Temporal Pattern of Vesicoureteral Reflux on Voiding Cystourethrogram Correlates with Dynamic Endoscopic Hydrodistention Grade of Ureteral Orifice

Author's Accepted Manuscript Temporal Pattern of Vesicoureteral Reflux on Voiding Cystourethrogram Correlates with Dynamic Endoscopic Hydrodistention Grade of the Ureteral Orifice Angela M. Arlen , Kristin M. Broderick , Kathy H. Huen , Traci Leong , Hal C. Scherz , Andrew J. Kirsch

PII: DOI: Reference:

S0022-5347(14)03550-2 10.1016/j.juro.2014.05.024 JURO 11469

To appear in: The Journal of Urology Accepted Date: 6 May 2014 Please cite this article as: Arlen AM, Broderick KM, Huen KH, Leong T, Scherz HC, Kirsch AJ, Temporal Pattern of Vesicoureteral Reflux on Voiding Cystourethrogram Correlates with Dynamic Endoscopic Hydrodistention Grade of the Ureteral Orifice, The Journal of Urology® (2014), doi: 10.1016/ j.juro.2014.05.024. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain. All press releases and the articles they feature are under strict embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date.

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Temporal Pattern of Vesicoureteral Reflux on Voiding Cystourethrogram Correlates with Dynamic Endoscopic Hydrodistention Grade of the Ureteral Orifice

Hal C. Scherz1 and Andrew J. Kirsch1

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Angela M. Arlen1, Kristin M. Broderick1, Kathy H. Huen1, Traci Leong2,

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Emory University, Children’s Healthcare of Atlanta, Atlanta, Georgia USA

Please address all correspondence to:

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Andrew J. Kirsch, MD

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From the Departments of Pediatric Urology1, Children’s Healthcare of Atlanta and Biostatistics and Bioinformatics2, Rollins School of Public Health, Emory University School of Medicine, Atlanta, GA

5445 Meridian Mark Rd, Suite 420 Atlanta, GA 30342, USA Telephone: 1(404) 252-5206

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Fax number: 1(404) 252-1268

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Email address: [email protected]

Key Words: Vesicoureteral Reflux; Voiding Cystourethrogram; Ureteral Hydrodistention Running Title: Timing of Vesicoureteral Reflux Correlates with Hydrodistention Grade

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Abstract

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Purpose: Double HIT (hydrodistention implantation technique) utilizes ureteral hydrodistention (HD) to visualize injection site(s) and determine bulking agent volume. Along with grade, early vesicoureteral reflux (VUR) on voiding cystourethrogram (VCUG) provides prognostic information regarding

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spontaneous resolution. We hypothesized that VUR timing is predictive of endoscopic HD grade.

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Materials and Methods:

Children undergoing Double HIT for primary VUR between 2009 and 2012 were identified. HD grade (H0-H3) was assigned prospectively, and compared to VUR grade and timing on VCUG.

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Results:

One hundred and ninety-six children (mean age 3.94 ± 2.58 years) underwent injection of 332 ureters. Mean VUR grade was 2.8 ± 0.9. 52.4% of ureters demonstrated early to mid-filling VUR,

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39.2% late filling and 8.4% voiding only VUR. Mean VUR grade for early reflux was 3.1 ± 0.81 vs. 2.6 ± 0.81 for late filling vs. 2.1 ± 1.1 for voiding only (p<0.0001). VUR and HD grades correlated, with

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higher VUR grades associated with H3 ureters (p<0.001). There was a significant relationship between VUR timing and HD grade (p<0.001), with a high percentage of H3 ureters demonstrating early VUR compared to H1 ureters. Significantly (p<0.001) increased mean injected volume for H3 ureters (1.6 mL) was observed when compared to H1-2 ureters (1.25 mL). Conclusions:

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HD grade correlates with VUR grade, timing of reflux and injected volume. Early to mid-filling VUR is associated with abnormal hydrodistention (H2-H3). Temporal pattern of VUR on VCUG may

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be used to predict ureteral orifice competency and therefore aid in prognosticating resolution of VUR.

