Renal volumetry and functional impairment prediction in pediatric vesicoureteral reflux based on contrast-enhanced voiding urosonography

Introduction

Vesicoureteral reflux (VUR) is a phenomenon in which the valve function of the vesicoureteral junction is impaired, causing urine to flow backward into the ureter and renal pelvis. It is usually divided into primary and secondary; the former is attributed mainly to structural and functional immaturity of the ureterovesical junction, while the latter is often secondary to lower urinary tract obstruction, such as posterior urethral valve disease, neurogenic bladder, etc.

VUR is a major underlying cause of urinary tract infections (UTIs) in children, potentially leading to hypertension, renal impairment, and even end-stage renal disease. Intrarenal reflux (IRR), the extension of VUR into the tubular system, is recognized as pivotal in the pathophysiology of reflux nephropathy (1). Ultrasound serves as a pivotal tool throughout the management of primary VUR in children, spanning from prenatal screening and postnatal diagnosis to intraoperative guidance and long-term follow-up (2). Contrast-enhanced voiding urosonography (CeVUS) is a radiation-free alternative to voiding cystourethrography (VCUG), as it enables real-time dynamic observation and tends to detect more high-grade VUR and IRR (3). Its diagnostic performance, with a pooled sensitivity of 86% and specificity of 92% against VCUG, supports its emerging role as a potential first-line modality (4). Baseline Tc-^99m dimercaptosuccinic acid (^99mTc-DMSA) scan enables early detection of split renal function (SRF) impairment and serves as the gold standard to diagnose renal scarring (RS) (5-7).

This study aimed to: (I) quantify the impact of VUR and IRR on renal volume; (II) identify independent risk factors for SRF impairment and RS; and (III) develop and validate a clinical prediction model based on CeVUS findings. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1-2808/rc).

Methods

Participant selection

We reviewed all CeVUS examinations in the Picture Archiving and Communication System (PACS) from January 2022 to December 2024. All patients were recruited from the Department of Ultrasound at West China Second University Hospital, Sichuan University. Participants were included if they met any of the following criteria: (I) symptoms suggestive of urinary tract disorders [e.g., ≥2 episodes of febrile UTI with fever ≥38 ℃ accompanied by positive urine culture (8), or dysuria]; (II) abnormal urinalysis findings; (III) ultrasonographic evidence of pelvicalyceal or ureteral dilation; (IV) history of fetal hydronephrosis; and (V) congenital ureteral anomalies. Participants were excluded if they met any of the following criteria: (I) previous continuous antibiotic prophylaxis (CAP) treatment; (II) history of ureteral reimplantation or partial nephrectomy; (III) severe systemic comorbidities or traumatic injuries; (IV) poor general condition, unable to tolerate CeVUS.

Acquisition of CeVUS

Ultrasonography was performed on IU 22 (Philips Healthcare, Hamburg, Germany), or Resona (Mindray, Shenzhen, China) with a harmonic imaging modality and low or intermediate mechanical index (MI, 0.04–0.10), equipped with dedicated software for contrast-enhanced studies. A high-frequency linear transducer (7.5–10 MHz) was used for infants and a low-frequency convex transducer (1–5 MHz, 2–9 MHz) for older children.

Bladder catheterization was performed by a trained pediatric nurse. The contrast medium (SonoVue, Bracco) was prepared as 5 mL of microbubble suspension following the manufacturer’s instructions and 1–2 mL was reserved for later use. On conventional ultrasound, the urinary tract was thoroughly evaluated, including renal contour, parenchymal echogenicity, dilation of the renal pelvis and ureter, bladder wall thickness, and renal blood flow signals. Warm saline (approximately one-third to one-half of the estimated bladder capacity) was slowly instilled, followed by injection of 1 mL of microbubble suspension; saline instillation was then continued to reach full bladder capacity. Bladder capacity (in milliliters) was calculated using the following formula: volume = (age +2)×30, for children more than 1 year, or volume =38+2.5× month, for infant less than 12 months of age. The system was then switched to contrast mode, and the timer was started. During bladder filling and voiding, reflux of intravesical contrast agent into the ureters and renal pelvis was monitored in real time. After the catheter was removed, the child was asked to urinate, and the operator would continue to observe whether there was abnormal enhancement in anterior and posterior urethra. No sedation was required during the whole procedure. All cine clips were saved for subsequent review.

