Abstract
Arab Journal of Urology (2013) 11,8–12 Arab Journal of Urology (Official Journal of the Arab Association of Urology) www.sciencedirect.com PEDIATRIC UROLOGY REVIEW Primary vesico-ureteric reflux: The need for individualised risk stratification Guy Hidas, Alexander Nam, Tandis Soltani, Maryellen Pribish, Blake Watts, Antoine E. Khoury Urology Department, University of California, Irvine, Orange, CA, USA Received 17 October 2012, Accepted 8 November 2012 Available online 24 January 2013 KEYWORDS Abstract The management of paediatric primary vesico-ureteric reflux (VUR) has undergone serial changes over the last decade. As this disorder is extremely Vesico-ureteric reflux; heterogeneous, and high-quality prospective data are limited, the treatment strat- Urinary tract infection; egies vary among centres. Current treatment options include observation only, Renal scars; continuous antibiotic prophylaxis, and surgery. Surgical intervention is indicated Dimercaptosuccinic if a child has a breakthrough urinary tract infection (UTI) while on continuous acid (DMSA); antibiotic prophylaxis or if there are renal scars present. After excluding a second- Continuous antibiotic ary cause of VUR the physician should consider the risk factors affecting the prophylaxis; severity of VUR and manage the child accordingly. Those factors include demo- Bladder and bowel graphic factors (age at presentation, gender, ethnicity) and clinical factors (VUR dysfunctions; grade, unilateral vs. bilateral, presence of renal scars, initial presentation, the Voiding cysto- number of UTIs, and presence of any voiding or bowel dysfunction). In this urethrography review we summarise the major controversial issues in current reports on VUR Corresponding author. Address: Walter R. Schmid Professor of Pediatric Urology, Department of Urology, University of California, Irvine, Children’s Hospital of Orange County, 505 S. Main Street, Suite 100, Orange, CA 92868, USA. Tel.: +1 714 512 3914; fax: +1 714 512 3916. E-mail address: aekhoury@uci.edu (A.E. Khoury). Peer review under responsibility of Arab Association of Urology. Production and hosting by Elsevier 2090-598X ª 2012 Arab Association of Urology. Production and hosting by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.aju.2012.11.006 Primary vesico-ureteric reflux: The need for individualised risk stratification 9 ABBREVIATIONS and highlight the importance of individualised patient management according to their risk stratification. BBD, bladder and ª 2012 Arab Association of Urology. Production and hosting by Elsevier B.V. bowel dysfunction; All rights reserved. CAP, continuous anti- biotic prophylaxis; US, ultrasonography; VCUG, voiding cysto- urethrography; RCT, randomised control trial Introduction from cessation of antibiotic prophylaxis remains unclear at best. VUR is defined as the back flow of urine from the blad- Many large-scale multivariate analyses show that the der into the upper urinary tract. VUR is one of the most factors affecting the spontaneous resolution of VUR in- common paediatric urology entities and has a spectrum clude demographic factors (age at presentation, gender, of severity that ranges from an asymptomatic self- ethnicity) and clinical factors (VUR grade, unilateral vs. limiting incidental finding to a condition which is bilateral, presence of renal scars, initial presentation, the associated with pyelonephritis, renal scarring and even number of UTIs, and the presence of bladder and bowel deterioration of kidney function. This variability in the dysfunction; Fig. 1). presentation and outcome of the disease raises tremen- In this review we summarise the major controversial dous controversy about the optimal diagnosis and man- issues raised by current reports on VUR, and highlight agement strategies. the importance of individualised patient management The challenge with managing VUR is that there is according to their risk stratification. much information that has been published on the topic, comprising 2280 articles in the past 10 years. Most of this information comes from retrospective studies that The diagnosis of VUR and renal scars have not led to a proportionate amount of useful clinical The diagnosis of VUR is made by voiding cysto-ureth- knowledge. Ideally, relative risk for UTI and renal in- rography (VCUG), a relatively invasive procedure as it jury should be what drives the clinical management of requires bladder catheterisation as well as radiation these patients. The selection of patients, based on risk, exposure to the infant pelvis and gonads. The awareness who would benefit from early correction of VUR or of these two major drawbacks has increased tremen- dously over the last decade, and many physicians and parents try to avoid this diagnostic study whenever possible. The classic indications for