An elevated level of the phosphate regulating hormone fibroblast growth factor 23 (FGF23) is an independent risk factor for cardiovascular disease (CVD) and mortality across the spectrum of chronic kidney disease (CKD). Elevated FGF23 contributes directly to the pathogenesis of left ventricular hypertrophy, suggesting one potential mechanism for the high risk of CVD and death that is attributable to elevated FGF23. Preliminary data that demonstrate that elevated FGF23 is a powerful risk factor for congestive heart failure confirms the clinical relevance of FGF23-mediated LVH. Thus, data generated during the first 4 years of support under this award established elevated FGF23 as a novel biomarker and mechanism of adverse outcomes in CKD, and thus, novel therapeutic target. Additional work from our group was also the first to suggest a survival benefit of active vitamin Dtherapy in ESRD. However, active vitamin D raises FGF23, which might be expected to accelerate mortality. Reconciling this potential paradox is a central theme of this application. Based on preliminary data, we hypothesize that vitamin D may attenuate cardiac toxicity of FGF23 despite raising FGF23 levels, and that CKD patients' variable FGF23 response to active vitamin D, ranging from minimal to large increases, modifies their CVD risk and survival experience.
In Aim 1, we will test the hypothesis that the magnitude of change in FGF23 in response to active vitamin D therapy modulates risk of mortality in a large prospective cohort of incident hemodialysis patients.
In Aim 2, we will analyze FGF23 in a secondary analysis of a recently completed randomized trial of active vitamin D versus placebo in CKD stage 3-4 patients to test the hypothesis that baseline and follow-up FGF23 levels modify the cardiac structural and functional response to active vitamin D therapy. Previous studies suggest that non-calcium based phosphate binders lower FGF23, but there have been no placebo-controlled studies >2 weeks duration, and no studies examined the impact of FGF23 reduction on intermediate measures of CVD risk in CKD stage 3-4 patients with normal serum phosphate. Furthermore, no studies investigated the utility of combining phosphate binders with active vitamin D to potentially maximize their dual benefits on mineral metabolism and CVD.
In Aim 3, we will conduct a one- year, placebo-controlled, 2 x 2 factorial, randomized study of CKD stage 3-4 patients to test the effects of active vitamin D and phosphate binders alone and in combination on FGF23, other mineral metabolites, and a comprehensive set of intermediate measures of CVD risk. Extensive preliminary data support our hypotheses, and our research team has the requisite expertise in FGF23, vitamin D, observational cohorts, and randomized studies with repeated measures to successfully complete these Aims. Renewed support will enable us to generate data that are critical for the rational design of larger trials in the futureand thereby support our long- term goal of translating FGF23 research into meaningful improvements in the management of CKD.

Public Health Relevance

A high circulating level of the phosphate regulating hormone fibroblast growth factor 23 (FGF23) is a strong risk factor for kidney failure; cardiovascular disease and death among patients with chronic kidney disease. Since FGF23 levels increase early in the course of chronic kidney disease; testing for FGF23 could be used to identify candidates for earlier treatment of abnormal phosphate metabolism than is the current standard practice. This application will investigate strategies to lower FGF23 levels and the effect these approaches have on the cardiovascular system and survival. Since chronic kidney disease affects 23 million adults in the US; identifying novel therapeutic strategies to prevent its complications could have a major public health impact.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK076116-07
Application #
8841986
Study Section
Special Emphasis Panel (ZDK1-GRB-N (O4))
Program Officer
Kusek, John W
Project Start
2013-09-07
Project End
2017-07-31
Budget Start
2013-09-07
Budget End
2014-07-31
Support Year
Fiscal Year
2013
Total Cost
$212,185
Indirect Cost
$62,185
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Scialla, Julia J; Xie, Huiliang; Rahman, Mahboob et al. (2014) Fibroblast growth factor-23 and cardiovascular events in CKD. J Am Soc Nephrol 25:349-60
Scialla, Julia J; Wolf, Myles (2014) Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease. Nat Rev Nephrol 10:268-78
Leaf, David E; Waikar, Sushrut S; Wolf, Myles et al. (2013) Dysregulated mineral metabolism in patients with acute kidney injury and risk of adverse outcomes. Clin Endocrinol (Oxf) 79:491-8
Leaf, David E; Wolf, Myles (2013) A physiologic-based approach to the evaluation of a patient with hyperphosphatemia. Am J Kidney Dis 61:330-6
Scialla, Julia J; Astor, Brad C; Isakova, Tamara et al. (2013) Mineral metabolites and CKD progression in African Americans. J Am Soc Nephrol 24:125-35
Isakova, T; Xie, H; Messinger, S et al. (2013) Inhibitors of mTOR and risks of allograft failure and mortality in kidney transplantation. Am J Transplant 13:100-10
Smith, Kelsey; deFilippi, Christopher; Isakova, Tamara et al. (2013) Fibroblast growth factor 23, high-sensitivity cardiac troponin, and left ventricular hypertrophy in CKD. Am J Kidney Dis 61:67-73
Cortazar, F; Molnar, M Z; Isakova, T et al. (2012) Clinical outcomes in kidney transplant recipients receiving long-term therapy with inhibitors of the mammalian target of rapamycin. Am J Transplant 12:379-87
Gutierrez, Orlando M; Smith, Kelsey T; Barchi-Chung, Allison et al. (2012) (1-34) Parathyroid hormone infusion acutely lowers fibroblast growth factor 23 concentrations in adult volunteers. Clin J Am Soc Nephrol 7:139-45

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