RNA markers of renal damage due to obstruction

Stanford University, Stanford CA

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Abstract

? DESCRIPTION (provided by applicant): Obstruction of the kidney is a common cause of renal failure in the adult and pediatric populations. However, obstruction causes renal damage in only a subset of patients while others show little or no functional compromise. Clinicians are often faced with a difficult decision on whether to intervene to address the obstruction or observe the patient. In many cases, such as in children born with congenital ureteropelvic junction obstruction, the decision to intervene is based on finding significant changes on imaging studies, which often are noted well after significant functional damage has occurred. In other cases, interventions are needlessly undertaken in patients with compromised renal function from other causes (such as renal drug toxicity) where the question of obstruction is raised based on minimal hydronephrosis on an imaging study, even though obstructive nephropathy is unlikely. Biomarkers of renal damage due to renal obstruction are needed to improve selection of patients for intervention to improve renal preservation while avoiding costly and potentially risky interventions. In this revised application, we hypothesize that RNA biomarkers of obstruction can be found by analyzing gene expression changes in the kidney and urine in mouse model systems of obstruction. Our preliminary data strongly suggest that these RNA expression changes can serve as urinary biomarkers of renal damage due to obstruction. To test this hypothesis we propose: 1) to measure gene expression changes in a mouse model of temporary complete obstruction in which short periods of obstruction cause no measurable renal compromise while longer periods of obstruction result in measurable renal compromise. 2) We will measure gene expression changes in a conditional knock-out model of the calcineurin ß1 gene which shows high grade bilateral ureteral obstruction in neonatal animals. 3) We will test urine samples from children without and without obstruction for expression of our candidate biomarkers and use these results to build a multiplex RNA expression assay for renal damage due to obstruction. These experiments will be a first step toward developing a biomarker panel of renal damage due to obstruction that can be used clinically.