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Introduction

Optimal management of vesicoureteral reflux (VUR) remains controversial, and options include

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observation with or without continuous antibiotic prophylaxis and surgical repair. Spontaneous resolution of VUR is dependent upon initial grade of reflux, gender, age, voiding dysfunction, presence of renal scarring and timing of VUR on a voiding cystourethrogram (VCUG).1 An individualized riskbased approach that takes into consideration a multitude of demographic, radiographic, and clinical

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factors should therefore guide management.2

The concept of dynamic ureteral hydrodistention and intraluminal submucosal injection (hydrodistention implantation technique, or HIT) was introduced in 2002 and has led to improved

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success rates for endoscopic management of VUR.3 Modifications of the Double HIT technique now include proximal and distal intraluminal injections that result in coaptation of both the ureteral tunnel

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and orifice.4 The correlation between HD and VUR grade has been reported, with H2 and H3 ureters considered abnormal secondary to increased likelihood of higher grades of VUR when compared to lower grades of VUR as well as non-refluxing ureters.4 In the current study, we compared the timing of VUR on initial VCUG to dynamic ureteral HD at endoscopic evaluation and hypothesized that HD grade could be predicted based on VUR timing.

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Materials and Methods Institutional review board approval was obtained. Between January 1, 2009 and December 31,

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2012, 196 children with primary VUR underwent endoscopic HD and injection with dextranomer hyaluronic acid co-polymer (Dx/HA) using the Double HIT method as previously described.4,5 Briefly, the ureter is hydrodistended in order to facilitate intraluminal needle placement. HD is performed

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with the tip of the cystoscope placed at the ureteral orifice; a pressurized stream is achieved by placing the irrigation bag approximately 1 meter above the pubic symphysis on full flow. Loss of

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HD following injection provides an objective means by which the procedure is completed. Dynamic HD grading is routinely performed prior to injection in all refluxing and non-refluxing ureters. A total of 332 refluxing ureters were evaluated and injected with Dx/HA. VUR timing on VCUG was designated by the interpreting pediatric radiologist according to the following scale: 1 – early to

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mid-filling, 2 – late filling and 3 – voiding. In studies performed at our institution, timing was indexed by ureter according to volume of contrast infused and estimated bladder capacity according to age using the formula [age + 2] x 30 mL. Late filling VUR was defined as reflux onset

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at >75% estimated bladder capacity. HD grading was assigned prospectively at the time of

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cystoscopy by one of two experienced pediatric urologists (HCS and AJK). HD classification included H0 – no hydrodistention, H1 – ureteral orifice open but tunnel not evident, H2 – intramural tunnel visualized and H3 – extramural ureter visualized.4 Children with secondary VUR, prior reflux surgery or aberrant anatomy (i.e. complete ureteral duplication, paraureteral diverticulum) were excluded from study. Electronic medical records of patients were retrospectively reviewed. HD grade was compared to grade and timing of VUR as well as volume of Dx/HA injected. In children with more than one

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VCUG, VUR timing was obtained from the most recent imaging. Data was analyzed by ureter. Kendall’s tau was utilized to non-parametrically correlate VUR grade and VUR timing, VUR grade and

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HD grade and VUR timing and HD grade. ANOVA and then Tukey post-hoc tests were used to compare injected volume by VUR and HD grades. Statistical analysis was performed using SAS® 9.2, with p <

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0.05 representing statistical significance.

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Results

One hundred and ninety-six children (175 females, 21 males) with a mean age of 3.9 ± 2.6 years underwent Double HIT injection of 332 ureters. Patients had an average of 1.8 ± 1 preoperative VCUGs (range 1 to 4). Eighty-nine children (45.4%) underwent a single VCUG. Mean VUR grade was 2.8 ±

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0.9 with the following breakdown: grade 1 (n = 26), grade 2 (n = 86), grade 3 (n = 149), grade 4 (n = 65) and grade 5 (n = 6). One hundred and seventy-four ureters (52.4%) demonstrated early to mid-filling VUR, 130 ureters (39.2%) had late filling and 28 (8.4%) ureters had voiding only VUR [Table 1].

