Medical Professional Publications

When Does Vesicoureteral Reflux Lead to UTI?

Columbus, OH - September 2016

Approximately 30 percent of children with vesicoureteral reflux (VUR) develop a urinary tract infection (UTI). Those children may benefit from antibiotic prophylaxis. But to limit side effects and resistance, the other 70 percent should not be exposed to antibiotics they don’t need. So how can you tell which child will develop a UTI?

A recent study led by physician-researchers at Nationwide Children’s Hospital and Le Bonheur Children’s Hospital in Memphis has revealed that the number of copies of the gene DEFA1A3 – which encodes the antimicrobial peptide HNP1-3 – may play a role. Pediatric patients with both VUR and UTI are more likely to have a low number of copies than a control group; those same patients placed on antibiotics have a 47 percent reduced risk of recurrent UTI for every additional copy of the gene they have.

“We are looking for genetic risk factors so we can prospectively identify patients to treat aggressively,” says Andrew Schwaderer, MD, first author of the study and research director in the Section of Nephrology at Nationwide Children’s. “Identification of this gene’s role is a way to incorporate a genetic profile into patient screening.”

The study, published in the Journal of the American Society of Nephrology, used data from 298 children enrolled in the multicenter Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial. The trial divided children with a history of UTI and VUR into groups that were given daily antibiotic prophylaxis or a placebo for two years.

Real-time polymerase chain reaction was used to determine DEFA1A3 copy numbers in the RIVUR trial children and in a similar number of control children with no history of VUR and UTI. Five or fewer copies were considered low, and eight or more copies were considered high.

Approximately 29 percent of the VUR/UTI group had a low DEFA1A3 copy number, compared with 16 percent of the control group, while 18 percent of the VUR/UTI group had a high copy number, compared with 31 percent of the control group. Further analysis of the VUR/UTI group on antibiotics suggested that those with a high copy number had a reduced risk of UTI infection, and those with a low copy number had an increased risk of infection.

“We have identified a subset of patients with VUR that antibiotics could help,” says Dr. Schwaderer, who is also a principal investigator in the Center for Clinical and Translational Research at The Research Institute at Nationwide Children’s.

Other notable findings of the study include:

  • The HNP1-3 peptide, previously thought to be only a white blood cell protein, is expressed in the kidney as well
  • A higher copy number of DEFA1A3 is potentially tied to greater expression of the peptide

“Our long-term goal is to create a multigene panel that allows us to help screen patients who may develop UTI,” Dr. Schwaderer says. “We have several genes we are working on, but this is the first.”

Schwaderer AL, Wang H, Kim S, Kline JM, Liang D, Brophy PD, McHugh KM, Tseng GC, Saxena V, Barr-Beare E, Pierce KR, Shaikh N, Manak JR, Cohen DM, Becknell B, Spencer JD, Baker PB, Yu CY, Hains DS.  Polymorphisms in α-defensin-encoding DEFA1A3 associate with urinary tract infection risk in children with vesicoureteral reflux. Journal of the American Society of Nephrology. 2016 Mar 3. [Epub ahead of print] 

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