Vesicoureteral Reflux

Transcription

1 EUROPEAN UROLOGY SUPPLEMENTS 11 (2012) available at journal homepage: Vesicoureteral Reflux Guy A. Bogaert *, Koen Slabbaert Urology Pediatric Urology, UZ Leuven Article info Keywords: Vesicoureteral reflux Urinary tract infection Pediatric Bladder dysfunction Antireflux surgery Abstract In the past 30 yr, the therapeutic approach to children with vesicoureteral reflux (VUR) has undergone a dynamic evolution from mainly surgery, as soon as VUR was detected, toward a conservative approach with antibiotic prophylaxis (stimulated and supported by results from the International Reflux Study in Children), to an endoscopic approach, and to the currently used active surveillance approach without prophylaxis. During those 30 yr, the diagnostic approach has not changed as much, although there is always an attempt to make the diagnosis of VUR while avoiding the classic voiding cystourethrogram (VCUG), which is one of the most stressing exams for a child and his or her family. Initially, radiographic grading of VUR was the only method of measuring the severity of VUR and of calculating the chance of spontaneous resolution. However, several other factors such as age, sex, presence of bladder and/or bowel dysfunction, presence of associated anatomic abnormalities, and laterality have been shown to have an influence on the spontaneous resolution rate. Based on the results of recent randomized studies (PRIVENT, Randomized Intervention for Children with Vesicoureteral Reflux [RIVUR], Swedish reflux study) and the updated VUR guidelines from the American Urological Association and the European Association of Urology European Society for Pediatric Urology, this review will give an overview of the important clinical features of VUR, the diagnostic methods, the computer models and nomograms to detect which children with VUR should be treated, and the options their respective chances of success for treating patients. It will become clear that the treatment selection and decision for treating VUR in a child is an individualized process. # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. address: guy.bogaert@uzleuven.be (G.A. Bogaert). 1. Introduction In the past 30 yr, the therapeutic approach to children with vesicoureteral reflux (VUR) has undergone a dynamic evolution from mainly surgery, as soon as VUR was detected, toward a conservative approach with antibiotic prophylaxis (stimulated and supported by results from the International Reflux Study in Children), to an endoscopic approach, to the currently used active surveillance approach without prophylaxis. During those 30 yr, the diagnostic approach has not changed as much, although there is always an attempt to make the diagnosis of VUR while avoiding the classic voiding cystourethrogram (VCUG), which is one of the most stressing exams for a child and his family. Initially, radiographic grading of VUR was the only method of measuring the severity of VUR and of calculating the chance of spontaneous resolution. However, several other factors such as age, sex, presence of bladder and/ or bowel dysfunction, presence of associated anatomic /$ see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eursup

2 EUROPEAN UROLOGY SUPPLEMENTS 11 (2012) abnormalities, and laterality have been shown to have an influence on the spontaneous resolution rate. In 1981, John Woodard, a world expert opinion leader on VUR, stated, As one looks back over the last 30 years of reflux history, it is ironic that urologists have become so expert at its surgical correction before understanding much about its natural history and true clinical significance [1]. Without doubt, his statement is still true today. Based on the results of recent randomized studies (PRIVENT, Randomized Intervention for Children with Vesicoureteral Reflux [RIVUR], Swedish reflux study) and the updated VUR guidelines from the American Urological Association (AUA) and the European Association of Urology (EAU) European Society for Pediatric Urology (ESPU), this review will give an overview of the important clinical features of VUR, the diagnostic methods, the computer models and nomograms to detect which children with VUR should be treated, and the options and their respective chances of success for treating patients. It will become clear that the treatment selection and decision for treating VUR in a child is an individualized process. 