It is generally thought that vesicoureteral reflux (VUR) is a pathological condition in humans. It has been claimed to be a common phenomenon in children with urinary tract infection (UTI), but rare in healthy children [1, 2]. In a historical survey in Germany it was found, however, that VUR is a common finding in infants without any renal disease, and the presence of VUR was inversely related to the age of the patients studied [3]. By an active transport of microbes from the urinary bladder to the kidney(s), VUR is thought to predispose the child with UTI to pyelonephritis and renal scarring and, ultimately, later in life, to hypertension and end-stage renal disease (ESRD) [4]. Guidelines for clinicians to detect, follow-up and treat UTI and VUR have been published in several countries by paediatric or paediatric nephrology societies [5–8]. According to these guidelines, children with their first UTI should be examined for VUR. By identifying and treating the children with VUR and preventing recurrent UTI, we could, supposedly, decrease the occurrence of renal scarring and ESRD. Yet Feldman and Dick, in their systematic review of the literature, could not find any evidence of the value of routine examinations for VUR [9]. Recently, several authors have challenged the rationale of routinely examining a child for VUR after UTI [10–12].

The occurrence of vesicoureteral reflux

The true prevalence of VUR in humans is uncertain, and the often-cited occurrence rates of 1–2% are based on estimates. Owing to the invasive nature of imaging for VUR and the radiation burden involved, it is no longer ethically possible to evaluate the prevalence of VUR in healthy children. In 1967 Kollermann and Ludwig published their study of VUR in children and found that the prevalence of VUR was over 60% in infants without any renal disease and that this gradually decreased to 5% in children 4 years of age [3]. Other authors have reported a lower occurrence of VUR, but the qualities of their investigations have varied a lot [13–15]. The prevalence of VUR is age- and gender-dependent; girls predominate when VUR is diagnosed in the evaluation of childhood UTI, and male infants have a preponderance when VUR is found in imaging for antenatal hydronephrosis or infant pyelonephritis [4]. Vesicoureteral reflux is found in approximately 30% of children with UTI, and about 30% of such patients have renal scarring [16, 17]. Mild renal scarring seems predominantly to have a female preponderance and relates to recurrent UTI and moderate grades of VUR. Moderate or severe renal scarring is associated with high grades of VUR, male gender, and, seemingly, is of congenital origin [18].

The prevalence of VUR in siblings of children with VUR has been reported to be as high as 30–50% [19–21]. This has been claimed to prove that VUR is hereditary in nature. Unfortunately, the studies of siblings with VUR lack control groups and, thus, can overestimate the possible genetic nature of VUR. There is also a racial difference in the occurrence of VUR [22].

In the intervention studies it has been found that the prevalence and grade of VUR are highest in infants, and, when the child matures, the grade and occurrence of VUR gradually diminishes, even among the control groups receiving only antimicrobial prophylaxis for UTI. Spontaneous resolution of moderate VUR has been observed in 60–85% of children after a few years’ follow-up [23].

Urinary tract infection, renal scarring and vesicoureteral reflux

Vesicoureteral reflux can be a risk factor for renal scarring in the presence of UTI by the active transport of microbes from the urinary bladder to the kidney(s), but a causal connection between VUR alone and renal scarring has not been established. New renal scars develop only after UTI, with or without VUR, and evidence supporting the role of VUR leading to pyelonephritis is controversial [24]. In adults new renal scarring is noted only in previously scarred kidneys and is associated with recurrent UTI [25]. Similar findings have been found in children [24]. Focal or generalised renal scarring is often seen in kidneys without VUR, and it seems that VUR has only marginal impact on new renal scarring [26].

Vesicoureteral reflux can predispose the child to recurrent UTI by marked residual urine, and VUR exposes the child to UTI by low-virulence microbes [27]. Surgical correction of VUR can reduce the rate of febrile recurrent UTI, but there seems to be no difference in the total numbers of recurrent UTIs between refluxing and non-refluxing children, as was noted in The International Reflux Study in Children (IRSC) [28]. The rates of new renal scarring, or the progression of old scars, were equal in both conservative and surgical treatment groups in this international randomised and controlled trial (RCT) on VUR [28]. The incidence of renal scarring thus seems to be unaffected by the presence of VUR, and UTI plays the major role here [24]. Vesicoureteral reflux is commonly noted in transplanted kidneys in children, but VUR does not seem to affect the survival of the transplant or the rate of recurrent UTI [29].

