Mechanistic Insights into Vascular Calcification in CKD

Abstract

Cardiovascular disease begins early in the course of renal decline and is a life-limiting problem in patients with CKD. The increased burden of cardiovascular disease is due, at least in part, to calcification of the vessel wall. The uremic milieu provides a perfect storm of risk factors for accelerated calcification, but elevated calcium and phosphate levels remain key to the initiation and progression of vascular smooth muscle cell calcification in CKD. Vascular calcification is a highly regulated process that involves a complex interplay between promoters and inhibitors of calcification and has many similarities to bone ossification. Here, we discuss current understanding of the process of vascular calcification, focusing specifically on the discrete and synergistic effects of calcium and phosphate in mediating vascular smooth muscle cell apoptosis, osteochondrocytic differentiation, vesicle release, calcification inhibitor expression, senescence, and death. Using our model of intact human vessels, factors initiating vascular calcification in vivo and the role of calcium and phosphate in driving accelerated calcification ex vivo are described. This work allows us to link clinical and basic research into a working theoretical model to explain the pathway of development of vascular calcification in CKD.

NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency

“…Vascular calcification is a hallmark of aging. 8,[57][58][59] It is triggered by increased extracellular phosphate concentration, 14 a predictor of mortality. 60 NH 4 Cl treatment inhibits tissue calcification in kl/kl mice without appreciably affecting plasma 1,25(OH) 2 D 3 , Ca 2+ , and phosphate concentrations.…”

“…7 Vascular calcification is a major pathophysiologic mechanism limiting the life span of patients with CKD. 8 Mineral bone disorder is closely associated with survival of patients with CKD, which is determined by vascular calcification. 9 In patients with CKD, the impaired phosphate excretion is compounded by decreased klotho levels.…”

Vascular Calcification in Predialysis CKD

“…However, medial calcification is a characteristic feature of CKD. This was supported by the presence of VC in young patients with CKD without the traditional risk factors of atherosclerosis and the high percentage of medial calcification without classic atherosclerosis in the epigastric arteries of patients with ESRD at the time of kidney transplantation (8,9).…”

“…The findings of associations with anticoagulant therapy and statins are unclear and require further investigation. Although this study is cross-sectional and cannot establish causality, elevated phosphorus levels have been associated with VC in multiple human and animal studies (9). In the cohort, only 21% of the participants were taking a phosphate binder.…”

Dietary L-Lysine Prevents Arterial Calcification in Adenine-Induced Uremic Rats

“…Both passive and active pathways play roles in the pathogenesis of vascular calcification. 26,27 Among several active pathways, apoptosis of VSMCs is one of the key phenomena that promote vascular calcification. [28][29][30] Therefore, using cultured human VSMCs (hVSMCs), we examined the effects of L-Ala, L-Pro, L-Arg, and L-homoarginine on apoptosis.…”