Image analysis

Two board-certified pediatric radiologists (M.H. and L.D., each with >6 years of pediatric ultrasound experience and having each independently performed >80 CeVUS examinations prior to this study), blinded to patient information and previous reports, independently reviewed all CeVUS images and video recordings. Renal volume was calculated using the ellipsoid formula (length × width × depth ×0.523) from two-dimensional (2D) ultrasound measurements. The diagnosis of VUR followed the grading system proposed by Darge and Troeger (Figure 1) (9), in line with the internal reflux grading system for VCUG (10). In this study, VUR was stratified into three subgroups based on the International Reflux Study Committee criteria (11): low-grade VUR (grade I–II), moderate-grade VUR (grade III), and high-grade VUR (grade IV–V). IRR was characterized by the appearance of microbubbles within the renal parenchyma on CeVUS (Figure 2). Inter-rater discrepancies in VUR grading and the presence of IRR were resolved by consensus of the operators.

Figure 1 VUR grades on CeVUS. (A) Grade 1: microbubbles detected only in the ureter. (B) Grade 2: microbubbles detected in the renal pelvis; no significant renal pelvic dilatation. (C) Grade 3: microbubbles detected in the renal pelvis, significant renal pelvic dilatation and moderate calyceal dilatation. (D) Grade 4: microbubbles detected in the renal pelvis, significant renal pelvic dilatation and significant calyceal dilatation. (E) Grade 5: microbubbles detected in the renal pelvis, significant renal pelvic dilatation, significant calyceal dilatation, loss of renal pelvis contour and dilated tortuous ureter. CeVUS, contrast-enhanced voiding urosonography; VUR, vesicoureteral reflux.

Figure 2 CeVUS images showing IRR in the renal poles according to different degrees. (A) Grade III with minor IRR. (B) Grade IV with moderate to massive IRR. (C) Grade V with diffuse IRR. CeVUS, contrast-enhanced voiding urosonography; IRR, intrarenal reflux.

Among the VUR-positive patients, those who underwent ^99mTc-DMSA scintigraphy within 2 weeks of CeVUS were included for functional analysis (n=86), consistent with established guidelines (12). DMSA was typically obtained to evaluate SRF and assist in surgical decision-making. SRF impairment was graded as slightly reduced, markedly reduced, or non-functioning. RS was defined as reduced radiotracer uptake with deformed outline in the affected renal region.

Clinical information included age (month), sex, laterality (left or right), UTI frequency, symptoms, surgical history, etc.

Statistical analysis

Statistical analysis was performed with Statistical Package for Social Sciences 25.0 for MacOS (SPSS, IBM, Armonk, NY, USA) and GraphPad Prism 9.0 for MacOs (GraphPad inc, LaAcute Jolla, CA, USA). Continuous data with a normal distribution were presented as mean ± standard deviation (x¯±s), while non-normally distributed data or data with heterogeneous variance were expressed as median (P₂₅, P₇₅). Categorical data were summarized as n (%). To compare quantitative variables, Student’s t test, Mann-Whitney test or Wilcoxon test were performed according to sample distribution; to compare nominal variables, chi-square (χ²) test or Fisher’s test were performed. Propensity score matching (PSM) for age and sex was implemented to: (I) match contralateral negative ureteral-renal units (URUs) with VUR-negative controls; and (II) match the IRR group against non-IRR counterparts within the high-grade VUR cohort. Logistic regression models were used to perform a univariate and multivariate analysis of predictors of SRF impairment and RS. All variables with P≤0.10 in the univariate analysis were included in the multivariate regression model. Model performance was assessed using receiver operating characteristic (ROC) curves and area under the curve (AUC). Multicollinearity was assessed by calculating variance inflation factors (VIF); a VIF value greater than 5 was considered indicative of concerning collinearity. To quantify the spatial relationship between IRR and both SRF impairment and RS, we calculated the Jaccard similarity coefficient based on the sets of affected poles for each kidney. This metric directly measures the overlap in pole-specific involvement, accounting for partial overlaps among categories (e.g., ‘upper pole’ being a subset of ‘upper + lower poles’). Inter-observer reliability was assessed on a random sample of 34 participants evaluated independently by two blinded radiologists. For interobserver reliability assessment, weighted kappa (w_κ) with quadratic weights was used for VUR grade (I–V), given its ordinal nature, and Cohen’s kappa (κ) was used for the presence of IRR. Agreement strength was interpreted as slight (w_κ/κ ≤0.20), fair (0.21–0.40), moderate (0.41–0.60), substantial (0.61–0.80), or almost perfect (0.81–1.00). Results are reported with 95% confidence intervals (CIs).

