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  1. 1. nature reviews | urology aDvanCe OnLine PuBLiCatiOn | 1 reviews Department of Urology, University of iowa, iowa City, iA, UsA. Correspondence: University of iowa, Department of Urology, 200 Hawkins Drive, 3 rCP, iowa City, iA 52242‑1089, UsA christopher‑cooper@ Diagnosis and management of vesicoureteral reflux in children Christopher S. Cooper Abstract | Critical evaluation of previously accepted dogma regarding the evaluation and treatment of vesicoureteral reflux (vUr) has raised significant questions regarding all aspects of vUr management. whereas the standard of care previously consisted of antibiotic prophylaxis for any child with vUr, it is now unclear which children, if any, truly benefit from antibiotic prophylaxis. Operative intervention for vUr constitutes overtreatment in many children, yet there are limited data available to indicate which children benefit from vUr correction through decreased rates of adverse long‑term clinical sequelae. studies with longer follow‑up demonstrate decreased efficacy of endoscopic therapy that was previously hoped to approach the success of ureteroneocystostomy. Prospective studies might identify risk factors for pyelonephritis and renal scarring without antibiotic prophylaxis. Careful retrospective reviews of adults with a history of reflux might allow childhood risk factors for adverse sequelae to be characterized. Through analysis of multiple characteristics, better clinical management of vUr on an individualized basis will become the new standard of care. Cooper, C. s. Nat. Rev. Urol. advance online publication 11 August 2009; doi:10.1038/nrurol.2009.150 Introduction Over the last decade there has been increased recognition that many children with vesicoureteral reflux (vur) do not benefit from either diagnosis or treatment of their condition.1 the disease in these children is self-limiting and innocuous; however, a subset of children with vur will benefit from both diagnosis and treatment. Clarification of which children constitute this subset remains the greatest challenge to the advancement of vur management. this review presents an overview and update of key developments and controversies in the management of primary vur, including incidence, etiology, clinical fea- tures, the use of different imaging techniques in diagnosis and follow-up of vur, and treatment options. Background, incidence and etiology vur is the retrograde flow of urine from the bladder into the ureter. it occurs in approximately 1–3% of children and is associated with 7–17% of children diagnosed with end-stage renal disease worldwide.2–5 treatment of vur is aimed at preventing the sequelae of pyelonephritis, renal parenchymal injury, hypertension, and chronic renal insufficiency.aperiodof30–40yearscanpassbetweenthe first renal-scarring pyelonephritis and the development of hypertension or end-stage renal disease.6 if the challenge of identifying children that will benefit from diagnosis and treatment of vur is to be met, long-term follow-up of patients over the duration between the initial renal insult and the clinically apparent sequelae is essential. an estimated 30–40% of children under the age of 5 years who develop a urinary tract infection (uti) have vur.5,7 vur can be further categorized as either primary Competing interests The author, the Journal editor A. Hay and the CMe questions author declare no competing interests. Continuing Medical Education online This activity has been planned and implemented in accordance with the essential Areas and policies of the Accreditation Council for Continuing Medical education through the joint sponsorship of MedscapeCMe and Nature Publishing Group. MedscapeCMe is accredited by the Accreditation Council for Continuing Medical education (ACCMe) to provide continuing medical education for physicians. MedscapeCMe designates this educational activity for a maximum of 0.75 AMA PrA Category 1 CreditsTM . Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CMe activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post‑test and/or complete the evaluation at public/naturereviews; and (4) view/print certificate. learning objectives Upon completion of this activity, participants should be able to: 1 Describe the prevalence of vesicoureteral reflux (vUr) in the general pediatric population and in children with urinary tract infections. 2 Describe the grading system of the international reflux study for classification of vUr. 3 Describe the inheritance pattern of vUr and guidelines for its management. 4 Describe the efficacy of surgery for the management of vUr. 5 identify the most reliable tests for the diagnosis of vUr. © 2009 Macmillan Publishers Limited. All rights reserved
