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

Abstract

BackgroundNon-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 particularly critical 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). In the present study, the objective was to determine whether the processes involved in the development and progression of VC are also normally involved in the systemic acute response to oral phosphate.MethodsAcute circulating and physiological phosphate movement and tissue deposition was assessed in two experimental rat models of VC using radio-labelled phosphate challenge. In an adenine-induced model of CKD, VC was induced with high dietary phosphate. Animals were euthanized 2 and 6 hours after oral consumption of radiolabelled phosphate. A non-CKD model of VC was induced with 0.5ug/kg calcitriol and then withdrawn, and radiolabelled phosphate was then given to assess for vascular preference for phosphate uptake with and without the presence of an active calcification stimulus. Samples of 50 different tissues were collected to assess tissue accumulation of de novo phosphate in response the challenges.ResultsAnimals with CKD and VC have a blunted elevation of circulating 33PO4 following oral phosphate administration and the discordant deposition can be traced to the calcifying vasculature. Deposition of de novo phosphate is present until at least 6 hours, which after active gut absorption. The accrual is stimulated by a phosphate challenge, and not present in the same degree during passive disposition of circulating phosphate. The extent of 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.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.

Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling

“…Type III Na/Pi cotransporters, PiT-1 and PiT-2, are ubiquitously expressed and mediate cellular Pi homeostasis in all cells ( Lederer and Miyamoto, 2012 ). Pathologic Pi accumulation in vasculature is mediated by PiT-1 and PiT-2, loading Pi into vascular smooth muscle cells where it activates signaling networks such as Ras/mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) ( Chavkin et al, 2015 ; Turner et al, 2020 ; Zhao et al, 2011 ). These pathways provide plausible pathomechanisms that support excess Pi as a potential culprit behind the clinical association between hyperphosphatemia and CKD-associated vascular calcification.…”

Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling

“…Type III Na/Pi cotransporters, PiT-1 and PiT-2, are ubiquitously expressed and mediate cellular Pi homeostasis in all cells (Lederer and Miyamoto, 2012). Pathologic Pi accumulation in vasculature is mediated by PiT-1 and PiT-2, loading Pi into vascular smooth muscle cells where it activates signaling networks such as Ras/mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFB) (Chavkin et al, 2015;Turner et al, 2020;Zhao et al, 2011). These pathways provide plausible pathomechanisms that support excess Pi as a potential culprit behind the clinical association between hyperphosphatemia and CKD-associated vascular calcification.…”