On the fifth floor of Nationwide Children’s Hospital Outpatient Care Center, Dr. Andy Schwaderer enters an exam room to greet a mother and her 4-month-old son. The boy is the second child Dr. Schwaderer has seen today referred to the Nephrology clinic to be evaluated for vesicoureteral reflux, the backflow of urine from the bladder up to the kidney.
Although Dr. Schwaderer will obtain a detailed patient history, perform a physical exam, listen and take detailed notes as mother describes symptoms, doctors do not know which management strategy is best for this child. Some children with this condition will have multiple urinary tract infections, which may scar the kidneys and cause permanent kidney damage. In some cases these children are given a daily antibiotic to prevent urinary tract infections while in others they are watched closely and only given antibiotics if a urinary tract infection occurs. Despite being common among children, science has yet to determine who will develop a urinary tract infection or a kidney infection.
“Kidney problems are the most common anomaly identified by prenatal ultrasound,” said Dr. Schwaderer. “One to 2 percent of all children develop vesicoureteral reflux postnatally. That’s pretty prevalent in terms of the pediatric disease world.”
Dr. Schwaderer says the primary risk factor for long-term problems in kidney conditions like vesicoureteral reflux is infections. “Children who get repeat urinary tract infections are the ones most likely to have chronic kidney disease and need dialysis or kidney transplant,” said Dr. Schwaderer. “Only one out of 15 kids who have vesicoureteral reflux is going to have recurrent infection. Still, we provide all 15 children with the same treatment. We don’t know which patients are going to have problems and which ones won’t.”
Yet Dr. Schwaderer’s research partnership with physician scientist Dr. David Hains may one day put an end to this clinical challenge. By studying genetic samples from children with reflux, Drs. Schwaderer and Hains are investigating why children get urinary tract infections. It’s an approach they say, surprisingly, no one else is taking.
“The most common prenatal kidney anomaly is called hydronephrosis, which is widening of the tubes that drain the kidneys,” said Dr. Schwaderer. “The most common reason for hydronephrosis is vesicoureteral reflux."
“Most children who have reflux don’t have any problems,” said Dr. Hains. “However, those with reflux who have recurrent urinary tract infections may develop kidney scaring. On the other hand, kids who don’t have reflux, but who develop recurrent urinary tract infections often get kidney scarring and have the same problems that kids with reflux get. And, kids who have their reflux surgically repaired still get urinary tract infections. So reflux might not mean anything at all.”
Dr. Hains and Schwaderer’s theory is that the important question is not whether or not kids have reflux; rather, who is at risk for developing urinary tract infections.
“This may be surprising, but scientists really haven’t asked why kids get infections,” said Dr. Schwaderer. “They have asked why they get reflux. Part of the reason we started focusing on why kids get urinary tract infections is because others aren’t studying it.”
Funded by the National Institutes of Health, Drs. Schwaderer and Hains have linked in to the national, multi-center RIVUR (Randomized Intervention for Children with Vesicoureteral Reflux) study. The RIVUR study involves 600 children with reflux who have had at least one urinary tract infection. The children are separated into two groups: those who have been on antibiotics and those who have not. This two-year study will investigate whether being on an antibiotic makes a difference in infection rate in children with reflux. Using these groups, Drs. Schwaderer and Hains are performing an ancillary study to examine each child’s entire genome in search of genes that might cause reflux and factors that cause infections. So far, Drs. Schwaderer and Hains are the only scientists who have been granted access to the RIVUR DNA repository.
They have already identified 10 candidate genes in the kidney and urinary tract that may prevent infections from developing in the bladder and subsequently in the kidney. With a current focus on the genes RNase7 and DEFA5, Drs. Schwaderer and Hains are working to define what these genes do and how they can be manipulated.
“The genetic work is important because we may one day be able to use genetic screening to identify children at risk for infections,” said Dr. Hains. “And if we can identify genes and their proteins that are key for keeping the urine sterile and preventing infections, we might be able to replace these proteins to fight bacteria, instead of using antibiotics.”
Their genetic work could extend beyond children with reflux, as Drs. Schwaderer and Hains have started a search for candidate genes among other populations who often develop urinary tract infections, including pregnant women and premature infants. Still, they think their studies will gain their greatest momentum when the RIVUR study is completed in 2013, and they can combine their DNA studies with clinical data to look closely at which children developed additional infections or kidney scarring. “We will be answering questions no one has really posed before,” said Dr. Hains.
Spencer JD, Schwaderer AL, Dirosario JD, McHugh KM, McGillivary G, Justice SS, Carpenter AR, Baker PB, Harder J, Hains DS. Ribonuclease 7 is a potent antimicrobial peptide within the human urinary tract. Kidney Int. 2011 Jul;80(2):174-80.
Spencer JD, Schwaderer AL, McHugh K, Vanderbrink B, Becknell B, Hains DS. The demographics and costs of inpatient vesicoureteral reflux management in the USA Pediatr Nephrol. 2011 Nov;26(11): 1995-2001.