Beyond Reflux Grade: Long-Term Outcomes of Children with Grade 1 Vesicoureteral Reflux

1. Introduction

Vesicoureteral reflux (VUR) is a common pediatric urinary tract condition and remains clinically important because of its association with urinary tract infection (UTI), pyelonephritis, renal scarring, hypertension, proteinuria, and long-term renal morbidity [1,2]. Although the clinical relevance of VUR has traditionally been interpreted according to reflux grade, the relationship between anatomical reflux severity and renal outcome is not always straightforward [1,2]. Patient-specific factors, including recurrent infection, bladder-bowel dysfunction, voiding dysfunction, congenital renal or urinary tract anomalies, and baseline renal parenchymal abnormalities, may substantially modify clinical risk [1,2,3].

Grade 1 VUR is usually regarded as the mildest form of reflux because retrograde flow is limited to a non-dilated ureter without involvement of a dilated collecting system [4]. Consequently, it is often assumed to have a benign clinical course and may receive less attention than dilating or high-grade reflux [1]. This perception is partly understandable, as high-grade reflux is more clearly associated with renal injury and has formed the basis of many historical treatment strategies [1,5]. However, the assumption that Grade 1 reflux is clinically negligible may be overly simplistic [6].

Importantly, Grade 1 VUR has not been adequately characterized as an isolated clinical subgroup in the major VUR literature. Classic randomized surgical versus medical management trials predominantly focused on moderate- and high-grade reflux, whereas more recent studies frequently grouped Grade 1 reflux with other low-grade categories [7,8,9,10,11,12,13,14]. In the RIVUR trial, children with Grade I–IV reflux were included, but Grade I reflux represented only 11% of the cohort, while Grade II and III reflux predominated [11]. Therefore, long-term outcome data specifically focused on Grade 1 VUR remain limited.

This evidence gap may have contributed to the underestimation of Grade 1 reflux in clinical practice. Anatomically, Grade 1 VUR is low grade; however, the patient carrying Grade 1 reflux may not necessarily be low risk. In some children, Grade 1 reflux may coexist with recurrent UTI, voiding dysfunction, renal anomalies, stone disease, familial Mediterranean fever, abnormal DMSA findings, or other conditions that determine renal prognosis more strongly than reflux grade itself [15,16]. In this context, Grade 1 reflux may function less as an isolated benign radiologic finding and more as a marker accompanying a broader urinary or systemic phenotype [2].

The aim of the present study was to evaluate the long-term renal and infectious outcomes of children with Grade 1 VUR and to describe the spectrum of principal associated clinical phenotypes in this group. We specifically assessed breakthrough UTI, proteinuria, and new renal scar formation during follow-up, with the hypothesis that Grade 1 VUR should not be dismissed solely on the basis of its low anatomical grade.

2. Materials and Methods

2.1. Study Design and Patient Population

Following approval from the Institutional Ethics Committee (Approval No: KAEK 2021/14-232), a retrospective cohort study was conducted at a tertiary pediatric urology center. Medical records of children diagnosed with Grade 1 vesicoureteral reflux (VUR) between January 2008 and January 2025 were reviewed. Patients younger than 18 years with unilateral or bilateral Grade 1 VUR confirmed by voiding cystourethrography (VCUG) were eligible for inclusion. Grade 1 VUR was defined according to the International Reflux Study Classification as reflux into a non-dilated ureter without pelvicalyceal involvement.

Patients with incomplete follow-up data, unavailable baseline imaging, or reflux grades higher than Grade 1 in either renal unit were excluded. Patients with associated urinary tract abnormalities, voiding dysfunction, recurrent urinary tract infection (UTI), stone disease, familial Mediterranean fever (FMF), or other accompanying conditions were not excluded, as one of the primary aims of the study was to evaluate the clinical significance of associated pathology in children with Grade 1 reflux.

2.2. Data Collection

Demographic, clinical, laboratory, imaging, treatment, and follow-up data were collected from institutional electronic medical records.

The following variables were recorded: age at diagnosis, sex, laterality of reflux, number of refluxing renal units, duration of follow-up, history of recurrent UTI, principal associated clinical phenotype, renal ultrasonography findings, DMSA scintigraphy findings, serum creatinine levels, medical and surgical interventions, breakthrough UTI during follow-up, proteinuria during follow-up, and new renal scar formation during follow-up.

