitz R et al: Endoscopic therapy for vesicoureteral reflux: a meta-analysis. I. Reflux resolution and urinary tract infection. J Urol 2006; 175: 716. Mackie GG and Stephens FD: Duplex kidneys: a correlation of renal dysplasia with position of the ureteral orifice. J Urol 1975; 114: 274. O’Donnell B and Puri P: Technical refinements in endoscopic correction of vesicoureteral reflux. J Urol 1988; 140: 1101. Snodgrass WT: Obstruction of a dysmorphic ureter following dextranomer/hyaluronic acid copolymer. J Urol 2004; 171: 395. Elmore JM, Scherz HC and Kirsch AJ: Dextranomer/hyaluronic acid for vesicoureteral reflux: success rates after initial treatment failure. J Urol 2006; 175: 712. Diamond DA, Caldamone AA, Bauer SB and Retik AB: Mechanisms of failure of endoscopic treatment of vesicoureteral reflux based on endoscopic anatomy. J Urol 2003; 170: 1556.
Purpose: Factors influencing outcomes of dextranomer/hyaluronic acid injection for vesicoureteral reflux remain poorly defined. We performed multivariate analysis of the experience of 1 surgeon (WS). Materials and Methods: The study group contained 168 patients and 259 refluxing units. Goal of injection was coaptation of the orifice with creation of a volcanic mound. Outcomes were determined by cystography obtained 12 weeks following injection. Intraoperative photographs of mounds were independently reviewed by 2 authors (WS, SY) without knowledge of results, and classified as “satisfactory” or “other.” Univariate and multivariate logistic regression analysis was done evaluating influence of gender, age, voiding dysfunction, reflux grade, unilateral vs bilateral reflux, ureteral duplication, orifice laterality, subureteral vs intraureteral injection, volume injected and mound appearance. Results: A single injection resolved reflux in 70% of patients and 78% of ureters. Additional injection resulted in overall success in 82% of patients and 86% of ureters. Multivariate analysis demonstrated that reflux grade, volume of dextranomer/ hyaluronic acid injected and mound appearance correlated with outcomes. A satisfactory mound was achieved in 81% of ureters, of which 87% no longer refluxed. Conclusions: The ability to create a satisfactory mound was the most important factor determining success of dextranomer/ hyaluronic acid injection. Increasing reflux grade was associated with a decreased likelihood of achieving a volcanic mound, and increasing volume injected suggested difficulty in creating a mound. Key Words: vesico-ureteral reflux, dextranomer-hyaluronic acid copolymer
espite increasing use of Dx/HA injection to resolve vesicoureteral reflux, there is uncertainty regarding factors influencing success, with few published reports of outcomes. In the original clinical trials Lackgren et al emphasized therapy for children with dilating reflux.1 Accordingly, only 5% of patients had grade II reflux, while 26% had grade IV reflux. Consequently, their series is not representative of cases referred in the United States for management, the majority of which are grades I to III reflux. Subsequently, Kirsch et al published their observations following Dx/HA injection in children with grades I to IV reflux, and examined factors potentially predicting outcomes.2 They noted a learning curve with improvement after their initial 20 cases but otherwise found no difference in success vs failure on the basis of reflux grade or injected volume. However, in a subsequent article these authors reported increased success after modifying the injection technique and using greater injection volumes.3 Lavelle et al analyzed outcomes and similarly found no difference in success by reflux grade or injected volume, noting creation of a desired mound was the only factor identified correlating with outcome.4 In contrast, Elder et al performed meta-
D
Submitted for publication September 1, 2006. * Correspondence: Department of Urology, Pediatric Urology Section, Children’s Medical Center and University of Texas Southwestern Medical Center, 6300 Harry Hines Blvd., Suite 1401, Dallas, Texas 75235 (telephone: 214-456-2481; FAX: 214-456-8803; e-mail: [email protected]).
For another article on a related topic see page 1546.
