Recent advances in the pathophysiology of chronic kidney disease (CKD) and its complications have called attention to the relationship between hyperphosphatemia, vascular calcification and excess mortality of CKD. A recent discovery demonstrates that skeletal apposition of hydroxyapatite plays an important role in the levels of serum phosphate in CKD. This concept has emerged from studies that further define the role of the kidney as an endocrine organ interacting in the function of different tissues. Two new pathophysiologic principles have emerged from these recent studies that will be tested in this application. The first new principle is that chronic renal injury directly impairs skeletal anabolism. The second is that renal osteodystrophy and vascular calcification are directly linked in part by hyperphosphatemia. Until now, renal osteodystrophy was thought to result from secondary hyperparathyroidism produced by hypocalcemia due to hyperphosphatemia and calcitriol deficiency. Recently, however, when abnormalities of calcium, phosphorus parathyroid hormone and calcitriol were avoided in CKD, the disease has been shown to be associated with an adynamic bone disorder. The hypothesis deriving from this observation that will be tested by studies in this application is that CKD impairs skeletal anabolism, and that this occurs before abnormalities in divalent ion metabolism and even participates in their production. Studies in the first aim are designed to further establish this principle and determine the pathophysiologic mechanism of anabolic loss in the skeleton associated with CKD. A therapeutic agent in development for CKD, bone morphogenic protein-7 (BMP-7), is an effectivetreatment for renal osteodystrophy and vascular calcification. The mechanisms of action of this agent are sought in this application which should provide new insights and new therapeutic targets for treatment and prevention of CKD and its complications. Recent studies have discovered a significant reduction of bone formation in an animal model of the metabolic syndrome (insulin resistance, obesity, hypertension and dyslipidemia). When ablative CKD was produced in these animals, the skeletal outcome was the adynamic bone disorder despite the presence of secondary hyperparathyroidism. Since CKD also stimulated vascular calcification in this model, these studies raise the hypothesis that renal osteodystrophy and vascular calcification are directly linked. Studies in the second specific aim test the hypothesis that reductions in the serum phosphorus produced by increasing bone formation result in reduced vascular calcification.
The specific aims of the application are: 1, Determine the mechanisms of the loss of skeletal anabolism induced by CKD and the metabolic syndrome;2, Demonstrate the mechanisms of BMP-7actions in the vascular calcification produced by chronic kidney disease;3, Demonstrate the interactions between high fat diets and Wnt signaling on one hand, and Wnt signaling and BMP-7 on the other in the vascular smooth muscle stimulated by CKD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK070790-05
Application #
7741219
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Kimmel, Paul
Project Start
2005-12-23
Project End
2011-06-30
Budget Start
2009-12-01
Budget End
2011-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$293,547
Indirect Cost
Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Hruska, Keith A; Lanske, Beate; Moe, Orson W (2017) Crosstalk between kidney and bone - Bench to bedside. Bone 100:1-3
Sugatani, Toshifumi; Agapova, Olga A; Fang, Yifu et al. (2017) Ligand trap of the activin receptor type IIA inhibits osteoclast stimulation of bone remodeling in diabetic mice with chronic kidney disease. Kidney Int 91:86-95
Hruska, Keith A; Sugatani, Toshifumi; Agapova, Olga et al. (2017) The chronic kidney disease - Mineral bone disorder (CKD-MBD): Advances in pathophysiology. Bone 100:80-86
Agapova, Olga A; Fang, Yifu; Sugatani, Toshifumi et al. (2016) Ligand trap for the activin type IIA receptor protects against vascular disease and renal fibrosis in mice with chronic kidney disease. Kidney Int 89:1231-43
Seifert, Michael E; Hruska, Keith A (2016) The Kidney-Vascular-Bone Axis in the Chronic Kidney Disease-Mineral Bone Disorder. Transplantation 100:497-505
Seifert, Michael E; Ashoor, Isa F; Chiang, Myra L et al. (2016) Fibroblast growth factor-23 and chronic allograft injury in pediatric renal transplant recipients: a Midwest Pediatric Nephrology Consortium study. Pediatr Transplant 20:378-87
Sugatani, Toshifumi; Agapova, Olga; Malluche, Hartmut H et al. (2015) SIRT6 deficiency culminates in low-turnover osteopenia. Bone 81:168-77
Freedman, Barry I; Divers, Jasmin; Russell, Gregory B et al. (2015) Plasma FGF23 and Calcified Atherosclerotic Plaque in African Americans with Type 2 Diabetes Mellitus. Am J Nephrol 42:391-401
Hruska, Keith A; Seifert, Michael; Sugatani, Toshifumi (2015) Pathophysiology of the chronic kidney disease-mineral bone disorder. Curr Opin Nephrol Hypertens 24:303-9
Anyaegbu, Elizabeth I; Shaw, Andrey S; Hruska, Keith A et al. (2015) Clinical phenotype of APOL1 nephropathy in young relatives of patients with end-stage renal disease. Pediatr Nephrol 30:983-9

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