title: The chronic kidney disease - Mineral bone disorder (CKD-MBD): Advances in pathophysiology.
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.affiliation: 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.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Hruska
authors.affiliation: Department of Pediatrics, Nephrology, Washington University Saint Louis, MO, United States.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Sugatani
authors.affiliation: Department of Pediatrics, Nephrology, Washington University Saint Louis, MO, United States.
authors.forename: Olga
authors.initials: O
authors.lastname: Agapova
authors.affiliation: Department of Pediatrics, Nephrology, Washington University Saint Louis, MO, United States.
authors.forename: Yifu
authors.initials: Y
authors.lastname: Fang
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism*; D012080:Chronic Kidney Disease-Mineral and Bone Disorder; D000089703:Fibroblast Growth Factor-23; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors
chemical_list: C000717427:FGF23 protein, human; D010281:Parathyroid Hormone; D000089703:Fibroblast Growth Factor-23
keywords: Activin; CKD-MBD; Dickkhopf 1; FGF23; Klotho; Parathyroid hormone; Renal osteodystrophy; Vascular calcification