Renal obstruction, or ureteropelvic junction obstruction (UPJO), can result in loss of kidney function and abnormal renal maturation. Appropriate early surgical intervention may prevent renal damage. The clinical dilemma is identifying which children need intervention and when. Renal obstruction always results in hydronephrosis, or dilation of the kidney;however, hydronephrosis does not always indicate clinically significant obstruction. To further compound the quandary, up to 5% of all pregnancies have a diagnosis of prenatal hydronephrosis, in which 30% may be caused by UPJO. This considerably increases the number of children who may need screening after birth. Current diagnostics are constrained to imaging modalities that are invasive, expose the children to ionizing radiation, may require general anesthesia, and are limited by their subjective nature. Although excellent surgical treatment exists, there are (1) NO definitive clinical tests that determine who with hydronephrosis requires surgery;(2) NO established clinical guidelines for postnatal diagnostic testing or intervention;and (3) NO ability to determine who is at risk for future long-term renal damage. A more accurate non-invasive test to standardize clinical guidelines, diagnosis, and management is sorely needed. Using a mass spectrometry (MS) based method developed in our laboratory;we identified a candidate list of 76 potential urinary biomarkers of UPJO from over 1114 proteins identified in an unbiased quantitative discovery study of the obstructed urinary proteome. Interestingly, there was a particular subset of proteins (24) involved with oxidative stress that had dramatic quantitative fold differences in the urine. I addition, data generated from an additional cohort identified a potential role of urinary matrix metalloproteinases (MMP) as a clinical biomarker for UPJO. Our data suggests that there are specific urinary biomarkers that have the potential to determine which children with hydronephrosis require surgical intervention for UPJO. In this proposal we present the first rigorous early-validation trial of candidate urinary markers as diagnostic tools for UPJO. We hypothesize that the urinary proteome of children with UPJO contains clinically useful biomarkers of renal obstruction that will non-invasively determine which children should undergo surgical intervention versus observation. We will challenge this hypothesis with the following specific aims: 1) Identify the "best" panel of markers in noninvasively obtained urine from the bladder of UPJO patients using directed MS and MMP profiling. 2) Determine if the "best" panel of UPJO markers allows for stratification of patients with hydronephrosis in a longitudinal mixed disease cohort. These studies are specifically designed to pre-validate urinary biomarkers that have the potential to significantly alter and improve the clinical management of a very large population of children with hydronephrosis. The findings of these highly translational experiments may be the basis for a prospective clinical trial.

Public Health Relevance

Renal obstruction, or ureteropelvic junction obstruction (UPJO), can result in loss of kidney function and abnormal renal maturation, and is the most common cause of renal failure in children. Appropriate early surgical intervention may prevent renal damage. The clinical dilemma is identifying which children need intervention and when. Renal obstruction always results in hydronephrosis, or dilation of the kidney;however, hydronephrosis does not always indicate clinically significant obstruction. Although excellent surgical treatment exists, there are no definitive clinical tests that determine who with hydronephrosis requires surgery. Our data suggests that there are specific proteins in the urine that have the potential to determine which children with hydronephrosis require surgical intervention for UPJO. Our approach has evolved from discovery-based studies to directed validation. Our primary goal is to determine the best panel of markers in noninvasively obtained urine from the bladder that can identify which children with hydronephrosis require surgical intervention versus observation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK096238-01A1
Application #
8505708
Study Section
Special Emphasis Panel (UGPP)
Program Officer
Moxey-Mims, Marva M
Project Start
2013-07-01
Project End
2018-04-30
Budget Start
2013-07-01
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$262,500
Indirect Cost
$112,500
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115