  2. 2. 2 | aDvanCe OnLine PuBLiCatiOn reviews or secondary. Primary vur in children is frequently attributed to an abnormally short intravesical tunnel at the ureterovesical junction (Figure 1); the more severe the abnormality, the worse the vur.8 secondary vur occurs when reflux is induced by abnormally increased bladder pressures, such as those seen with urethral obstruction or neurogenic bladder dysfunction. the severity of vur has been most commonly reported using the classification of the international reflux study (Figure 2).9 this classification defines grade i as reflux into the ureter only, and grade ii as reflux into a non-dilated pyelocalyceal system. Grade iii vur demonstrates dilatation of the collecting system. Grade iv involves more-extensive dilation with blunting of the calyces and tortuosity of the ureter, and grade v vur is associated with massive dilation of the collecting system and severe tortuosity of the ureter. in general, the severity or grade of vur has been used as the main factor to determine the likelihood of sponta- neous reflux resolution and risk of renal injury. Higher grades of reflux are associated with decreased resolu- tion rates and increased prevalence of renal scars.10,11 in addition to grade, other factors have been shown to be Key points Many children with vesicoureteral reflux (vUr) do not benefit from either■ diagnosis or treatment of their condition Prospective studies have not demonstrated utility of antibiotic prophylaxis in■ preventing urinary tract infections in many children with vUr Prospective studies generally showed no difference in renal function or growth,■ progression or development of new scars, or urinary tract infections in those treated by operative intervention versus prophylactic antibiotics increasing grades of reflux and renal scars identify a higher risk group for■ subsequent renal damage and long‑term clinical sequelae Better definition of children likely to benefit from intervention remains the■ greatest challenge to the advancement of vUr management Management decisions are complex and require an individualized approach,■ taking into account numerous variables predictive of reflux resolution and/or the risk of renal injury. these factors include age, sex, laterality, bladder volume and pressure at the onset of reflux, presence of renal scars, presence of voiding dysfunction, and a history of uti.12–19 the importance of vur as a factor leading to renal injury due to infection was originally discovered in patients with spinal cord injuries. when vur was surgically corrected, patients had fewer problems with pyelonephritis and urosepsis.20 this association with renal injury or scarring secondary to vur is what led to its discovery as a primary factor in children developing pyelonephritis. subsequent studies demonstrated a lower rate of new scars developing in children with primary reflux compared to those with secondary reflux due to neurogenic bladders or voiding dysfunction.21,22 Children with voiding dysfunction or dysfunctional elimination not only have a higher incidence of break- through infections while on antibiotic prophylaxis, but also more renal scarring, a lower spontaneous resolu- tion rate, and a higher failure rate following anti-reflux surgery.23 as the chance of reflux resolution or renal injury with secondary reflux is dependent on the type and extent of bladder abnormality, it is now recognized that secondary vur is more appropriately prevented by improvements in the management of bladder dys- function. Discussion of the management of neurogenic or non-neurogenic bladder dysfunction is beyond the scope of this review, which focuses on primary vur. a strong inheritance pattern exists for primary vur. the chance of a sibling of a child with vur also having reflux is about 25%, and the offspring of affected indivi- duals have a 27–51% increased risk of having reflux.24 the utility of sibling screening for reflux is questionable; however, one study has noted that renal damage is more prevalent in screened siblings with vur and a history of uti compared to those without a history of uti.24 this finding is consistent with the known increased risk of renal scars developing in children with febrile utis who have reflux. it remains to be demonstrated that detection and management of vur in an asymptomatic screened sibling will result in significantly decreased adverse sequelae and, therefore, there is currently no consensus regarding the practice of asymptomatic sibling screening for vur. a lack of consensus also exists regarding the need to screen newborns with a history of low-grade prenatal hydronephrosis for vur. a study demonstrated that in childrenwithahistoryofprenatalhydronephrosiswhohad persistent grade ii hydronephrosis, identification of vur and use of prophylactic antibiotics significantly reduced the risk of febrile utis.25 reviewing similar data, others suggest that mass screening and treatment of asymptom- atic siblings of those with prenatal hydronephrosis pro- vides little, if any, benefit, and is not cost-effective.26,27 these controversies emphasize that appropriate clini- cal assessment and management of children with vur requiresthetreatingphysiciantodevelopanindividualized approach that considers multiple factors. a b x Figure 1 | Diagram of the bladder submucosal tunnel. a | Normal submucosal tunnel. Pressure in the lumen of the bladder increases as the bladder fills with urine, compressing the ureter within the bladder wall (arrows), stopping reflux (indicated by x). b | A short submucosal tunnel permits reflux as the section of ureter in the bladder wall is not long enough to be compressed by rising pressure in the filling bladder (arrows). © 2009 Macmillan Publishers Limited. All rights reserved
