Role of prophylaxis in vesicoureteral reflux William C. Faust a and Hans G. Pohl b

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1 Role of prophylaxis in vesicoureteral reflux William C. Faust a and Hans G. Pohl b Purpose of review Traditional management of vesicoureteral reflux focuses on preventing renal complications associated with ascending urinary tract infection by either providing continuous antibiotic prophylaxis to sterilize the urine and thus prevent recurrent infection, or abolishing reflux via surgical intervention. This review will consider the rationale for antibiotic prophylaxis in light of contemporary data regarding the natural history of vesicoureteral reflux, urinary tract infection and renal scarring, as well as the efficacy of various treatment strategies. Recent findings Recent studies have shown that in grades I IV vesicoureteral reflux, open surgical intervention compared with antibiotic prophylaxis is no better at preventing renal complications. Endoscopic subureteral injection of biomaterials has been proposed as a cost-effective, minimally invasive alternative to surgical or medical intervention; however, given the variety of materials and techniques, the literature has yet to achieve consensus on its efficacy. The first study to compare antibiotic prophylaxis with increased surveillance and prompt treatment of urinary tract infection shows no difference between the two approaches in low-grade (grades I II) vesicoureteral reflux. Summary Recent studies have challenged the traditional paradigm of aggressive vesicoureteral reflux management with surgery or antibiotic prophylaxis. In light of these findings, pediatric urologists will need to reexamine treatment modalities for vesicoureteral reflux. Keywords antibiotic prophylaxis, pyelonephritis, renal scarring, vesicoureteral reflux Curr Opin Urol 17: ß 2007 Lippincott Williams & Wilkins. a Georgetown University School of Medicine and b Department of Urology, Children s National Medical Center, Washington, DC, USA Correspondence to Hans G. Pohl MD, FAAP, Department of Urology, Children s National Medical Center, 111 Michigan Ave NW, Washington, DC 20010, USA Tel: ; hpohl@cnmc.org Current Opinion in Urology 2007, 17: Abbreviations APN acute pyelonephritis CKD chronic kidney disease DMSA 99-m-technetium dimercapto succinic acid GFR glomerular filtration rate UTI urinary tract infection VCUG voiding cystourethrography VUR vesicoureteral reflux ß 2007 Lippincott Williams & Wilkins Introduction Vesicoureteral reflux (VUR) had been considered the primary risk factor predisposing children to acquired renal cortical scarring and, based on this association, the historical management of VUR was primarily surgical. The recognition that urinary tract infection (UTI), specifically infection of the renal parenchyma (acute pyelonephritis, APN), could result in renal scarring, both in the presence of VUR as well as in its absence, changed the paradigm of VUR management such that most patients initially receive a subtherapeutic dose of antibiotic daily in order to prevent UTI, with surgical management reserved for when medical management is deemed unsuccessful. It is not disputed that in general the nonoperative approach to VUR is rational; however, not all children benefit from the recommendation to remain on prophylaxis until VUR resolves completely by virtue of breakthrough UTI or poor compliance, both of which may result in recurrent UTI with the risk of renal scarring. In other circumstances, the child with VUR may be at low risk of recurrent infection or renal scarring, thereby obviating one goal of prophylaxis. Thus, the role of continuous prophylaxis in VUR management may not be appropriate for every child. We will consider the rationale for antibiotic prophylaxis in light of contemporary data regarding the natural history of VUR, UTI and renal scarring, as well as the efficacy of various treatment strategies. The incidence of vesicoureteral reflux Historically, it has been reported that VUR occurs in 1 2% of healthy newborns. Since its diagnosis requires invasive procedures such as voiding cystourethrography (VCUG) that entails bladder catheterization and ionizing radiation, the true incidence of VUR cannot be reliably determined. A recent metaanalysis [1] of more than 250 studies of VCUG performed for standard indications such as febrile UTI, antenatal hydronephrosis, or a sibling with VUR, as well as studies in which VCUGs were 252

