Prophylaxis Versus No Prophylaxis for Reflux

Opposing Views

Prophylaxis Versus No Prophylaxis for Reflux PROPHYLAXIS THE primary goal in the treatment of children with vesicoureteral reflux (VUR) is to prevent urinary tract infection (UTI), pyelonephritis (APN) and renal damage (RD). Continuous antibiotic prophylaxis (CAP) has been the cornerstone of VUR treatment since its initial success was documented in the mid 1970s. Those studies, although not Level 1 evidence, documented a significant decrease in pyelonephritis and renal scarring risk with CAP compared to intermittent antibiotic treatment for acute urinary infection. CAP was the primary initial treatment recommended in the 1997 AUA guideline for grades 1 to 4 VUR which spontaneously resolved, with surgery recommended initially only for grade 5 reflux.1 Thus, medical therapy with CAP prevented surgical intervention in the majority of children. In 2006 Garin et al published the results of a randomized controlled trial (RCT) of patients with APN with and without VUR in which CAP was compared to no treatment in both groups.2 At 1-year followup CAP was not effective in preventing UTIs or renal scarring in either group. Several more RCTs in 2008 had variable results and recommendations on the use of CAP in patients with reflux but a number of confounding factors were present in these studies. None of the trials was blinded. Patient age ranged from birth to 18 years and most included children with only grades 1 to 3 VUR. Bowel/bladder dysfunction (BBD) was not assessed. All of these trials were performed outside of the United States and bagged urine specimens for uncircumcised infants were used to diagnose UTIs. Compliance with taking the antibiotic was assessed in only 2 studies. These methodological flaws tended to misclassify the diagnosis of UTI, diluting the therapeutic effect of CAP and biasing the result to the null hypothesis that CAP was ineffective. However, perhaps the most important criticism was that the numbers of patients enrolled in all of these trials were underpowered to detect even a large difference in recurrent UTIs between the CAP and non-treated groups. These concerns raised questions personal to me about the conclusions regarding the effectiveness of CAP. None of these studies showed evidence con0022-5347/12/1874-1161/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION

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vincing enough to discontinue the use of CAP in all patients with reflux. I continue to rely on my own practice experience of 25 years during which I have been favorably impressed with CAP. More recent clinical trials of CAP have had more favorable results with prevention of UTIs. Craig et al reported a statistically significant difference in the rate of UTI recurrence in 576 children randomized to receive CAP or placebo in the PRIVENT trial.3 Of the patients 42% had VUR and 71% had an initial UTI. The overall decrease in UTIs after 1 year was 6% in the CAP group with recurrence rates of 19% in the placebo arm and 13% in the CAP arm. One has to determine for themselves whether a 6% difference is clinically important. For a young infant or child who had a previous severe APN episode requiring hospitalization, the family and treating physician may choose this option. The Swedish Reflux studies have provided more specific information on the use of CAP in patients with grades 3 to 4 VUR.4 In this RCT surveillance was compared to CAP and endoscopic treatment. Antibiotic prophylaxis significantly decreased the recurrent febrile UTI rates in girls compared to surveillance. In addition, new renal damage due to infection was 3 times greater in the surveillance group than the prophylaxis group. The Swedish study affirms the benefits of CAP in girls 1 to 4 years old with grades 3 to 4 VUR. As we prepared the 2010 AUA guideline for the treatment of VUR, we intentionally delayed the process to include these studies in our analysis and recommendations as they are the best evidencebased studies to date. In the new guideline CAP is not universally recommended for all children with reflux as its efficacy could not be established based on current data.5 Analysis of risk factors for renal damage and recurrent UTIs should guide our use of CAP. The meta-analysis identified increased frequency of UTIs, reflux grade and the presence of BBD as unique risk factors for renal scarring. Risk factors for recurrent UTIs have included gender, circumcision status, age less than 6 months at first UTI, white race and reflux grades 3 to 5. Other studies have identified infrequent voiding, poor fluid Vol. 187, 1161-1163, April 2012 Printed in U.S.A. DOI:10.1016/j.juro.2012.01.023