0022-5347/07/1774-1505/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION
analysis of injection therapy for reflux and found outcomes depended on reflux grade.5 Given these conflicting observations, we performed multivariate analysis of the experience of 1 surgeon (WS) with Dx/HA injection for reflux resolution. MATERIALS AND METHODS A total of 213 children (32 males, 181 females) underwent Dx/HA injection for vesicoureteral reflux by 1 surgeon (WS) between March 2002 and June 2005. For this analysis patients with neurogenic bladder (12) and those without postoperative cystography (33) were excluded from further consideration, resulting in a study group of 168 patients (26 males, 142 females) and 259 refluxing renal units. Mean patient age was 4.2 years (range 7 months to 15 years). Indications for injection included breakthrough febrile urinary tract infection despite antibiotic prophylaxis, persistent reflux and/or parental preference for injection over antibiotic prophylaxis. Preoperative evaluation included renal ultrasonography and voiding cystourethrography. Detailed questioning was used to diagnose the urge syndrome, infrequent voiding and/or constipation with therapy, including timed voiding, anticholinergics and/or laxatives as indicated, initiated before injection. Grade I reflux was treated when associated with contralateral reflux of higher grade, and in 4 patients following febrile urinary tract infection whose parents preferred injection over antibiotic prophylaxis. Cystoscopy was performed with the bladder nearly empty, with the orifice location visually categorized as “A” to “D,” following the description of Mackie and Stephens.6
1505
Vol. 177, 1505-1509, April 2007 Printed in U.S.A. DOI:10.1016/j.juro.2006.11.077
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FACTORS PREDICTING DEXTRANOMER/HYALURONIC ACID INJECTION SUCCESS
A, example of volcano-like mound morphology designated “satisfactory.” B, example of mound morphology designated “other”
Two different injection techniques were used. In the first 80 patients subureteral injection was performed as popularized by O’Donnell and Puri,7 which involves inserting the needle 2 to 3 mm below the orifice and advancing the tip under the distal ureter. For the subsequent 88 patients the needle was placed directly into the orifice and advanced into the subureteral space. In both procedures Dx/HA was injected with the intention to create a mound elevating and coapting the orifice. When initial puncture did not result in a symmetrical bulge coapting the orifice additional sites were injected to achieve the desired appearance. Satisfactory coaptation was confirmed visually by directing the irrigating stream toward the orifice after treatment was completed. Pre-injection and post-injection photographs were taken in all cases. Antibiotic prophylaxis continued after injection until reflux resolution was confirmed by postoperative cystography at 12 weeks. Followup renal ultrasonography was also obtained. Success was defined as complete reflux resolution. Cases with reflux resolution were released from followup, while those with persistent reflux were recommended for a 2nd injection. Cystography and renal ultrasonography were again performed at 12 weeks after repeat injections. Photographs were independently reviewed by 2 of the authors (SY, WS) to categorize posttreatment orifice configuration after first injection as a “satisfactory mound” or “other morphology” while blinded to results of subsequent cystography (see figure). Outcomes were determined for patients and ureters. In instances of bilateral reflux the higher grade was used for analysis of patient results. Reflux grade and volume of Dx/HA injected were analyzed as continuous and categorical variables. Continuous variables were compared using the t test. Categorical variables were compared by Chisquare or Fisher’s exact test. Univariate and multivariate logistic regression analysis was performed to identify factors predicting outcomes. Statistical significance was considered p ⱕ0.05, and all p values were 2-sided. Analyses were done with commercially available computer software (SAS® version 8.02).
