Figure 1.

Diagram illustrating the complex systems biology between the kidney, skeleton, and cardiovascular system that is perturbed in native and transplant kidney disease, producing the components of the CKD-MBD. Recent mechanistic studies suggest that native and transplant kidney diseases produce circulating renal repair factors (e.g., DKK1, sclerostin, and activin-A) that may have systemic effects on the skeleton and cardiovascular system. (Top) In the skeleton, CKD alters calcium-phosphate homeostasis that contributes to varying degrees of hypocalcemia and hyperphosphatemia. Also, there is stimulation of osteocyte function with increased FGF23 secretion, along with decreased renal, parathyroid, and circulating klotho expression. Hypocalcemia, hyperphosphatemia, increased FGF23 levels, and decreased klotho expression all contribute to secondary hyperparathyroidism and vitamin D deficiency in CKD, and collectively have been associated with cardiovascular risk. In addition, there is inhibition of osteoblast function and stimulation of osteoclast function in this setting that produces abnormal skeletal remodeling and high-turnover renal osteodystrophy. (Bottom) In the cardiovascular system, studies in humans and animal models suggest that circulating renal repair factors and mineral-bone disturbances all contribute to cardiovascular risk in the CKD-MBD. Specifically, circulating renal repair factors have been implicated in key cellular events such as cardiac myocyte hypertrophy, endothelial dysfunction, endothelial-to-mesenchymal transition (EndMT), and osteoblastic transition of dedifferentiated vascular smooth muscle cells (VSMC). Paired with mineral-bone disturbances derived from the skeletal component of the CKD-MBD, this may contribute to vascular calcification, vascular stiffness, hypertension, and cardiac hypertrophy, all of which are associated with cardiovascular risk.