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OPPOSING VIEWS

intake, stool retention, inadequate genital hygiene, dysfunctional voiding and bladder instability to be associated with recurrent UTI. With these risk factors in mind, use of CAP is recommended in the 2010 AUA guideline for children 1) younger than age 1 year with a history of febrile UTI, 2) younger than age 1 year with grades 3 to 5 VUR identified via screening, 3) with BBD and 4) not receiving CAP in whom a febrile UTI develops. Observation without CAP is an option in children 1) younger than age 1 year with grades 1 to 2 VUR diagnosed via screening and 2) older than 1 year with VUR and no BBD.5 It is clear that times have changed and so has the use of CAP. Issues of antibiotic resistance and medication compliance are real and enter our risk assessment. However, I am not yet convinced of the ineffectiveness of CAP in children with reflux. The RIVUR (Randomized Intervention for Children with Vesicoureteral Reflux) study is a carefully designed trial that avoids many of the pitfalls of the aforementioned trials. It is double-blinded, placebo controlled, medication compliance assessed, with strictly defined UTIs in children 2 months to 6 years old with grades 1 to 4 VUR. BBD is assessed and the primary outcome measure is UTI recurrence. The RIVUR study was statistically designed to answer the “effectiveness” question of CAP in children with VUR. We anxiously await its results but in the meantime we need to assess each child with VUR and ask if the risk of UTI is low enough to rationalize not using CAP. Steven J. Skoog Division of Pediatric Urology Oregon Health Sciences University Portland, Oregon

NO PROPHYLAXIS “It ain’t what you don’t know that gets you into trouble. It’s what you know for sure that just ain’t so.” —Mark Twain “The desire to take medicines is perhaps the feature that distinguishes man from animals.” —William Osler

Notwithstanding prior practice and cherished beliefs, recent publications, specifically the AUA guideline for VUR5 and the AAP Guideline for UTI,6 have highlighted the lack of evidence supporting the use of continuous antibiotic prophylaxis in the treatment of infants and children with VUR. This represents a sea change in our thought on UTI and VUR. To be sure, the goal of reducing renal damage in patients with VUR by preventing pyelonephritis is worthy but the last decade has seen a paradigm shift

in understanding the relationships among VUR, renal damage and urinary tract infection. Previously VUR was diagnosed in children subjected to cystography to evaluate the occurrence of UTI. Concurrent renal damage was attributed to the damaging effects of renal involvement with infection. In studies of fetally diagnosed hydronephrosis in patients evaluated before the occurrence of UTI, those with VUR have dysplasia, and the higher the VUR grade, the greater the likelihood of congenital damage. In longitudinal population studies, while many children with renal failure have VUR, no child with end stage renal failure will initially have normal kidneys and then experience progression to renal failure due to the ravages of recurring pyelonephritis.7 It is undeniably true that clinical circumstances and kidney infections can result in renal damage, which is perhaps most commonly seen when VUR is associated with BBD. While it is our task to protect patients from experiencing this new renal damage, such scarring may not be of much clinical importance.8 However, it still seems reasonable to decrease renal scarring by whatever means possible. We need to ask if CAP is effective in reducing the occurrence of new renal scars in children with VUR and UTI. As an aside, it is worth noting that physician recommendation for CAP does not necessarily mean that the patient will actually receive the medication as prescribed. Numerous studies on parental compliance suggest that perhaps as few as 40% of patients get the medicine 80% of the time. More to the point, in the meta-analysis performed by the AUA reflux guideline committee 17.1 new scars per 100 children with VUR given CAP were found. Is this a good standard? As most believe that prompt adequate treatment minimizes scar development, could management without CAP be worse? Accepting this uncertainty, the committee had no standard or even recommendation regarding CAP in a 4-yearold child without BBD. It is interesting to note that the meta-analysis in this scenario clearly showed that while the rate of UTI was no different in patients with VUR on or off CAP, the rate of febrile UTI was more than twice as high in patients on CAP. Our own review of 196 patients past the age of toilet training with reflux revealed that UTIs occurred most often in patients with a history of UTI while taking CAP.9 The rate of new renal scars in patients off CAP was less than 4% in the 3-year followup period. The AUA guideline recommends CAP for patients younger than 1 year with higher grades of VUR and a history of UTI.5 This recommendation has neither the rigor nor importance of a standard. The AAP guideline notes that “several studies suggest that CAP is ineffective in preventing pyelonephritis” for