VCUG include febrile UTI, high-grade or bilateral hydronephrosis and/or ure- teric dilatation. These indications have been challenged by numerous publications questioning the yield of this diagnostic test in different patient populations. Hober- man et al. [1] showed, in a prospective trial involving 309 patients, that renal scarring 6 months after the infec- tion is significantly more prevalent in infants with VUR (15% vs. 6%, P = 0.03). Because of this statistically sig- nificant finding, and if antimicrobial prophylaxis is effective in reducing re-infections and renal scarring, then VCUG might be a useful test. However, Tseng et al. [2] showed that children with a negative DMSA scan taken after the first UTI episode rarely have VUR and almost never have high-grade VUR. As the yield of continuous antibiotic prophylaxis (CAP) to pre- vent UTI in patients with low-grade VUR is low, VCUG might not be necessary in all young children having their first febrile UTI when the DMSA scan is negative. Figure 1 Risk factors and risk groups for VUR. 10 Hidas et al. Merguerian et al. [3] suggested that high-resolution the endoscopic correction therapy (57% vs. 90%, ultrasonography (US) of the kidney can accurately de- respectively); however, this association was not found tect diffuse renal scars and can be used as a screening after open ureteric reimplantation. The UTI rate after tool to determine the need for a DMSA renal scan. In the procedure was also higher in patients with BBD. that study a DMSA renal scan resulted in a change in management strategy in only 13% of the patients. The Cap authors recommended the use of a DMSA scan only The principle rationale for antibiotic use in the manage- for very young infants with high-grade VUR, recurrent ment of VUR is to prevent UTI and febrile pyelonephri- breakthrough UTI, and/or severe bowel and bladder tis, which can lead to permanent renal scarring after the dysfunction (BBD). infection. Recently, questions about the effectiveness vs. the potential harm of this strategy have been raised, thus Renal scars are associated with UTIs resulting in many controversial publications with con- Swerkersson et al. [4] reported on the relationship be- fusing messages. tween VUR, UTI, and renal damage. In their study, Roussey-Kesler et al. [9] randomised 225 children 303 children aged <2 years were assessed by US, aged 1–3 years with VUR grade I–III into either contin- VCUG, and DMSA renal scan within 3 months of their uous cotrimoxazole or no CAP. After a follow-up of first UTI. They also repeated the DMSA at 1–2 years 18 months there were no significant differences in the afterwards. In that study the risk for new febrile UTI in- incidence of UTI (7% vs. 26% P = 0.2). Interestingly, creased with the presence and severity of VUR, despite CAP significantly reduced the incidence of UTI in boys being on CAP, with the risk (95% CI) being: grade I, with grade III VUR (P = 0.013). Another example is 1.20 (0.43–3.35); grade II, 2.17 (1.33–3.36); grade III, the study of Garin et al. [7], who completed a multicentre 2.50 (1.55–4.01), and grades IV–V, 4.61 (3.23–6.57). RCT of the role of CAP in patients aged <18 months Interestingly, in boys the renal damage was often con- and with a history of acute pyelonephritis with or with- genital, while in girls the scars were acquired and found out VUR. That study did not support any role for to be related to severe inflammatory processes. CAP in preventing the recurrence of UTI or in develop- ing renal scars. Furthermore, they found that mild to Management strategies moderate VUR did not increase the incidence of UTI, pyelonephritis or renal scars in this patient population. The physician managing a child with VUR must first ex- Pennesi et al. [8] showed, in an open-labelled RCT, clude any cause of secondary VUR; the latter is defined that CAP is ineffective in reducing the rate of recurrence as VUR caused by any anatomical or functional abnor- of pyelonephritis and the induction of renal damage in mality of the bladder, bladder outlet or ureter with a children aged <30 months who had VUR grade II– normal functioning vesico-ureteric junction. The most IV. This study was criticised as being open-labelled common secondary cause comes from bladder pathol- and under-powered, with questionable compliance with ogy that creates excessive storage and emptying pres- CAP treatment. Also contributing to this scrutiny, nei- sures, which eventually overwhelm a normal antireflux ther BBD nor the circumcision status of the patient intramural flap-valve mechanism (neurogenic bladder, was accounted for in the study. Leslie et al. [9] showed bladder exstrophy, PUV, etc.). In this review we focus that patients with ongoing VUR in whom CAP had on the discussion on the patients with primary VUR. been withdrawn had no greater incidence