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Timing of VUR was related to grade with lower VUR grades more often detected later during bladder filling or voiding. Of the 71 ureters with high grade (IV-V) VUR, 55 (77.5%) had

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early VUR compared to only 3 (4.2%) with voiding only VUR. In contrast, early reflux was demonstrated in 34 of 112 (30.4%) of ureters with low grade (I-II) reflux while 18 (16.1) had voiding only VUR. The 174 ureters associated with early reflux had a mean VUR grade of 3.1 ± 0.81 compared to 2.6 ± 0.81 for late filling and 2.1 ± 1.1 for voiding only (p<0.0001). Patients with high grade VUR tended to have higher HD grade [Table 2]. Of the 71 ureters with VUR grade IV-V, 54 (76%) had H3 ureters, compared to only 47 of 112 (41.9%) ureters associated with

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grade I-II VUR. While all refluxing ureters were noted to HD, there was a statistically significant relationship between VUR and HD grades, with higher VUR grades associated with H3 ureters

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(p<0.001). There was a statistically significant relationship between VUR timing and HD grade (p<0.001), with a high percentage of H3 ureters demonstrating early VUR compared to H1 ureters [Figure 1]. Of

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the 195 ureters with HD grade 3, 146 (74.9%) had early filling reflux compared to just 29.2% of ureters

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with HD grade 1 and 18.6% of H2 ureters.

Injected Dx/HA volume was significantly related to VUR and HD grades (p<0.001 for both comparisons). The average injected volume for VUR grade I (1.3 mL) was significantly different than volumes injected for VUR grades IV-V (1.71 mL; p<0.001). The average injected volume for VUR grade II (1.3 mL) differed significantly from grades III (1.5 mL) and IV (1.7 mL; p<0.01). The average

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injected volume by HD grade was also statistically significant (p<0.001), with increased mean injected

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Discussion

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volume (1.6 mL) for H3 ureters compared to H1-2 ureters (1.25 mL; Table 3).

The diagnosis and subsequent management of VUR has become increasingly controversial, with debate over which children should be evaluated for reflux, and when detected, who should undergo VUR treatment.6-8 Factors influencing the decision to surgically correct VUR include risk of UTI, risk of developing new renal parenchyma scarring and likelihood of spontaneous resolution. It has been welldocumented that higher grades of reflux are associated with increased rates of renal scarring and decreased chance of spontaneous VUR resolution.1, 9-11 Multiple studies have shown that the renal

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scarring rate also increases with increasing grades of VUR.12,13 Bilateral VUR has also been associated with decreased resolution rates.14 In predicting early resolution (within two years of diagnosis), age less

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than 2 years has been shown to be a significant factor independent of reflux grade.1 In general, the resolution rates for boys and girls are similar; however, some studies have shown a slightly higher resolution rate for boys, particularly in those who present with high grade reflux in the first year of

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life.10,11

Clinicians and parents often opt for surgical intervention based on clinical course and the

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likelihood of spontaneous resolution as determined by the aforementioned risk factors. Endoscopic injection of Dx/HA is an outpatient procedure with minimal morbidity, and success rates with the Double HIT methodology have approached those of ureteral reimplantation making it a desirable surgical option for most patients.15,16 It has been previously demonstrated that non-resolution of VUR

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correlates with abnormal ureteral HD; the percentage of H3 ureters within each radiographic grade parallels that of reflux non-resolution with increasing likelihood of abnormal HD with higher VUR grades.4 VUR timing is also a significant prognostic factor for spontaneous resolution, with onset of

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reflux at greater than 75% of predicted bladder capacity by age demonstrating higher rates of resolution.17 Given this association, we evaluated the correlation between HD grading and timing of

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reflux on preoperative VCUG in children with primary VUR. Classification of the ureteral orifice has long been performed to determine the potential for spontaneous resolution of reflux. In the past, cystoscopy was performed to help determine need for future surgery. Ureters have been classified based on their configuration, location and tunnel length.18,19 The use of diagnostic preoperative cystoscopy has fallen out of favor delegating its use to the time of surgical intervention. As we previously reported, the dynamic ureteral HD classification is a highly

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reliable grading system that provides a simplified way to document endoscopic findings as they correlate with degree of VUR.4 In our current study, we have shown that early reflux on initial VCUG was

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significantly associated with abnormal ureteral HD (i.e. H2 and H3 ureters). This observation has the potential to provide additional prognostic information for the clinician; if a child has early cycle VUR regardless of reflux grade, they are more likely to have anatomically incompetent ureteral orifices as

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illustrated by abnormal ureteral HD and are less likely to have spontaneous resolution of reflux. As verified in previous studies, the timing of reflux in our patient cohort was related to VUR