RESULTS Patients A single Dx/HA injection resolved reflux in 117 of the 168 patients (70%). Of the 51 patients with treatment failure 33 consented to a 2nd injection, with 20 (61%) achieving complete reflux resolution. One child received a 3rd injection, which was successful. Therefore, overall success was achieved in 138 patients (82%, table 1). Table 2 provides descriptive statistics and comparison between patients successfully and unsuccessfully treated. Of analyzed factors, including gender, age, unilateral vs bilateral reflux, ureteral duplication, maximum reflux grade and dysfunctional voiding, only reflux grade differed significantly. On univariate logistic regression analysis higher reflux grade (OR 0.56, 95% CI 0.37– 0.83, p ⫽ 0.004) and bilateral reflux (OR 0.51, 95% CI 0.26 –1.01, p ⫽ 0.053) correlated with decreased reflux resolution. However, on multivariate logistic regression analysis only reflux grade significantly predicted outcomes. We did not observe a learning curve in this study, since the success rate was 70%, 70%, 66% and 73% for successive patient quartiles. Ureters A single Dx/HA injection resolved reflux in 201 of 259 ureters (78%, table 3). Of the remaining 58 refluxing ureters reflux grade diminished in 30, remained unchanged in 27 and increased in 1 (table 4). Second injections were performed in 34 ureters, with reflux resolution in 20 (59%), and a third injection
TABLE 1. Reflux resolution in patients treated with Dx/HA injection No. Successes/No. Pts (%) Reflux Grade I II III IV V Totals
First Injection 4/4 69/93 36/52 6/12 2/7
(100) (74) (69) (50) (29)
117/168 (70)
Second Injection 12/17 (71) 5/10 (50) 2/4 (50) 1/2 (50) 20/33 (61)
Third Injection
1/1 (100)
1/1 (100)
FACTORS PREDICTING DEXTRANOMER/HYALURONIC ACID INJECTION SUCCESS TABLE 2. Reflux resolution in patients and related factors No. Success (%)* Gender: M F Reflux laterality: Unilat Bilat Max reflux grade: I II III IV V Dysfunctional voiding: Yes No Not toilet trained Ureteral duplication: No Unilat Bilat
No. Failure (%)†
p Value (chi-square test)
11 (42.3) 40 (28.2)
59 (76.6) 58 (63.7)
18 (23.4) 33 (36.3)
4 (3.4) 69 (59) 36 (30.8) 6 (5.1) 2 (1.7)
0 (0) 24 (47.1) 16 (31.4) 6 (11.8) 5 (9.8) 0.41
32 (27.4) 36 (30.8) 49 (41.9)
11 (21.6) 13 (25.5) 27 (52.9)
104 (88.9) 13 (11.1) 0 (0)
43 (84.3) 6 (11.8) 2 (3.9)
0.1
TABLE 3. Reflux resolution in ureters treated with Dx/HA injection No. Successes/No. Ureters Injected (%)
Totals
I
II
III
IV
V
0 I II III IV V
11 11 0 0 0 0 0
147 122 4 20 1 0 0
79 58 2 13 6 0 0
15 8 0 4 3 0 0
7 2 1 0 3 0 1
0.03
was successful in 1 ureter. Therefore, overall success was 222 of 259 ureters (86%). Of the 259 ureters treated 27 (10%) were duplicated (table 5). Because univariate analysis showed no difference in outcomes for single vs duplicated ureters with reflux, these rates were combined in all calculations. Table 6 provides descriptive statistics and comparison between successful and failed injections for ureters. Reflux grade, orifice location, volume injected and mound morphology were significantly different between patients with resolved vs persistent reflux. Increasing reflux grade and laterality of orifices were associated with decreased success. Mean volume injected was 0.54 cc (SD 0.27), and volumes less than 0.5 cc were more likely to be successful than those greater than 0.5 cc. A “satisfactory” mound was achieved in 196 of 243 ureters (81%), of which 170 (87%) no longer refluxed and 26 (13%) persistently refluxed. “Other” morphology was seen in 47 ureters (19%), of which 17 (36%) nevertheless had reflux resolution, while 30 (64%) continued to reflux. There was no significant difference in subureteral vs intraureteral injection outcomes. Table 7 shows results of univariate and multivariate logistic regression analyses. Multivariate analysis of these factors by ureters treated indicated reflux grade (OR 0.46, p ⫽ 0.0008, 95% CI 0.29 – 0.72), injected volume (OR 0.3, p ⫽ 0.046, 95% CI 0.09 – 0.98) and mound appearance (OR 11.5, p ⬍0.0001, 95% CI 5.3–25) predicted outcomes. Achievement of a satisfactory mound was the strongest determinant of results. One patient had asymptomatic ob-
I II III IV V
Preop Reflux Grade Postop Reflux Grade
0.07
* Mean age 4.3 years (SD 3.1). † Mean age 3.9 years (SD 2.8).