Ethical statement

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional review board of West China Second University Hospital, Sichuan University (No. 20240424). As it was a retrospective study, the requirement for informed consent was waived.

Results

General description

Initial screening of 362 CeVUS examinations in the PACS database excluded 11 children meeting predefined exclusion criteria. Subsequent exclusions comprised: severe hydronephrosis [anterior-posterior renal pelvis diameter (APD) ≥15 mm, with/without caliectasis or parenchymal thinning; n=60], duplicated collecting systems (n=21), or renal dysplasia (n=9). The flow chart was shown in Figure 3. The final cohort included 119 VUR-positive cases (66 males, 53 females; 238 URUs) and 142 VUR-negative controls (69 males, 73 females; 284 URUs). The demographic characteristics of VUR group are summarized in Table 1. The baseline grayscale ultrasonographic features are summarized in Table 2 (13).

Figure 3 The flow chart of this study. ^99mTc-DMSA, Tc-^99m dimercaptosuccinic acid; CeVUS, contrast-enhanced voiding urosonography; URU, ureteral-renal unit; VUR, vesicoureteral reflux.

UTIs represented the predominant clinical presentation in both VUR-positive and negative groups (68.3% vs. 64.1%, respectively). VUR-positive cohort demonstrated higher prevalence of ureteral abnormalities (20.1%) and congenital hydronephrosis (18.9%). In contrast, the VUR-negative cohort exhibited a more diversified clinical spectrum, with comparatively higher prevalence of systemic infections (8.9%) and bladder dysfunction (encompassing dysuria and overactive bladder syndrome, 5.6%). Notably, the incidence of renal parenchymal diseases showed no significant intergroup difference (4.2% vs. 5.6% in positive vs. negative groups).

Patients in the VUR-positive group were significantly younger than those in the VUR-negative group (median 8 months, IQR 4–38 vs. median 13 months, IQR 6–83; P=0.002). The median age across the VUR subgroups was 10.25 (4.0–39.3) months for contralateral negative, 7.0 (4.0, 56.5) months for low-grade, 9.0 (4.5, 56) months for moderate-grade, and 7.25 (4.0, 25.3) months for high-grade. No significant age differences were observed across these subgroups (Kruskal-Wallis P=0.398; Dunn’s post-hoc all P>0.05). No statistically significant difference in gender distribution was observed between the VUR-positive and VUR-negative groups (P=0.320). In VUR-positive group, unilateral involvement occurred in 54 cases (45.4%) and bilateral involvement occurred in 65 cases (54.6%). Of the patients with bilateral VUR, 48 (73.8%) had moderate to high-grade reflux. Among 184 refluxing URUs, IRR was observed in 53 units (28.8%), all in grade III or higher VUR (~90% in grades IV–V), consistent with prior studies (14-17). A total of 86 patients with 172 URUs in the VUR-positive cohort underwent ^99mTc-DMSA scans. SRF impairment was observed in 62 URUs (36.05%), and RS was observed in 48 URUs (27.91%). Inter-observer reliability was good among the 34 participants (w_κ for VUR =0.74, 95% CI: 0.62–0.86; κ for IRR =0.72, 95% CI: 0.61–0.83).

Impact of VUR on renal volume

Renal volumes in all subgroups were: VUR negative controls 22.35 mL (16.04, 36.59 mL), contralateral negative group 24.42 mL (17.82, 37.54 mL), low-grade VUR 26.13 mL (20.48, 31.97 mL), moderate-grade VUR 22.84 mL (17.94, 37.51 mL), and high-grade VUR 19.07 mL (15.42, 26.37 mL). High-grade VUR group demonstrated significant volumetric reductions compared with contralateral negative (P=0.047), low-grade VUR (P=0.048), and moderate-grade VUR (P=0.024) groups. No significant differences were detected among the other VUR subgroup (Figure 4A). Additionally, among patients with high-grade VUR, less renal volume was observed in those with IRR compared to those without IRR [16.51 (14.65, 23.71) vs. 19.05 mL (17.02, 25.17 mL)], although the difference was not statistically significant (P=0.11; Figure 4B).

Figure 4 Boxplots comparing renal volumes across subgroups. (A) Renal volume distribution in control group, contralateral group, low-grade, moderate-grade, and high-grade VUR. Asterisks indicate statistically significant differences compared with the high-grade VUR group (P<0.05). (B) Renal volume comparison within high-grade VUR group between kidneys with and without IRR. The difference was not statistically significant (P=0.11). IRR, intrarenal reflux; VUR, vesicoureteral reflux.