of UTI than age-matched VUR control patients who remained on prophylaxis. BBDs are associated with UTIs A recent Swedish VUR trial [10] gave results that are In 2010 the AUA published guidelines on the manage- in sharp contrast with other recent studies. The Swedish ment of primary VUR in children [5]. This report used study was prospectively designed and randomised pa- a structured formal meta-analytical technique with rig- tients into three arms, i.e. CAP, surveillance only (no orous assessment of data-quality and selection. Despite antibiotics), and endoscopic VUR correction. In all, the lack of robust prospective high-quality randomised 203 patients with grade III–IV VUR (128 girls and eight control trials (RCTs) available, these guidelines suc- boys) aged 1–2 years, who mostly presented with a feb- ceeded in emphasising the main diagnostic and treat- rile UTI, were followed. Recurrent febrile UTIs were ment clinical points, with a focus on the important significantly more common in girls (P < 0.001) and role that BBD plays in the pathophysiology of VUR. were more common on the surveillance protocol than In this meta-analysis, BBD was associated with a greater for CAP or endoscopic therapy (57% vs. 19% vs. risk of breakthrough UTI while on CAP (44% vs. 13%, 23%, respectively, P = 0.01). Interestingly and more respectively), and a decrease in the rate of spontaneous importantly, the CAP group had a significantly lower resolution (31% vs. 61%, respectively). Abnormal blad- incidence of new renal scars than those randomised to der function was also associated with reduced success of surveillance and endoscopic treatment; new scars were Primary vesico-ureteric reflux: The need for individualised risk stratification 11 more prevalent after febrile UTIs (11/49, 22%) and the In paediatric urology these techniques have been ap- rate of new renal damage was low in boys (in two of 75 plied to VUR, specifically to predict the probability of boys enrolled). These data support the use of CAP in the spontaneous resolution of VUR. The Children’s girls aged <2 years and with grade III–V VUR. Hospital of Boston developed a calculator to predict The controversy between the results of the aforemen- the spontaneous resolution of VUR by using logistic tioned study might be explained by the different patient regression analysis of their retrospectively collected data population that was studied. In addition, it again must on 2462 patients [14]. Another example is the computa- be highlighted that VUR is a spectrum of disease sever- tional model from Iowa University, which used the neu- ity that should not be treated equally. While the studies ronal network method to predict the same point [15]. All of Roussey-Kesler et al. [6] and Garin et al. [7] included those predictive tools are used to predict the resolution patients with and without VUR, low-grade VUR and of VUR. The next relevant scoring system to be gener- minimal renal scars at entry, the Swedish study showed ated is to compute the risk that the individual patient a significant benefit for CAP in the high-risk group of will undergo a complicated clinical course that will re- girls with VUR grade III or above. quire intervention. The surgical correction of VUR Conclusions An absolute indication for correcting VUR includes any The management of paediatric primary VUR is under failure of other conservative measures, which includes continuous development. Treatment varies among cen- breakthrough UTI while on CAP, noncompliance with tres and VUR might be over-treated. Treatment options CAP, new renal scars during CAP and no resolution include observation only, CAP, and surgery. Manage- after 4 years of follow-up. ment goals should be the prevention of breakthrough The endoscopic correction of VUR is done by injection UTIs and new renal scars. After excluding a secondary with a bulking agent beneath the intramural ureter and cause of VUR, the physician should consider the risk ureteric orifice. The minimal invasiveness, with the rela- factors affecting the severity of VUR and manage the tively high success rate (>71% in most series) [11] made child accordingly. Risk factors for severe VUR include this procedure very popular over the last decade [12]. demographics (age at presentation, gender, ethnicity) As many parents and physicians are opposed to long- and clinical factors (VUR grade, unilateral vs. bilateral, term CAP and follow-up with another VCUG, manage- presence of renal scars, initial presentation, the number ment trends have been changing over the last decade. of UTIs, and presence of BBD). Lendvay et al. [12] showed, when reviewing a paediatric health information system database, that during 2002– Conflict of interest 2004 the incidence of open reimplantation for the surgi- None. cal correction of VUR decreased by 