Genetic factors

Published On 08/08/2014

Researchers look for innate immunity to guide urinary tract infections treatment

Lizzie Work was 6 weeks old when she contracted her first urinary tract infection (UTI). Then came another, and another – every six to eight weeks.

“She would not eat and had a super high fever,” said her mom, Wendi. “It’s constant worry. We don’t sleep through the night. It’s really hard to watch.”

Lizzie’s diagnosis: vesicoureteral reflux, a condition where urine backflows from the bladder to the upper urinary tract, allowing bacteria to enter the bladder and kidney. Testing later showed scarring and hydronephrosis in her left kidney.

Vesicoureteral reflux is present in a third of children who have had a urinary tract infection. Of those children, one in 15 will have recurrent UTIs, which can lead to kidney scarring, permanent damage and even the need for dialysis.

Le Bonheur Nephrologist David Hains, MD, is trying to learn why kids like Lizzie get repeat infections while other kids with reflux can go through childhood without infection. His theory: genetic factors, especially those in the urinary tract, are game changers for some patients. By understanding genetic makeup, treatment can be tailored for each child.

RIVUR study: Antibiotics reduce UTIs for kids with reflux

In May, the RIVUR study published its primary outcome paper in the New England Journal of Medicine, showing that long-term antimicrobial prophylaxis can significantly reduce the risk of recurrent urinary tract infections in children with vesicoureteral reflux. The two-year, 19-site study enrolled more than 600 children with vesicoureteral reflex.

Le Bonheur Children’s Nephrologist Russell Chesney, MD, serves as chairman of the RIVUR study steering committee and was a co-author of the recent article. The study was funded by the National Institutes of Health.

“We hope these findings will help inform physicians – and parents – on the best ways to treat children with reflux who develop urinary tract infections, depending their grade of reflux,” said Chesney. “We also think this may lead to more debate about the need for imaging studies in children with reflux.”

Finding answers in the genetic code

To find answers, Hains has established the first genetic ancillary study to the national RIVUR (Randomized Intervention for Children with Vesicoureteral Reflux) trial. The RIVUR trial includes 600 children with reflux who have had at least one urinary tract infection. Half have been given prophylactic antibiotics; half have not.

“We are studying the entire genetic code of children with reflux to determine the genetic causes of developing multiple infections,” Hains said. “We are looking for genes that are clearly important in our innate immune system for kids with reflux. We hope it will help us better understand what makes some children with reflux more or less susceptible to infection.”

In the newly formed Innate Immunity Translational Research Center at Le Bonheur’s Children’s Foundation Research Institute, Hains and his lab members study antimicrobial peptides within the urinary tract, specifically those that occur in multiple copies.

These peptides are natural antibiotics, so if someone has a genetic predisposition to making fewer of these peptides, perhaps bacteria gain an advantage and cause urinary tract infections, he believes. Children with higher copies, he suspects, have higher immunity to infection.

With access to the RIVUR study’s clinical data, he is now using results from RIVUR to validate potential genetic candidates that may play a role in providing immunity from UTIs.

Eventually, Hains hopes discoveries in his lab will help scientists better understand the role genes play in disease, and help physicians cater treatment for children with reflux. Knowing if a child is prone to UTIs – based on his or her genetic makeup – can ensure treatment is specific to his or her needs and antibiotics aren't overused.

Today, Lizzie, now 7, continues to take prophylactic antibiotics to avoid additional UTIs. She hasn’t had an infection in more than 15 months and is relatively healthy. Both kidneys are working, though one has lost a “good deal of function,” Wendi said.

“If we had known prenatally that Lizzie would develop the number of UTIs that she did, I think we might have gone ahead and pushed for earlier intervention,” said Wendi. “The recurring infections are so miserable, especially when they are so tiny.”