Arterial calcification in chronic kidney disease: key roles for calcium and phosphate

Abstract

Vascular calcification contributes to the high risk of cardiovascular mortality in chronic kidney disease (CKD) patients. Dysregulation of calcium (Ca) and phosphate (P) metabolism is common in CKD patients and drives vascular calcification. In this article, we review the physiological regulatory mechanisms for Ca and P homeostasis and the basis for their dysregulation in CKD. In addition, we highlight recent findings indicating that elevated Ca and P have direct effects on vascular smooth muscle cells (VSMCs) that promote vascular calcification, including stimulation of osteogenic/chondrogenic differentiation, vesicle release, apoptosis, loss of inhibitors, and extracellular matrix degradation. These studies suggest a major role for elevated P in promoting osteogenic/chondrogenic differentiation of VSMC, whereas elevated Ca has a predominant role in promoting VSMC apoptosis and vesicle release. Furthermore, the effects of elevated Ca and P are synergistic, providing a major stimulus for vascular calcification in CKD. Unraveling the complex regulatory pathways that mediate the effects of both Ca and P on VSMCs will ultimately provide novel targets and therapies to limit the destructive effects of vascular calcification in CKD patients.

Figure 1. Vascular calcification is mediated by VSMCs

Alterations in Ca and P levels and/or vascular insult lead to osteo/chondrogenic conversion of VSMCs in the vascular wall. This is associated with dramatic loss of mineralization inhibitors, the production of calcifying matrix vesicles and ECM degradation. In addition, Ca and P induce VSMC apoptosis and release of apoptotic bodies, which in turn, form the initial nidus for vascular calcification.

Figure 2. Overview of the factors involved in dysregulated Ca and P homeostasis in CKD

In early CKD renal insufficiency leads to a decline in klotho levels and impaired P excretion, but serum P levels are maintained in the normal range by upregulation of FGF23 from bone and PTH from the parathyroid gland. Declining renal function in CKD leads to 1, 25-dihydroxyvitamin D deficiency due to diminished activity of 1-alpha hydroxylase in the kidney as well as increased serum FGF23 levels (a direct inhibitor of 1 alpha hydroxylase activity). Low 1, 25-dihydroxyvitamin D levels lead to initial hypocalcemia, which together with hyperphosphatemia, provide a powerful stimulus for further PTH secretion and lead to the secondary hyperparathyrodism of CKD, and increased bone remodelling. Normal defence mechanisms (PTH, FGF23, and klotho) are overwhelmed as renal function continues to fall. Vitamin D deficiency and secondary hyperparathyroidism are treated with VDRAs that stimulate Ca and P uptake in the gut, often leading to transient hypercalcemic episodes (denoted by parentheses). Furthermore, Ca-containing P binders are commonly used to treat hyperphosphatemia, further increasing Ca burden in these individuals. Together with disordered bone remodelling, these factors contribute to dysregulated P and Ca metabolism, and promote vascular calcification in CKD.

Figure 3. Role of P in VSMC Calcification

Elevated extracellular P affects multiple signalling pathways that increase the susceptibility of VSMC to calcification including decreased calcification inhibitors, increased ECM degradation, osteo/chondrogenic differentiation, apoptosis and vesicle release. Some of the effects of P are mediated through sodium dependent phosphate co-transporters, Pit-1 and Pit-2, potentially via P transport-dependent and -independent activities. Whether other receptors exist that mediate specific downstream signalling pathways in response to P is not yet known, but cannot be excluded.

Figure 4. Role of Ca in VSMC Calcification

Ca elevation induces vesicle production and can lead to cell apoptosis and necrosis. High local levels of Ca triggers mineral nucleation in the matrix vesicles and apoptotic bodies. Accumulation of mineralized matrix vesicles and apoptotic bodies and their uptake accelerate cell death and facilitate further crystal growth. Degradation of ECM and nucleation of Ca apatite induces ECM protein mineralization.

Figure 5. Overview of distinct and overlapping pathways initiated by elevated Ca and P in VSMC

Pink shading indicates pathways specific to elevated serum Pi, green shading indicates pathways specific to elevated serum Ca, and brown area shows common pathways.