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 In a non-CKD model of VC, calcification was induced with 0.5ug/kg calcitriol and then withdrawn (N = 24).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.
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.
Mineral bone disorder and vascular calcification (VC) are substantial contributors to the elevated cardiovascular disease (CVD) burden in chronic kidney disease patients. The degree to which the uremic milieu and mineral dysregulation individually contribute to this CVD is poorly understood. Calcitriol, the active form of vitamin D, is a key regulator of mineral metabolism. In this study, we present a model of rapid calcitriol‐induced VC in rats with normal kidney function, with findings that point to active and non‐active processes of calcification being fundamentally different phenotypes.Male Sprague Dawley rats (n=17, 15 weeks) were injected with 0.5 μg/kg/day calcitriol SQ for 8 days. On the 9th day, half of the animals were sacrificed (n=8, CxE), and the remainder were sacrificed 14 days after the cessation of calcitriol (n=9, CxL). Control animals (n=6) followed the same protocol. Circulating calcium, phosphate, and hormones regulating mineral metabolism (parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF‐23)) were measured every two days. At sacrifice, animals underwent an IV infusion of 300μmol PO4 spiked with radioactive 33PO4. Forty body tissues, including 14 across the vascular tree, were harvested and analyzed for mineral content/VC (calcium and phosphate) as well as acute phosphate deposition (33PO4 accrual).Daily administration of high‐dose calcitriol significantly elevated FGF‐23 and calcium, and suppressed PTH after only 2 doses, however, 14 days after calcitriol withdrawal, the analytes had fully normalized (Figure 1). Substantial VC was generated over the 8 days of treatment (7.8±4.2 v. 166±142 nmol Ca/mg tissue, p<0.001) and persisted 14 days after stopping treatment (540±492 nmol Ca/mg tissue). Following IV infusion of phosphate labelled with 33PO4, animals sacrificed directly following calcitriol treatment (CxE) had greater accrual of phosphate acutely in the vascular bed compared to those sacrificed 14 days after the cessation of treatment (CxL; −50.4%, p<0.001), despite having sustained levels of resident VC (Figure 2).Despite the similar magnitude of VC, acute deposition of phosphate following the IV load, a potential measure of calcification activity, was significantly greater during calcitriol treatment (CxE) than after stopping it (CxL). This suggests that the VC itself does not mediate the increased accrual of phosphate, but rather the cellular phenotype of the tissue. Also, it was this acute activity, not the resident VC, that aligned with dysregulated mineral metabolism markers. The transcriptional, cellular, and physiological differences of these two states, as well as their differential associations with circulating analytes are not currently differentiated in VC research. These differences likely have an important role in VC present in humans.Support or Funding InformationThis research was funded by Canadian Institutes of Health Research and Vanier Canada Graduate Scholarships.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
25 Background: Population level data show strong associations between race and other SDOH including income, education, and geographic region of residence. The relationship between SDOH and clinical outcomes has become increasingly recognized. This review examines the impact of SDOH on survival in patients with mPC in real-world (RW) settings. Methods: A systematic literature search in accordance with Cochrane guidelines was conducted on July 7, 2022, searching for RW studies published as full-text (Jan 2012-July 2022) and conferences (Jan 2019-July 2022) using Ovid MEDLINE, Embase, and Cochrane. A manual search of key congress websites for conference abstracts was also conducted. Studies which assessed the impact of SDOHs on survival, treatment access, and other clinical outcomes in patients with mPC were included in the overall SLR. Here, we present results from studies which assessed the impact of SDOH on overall survival (OS) and prostate cancer specific mortality (PCSM). Clinical trials were excluded. Results: Of 3,228 records screened, 86 studies were included, with findings reported in 67 full-text publications (60 US and 7 ex-US) and 28 conference abstracts (22 US and 6 ex-US). The impact of race on survival was reported in 54 studies. While most studies showed no difference between Black vs White for both OS (n=22) and PCSM (n=8), for patients on specific mPC treatments, there was an association between Black race and improved OS (n=5). Asian patients had improved OS vs White patients (n=4), and reduced PCSM vs White (n=6) and Black patients (n=1). Higher income was generally associated with improved OS (n=7), but no difference in PCSM (n=3). Although the regions compared differed, most studies found disparities in OS among US geographic regions (n=5). Education level was generally not associated with OS (n=2) or PCSM (n=3). Most studies showed that married patients had improved OS (n=4) and reduced PCSM (n=3) compared to unmarried patients. Conclusions: This SLR demonstrated that various SDOH are associated with disparities in survival among mPC patients. Asian race, which is generally associated with higher frequency of better SDOH risk factors, was linked with better OS. In contrast, Black race, which is generally associated with higher frequency of worse SDOH risk factors, was associated with similar or better OS. Having lower income and being unmarried were both associated with reduced OS, while disparities in OS were reported across geographic regions of the US. More studies are needed to understand why SDOH are linked with poor outcomes, including their connection with access to care.
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