Assessment of SRF impairment and RS

Overall, the incidence of SRF impairment and RS demonstrated a positive correlation with VUR grade. However, IRR occurred exclusively in high-grade VUR cases, whereas isolated cases of SRF impairment and RS were also sporadically observed in both low- and moderate-grade VUR groups (Table 1).

Table 3 shows the distribution characteristics of renal poles involvement in IRR, SRF impairment and RS. The upper renal pole was the predominant site of IRR, involved in 83% of cases—encompassing isolated upper pole (27%), combined upper and lower pole (31%), and pan-renal (25%) involvement. Isolated upper pole involvement and pan-renal involvement represented the primary distribution patterns for both SRF impairment and RS, collectively accounting for 67% and 52% of affected cases, respectively. Notably, SRF impairment demonstrated greater tendency for pan-renal involvement (37%), whereas RS showed stronger predilection for the isolated upper pole (30%). However, middle pole, lower pole, and middle + lower pole combinations involvement remained infrequent (ranging from 5% to 9%) in these three manifestations. The mean Jaccard similarity was 0.72 (95% CI: 0.65–0.78) for IRR vs. SRF and 0.69 (95% CI: 0.62–0.75) for IRR vs. RS. A paired Wilcoxon test showed no significant difference between the two similarities (P=0.207), suggesting that IRR is similarly associated with functional and structural injury at the regional level.

We performed multivariate logistic regression analysis incorporating six covariates: UTI frequency, sex, age (in months), laterality (unilateral/bilateral), VUR grade, and IRR. For SRF impairment, higher UTI frequency, VUR grade, and IRR were identified as independent predictors (all P<0.05). While for RS, age (in months) emerged as an additional significant predictor alongside these three factors (P<0.05; Figure 5). The logistic regression model showed excellent discriminative performance, with AUCs of 0.89 (95% CI: 0.86–0.94) for SRF impairment and 0.92 (95% CI: 0.87–0.96) for RS (Figure 6). All VIF values were below 2 (range: 1.305–1.998), indicating no significant collinearity. This confirms that the estimated regression coefficients—particularly those for VUR grade and IRR—are stable and not compromised by correlated predictors.

Figure 5 Forest plots of multivariable analysis for SRF impairment (A) and RS (B). The model included UTI frequency, IRR, and VUR grade. An OR >1 indicates increased risk. CI, confidence interval; IRR, intrarenal reflux; OR, odds ratio; RS, renal scarring; SRF, split renal function; UTI, urinary tract infection; VUR, vesicoureteral reflux.

Figure 6 ROC curves of the logistic regression models in predicting SRF impairment and RS. The AUC was 0.89 (95% CI: 0.86–0.94) for SRF impairment and 0.92 (95% CI: 0.87–0.96) for RS, respectively. AUC, area under the curve; CI, confidence interval; ROC, receiver operating characteristic; RS, renal scarring; SRF, split renal function.

Discussion

The reported prevalence of VUR ranges from 0.4% to 1.8% in normal children, increasing significantly to 31.1% (95% CI: 29.9–32.8) among children with UTIs (18). In our cohort of patients with UTI, the observed rates were slightly higher: VUR was identified in 35.2% of evaluated URUs, with concomitant IRR in 9.2%.

Prenatal hydronephrosis and congenital renal injury

The observed prevalence of fetal hydronephrosis in our VUR-positive cohort (18.9%) aligns with the 16.2% reported in the AUA guidelines panel (19). However, unlike most congenital anomalies of the kidney and urinary tract, VUR cannot be predicted from the degree of prenatal urinary tract dilatation (UTD) (13,20). This explains why VUR may be present across the entire spectrum of prenatal UTD, from mild to severe, and why approximately 15% of children with VUR have no history of antenatal dilatation at all (21). In our cohort, most patients with a history of fetal hydronephrosis had moderate to high-grade VUR, consistent with the observation that when VUR coexists with prenatal UTD, it tends to be of higher grade and often associated with other urinary tract anomalies.

This unique relationship stems from the underlying etiology of VUR—structural and/or functional abnormalities of the ureterovesical junction. Such abnormalities disrupt the anti-reflux mechanism, permitting retrograde urine flow and predisposing the kidney to infection (22,23). The resulting urinary stasis and increased voiding pressure create an environment conducive to bacterial colonization and ascending pyelonephritis, explaining the strong association between anatomical defects and recurrent, complex UTIs.

