Phosphate: an old bone molecule but new cardiovascular risk factor

Shobeiri, Navid; Adams, Michael; Holden, Rachel M.

doi:10.1111/bcp.12117

Cited by 23 publications

(14 citation statements)

References 175 publications

(234 reference statements)

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“…Multiple experiments have demonstrated that culturing VSMC in a high-phosphate medium will increase calcification in a dose-dependent manner. This is also associated with the upregulation of proteins involved in bone formation and the phenotypic differentiation seen in the VSMC (29,104). Calcification of the coronary arteries is independently associated with hyperphosphatemia in ESRD patients, and elevated serum phosphate levels, even those in the high-normal range, are correlated with a higher risk of myocardial infarction and mortality in CKD patients (53,123).…”

Section: Risk Factors For Vascular Calcification In Ckdmentioning

confidence: 99%

A current understanding of vascular calcification in CKD

Paloian

Giachelli

2014

American Journal of Physiology-Renal Physiology

279

264

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Patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) have significant cardiovascular morbidity and mortality that is in part due to the development of vascular calcification. Vascular calcification is an active, highly regulated process that shares many similarities with normal bone formation. New discoveries related to extracellular vesicles, microRNAs, and calciprotein particles continue to reveal the mechanisms that are involved in the initiation and progression of vascular calcification in CKD. Further innovations in these fields are critical for the development of biomarkers and therapeutic options for patients with CKD and ESRD.

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Section: Risk Factors For Vascular Calcification In Ckdmentioning

confidence: 99%

A current understanding of vascular calcification in CKD

Paloian

Giachelli

2014

American Journal of Physiology-Renal Physiology

279

264

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“…Increasing evidence, however, supports a role for phosphate in the pathogenesis of medial and intimal calcification. 16,17 For example, Ix et al evaluated the effect of serum phosphate on arterial calcification in patients with normal to moderate kidney function and found elevated serum levels were strongly associated with non-compressible vessels and increased ankle-brachial index after adjusting for renal function and cardiovascular risk factors. The authors suggest that increased cardiovascular events might be explained by increased arterial stiffness related to medial artery calcification.…”

Section: Discussionmentioning

confidence: 99%

Elevated serum phosphate levels are associated with decreased amputation-free survival after interventions for critical limb ischemia

Zettervall

Soden

Ultee

et al. 2017

Journal of Vascular Surgery

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Objectives Elevated serum phosphate levels have been associated with increased risks of cardiovascular events and death in several patient populations. The effects of serum phosphate on outcomes in patients with critical limb ischemia (CLI) have not been evaluated. In this study, we assessed the effect of abnormal phosphate levels on mortality and major limb events following surgical intervention for critical limb ischemia (CLI). Methods A retrospective review was undertaken to identify all patients at a single institution who underwent a first-time open or endovascular intervention for CLI between 2005 and 2014. Patients without recorded post-operative phosphate levels were excluded. Post-operative phosphate levels within 30-days of the initial operation were recorded and the mean was calculated. Patients were stratified according to mean phosphate levels (low <2.5, normal 2.5–4.5, high >4.5). Patient demographics, comorbidities, and operative details were compared in univariate analysis. Multivariable regression and cox-proportional hazard modeling were utilized to account for patient demographics and comorbid conditions. Results 941 patients were identified including 42(5%) with low phosphate, 768(82%) with normal phosphate, and 131(14%) with high phosphate. Patients with elevated phosphate were younger and had higher rates of congestive heart failure, diabetes, and dialysis dependence. Bypass was more common among patients with normal phosphate as compared to high or low phosphate levels. There was no difference in WiFi or TASC classification between cohorts. There were significant differences in 1-year mortality (low: 19%, normal: 17%, high: 33%, p < .01) and 3-year mortality (low 38%, normal: 34%, high: 56%, p <.01) between phosphate cohorts. Major amputation (low: 12%, normal: 12%, high: 15%) and restenosis (low: 21%, normal: 24%, high: 28%) tended toward worse outcomes among patients with elevated phosphate levels, but did not reach statistical significance. After adjustment for baseline characteristics, mortality was higher (HR: 1.7, 95% CI: 1.3–2.2) and amputation free survival was lower (HR: 1.5, 95% CI: 1.2–1.9) among patients with elevated as compared with normal phosphate levels. A subgroup analysis was then performed to assess dialysis and non-dialysis patients separately. Patients with elevated serum phosphate levels maintained a significantly higher risk of mortality in each group (Dialysis HR: 1.8 95% CI 1.2–2.6, Non-dialysis: HR 1.5, 95% CI 1.04–2.10). Conclusion Elevated phosphate levels are associated with increased mortality and decreased amputation free survival following interventions for critical limb ischemia. Future studies evaluating the effects of phosphate reduction in patients with CLI are warranted.

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“…However Cox and others developed a reproducible in vitro model using the metastatic mammary adenocarcinoma 4T1 cell line that ultimately allowed them to propose a mechanism for hydroxyapatite calcification [ 136 ]. They hypothesized that alkaline phosphatase (ALP) not only hydrolyses β-glycerophosphate to glycerol and phosphate (Pi) [ 136 ], which is similar to the initial osteoblastic differentiation process in ossification [ 142 ], but ALP also dephosphorylates OPN and hydrolyzes pyrophosphate (PPi) to Pi on the surface of mammary cells [ 143 ]. The produced Pi is then believed to be transported into the 4T1 cells by type II Na-Pi co-transporters, which have been found to be expressed in higher levels in cancer tissue as opposed to normal tissue [ 136 ].…”

Section: Vascular Calcification and Stone Formation Similarities Tmentioning

confidence: 99%

Vascular Calcification and Stone Disease: A New Look towards the Mechanism

Yiu

Callaghan

Sultana

et al. 2015

JCDD

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Calcium phosphate (CaP) crystals are formed in pathological calcification as well as during stone formation. Although there are several theories as to how these crystals can develop through the combined interactions of biochemical and biophysical factors, the exact mechanism of such mineralization is largely unknown. Based on the published scientific literature, we found that common factors can link the initial stages of stone formation and calcification in anatomically distal tissues and organs. For example, changes to the spatiotemporal conditions of the fluid flow in tubular structures may provide initial condition(s) for CaP crystal generation needed for stone formation. Additionally, recent evidence has provided a meaningful association between the active participation of proteins and transcription factors found in the bone forming (ossification) mechanism that are also involved in the early stages of kidney stone formation and arterial calcification. Our review will focus on three topics of discussion (physiological influences—calcium and phosphate concentration—and similarities to ossification, or bone formation) that may elucidate some commonality in the mechanisms of stone formation and calcification, and pave the way towards opening new avenues for further research.

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Phosphate: an old bone molecule but new cardiovascular risk factor

Cited by 23 publications

References 175 publications

A current understanding of vascular calcification in CKD

A current understanding of vascular calcification in CKD

Elevated serum phosphate levels are associated with decreased amputation-free survival after interventions for critical limb ischemia

Vascular Calcification and Stone Disease: A New Look towards the Mechanism

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