Vascular calcification (VC) is accelerated in patients with chronic kidney disease (CKD), resulting in increased risk of cardiovascular disease and mortality. Although the consequences of VC are associated with elevated pulse wave velocity (PWV) and left ventricular hypertrophy (LVH), the temporal impact on blood pressure changes is unknown. Mineral imbalance in CKD greatly contributes to the development of VC, and elevated serum phosphate is a major risk factor. Magnesium, which plays an important role in bone regulation, has been recently shown to be a modifier of VC, but whether magnesium inhibits calcification in CKD is unknown.
A modified adenine model of CKD was developed in rats, characterized by mineral imbalance and progressive VC. During the development of VC, pulse pressure increased, which was driven by a drop in diastolic blood pressure, rather than systolic hypertension. Continuous pressure recordings in conscious rats using radiotelemetry revealed a significant increase in systolic variability associated with development of VC. Regional VC was associated with regional changes in the hemodynamic profile of the CKD rats. For example, only thoracic aortic calcification was associated with elevated PWV and pulse pressure. In contrast, the presence of abdominal and thoracic calcification differentially affected proximal and distal arterial pressure wave forms. CKD animals exhibited LVH, which was further increased by the presence of VC. In addition, fibroblast growth factor 23, which regulates renal excretion of phosphate, was elevated in CKD animals at every time point and was associated with LVH independently from VC. Development of VC was characterized in an in vitro organ model. Phosphate elevation in vitro caused VC in aortas. In vitro, magnesium supplementation inhibited initiation and progression of VC. CKD animals given a magnesium diet also demonstrated attenuated development of VC. In patients with stage 3-5 CKD (excluding dialysis), dietary phosphate was associated with the progression of coronary artery calcification even after adjusting for use of phosphate binders, total dietary energy and total dietary protein. Given the serious negative outcomes associated with development of VC, these findings fill key gaps in knowledge regarding the detection, management, prevention and treatment of VC in CKD. / Thesis (Ph.D, Pharmacology & Toxicology) -- Queen's University, 2013-12-01 15:12:54.388
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OKQ.1974/8498 |
| Date | 04 December 2013 |
| Creators | SEYED SHOBEIRI, NAVID |
| Contributors | Queen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.)) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English, English |
| Detected Language | English |
| Type | Thesis |
| Rights | This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner. |
| Relation | Canadian theses |
Page generated in 0.0027 seconds