Importantly, the impact of VUR on the kidney must be interpreted in the context of disease onset and duration. In cases of high-grade reflux evident in utero, functional impairment may already be present at birth, independent of any history of UTI (24). This aligns with the concept of congenital reflux nephropathy, in which high-grade intrauterine reflux is thought to interfere with normal nephrogenesis, potentially leading to renal hypoplasia or dysplasia (25). Such congenital damage is distinct from the acquired scarring that results from postnatal febrile UTIs and helps explain why some infants in our cohort with high-grade VUR exhibited SRF impairment despite no documented infections.

Renal volume and functional impairment

After controlling for the effects of age and gender, we observed that renal volume decreased progressively with increasing VUR grade, but no statistically significant difference in renal volume was detected between low/moderate-grade VUR and the contralateral side. Moreover, the renal volume of the contralateral negative group did not demonstrate a significant compensatory enlargement compared with control group. Within the high-grade VUR group, renal volumes were smaller in kidneys with IRR compared to those without IRR, although this difference did not reach statistical significance. This discrepancy may be attributed to our cross-sectional study design, which inherently limits the elimination of inter-individual variations.

The relationship between renal volume loss and functional impairment in children with VUR must be interpreted within a temporal framework that accounts for age-appropriate growth dynamics. In Yang’s longitudinal study (26), kidneys with moderate-to-high-grade VUR and IRR grew in parallel with unaffected kidneys, whereas non-IRR kidneys showed catch-up growth after surgery (26). Based on these findings, we propose the following sequence: in kidneys with persistent IRR, functional impairment (reflected by reduced SRF) likely occurs first, followed by impaired compensatory growth, manifesting as slower renal growth compared with unaffected kidneys. At this stage, the volume deficit is primarily a growth delay rather than absolute shrinkage and remains partially reversible. In the later stage, when irreversible scarring develops, parenchymal fibrosis leads to permanent volume loss that is no longer reversible. At this point, volume reduction becomes inseparable from scarring itself. Therefore, the “disease duration” encapsulates not merely the presence of VUR, but the prolonged exposure to the tubulotoxic and inflammatory milieu driven by IRR, which ultimately manifests as failed compensatory renal growth and volume loss (27,28).

Spatial distribution and clinical significance of IRR

The predominance of upper renal region involvement across all injury types suggests this area’s heightened vulnerability to reflux nephropathy (29). Compared to RS, SRF impairment showed a greater tendency for diffuse involvement, raising the question of whether this reflects early-stage disease or heightened nephron susceptibility—a question requiring further cellular-level investigation.

The high Jaccard similarities between IRR and both SRF impairment (0.72, 95% CI: 0.65–0.78) and RS (0.69, 95% CI: 0.62–0.75) indicate strong spatial concordance. The comparable strength of these associations suggests that IRR concurrently affects renal function and parenchymal integrity in the same poles.

Clinical implications and the role of CeVUS

The multivariate logistic regression analysis identified distinct predictive profiles for SRF impairment and RS development in children with VUR. Frequent febrile UTIs, higher VUR grades, and IRR emerged as shared independent risk factors for both outcomes (all P<0.05), underscoring their fundamental role in reflux nephropathy pathogenesis. Notably, older age was a specific predictor of RS (P<0.05), indicating the importance of cumulative injury over time. The model demonstrated robust discriminative capacity, with AUCs of 0.89 (95% CI: 0.86–0.94) for SRF impairment and 0.92 (95% CI: 0.87–0.96) for RS prediction, supporting the integration of these predictors into clinical risk stratification algorithms.

Accurate assessment of RS is essential for guiding management decisions. According to current guidelines, ^99mTc-DMSA scintigraphy for evaluating established RS should be deferred until at least 6 months after the most recent febrile UTI to distinguish irreversible defects from transient inflammatory changes (5).

High-grade VUR with recurrent UTI can easily cause acute pyelonephritis, leading to reduced glomerular filtration rate and in the long run, impaired renal function, RS, hypertension and end-stage renal disease (30), posing a serious threat to children’s growth and development. Moreover, tissue scars could serve as a prognostic factor for both glomerular and tubular function evolution even if renal function remains stable through years (31). According to an early report, the self-recovery rate of VUR under 4–5 years old is 80% for low-grades and 30–50% for high-grades (32). The management of VUR is centered on renal preservation, with initial strategies ranging from CAP and regular follow-up to definitive surgical correction based on individualized risk assessment. According to the updated EAU/ESPU guidelines, for children older than 1 year presenting with high-grade VUR (grades IV–V), documented RS, and a history of frequent UTIs, ureteral reimplantation is recommended (23). In addition, endoscopic injection of dextranomer/hyaluronic acid copolymer (Dx/HA; Deflux^®) offers a minimally invasive alternative, particularly for intermediate-grade VUR and selected high-grade cases. Notably, intraoperative ultrasound guidance during endoscopic treatment has been shown to enhance procedural accuracy and predict treatment success, further underscoring the expanding role of ultrasound in VUR management from diagnosis to therapy (33-36).