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grade with higher grades detected earlier in the bladder cycle. Timing of reflux has been shown to predict VUR resolution independent of grade.1 VUR timing can therefore be utilized to help stratify children with a given grade of reflux regarding likelihood of spontaneous resolution. Furthermore, we again demonstrated that VUR and HD grading are strongly correlated, with higher

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grades of reflux associated with abnormal ureteral HD.4,5 Despite the strong correlation between HD and VUR grades, a considerable percentage of lower VUR grade ureters were also designated as H3. Likewise, 24% of ureters associated high grade VUR were not classified as H3. This overlap

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highlights the interplay of numerous variables affecting spontaneous resolution rates, and perhaps also helps to explain why some cases of high grade VUR resolve while low grade reflux persists in

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some children. Not unexpectedly, ureters with their intra +/- extramural tunnel evident during endoscopic HD required higher volumes of Dx/HA to achieve adequate coaptation.20 Patients with high grade VUR occurring early in the bladder cycle are therefore more likely to have abnormal ureteral HD, and are more likely to require an increased volume of Dx/HA to achieve satisfactory coaptation of the both the ureteral tunnel and orifice resulting in optimal clinical and radiographic success.15,16

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Our study has several limitations that warrant acknowledgement. While HD grades and VUR timing were assigned prospectively, the data was collected retrospectively, subjecting it to flaws

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inherent with such study design. VUR grade was assigned by varying interpreting pediatric radiologists according to the standardized international scale, which has been associated with discrepancies particularly when evaluating intermediate VUR grades.21 Furthermore, while VCUGs obtained at

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outside institutions were reviewed by our pediatric radiology department, the exact volume at which VUR was initially detected was not uniformly available and the determination of VUR

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timing was therefore more subjective. The data was analyzed by ureter rather than by patient, assuming that in cases of bilateral VUR treatment, laterality had no relation to evaluated variables (i.e. the grade, timing and volume of the right side side was not related to the left side). All children were treated with HD and endoscopic injection, therefore there was no control group in our study, and the rate of spontaneous resolution is unknown. Finally, since preoperative clinical risk factors and

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postoperative outcomes were not included in our analysis, we want to emphasize that the risk of VUR non-resolution should not be interpreted to correlate with clinical risk. Despite these limitations, our

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study demonstrated a strong correlation between VUR timing and endoscopic ureteral HD grade while also confirming the association between VUR grade and volume of bulking agent necessary to achieve

Conclusions

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ureteral coaptation and HD grade.

VUR occurring early in the bladder cycle is associated with anatomically incompetent ureteral orifices as evidenced by abnormal ureteral hydrodistention, which has previously been shown to correlate with higher VUR grades and decreased rate of reflux resolution. These findings provide

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further validation of the HD classification system, as well as emphasizing the importance of noting the timing of VUR onset on VCUG. In an era where the need for diagnosis and subsequent surgical

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correction of VUR is being debated, the correlation between VUR timing and HD grade may provide additional prognostic information about spontaneous resolution of reflux which may assist with clinical

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decision making and parental counseling.

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Funding Sources None. Conflict of Interest

Andrew J. Kirsch, MD - Consultant and Speaker's Bureau - Salix; Consultant - Cook Medical;

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Royalties.

Hal C. Scherz, MD - Cook Medical; Royalties.

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Ethical Approval

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All other authors declare no financial relationships.

Approved under Children’s Healthcare of Atlanta IRB 13-106.

References 1. Knudson MJ, Austin JC, McMillan ZM, et al. Predictive factors of early spontaneous resolution in children with primary vesicoureteral reflux. J Urol, 178:1684, 2007.

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2. Koyle M, Kirsch A, Barone C, et al. Challenges in childhood urinary tract infection/vesicoureteral reflux investigation and management: calming the storm. Urology, 80:503, 2012.

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3. Kirsch AJ, Perez-Brayfield M, Smith EA, et al. The Modified STING Procedure to Correct

Vesicoureteral Reflux: Improved Results with Submucosal Implantation Within the Intramural Ureter. J Urol, 171:2413, 2004.

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4. Kirsch AJ, Kaye JD, Cerwinka WH, et al. Dynamic Hydrodistention of the Ureteral Orifice: A Novel

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Grading System with High Interobserver Concordance and Correction with Vesicoureteral Reflux Grade. J Urol, 182:1688, 2009.

