NIMBLE: Non-Invasive Markers of Bladder Deterioration

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Project Abstract Neurogenic bladder from congenital myelodysplasia (Spina Bifida) presents lifelong challenges in bladder management. Even with improved clinical management up to 50% of patients with SB are at increased risk for development of chronic kidney disease associated with urologic complications of neurogenic bladder. Bladder management for patients with neurogenic bladder comprises catheterization to promote emptying, medication to decrease intravesical pressures and inhibit detrusor overactivity, and regular monitoring of bladder function by urodynamics (UDS). If conservative therapy fails, patients may undergo surgical intervention to enhance capacity and reduce intravesical pressure to minimize upper tract damage. Regardless, controversy exists over the best management protocol for the neurogenic bladder. UDS is considered the gold standard for evaluation of lower urinary tract function and the impetus for intervention. However, UDS is invasive, expensive, subject to substantial inter-observer variability and not routinely available beyond tertiary care centers. The availability of a quantitative, non-invasive approach to signal bladder changes that serve as a harbinger of renal deterioration would advance clinical management of this patient population significantly. Notably, no such markers have been validated prospectively as independent markers of functional bladder deterioration. In preliminary studies, we have identified a panel of urine biomarkers enriched in urine from two models of neurogenic bladder (human and rodent), but not detected in kidney urine from human patients with ureteropelvic junction obstruction. This, together with their detection in bladder tissue from rats with neurogenic bladder strongly suggests that this unique panel reflects pathological bladder wall remodeling as opposed to renal damage. Based on these observations we hypothesize that our Non-Invasive Markers of Bladder Deterioration (NIMBLE) represent prognostic markers of deterioration in bladder function in neurogenic bladder patients. We believe that these markers may also serve as early predictors of upper tract damage in this population. We will test the hypothesis with the following aims: Aim 1. Determine the association between bladder-enriched urine biomarkers and functional parameters in a well characterized prospective cohort of children with neurogenic bladder. Aim 2. Investigate bladder-enriched urine biomarkers, their association with function and their response to treatment in a longitudinal cohort of children and rodents with neurogenic bladder. In each aim we will use mass spectrometry-based proteomics to quantify our unique panel in sample cohorts with neurogenic bladder, determine their association with functional UDS and their response to pharmacological intervention. We will also profile the remaining urinary proteome to refine the biomarker panel. At the end of the project we will know the extent to which our NIMBLE panel reflects functional deterioration of the neurogenic bladder and how it could be implemented clinically to improve management of SB patients.