Pathophysiology of Chronic Kidney Disease Mineral Bone Disorder (CKD‐MBD)

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 (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, and whose discovery lead 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, wherein it stimulates fibrosis, and decreases tubular klotho expression.The type 2 activin A receptor, ActRIIA, is induced by CKD in atherosclerotic aortas specifically in vascular smooth muscle cells (VSMC). Inhibition of ActRIIA signaling by a ligand trap inhibited CKD induced VSMC dedifferentiation, osteogenic transition and atherosclerotic calcification. Inhibition of ActRIIA signaling in the kidney decreased renal fibrosis and proteinuria.Summary-These studies demonstrate that circulating renal repair factors are causal of 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.

Persistent fibroblast growth factor 23 signalling in the parathyroid glands for secondary hyperparathyroidism in mice with chronic kidney disease

“…The sensor that triggers bone cells to release FGF23 has not yet been identified. FGF23 compensates for the decrease in the number of nephrons by accelerating the rate of phosphaturia per nephron by inhibiting the reabsorption of phosphate from the proximal tubule, and thus reduces the phosphate load1929. The other outstanding features of advanced CKD are low 1,25(OH) 2 D levels, secondary hyperparathyroidism, and hypocalcaemia.…”

“…The other outstanding features of advanced CKD are low 1,25(OH) 2 D levels, secondary hyperparathyroidism, and hypocalcaemia. FGF23 suppresses the production of 1,25(OH) 2 D from the kidney due to decreased 1α hydroxylation of 25-hydroxy vitamin D. The resulting low concentrations of 1,25(OH) 2 D lessen the suppression of the parathyroid glands by this active form of vitamin D5, leading to the enhanced secretion of PTH, and also the induction of hypocalcaemia by decreasing calcium absorption from the colon19. The high levels of circulating phosphate in late-stage CKD decrease the concentration of ionised calcium.…”

“…Patients with advanced chronic kidney disease (CKD) typically exhibit secondary hyperparathyroidism associated with high serum FGF23, high serum phosphate, and low 1,25(OH) 2 D levels19. FGF23 normally suppresses αKlotho expression, while 1,25(OH) 2 D promotes it.…”

“…Thus, reduced FGF23 signalling may explain the resistance to the putative inhibitory effects of FGF23 on the parathyroid glands, but cannot disprove the involvement of FGF23 in the pathogenesis of secondary hyperparathyroidism. FGF23 is known to be elevated in patients with CKD from the early phase of the disease19.…”

Vitamin D and Organ Transplantation

“…In patients with CKD, glomerular loss leads to declining renal function and subsequent calcitriol [39,40]. Patients with CKD also have 25(OH)D deficiency [29,30,40], and lower 25(OH)D is associated with poorer kidney function [41].…”