Patients with VUR demonstrate a wide range of severity, and a good percentage of reflux patients do not develop renal scars and do not need any intervention as VUR tends to resolve spontaneously over time [4, 7]. Improved ability to predict individualized early reflux resolution will assist the parent and physician with VUR management decisions. In our study, we aimed to identify the potential prognostic factors that affect primary VUR resolution in a cohort of conservatively managed patients.
The main objective of VUR treatment is to avoid the occurrence of febrile UTIs and subsequent renal scarring [2, 4]. Conservative therapy requires diligent waiting, intermittent or continuous antibiotic prophylaxis, and bladder rehabilitation in cases with bladder dysfunction [1].
In 2015, de Bessa et al.’s meta-analysis findings endorsed continuous antibiotic prophylaxis (CAP) in all children with VUR regardless of reflux grade. For asymptomatic patients, the correct length of antibiotic prophylaxis is uncertain. Annual performance of a VCUG control is a choice. Prophylaxis may be discontinued if VUR is not observed in the control imaging after the first year. If breakthrough infections occur under this antibiotic prophylaxis, surgical treatment should be attempted [16].
In our study, spontaneous resolution including improvement was 72%, persistent VUR in 12% while the surgical intervention was indicated in 16%. Comparable results were reported in the Arlen et al. 2016 study where spontaneous resolution including improvement was 56.5%, persistent VUR in 26% while surgical intervention was necessitated in 17.5% [17].
A decreasing incidence of VUR with age reflects spontaneous resolution in many patients. As expected, VUR grade was significantly associated with resolution. Children with high-grade VUR have a higher risk of renal scarring after a febrile UTI, and the possibility of spontaneous VUR resolution is low [10]. VUR has a high spontaneous resolution rate within the first 4–5 years of life (80% VUR grade III, 30–50% VUR grade IV–V). The anatomic maturation probability is highest during these years [4, 10].
The rate of spontaneous resolution depends not only on the degree of reflux, but also on clinical presentation, patient age, sex, laterality, and associated LUT dysfunctions [10, 12]. Several variables were identified as negative predictive factors for VUR resolution [11, 12]. Sjostrom and her colleagues evaluated the predictive factors for the resolution of congenital high-grade VUR in infants [11]. They reported an overall spontaneous reflux resolution rate of 38%, including cases downgraded to grade I to II. Variables that were substantially associated with VUR resolution were breakthrough febrile UTI, bladder dysfunction, higher grade of reflux, and renal abnormality. There were no differences in VUR resolution depending on gender, or prenatal or postnatal diagnosis. These findings were consistent with our current study.
Knudson et al. analyzed the predictive factors for spontaneous primary VUR resolution and found that initial VUR grade, bladder volume at reflux onset, age at diagnosis and history of prenatal HN were independent factors affecting VUR resolution rate [18]. After an average follow-up of around 2 years, 60% achieved spontaneous resolution (64% for grade I–III vs. 17% for grades IV and V). Those findings were also comparable to our study in terms of high spontaneous VUR resolution rate.
In their study, they found that VUR during the filling phase of VCUG or passive VUR is a negative predictor for VUR resolution. When bladder volume at VUR onset was greater than 50% of predicted bladder capacity, improved resolution was observed. They also found that VUR resolution was higher in patients with prenatal HN than those presented later, and this might due to patients with early VUR diagnosis are more likely to have transient VUR that resolves rapidly. After early infancy period, the VUR chance for resolution will be like those presenting at older age. They also compared children younger versus older than 2 years of age and they found that diagnostic age is an important factor affecting the annual resolution rate of VUR; however, the overall resolution rate was not significantly affected [18].
Similar to our study findings, spontaneous resolution rates have been shown to be significantly higher in grade I–III VUR, whereas high-grade reflux is much less likely to resolve irrespective of long-term monitoring and antibacterial therapy [11]. In their long-term follow-up, Schwab et al. 2002 recorded a 68% overall rate of VUR resolution and found that grades I to III VUR resolved at the same rates and significantly more rapidly than grades IV to V (76% vs. 35%) [19].
Spontaneous VUR resolution was observed in 25 out of 56 renal units (45%) after a median follow-up of 5.5 years of conservative treatment in another study by Silva et al. 2006; 75% for moderate reflux (I–III) and 37% for severe reflux (IV–V) [12]. Furthermore, Estrada et al. conducted a study of 2462 VUR patients and found an overall resolution rate of 51% [55% for grades I–III vs. 32% for grade IV and V]. They reported that VUR resolution is influenced by a combination of factors that include gender, age at presentation, laterality and grade of reflux, ureteral anatomy and mode of presentation [10].
Yeung et al. reported that 70% of the cases of mild reflux and 43% of the cases of severe reflux resolved by 15 months of follow-up [20]. A low-resolution rate has been reported for grade V reflux [0–30%] during a follow-up of 2–5 years, whereas grade IV was often reported to have a resolution rate of more than 50%. In contrary, Garcia Roig and colleagues reported that high-grade (IV or V) reflux was not associated with a resolution at any point [9].
The presence of renal damage is an additional variable examined in relation to spontaneous resolution of VUR [10, 12, 21]. Among 506 Brazilian children with VUR, Silva et al. performed a multivariate study and found that VUR resolution was predicted among other variables by the absence of renal scars [12]. The survival study found that VUR resolves in only 17% of children with renal damage versus 62% of children without renal damage. In our study, we discovered that kidneys with split renal function less than 40% had a lower VUR resolution rate than those above 40% (77% vs. 45%).
The presence of associated HN with VUR was also studied. In the classical study of Edwards et al., VUR was resolved in more than 80% of undilated ureters but only in 40% of dilated units after 7–15 years of follow-up [22]. In our research, we observed that VUR associated with HN has a lower probability of resolution than non-dilated systems.
We recognized from previous studies that impaired bladder function adversely affected VUR resolution rate, we likewise did not use voiding dysfunction as a factor in our statistical analysis, and we omitted children with secondary VUR because of underlying bladder pathology.
There should be recognition of several limitations of our study. It is a retrospective analysis and selection bias can occur because the decision on care relied on the choice of pediatric urologists and parents. The sample size was relatively small because our center has a medium volume that could predispose the results to statistical errors of type I and type II and restricted our ability to perform subgroup analyses. We excluded patients with bladder dysfunction from the study based on clinical history, but some patients with irregular bladder function may not have been detected and included in our research. Nonetheless, we believe that in the treatment of unilateral primary VUR, our study provided valuable information to enable risk stratification. By identifying the predictive factors, pretreatment counseling could be also improved. Patients with high-grade VUR associated with high-grade HN might benefit from early active intervention to minimize the need for repeated VCUG and protect future renal damage.
