Does hyponatremia contribute to arterial calcification?

Hyponatremia and Arterial Calcification

Hyponatremia accelerates vascular calcification through multiple cellular mechanisms, including oxidative stress, osteogenic differentiation of vascular smooth muscle cells, and enhanced formation of calciprotein particles. 1

Pathophysiological Mechanisms

• Recent evidence demonstrates that hyponatremia and low osmolality directly promote vascular calcification through activation of the Rac1-Akt pathway and reduction of NCX1 (Na-Ca exchanger 1) expression in vascular smooth muscle cells 1
• Hyponatremia induces oxidative stress and cell death, both of which are known contributors to vascular calcification, particularly in patients with chronic kidney disease 1
• Low osmolality accelerates the generation and maturation of calciprotein particles, which are key mediators in the development of vascular calcification 1
• A cross-sectional study using human autopsy specimens showed that hyponatremia and low osmolality were associated with a greater area of arterial intimal calcification 1

Relationship to Chronic Kidney Disease

• In chronic kidney disease (CKD), hyperphosphatemia leads to secondary hyperparathyroidism through multiple mechanisms, including lowering ionized calcium levels and interfering with vitamin D production 2, 3
• Prolonged hyperphosphatemia causes soft-tissue and vascular calcification due to increased calcium-phosphate product, which is associated with increased morbidity and mortality in CKD patients 2
• Vascular calcification in CKD is a complex multisystem disease requiring modification of multiple parameters 2
• Calcification of coronary arteries, cardiac valves, and pulmonary tissues produces cardiac disease, which is the leading cause of death in patients with CKD 2

Clinical Significance

• Hyponatremia is frequently observed in patients with chronic kidney disease and is associated with increased cardiovascular morbidity and mortality 1
• The calcium-phosphate product (Ca × P) is a critical value to monitor, as elevated levels (>55 mg²/dL²) increase the risk of soft tissue and vascular calcification 3
• In CKD patients, maintaining serum phosphorus levels between 3.5-5.5 mg/dL (1.13-1.78 mmol/L) is recommended to prevent secondary hyperparathyroidism and its complications, including vascular calcification 2
• Hyponatremia has been identified as a risk factor for increased morbidity and mortality in patients with congestive heart failure and other edematous disorders 4

Mechanisms of Hyponatremia in Various Conditions

• In patients with arterial hypertension, the risk of hyponatremia is 1.5 times higher than in the general population, often due to the use of thiazide or thiazide-like diuretics 5
• In liver diseases, hyponatremia can be multifactorial, not just due to the hemodynamic compromise of cirrhosis 6
• In hyponatremic hypertensive syndrome, an excessively stimulated renin-angiotensin-aldosterone system is mainly responsible for electrolyte disturbances 7

Clinical Implications and Management

• Treatment of underlying conditions that cause hyponatremia may help reduce the risk of vascular calcification 1
• In CKD patients, maintaining serum phosphorus within the normal range is critical for preventing abnormalities in parathyroid hormone metabolism and for reducing morbidity and mortality 2
• The calcium-phosphate product should be maintained below 55 to reduce the risk of vascular calcification 2
• Too rapid correction of hyponatremia might result in a potentially fatal osmotic demyelinating syndrome, requiring careful management 5

Emerging Research

• The role of glycosaminoglycans in the subcutaneous tissue and glycocalyx on vascular endothelial cells has been documented in the regulation of sodium metabolism, which may have implications for understanding the relationship between hyponatremia and vascular health 5
• Live imaging studies have shown synchronic calcium ion efflux and sodium ion influx via NCX1 when extracellular sodium ion concentrations change, suggesting a direct mechanism by which sodium levels affect calcium metabolism in vascular tissue 1

The evidence clearly demonstrates that hyponatremia is not merely a marker of disease severity but an active contributor to arterial calcification through multiple cellular and molecular mechanisms. Addressing hyponatremia may be an important therapeutic target for reducing vascular calcification risk, particularly in patients with chronic kidney disease.