  3. 3. nature reviews | urology aDvanCe OnLine PuBLiCatiOn | 3 reviews Clinical management Antibiotics versus operative intervention several large prospective studies have attempted to address the efficacy of operative intervention versus antibiotic prophylaxis in children with vur.10,28–31 the outcomes of these studies have generally demonstrated that no significant differences exist in renal function or growth, the progression or development of new scars, or utis in patients treated with one intervention com- pared to the other. Pyelonephritic symptoms, including febrile utis, tended to be more common in the medically treated groups compared with the surgical groups.32–34 in general, new scars occurred earlier in children treated surgically compared with those in the medical treatment groups, but, as noted, no significant difference occurred overall with longer follow-up in terms of new renal scars in those treated with antibiotics compared to those undergoing surgery.5,35 these observations suggested that a potential benefit of anti-reflux surgery might be a reduction in pyelonephritis in some patients; however, other researchers suggested that, once renal scarring occurs, the disease tends to run its course and operative treatment has little benefit.6,36 a recent Cochrane review concluded that nine re-implantation procedures would be required in order to prevent one incidence of febrile uti, with no reduction in the number of children devel- oping any uti or renal damage.5 these studies reinforce the need to better define the subset of children with vur who might benefit from intervention. Antibiotics versus observation Multiple studies question the need for antibiotic pro- phylaxis, indicating that, in selected individuals, the risk of developing pyelonephritis and renal damage in the absence of prophylactic antibiotics is low.32,37–39 Between 30% and 50% of children diagnosed with a uti will suffer from a recurrence of infection. there is often an incorrect assumption that vur is responsible for utis, mainly because the diagnosis of reflux often follows a uti. unless reflux is severe enough to induce stasis, it does not predispose a child to developing utis.29,39 More often, the infections are the result of predisposing condi- tions, such as a previous history of utis, female sex, constipation, infrequent voiding, incomplete emptying and impaired host defenses. although generally safe and well tolerated, daily anti- biotic prophylaxis incurs financial costs and potential health risks to children. antibiotic prophylaxis for reduc- ing the likelihood of developing a uti has been associated with a 24-fold increased risk of Escherichia coli devel- oping resistance to trimethoprim–sulfamethoxazole.40 Other studies have demonstrated the emergence of bacteria (aside from E. coli) with high rates of antibiotic resistance in children receiving prophylactic antibiotics.41 Questions have also been raised as to the efficacy of antibiotic prophylaxis for the prevention of utis.42,43 some investigators contend that antibiotic prophy- laxis is safe and effective in the prevention of utis;44 however, antibiotic prophylaxis has not been proven to reduce the incidence of pyelonephritis in children with vur. Because of the lack of proven efficacy and potential adverse effects of antibiotic prophylaxis, several studies have attempted to evaluate the efficacy of antibiotic prophylaxis in children with vur. these studies have included randomizing children with vur to observa- tion or antibiotic prophylaxis.3,44–46 in general, these studies failed to show a significant reduction in acute pyelonephritis or renal scars in children with vur being treated with antibiotic prophylaxis. some studies actu- ally demonstrated an increased incidence of utis in children receiving antibiotics, as well as an increase in antibiotic-resistant bacteria causing the utis.3,44,45 By subset analysis, other studies identified younger age and increasing grade of reflux as risk factors for recurrent febrile utis.44,47 Currently, there is an ongoing niH- funded multicenter, randomized, placebo-controlled trial (rivur trial) of prophylactic trimethoprim–sulfa- methoxazole for children aged 2–72 months diagnosed with grade i–iv vur after a first or second uti.23 it seems likely that this large trial of 600 children will confirm the findings of the smaller studies noted above, and perhaps a subset analysis will identify characteristics of children at the greatest risk for recurrent pyelonephritis and development of new scars. unfortunately, as previ- ously noted, the lag time between development of renal injury and apparent clinical sequelae of hypertension Normal Grade I Grade II Grade VGrade III Grade IV Figure 2 | international reflux Grading system. © 2009 Macmillan Publishers Limited. All rights reserved
