Disordered phosphate metabolism, marked by elevated levels of the phosphate regulating hormone, fibroblast growth factor 23 (FGF23), is a novel risk factor for cardiovascular disease and mortality in the millions of patients suffering from chronic kidney disease (CKD). High dietary phosphate intake and presence of CKD are major stimuli for FGF23 secretion. In these settings, a progressive increase in FGF23 levels is an appropriate adaptation to maintain normal phosphate balance. However, studies from our team and others demonstrate that elevated FGF23 is a powerful, independent risk factor for more rapid CKD progression and mortality. As a potential mechanism of increased mortality, we recently demonstrated that elevated FGF23 contributes causally to the frequent development of left ventricular hypertrophy in CKD patients. These data suggest that elevated FGF23 may represent not only a potentially powerful risk-stratifying biomarker but also a novel therapeutic target to improve outcomes in CKD. The PI's overarching scientific career goal is to demonstrate by randomized trial that early delivery of interventions based on FGF23 testing, or specifically targeting elevated FGF23 levels, will slow progression of CKD, reduce cardiovascular disease events and improve survival. Justifying a large-scale clinical trial requires further knowledge of FGF23 biology, the mechanisms of its toxicity, validation of its impact on outcomes in epidemiological studies that analyze FGF23 repeatedly over time, and detailed patient-oriented research studies to characterize the efficacy of candidate interventions on reducing FGF23 levels.
In Aim 1 of this K24 application, we will perform a secondary analysis of the African American Study of Kidney Disease and Hypertension. We will test the association between FGF23 and cardiac structure and function as determined by echocardiography~ we will examine single and repeated measures of FGF23 as a novel risk factor for adverse renal and cardiovascular outcomes~ and we will use emerging tools to quantify the utility of FGF23 testing as a risk-stratifying biomarker in CKD.
In Aim 2, we will tes the effect of dietary phosphate restriction and phosphate binders alone and in combination as candidate interventions to lower FGF23 levels in CKD stage 3-4 patients. These studies will be excellent training vehicles for the PI's trainees and will be further enhanced by an ongoing parallel program in translational research that the PI will continue to cultivate as one of his career development activities during this award. Other career development activities include formal coursework in leadership and the implementation of a new educational initiative in the Division of Nephrology to attract additional fellows to patient-oriented research. The K24 will provide the PI with critically important protected time and dedicated resources to expand his mentorship activities, grow his own research program and further advance his career as a leader in patient-oriented research in nephrology.
This proposal will investigate whether elevated FGF23 is an independent risk factor for progression of chronic kidney disease and cardiovascular disease, and whether elevated FGF23 levels can be lowered with widely available interventions. If FGF23 is found to be an independent risk factor for adverse outcomes and FGF23 levels can be successfully lowered, the results would help justify a randomized trial that targets FGF23 and disordered phosphate metabolism in an effort to improve clinical outcomes.
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|Singh, Saurav; Grabner, Alexander; Yanucil, Christopher et al. (2016) Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int 90:985-996|
|Ali, Farah N; Josefson, Jami; Mendez, Armando J et al. (2016) Cord Blood Ferritin and Fibroblast Growth Factor-23 Levels in Neonates. J Clin Endocrinol Metab 101:1673-9|
|David, Valentin; Wolf, Myles (2016) Pruning the ricket thicket. J Clin Invest 126:473-6|
|GutiÃ©rrez, Orlando M; Parsa, Afshin; Isakova, Tamara et al. (2016) Genetic African Ancestry and Markers of Mineral Metabolism in CKD. Clin J Am Soc Nephrol 11:653-62|
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