The treatment of vesicoureteral reflux

If VUR were a significant and modifiable factor in development of recurrent UTI or new renal scarring, we should have a marked reduction of these outcomes in randomised controlled trials and in the results of the meta-analyses based on the published RCTs on this subject. The unanimous conclusion of recent meta-analyses on the treatment of VUR has been that surgical abolishment of VUR, compared with microbial UTI prophylaxis and spontaneous resolution of VUR, has the same risk of new renal parenchymal injury or recurrent non-febrile UTI [30, 31]. Surgery gives protection against febrile recurrent UTI, but the benefit of surgery over the use of antimicrobials is only small at best, however. The RCTs published so far have either had too short a follow-up time or are not powered enough to show significant differences in hypertension or ESRD between surgical or conservative treatment of VUR [31, 32]. In a cohort study Craig et al. could not demonstrate any decrease in patients with ESRD attributable to reflux nephropathy despite the active surgical correction of VUR [33]. Open surgery for VUR is a major intervention and can entail serious complications [24]. Thus, endoscopic treatment of VUR has gained popularity, but the success rates are inferior to those of open techniques, particularly in high-grade VUR, and the modality’s long-term safety is unclear [34]. The most worrisome aspect of endoscopic treatment of VUR is, however, the seemingly uncritical use of this invasive procedure in children with low grades of VUR. The antimicrobial prophylaxis of recurrent UTI is controversial too, and it may have unpleasant short-term side effects and increase the antimicrobial resistance of bacteria [35, 36]. Wheeler et al., in their meta-analysis, could find one randomised prospective study comparing continuous, intermittent or no treatment with antimicrobials in children with VUR [31]. In that trial there was no difference between the groups studied in the risk of recurrent UTI or renal parenchymal injury.

Conclusions

Vesicoureteral reflux is a fairly common phenomenon that can be associated with congenital renal dysplasia. Vesicoureteral reflux does not markedly increase the risk of recurring UTI or new acquired renal scars. The surgical correction of VUR does not prevent recurrences of non-febrile UTI or new renal scars. In some children VUR is a symptom of developmental maturation defect of the “uretero-vesical valve”, as presented by Mackie and Stephens [37]. This type of VUR is usually found in young girls monitored after their UTI, and is characterised by a fairly low grade and rapid spontaneous resolution and clinically irrelevant focal renal scarring, if any, in the kidneys. In infant boys the VUR is often high grade, resistant to spontaneous resolution, and associated with coarse congenital renal dysplasia, and is usually found after clinical pyelonephritis or on imaging because of antenatal hydronephrosis. It seems doubtful whether VUR is an important and modifiable risk factor for recurrent UTI, new renal scarring or ESRD. Since new renal scarring develops only after recurrent UTI, the prompt diagnosis and treatment of UTI is crucial. Long-term antimicrobial prophylaxis of UTI in children with VUR is controversial, and the endoscopic treatment of VUR in these children is still of doubtful benefit over prompt treatment of recurrent UTI. The present evidence on VUR does not provide a firm basis for searching for it among all children who have had UTI. Thus, the prevailing guidelines should be re-evaluated. Children showing gross congenital dysmorphology of their kidneys and high grade VUR could benefit from surgical correction of VUR, but it is doubtful whether we can surgically prevent the progression, even of these kidneys, to ESRD. We suggest that these are children for whom we should undertake voiding cystograms, but, otherwise, renal ultrasound should be sufficient for children after UTI (to rule out obstruction and significant anatomical abnormalities). Whether new measures, such as procalcitonin, could help us to identify patients at risk of renal damage better, remain to be seen [38]. In patients with mild focal renal scarring and mild to moderate grade of VUR the emphasis should be on UTI control, and we should allow time for the spontaneous resolution of VUR as the child matures.