Reflux Grade
TABLE 4. Results in ureters following single Dx/HA injection
0.15 15 (57.7) 102 (71.8)
First Injection
Second Injection
11/11 (100) 122/147 (83) 58/79 (73) 8/15 (53) 2/7 (29)
9/16 (56) 7/12 (58) 3/4 (75) 1/2 (50)
201/259 (78)
20/34 (59)
struction of 1 ureter following Dx/HA injection, which required surgical correction. This case has been described previously.8 DISCUSSION A single Dx/HA injection was successful in 70% of our patients and 78% of refluxing ureters. These results are similar to those reported in a meta-analysis of endoscopic therapy by Elder et al, which showed 67% of patients and 76% of ureters were successfully treated with 1 injection.5 Although Kirsch et al2 excluded patients with grade V reflux, outcomes from 1 Dx/HA injection were nearly identical to ours, with 72% of patients and 77% of ureters successfully treated.2 Similarly, Lavelle et al noted success in 71% of patients and 80% of ureters with grades I to IV reflux after 1 Dx/HA injection.4 Additional injection was successful in another 64% of our patients and 62% of ureters. Therefore, reflux resolution was achieved with 1 to 3 injections in 82% of our patients and 86% of refluxing ureters. In the meta-analysis by Elder et al5 second treatments were successful in 54% of patients and 68% of ureters, while Elmore et al9 reported on 39 patients and 53 ureters undergoing second injections with Dx/HA, noting success in 90% and 89%, respectively. The apparent difference in our results and those of Elmore et al9 probably relate to differences in reflux grade, since their mean grade was 2.2, with 15% of ureters grade I and none greater than grade III, vs our mean grade of 2.7, with no grade I and 18% grades IV and V. In our series reflux grade correlated with success of Dx/HA injection, with 100% of grade I, 83% of grade II, 73% of grade III, 53% of grade IV and 29% of grade V cases successfully managed by a single injection (p ⫽ 0.0003). When additional injections are considered success was 100%, 89%, 84%, 73% and 43% for grades I to V, respectively. Neither Kirsch2 nor Lavelle4 et al reported correlation of reflux grade with outcome. Additionally, Lavelle et al did not provide the number of ureters with each grade in their series.4 Since results by ureter in our patients and those of Kirsch et al2 appear similar, it is not clear why their analysis failed to achieve statistical significance for reflux
TABLE 5. Reflux resolution in duplicated ureters treated with Dx/HA injection No. Successes/No. Ureters Injected (%)
Third Injection Reflux Grade 1/1 (100)
1/1 (100)
1507
II III IV V Totals
First Injection
Second Injection
8/13 (62) 5/9 (56) 2/3 (67) 0/2 (0)
0/1 (0) 4/4 (100) 0/1 (0) 0/1 (0)
15/27 (56)
4/7 (57)
1508
FACTORS PREDICTING DEXTRANOMER/HYALURONIC ACID INJECTION SUCCESS
TABLE 6. Reflux resolution in ureters after 1 Dx/HA injection by univariate analysis
Reflux grade: I II III IV V Orifice location (257 ureters): A B C D Vol injected (257 ureters): Less than 0.5 cc More than 0.5 cc Mound morphology: Satisfactory Other Injection technique: Subureteral Intraureteral
No. Ureters (%)
No. Success (%)
No. Failure (%)
11 (4) 147 (57) 79 (31) 15 (6) 7 (3)
11 (100) 122 (83) 58 (73) 8 (53) 2 (29)
0 25 (17) 21 (27) 7 (47) 5 (71)
p Value 0.0003*
0.01† 3 (1) 93 (36) 147 (57) 14 (5)
2 (67) 76 (82) 116 (79) 6 (43)
1 (33) 17 (18) 31 (21) 8 (57)
156 (61) 101 (39)
130 (83) 70 (69)
26 (17) 31 (31)
196 (81) 47 (19)
170 (87) 17 (36)
26 (13) 30 (64)
122 137
94 (77) 107 (78)
28 (23) 30 (22)
0.008* ⬍0.0001* 0.84*
* Chi-square test. † Fisher’s exact test.