2. Symptomatology Clinical symptoms due to VUR can be symptomatic or asymptomatic. Symptoms can be recurrent urinary tract infections (UTIs) with and without fever. Recurrent UTIs are due to incomplete emptying of the bladder with urinary stasis caused by the VUR and subsequent risk of bacterial colonization and bacterial ascension. In smaller children, failure to thrive or recurrent otitis media can mask and delay the diagnosis of VUR. Sudden onset of urge and urge incontinence with or without bowel dysfunction in older children and otherwise dry children can also suddenly reveal VUR. The voiding symptoms will often result in a dysfunctional elimination syndrome and may add bowel dysfunction, such as constipation, to the problem. The constipation will worsen the incidence of bacteriuria or recurrent UTIs. Voiding dysfunction as such, without clinical UTI, can be one of the first signs of VUR. Asymptomatic features are a family history of VUR or findings on ultrasound such as hydronephrosis, hydroureteronephrosis, renal parenchymal changes, renal dysplasia, or hypoplasia. However, a difficult question remains in the event of an abnormal technetium Tc 99m dimercaptosuccinic acid (DMSA) isotope renal scan: Is it (congenital) renal dysplasia or (acquired) renal parenchymal damage? The recent Swedish reflux study has found some interesting results [2]. At the beginning of the prospective randomized trial, 124 of 201 children had an abnormal renal DMSA scan. Symptoms of parenchymal damage were found in 30 of 128 girls (23%) and 44 of 75 boys (59%). After 2 yr, new renal parenchymal damage was found in 11 of 49 children (22%) with recurrent UTIs and in 4 of 152 children (3%) without recurrent UTIs. If VUR is suspected or should be excluded, the diagnostic work-up should be performed using as few examinations as possible and with special respect for radiation exposure. Indications for the following work-up are one febrile UTI in boys or girls, one proven nonfebrile UTI in boys, or recurrent nonfebrile UTI in girls [3]. Clinical exam, height, weight, blood pressure, serum creatinine, urinalysis for proteinuria and bacteriuria, a urine culture, and sensitivity are [3,4]. A renal ultrasound is considered a noninvasive exam that provides information on both kidneys with regard to renal structure and function; however, in the work-up of a child with a UTI, a renal ultrasound cannot be considered a specific exam predicting VUR [5]. The importance of voiding dysfunction as a prognostic factor in the resolution rate of VUR was mentioned by Schwab et al in 2002 [6] and was confirmed more recently in the prospective Swedish Reflux Trial [7]. It is important to include a voiding diary, (several) uroflowmetry studies, and residual volume measurements in the work-up for VUR. A classic radiologic VCUG, using modern digital enhanced techniques, is still the standard exam demonstrating VUR, timing and laterality of the reflux, grade of reflux, exact anatomy of the upper and lower urinary tracts (duplication, paraureteral diverticula), voiding phase, and anatomy of the bladder outlet and urethra. Examples of VCUG and the grading system according to the International Reflux Study Committee are demonstrated in Figure 1 [8]. There is no doubt that VCUG is an exam that causes distress and anxiety for the child and his or her family; however, to date, no alternative exam provides all of the information previously mentioned. Midazolam combined with simple analgesia is an effective method to reduce distress in children undergoing VCUG without interfering with the voiding dynamics [9]. Indirect methods of VCUG using intravenous isotopes require continent children and provide images with much lower quality than conventional fluoroscopy. Urosonography using a contrast-enhanced medium can eliminate radiation exposure but requires special expertise of the pediatric radiologist and the placement of a catheter and will not provide the urologist with specific images regarding anatomic specificities such as renal duplication [10]. A direct VCUG using isotopes as a contrast medium does not eliminate the stress of catheterization and cannot reach the excellent imaging quality of conventional radiology. A possible future modality to screen noninvasively for VUR could be microwave heating of the urine in the bladder and measuring the temperature in the kidneys [11,12]. A renal DMSA scan is part of the work-up of every child with a proven VUR or a febrile UTI. The renal DMSA scan is a static examination that images the functional distal tubules of the kidney and allows demonstration of small parenchymal damage [13]. In addition, the renal DMSA scan is important for follow-up; therefore, it is important that DMSA should be combined with the chromium-51 ethylenediaminetetraacetate (EDTA) isotope, allowing the measurement of the exact glomerular filtration rate (GFR) and calculation of the single-kidney GFR. This split renal function in combination with the anatomic images will allow the clinician to make a correct statement if one kidney has improved or deteriorated [14]. Both studies, classic VCUG and DMSA scan, are necessary and complementary in the work-up of a child with VUR.