  4. 4. 4 | aDvanCe OnLine PuBLiCatiOn reviews or renal insufficiency will require decades of follow-up to characterize the group of children who may truly benefit from intervention. Clinical evaluation Assessment of reflux the only tests that routinely and reliably detect reflux are voiding cystourethrography (vCuG) and nuclear cystography. an initial vCuG provides better ana- tomic details regarding reflux, including the presence or absence of periureteral diverticuli, ureteral duplica- tion, and abnormalities of the bladder, such as trabecula- tions or urethral obstruction (Figure 3). the vCuG also allows more-precise grading of reflux. typically, follow- up studies are performed with nuclear cystography, as there is a decreased exposure to radioactivity with this study. Despite concern regarding exposure of the pelvic organs to ionizing radiation during cystography in chil- dren, there is little or no reported evidence suggesting any future effect on gonadal function or an increased risk of pelvic malignancies. nuclear cystography reliably detects all grades of vur.48 at the university of iowa, bladder pressures are routinely monitored through a dual-lumen catheter during the filling phase of a nuclear cystogram providing a nuclear cystometrogram; however, this technique is not widely used.18 this technique permits the measurement of the intravesical pressure at the onset of reflux. using this information, bladder pressure at the onset of reflux was demonstrated as a predictor of spontaneous vur resolution independent of the grade of vur.17 in addi- tion to higher bladder pressure, independent predictors of vur resolution on nuclear cystometrogram included the onset of reflux occurring at greater instilled bladder volumes, as well as reflux occurring during voiding compared to filling.16 Catheterization can be a traumatic experience for a young child. efforts to decrease the traumatic nature of the procedure include the use of lubricants containing local anesthetics and conscious sedation.49,50 typically, cystography is repeated on a yearly basis; however, it has been suggested that, for children in whom vur is less likely to resolve, the interval between cysto- grams should be longer in order to reduce exposure to radiation, the number of traumatic studies, and the associated cost.51 advances in the ability to predict timing of spontaneous vur resolution should assist the physician in determining the duration between follow-up visits in order to minimize the number of repeat cystograms.15,16,52 Assessment of renal scars in a meta-analysis examining the presence of renal damage in children hospitalized with uti, one study found that approximately 34% of children with pyelo- nephritis had vur, and of those with vur and pyelonephritis, 72% had an abnormal dimercapto- succinic acid (DMsa) scintigraphy findings (Figure 4).53 DMsa scintigraphy has been found to be a more sensi- tive study than intravenous pyelography (ivP) for the detection of reflux nephropathy.54 in addition, the scan can detect changes of acute pyelonephritis with greater sensitivity and specificity than Ct, Mri, or ultrasono- graphy.55 Mercaptoacetyltriglycine (MaG3) has also been used for renal imaging and has an improved capability in the detection of renal scarring compared to ivP. renal scans obtained by MaG3 imaging enable physicians to determine a patient’s relative renal function, and show a high degree of correlation with the relative renal func- tion results determined by other types of renal scan.56 the DMsa scan is considered by many as the most sensitive test for detection of renal scars; however, the reported sensitivity rate of MaG3 imaging compared to DMsa scintigraphy varies from 88% to equal to or slightly better than a DMsa scan.56–58 the advantages of MaG3 imaging compared to DMsa scintigraphy include reduced radiation exposure, lower cost, and shorter time requirements, as well as improved visualization of the collecting system, which might improve specificity com- pared to DMsa scintigraphy in children with marked dilation of the collecting system.56 a b Figure 3 | voiding cystourethrogram, demonstrating right‑sided reflux with a periureteral diverticulum (arrows). a | The bladder is filled with contrast medium. b | The patient has voided and emptied the bladder of contrast medium, although some remains within the diverticulum. a b % RT LTANT RTLT POST% 83 82 0 0 Figure 4 | Dimercaptosuccinic acid scintigraphy with single photon emission computed tomography imaging demonstrating a cortical defect in the upper pole of the left kidney. © 2009 Macmillan Publishers Limited. All rights reserved