Although VCUG is the standard modality for diagnosis of VUR, its inherent radiation exposure limits its application in long-term follow-up. CeVUS has emerged as a patient-friendly alternative due to its non-invasiveness, repeatability, and real-time dynamics. A nationwide survey involving 5,079 European children who underwent CeVUS examination (37) demonstrated that microbubbles are safe contrast agent for children. No adverse reactions (e.g., nausea, vomiting, abdominal pain) or catheterization-related complications occurred in our center.

Limitations

There are several limitations of this study. First, its retrospective design introduces inherent selection bias. Second, the modest sample size limited statistical power for subgroup analyses (e.g., by sex, age, or VUR etiology). Reliable differentiation between primary and secondary VUR was not systematically recorded, further restricting etiology-based subgroup analysis. The potential impact of this mixed etiology on our findings should be considered. Third, renal volume was not adjusted for body surface area. Fourth, the study design did not permit extended follow-up to compare long-term changes in renal growth rates between conservatively and surgically managed groups. Fifth, the voiding phase is difficult to capture on CeVUS in young children, so it is not possible to determine whether the VUR grade and IRR worsen during transient increases in bladder and collecting system pressure. Finally, the short interval between CeVUS and DMSA (≤2 weeks) may not meet the guideline-recommended 6-month interval for confirming permanent RS (5), thus, the true prevalence of permanent RS may be overestimated.

Conclusions

Our findings indicate that high-grade VUR is significantly associated with reduced renal volume (P<0.05), whereas IRR is associated with a trend towards greater renal volume loss and a higher likelihood of SRF impairment. There was no substantial renal volumetric compromise in low/moderate-grade VUR compared to controls, a distinction critical for risk-stratified management. The core contribution of this work resides in a validated predictive model integrating four clinically accessible parameters: UTI frequency, VUR grade, IRR status, and patient age. This model demonstrates excellent discriminative capacity for both SRF impairment and RS, enabling early identification of high-risk children. Overall, CeVUS provides a safe and convenient alternative to VCUG for diagnosing VUR, and IRR is important radiographic predictor of RS.

Acknowledgments

We thank all the participants for their cooperation in this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1-2808/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1-2808/dss