3 18 [(Fig._1)TD$FIG] EUROPEAN UROLOGY SUPPLEMENTS 11 (2012) Fig. 1 Clinical examples of the International Reflux Study in Children vesicoureteral reflux grading system: (a) Left-sided grade II and right-sided grade III (note the voiding phase, allowing judgment of the bladder neck and the moment of high voiding pressure in the image); (b) left-sided grade III and rightsided grade IV; (c) left-sided grade IV and right-sided grade II (note the bilateral paraureteral Hutch diverticula); (d) bilateral grade V. Several studies have tried to identify patients who underwent either a DMSA scan or a VCUG and who would not require the other exam, but it is a fact that there are children without VUR and with renal damage and children with VUR and without renal damage. Consequently, it is not possible to identify not dangerous VUR looking only at a DMSA scan [13,15]. Initially, Rubenstein et al introduced a novel but (still) controversial technique to identify VUR in children presenting with febrile UTIs and a negative VCUG: positional instillation of contrast (PIC) cystography. This cystogram is performed by positioning the cystoscope close to the ureteral orifice with the bladder empty and instilling contrast in a gravity-aided manner from a height of 1 m using the irrigation port of the cystoscope [16]. The argument that this technique could induce VUR in anyone was countered by using a control group of children without UTI and VUR in whom the PIC cystogram did not demonstrate reflux. It was a logical step from undetected contralateral VUR to situations in which we suspect VUR but are unable to demonstrate it. It is a well-known phenomenon that, most frequently, girls suffering from

4 EUROPEAN UROLOGY SUPPLEMENTS 11 (2012) Table 1 Grading system for vesicoureteral reflux, according to the International Reflux Study Committee [8] Grade I Grade II Grade III Grade IV Grade V Reflux does not reach the renal pelvis; varying degrees of ureteral dilatation Reflux does reach the renal pelvis; no dilatation of the collecting system; normal fornices Mild or moderate dilatation of the ureter, with or without kinking; moderate dilatation of the collecting system; normal or minimally deformed fornices Moderate dilatation of the ureter, with or without kinking; moderate dilatation of the collecting system; blunt fornices but impressions of the papillae still visible Gross dilatation and kinking of the ureter, marked dilatation of the collecting system; papillary impressions no longer visible; intraparenchymal reflux recurrent UTIs with or without renal parenchymal scars on the DMSA scan will have a negative VCUG. In these patients, PIC cystography can reveal undetected VUR, and appropriate treatment has been proven to reduce the incidence of UTIs [17,18]. Biomarkers are a point of research but are not clinically relevant today [19]. Intravenous pyelography should not be performed because it does not add relevant information and uses radiation. Videourodynamic studies should be reserved for patients in whom secondary reflux is suspected, such as those with neuropathic bladder dysfunction or boys whose VCUG is suggestive for posterior urethral valves. 3. Pathophysiology Is there a difference in VUR in a duplex system? In general, <1% of the general population has a duplex kidney, and VUR is the most commonly associated anomaly found in duplex kidneys, especially in those presenting with a UTI (70%) [25]. VUR almost always occurs in the lower pole moiety, due to its lateral entry and shorter intravesical pathway. If VUR is also seen in the upper pole, one must suspect an incomplete duplication or an ectopic orifice in the bladder neck or urethra and misplacement of the transurethral catheter at the time of the VCUG. VUR in duplex kidneys can resolve, but it will take longer than in a single system. Surgery, including the eventual correction of the ureterocoele of the upper pole, is challenging but provides excellent results [26]. The incidence of VUR in neonates varies between 0.5% and 1%. However, in children with a proven febrile UTI, the incidence of VUR is 30 40%, with a female predominance of 4:1 if the child is >1 yr of age [20]. At<1 yr of age, VUR is more frequent in boys. VUR is defined as the nonphysiologic retrograde flow of urine from the bladder up the ureter into the kidney and is the result of an insufficient vesicoureteral junction. The severity of VUR is measured using the grading system according to the International Reflux Study Committee (Table 1) [8]. Primary or congenital VUR is caused by a congenital maldevelopment of the vesicoureteral junction, which is too short and has a possible lack of a fixed attachment between the ureter and the detrusor [21]. Based on observations of incidence of VUR among siblings and twins, it is now known that primary or congenital VUR is autosomal dominantly inherited and is polygenic with variable penetrance and expressivity [22,23]. The recommendations for screening in siblings are from both the AUA [4] and the EAU [3]: The parents of a child