Associated clinical phenotypes were classified into five predefined categories: (1) voiding dysfunction, (2) recurrent UTI without another identifiable underlying pathology, (3) renal anomaly, (4) stone disease, and (5) familial Mediterranean fever (FMF). When multiple associated conditions coexisted, each patient was assigned to a single principal associated clinical phenotype based on the dominant clinical condition considered most relevant to the patient's presentation and subsequent management.

2.3. Clinical Management and Follow-Up

Patients were managed according to contemporary institutional practice and individualized clinical assessment. Management decisions were based on the overall clinical phenotype rather than reflux grade alone and included evaluation and treatment of associated conditions such as voiding dysfunction, recurrent UTI, constipation, renal anomalies, and urinary stone disease when present. Continuous antibiotic prophylaxis, endoscopic treatment, or additional interventions were performed when clinically indicated.

After clinical stabilization, routine repeat VCUG was not performed. Follow-up consisted of clinical assessment, urinalysis, urine culture when indicated, renal ultrasonography, and DMSA scintigraphy in selected patients according to clinical requirements.

2.4. Outcome Definitions

The primary infectious outcome was breakthrough urinary tract infection (UTI). The primary renal outcomes were proteinuria and new renal scar formation. Breakthrough UTI was defined as a culture-proven symptomatic urinary tract infection occurring during follow-up after initiation of treatment and clinical surveillance. Proteinuria was defined as persistent proteinuria detected during follow-up and confirmed by 24-hour urine protein quantification. New renal scar formation was defined as a newly detected cortical defect or scar on follow-up DMSA scintigraphy that was absent on baseline imaging.

A secondary renal adverse outcome was defined as the occurrence of proteinuria and/or new renal scar formation during follow-up. An exploratory overall adverse outcome was defined as the occurrence of breakthrough UTI or renal adverse outcome during follow-up.

2.5. Statistical Analysis

Statistical analyses were performed using SPSS version 27 (IBM Corp., Armonk, NY, USA).

Continuous variables were assessed for normality using the Shapiro–Wilk test. Normally distributed variables were presented as mean ± standard deviation (SD), whereas non-normally distributed variables were reported as median and interquartile range (IQR). Categorical variables were expressed as frequencies and percentages. Patient-level analyses were performed for all clinical outcomes. Renal-unit-level analyses were used when describing reflux laterality and distribution. Comparisons between groups were performed using the chi-square test or Fisher’s exact test for categorical variables and Student’s t-test or Mann–Whitney U test for continuous variables, as appropriate. Factors associated with breakthrough UTI and renal adverse outcomes were explored using univariable analyses. Because of the limited number of proteinuria and new scar events, multivariable regression analyses were not performed in order to avoid model overfitting. All statistical tests were two-sided and a p value <0.05 was considered statistically significant.

3. Results

Patient Characteristics

A total of 132 children with Grade 1 vesicoureteral reflux (VUR) involving 154 refluxing renal units were included in the study. Ninety patients (68.2%) were female and 42 (31.8%) were male. Bilateral reflux was present in 22 patients (16.7%), whereas 110 (83.3%) had unilateral reflux. The median age at diagnosis was 6 years (IQR 4–9.25). Median follow-up duration was 8 years (IQR 5–9), with a mean follow-up of 7.13 ± 2.58 years. DMSA scintigraphy was available in 102 patients (77.3%), whereas 30 patients (22.7%) did not undergo DMSA evaluation. Baseline demographic and clinical characteristics are summarized in Table 1.

Principal Associated Clinical Phenotype

A principal associated clinical phenotype was identified in all patients. Voiding dysfunction represented the most common underlying condition and was present in 51 patients (38.6%), followed by recurrent urinary tract infection in 37 (28.0%) and renal anomalies in 33 (25.0%). Stone disease and familial Mediterranean fever were identified in 8 (6.1%) and 3 (2.3%) patients, respectively (Table 2).

Long-Term Outcomes

During follow-up, breakthrough urinary tract infection occurred in 46 patients (34.8%). Proteinuria developed in 6 patients (4.5%), while new renal scar formation was detected in 7 patients (5.3%). Overall, 10 patients (7.6%) developed a renal adverse outcome, defined as proteinuria and/or new renal scar formation. An exploratory overall adverse outcome, defined as breakthrough UTI or renal adverse outcome, occurred in 54 patients (40.9%) (Table 3).