  5. 5. nature reviews | urology aDvanCe OnLine PuBLiCatiOn | 5 reviews reflux nephropathy and renal scarring One-third of patients with vur have renal scars.33,59 the presence of scars implies regions of renal damage, and increases the risk of long-term adverse sequelae. in the newborn with vur, however, scars associated with high- grade reflux have been detected before the occurrence of infection.60 these ‘congenital scars’ are thought to be regions of focal dysplasia or hypoplasia resulting from abnormal nephrogenesis as opposed to damaged normal tissue following pyelonephritis. it is not known what pro- portion of renal scars attributed to infectious injury are actually due to abnormalities of embryogenesis. the ulti- mate significance of these regions of dysplasia remains to be determined; however, they are regions of diminished renal function and can be associated with significant morbidity and mortality.61 Children with pre-existing renal scars are more likely to develop additional scars than children without renal scars.62–64 a retrospective study of 120 patients demon- strated a significantly higher chance of developing a breakthrough uti in children with grades iii to v reflux and an abnormality on baseline DMsa scintigraphy compared to those without an abnormality (60% versus 6%).65 in one study with a mean follow-up of 12 years after anti-reflux surgery, children with unilateral renal scars had an 11% chance of developing hypertension and an 18.5% chance if they had bilateral renal scars.66 Other investigators have suggested the incidence of hypertension in children with bilateral renal scars is about 20%.67 Children with severe bilateral renal scars are significantly more likely to develop proteinuria, chronic renal insufficiency and failure than those with unilateral scars or unscarred kidneys.68,69 these data strongly suggest that children with renal scars are at an increased risk for further development of scars and long-term clinical sequelae. grade of Vur and renal scarring Children with vur and concomitant utis are at an increased risk of developing renal scarring compared to children without vur suffering with utis. in the international reflux study, 50% of children with vur grades iii or iv had scars at study entry.54 several studies have demonstrated a direct correlation between increased prevalence of renal scarring and higher grades of vur.70 renal scarring develops less often in non-dilating forms of reflux.61,62,71 the chance of developing further renal parenchymal loss has also been shown to be higher in children with grade iii or higher vur than in those with grade ii or lower vur.31,72 renal scars have also been demonstrated to be a negative predictor of reflux resolution, independent of reflux grade.13 the association of renal scars with higher grades of reflux and risk for subsequent scars, as well as decreased resolution of vur, led some investigators to conclude that the standard initial evaluation of a child with a febrile uti should begin with a renal scan rather than vCuG. Only in those children with an abnormal scan should vCuG be performed. the benefit of such an approach would be a reduction in the number of children under- going vCuG and the identification of reflux in a higher risk group. the use of ultrasonography instead of a renal scan has been questioned because of the lower sensitivity of the former, compared to renal scans, in diagnosing renal scars. One study noted that up to 25% of patients with cortical defects on DMsa scintigraphy had normal ultrasound findings, providing further data regarding the utility of renal scans in the evaluation of children with febrile utis.73 Operative management Endoscopic treatment of Vur Following FDa approval of the use of dextranomer/ hyaluronic acid copolymer (DX/Ha) (Deflux®, Q-Med, uppsalla, sweden) for the treatment of primary vur, a growing number of parents and physicians began to view endoscopic treatment of vur as an alternative to beginning their child on an undefined duration of prophylactic antibiotics (Figure 5).74 DX/Ha, a syn- thetic mixture of dextran microspheres in a hyaluronic acid gel, is the only commercially available injectable treatment for vur in the us. the dextranomer par- ticle size is larger than that of polytetrafluoroethylene particles, which should prevent the complication of lymphatic migration previously demonstrated with polytetrafluoroethylene.75 although not as effective as open ureteral re-implanta- tion, endoscopic correction of vur offers a mini- mally invasive, outpatient procedure with a low risk of complications. although a seemingly simple procedure, several studies have demonstrated that a considerable learning curve exists, with improved results obtained with increasing experience.76–78 Other factors associ- ated with successful endoscopic correction include a lower grade of vur, lack of lower urinary tract voiding dysfunction symptoms, increased volume of DX/Ha injected, mound configuration following injection, and surgical technique.78–80 a b Needle Bladder Ureter DX/HA Figure 5 | endoscopic injection for vesicoureteral reflux. reproduced from Deflux® patient education brochure (Q‑Med, Uppsala, sweden). Abbreviation: DX/HA, dextranomer/hyaluronic acid copolymer. © 2009 Macmillan Publishers Limited. All rights reserved