Funding: This study was supported by the Sichuan Science and Technology Program (No. 2025ZNSFSC0345).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1-2808/coif). H.L. reports that this study was funded by the Sichuan Science and Technology Program (No. 2025ZNSFSC0345). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional review board of West China Second University Hospital, Sichuan University (No. 20240424). As it was a retrospective study, the requirement for informed consent was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Gotoh T, Asano Y, Nonomura K, Togashi M, Koyanagi T. Intrarenal reflux in children with vesicoureteral reflux. Nihon Hinyokika Gakkai Zasshi 1991;82:1480-6. [Crossref] [PubMed]
2. Pensabene M, Spataro B, Baldanza F, Grasso F, Serra G, Notarbartolo V, Giuffrè M, Corsello G, Zambaiti E, Di Pace MR, Sergio M. Application of Ultrasound in Primary Vesicoureteral Reflux: From Diagnosis to Follow Up. Children (Basel) 2025;12:1363. [Crossref] [PubMed]
3. Ključevšek D, Battelino N, Tomažič M, Kersnik Levart T. A comparison of echo-enhanced voiding urosonography with X-ray voiding cystourethrography in the first year of life. Acta Paediatr 2012;101:e235-9. [Crossref] [PubMed]
4. Hayatghaibi SE, Alves VV, Coley BD, Previtera MJ, Zhang B, Ayyala RS, Iyer R, Trout AT. Contrast-Enhanced Voiding Urosonography and Radionuclide Cystography for Diagnosing Vesicoureteral Reflux Using VCUG as the Reference Standard: Systematic Review and Meta-Analysis. AJR Am J Roentgenol 2025;225:e2532739. [Crossref] [PubMed]
5. Vali R, Armstrong IS, Bar-Sever Z, Biassoni L, Borgwardt L, Brown J, et al. SNMMI procedure standard/EANM practice guideline on pediatric [99mTc]Tc-DMSA renal cortical scintigraphy: an update. Clin Transl Imaging 2022;10:173-84.
6. Putri UMA, Raharja PAR, Situmorang GR, Wahyudi I, Rodjani A, Puspitasari HA, Imam A, Saraiva LR, Vallasciani S, Abbas TO. Biomarker for renal scarring screening in children with vesicoureteral reflux: a systematic review. Front Pediatr 2025;13:1621716. [Crossref] [PubMed]
7. Özdemir H, Girişgen İ, Yaylalı O, Becerir T, Herek Ö, Şenol H, Yüksel S. Determining Split Renal Function in Children With Ureteropelvic Junction Stenosis: Technetium-99m Mercaptoacetyltriglycine (Tc-99m MAG-3) or Technetium-99m Dimercaptosuccinic Acid (Tc-99m DMSA)? Cureus 2024;16:e65075. [Crossref] [PubMed]
8. Reaffirmation of AAP Clinical Practice Guideline. The Diagnosis and Management of the Initial Urinary Tract Infection in Febrile Infants and Young Children 2-24 Months of Age. Pediatrics 2016;138:e20163026.
9. Darge K, Troeger J. Vesicoureteral reflux grading in contrast-enhanced voiding urosonography. Eur J Radiol 2002;43:122-8. [Crossref] [PubMed]
10. Lebowitz RL, Olbing H, Parkkulainen KV, Smellie JM, Tamminen-Möbius TE. International system of radiographic grading of vesicoureteric reflux. International Reflux Study in Children. Pediatr Radiol 1985;15:105-9.
11. Zhang G, Day DL, Loken M, Gonzalez R. Grading of reflux by radionuclide cystography. Clin Nucl Med 1987;12:106-9. [Crossref] [PubMed]
12. Mandell GA, Eggli DF, Gilday DL, Heyman S, Leonard JC, Miller JH, Nadel HR, Treves ST. Procedure guideline for renal cortical scintigraphy in children. Society of Nuclear Medicine. J Nucl Med 1997;38:1644-6.
13. Nguyen HT, Benson CB, Bromley B, Campbell JB, Chow J, Coleman B, Cooper C, Crino J, Darge K, Herndon CD, Odibo AO, Somers MJ, Stein DR. Multidisciplinary consensus on the classification of prenatal and postnatal urinary tract dilation (UTD classification system). J Pediatr Urol 2014;10:982-98. [Crossref] [PubMed]
14. Cvitkovic-Roic A, Turudic D, Milosevic D, Palcic I, Roic G. Contrast-enhanced voiding urosonography in the diagnosis of intrarenal reflux. J Ultrasound 2022;25:89-95. [Crossref] [PubMed]
15. Simicic Majce A, Arapovic A, Saraga-Babic M, Vukojevic K, Benzon B, Punda A, Saraga M. Intrarenal Reflux in the Light of Contrast-Enhanced Voiding Urosonography. Front Pediatr 2021;9:642077. [Crossref] [PubMed]
16. Klein EL, Wyers MR, Prendergast FM, Arzu J, Benya EC. Prevalence of intrarenal reflux in pediatric patients on contrast-enhanced voiding urosonography. Pediatr Radiol 2023;53:387-93. [Crossref] [PubMed]
