Autosomal dominant polycystic kidney disease (ADPKD) is the most common life threatening hereditary disorder. Although progressive cyst enlargement leads to end-stage renal disease in 50 percent of affected individuals by the fifth decade, cardiovascular disease is the leading cause of death in ADPKD. Left ventricular hypertrophy is an important manifestation of cardiovascular disease in ADPKD with an incidence that is twice as high in ADPKD compared with essential hypertension. Understanding modifiable mechanisms of the high rates of left ventricular hypertrophy, cardiovascular events and mortality in ADPKD is essential to designing novel therapeutic strategies to improve clinical outcomes. An elevated level of the phosphate regulating hormone, fibroblast growth factor 23 (FGF23), is an independent risk factor for progression of chronic kidney disease (CKD), cardiovascular disease, and death, and published data by our group suggest a causal role for FGF23 in the pathogenesis of left ventricular hypertrophy. Although one study of ADPKD patients suggested that FGF23 levels are increased early in the course of disease, the mechanisms underlying FGF23 elevation in ADPKD are unknown. Furthermore, there are no data on FGF23 as a risk factor for left ventricular hypertrophy, CKD progression and clinical outcomes in ADPKD, and how these relationships differ versus other causes of CKD. In the first aim, we will determine whether FGF23 levels increase earlier and more markedly in adults and children with ADPKD compared with other etiologies of CKD or healthy subjects. We will compare FGF23 and other mineral metabolites from ~1000 adults with ADPKD in the HALT-PKD trial and 107 children with ADPKD in the statin-PKD trial with comparable data from non-ADPKD cohorts, including the Chronic Kidney Disease in Children (CKiD) and the Chronic Renal Insufficiency Cohort (CRIC) studies that are frequency matched by race and estimated glomerular filtration rate. In the second aim, we will perform the first ever bone biopsy study dedicated to ADPKD to investigate the regulation of FGF23 production by bone. We will assess standard bone histomorphometry and use novel translational techniques of bone research to precisely study subtle bone microarchitecture (using ?CT), total bone phosphate content (using Raman spectroscopy), and expression of FGF23 and DMP1, which is a critical molecular regulator of FGF23 in bone. In the third aim, we will examine FGF23 as a novel risk factor for kidney cyst enlargement, progression of CKD, left ventricular hypertrophy, and cardiovascular disease events. Extensive preliminary data support our hypotheses and our research team has the requisite expertise in clinical research, FGF23, analysis of bone biopsy data, and ADPKD to successfully complete these aims. By using data from 4 ongoing NIDDK- supported studies, we will efficiently characterize FGF23 in ADPKD in an effort to guide the design of novel interventions to improve outcomes in ADPKD.

Public Health Relevance

Autosomal dominant polycystic kidney disease is the most common life-threatening hereditary disease. Despite emerging evidence that abnormalities of the fibroblast growth factor 23-phosphate axis are related to an increased incidence of cardiovascular disease and progression of renal disease in subjects with chronic kidney disease, similar studies in ADPKD are lacking. Hence, we propose to investigate the role of the fibroblast growth factor 23 on progression of kidney and cardiovascular disease in children and adults with ADPKD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK094796-02
Application #
8541851
Study Section
Special Emphasis Panel (ZDK1-GRB-N (O4))
Program Officer
Flessner, Michael Francis
Project Start
2012-09-30
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$454,586
Indirect Cost
$84,547
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Wolf, Myles; White, Kenneth E (2014) Coupling fibroblast growth factor 23 production and cleavage: iron deficiency, rickets, and kidney disease. Curr Opin Nephrol Hypertens 23:411-9
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
Jablonski, Kristen L; Chonchol, Michel (2013) Vascular calcification in end-stage renal disease. Hemodial Int 17 Suppl 1:S17-21
Tang, Jie; Mettler, Pam; McFann, Kim et al. (2013) The association of prevalent kidney stone disease with mortality in US adults: the National Health and Nutrition Examination Survey III, 1988-1994. Am J Nephrol 37:501-6
Tang, Jie; Chonchol, Michel B (2013) Vitamin D and kidney stone disease. Curr Opin Nephrol Hypertens 22:383-9