Reflux nephropathy (RN) is a syndrome of renal scarring associated with primary vesico-ureteral reflux (VUR). Primary VUR is known to exhibit autosomal dominant inheritance. However, the genetic defect of primary VUR and its molecular pathogenesis are not well understood. The current diagnosis of VUR and RN involves radiologic tests which are invasive and costly. Therefore VUR screening in siblings and offspring and RN screening in patients with primary VUR are not routinely practised. Early detection of VUR is valuable for the prevention of RN since the incidence of scarring can be reduced effectively by antiobiotic prophylaxis. The long-term goals of this proposal are to develop less-invasive tests for early diagnosis and monitoring of VUR and RN as well as to develop therapeutic strategies based on a better understanding of the molecular pathogenesis. The hypothesis is that characteristic gene and protein expression patterns exist in ureteric tissue as well as in urine of patients with primary VUR and RN. Custom-spotted cDNA microarrays will be used to study differential gone expression. Surface-enhanced laser desorption/ionization time-of-flight mass spectroscopy coupled with tandem mass spectroscopy will be used to study differential protein expression. This latter method is however limited to molecules smaller than 70 kD. For larger molecules, two-dimensional gel electrophoresis will be employed. Ureteric tissue from patients with primary VUR will be compared with those from patients with secondary VUR and normal controls from renal transplant donors. Urine samples from patients with primary and secondary VUR with and without RN will be compared with age- and gender-matched normal children. State-of-the-art bioinformatics methodologies will be used for data analysis. Confounding variables, including age, gender and presence of glomerular proteinuria will be considered. Identification of specific urinary biomarkers in patients with VUR and RN may lead to further understanding of the molecular pathogenesis, as well as the development of less-invasive screening tests for primary VUR and RN. A clinical database of primary VUR and RN will be set up to establish correlations between biomarkers and phenotype and to test the sensitivity and specificity of these markers for detecting primary VUR and RN.
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