Glomerular diseases contribute significantly to the End Stage Kidney Disease burden in the United States. Although there are a number of specific therapies for glomerular diseases, and many more under development, several factors mitigate the effectiveness of these treatments. Most glomerular diseases need to be diagnosed by kidney biopsy, and the invasive nature of this procedure often causes it to be put off until the clinical signs of kidney injury are significant. This waiting period may result in accrual of chronc, irreversible damage that could have been prevented with earlier diagnosis and intervention. Furthermore, the therapies used for glomerular diseases often involve immunosuppressive drugs with their associated toxicities. Because native kidney biopsies are not done serially, these toxic therapies are monitored clinically. However, treatment efficacy could be improved if renal pathology was monitored in real time and used to titrate therapy. We therefore propose using combinations of novel urine and traditional clinical biomarkers (e.g. proteinuria) to derive composite biomarkers that accurately reflect kidney pathology. Unlike previous studies of urine biomarkers using a non-targeted total urine proteomics approach, or a candidate approach based on the literature, the individual urine biomarkers for this study will be informed by proteomic analysis of laser-captured microdissected glomeruli and tubulointerstitium collected from defined glomerular diseases and specific pathologic lesions important across a spectrum of glomerular diseases. Differentially-expressed tissue proteins will be considered candidate biomarkers. The presence of these candidate biomarkers in urine will be verified and then candidates present in the urine will be quantified. Combinations of the excreted candidate biomarkers and clinical data will be tested mathematically to determine the optimal composition of a biomarker for each type of glomerular disease or pathologic lesion. These composite biomarkers will be validated in independent urine samples collected prospectively from patients undergoing diagnostic kidney biopsy. It is expected that this work will result in a panel of composite biomarkers that can be used to non-invasively diagnose glomerular diseases and follow changes in kidney histology during therapy so as to improve management of glomerular diseases.
This work will develop a series of urine tests that can be used to understand what is going on in the kidneys of patients with glomerular diseases. These tests will provide information that currently can only be obtained by kidney biopsy. It is expected that these tests will provide a non-invasive way to diagnose glomerular diseases, and to follow changes in the kidney during treatment of glomerular diseases. Using these urine tests, treatments can be adjusted more precisely to an individual patient's response, and will lead to improved patient outcomes.
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