with VUR should be informed about the higher incidence among siblings. It is that a renal ultrasound be performed in siblings that are not toilet trained. If the renal ultrasound shows any abnormality, VCUG is. If no ultrasound screening is performed, special attention for UTI and early treatment should be initiated, followed by a complete investigation for VUR. Secondary reflux develops under the influence of anatomic or functional infravesical obstructions due to inflammatory or neuropathic disorders of the bladder. Although most children with VUR will have excellent long-term prognosis, a small group has a significant risk. This risk can be minimized in areas with good medical health care where prompt diagnosis and treatment of acute UTI is possible [24]. 4. Indications for treatment The goals of management of the child with VUR are prevention of recurrent febrile UTIs, prevention of renal injury, and minimization of the morbidity of treatment and follow-up [4]. The choice or advice for treatment will depend on several individual parameters such as gender, age of the child, grade of reflux, laterality, symptoms, renal function, renal damage, associated functional bladder and/ or bowel problems, compliance, and choice of the parents [27]. There are mainly two methods of treatment: conservative (waiting for spontaneous resolution) or interventional (minimal or surgical). If a child presents with breakthrough UTIs or renal damage several years after conservative waiting, this will determine the treatment option, with its advantages and disadvantages, that will be chosen by the parents and the doctors (Table 4). The AUA guidelines make a clear distinction for children <1 yr of age (Table 2), whereas the EAU-ESPU guidelines mention childhood and have three age categories: <1 yr of age, 1 5 yr of age, and >5 yr of age (Table 3). It is that the possible advantages and disadvantages of every treatment option be listed, as mentioned in Table Surveillance A surveillance treatment method combines watchful waiting without medication or additional treatment as well as antiseptic or antibiotic prophylaxis and treatment of the dysfunctional elimination syndrome. Prophylactic antiseptic or antibiotic treatment is based on the hypothesis that neither VUR as such nor a lower UTI

5 20 EUROPEAN UROLOGY SUPPLEMENTS 11 (2012) Table 2 Management of the child with primary vesicoureteral reflux according to the American Urological Association guidelines [4] <1 yr of age History febrile UTI grade I V Continuous AB prophylaxis: No history febrile UTI grade III V Continuous AB prophylaxis: No history febrile UTI grade I II Continuous AB prophylaxis: offered >1 yr of age Grade I V with bladder/bowel dysfunction Grade I V without bladder/bowel dysfunction Bladder/bowel dysfunction treatment (not specified) Continuous AB prophylaxis: Continuous AB prophylaxis: considered (in the event of renal cortical abnormality) Consider circumcision Consider circumcision Consider circumcision If on AB prophylaxis plus breakthrough infection, then option of endoscopic or surgical VUR correction (if no renal scar possible, change AB prophylaxis); if not on AB prophylaxis, then start AB prophylaxis If on AB prophylaxis plus breakthrough infection, then option of endoscopic or surgical VUR correction (if no renal scar possible, change AB prophylaxis); if not on AB prophylaxis, then start AB prophylaxis AB = antibiotic; UTI = urinary tract infection; VUR = vesicoureteral reflux. Table 3 Management of the child with primary vesicoureteral reflux according to the European Association of Urology guidelines [3] <1 yr of age Grade I V Continuous AB prophylaxis: 1 5 yr of age Grade I III Continuous AB prophylaxis: Grade IV V Endoscopic or surgical VUR correction: Advise circumcision in low-grade VUR If on AB prophylaxis plus breakthrough infection or noncompliance with AB prophylaxis or new renal scars or associated malformations, then recommend endoscopic or surgical VUR correction >5 yr of age Boys No treatment If UTI, then recommend endoscopic or surgical VUR correction Girls Endoscopic or surgical VUR correction: AB = antibiotic; UTI = urinary tract infection; VUR = vesicoureteral reflux. is harmful to the kidney. However, a UTI in a situation of VUR presents a real chance of renal damage. Recent randomized controlled trials suggest that antibiotic prophylaxis offers no advantage over intermittent antibiotic therapy for UTIs in terms of prevention of recurrent UTIs or new renal damage [28]. However, under the age of 1 yr, it is and has been demonstrated in the recent prospective randomized controlled Swedish reflux trial that UTIs can be prevented using prophylaxis [29]. Beyond the age of 1 yr, mainly girls will benefit from prophylaxis [2,29]. The choice for antiseptic or antibiotic treatment is also age dependent. For a child <3 mo, cefaclor 15 mg/kg of body weight or trimethoprim 2 mg/kg of body weight should be given once daily, preferably at night. For a child >3 mo, nitrofurantoin 2 mg/kg of body weight or