  6. 6. 6 | aDvanCe OnLine PuBLiCatiOn reviews the short-term results of vur resolution following a single endoscopic treatment with DX/Ha range from 59% to 95% per ureter treated.78 if patients undergo a second injection for persistent vur, the success rate is improved; however, studies have demonstrated that a third injection is rarely curative.74,76,81 the long-term efficacy of the endoscopic correction of reflux is not well documented. a single long-term study documented a persistent 95% efficacy in vur resolution in patients treated with endoscopic polytetrafluoroethylene, with a mean follow-up of 14 years.82 Most studies of DX/Ha only report the results of cystography at 3 months or 1 year following the procedure. in studies using bovine cross-linked collagen, the high failure rate did not occur until years later, raising concerns regarding the long- term efficacy of DX/Ha.83 Despite the relatively short follow-up, recurrent reflux rates of between 11% and 26% occurring between 3 months and 12 months fol- lowing a single DX/Ha injection have already been reported.84,85 in a longer-term study of 49 patients who had resolution of reflux at both 3 months and 12 months after DX/Ha injection, 13% recurred at a mean of 3 years post-injection.76 the lack of durable success with DX/Ha has led some researchers to suggest a need for continued monitoring of children treated in this manner. aside from potential failure of DX/Ha, calcification of the implant has been reported as another potential long-term factor requiring recognition.86 Mound calcification is not unique to DX/ Ha, and has been described with many endoscopically injected agents.87,88 the chance of ureteral obstruction following DX/Ha seems to be about 0.6%.89 ureteral re-implantation the surgical treatment of vur has evolved over the past 50 years. a lower abdominal transverse incision is now typically used, leaving a small scar in the skin crease that frequently becomes inconspicuous. while multi- ple different techniques for ureteral re-implantation have been performed, most fall under one of two main categories: intravesical surgery, in which the bladder is opened and the ureters are dissected intravesically (Figure 6a); and extravesical re-implantation (Figure 6b), where the ureters are dissected away from the bladder wall without opening the bladder and are left attached 1 2 3 1 2 3 4 a b Figure 6 | Common ureteral re‑implantation techniques for correction of vesicoureteral reflux. a | intravesical Cohen ureteral re‑implantation. b | extravesical Lich–Gregoir ureteral re‑implantation. Figure 7 | User interface of a neural network for predicting the chance and timing of spontaneous resolution of vesicoureteral reflux based on a 2‑year resolution model. Data input page.98 © 2009 Macmillan Publishers Limited. All rights reserved
  7. 7. nature reviews | urology aDvanCe OnLine PuBLiCatiOn | 7 reviews to the bladder mucosa and re-implanted under flaps of bladder muscle. there is no clear documentation of any of the multiple techniques being superior to the others in terms of vur resolution.10 improvements in analgesia, surgical techniques, and the understanding that children undergoing ureteral re- implantation for primary vur rarely need ureteral stents or prolonged catheterization has reduced the length of hospital stay and decreased morbidity associated with the procedure.90 series of patients undergoing intra- vesical and extravesical ureteral re-implantation surgery as outpatients have been reported.91–93 recent studies have documented the use of laparoscopic and robotic ureteroneocystostomy in attempts to further reduce perioperative morbidity.94 results of multiple series docu- ment success rates with open ureteral re-implantation of >95%, and close to 100% for lower grades of reflux.95–97 the procedures, however, carry the risks associated with anesthesia and potential complications, including ureteral obstruction, persistent reflux, infection and bleeding.10 Individualized management the answers to many questions regarding vur remain unknown; however, it is clear that definitive treatment and even diagnosis of vur is unnecessary for many patients. at present, the decision to operate on a child with reflux or to continue or stop antibiotic prophy- laxis is based on physician and parent assessment of the associated risks and