Calcium, calcification and cardiovascular risk in chronic kidney disease

Vascular calcification (VC), induced by imbalances of mineral metabolism, is a major precipitant to cardiovascular (CV) disease in patients with chronic kidney disease (CKD). VC has intimate interactions with bone mineralization and is associated with enhanced bone resorption. Arterial stiffness represents the functional disturbance of VC and is also greater in CKD than the general population. Both VC and arterial stiffness can be measured and monitored through non-invasive techniques involving computed tomography (CT), ultrasound, echocardiography, and pulse wave velocity (PWV). Management of these complications in CKD is difficult but detection, prevention and treatment is crucial to reduce CV mortality. This thesis examines the area of VC and CV risk in patients with CKD, with the use of different imaging modalities to determine and measure VC and arterial stiffness and different interventions to address the progression of these surrogate markers of CV disease. Using CT scans, the extent of VC in the aorta, superficial femoral arteries and arteriovenous fistulae has been studied, the latter vascular site never reported in the literature previously with regards to VC. The use of bone densitometry or dual-energy X-ray absorptiometry (DXA) to determine VC is also explored, with the first reports of its potential use in measuring VC in the aorta of CKD patients. Associations of VC and arterial stiffness are also presented with analyses of risk factors for these predictors of CV morbidity and mortality in the Australian CKD population. This thesis outlines the significant prevalence of VC and arterial stiffness in CKD patients in Australia, which has never been reported previously. The relationship between bone mineral density (BMD) and VC is strongly highlighted and the use (benefits and limitations) of DXA scans in patients with CKD is explored. With limited interventions reported to prevent the progression of VC in CKD, this thesis examines the use of bisphosphonates to reduce VC and atherosclerosis, as well as to reduce loss of BMD. Experimental studies report the benefits of bisphosphonates to treat extra-osseous calcification, however there are few reported clinical studies in CKD. A randomised placebo-controlled trial is presented showing no significant effect of bisphosphonates on VC in CKD patients with moderate to severe renal impairment (not yet on dialysis). Another randomised study in his thesis addresses the impact of regular exercise as a further intervention to reduce CV risk. The use of intra-dialytic exercise is assessed showing an improvement of arterial compliance in haemodialysis patients with this strategy. Finally, this thesis also examines the impact of dialysate calcium for haemodialysis patients and the effect that differing concentrations may have on bone and CV complications. Particular emphasis is on dialysate calcium in nocturnal haemodialysis patients, given limited literature in this area, and the importance of this exogenous calcium load on the development of VC in CKD as well as the beneficial effect that longer and more frequent dialysis may have on CV outcomes. [Author edited abstract].