OPPOSING VIEWS

children younger than 2 years with or without VUR. Given that the AUA found 17% of infants on CAP to have UTI, one wonders about the effectiveness of CAP. Additionally it is hard to argue for CAP in those infants with high grade reflux who are most likely males with a low risk of UTI by virtue of gender and circumcised status. For those older patients with BBD and VUR, the AUA guideline recommends CAP because of the obvious causality of BBD with UTI. The report notes an occurrence of UTI in 44% of patients with BBD and VUR on CAP. While the recommendation is for CAP, again one can ponder if not providing CAP could be any worse. Regardless of the well described public health effects of antibiotic overuse, the elephant in the room is that UTIs do occur in patients on CAP with or without BBD, and the infecting organisms are predictably resistant to the most commonly used antibiotics, thereby complicating therapy. While Osler described a human need to take medicine, most parents believe that daily antibiotic use for however long a period is not sensible for children with VUR. Scientific publications, the popular press and the Internet provide even the most casually interested

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parent with a plethora of cautions regarding the hazards of antibiotics. The most important standard in the AUA guideline describes our obligation to discuss the issues with parents, thereby empowering them to choose the management option that seems most reasonable from an informed perspective. Our mandate is to avoid new renal scars by recognizing and treating the risk factors for infection. Some notable reports notwithstanding, the AUA and AAP argue strongly that prompt treatment of UTI can go a long way to lessen the risk of renal damage with or without CAP. In a perfect world we could relate with certainty to parents the optimal management protocol for children with VUR. However, it is not a perfect world, and the best available evidence suggests that avoidance of CAP is reasonable and not likely to result in worse outcomes than for those patients with VUR maintained on low doses of daily antibiotics for long periods. George Steinhardt Department of Urology, Wayne State University Helen DeVos Children’s Hospital Grand Rapids, Michigan

REFERENCES 1. Elder JS, Peters CA, Arant BS et al: Report on the management of primary vesicoureteral reflux in children. Baltimore: American Urological Association, Inc. 1997. 2. Garin EH, Olavarria F, Nieto VG et al: Clinical significance of primary vesicoureteral reflux and urinary tract prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics 2006; 117: 626. 3. Craig JC, Simpson JM, Williams GJ et al: Antibiotic prophylaxis and recurrent urinary tract infection in children. N Engl J Med. 2009; 361: 1748.

4. Brandstrom P, Esbjorner E, Herthelius M et al: The Swedish Reflux Trial in children: III. Urinary tract infection pattern. J Urol 2010; 184: 286. 5. Peters CA, Skoog SJ, Arant BS et al: Summary of the AUA guideline on management of primary vesicoureteral reflux in children. J Urol 2010; 184: 1134. 6. Subcommittee on Urinary Tract Infection: Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011; 128: 595.

7. Ardissino G, Avolio L, Dacco V et al: Long-term outcome of vesicoureteral reflux associated chronic renal failure in children. Data from the Italkid Project. J Urol 2004; 172: 305. 8. 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: 195. 9. Thompson R, Chen J, Pugach J et al: Cessation of prophylactic antibiotics for managing persistent vesicoureteral reflux. J Urol 2001; 166: 1465.