trimethoprim 2 mg/kg of body weight should be given once daily, preferably at night. Trimethoprim is still, but a relative higher incidence of resistance toward Escherichia coli of 33% is known [30]. Sillén et al have shown that bladder dysfunction in young infants exists and is associated with a higher incidence of UTI and renal scarring [7]. Schwab et al have clearly demonstrated in a 15-yr retrospective study that the spontaneous resolution rate in grade I III is 13% per year and drops thereafter to 3.5% (exponential curve); in grade IV V, it is only 5% [6]. The authors recommend performing an early correction for grade IV V from 18 mo on. Ismaili et al concluded in an earlier report for the EAU-EBU Update Series on VUR that long-term antibiotic prophylaxis does not fully prevent UTI and renal scarring [24]. This has been Table 4 Advantages and disadvantages of treatment options Surveillance Continuous AB prophylaxis Endoscopic correction Surgical correction Advantages Chance of spontaneous resolution (grade I III: 13% per year; grade IV V: 5% per year) Chance of spontaneous resolution (grade I III: 13% per year; grade IV V: 5% per year) Outpatient procedure Minimally invasive procedure Immediate and permanent success Low complication rate No follow-up VCUG necessary Disadvantages Risk of renal damage (febrile UTI) Risk of renal damage (febrile UTI) Questionable intake compliance Development AB resistance Variable: 70 90% (long-term) success rate Follow-up VCUG necessary 2 3 days in hospital Surgical procedure morbidity AB = antibiotic; UTI = urinary tract infection; VCUG = voiding cystourethrogram.

6 EUROPEAN UROLOGY SUPPLEMENTS 11 (2012) confirmed in the RIVUR and the Swedish reflux study. Based on the greater morbidity of UTIs in children <1 yr of age, continuous prophylaxis is [4]. Children with functional bladder and/or bowel dysfunction should undergo specific treatment, together with their parents, with drinking and voiding recommendations, relaxed and correct voiding conditions at regular intervals, eventual double voiding, biofeedback of the pelvic floor muscles, anticholinergic medication in the situation of overactive bladder, healthy food recommendations, and eventual pharmaceutical support for regular bowel movements. These recommendations are part of empathic doctoring and may require regular follow-up by a urotherapist or doctor. However, whether treatment of voiding dysfunction influences the resolution rate of VUR in children remains unclear and would require prospective randomized trials [31]. Possible advantages and disadvantages of conservative treatment are summarized in Table 4. A clear disadvantage or possible danger is the fact that compliance of children with VUR taking (or should we rather say, being given by their parents ) prophylaxis is as low as 40% [32]. 6. Minimally invasive treatment O Donnell and Puri in 1984 were the pioneers for the endoscopic correction of VUR using Teflon as a bulking agent [33]. Their original technique was called STING, for subureteral polytetrafluoroethylene (Teflon) injection. Very soon after the first injections, studies in animal models found migration and granulomatous reaction after periurethral injection of polytetrafluoroethylene [34]. Strangely enough, this did not stop the original pioneers from injecting polytetrafluoroethylene into ureters and bladders, and years later, they reported continuous good results and no complications [35]. However, the possibility of migration has urged more suitable and safer bulking agents. Collagen, crosslinked collagen, autologous lipocytes, chondrocytes or myoblasts, coaptite, and several other bulking agents have been tested and proposed. Today, however, only dextranomer microspheres and hyaluronic acid of nonanimal origin (Deflux) and solid silicone elastomer suspended in a water-soluble, bioexcretable carrier gel (Macroplastique) are approved by the US Food and Drug Administration and are used commonly as bulking agents. So far, both implants are stable long term, remain in position, and do not disappear over time. In addition, the particles are too large to be able to merge into capillaries or lymphatics. The success rates of the STING injection technique (70 85%) have never reached those of surgical correction. However, Kirsch et al [36] introduced the intraureteral injection technique after hydrodistention of the ureter, a technique they popularized while trying to categorize the refluxing ureters by flushing the ureteral orifices with the cystoscope and its flushing channel. Kirsch et al were able to improve the success rates of the endoscopic injection technique by another 10% (reported success rate up to 90%) [37]. Depending on the grade of VUR, the ultimate success rate for the individual patient will be determined by the injection technique, the injected volume, the mound morphology and location, the abnormal anatomy and/or physiology (eg, as in renal duplication), the presence of dysfunctional voiding, and the experience of the surgeon. Another unanswered