Management

Continuous antibiotic prophylaxis was the initial management strategy in 106 patients (80.3%), whereas 14 patients (10.6%) were managed with clinical follow-up alone. Primary endoscopic treatment was performed in 11 patients (8.3%), and one patient (0.8%) underwent ureteroneocystostomy. During follow-up, four additional patients subsequently underwent endoscopic treatment because of persistent clinical indications.

Factors Associated with Renal Adverse Outcomes

Patients were stratified according to the presence of renal adverse outcomes, defined as proteinuria and/or new renal scar formation. Ten patients developed renal adverse outcomes during follow-up.

Patients with renal adverse outcomes were significantly older at diagnosis than those without renal adverse outcomes [13.0 years (IQR 9.8–14.5) vs. 6.0 years (IQR 3.6–9.0), p<0.001]. Among patients with available DMSA scintigraphy, abnormal DMSA findings were more frequent in the renal adverse outcome group than in patients without renal adverse outcomes [8/10 (80.0%) vs. 38/91 (41.8%), p=0.040]. No statistically significant association was observed between renal adverse outcomes and sex, reflux laterality, renal anomaly, voiding dysfunction, recurrent UTI phenotype, stone disease, FMF, or breakthrough UTI. Detailed comparisons are presented in Table 4.

Factors Associated with Breakthrough Urinary Tract Infection

Breakthrough UTI occurred in 46 patients during follow-up. Female sex was significantly more frequent among patients with breakthrough UTI than among those without breakthrough infection [38/46 (82.6%) vs. 52/86 (60.5%), p=0.009]. Age at diagnosis, reflux laterality, DMSA abnormality, renal anomaly, voiding dysfunction, recurrent UTI phenotype, stone disease, and FMF were not significantly associated with breakthrough UTI. Detailed comparisons are presented in Table 5.

4. Discussion

The present study evaluated the long-term clinical course of 132 children with Grade 1 vesicoureteral reflux (VUR) over a median follow-up period of 8 years. The principal findings were threefold. First, clinically relevant infectious and renal outcomes, including breakthrough urinary tract infection (UTI), proteinuria, and new renal scar formation, occurred despite the presence of only Grade 1 reflux. Second, each child in our cohort could be classified into a principal associated clinical phenotype based on the dominant associated condition contributing to clinical presentation and management. Third, renal adverse outcomes were associated with baseline renal parenchymal abnormalities on DMSA scintigraphy and older age at diagnosis. Together, these findings suggest that, in selected referral populations, the clinical significance of Grade 1 VUR may extend beyond its anatomical classification.

Although VUR has been extensively investigated for decades, Grade 1 reflux remains relatively underrepresented as a distinct clinical entity in the literature. Historically, landmark surgical and medical management trials focused predominantly on moderate- and high-grade reflux, whereas more contemporary studies frequently combined Grade 1 reflux with other low-grade categories [7,8,9,10,11,12,13,14]. Consequently, long-term outcome data specifically addressing Grade 1 VUR as an independent clinical entity remain limited. Direct comparison with previous studies is therefore difficult because available evidence largely reflects mixed low-grade reflux populations rather than isolated Grade 1 disease. The RIVUR trial, for example, included children with Grades I–IV reflux, but Grade I represented only a small proportion of the study population [11]. Thus, many of the assumptions regarding the benign nature of Grade 1 reflux have been extrapolated from studies in which these patients constituted only a minority. The present study helps address this gap by examining a relatively large cohort composed exclusively of children with Grade 1 VUR and long-term follow-up.

The most striking observation of the present study was not the presence of Grade 1 reflux itself, but the remarkable heterogeneity of the patients carrying this diagnosis. Each child was classified into a principal associated clinical phenotype based on the dominant associated condition contributing to presentation and management. Nearly two thirds of the cohort demonstrated either voiding dysfunction or a recurrent UTI phenotype, while one quarter had an underlying renal anomaly. These findings suggest that Grade 1 reflux rarely occurred as an isolated radiological finding in our population and instead appeared as part of a broader clinical context. Importantly, reflux grade remained constant across all patients, whereas patient phenotype varied considerably. Within this grade-restricted cohort, variability in infectious and renal outcomes appeared to be more closely related to associated clinical features than to reflux grade itself.