2 Prophylaxis in vesicoureteral reflux Faust and Pohl 253 performed for other nonstandard indications, including renal anomalies, normal kidneys and undescended testes determined that clinically occult VUR was identified in up to 9% of healthy children. In clinical practice, it is more useful to consider the prevalence of identifying VUR based on presentation since this rate is more likely to affect how and when a VCUG should be considered, if at all. In patients with antenatally detected hydronephrosis, as defined by renal pelvis dilatation between 4 and 7 mm, VUR is found in up to 9% of infants [2,3]. VUR may be identified in 25 30% of siblings of children with known VUR [4 8] and in 30 40% [9 12] of children presenting with APN, as defined by fever (>101.58F), bacteruria (> cfu/ml of a single organism) and evidence of inflammation on 99-m-technetium dimercapto succinic acid (DMSA) renal scan. Vesicoureteral reflux: management guidelines Traditionally, the rationale for treating VUR focuses on preventing UTI and thus diminishing the likelihood of new renal scarring, which has been associated with decreased renal function, hypertension, and in severe cases chronic kidney disease (CKD). In 1997, the American Urological Association (AUA) published guidelines to facilitate the treatment of VUR, recommending that continuous antibiotic prophylaxis be the initial management in all children with VUR with or without renal scarring. Surgical treatment was a preferred option in those 1 5 years old with bilateral grade V reflux and those 6 10 years old with bilateral grade III V reflux. No consensus was generated for persistent low-grade VUR (grade I II). The panel recommended that in children with renal scarring at presentation, surgery should be considered more strongly when VUR persists in follow up [13]. Since most children with VUR do not have significant renal scarring, prophylaxis is generally the initial treatment applied. This year, the European arm of the International Reflux Study published their 10-year results of children treated with severe nonobstructive grade III/IV VUR. Patients who had a prior history of at least one symptomatic UTI and good preexisting renal function as measured by a glomerular filtration rate (GFR) greater than 70 ml/min/ 1.73 m 2 were randomly selected to receive medical or surgical treatment. The rates of renal scarring, defined by new abnormalities on both serial intravenous urogram (IVU) and DMSA scans, of impairment of renal growth measured by serial urogram tracings, of renal function measured by GFR, of somatic growth, of progression of reflux, and of development of hypertension (systolic or diastolic pressure 95% on two separate occasions) was no different in groups of children receiving antibiotic prophylaxis compared with those who underwent ureteral reimplantation [14 ]. Similarly, in a 2003 metaanalysis by Wheeler et al. [15], seven studies comparing open ureteral reimplantation (six studies) or endoscopic treatment with dextranomer/hyaluronic acid (Deflux) (one study) with antibiotic prophylaxis were evaluated with no significant difference found between the therapeutic options in terms of the risk of UTI or the likelihood of new renal damage, as measured by either IVU or DMSA scanning at 5 years. This year, another metaanalysis showed that the only significant difference between surgical and medical management was in terms of abolishing reflux since no difference was found between the groups for incidence of new renal scarring and mean increase in renal length [16 ]. Concerns with continuous antibiotic prophylaxis One of the biggest concerns of the widespread use of antibacterial chemotherapy is the growing prevalence of antibiotic-resistant pathogens. In a study of children with neuropathic bladder secondary to spina bifida, those who perform clean intermittent catheterization (CIC) with continuous antibiotic prophylaxis to prevent recurrent UTI were actually more likely to have a clinical UTI, as defined by positive urine culture plus the presence of clinical signs, than those children who performed CIC without prophylaxis (64% versus 14%), and that infecting organisms for those children on prophylaxis were resistant to the antimicrobial given [17]. Studies published worldwide have shown increasing rates of antibiotic resistance to pathogens commonly involved in UTI. Resistance of Escherichia coli isolates from various institutions including Madagascar, Saudi Arabia, Brazil, the Gaza Strip, Iran, and Nigeria ranged from 33% to 65.7% for trimethoprim-sulfamethazole, 50% to 