17. Kim D, Choi YH, Choi G, Lee S, Lee S, Cho YJ, Lim SH, Kang HG, Cheon JE. Contrast-enhanced voiding urosonography for the diagnosis of vesicoureteral reflux and intrarenal reflux: a comparison of diagnostic performance with fluoroscopic voiding cystourethrography. Ultrasonography 2021;40:530-7. [Crossref] [PubMed]
18. Sargent MA. What is the normal prevalence of vesicoureteral reflux? Pediatr Radiol 2000;30:587-93. [Crossref] [PubMed]
19. Skoog SJ, Peters CA, Arant BS Jr, Copp HL, Elder JS, Hudson RG, Khoury AE, Lorenzo AJ, Pohl HG, Shapiro E, Snodgrass WT, Diaz M. Pediatric Vesicoureteral Reflux Guidelines Panel Summary Report: Clinical Practice Guidelines for Screening Siblings of Children With Vesicoureteral Reflux and Neonates/Infants With Prenatal Hydronephrosis. J Urol 2010;184:1145-51. [Crossref] [PubMed]
20. Herthelius M. Antenatally detected urinary tract dilatation: long-term outcome. Pediatr Nephrol 2023;38:3221-7. [Crossref] [PubMed]
21. Balthazar A, Herndon CDA. Prenatal Urinary Tract Dilatation. Urol Clin North Am 2018;45:641-57. [Crossref] [PubMed]
22. Houat AP, Guimarães CTS, Takahashi MS, Rodi GP, Gasparetto TPD, Blasbalg R, Velloni FG. Congenital Anomalies of the Upper Urinary Tract: A Comprehensive Review. Radiographics 2021;41:462-86. [Crossref] [PubMed]
23. Gnech M, 't Hoen L, Zachou A, Bogaert G, Castagnetti M, O'Kelly F, Quaedackers J, Rawashdeh YF, Silay MS, Kennedy U, Skott M, van Uitert A, Yuan Y, Radmayr C, Burgu B. Update and Summary of the European Association of Urology/European Society of Paediatric Urology Paediatric Guidelines on Vesicoureteral Reflux in Children. Eur Urol 2024;85:433-42. [Crossref] [PubMed]
24. Farrugia MK, Montini G. Does vesicoureteric reflux diagnosed following prenatal urinary tract dilatation need active management? A narrative review. J Pediatr Urol 2025;21:115-22.
25. Demède D, Cheikhelard A, Hoch M, Mouriquand P. Evidence-based medicine and vesicoureteral reflux. Ann Urol (Paris) 2006;40:161-74. [Crossref] [PubMed]
26. Xiuzhen Y, Zheming X, Li L, Jingjing W, Chang T, Ran T, Jingjing Y. Effects of Intrarenal Reflux on Renal Growth in Children With Grades III-V Primary Vesicoureteral Reflux. J Ultrasound Med 2024;43:2295-302. [Crossref] [PubMed]
27. Gkalonaki I, Schoina E, Anastasakis M, Patoulias I. Pathogenesis and prognosis of intrarenal reflux. Folia Med Cracov 2023;63:57-64. [Crossref] [PubMed]
28. Rose JS, Glassberg KI, Waterhouse K. Intrarenal reflux and its relationship to renal scarring. J Urol 1975;113:400-3. [Crossref] [PubMed]
29. Ransley PG, Risdon RA. The pathogenesis of reflux nephropathy. Contrib Nephrol 1979;16:90-7. [Crossref] [PubMed]
30. Mathias S, Greenbaum LA, Shubha AM, Raj JAM, Das K, Pais P. Risk factors for renal scarring and clinical morbidity in children with high-grade and low-grade primary vesicoureteral reflux. J Pediatr Urol 2022;18:225.e1-8.
31. Marcellino A, Bloise S, Fraternali R, Pirone C, Brandino G, Testa A, Filippi L, Lubrano R. Evaluation of Renal Function and Scars in Children With Primary Vesicoureteral Reflux. Urology 2022;168:195-200. [Crossref] [PubMed]
32. Elder JS, Peters CA, Arant BS Jr, Ewalt DH, Hawtrey CE, Hurwitz RS, Parrott TS, Snyder HM 3rd, Weiss RA, Woolf SH, Hasselblad V. Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol 1997;157:1846-51.
33. Pensabene M, Cimador M, Spataro B, Serra G, Baldanza F, Grasso F, Corsello G, Salerno S, Di Pace MR, Sergio M. Intraoperative ultrasound-assisted endoscopic treatment of primary intermediate and high-grade vesicoureteral reflux in children in a long-term follow-up. J Pediatr Urol 2024;20:132.e1-11.
34. Zambaiti E, Pensabene M, Montano V, Casuccio A, Sergio M, Cimador M. Ultrasonographic mound height as predictor of vesicoureteral reflux resolution after endoscopic treatment in children. J Pediatr Surg 2016;51:1366-9. [Crossref] [PubMed]
35. Zambaiti E, Sergio M, Di Pace MR, Casuccio A, Cimador M. The fate of implant after endoscopic injection of dextranomer/hyaluronic acid in vesicoureteral reflux: time to partial reabsorption and stabilization. J Pediatr Urol 2020;16:191.e1-6.
36. Zambaiti E, Sergio M, Casuccio A, Salerno S, Cimador M. Intraoperative ultrasound-assisted approach for endoscopic treatment of vesicoureteral reflux in children. J Pediatr Surg 2017;52:1661-5. [Crossref] [PubMed]
37. Torres A, Koskinen SK, Gjertsen H, Fischler B. Contrast-enhanced ultrasound using sulfur hexafluoride is safe in the pediatric setting. Acta Radiol 2017;58:1395-9.