Contribution of Urinary Phosphate to CKD Progression

University Of Kansas Medical Center, Kansas City KS

Investigators

Abstract

Project Summary/Abstract Chronic kidney disease (CKD) affects approximately 15% of the U.S. population and is a leading cause of morbidity and mortality due to an exceedingly high rate of cardiovascular, skeletal, hematologic, immune, and cognitive abnormalities that accompany this disorder. There are limited therapies available to slow CKD progression, underscoring the importance of research aimed at developing novel interventions for this condition. When kidney function is reduced urinary phosphate excretion increases to maintain normal serum phosphorus balance. This is driven by two phosphaturic hormones, fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH). Elevated levels of these hormones is associated with more rapid CKD progression. Additionally, mineral deposition is frequently observed in CKD kidneys, regardless of clinical context, and may be a stimulus for chronic inflammation that promotes CKD progression. We hypothesize that high concentrations of urinary phosphate contribute to CKD progression by promoting phosphate-based nanocrystal formation, tubular epithelial cell injury, and interstitial inflammation which could be prevented by reducing urinary phosphate excretion or enhancing urinary phosphate solubility. Studies in this proposal aim to define the role of phosphaturia in mechanisms of CKD progression. By analysis of a mouse model of chronic phosphaturia and human kidney biopsy samples, the following specific research aims will be accomplished: (1) define how chronic phosphaturia impacts CKD progression in mice, (2) determine if enhancing tubular phosphate solubility with phosphorylated ASARM peptides prevents CKD progression, and (3) define the prevalence of kidney mineral deposition in a cohort of human kidney allografts and determine clinical risk factors associated with increased mineral deposition. Data from these studies will provide details on the pathophysiology of chronic phosphaturia in CKD and support the development of future innovative therapies to slow CKD progression. These research aims will be completed within a comprehensive, five-year career development plan that is overseen by a robust, experienced mentorship team. This proposal includes training and didactics that will further develop the candidate’s knowledge of research techniques and biostatistics important for translating basic science findings to innovative clinical applications. The candidate is currently an assistant professor in the Division of Nephrology and Hypertension at the University of Kansas Medical Center (KUMC) and has 75% protected time for research, independent laboratory and office space, and regular interaction with a multidisciplinary, collaborative group of researchers in the Jared Grantham Kidney Institute at KUMC. Completion of this proposal will build on the candidate’s extensive research background and provide a strong foundation for the candidate’s long-term goal of establishing a successful, independent career aimed at developing novel therapies to slow CKD progression.