What is calcification?

What is Calcification?

Calcification is an active, regulated biological process involving the deposition of calcium phosphate in tissues, which can be either physiological (as in bone and teeth formation) or pathological (occurring in soft tissues such as blood vessels, heart valves, and other organs). 1

Pathophysiology

Calcification is not a passive accumulation of calcium but rather an active process of ossification involving cellular transformation and molecular regulation. 1

Cellular Mechanisms

• Vascular smooth muscle cells and circulating hematopoietic stem cells can undergo osteogenic or chondrogenic differentiation, producing bone-forming proteins and matrix vesicles that serve as nucleation sites for calcium deposition 1, 2
• Prior to calcium deposition in medial smooth muscle cells, bone matrix proteins become detectable, indicating active cellular transformation 1
• Phosphorus exposure at concentrations found in CKD patients induces expression of osteogenic factors in cultured human aortic smooth muscle cells 1
• Apoptosis and cell death play a central role, as membranous cellular degradation products and blebs formed by apoptotic cells accumulate calcium and phosphate, serving as the primary nidus for calcification 3

Regulatory Factors

• Calcification inhibitors normally prevent ectopic mineralization, including fetuin-A, matrix Gla protein, osteoprotegerin, and pyrophosphates 4
• Pathological calcification occurs when there is dysregulation or deficiency of these protective factors 4, 5
• Calcium signaling pathways regulate both physiological bone calcification and pathological soft tissue calcification 5

Types of Calcification

Vascular Calcification

• Intimal calcification occurs within atherosclerotic plaques and is associated with increased risk of stroke and myocardial infarction 1, 4
• Medial calcification (arteriosclerosis) affects the arterial media layer, causing arterial stiffness, left ventricular dysfunction, and heart failure 1, 4
• Current imaging techniques cannot reliably differentiate between calcified atherosclerotic plaques and medial calcification, though this distinction may be clinically significant 1

Microcalcification vs. Macrocalcification

• Dense macrocalcification (>400 HU) is typically associated with stable atherosclerotic plaques 2
• Microcalcification (spotty calcification) represents nascent, active calcium deposition and is more commonly found in vulnerable, rupture-prone plaques 1, 2
• Microcalcification in fibrous caps increases local tissue stress and plaque instability, depending on the proximity and orientation of calcific deposits 2
• 18F-sodium fluoride PET imaging can distinguish between areas of macrocalcification and "active" microcalcification, with the latter indicating unstable atherosclerosis 1

Valvular Calcification

• Valvular calcification is significantly more common in CKD patients on hemodialysis compared to age-matched controls (mitral valve: 29% vs. 6%; aortic valve: 22% vs. 6%) 1
• Calcification affects 45% of mitral valves and 34% of aortic valves in HD patients versus 3-5% in controls 1
• Valvular calcification is associated with worse survival, increased left ventricular hypertrophy, and sudden death risk 1
• No convincing evidence links valvular calcification to specific abnormalities in serum calcium, phosphorus, or PTH levels 1

Clinical Significance in CKD

Mineral Metabolism Disturbances

• Hyperphosphatemia is central to CKD-associated vascular calcification, with serum phosphorus >6.5-6.6 mg/dL associated with increased all-cause and cardiovascular mortality 1
• Disturbed mineral metabolism drives CKD-associated cardiovascular disease, though vascular pathology does not directly correlate with serum calcium and phosphate levels 1
• Elevated FGF23 levels contribute to left ventricular hypertrophy and congestive heart failure in CKD 1

Bone Disease Interactions

• Patients with adynamic bone disease have decreased ability to buffer exogenous calcium loads, predisposing them to hypercalcemia and metastatic calcification 1
• With impaired bone regulatory function, calcium is neither released from nor taken up by bone normally, making other tissues vulnerable to calcium accumulation 1
• Progression of vascular calcification in coronary arteries is associated with high doses of calcium-based phosphate binders (mean dose 1,500 mg elemental calcium daily) 1

Diagnostic Imaging

• Calcification detected by electron-beam CT, multidetector CT, echocardiogram, and X-ray scoring systems is associated with adverse outcomes in CKD 1
• Coronary artery calcium score and aortic calcification scores predict all-cause mortality 1
• Only CT scans are sensitive enough to detect changes in calcification for clinical trial purposes 1
• Whether slowing calcification progression improves prognosis or reduces mortality remains unknown 1

Common Pitfalls

• Assuming calcification is a passive, inevitable process rather than an active, potentially modifiable pathological mechanism 1
• Failing to recognize that dense calcification may represent stable disease while microcalcification indicates high-risk, vulnerable plaques 1, 2
• Overlooking the role of adynamic bone disease in promoting soft tissue calcification in CKD patients 1
• Using serum calcium and phosphate levels alone to predict or diagnose calcification risk, as vascular pathology does not directly correlate with these values 1