This study will be discussed as part of the online, twitter-based Nephrology Journal Club on July 22,2014. More information about the workings of #NephJC can be found here.
The Problem of Reflux
Vesicoureteroreflux (VUR) occurs in approximately 10% of children overall, but about one-third of those with a febrile or otherwise symptomatic urinary tract infection (UTI). VUR is associated with an increased risk of renal "scars." Since it was first described in the 1960's, treatment of this backflow of urine from the bladder to the ureter has been recommended for all affected children. Surgery can create a competent valve at the vesicoureteral junction during voiding, but an early randomized trial showed that prophylactic antibiotics to prevent infection were just as effective as surgery in the scarring outcome.
Despite the recommendations for treatment for 50 years, permanent kidney failure attributed to VUR has not declined in the end-stage database of any country. Improved prenatal diagnosis of infant renal anomalies have allowed us to diagnose VUR in the first weeks of life, prior to any UTIs. Some children without UTIs still get renal scarring, leading some to suspect that "scars" may actually be areas of hypoplasia or other abnormal development due to an abnormal ureteric bud.
The original study showed equivalent results from surgery and antibiotic prophylaxis, but it included no untreated control group to assess the strategy of intermittent treatment of UTIs when they occurred. The Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial set out to determine if long-term prophylaxis prevented recurrence of UTIs, occurrence of "scars," or contributed to antimicrobial resistance.
The study was a randomized, double-blind, placebo-controlled trial of prophylaxis with trimethoprim-sulfamethoxazole (TMPS). Children were screened and enrolled after 1 or 2 febrile or otherwise symptomatic UTIs, including positive culture. Bagged urine samples were not allowed. Children in the study ranged in age from 2 months to 6 years and had grades I to IV VUR (severe grade V patients were excluded). Exclusion criteria included other urinary abnormalties, chronic kidney disease, inability to take TMPS, and other selected medical issues.
Studies included dimercaptosuccinic acid (DMSA) scans at baseline and 1 and 2 years later. These scans (the gold standard for kidney scars) were read and scored centrally by two pediatric nuclear medicine radiologists.
Treatment failure was defined as:
- 2 febrile UTIs
- 1 febrile and 3 symptomatic UTIs
- 4 symptomatic UTIs
- New or worsening "scars" at 1 year
Baseline characteristics of the children enrolled can be seen here. No significant differences on any parameter existed between the treatment and control groups. Time to first febrile or symptomatic UTI after trial enrollment is shown below:
As shown in the paper’s figure 2 above, the two groups separated significantly within the first 6 months of treatment, with TMPS prophylaxis clearly preventing UTIs. By the end of 2 years, approximately one quarter of the placebo group had experienced an infection, while only half that many in the prophylaxis group had fallen ill.
A number of potential modifying factors were assessed for impact on the results, shown in the figure below:
As shown prophylaxis was more valuable for children who presented with febrile, as opposed to symptomatic but afebrile, UTI. Bowel and bladder dysfunction, determined via a standardized survey, also favored the use of TMPS.
Renal “scars” showed no difference throughout the study. Rectal swabs showed no significant difference in the rate of resistance of E. coli to TMPS between the prophylaxis and control groups.
Clearly antibiotic prophylaxis reduces the risk of recurrence of UTIs in children with VUR. However, about 75% of children receiving placebo had not suffered a recurrence after 2 years of study. UTIs cause discomfort, school absence, and lost work for parents; even after this trial we have no evidence of long-term damage prevention through the use of TMPS. Antibiotic resistance does not seem to be a big problem in this patient population.
So the question remains: what should we do about VUR?
In my mind, the question is still open. Many families today have qualms about long-term exposure to these medications. Other families dread missing a UTI and would far prefer to take the antibiotic. The tolerance of the family for illness vs the small risks of prophylaxis often prove to be a big factor driving therapy.
That leaves us each a lot of flexibility in our approach to VUR. My personal preference is to watch most cases without prophylaxis initially. Those who have further UTIs in the first few months after diagnosis are encouraged to start prophylaxis and consider surgical treatment. Those without significant recurrences receive follow-up on a regular basis. All of this requires ongoing discussion with the parents and input regarding their tolerance for urinary symptoms.
The pediatric nephrology community hoped that RIVUR would answer our managment questions about VUR. It would appear that we still have more we need to know.