Chronic kidney disease (CKD) is a debilitating health problem with a high rate of mortality. Early stages of CKD are characterized by elevated circulating levels of fibroblast growth factor 23 (FGF23), a key endocrine regulator of phosphate homeostasis and vitamin D metabolism. Elevated FGF23 is an independent risk factor for mortality in CKD patients and individuals with normal renal function but the underlying physiological mechanism for this is unclear. FGF23 is known to suppress renal synthesis of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) but its effects on other peripheral tissues have yet to be defined. In preliminary studies in vitro we have shown that FGF23 suppresses synthesis of 1,25(OH)2D by human monocytes, suggesting an entirely novel link between the endocrine and immune systems. We hypothesize that elevated levels of FGF23 in CKD patients act to suppress antibacterial innate immune responses by inhibiting the vitamin D-activation system in monocytes. Local synthesis of 1,25(OH)2D is known to stimulate production of antibacterial proteins such as cathelicidin (LL37), and this may be a pivotal mechanism by which humans respond to infection. Thus for CKD patients who are already vitamin D-insufficient, the exposure of immune cells to high levels of FGF23 will provide an additional impediment to adequate protection against infection. The proposed project will characterize the relationship between vitamin D and FGF23 as positive and negative regulators of human immunity. Planned experiments will determine whether the suppressive effects of FGF23 can be abrogated by active 1,25(OH)2D or its precursor 25-hydroxyvitamin D (25OHD). In this way the proposal will assess potential therapeutic strategies for maintaining optimal immune function in CKD patients. Further innovation in the project will be provided by the use of both peripheral blood and peritoneal monocytes. By using the latter we will aim to define the role of vitamin D as an activator of human antibacterial function at a tissue site where there is high risk of infection. Collectively these studies will seek to identify an entirely novel function for FGF23 at the interface between endocrine and immune function. In doing so, the project will help to shed light on a key mechanism that may explain the pathological impact of FGF23 in CKD and the unchanged high mortality rate in adult and pediatric dialysis patients.

Public Health Relevance

Serum levels of fibroblast growth factor 23 (FGF23) are an early marker of chronic kidney disease (CKD), and appear to be an independent risk factor for patient mortality. We hypothesize that high levels of FGF23 in CKD patients exert an adverse effect on human antimicrobial activity by inhibiting normal vitamin D function in cells from the immune system. This novel mechanism may provide new strategies for the prevention and/or treatment of infection associated with CKD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DK091672-01A1
Application #
8299287
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Kimmel, Paul
Project Start
2012-05-15
Project End
2014-04-30
Budget Start
2012-05-15
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$231,000
Indirect Cost
$81,000
Name
University of California Los Angeles
Department
Orthopedics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Bacchetta, Justine; Zaritsky, Joshua J; Sea, Jessica L et al. (2014) Suppression of iron-regulatory hepcidin by vitamin D. J Am Soc Nephrol 25:564-72