5. Cerwinka WH, Scherz HC, Kirsch AJ. Dynamic hydrodistention classification of the ureter and the double HIT method to correct vesicoureteral reflux. Arch Esp Urol, 61:882, 2008.

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6. Austin JC, Cooper CS. Vesicoureteral reflux: who benefits from correction. Urol Clin North Am, 37:243, 2010.

7. Peters CA, Skoog SJ, Arant BS Jr., et al. Summary of the AUA guideline on management of primary

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vesicoureteral reflux in children. J Urol, 184:1134, 2010.

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8. Roberts KB. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics, 128:595, 2011. 9. Lebowitz RL, Olbing H, Parkkulainen KV, et al. International system of radiographic grading of vesicoureteric reflux. International Reflux Study in Children. Pediatr Radiol, 15:105, 1985. 10. Schwab CW, Wu H, Selman H, et al. Spontaneous resolution of vesicoureteral reflux: a 15-year perspective. J Urol, 168:2594, 2002.

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11. Sjostrom S, Sillen U, Bachelard M, et al. Spontaneous resolution of high grade infantile vesicoureteral reflux. J Urol, 172:694, 2004.

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12. Mingin GC, Nguyen HT, Baskin LS. Abnormal dimercapto-succinic acid scans predict an increased risk of breakthrough infections in children with vesicoureteral reflux. J Urol, 172:1075, 2004.

low grade vesicoureteral reflux. J Urol, 180:1643, 2008.

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13. Nepple KG, Knudson MJ, Austin JC, et al. Abnormal renal scans and decreased early resolution of

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14. Estrada CR, Passerotti CC, Graham DA, et al. Nomograms for predicting annual resolution rate of primary vesicoureteral reflux: results from 2,462 children. J Urol, 182:1535, 2009. 15. Kaye JD, Srinivasan AK, Delaney C, et al. Clinical and radiographic results of endoscopic injection for vesicoureteral reflux: Defining measures of success. J Pediatr Urol, 8:297, 2012.

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16. Kalisvaart JF, Scherz HC, Cuda S, et al. Intermediate to long-term follow-up indicates low risk of recurrence after Double HIT endoscopic treatment for primary vesicoureteral reflux. J Pediatr Urol,

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8:359, 2012.

17. McMillian ZM, Austin JC, Knudson MJ, et al. Bladder volume at onset of reflux on initial

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cystogram predicts spontaneous resolution. J Urol, 176:1838, 2006. 18. Lyon RP, Marshall S, Tanagho EA. The ureteral orifice: its configuration and competency. J Urol, 102:504, 1969.

19. King LR, Kazmi SO, Belman AB. Natural history of vesicoureteral reflux. Outcome of a trial of nonoperative therapy. Urol Clin North Am, 1:441, 1974. 20. Lackgren G, Kirsch AJ. Endoscopic treatment of vesicoureteral reflux. BJUI, 105:1332, 2010.

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21. Greenfield SP, Carpenter MA, Chesney RW, et al. The RIVUR voiding cystourethrogram pilot

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study: experience with radiologic reading concordance. J Urol, 188:1608, 2012.

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Table 1. Contingency table summarizing cross tabulation of VUR timing and VUR grade.

VUR Grade III

IV

4

30

85

50

Late

11

49

57

12

Voiding

11

7

7

3

26

86

149

Total

65

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VUR Timing Early

V

Total

5

174

1

130

0

28

6

332

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II

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I

I

II

III

IV

V

Total

5

7

6

0

24

5

H2

13

41

48

10

1

113

8

39

94

49

5

195

86

149

65

6

332

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H3

Total

VUR Grade

H1

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HD Grade

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Table 2. Contingency table summarizing cross tabulation of HD grade and VUR grade.

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Table 3. Distribution of volume injected by HD grade. Injected Volume HD Grade

Mean (SD)

Median

Range

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1.2 (0.3)

1.2

0.5-1.8

H2

113

1.3 (0.39)

1.3

0.5-2.4

H3

195

1.6 (0.47)

1.4

0.8-2.8

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H1

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Figure 1. Correlation of VUR timing and HD grade.

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Hydrodistention implantation technique (HIT) Ureteral hydrodistention (HD) Vesicoureteral reflux (VUR)

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Voiding cystourethrogram (VCUG)

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Dextranomer hyaluronic acid co-polymer (Dx/HA) (Deflux®)