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.

Klotho and activin A in kidney injury: plasma Klotho is maintained in unilateral obstruction despite no upregulation of Klotho biosynthesis in the contralateral kidney

“…Activin A is induced in the obstructed kidney and plasma levels are increased in the UUO model. Activin A has been proposed to be a kidney-derived factor that is induced in the injured kidney with systemic effects on vasculature and bone (16). Plasma levels of activin A were increased in UUO rats after 10 days of (16).…”

“…This is with focus on how a new concept of kidney disease might cause induction of factors in the injured kidney, which are released into the circulation and thereby potentially initiate and maintain renal fibrosis and development of CKD-mineral and bone disorder (CKD-MBD). As such, this new paradigm of etiology related to CKD-MBD has recently been proposed by Hruska et al (16). The potential factors and hormones that may influence the progressive fibrogenetic changes evident in acute renal injury are examined.…”

“…Recently, sclerostin and activin A have been associated with renal fibrosis and CKD-MBD (16), where sclerostin functions as a tissue-specific Wnt inhibitor and is an osteocyte-specific protein related to bone mass and embryogenesis (43).…”

Paratireoidectomia na doença renal crônica: efeitos no ganho de peso e na melhora da qualidade de vida

“…Reduced renal function leads to several adaptive changes involving serum levels of calcium, phosphorus, and regulatory hormones, such as parathyroid hormone (PTH) and 1,25-hydroxy-vitamin D 1 . Metabolic changes due to renal failure result not only in bone mineral disease with its effects on the skeleton generating pain, deformities and incapacity due to changes in remodeling and errors in bone mineralization, but they are associated with high mortality mainly due to cardiovascular disease [5][6][7] . Regarding bone mineral disease, secondary hyperparathyroidism (HPT) is characterized by elevated levels of PTH, usually greater than 800 pg/mL, associated with bone lesions, increased resting energy expenditure (REE) and worsening of quality of life 2,7 .…”

Nutrients of Cubiu Fruits (<i>Solanum sessiliflorum</i> Dunal, Solanaceae) as a Function of Tissues and Ripening Stages

“…In the second scenario, knowledge of elevated P levels in ripe cubiu pulp and placenta is of interest due to the pathophysiological implications (e.g., mineral bone disorder syndrome, heart disease) of hyperphosphatemia, i.e., a serum P greater than 4.5 mg/dL in CKD [13,73,74,75]. Importantly, CKD is more common in subjects with diabetes mellitus [76].…”