question in the endoscopic treatment for VUR is the long-term efficacy of the bulking agent. One of the unclear results from the recent Swedish reflux study was the fact that the children in the endoscopic treatment group with Deflux had the highest success rate of VUR resolution and the lowest incidence of UTIs but with one of five children presenting with a recurrence of dilating VUR after 2 yr [38]. It is necessary for children having an endoscopic treatment for VUR to undergo regular follow-up with the possibility of VCUGs. It is also important to discuss all possible advantages and disadvantages of the endoscopic technique with the child and his or her parents (Table 4). In summary, the endoscopic treatment was initially developed as an alternative to open surgical correction, but today it is considered an alternative to long-term prophylactic treatment [27]. 7. Surgical treatment The first surgical treatment one should think of in the event of a newborn boy with VUR should be circumcision. Singh- Grewal et al found in a meta-analysis of 12 studies that circumcision definitely reduces the risk of UTI [39]. However, in normal boys, the number needed to treat (NNT) to prevent one UTI is 111. In boys with recurrent UTI or high-grade VUR, the risk of UTI recurrence is 10% and 30%, respectively, and the NNTs are 11 and 4, respectively. The authors concluded that, assuming equal utility of benefits and harms, net clinical benefit is likely only in boys at high risk of UTI. Surgical correction of VUR, by definition, creates an antirefluxive valve mechanism for the ureter. Placing the ureter in a long or longer channel between the submucosal layer and the detrusor can create this antireflux valve mechanism. Dewan described in a review article how the different ureteral reimplantation techniques have evolved over time [40]. Creation of a longer intramucosal tunnel can be performed intra- or extravesically, by open surgery, laparoscopically, or by using robotic instrumentation. This is the fastest and most successful method to correct VUR in >95% of cases. The main benefit of surgical correction is the fact that the incidence of febrile UTIs is significantly decreased, and this has been shown in studies comparing different treatment strategies [41,42]. Indications for surgical correction are breakthrough UTIs, renal function impairment (preexisting or developing under surveillance or prophylactic treatment), associated anatomic anomalies (renal duplication with upper pole ureterocoele, paraureteral diverticulum), problematic parental compliance, and parental preference. The intravesical cross-trigonal ureteral reimplantation (Cohen) is probably the safest and perhaps the most widely used surgical technique for the correction of VUR [43].

7 22 EUROPEAN UROLOGY SUPPLEMENTS 11 (2012) However, this technique is always on the table for discussion, along with possible difficulties for eventual ureterorenoscopy later in life. The incidence of later in life issues that would require endoscopic intervention are extremely rare but are nevertheless possible [44]. The technique described by Politano-Leadbetter is an excellent method for ureteral reimplantation, but its complication rate is higher (up to 7 10%) than the cross-trigonal technique [45]. The psoas-hitch ureteral reimplantation deals with an even higher rate and more severe complications and should be reserved for repeat interventions or specific indications [46,47]. The extravesical ureteral reimplantation technique described by Lich-Grégoir is very popular because it has excellent success rates and is associated with low morbidity [48]. However, due to the possible pelvic plexus damage during the extravesical dissection and the consequent possible temporary voiding dysfunction, it is that this technique be performed unilaterally and eventually repeated in a second step on the contralateral side [49]. Intravesical cross-trigonal and extravesical ureteral reimplantation have been performed successfully using laparoscopic techniques [50,51]. Recently, these techniques have also been performed using the assistance of robotic techniques [52,53]. It has been proven that it is feasible to perform surgical correction using laparoscopy or robotic assistance, although it has to be proven if there is any benefit for the patient. 