Determining Ureteropelvic Junction Obstruction Surgical Success Using Biomarkers

A follow-up study of a trial that initially identified four biomarkers that differ between healthy controls and pediatric patients about to undergo surgery for ureteropelvic junction obstruction (UPJO) has confirmed that two of these biomarkers may also be useful in determining whether the obstruction has successfully resolved post-surgery.

The study, published in the Journal of Pediatric Urology, found that levels of beta defensin 1 (BD-1) and hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP)—both of which were significantly elevated pre-surgery compared to healthy control patients—significantly decreased after successful UPJO surgery, with BD-1 returning to normal, healthy control levels.

“Diagnosis of obstruction currently relies exclusively on the use of radiologic studies, which can take their toll on families because they’re often invasive and time-consuming, and they can be ambiguous in many cases of UPJO,” says Brian Becknell, MD, PhD, a pediatric nephrologist and principal investigator in the Center for Clinical and Translational Research at Nationwide Children’s Hospital. “It would be nice to have urine biomarkers we could serially monitor and measure noninvasively over time to determine which patients might need surgery and which can be monitored on a conservative, nonoperative basis.”

The clinician-scientists behind the research examined follow-up urine samples at least 6 months after surgery (to allow time for complete surgery-related healing) for 13 of the original study’s 30 patients. All had successful resolution of their obstruction after surgery, as demonstrated via improved radiologic imaging and symptom resolution.

Their work is the first to demonstrate that HIP/PAP and BD-1 may offer clinicians not only a noninvasive and non-imaging-based method of detecting ureteral obstruction but also of monitoring its resolution post-surgery.

“We now need to show how these biomarkers behave in a larger group of patients,” says Christina Ching, MD, a pediatric urologist and physician-scientist at Nationwide Children’s. “In addition, while this study was the first step in demonstrating the potential of these markers in evaluating for resolution of obstruction, it was actually a drawback of this study that all patients had a successful outcome from surgery. We need to follow some patients who do not respond to surgery to determine if biomarkers follow a different trajectory in that situation.”

Two biomarkers that were elevated in those undergoing surgery compared to healthy controls, cathelicidin (LL-37) and neutrophil gelatinase-associated lipocalin (NGAL), did not consistently decrease following successful surgery in this study. These findings could simply be a result of the relatively small sample size studies but also could indicate ongoing renal damage as a result of the original obstruction, according to the team.  Further study is required.

“What we’re looking for in pediatric urologic biomarkers is a way to discriminate in populations that otherwise are very difficult to tease apart based on current evaluation tools,” says Dr. Ching, senior author on the publication. “Biomarkers have the potential to more finely tune our approach so we can better counsel patients and offer treatment options individualized to them.”

To learn more about a wide range of obstruction-related biomarkers, the team will use a recently awarded R01 grant (Brian Becknell, lead investigator) to prospectively follow about 300 young children with UPJO, with the hope of correlating serial urine findings with radiologic imaging and kidney function testing as needed.

“It’s very novel and valuable to develop biomarkers in the space of benign urologic disorders,” says Dr. Becknell. “Having biomarkers that are correlated with imaging and function tests could help clinicians monitor patients much less invasively and more cost-effectively, especially for common ailments in pediatrics, like bladder dysfunction, urinary tract obstruction or vesicoureteral reflux.”

The team is also evaluating a number of biomarkers in end-stage renal disease, bladder outlet obstruction and urinary tract infections. They hope their work will eventually reveal who requires intervention and which patients are at risk for a deleterious outcome. Their ideal scenario would be to identify a window of therapeutic opportunity for the most at-risk patients, so that action can be taken prior to a decrease in kidney function.

References

1. Gupta S, Jackson AR, DaJusta DG, McLeod DJ, Alpert SA, Jayanthi VR, McHugh K, Schwaderer AR, Becknell B, Ching CB. Urinary antimicrobial peptides: Potential novel biomarkers of obstructive uropathy. Journal of Pediatric Urology. 2018 Jun;14(3):238.e1-238.e6.
2. Gupta S, Nicassio L, Junquera GY, Jackson AR , Fuchs M, McLeod D, Alpert S, Jayanthi VR, DaJusta D, McHugh KM, Becknell B, Ching CB. Impact of successful pediatric ureteropelvic junction obstruction surgery on urinary HIP/PAP and BD-1 levels. Journal of Pediatric Urology. 2020;S1477-5131(20)30059-0. [published online ahead of print, 2020 Mar 29]

Image credits: Nationwide Children’s