VANCOUVER, British Columbia — A new study of children with vesicoureteral reflux (VUR) indicates that antibiotic prophylaxis can reduce the incidence of future urinary tract infections (UTIs) by about half. However, the study did not show a reduction in renal scarring, and left some in doubt as to the overall value of voiding cystourethrography (VCUG) to diagnose VUR because the procedure is painful, costly, and involves radiation exposure.

Renal scarring was a secondary end point, and the study — called the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial — might not have been well enough powered to find it, according to lead author Alejandro Hoberman, MD, chief of the division of general academic pediatrics at Children's Hospital of Pittsburgh. Physicians were also warned to keep an eye out for UTIs, so early detection could have prevented scarring that might otherwise have occurred. "We don't know what would have happened if we followed them for 10 years," Dr. Hoberman said.

VCUG identifies VUR in 30% to 40% of children who undergo the procedure after a UTI. VUR makes children more prone to additional UTIs, which can, in turn, lead to renal scarring, although scarring can also occur in children without VUR.

In 2011, after a series of studies suggested that prophylactic antibiotics are ineffective in preventing additional UTIs in subjects with VUR, the American Academy of Pediatrics (AAP) issued a recommendation that children not routinely undergo VCUG after a first UTI. Instead, the guidance suggested waiting until a second UTI before considering a VCUG unless renal and bladder ultrasonography leads to suspicion of high-grade VUR, obstructive uropathy, or unusual clinical concerns.

However, the studies that informed the recommendation were flawed, according to Dr. Hoberman, who presented the new research here at the Pediatric Academic Societies and Asian Society for Pediatric Research Joint Meeting. The study was simultaneously published online in the New England Journal of Medicine.

"The original studies compared surgery to correct VUR with antimicrobial prophylaxis, and they left us with the unknown of what would happen if we did nothing. There were no controls, so we didn't know if surgery or antimicrobial prophylaxis were effective," he told Medscape Medical News. Other more recent trials were generally unblinded and gave mixed results.

The prospective multisite randomized trial involved 558 girls and 49 boys with primary VUR who were 2 to 71 months of age (median, 12 months).

Participants from 19 pediatric sites in the United States with grades I to IV VUR were recruited after a first or second febrile or symptomatic UTI. The children were followed for up to 2 years.

Prophylaxis with trimethoprim 3 mg plus sulfamethoxazole 15 mg/kg body weight was compared with placebo.

Baseline sonography and VCUG were obtained within 16 weeks of the index UTI, and dimercaptosuccinic acid (DMSA) renal scans were obtained within 2 weeks of randomization and within 16 weeks of the index UTI. VCUG was conducted again at 2 years, and DMSA scans were conducted at 1 and 2 years. Masked experts used standard methods and definitions to determine febrile or symptomatic UTI and renal scarring.

The UTI was febrile and symptomatic in 325 children, febrile only in 196 children, and symptomatic only in 86. Cortical defects were present in 15% of cases, and 56% (71 of 126) of the toilet-trained children had bladder and bowel dysfunction.

Of the participants, 111 had 171 UTI recurrences during the trial, and 80 (72.1%) were febrile. Subjects who received prophylaxis had a 50% reduction in risk, compared with those in the placebo group (hazard ratio, 0.50; 95% confidence interval, 0.34 - 0.74).

To prevent 1 case of febrile or symptomatic UTI, 8 children would have had to be treated for 2 years.

Secondary End Point

A secondary end point of the trial was the effect of prophylactic treatment on renal scarring.

Baseline scans were obtained within 31 days of the index infection for 98 of 582 (16.8%) children, and 31 to 112 days after the index infection for 484 (83.2%).

Renal scarring was evident on scanning for 21 (3.6%) children, and acute pyelonephritis was evident for 71 (12.2%).

Outcome scans showed no significant difference between the prophylaxis and placebo groups in renal scarring (11.9% vs 10.2%; P = .55), severe renal scars (4.0% vs 2.6%; P = .37), or new renal scars since baseline (8.2% vs 8.4%; P = .94).

 
It was a gargantuan effort to do a study like this, and it's very informative. Dr. Stephen Downs
 

The study drew heated discussion from the audience, particularly on whether the results should prompt a re-evaluation of the AAP guidelines. Dr. Hoberman said he believes it should, but others weren't so sure, citing the lack of difference in renal scarring between the 2 groups.

"I was disappointed that this study didn't show that prophylaxis prevents scarring, which is the real reason to put kids through VCUG," said Stephen Downs, MD, director of children's health services research at Indiana University in Indianapolis.

"It was a gargantuan effort to do a study like this, and it's very informative. We'll see what happens. It all has to shake out a little bit," Dr. Downs told Medscape Medical News.

It was noted by some in attendance that the AAP recommendations don't discourage VCUG altogether, but suggest a watch-and-wait approach after the first UTI and consideration of the procedure if a second UTI occurs.

Dr. Hoberman explained that he doesn't recommend VCUG after every initial UTI; it depends on patient characteristics like family history, sex, race, the presence of bladder dysfunction, and how problematic a recurrence might be. "The findings of our study may make us rethink automatically waiting for the second UTI," he said.

Dr. Hoberman and Dr. Downs have disclosed no relevant financial relationships.

Pediatric Academic Societies (PAS) and Asian Society for Pediatric Research (ASPR) Joint Meeting: Abstract 28239. Presented May 4, 2014.

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