Elsevier

Bone

Volume 100, July 2017, Pages 80-86
Bone

Review Article
The chronic kidney disease — Mineral bone disorder (CKD-MBD): Advances in pathophysiology

https://doi.org/10.1016/j.bone.2017.01.023Get rights and content

Highlights

  • •

    This review discusses novel aspects of CKD-MBD pathogenesis.

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.

Section snippets

Introduction and epidemiology of the CKD-MBD

The kidney disease pandemic [1] is associated with high mortality rates, in part due to cardiovascular complications [2], [3], [4], [5]. The kidney disease produced increase in cardiovascular risk extends to type 2 diabetes [6], where the presence of mild to moderate kidney disease increases atherosclerotic cardiovascular disease risk by 87% [7]. The causes of the increased cardiovascular risk associated with kidney diseases partly reside in the chronic kidney disease – mineral bone disorder

Conclusion and future directions

The CKD-MBD defines a disruption in the systems biology between the injured kidney, skeleton, and cardiovascular system that has a profoundly negative impact on survival in CKD. Recent translational discoveries have introduced a new paradigm where kidney injury directly leads to skeletal and cardiovascular injury through the production of pathogenic circulating factors during attempted renal repair, including molecules that inhibit the canonical Wnt pathway and activin, both processes that have

Financial support and sponsorship

This work was funded by NIH grants, RO1DK070790 (KAH) and RO1DK089137 (KAH), an investigator stimulated grant from Celgene, and by NIH grants UL1 TR000448, KL2 TR000450, and L40 DK099748-01 (MS).

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