grade, although our inclusion of grade V ureters may contribute to the disparity. The goal of injection was to create a subureteral mound that would elevate and coapt the ureteral orifice. Diminishing success with increasing reflux grade and lateral position of the orifice as determined cystoscopically with the bladder nearly empty most likely indicates increasing difficulty in achieving the desired implant. Similarly, increasing volume of injected Dx/HA meant difficulty achieving the desired appearance and so correlated with failure. Our mean injected volume of 0.54 cc compares to 0.6 cc and 0.83 cc reported by Lackgren1 and Kirsch2 et al, respectively. We found no difference in outcomes based on subureteral vs intraureteral injection, demonstrating either technique may be useful to achieve a satisfactory mound. Nevertheless, we subjectively considered intraureteral injection superior for visualizing changes in orifice configuration during injection. From the earliest descriptions of endoscopic injection therapy for reflux resolution creation of a subureteral mound has been the stated goal.7 We found satisfactory mound morphology most strongly correlated with outcomes. When the implant elevated and coapted the orifice, as achieved in 81% of ureters at first treatment, reflux resolved in 87%. Conversely, failure to achieve elevation and coaptation corresponded to success in only 36% of ureters. Although there were too few cases to
demonstrate statistical significance, we noted a trend for lower reflux grades to have a greater likelihood of resolution when suboptimal mound morphology occurred with injection. Lavelle et al also found mound morphology predicted outcomes of Dx/HA injection.4 In their smaller series of 80 ureters a subureteral mound with coapted orifice correlated with reflux resolution in 87%. The importance of the mound is further suggested by analysis of treatment failures, in which volume loss of the implant and/or shifting of the mound from under the orifice is noted in 90% of cases.10 Given the results of our series and similar outcomes reported in the literature, it appears that the ability to achieve a mound with ureteral coaptation and then to have it maintained for at least 3 months after implantation provides reflux resolution in 70% of patients with 1 injection, increasing to approximately 80% with an additional treatment for initial failures. This finding may represent the limits of success to be expected from injection therapy using current implant substances and injection techniques. Accordingly, we advise parents that the decision to pursue Dx/HA therapy for reflux resolution should take into account a 2-injection process before alternative treatments are considered. Recently, Kirsch et al modified the injection technique, emphasizing bulking the entire intravesical ureter (hydrodistention implantation technique) over creation of a mound under the orifice.3 This approach required increased injection volumes averaging 1 cc for successful cases, whereas this group previously reported mean volumes of 0.83 cc.2 Patient (89%) and ureteral (92%) reflux resolution success rates reportedly were significantly greater with the modified technique over the “standard subureteral transurethral injection” method they had used previously. However, there are several uncertainties arising from this report. For example it is not clear if “standard subureteral transurethral injection” refers to the intraureteral injection reported by Kirsch et al in 2003,2 or to the subureteral injection described by O’Donnell and Puri.7 Furthermore, of 181 patients with 3 months of followup the authors selected 52 to represent “standard subureteral transurethral injection” and 70 for the new method but did not state how these subgroups were chosen and why the remaining 59 patients were not evaluated. Finally, although outcomes by ureter reportedly were significantly improved with the modified technique, statistical significance was achieved only for grade III cases. Thus, it remains unclear if injection with the intention to coapt a greater length of ureter than the orifice yields better results than injection to create a mound coapting the orifice. We currently perform injection to bulk the intravesical ureter and obtain a mound under the orifice but do not yet have sufficient experience to state whether our results are im-