97% for ampicillin and 14% to 33% for ciproflaxicin [18 23]. Amongst the US pediatric population, resistance to commonly used antibiotics was also elevated, reaching 36.7%, 44.6%, and 2.4% for trimethoprim-sulfamethazole, ampicillin, and ciproflaxicin, respectively [24]. Considering that resistance is due to selection pressures from the widespread use of antibiotics [25], this highlights the need for more selective utilization of antibiotics based on evidence of clinical need. There are conflicting data regarding the influence of bacterial resistance patterns in the genesis of recurrent UTI in children on prophylaxis. In the Wheeler et al. and Venhola et al. studies [15,16 ], no difference in the rate of recurrent UTI was found in children receiving prophylaxis versus those having undergone antireflux surgery. By contrast, the International Reflux Study [14 ] found a

3 254 Paediatric urology 33% increase in incidence of febrile UTIs in those receiving continuous prophylaxis, which approximates the incidence of bactrim resistance among uropathogenic bacteria. Rethinking the severity of vesicoureteral reflux complications Even when antibiotic prophylaxis fails to prevent breakthrough UTI in patients with reflux, a common indication for surgical correction of reflux, studies have shown that the risk of long-term consequences such as new renal scarring or progression to hypertension or CKD is quite low. Szlyk et al. [26] found that only 14.7% of patients with breakthrough, febrile, culture documented (> cfu) UTI, who were on continuous antibiotic prophylaxis for all grades of VUR, had radiographic evidence of acute renal inflammatory changes on DMSA scan. Similarly, Silva et al. [27 ] in a retrospective study of 735 patients with primary VUR, 624 of which were treated with antibiotic prophylaxis, found that only 21 patients (3%) progressed to CKD with an average GFR of 31.2 ml/min and only 20 patients (3%) developed hypertension, defined as systolic or diastolic pressure greater than 95% for age, height, and gender, despite the fact that 125 (27%) had three or more episodes of UTI during the mean follow-up time of 76 months. When studied over time, they calculated the estimated probability of developing hypertension was 2%, 6%, and 15% at 10, 15, and 21 years of age [28]. Can endoscopic management supplant prophylaxis? Despite the fact that the long-term clinical impact of VUR may not be as prevalent as once was thought, if one does accept the traditional premise that VUR predisposes children to recurrent UTI and or pyelonephritis, then some form of treatment, either medically or surgically, could produce a significant economic benefit as well as benefit in quality of life for both child and parents. According to National Institutes of Health (NIH)/ National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) statistics, the number of annual inpatient hospitalizations for UTI treatment decreased from in 1994 to in This, however, still represents a tremendous healthcare burden. Assuming an average cost of US$4500 per inpatient visit, and hospitalizations a year, the annual economic burden for inpatient treatment is US$180 million dollars. Factoring lost work for parents is a difficult variable to quantify, and the indirect costs could be substantially more [29]. The economic burden of illness, coupled with the invasive and costly nature of open surgical correction for VUR and potential concerns over antibiotic prophylaxis, has led some researchers to explore endoscopic treatment as a safe and cost-effective method for treating reflux. Since rates of success with endoscopic treatment vary in the literature, two papers published in 2006 by Benoit et al. [30,31 ] instead determined the threshold success rate that would make endoscopic VUR treatment as cost-effective as other therapies. They looked at two scenarios, the first as a substitution for surgical management following traditional indications for open ureteral reimplantation that is, breakthrough infection or failure of reflux to resolve [30 ], and the second as a substitute for antibiotic prophylaxis at first diagnosis of VUR [31 ]. In the first case, the success rate for unilateral VUR would need to be 57.8% per ureter for patients with unilateral reflux and 75.3% per ureter for bilateral reflux. If, however, increasing grades of reflux required increasing amounts of polymer, then success rates would need to be 72.5% for patients with unilateral reflux and 93.8% for patients with bilateral reflux. In the