Vascular calcification maladaptively participates in acute phosphate homeostasis

Abstract

Aims Non-renal extravasation of phosphate from the circulation and transient accumulation into tissues and extracellular fluid is a regulated process of acute phosphate homeostasis that is not well understood. This process is especially relevant in the setting of chronic kidney disease (CKD), where exposure to increased phosphate is prolonged due to inefficient kidney excretion. Furthermore, CKD-associated mineral dysregulation induces pathological accumulation of phosphate causing vascular calcification (VC). Our objective was to determine whether the systemic response to acute phosphate challenges is altered by VC. Methods/Results After bolus phosphate administration, circulating and tissue deposition of this challenge was assessed in two rat models of VC using a radiolabelled phosphate tracer. In an adenine-induced model of CKD (N = 70), animals with VC had a blunted elevation of circulating 33PO4 following oral phosphate administration (p < 0.01), and the discordant deposition could be traced to the calcified arteries (11.4[7.5,13.1]vs.43.0[35.5, 53.7] pmol/ng tissue, p < 0.001). In a non-CKD model of VC, calcification was induced with 0.5ug/kg calcitriol and then withdrawn (N = 24). New phosphate uptake by the calcified vasculature correlated to the pre-existing burden of calcification (r = 38, p < 0.001) and was substantially attenuated in the absence of calcification stimulus (p < 0.01). Phosphate accrual was stimulated by the phosphate challenge, and not present to the same degree during passive disposition of circulating phosphate. Further, the form of phosphate that deposited to the vasculature was predominately amorphous inorganic phosphate, and not that which was bound in matured calciprotein particles. Conclusions In the process of calcification, arteries acutely deposit substantial amorphous phosphate while blunting the elevation in the circulation, thereby altering the systemic disposition of phosphate, and identifying VC as a participatory mineral homeostatic organ. This study demonstrates the negative vascular consequence of acute fluctuations in circulating phosphate, and supports the importance of phosphate bioavailability and diet management in CKD patients as a mediator of cardiovascular risk.

Obesity attenuates acute phosphate excretion after an oral challenge in females: A sex‐specific effect of obesity on phosphate handling

“…Preclinical studies demonstrate that diseased blood vessels provide a non-renal mechanism for acute clearance of phosphate from the circulation after an oral phosphate challenge. 9 Deposition into the vasculature following dietary exposure could predispose females with obesity to vascular calcification. Females with more coronary artery calcification have been reported to have higher BMI, LDL cholesterol, triglycerides and homeostatic model assessment of insulin resistance, and greater visceral fat areas.…”

“…Excess retained phosphate may deposit in extracirculatory spaces such as bone or the vasculature. Preclinical studies demonstrate that diseased blood vessels provide a non‐renal mechanism for acute clearance of phosphate from the circulation after an oral phosphate challenge 9 . Deposition into the vasculature following dietary exposure could predispose females with obesity to vascular calcification.…”

Cardiovascular Calcification Heterogeneity in Chronic Kidney Disease

“… 129 Indirect evidence from rodent CKD models suggests that increasing bone formation reduces phosphate levels and vascular calcification and that arteries participate in acute phosphate homeostasis by depositing significant amorphous phosphate. 130 , 131 There is no proof of this causal association hypothesis in humans.…”

“… 141 Hyperphosphatemia correlates with increased vascular calcification, and studies suggest that mineral formation in the arterial wall can serve as a reservoir to remove circulating phosphate and prevent systemic toxicity. 131 Serum proteins such as fetuin-A and albumin can chelate nascent calcium-phosphate complexes in circulation, preventing rapid mineral growth. However, as CKD progresses, the resultant calciprotein particles that form from the serum chelation can induce inflammation and promineralization responses in vascular tissues.…”

“…128 Indeed, excess bone resorption contributes to hyperphosphatemia. 129 130,131 There is no proof of this causal association hypothesis in humans. Despite their commonalities, recent studies have shown that cardiovascular calcification and skeletal tissue mineralization are not completely analogous.…”