TABLE 7. Univariate and multivariate analyses of factors associated with reflux resolution in ureters after Dx/HA injection Univariate Analysis Parameter Mound morphology (243 ureters): Other Satisfactory Preop grade Vol injected (ml) Orifice location (257 ureters): A⫹B C D
OR
95% CI
Multivariate Analysis p Value
OR
95% CI
⬍0.0001 1 11.5 0.45 0.24
5.6–23.8 0.31–0.66 0.09–0.7
1 0.86 0.17
0.45–1.65 0.05–0.56
⬍0.0001 0.007 0.012 0.04 0.003
p Value ⬍0.0001
1 11.5 0.46 0.3
5.3–25 0.29–0.72 0.09–0.98
0.0008 0.046
FACTORS PREDICTING DEXTRANOMER/HYALURONIC ACID INJECTION SUCCESS proved. Even if the results we obtained in these patients represent the limits of Dx/HA injection success, the ability to resolve reflux in the majority of patients with 1 or 2 brief outpatient procedures is an advance that we believe should be discussed objectively along with expected outcomes of other treatment options for children with reflux. CONCLUSIONS Multivariate analysis demonstrated that reflux grade, volume of Dx/HA injected and creation of a volcanic mound coapting the orifice predicted outcomes of endoscopic Dx/HA injection in resolving reflux. The most important factor was the ability to achieve the desired mound, which was less likely as reflux grade increased. Similarly, smaller volumes of Dx/HA injected meant success in creating a mound and an increased likelihood of reflux resolution, in contrast to larger injected volumes, which indicated difficulty achieving the desired implant and a lower probability of resolving reflux. Reflux resolution in 70% of patients and 78% of ureters from a single injection correlates with reports in the literature, suggesting that this is the expected outcome using current implants and techniques.
2.
3.
4.
5.
6.
7.
8.
Abbreviations and Acronyms Dx/HA ⫽ dextranomer/hyaluronic acid REFERENCES 1.
Lackgren G, Wahlin N, Skoldenberg E and Stenberg A: Longterm followup of children treated with dextranomer/hyal-
9.
10.
1509
uronic acid copolymer for vesicoureteral reflux. J Urol 2001; 166: 1887. Kirsch AJ, Perez-Brayfield MR and Scherz HC: Minimally invasive treatment of vesicoureteral reflux with endoscopic injection of dextranomer/hyaluronic acid copolymer: the Children’s Hospitals of Atlanta experience. J Urol 2003; 170: 211. Kirsch AJ, Perez-Brayfield M, Smith EA and Scherz HC: The modified STING procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol 2004; 171: 2413. Lavelle MT, Conlin MJ and Skoog SJ: Subureteral injection of Deflux for correction of reflux: analysis of factors predicting success. Urology 2005; 65: 564. Elder JS, Diaz M, Caldamone AA, Cendron M, Greenfield S, Hurwitz R et al: Endoscopic therapy for vesicoureteral reflux: a meta-analysis. I. Reflux resolution and urinary tract infection. J Urol 2006; 175: 716. Mackie GG and Stephens FD: Duplex kidneys: a correlation of renal dysplasia with position of the ureteral orifice. J Urol 1975; 114: 274. O’Donnell B and Puri P: Technical refinements in endoscopic correction of vesicoureteral reflux. J Urol 1988; 140: 1101. Snodgrass WT: Obstruction of a dysmorphic ureter following dextranomer/hyaluronic acid copolymer. J Urol 2004; 171: 395. Elmore JM, Scherz HC and Kirsch AJ: Dextranomer/hyaluronic acid for vesicoureteral reflux: success rates after initial treatment failure. J Urol 2006; 175: 712. Diamond DA, Caldamone AA, Bauer SB and Retik AB: Mechanisms of failure of endoscopic treatment of vesicoureteral reflux based on endoscopic anatomy. J Urol 2003; 170: 1556.