Laycock, JL; (2017) Effects of vitamin D receptor activators on vascular calcification in patients with CKD. Doctoral thesis , UCL (University College London).

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Abstract

Chronic kidney disease (CKD) patients are at high risk of vascular calcification due to abnormal mineral metabolism, and potentially their treatment with vitamin D receptor activators (VDRAs; calcitriol, alfacalcidol and paricalcitol). The effect of VDRAs on calcification is not fully understood. This thesis compares physiological doses of VDRAs on vascular smooth muscle cell (VSMC) calcification in vessels from children and adults with CKD. The inferior epigastric artery was harvested during renal transplantation and vessel rings cultured in different calcium (Ca) and phosphorous (P) media with physiological doses of VDRAs. The Ca load and alkaline phosphatase (ALP) activity were quantified and histological analysis performed. In children’s vessel rings, calcitriol increased Ca load by 3.6 fold and ALP activity by 2.2 fold compared to vehicle in high Ca and P medium, but two distinct groups of responders and non-responders to calcitriol were noted. Alfacalcidol increased Ca load by 3.4 fold but had no effect on ALP activity and paricalcitol had no effect on Ca load or ALP activity in any vessel rings. Patient variation was observed: this was independent of dialysis status and renal diagnosis. None of the VDRAs tested affected Ca load or ALP activity in adult vessel rings. VSMCs were explanted and their dose dependent responses to calcitriol (1, 10 and 100nM) documented. 100nM calcitriol elicited the greatest upregulation in vitamin D dependent gene expression, including the vitamin D receptor (VDR) whose expression was greater in VSMCs explanted from dialysis patients than non-renal controls. Expression of two VDR isoforms (VDR-A and VDR-B) were shown by Western blot analysis. VDR-A expression as a percentage of total VDR was 30+6.5% in control VSMCs compared to 65+12% in dialysis VSMCs. VSMCs in which 100nM calcitriol activated the vitamin D response element (VDRE) luciferase, expressed 70+17% VDR-A compared to 6.8+2.5% in VSMCs with no VDRE luciferase activation. Patient variation in VDR isoform expression may contribute to the individual patient’s responses to VDRAs in both vessel rings and VSMCs.

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