second scenario, as a replacement for medical management, they calculated that for grades III, IV, and V respective success rates of 88.5%, 66.6% and 55.6% for unilateral reflux and 97.5%, 89.7% and 91.4% for bilateral reflux would need to be achieved in order to reach cost-effectiveness compared with traditional management. In a metaanalysis [32 ] of 63 articles studying 5257 patients and 8101 renal units, reflux resolution per ureter was 78.5% for grades I and II, 72% for grade III, 63% for grade IV, and 51% for grade V. Although one criticism of the review was that it included all bulking agent materials in its study, given the present day variability in technique and materials, whether or not these success rates will be achieved remains to be seen [32,33 35]. New directions in vesicoureteral reflux treatment: is treatment even necessary? If the long-term consequences of VUR are not as severe as once was thought, then either antibiotic prophylaxis or surgical intervention may not be necessary at all. In fact, one criticism of the aforementioned AUA VUR guidelines is that the recommendation for continuous prophylaxis is not so much based on clinical data, but instead on the consensus of expert opinion on the subject [36]. Recently, Garin et al. [37 ] followed 218 patients with grade I III VUR for 1 year who were randomly assigned to either continuous antibiotic prophylaxis or no treatment. They found no difference in the rate of recurrent UTI, nor the rate of recurrent APN or new renal cortical scarring as measured by DMSA scintigraphy in both groups. Additionally, seven of the eight episodes of recurrent pyelonephritis occurred in the group receiving antibiotic prophylaxis, all seven of which showed resistance to the antibiotic used. This study did have its limitations, including lack of a placebo, lack of standardization of treatment, and no intention-to-treat analysis, with a large number of the prophylaxis group lost to follow up [37 ]. The only other study to date comparing

4 Prophylaxis in vesicoureteral reflux Faust and Pohl 255 antibiotic prophylaxis with no treatment for VUR has shown similar results with no significant difference between treatment groups for renal scarring as measured by DMSA scan [38]. Williams et al., in a Cochrane review [39 ], reiterated that the evidence to support the widespread use of antibiotics to prevent recurrent symptomatic UTI is weak. Of the eight studies reviewed, seven measured positive urine culture as a primary outcome, not symptomatic UTI, and of two papers that correlated urine sterility to VUR, a statistically significant conclusion could not even be reached. Clearly, the need for more studies comparing prophylaxis with surveillance are necessary, but initial findings suggest that for at least low-grade VUR, antibiotic prophylaxis, or any kind of treatment, may not be necessary at all. Conclusion VUR represents a particular challenge for pediatric urologists. The traditional paradigm of aggressive management with surgical intervention for grade I IV VUR has been called into question in light of compelling data demonstrating that surgical correction is not significantly better than antibiotic prophylaxis in preventing longterm complications, such as renal scarring, hypertension, CKD or end-stage renal disease, as well as the diminished risk of renal scarring following breakthrough UTI. Endoscopic therapy has been proposed as a safe, minimally invasive, and cost-effective alternative to open surgical correction, however consistent data on rates of success have yet to reach the calculated rates of success necessary to become a preferred option based on the argument of cost-effectiveness and on that basis cannot supplant continuous prophylaxis in the management of VUR. Given that even antibiotic prophylaxis may have no demonstrated advantage over prompt recognition and treatment of UTI in prevention of renal scarring, and may only result in the selection of antibiotic-resistant strains of bacteria, future studies are needed that compare antibiotic prophylaxis to surveillance, as well as determining the pathophysiology and risk factors that may predispose patients to recurrent UTI or renal scarring such that treatment can be tailored appropriately. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp ). 