There is a current ongoing pandemic of chronic kidney disease (CKD). CKD is associated with high mortality rates related to cardiovascular complications associated with kidney disease. The nature of the cardiovascular risk in CKD is incompletely understood, but CKD stimulated vascular calcification and vascular stiffness are important components. Observational studies suggest that the serum phosphate is associated with mortality risk in CKD, and that the association is due to the relationship between hyperphosphatemia and vascular calcification. Recent studies have suggested that the serum phosphorus is associated with cardiovascular risk in the general population, and the role of Pi as a cardiovascular risk factor has been supported by our discovery of putative mechanisms of action in traslational studies. Hyperphosphatemia, in part deriving from the skeleton, stimulates osteoblastic transition of cell in atherosclerotic plaques leading to vascular calcification. In CK hyperphosphatemia stimulated the expression of a second osteoblast specific transcription factor, osterix in the atherosclerotic aorta, and increased vascular calcification. These studies were the first to suggest that the skeleton participated in vascular calcification in CKD. An important complication of CKD linked to vascular calcification and cardiovascular risk is the adynamic bone disorder. New pathophysiology linking kidney disease to the adynamic bone disorder will be pursued in this application. Recent studies demonstrate that CKD causes reactivation and release to the circulation of skeletal inhibitory factors. This concept will be pursued in the application. The long-range objective of this application is to pursue treatment of chronic kidney disease complications through attacking the mechanisms of pathophysiology. The central hypothesis of the application is that kidney disease directly inhibits skeletal functio causing the CKD-MBD, and that the CKD-MBD is a critical factor in the cardiovascular complications of CKD.
The specific aims of the application are to: 1) Determine the mechanisms of skeletal inhibition produced by CKD: The hypothesis of aim one is that kidney disease directly inhibits skeletal function by producing circulating factors that decrease bone formation. 2) Determine the mechanisms by which the CKD-MBD causes cardiovascular risk in CKD. The hypotheses of aim two are that the skeletal remodeling disorder produced by CKD causes stimulation of cardiovascular complications associated with kidney diseases, and that interventions, which normalize skeletal remodeling in CKD but have no direct vascular efficacy actions, will diminish the cardiovascular disease associated with kidney failure.

Public Health Relevance

The studies proposed in this application prove that kidney disease releases substances into the bloodstream that migrate to the skeleton where they inhibit bone formation. The second set of studies show how decreasing bone formation increases calcium deposits in blood vessels causing them to become stiff.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK089137-02
Application #
8507216
Study Section
Special Emphasis Panel (ZRG1-MOSS-D (02))
Program Officer
Kimmel, Paul
Project Start
2012-08-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$319,030
Indirect Cost
$109,142
Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Fang, Yifu; Ginsberg, Charles; Seifert, Michael et al. (2014) CKD-induced wingless/integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder. J Am Soc Nephrol 25:1760-73
Fang, Yifu; Ginsberg, Charles; Sugatani, Toshifumi et al. (2014) Early chronic kidney disease-mineral bone disorder stimulates vascular calcification. Kidney Int 85:142-50
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Seifert, Michael E; de las Fuentes, Lisa; Rothstein, Marcos et al. (2013) Effects of phosphate binder therapy on vascular stiffness in early-stage chronic kidney disease. Am J Nephrol 38:158-67