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.

Keywords: Activin; CKD-MBD; Dickkhopf 1; FGF23; Klotho; Parathyroid hormone; Renal osteodystrophy; Vascular calcification.

Figure 1

Renal Expression of Sclerostin. A, Westerns of kidney homogenates. Sclerostin is expressed in 200 day old normal mouse kidneys. Sclerostin expression is increased in 200 day old Col4a5 deficient mice with severe kidney failure (GFR 15% of normal). Treatment of Col4a5 deficient Alport syndrome mice with BMP-7 decreased sclerostin expression. B, Immunohistochemistry of renal sclerostin. Renal cortical sections from kidneys of normal 200 day old C57BL6J mice show patches of tubular sclerostin expression. Tubular sclerostin expression was increased in 200 day old Col4a5 Alport mice.

Figure 2

Renal αklotho mRNA and activin A (inhibin β-A homodimer) signaling in renal homogenates. A, Compared to sham operated ldlr−/− high fat fed mice, ldlr−/− high fat fed CKD mice (CKD V) had reduced αklotho expression that was restored by treatment with a ligand trap for the activin receptor type IIA (ActRIIA) (CKD R). B, Inhibin β-A (activin A) expression was increased in homogenates of ldlr−/− high fat fed CKD kidneys and reduced by treatment with the ActRIIA ligand trap. B and C, Homogenates of ldlr−/− high fat fed CKD kidneys had increased levels of p-Samd2/3, the transcription factor activated by ActRIIA signaling. C, Smad2/3 transcriptional targets, fibronectin and Col1a1, were increased by CKD and decreased by treatment with the ActRIIA ligand trap. (Reproduced with permission from Agapova et al., Kid Int 89: 1231–1243, 2016).

Figure 3

Osteoclast number, surfaces, and eroded surfaces in trabecular bones of sham operated ldlr−/− high fat fed mice, ldlr−/− high fat fed CKD mice (CKD V), and ldlr−/− high fat fed CKD mice treated with RAP-011, an ActRIIA ligand trap, (CKD R). CKD increased and RAP-011 treatment reversed the increase in osteoclast numbers, surfaces and eroded surfaces. (Reproduced with permission from Sugatani et al., Kid Int 91: 86–95, 2107).