1 Sargent MA. What is the normal prevalence of vesicoureteral reflux? Pediatr Radiol 2000; 30: Ismaili K, Hall M, Piepsz A, et al. Primary vesicoureteral reflux detected in neonates with a history of fetal renal pelvis dilatation: a prospective clinical and imaging study. J Pediatr 2006; 148: Woodward M, Frank D. Postnatal management of antenatal hydronephrosis. BJU Int 2002; 89: Pirker ME, Colhoun E, Puri P. Renal scarring in familial vesicoureteral reflux: is prevention possible? J Urol 2006; 176 (4 Pt 2): Hollowell JG, Greenfield SP. Screening siblings for vesicoureteral reflux. J Urol 2002; 168: Chertin B, Puri P. Familial vesicoureteral reflux. J Urol 2003; 169: Wan J, Greenfield SP, Nq M, et al. Sibling reflux: a dual center retrospective study. J Urol 1996; 156 (2 Pt 2): Noe HN. The long-term results of prospective sibling reflux screening. J Urol 1992; 148 (5 Pt 2): Kanellopoulos TA, Salakos C, Spiliopoulou I, et al. First urinary tract infection in neonates, infants and young children: a comparative study. Pediatr Nephrol 2006; 21: Smellie JM, Prescod NP, Shaw PJ, et al. Childhood reflux and urinary infection: a follow-up of years in 226 adults. Pediatr Nephrol 1998; 12: Hoberman A, Charron M, Hickey RW, et al. Imaging studies after a first febrile urinary tract infection in young children. N Engl J Med 2003; 348: American Academy of Pediatrics, Committee on Quality Improvement, Subcommittee on Urinary Tract Infection. Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics 1999; 103: Elder JS, Peters CA, Arant BS, et al. Report on the management of primary vesicoureteral reflux in children. Baltimore, Maryland: American Urological Association; Jodal U, Smellie JM, Lax H, Hoyer PF. Ten-year results of randomized treatment of children with severe vesicoureteral reflux: final report of the International Reflux Study in Children. Pediatr Nephrol 2006; 21: This is an important randomized, clinical study comparing operative management of VUR with continuous antibiotic prophylaxis over a 10-year period. 15 Wheeler D, Vimalachandra D, Hodson EM, et al. Antibiotics and surgery for vesicoureteric reflux: a meta-analysis of randomised controlled trials. Arch Dis Child 2003; 88: Venhola M, Huttunen NP, Uhari M. Meta-analysis of vesicoureteral reflux and urinary tract infection in children. Scand J Urol Nephrol 2006; 40: This is another well done metaanalysis that looks at five studies that compare operative management of VUR with antibiotic prophylaxis with recurrent UTI, renal scarring, or kidney growth as primary endpoints. 17 Clarke SA, Samuel M, Boddy S. Are prophylactic antibiotics necessary with clean intermittent catheterization? A randomized controlled trial. J Pediatr Surg 2005; 40: Al-Tawfiq JA. Increasing antibiotic resistance among isolates of Escherichia coli recovered from inpatients and outpatients in a Saudi Arabian hospital. Infect Control Hosp Epidemiol 2006; 27: Randrianirinia F, Soares JL, Carod JF, et al. Antimicrobial resistance among uropathogens that cause community-acquired urinary tract infections in Antananarivo, Madagascar. J Antimicrob Chemother 2007; 59: Moreira ED Jr, De Siqueira IC, Alcantara AP, et al. Antimicrobial resistance of Escherichia coli strains causing community-acquired urinary tract infections among insured and uninsured populations in a large urban center. J Chemother 2006; 18: Elmanama AA, Elaiwa NM, El-Ottol AE, Abu-Elamreen FH. Antibiotic resistance of uropathogens isolated from Al-shifa Hospital in Gaza Strip in J Chemother 2006; 18: Sharifian M, Karimi A, Abatabaei SR, Anvaripour N. Microbial sensitivity pattern in urinary tract infections in children: a single center experience of 1,177 urine cultures. Jpn J Infect Dis 2006; 59: Andrade SS, Sader HS, Jones RN, et al. Increased resistance to first-line agents among bacterial pathogens isolated from urinary tract infections in Latin America: time for local guidelines? Mem Inst Oswaldo Cruz 2006; 101: Gaspari RJ, Dickson E, Karlowsky J, Doern G. Antibiotic resistance trends in paediatric uropathogens. Int J Antimicrob Agents 2005; 26: Rubin MA, Samore MH. Antimicrobial use and resistance. Curr Infect Dis Rep 2002; 4: Szlyk GR, William SB, Majd MA, et al. Incidence of new renal parenchymal inflammatory changes following breakthrough urinary tract infection in patients with vesicoureteral reflux treated with antibiotic prophylaxis: evaluation by 99MTechnetium dimercapto-succinic acid renal scan. J Urol 2003; 170: Silva JM, Santos Diniz JS, Diniz JS, et al. Clinical course of 735 children and adolescents with primary vesicoureteral reflux. Pediatr Nephrol 2006; 21: This study looks at the complications of children diagnosed with primary VUR over a mean study period of 76 months.

