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The chronic kidney disease - Mineral bone disorder (CKD-MBD): Advances in pathophysiology.
Bone. 2017 Jul; 100:80-86.BONE

Abstract

The causes of excess cardiovascular mortality associated with chronic kidney disease (CKD) have been attributed in part to the CKD-mineral bone disorder syndrome (CKD-MBD), wherein, novel cardiovascular risk factors have been identified. New advances in the causes of the CKD-MBD are discussed in this review. They demonstrate that repair and disease processes in the kidneys release factors to the circulation that cause the systemic complications of CKD. The discovery of WNT inhibitors, especially Dickkopf 1 (Dkk1), produced during renal repair as participating in the pathogenesis of the vascular and skeletal components of the CKD-MBD implied that additional pathogenic factors are critical. This lead to the discovery that activin A is a second renal repair factor circulating in increased levels during CKD. Activin A derives from peritubular myofibroblasts of diseased kidneys, wherein it stimulates fibrosis, and decreases tubular klotho expression. Activin A binds to the type 2 activin A receptor, ActRIIA, which is variably affected by CKD in the vasculature. In diabetic/atherosclerotic aortas, specifically in vascular smooth muscle cells (VSMC), ActRIIA signaling is inhibited and contributes to CKD induced VSMC dedifferentiation, osteogenic transition and neointimal atherosclerotic calcification. In nondiabetic/nonatherosclerotic aortas, CKD increases VSMC ActRIIA signaling, and vascular fibroblast signaling causing the latter to undergo osteogenic transition and stimulate vascular calcification. In both vascular situations, a ligand trap for ActRIIA prevented vascular calcification. In the skeleton, activin A is responsible for CKD stimulation of osteoclastogenesis and bone remodeling increasing bone turnover. These studies demonstrate that circulating renal repair and injury factors are causal of the CKD-MBD and CKD associated cardiovascular disease.

Authors+Show Affiliations

Department of Pediatrics, Nephrology, Washington University Saint Louis, MO, United States; Departments of Medicine, Washington University Saint Louis, MO, United States; Department of Cell Biology, Washington University Saint Louis, MO, United States. Electronic address: hruska_k@kids.wustl.edu.Department of Pediatrics, Nephrology, Washington University Saint Louis, MO, United States.Department of Pediatrics, Nephrology, Washington University Saint Louis, MO, United States.Department of Pediatrics, Nephrology, Washington University Saint Louis, MO, United States.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

28119179

Citation

Hruska, Keith A., et al. "The Chronic Kidney Disease - Mineral Bone Disorder (CKD-MBD): Advances in Pathophysiology." Bone, vol. 100, 2017, pp. 80-86.
Hruska KA, Sugatani T, Agapova O, et al. The chronic kidney disease - Mineral bone disorder (CKD-MBD): Advances in pathophysiology. Bone. 2017;100:80-86.
Hruska, K. A., Sugatani, T., Agapova, O., & Fang, Y. (2017). The chronic kidney disease - Mineral bone disorder (CKD-MBD): Advances in pathophysiology. Bone, 100, 80-86. https://doi.org/10.1016/j.bone.2017.01.023
Hruska KA, et al. The Chronic Kidney Disease - Mineral Bone Disorder (CKD-MBD): Advances in Pathophysiology. Bone. 2017;100:80-86. PubMed PMID: 28119179.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The chronic kidney disease - Mineral bone disorder (CKD-MBD): Advances in pathophysiology. AU - Hruska,Keith A, AU - Sugatani,Toshifumi, AU - Agapova,Olga, AU - Fang,Yifu, Y1 - 2017/01/22/ PY - 2016/08/29/received PY - 2017/01/19/revised PY - 2017/01/20/accepted PY - 2017/1/26/pubmed PY - 2018/3/20/medline PY - 2017/1/26/entrez KW - Activin KW - CKD-MBD KW - Dickkhopf 1 KW - FGF23 KW - Klotho KW - Parathyroid hormone KW - Renal osteodystrophy KW - Vascular calcification SP - 80 EP - 86 JF - Bone JO - Bone VL - 100 N2 - The causes of excess cardiovascular mortality associated with chronic kidney disease (CKD) have been attributed in part to the CKD-mineral bone disorder syndrome (CKD-MBD), wherein, novel cardiovascular risk factors have been identified. New advances in the causes of the CKD-MBD are discussed in this review. They demonstrate that repair and disease processes in the kidneys release factors to the circulation that cause the systemic complications of CKD. The discovery of WNT inhibitors, especially Dickkopf 1 (Dkk1), produced during renal repair as participating in the pathogenesis of the vascular and skeletal components of the CKD-MBD implied that additional pathogenic factors are critical. This lead to the discovery that activin A is a second renal repair factor circulating in increased levels during CKD. Activin A derives from peritubular myofibroblasts of diseased kidneys, wherein it stimulates fibrosis, and decreases tubular klotho expression. Activin A binds to the type 2 activin A receptor, ActRIIA, which is variably affected by CKD in the vasculature. In diabetic/atherosclerotic aortas, specifically in vascular smooth muscle cells (VSMC), ActRIIA signaling is inhibited and contributes to CKD induced VSMC dedifferentiation, osteogenic transition and neointimal atherosclerotic calcification. In nondiabetic/nonatherosclerotic aortas, CKD increases VSMC ActRIIA signaling, and vascular fibroblast signaling causing the latter to undergo osteogenic transition and stimulate vascular calcification. In both vascular situations, a ligand trap for ActRIIA prevented vascular calcification. In the skeleton, activin A is responsible for CKD stimulation of osteoclastogenesis and bone remodeling increasing bone turnover. These studies demonstrate that circulating renal repair and injury factors are causal of the CKD-MBD and CKD associated cardiovascular disease. SN - 1873-2763 UR - https://www.unboundmedicine.com/medline/citation/28119179/The_chronic_kidney_disease___Mineral_bone_disorder__CKD_MBD_:_Advances_in_pathophysiology_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S8756-3282(17)30023-6 DB - PRIME DP - Unbound Medicine ER -