Vascular calcification has a role in acute non-renal phosphate clearance

Turner, M. E.; Lansing, A. P.; Jeronimo, P. S.; Lee, L. H.; Svajger, B. A.; Zelt, J. G.; Petkovich, M. P.; Holden, R. M.; Adams, M. A.

doi:10.1101/2020.07.29.225532

bioRxiv · 10.1101/2020.07.29.225532

Vascular calcification has a role in acute non-renal phosphate clearance

Turner, M. E.·Lansing, A. P.·Jeronimo, P. S.·Lee, L. H.·Svajger, B. A.·Zelt, J. G.·Petkovich, M. P.·Holden, R. M.·Adams, M. A.

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Abstract

RationaleNon-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. Following oral consumption of phosphate, circulating levels normalize long before urinary excretion has been completed. This process is especially relevant in the setting of chronic kidney disease (CKD), where phosphate exposure is prolonged due to inefficient kidney excretion. Furthermore, CKD-associated dysregulation of mineral metabolism exacerbates pathological accumulation of phosphate causing vascular calcification (VC). ObjectiveDetermine whether the systemic response to acute phosphate challenges is altered by the development and progression of VC. Methods/ResultsAcute circulating and tissue deposition of an acute phosphate challenge was assessed in two rat models of VC using radio-labelled phosphate tracer. In an adenine-induced model of CKD with VC, animals with VC had a blunted elevation of circulating 33PO4 following oral phosphate administration and the discordant deposition could be traced to the calcifying vasculature. In a non-CKD model of VC, VC was induced with 0.5ug/kg calcitriol and then withdrawn. The radio-labelled phosphate challenge was given to assess for vascular preference for phosphate uptake with and without the presence of an active calcification stimulus. The new transport to the calcifying vasculature correlates to the pre-existing burden of calcification, and can be substantially attenuated by removing the stimulus for calcification. The accrual is stimulated by a phosphate challenge, and not present in the same degree during passive disposition of circulating phosphate. ConclusionsOur data indicate that calcifying arteries alter the systemic disposition of a phosphate challenge and acutely deposit substantial phosphate. This study supports the importance of diet as it relates to acute fluctuations of circulating phosphate and the importance of bioavailability and meal-to-meal management in CKD patients as a mediator of cardiovascular risk.

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Turner, M. E., Lansing, A. P., Jeronimo, P. S., Lee, L. H., Svajger, B. A., Zelt, J. G., Petkovich, M. P., Holden, R. M., Adams, M. A.. 2020-07-30. Vascular calcification has a role in acute non-renal phosphate clearance. https://doi.org/10.1101/2020.07.29.225532

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