Chronic kidney disease (CKD) is a public health epidemic that increases risks of end-stage renal disease (ESRD), cardiovascular disease (CVD) and death. Existing therapies for CKD improve outcomes only modestly. Therapeutic strategies that target novel CKD-specific mechanisms of CVD and CKD progression are desperately needed to improve health. Disordered mineral metabolism is a nearly universal complication of CKD, regardless of its underlying etiology. An elevated level of fibroblast growth factor 23 (FGF23) is the earliest manifestation of disordered mineral metabolism in CKD. FGF23 rises in response to high phosphate diets and in states of impaired phosphate excretion, such as CKD. Rising FGF23 in CKD maintains normal serum phosphate, but also inhibits renal calcitriol production, which causes secondary hyperparathyroidism, and reduces klotho expression, which accelerates arterial calcification. Elevated FGF23 powerfully predicts ESRD, CVD events and death, and data from our group, validated by new preliminary data, suggest potential underlying pathogenic mechanisms: FGF23 induces left ventricular hypertrophy and accelerates CKD progression, and phosphate excess and klotho deficiency induce arterial calcification independent of FGF23. Based on these data, FGF23 excess and disordered mineral metabolism are leading candidates to target in an outcomes trial. Our long-term goal is to prove by randomized trial that treatment of FGF23 excess and disordered mineral metabolism with phosphate binders, dietary phosphate manipulation, and active vitamin D, will reduce risks of ESRD, CVD events and death in CKD stages 3-4. In this Clinical Center application, we propose two pilot studies to fill remaining knowledge gaps that will inform the design of an outcomes trial. In Pilot Study 1, we will conduct a 6-month, randomized, 3 x 2 study of 150 CKD stage 3-4 patients of lanthanum versus sevelamer versus. placebo, alone and combined with dietary phosphate manipulation to compare their effects on FGF23, phosphate and other mineral metabolites. The results will define which binder should be advanced to an outcomes trial, and whether it should be accompanied by a dietary intervention. In Pilot Study 2, we will conduct a 12-month, randomized, 2 x 2 study of the """"""""winning"""""""" phosphate binder + diet arm in Pilot Study 1 versus placebo, and calcitriol vs. placebo in 220 CKD stage 3-4 patients to test the hypothesis that combining active therapies will synergistically improve surrogate markers of CVD and renal risk. A decade of work in the field and extensive preliminary data support our hypotheses. Our team has the requisite clinical research expertise in FGF23 and vitamin D to complete these studies. The University of Miami has a track record of recruiting minority participants in multi-center trials, which is critical in diseases that disproportionately affect minorities, such as CKD. Backed by a strong institutional environment energized by a new CTSA award, our participation in the U01 Consortium will enrich the diversity of study populations it recruits and allow us to contribute to the collaborative effort aimed at improving dismal clinical outcomes suffered by millions of patients with CKD.

Public Health Relevance

A high circulating level of fibroblast growth factor 23 (FGF23) is the earliest manifestation of disordered bone and mineral metabolism in chronic kidney disease, and it is a powerful risk factor for kidney failure, cardiovascular disease and death. The current application will investigate strategies to lower FGF23 levels in pilot studies of patients with chronic kidney disease. The results will inform the design of a future larger trial o test whether these strategies can improve patients'clinical outcomes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-N (M6))
Program Officer
Flessner, Michael Francis
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
United States
Zip Code
Jovanovich, Anna; Isakova, Tamara; Block, Geoffrey et al. (2018) Deoxycholic Acid, a Metabolite of Circulating Bile Acids, and Coronary Artery Vascular Calcification in CKD. Am J Kidney Dis 71:27-34
Haji-Valizadeh, Hassan; Rahsepar, Amir A; Collins, Jeremy D et al. (2018) Validation of highly accelerated real-time cardiac cine MRI with radial k-space sampling and compressed sensing in patients at 1.5T and 3T. Magn Reson Med 79:2745-2751
Prasad, Pottumarthi V; Li, Wei; Raj, Dominic S et al. (2018) Multicenter Study Evaluating Intrarenal Oxygenation and Fibrosis Using Magnetic Resonance Imaging in Individuals With Advanced CKD. Kidney Int Rep 3:1467-1472
Munoz Mendoza, Jair; Isakova, Tamara; Cai, Xuan et al. (2017) Inflammation and elevated levels of fibroblast growth factor 23 are independent risk factors for death in chronic kidney disease. Kidney Int 91:711-719
Middleton, John P; Wolf, Myles (2017) Second Chances to Improve ESRD Outcomes With a Second-Generation Calcimimetic. JAMA 317:139-141
Batacchi, Zona; Robinson-Cohen, Cassianne; Hoofnagle, Andrew N et al. (2017) Effects of Vitamin D2 Supplementation on Vitamin D3 Metabolism in Health and CKD. Clin J Am Soc Nephrol 12:1498-1506
Gutiérrez, 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
Lash, James P; Ricardo, Ana C; Roy, Jason et al. (2016) Race/Ethnicity and Cardiovascular Outcomes in Adults With CKD: Findings From the CRIC (Chronic Renal Insufficiency Cohort) and Hispanic CRIC Studies. Am J Kidney Dis 68:545-553
Mehta, Rupal; Cai, Xuan; Lee, Jungwha et al. (2016) Association of Fibroblast Growth Factor 23 With Atrial Fibrillation in Chronic Kidney Disease, From the Chronic Renal Insufficiency Cohort Study. JAMA Cardiol 1:548-56
Souma, Nao; Isakova, Tamara; Lipiszko, David et al. (2016) Fibroblast Growth Factor 23 and Cause-Specific Mortality in the General Population: The Northern Manhattan Study. J Clin Endocrinol Metab 101:3779-3786

Showing the most recent 10 out of 18 publications