10%, endoscopic correction increased by 300%, and the overall procedure Funding rate increased by 50%. To maintain credibility, physicians must determine if None. this shift is truly justifiable and ask if any surgical cor- rection is necessary, i.e. is the increased prevalence in References surgical procedures really leading to lower rates of renal injury and failure? Does it reduce the incidence of kid- [1] Hoberman A, Charron M, Hickey RW, Baskin M, Kearney DH, ney infection? Again, high-quality prospective data are Wald ER. Imaging studies after a first febrile urinary tract lacking and the decision is based on retrospective and infection in young children. N Engl J Med 2003;16:195–202. very selective data. [2] Tseng MH, Lin WJ, Lo WT, Wang SR, Chu ML, Wang CC. Does a normal DMSA obviate the performance of voiding cystourethrography in evaluation of young children after their VUR risk stratification and predictive models first urinary tract infection? J Pediatr 2007;150:96–9. [3] Merguerian PA, Jamal MA, Agarwal SK, McLorie GA, Bagli DJ, Predictive models are used in various medical disciplines Shuckett B, et al. Utility of SPECT DMSA renal scanning in the to help individualise treatment strategies. One of the evaluation of children with primary vesicoureteral reflux. Urology most famous prediction tools is the Framingham Risk 1999;53:1024–8. [4] Swerkersson S, Jodal U, Sixt R, Stokland E, Hansson S. Assessment Calculator [13] for estimating the 10-year Relationship among VUR, UTI and renal damage in children. J risk of having a heart attack. More specifically, this is Urol 2007;178:647–51. a risk calculator that is based on the prospectively col- [5] Peters CA, Skoog SJ, Arant Jr BS, Copp HL, Elder JS, Hudson lected data in the Framingham study. After entering ba- RG, et al. Summary of the AUA guideline on management of sic risk factors such as gender, age, smoking status and primary vesicoureteral reflux in children. J Urol 2010;184:1134–44. [6] Roussey-Kesler G, Gadjos V, Idres N, Horen B, Ichay L, Leclair serum lipid profile, the probability (as a percentage) of MD, et al. Antibiotic prophylaxis for the prevention of recurrent having a heart attack in the next 10 years is calculated. 12 Hidas et al. urinary tract infection in children with low grade vesicoureteral [11] Routh JC, Inman BA, Reinberg Y. Dextranomer/hyaluronic acid reflux: results from a prospective randomized study. J Urol for pediatric vesicoureteral reflux: systematic review. Pediatrics 2008;179:674–9. 2010;125:1010. [7] Garin EH, Olavarria F, Garcia Nieto V, Valenciano B, Campos [12] Lendvay TS, Sorensen M, Cowan CA, Joyner BD, Mitchell MM, L, Young L. Clinical significance of primary vesicoureteral reflux Grady RW. The evolution of vesicoureteral reflux management in and urinary antibiotic prophylaxis after acute pyelonephritis: a the era of dextranomer/hyaluronic acid copolymer: a pediatric multicenter, randomized, controlled study. Pediatrics 2006;117: health information system database. J Urol 2006;176:1867. 626–32. [13] D’Agostino Sr RB, Grundy S, Sullivan LM, Wilson P. CHD risk [8] Pennesi M, Travan L, Peratoner L, Bordugo A, Cattaneo A, prediction group. Validation of the Framingham coronary heart Ronfani L, et al. Is antibiotic prophylaxis in children with disease prediction scores: results of a multiple ethnic groups vesicoureteral reflux effective in preventing pyelonephritis and investigation. JAMA 2001;286:180–7. renal scars? A randomized, controlled trial. Pediatrics 2008;121: [14] Estrada Jr CR, Passerotti CC, Graham DA, Peters CA, Bauer SB, 1489–94. Diamond DA, et al.. Nomograms for predicting annual resolu- [9] Leslie B, Moore K, Salle JL, Khoury AE, Cook A, Braga LH, tion rate of primary vesicoureteral reflux: results from 2,462 et al. Outcome of antibiotic prophylaxis discontinuation in children. J Urol 2009;182:1535–41. patients with persistent vesicoureteral reflux initially presenting [15] Knudson MJ, Austin JC, Wald M, Makhlouf AA, Niederberger with febrile urinary tract infection: time to event analysis. J Urol CS, Cooper CS. Computational model for predicting the chance 2010;184:1093–9. of early resolution in children with vesicoureteral reflux. J Urol [10] Brandstro¨ m P, Esbjo¨ rner E, Herthelius M, Swerkersson S, Jodal 2007;178:1824–7. S, Hansson S. The Swedish reflux trial in children: III. Urinary tract infection pattern. J Urol 2010;184:286–91.
Journal
Arab Journal of Urology
– Taylor & Francis
Published: Mar 1, 2013
Keywords: Vesico-ureteric reflux; Urinary tract infection; Renal scars; Dimercaptosuccinic acid (DMSA); Continuous antibiotic prophylaxis; Bladder and bowel dysfunctions; Voiding cysto-urethrography; BBD, bladder and bowel dysfunction; CAP, continuous antibiotic prophylaxis; US, ultrasonography; VCUG, voiding cysto-urethrography; RCT, randomised control trial
