Pathophysiology of the Chronic Kidney Disease-Mineral Bone Disorder
Pathophysiology of the Chronic Kidney Disease-Mineral Bone Disorder
Purpose of review 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. The causes of the CKD-MBD are not well known and they will be discussed in this review
Recent findings The discovery of WNT (portmanteau of wingless and int) inhibitors, especially Dickkopf 1, produced during renal repair and participating in the pathogenesis of the vascular and skeletal components of the CKD-MBD implied that additional pathogenic factors are critical, leading to the finding that activin A is a second renal repair factor circulating in increased levels during CKD. Activin A derives from peritubular myofibroblasts of diseased kidneys, where it stimulates fibrosis, and decreases tubular klotho expression. The type 2 activin A receptor, ActRIIA, is decreased by CKD in atherosclerotic aortas, specifically in vascular smooth muscle cells (VSMC). Inhibition of activin signaling by a ligand trap inhibited CKD induced VSMC dedifferentiation, osteogenic transition and atherosclerotic calcification. Inhibition of activin signaling in the kidney decreased renal fibrosis and proteinuria.
Summary These studies demonstrate that circulating renal repair factors are causal for the CKD-MBD and CKD associated cardiovascular disease, and identify ActRIIA signaling as a therapeutic target in CKD that links progression of renal disease and vascular disease.
Kidney diseases are associated with an extremely high mortality, which is related to their production of cardiovascular disease. The kidney disease produced increase in cardiovascular risk even extends to type 2 diabetes, wherein the presence of mild-to-moderate kidney disease increases atherosclerotic cardiovascular disease risk by 87%. The causes of the increased cardiovascular risk associated with kidney diseases partly reside in the chronic kidney disease – mineral bone disorder (CKD-MBD) syndrome. Three novel cardiovascular risk factors [hyperphosphatemia, vascular calcification, and elevated fibroblast growth factor 23 (FGF23) levels] have been discovered within the CKD-MBD, and their risk factor status confirmed in the general population. The CKD-MBD begins early in CKD (stage 2) consisting of vascular dedifferentiation/calcification, an osteodystrophy, loss of klotho and increased FGF23 secretion. Progress has been made into the causes of CKD-MBD, but they remain largely unknown.
Abstract and Introduction
Abstract
Purpose of review 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. The causes of the CKD-MBD are not well known and they will be discussed in this review
Recent findings The discovery of WNT (portmanteau of wingless and int) inhibitors, especially Dickkopf 1, produced during renal repair and participating in the pathogenesis of the vascular and skeletal components of the CKD-MBD implied that additional pathogenic factors are critical, leading to the finding that activin A is a second renal repair factor circulating in increased levels during CKD. Activin A derives from peritubular myofibroblasts of diseased kidneys, where it stimulates fibrosis, and decreases tubular klotho expression. The type 2 activin A receptor, ActRIIA, is decreased by CKD in atherosclerotic aortas, specifically in vascular smooth muscle cells (VSMC). Inhibition of activin signaling by a ligand trap inhibited CKD induced VSMC dedifferentiation, osteogenic transition and atherosclerotic calcification. Inhibition of activin signaling in the kidney decreased renal fibrosis and proteinuria.
Summary These studies demonstrate that circulating renal repair factors are causal for the CKD-MBD and CKD associated cardiovascular disease, and identify ActRIIA signaling as a therapeutic target in CKD that links progression of renal disease and vascular disease.
Introduction
Kidney diseases are associated with an extremely high mortality, which is related to their production of cardiovascular disease. The kidney disease produced increase in cardiovascular risk even extends to type 2 diabetes, wherein the presence of mild-to-moderate kidney disease increases atherosclerotic cardiovascular disease risk by 87%. The causes of the increased cardiovascular risk associated with kidney diseases partly reside in the chronic kidney disease – mineral bone disorder (CKD-MBD) syndrome. Three novel cardiovascular risk factors [hyperphosphatemia, vascular calcification, and elevated fibroblast growth factor 23 (FGF23) levels] have been discovered within the CKD-MBD, and their risk factor status confirmed in the general population. The CKD-MBD begins early in CKD (stage 2) consisting of vascular dedifferentiation/calcification, an osteodystrophy, loss of klotho and increased FGF23 secretion. Progress has been made into the causes of CKD-MBD, but they remain largely unknown.
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