Ultrasound-based predictive indicators for treatment outcomes in pediatric vesicoureteral reflux

Vesicoureteral reflux (VUR) is a common condition in children with a reported prevalence of 1%. However, it is difficult to determine this rate precisely given the varied risk factors in this population. Previous studies have reported a VUR rate exceeding 30% in those with tract infections, and this rate decreases with age [1].

Several factors prevent the development of VUR, among which the anatomical structure of the ureterovesical junction is the most fundamental. The ureter has two fixation points that support it internally and externally [2], and a segment of the ureter between these two support points lying beneath the bladder mucosa creates a tunnel. The length of this subureteric tunnel is five times the diameter of the ureteral orifice and serves as an anti-reflux mechanism [3]. VUR occurs in the presence of a short intramural ureter when the anti-reflux mechanism is disrupted.

Treatment of VUR requires consideration of multiple factors, such as the patient’s age, reflux grade, presence of renal scarring, recurrent urinary tract infections, and bladder dysfunction. Treatment options include conservative approaches, antibiotic prophylaxis, and bladder training, although curative surgical methods, such as endoscopic subureteric injection therapy and ureteroneocystotomy (UNC), are also available.

The present study investigated the values of submucosal tunnel length, distal ureteral diameter, bladder wall thickness, and detrusor-ureteral orifice distance-to-distal ureteral diameter ratio (D/U ratio) measured using preoperative ultrasonography (US) to predict the success of subureteric injection therapy in patients with VUR.

The pre- and postoperative data of 35 patients (53 renal units) who underwent subureteric injection therapy for primary VUR between July 2020 and June 2022 were evaluated prospectively.

Of the 35 patients (53 renal units) who underwent subureteric injection therapy due to primary VUR, 32 (91.4%) patients were female and 3 (8.6%) were male, with a mean age of 6.83 ± 3.84 years (treatment failure group: 5.27 ± 3.64 years old; treatment success group: 7.05 ± 4.16 years old; p = 0.147) (Tables 1 and 2).

A comparison between the groups with regard to the laterality of the reflux, grade, presence of bladder–bowel dysfunction, and presenting complaints revealed no significant differences between the groups. VUR was unilateral in 17 patients (48.6%) and bilateral in 18 patients (51.4%); when these 18 patients were evaluated in terms of treatment success, VUR persisted bilaterally in 3 patients (16.7%) and improved bilaterally in 12 patients (66.6%) and unilaterally in 3 patients (16.7%). The overall success rate in patients with bilateral VUR was 83.3%. The success rate of subureteric injection therapy in 17 patients (48.6%) with unilateral VUR was 88.2%, with no significant difference in treatment success in terms of bilaterality (P = 0.678) (Table 2).

An assessment of renal scarring based on preoperative DMSA scans revealed renal scarring in 10 (90.9%) patients in the treatment failure group and 16 (38.1%) patients in the treatment success group. There was a significant difference in the presence of renal scarring between the treatment success and treatment failure groups (P = 0.002) (Table 2).

Bladder wall thickness and distal ureteral diameter measured by preoperative US had no association with the treatment success (p = 0.163 and p = 0.307, respectively) (Table 3). In the treatment failure group, the mean submucosal tunnel length was 7.32 ± 3.15 mm, while in the treatment success group, the mean submucosal tunnel length was 10.64 ± 3.78 mm (p = 0.004). The mean D/U ratio of 1.37 ± 0.45 in the treatment failure group was significantly lower than that in the treatment success group (2.12 ± 0.83) (p = 0.006). The submucosal tunnel length and D/U ratio were identified as significant parameters for predicting surgical success (Table 3) (Fig. 2). The likelihood of treatment failure was 81.82% [95 confidence interval (CI) 48.2%–97.7%] in patients with a detrusor-ureteral orifice distance of < 7.4 mm and a detrusor-ureteral orifice distance-to-ureteral diameter ratio of < 1.53 mm (Fig. 2).

The VUR can recover without producing any symptoms but can also result in end-stage kidney disease associated with hypertension and nephropathy. Therefore, it is crucial to prevent or reduce the risk of nephropathy caused by reflux, recognize at-risk patients early, and provide appropriate treatment to those requiring follow-up and treatment. Treatment planning should consider factors such as the sex, reflux grade, type of presentation, presence of lower urinary tract dysfunction, presence of bladder and bowel dysfunction, presence of renal scarring, split renal functions, and compliance of both the parents and the child with therapy [5].

The surgical methods used to treat VUR rely on correcting disturbances in the anti-reflux mechanism. There is no accurate sphincter mechanism between the ureter and bladder that prevents the backflow of urine, as the reflux of urine is prevented by the closure of the intramural ureter by the detrusor muscle with a flap-valve mechanism, making the intramural length of the ureteral orifice an important parameter [6]. Most surgical methods described for treatment are based on the principle that the submucosal tunnel created with sufficient length is closed because of the increasing pressure during the filling and emptying of the bladder. Ideally, the length of the submucosal tunnel should be five times the diameter of the ureter, as proposed by Paquin [3]. In subureteric injection therapy, no change is made in the length of the submucosal tunnel. The injection method provides posterior support to the intramural ureter and point attachment of the ureterovesical junction to the bladder trigone, thereby preventing urine reflux by narrowing, particularly the distal ureter [7].

Endoscopic subureteric injection therapy has become the preferred approach in recent years for the treatment of VUR, even in the presence of high-grade reflux [8]. In the case of a failed first injection attempt, the success rate of the second injection was reportedly 68.3%, and the success rate of the third injection was 34% [9]. Therefore, it is important to predict the success rate of injection therapy accurately. Patients deemed to have a low chance of resolution with injection therapy, even if they have low-grade reflux, may be offered open surgery as first-line therapy, which has a better success rate. The present study therefore investigated the factors that might affect the success of subureteric injection therapy.