benefits. although this decision has traditionally been based predominantly on the grade of reflux, a truly informed decision must consider other variables, including the patient’s age, sex, history of utis, renal status, and the chance and likely timing of sponta- neous resolution. a patient’s social situation and parental preferences must also be factored in to the individualized management analysis for a given child with vur. in attempts to improve individualized patient manage- ment, several reports from the university of iowa further defined multiple prognostic factors relative to a child’s chance of spontaneous vur resolution.12,13,16,17 One of the predictive factors in these studies, independent of vur grade identified by vCuG and nuclear cysto- graphy, included the instilled bladder volume at the onset of reflux. reporting the bladder volume at the onset of reflux as additional predictive information should become standard practice for those performing vCuG or nuclear cystography. trying to determine the chance and timing of sponta- neous vur resolution in a given individual taking into account multiple prognostic variables, such as age, sex, grade of vur, bladder volume at onset of reflux, pres- ence of dysfunctional voiding, history of utis, laterality and duplication, becomes extremely complex. to this end, a user-friendly neural network has been created and is available online (Figure 7).15,98 the utility and accuracy of this model was recently validated on an international basis in a group of Japanese children.52 For children who have had a renal scan, an updated computer model has been generated that incorporates the additional renal scan data to improve prognostic accuracy, and is available at the same website.16 Conclusions although improved accuracy regarding the chance and timing of spontaneous vur resolution permits better management decisions, additional information is needed. Further studies are necessary in order to define an indivi- dual child’s risk of subsequent pyelonephritis, renal damage, and, ultimately, clinical sequelae. while ongoing prospective studies, such as the rivur (randomized intervention for Children with vur) trial, should help define which children benefit from antibiotic prophy- laxis, retrospective studies assessing long-term outcomes in adults with a history of vur should be initiated in order to better define those at the greatest risk of develop- ing clinical sequelae. although retrospective studies have limitations relative to prospective studies, well-designed retrospective studies might minimize these limitations and have the advantage of providing the information required now as opposed to in 30–40 years’ time. Review criteria references were obtained by searching PubMed with terms including “vesicoureteral reflux”, “children”, “outcomes”, “incidence”, “etiology”, and “treatment”. The references content and relevance to the points made in this manuscript, as well as the author’s previously published studies, personal experiences and interests also influenced selection of the papers cited in this review. 1. Cooper, C. s. & Austin, J. C. vesicoureteral reflux: who benefits from surgery? Urol. Clin. North Am. 31, 535–541 (2004). 2. Cooper, C. s., Chung, B. i., Kirsch, A. J., Canning, D. A. & snyder H. M. 3rd . The outcome of stopping prophylactic antibiotics in older children with vesicoureteral reflux. J. Urol. 163, 269–273 (2000). 3. Garin, e. H. et al. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics 117, 626–632 (2006). 4. Craig, J. C., irwig, L. M., Knight, J. F. & roy, L. P. Does treatment of vesicoureteric reflux in childhood prevent end‑stage renal disease attributable to reflux nephropathy? Pediatrics 105, 1236–1241 (2000). 5. Hodson, e. M., wheeler, D. M., smith, G. H., Craig, J. C. & vimalachandra, D. interventions for primary vesicoureteric reflux. Cochrane Database of Systematic Reviews 2007, issue 3. Art. No.: CD001532. doi:10.1002/14651858. CD001532.pub3. 6. winberg, J. Management of primary vesico‑ ureteric reflux in children—operation ineffective in preventing progressive renal damage. Infection 22 (Suppl. 1), s4–s7 (1994). 7. Baker, r., Maxted, w., Maylath, J. & shuman, i. relation of age, sex, and infection to reflux: data indicating high spontaneous cure rate in pediatric patients. J. Urol. 95, 27–32 (1966). 8. Paquin, A. J. Ureterovesical anastomosis. The description and evaluation of a technique. J. Urol. 82, 573–583 (1959). 9. Lebowitz, r. L., Olbing, H., Parkkulainen, K. v., semllie, J. M. & Tamminen‑Möbius, T. e. international system of radiographic grading of vesicoureteric reflux. international reflux study in Children. Pediatr. Radiol. 15, 105–109 (1985). 10. elder, J. s. et al. Pediatric vesicoureteral reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J. Urol. 157, 1846–1851 (1991). © 2009 Macmillan Publishers Limited. All rights reserved
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