8. Outcome, follow-up, and recommendations The risks and benefits of diagnosing VUR are questioned today in terms of health and financial impact: What is the benefit of prescribing long-term prophylaxis? VUR is a clinical symptom that is not based on a simple disease but on a number of factors influencing the expression of the symptom and its consequences. Sex, age, renal function, voiding dysfunction, grade, laterality, associated anatomic anomalies, and genetic factors will determine how dangerous VUR will be for renal development and function [54 56]. The management of children with VUR has changed, and large studies (the International Reflux Study in Children, the PRIVENT study, the RIVUR study, and the Swedish reflux study) have helped influence our current opinion and treatment strategy [57 60]. The treatment strategy for children with VUR should be individual for every child. It should be based on several coexisting factors such as age, sex, laterality, grade of reflux, presence of voiding dysfunction, and renal damage. Computer models and nomograms should be used to analyze the child s specific situation and should be discussed with the parents. The computer-based model was created using a large database of VUR patients. It can be used to predict VUR resolution at 2 yr of age and is available on the UroComp Web site ( select SVM/VUR outcomes) [61]. This computer model was validated in a separate patient population in Japan and was found to have 81% accuracy with a receiver operating characteristic value of 0.79 [62]. In addition, an updated version, using additional renal scan data, further improves the predictive accuracy ( select SVM/VUR outcomes using renal scan data [updated]) [63]. Nomograms predicting the percentage of VUR resolution at 1 5 yr are based on a large patient population at Children s Hospital Boston [56]. These nomograms use age, sex, laterality, clinical presentation, ureter anatomy, and grade of reflux and are available through a Web-based calculator ( Wheeler and colleagues in a 2004 Cochrane review [41] and Nagler and colleagues in an updated review in 2011 on the interventions for VUR [42] performed meta-analyses of combined long-term antibiotic prophylaxis and surgical corrections. Both groups found that with the end points of UTI incidence, new or progressive renal damage, renal growth, hypertension, and GFR, the only difference was that surgical treatment resulted in a 60% reduction in febrile UTIs by 5 yr compared with antibiotic prophylaxis alone. However, this difference did not result in a difference in the risk of parenchymal injury. It is not clear whether any intervention does more good than harm, although some data show a dramatic decrease in reflux-related morbidity with an aggressive approach [64]. Should the first investigation following a febrile UTI be a DMSA scan or a VCUG? Regarding the diagnostic approach or suspicion of VUR, after the obligatory renal ultrasound, it is still requisite to perform a radiographic VCUG and a DMSA scan, regardless of the results of either. Febrile UTIs and acquired cortical defects can occur without VUR, cortical defects in children with VUR will predict recurrent UTI, and a positive DMSA scan identifies significant VUR in most instances [65]. However, better knowledge of which patients might benefit from early treatment may limit the number of children required to undergo VCUG [66]. The exact indication and value of the PIC cystography has to be determined. In addition, alternative noninvasive methods may identify the correct patients [12]. In the event of a family history or siblings with VUR, if asymptomatic and under the age of 5 yr, a renal ultrasound should be. However, if a child with a family history of VUR becomes symptomatic, a classic VCUG and an isotope DMSA scan should be an immediate part of the evaluation. In the follow-up of children with VUR, as few procedures as possible and as minimally invasive procedures as possible should be the absolute rule [65]. With regard to increasing resistance of E. coli strains and the relatively low compliance with prophylaxis intake, the treatment strategy should include options such as circumcision and subureteral or intraureteral injections in an early phase of diagnosis. Girls, more frequently a little older, should receive empathic doctoring, consisting of modified drinking habits, appropriate voiding and bowel recommendations, and close follow-up. It is interesting that the AUA and EAU-ESPU guidelines for VUR mention endoscopic treatment as a possible surgical correction, whereas it is clear from all studies that an endoscopic treatment is an alternative to the antibiotic prophylaxis [27]. A lot of studies and publications on VUR

8 EUROPEAN UROLOGY SUPPLEMENTS 11 (2012) are known, but good prospective and randomized controlled studies are still necessary to improve the work-up and the optimal management of children with VUR [42]. 9. Conclusions VUR and its evolution will depend on different factors; therefore, VUR is an individual problem for every single patient. Work-up with renal and bladder ultrasound; VCUG, including voiding images; a DMSA scan; and eventual voiding and bowel diary will facilitate the correct diagnosis. In the first year of life, circumcision should be offered for boys and antiseptic or antibiotic prophylaxis should be. Thereafter, individual calculation of the chance of spontaneous resolution using computer models and nomograms will help the clinician and the parents of children with VUR choose the best option for treatment. Conflicts of interest The authors have nothing to disclose. Funding support None. References [1] Woodard JR. Vesicoureteral reflux. J Urol 1981;125:79. 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