2014 Top Stories in Urology: Pediatric Urology
The ongoing and challenging question as to the most appropriate management of urinary tract infections (UTI) and vesicoureteral reflux (VUR) in children was aided greatly with the publication of the results of the NIH-sponsored RIVUR (Randomized Intervention for Vesicoureteral Reflux in Children) study in May 2014.1 This study addressed the question of the efficacy of prophylactic antibiotics in the prevention of recurrent UTI in children with vesicoureteral reflux.
As the largest study of VUR ever published, RIVUR demonstrated that continuous antibiotic prophylaxis (CAP) can reduce the recurrence rate of UTI by 50% with minimal side effects.
RIVUR was a multicenter, prospective, randomized, double-blinded, intention-to-treat study of CAP in children from 1 month to 6 years initially diagnosed with VUR after one or two UTIs.2 Children received the prophylactic antibiotic trimethoprim sulfamethoxazole or placebo and were followed for 2 years. Over 600 children were randomized to the study, and the two groups were very equivalent. The primary endpoint was the incidence of recurrent febrile UTI or multiple symptomatic UTIs. Secondary endpoints included new renal scarring, development of resistant organisms, and side effects of CAP. Renal scarring was assessed using DMSA scanning at enrollment and at 1 year and 2 years of the study. Family compliance with medication was assessed. Bladder dysfunction was assessed, but patients were not stratified for this. Medication compliance was very good, with >75% reporting every day or nearly every day administration. Completion rates were quite high, although 24% of patients did not complete the 2-year DMSA scan.
In the placebo-treated group, recurrent UTIs defined by very stringent criteria occurred in 24% of children, while in those on prophylaxis the rate was 13% (relative risk, 0.55). Children who presented with initial febrile UTIs and those with evidence of bladder and bowel dysfunction had even greater risk reductions with prophylaxis. The baseline rate of renal scarring was low at 3.6%, and new scarring occurred in 8% in both groups.
What does RIVUR tell us about caring for children with VUR?
While CAP has been the mainstay of expectant management of children with VUR, it has recently been challenged for efficacy. Several studies have not been able to demonstrate efficacy in prevention of UTI recurrence. However, RIVUR, with larger numbers, stricter diagnostic criteria, and appropriate power, clearly shows a benefit with CAP. This indicates that, in children with VUR, CAP can prevent UTIs. It does not mean that all children with VUR need CAP or that CAP will prevent all UTIs in children with VUR. The subgroups of children with abnormal bladder function and those who initially presented with a febrile UTI have a more robust benefit when on CAP. This is consistent with other developing knowledge that we need to risk-stratify patients with VUR to identify those who will benefit from treatment vs those who will not.3,4
Results from RIVUR demonstrated that there are few, if any, significant clinical risks associated with CAP. While there is a higher rate of resistant organisms in breakthrough UTIs in those on active medication, that is to be expected, and this did not lead to any greater difficulty in therapy, nor were there non-urological infectious complications. This too is consistent with other reports.5 While resistance to antibiotics is a serious problem, it does not seem that use of continuous low-dose prophylaxis is a major contributor to that risk.
Finally, RIVUR should tell us that looking for VUR in children with a first-time febrile UTI might still be of value, in contrast to the recommendations and re-affirmation of the AAP Guidelines Panel on pediatric UTI.6 Their conclusion was that a VCUG is not necessary after a first febrile UTI in the setting of a normal ultrasound in children under 2 years. This was based on several smaller studies in which no benefit was detected using CAP in children with VUR. If treatment is not beneficial, the rationale for making a diagnosis is weak. RIVUR should be seen as providing clear evidence of the value of detection and treatment in children with a first febrile UTI.
What does RIVUR not tell us about caring for children with VUR?
RIVUR could not answer all the important questions related to VUR treatment in children. It does not precisely tell us which patients will benefit from CAP, although it gives us the clues related to bladder dysfunction and initial presentation with a febrile infection. Further refinement will require clinical judgment and a careful dialogue with parents to define the appropriate pathway for an individual child.
RIVUR does not tell us whether CAP can reduce the risk of renal scarring from breakthrough UTI in children with VUR. RIVUR was not intended to assess this question and was not powered to do so. The baseline rate of renal injury was very low, and the rate of new scar formation in both arms was quite low. This is in marked contrast to the Swedish Reflux Trial, where nearly 80% of children had some renal abnormality at baseline.7,8 In that study, prophylaxis was beneficial in reducing new scars in girls. The overall spectrum of children with VUR in the RIVUR study is one of relatively low risk, again different from that studied in the recent Swedish Reflux Trial as well as the older IRS study. This may reflect subtle biases among investigators in the RIVUR trial to avoid patients with higher grades of VUR. It cannot be stated that CAP does not reduce renal injury, only that we do not know if it reduces renal injury. Further study is needed and can be more precisely refined using the RIVUR observations.
Finally, RIVUR does not tell us what might happen to children with VUR (whether diagnosed or not) who are not treated with CAP. It must be kept in mind tha,t in the study, families were contacted frequently and follow-up was very close. Patients had ready access to evaluation and care, and the parents were all aware of the reflux in their child. This creates a different clinical context than what might exist if the VUR diagnosis had never been sought, and the clinical outcomes may be very different in that different context.
RIVUR is an important clinical study of an important clinical question that remains incompletely defined. It does provide clear evidence for the value of CAP in children with VUR. It helps define a subset of children—those with bladder dysfunction and an initial presentation with febrile UTI—who are likely to benefit more from CAP. It does not tell us whether CAP can reduce renal scarring; that will need to be studied in the future using the new knowledge gained from RIVUR.
Additional Info
- Hoberman A, Greenfield SP, RIVUR Trial Investigators. Antimicrobial prophylaxis for children with vesicoureteral reflux. N Engl J Med. 2014;370(25):2367-2376.
- Chesney RW, Carpenter MA, Moxey-Mims M, et al. Randomized intervention for Children With Vesicoureteral Reflux (RIVUR): background commentary of RIVUR investigators. Pediatrics. 2008;122 Suppl 5: S233-S239.
- Tekgül S, Riedmiller H, Hoebeke P, et al. EAU guidelines on vesicoureteral reflux in children. Eur Urol. 212;62(3):534-542.
- Peters CA, Skoog SJ, Arant BS JR, et al. Summary of the AUA guideline on management of primary vesicoureteral reflux in children. J Urol. 2010;184(3):1134-1144.
- Craig JC, Simpson JM, Williams GJ, et al. Antibiotic prophylaxis and recurrent urinary tract infection in children. N Engl J Med. 2009;361(18):1748-1759.
- Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management, Roberts KB. 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(3):595-610.
- Brandström P, Esbjörner E, Herthelius M, et al. The Swedish reflux trial in children: I. Study design and study population characteristics. J Urol. 2010;184(1):274-279.
- Brandström P, Nevéus T, Sixt R,et al. The Swedish reflux trial in children: IV. Renal damage. J Urol. 2010;184(1):292-297.
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