Mendez et al. investigated the factors affecting the success of endoscopic injection therapy in 90 children with grade 3–4 reflux. They identified the degree of ureteral dilation as a factor affecting treatment success [10]. In the same study, bilateral reflux was identified as another factor affecting treatment success, with a reported failure rate of 28% in unilateral reflux children and 47% in bilateral reflux (p = 0.046). In their study, the degree of ureteral dilation was evaluated using VCUG, whereas US was used in the present study to evaluate the distal ureteral diameter. Similar to the study by Mendez et al., the present study identified a larger distal ureteral diameter in the treatment failure group than that in the treatment success group. However, the difference between these two outcome groups was not statistically significant. The success rate of the injection therapy was lower in patients with bilateral reflux than that of patients with unilateral reflux, although the difference was not statistically significant. The finding of bilateral reflux in 75 patients in the treatment failure group is also consistent with previous studies.

The distal diameter ratio (UDR), calculated by dividing the distance between the L1-L3 vertebra by the distal ureteral diameter at the level of the iliac, has recently emerged as a popular approach to predicting the success of injection therapy, and many studies have been conducted on this subject [11]. In a retrospective study of 70 refluxing children conducted by Helmy et al., the mean distal ureteral diameter was recorded as 5.5 mm, and the mean UDR was 0.38; the authors reported that the UDR was an objective tool for predicting the success of injection therapy for VUR [12]. In another retrospective study involving 79 children, Cooper et al. reported that radiological images of the distal ureter were superior to lower urinary tract imaging in delineating the ureterovesical junction anatomy. They reported that the UDR was higher in patients with high-grade reflux and in patients with treatment failure than that in others and stated that it could be used alone as a better predictor of treatment success than the reflux grade (p < 0.0001) [11].

In a study investigating the factors affecting the success of endoscopic injection therapy, Leung et al. identified the preoperative reflux grade and presence of renal scarring as predictive factors in univariate analyses [13]. However, the presence of renal scarring was identified as the only predictor of treatment success in a multivariate analysis. In another study assessing the success of injection therapy, Zambaiti et al. evaluated the correlation between treatment success and the height of the mound produced by bulking the injection material measured by US. They reported that a high mound could prevent reflux following injection therapy, while a mound of 9.8 mm on average could serve as an indicator of reflux resolution [14]. In fact, their study might show that the first postoperative follow-up was performed with US and then only selected patients underwent further VCUG examinations rather than trying to predict treatment success preoperatively.

In a retrospective study of 200 refluxing children conducted by Baydilli et al., the likelihood of treatment failure was 4.068-fold higher in those with VUR in the early phase of bladder filling, 3.076-fold higher in those with a UDR > 0.24, 2.666-fold higher in those with renal scarring on DMSA scans, 2.493-fold higher in those with bladder and bowel dysfunction, 2.341-fold higher in those with febrile urinary tract infection, and 2.745-fold higher in those with delayed contrast agent drainage of the upper urinary tract. A model considering all parameters related to VCUG was better able to predict the outcomes of endoscopic injection therapy than the reflux grade [15]. The authors further highlighted that such predictive parameters could help pediatric urologists select the best candidates for endoscopic injection therapy. The present study found no marked effect of bladder or bowel dysfunction, presenting complaints, or reflux grade on the treatment success.

In patients experiencing reflux, the risk of febrile urinary tract infection increases in parallel with reflux grade [16]. In a study by Payza et al., the UDR was higher in patients with recurrent febrile urinary tract infection as the presenting complaint and in those with a positive family history of VUR than that in those with none of these factors, although the difference was not statistically significant (p = 0.372). In the same study, a relationship was suggested between the UDR and the clinical course of reflux, consistent with the results of previous studies. Furthermore, the UDR was significantly higher in patients with moderate-to-severe renal scarring identified on the DMSA scan than that in patients with mild and non-renal scarring (p = 0.001). Similar to our findings, the authors reported no significant correlation between the presence of bladder and bowel dysfunction and UDR [17].

Many studies have demonstrated the value of the distal ureteral diameter measured using VCUG and the UDR in predicting the success of endoscopic injection therapy. To our knowledge, no study has evaluated the distal ureteral diameter, detrusor-to-entrance ureteral orifice distance, or D/U ratio measured by US. The present study, therefore, makes a significant contribution to the literature as the first study of this issue and in its reporting of results that are different from those of earlier studies. The present study found no relationship between the success of endoscopic injection therapy and the distal ureteral diameter, presence of bladder or bowel dysfunction, presenting complaints, or patient’s age and sex. Unlike previous studies, no relationship with distal ureteral diameter was identified, possibly due to the small sample size. However, the study findings suggest that the length of the submucosal tunnel is a protective factor against reflux, while the D/U ratio, together with renal scarring, is an independent predictor of success in endoscopic injection therapy, and a tunnel length of < 7.4 mm is associated with an 81.82% likelihood of failure.

Several limitations associated with the present study warrant mention, including the small sample size, concentration of radiological findings only, and short-term follow-up. The current results need to be confirmed in prospective randomized studies with larger patient series and long-term follow-up.

We believe that the prediction of treatment success in endoscopic injection therapy is crucial for selecting appropriate patients for injection therapy. In the current study, the tunnel length and D/U ratio measurements obtained by US examination indicated a likelihood of treatment failure and could be used as negative predictive values. Large-scale comprehensive studies are required to confirm the findings of this study.