This concept is further supported by the DMSA findings observed in our study. Among patients with available scintigraphic evaluation, abnormal baseline DMSA findings were significantly associated with subsequent renal adverse outcomes; 80% of patients who developed renal adverse outcomes had abnormal baseline DMSA findings compared with 41.8% of those without renal adverse outcomes. In contrast, reflux grade was identical in all patients and therefore could not account for differences in outcome. From a nephrological perspective, DMSA abnormalities represent evidence of pre-existing renal parenchymal involvement rather than merely an anatomical urinary tract abnormality [17,18,19]. Previous studies have consistently demonstrated that renal cortical defects and scarring detected on DMSA scintigraphy are among the strongest predictors of long-term renal morbidity in children with VUR [15,20]. Although this association should be interpreted cautiously because DMSA imaging was performed according to clinical indications rather than a standardized protocol, our findings nevertheless suggest that baseline renal parenchymal abnormalities may provide clinically relevant prognostic information beyond reflux grade alone.

Taken together, these observations support a broader conceptual view of Grade 1 reflux. Within a tertiary referral population, Grade 1 VUR may be encountered in association with clinically relevant urinary or systemic pathology rather than as an isolated benign anatomical finding. In this setting, Grade 1 reflux may be better interpreted as one component of a broader clinical phenotype rather than an isolated anatomical finding. Consequently, the diagnosis of Grade 1 reflux should not terminate clinical evaluation. Instead, clinicians should continue to assess accompanying conditions, particularly voiding dysfunction, recurrent infection, renal anomalies, and baseline renal parenchymal abnormalities [1,2]. Importantly, our findings do not imply that all patients with Grade 1 reflux require aggressive intervention or surgical treatment; rather, they support individualized management directed toward the accompanying pathology and overall clinical risk profile [2]. In our cohort, most children received continuous antibiotic prophylaxis as part of this individualized management strategy, reflecting contemporary risk-based clinical practice rather than treatment directed solely by reflux grade [2].

Another important strength of the present study is its prolonged duration of follow-up. Many previous investigations of low-grade reflux have focused primarily on spontaneous resolution or short-term outcomes [18,22]. In contrast, our cohort was followed for a median of 8 years, allowing evaluation of clinically meaningful renal endpoints such as proteinuria and new renal scar formation, outcomes that may be more clinically relevant to long-term renal prognosis than radiological persistence or resolution of reflux alone [17,20].

The present study has several limitations. Because this study was conducted in a tertiary pediatric urology center, the cohort likely represents a clinically enriched referral population rather than the full spectrum of children with Grade 1 VUR. Therefore, the frequency of clinical phenotypes and outcomes observed in this study should not be generalized to all children with Grade 1 reflux. Its retrospective design introduces the possibility of selection bias and dependence on the accuracy of medical records. DMSA scintigraphy was not available for all patients, and both baseline and follow-up imaging were performed according to clinical indications rather than a standardized protocol. Consequently, children undergoing DMSA evaluation may have represented a higher-risk subgroup, introducing ascertainment bias, while new renal scar formation may have been underestimated in patients who did not undergo repeat DMSA scintigraphy. In addition, the relatively small number of renal adverse outcome events precluded robust multivariable analyses, and the observed associations should therefore be regarded as exploratory. Nevertheless, the study possesses important strengths, including a relatively large cohort composed exclusively of Grade 1 VUR patients, long-term follow-up, and detailed characterization of clinical phenotypes.

Future prospective multicenter studies focusing specifically on Grade 1 VUR are needed to validate these findings, identify the phenotypic characteristics associated with long-term renal outcomes, and develop phenotype-based risk stratification models that move beyond reflux grade alone.

5. Conclusions

In this tertiary referral cohort, low anatomical reflux grade did not preclude clinically relevant infectious and renal outcomes during long-term follow-up. Variability in outcomes appeared to be more closely related to associated clinical phenotypes and baseline renal parenchymal abnormalities than to reflux grade itself. These findings suggest that, in selected children, Grade 1 vesicoureteral reflux should be interpreted within the context of accompanying urinary or systemic pathology rather than an isolated benign anatomical finding. Accordingly, the clinical significance of Grade 1 reflux should be interpreted within the broader clinical phenotype of the patient rather than according to reflux grade alone.