5 256 Paediatric urology 28 Simoes E Silva AC, Silva JM, Diniz JS, et al. Risk of hypertension in primary vesicoureteral reflux. Pediatr Nephrol 2007; 22: Freedman AL. Urinary tract infection in children. Urologic Diseases in America Compendium. NKUD Information Clearinghouse; Benoit RM, Peele PB, Cannon GM Jr, Docimo SG. The cost-effectiveness of dextranomer/hyaluronic acid copolymer for the management of vesicoureteral reflux. 2: Reflux correction at the time of diagnosis as a substitute for traditional management. J Urol 2006; 176 (6 Pt 1): An excellent article that calculates the threshold success rate necessary to make endoscopic treatment a more cost-effective procedure compared with surgical and antibiotic prophylaxis. 31 Benoit RM, Peele PB, Docimo SG. The cost-effectiveness of dextranomer/ hyaluronic acid copolymer for the management of vesicoureteral reflux. 1: Substitution for surgical management. J Urol 2006; 176 (4 Pt 1): An excellent article that calculates the threshold success rate necessary to make endoscopic treatment a more cost-effective procedure compared with surgical and antibiotic prophylaxis. 32 Elder J, Diaz M, Caldamone AA, et al. Endoscopic therapy for vesicoureteral reflux: a meta-analysis. I: Reflux resolution and urinary tract infection. J Urol 2006; 175: This is a very useful metaanalysis that outlines the current state of endoscopic treatment. 33 Mevorach R, Hulbert WC, Rabinowitz R, et al. Results of a 2-year multicenter trial of endoscopic treatment of vesicoureteral reflux with syinthetic calcium hydroxyapatite. J Urol 2006; 175: Ramseyer P, Meagher-Villemure K, Burki M, Frey P. (Poly)acrylonitrile-based hydrogel as a therapeutic bulking agent in urology. Biomaterials 2007; 28: Eryildirim B, Tarhan F, Kuyumcuoglu U, et al. Endoscopic subureteral injection treatment with calcium hydroxylapatite in primary vesicoureteral reflux. Int Urol Nephrol 2006; 17 October [Epub ahead of print]. 36 Wald ER. Vesicoureteral reflux: the role of antibiotic prophylaxis. Pediatrics 2006; 117: Garin EH, Olavarria F, Garcia Nieto V, et al. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics 2006; 117: This is the first prospective randomized study to look at antibiotic prophylaxis versus surveillance and prompt treatment of recurrent UTI in patients with lowgrade VUR, and demonstrates that there is no significant difference between the two groups in terms of recurrence of UTI, APN, or development of renal scarring. 38 Reddy PP, Evans MT, Hughes PA, et al. Antimicrobial prophylaxis in children with vesico-ureteral reflux: a randomised prospective study of continuous therapy vs. intermittent therapy vs. surveillance. Proceedings of the American Academy of Pediatrics. Pediatr Suppl Williams GJ, Wei L, Lee A, Craig JC. Long-term antibiotics for preventing recurrent urinary tract infection in children. Cochrane Database Syst Rev 2006; (3):CD This is another metaanalysis that analyzes the role of low-dose antibiotic prophylaxis for children to prevent recurrent UTI.