Shroff, R. (2009) Uraemic vascular damage and calcification in children with chronic kidney disease. Doctoral thesis, UCL (University College London).
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Summary of thesis: Cardiovascular disease is the most common cause of death in patients with chronic kidney disease. Structural and functional vascular abnormalities and arterial calcification begins early in the course of renal decline and can be found even in children, contributing to their high mortality risk. Through clinical and laboratory studies, this thesis sought to investigate the causes of uraemic vascular damage and calcification in children with chronic kidney disease and on dialysis. Dysregulated mineral metabolism, manifested by hyperparathyroidism and high phosphate, in association with low vitamin D levels, is key to the pathophysiology of ectopic vascular and soft tissue calcification. In addition, a number of treatment- related factors can potentially lead to a high calcium load, contributing to an increased risk of calcification. Importantly, these are modifiable risk factors and have been associated with an increased mortality risk in adult dialysis patients. Using established surrogate measures of vascular damage, carotid artery intima media thickness, pulse wave velocity and multi-slice CT scan, I have studied a cohort of children on chronic dialysis, and shown that those with mean parathyroid hormone levels above twice the upper limit of normal had increased vascular thickness, stiffer vessels and a higher prevalence of coronary artery calcification, whereas those with lower levels had vascular measures that were similar to age-matched controls. Also, a higher vitamin D dosage was associated with thicker vessels and coronary calcification. To explore this association, in a further study I have measured the levels of 25-hydroxy and 1,25-dihydroxy vitamin D and shown that both low and high levels of 1,25-dihydroxy vitamin D are associated with thicker vessels and calcification. Also, 1,25-dihydroxy vitamin D showed a strong inverse association with high sensitivity CRP, and we speculate that vitamin D’s influence on calcium-phosphate homeostasis and inflammation may be lead to this bimodal effect. Levels of the circulating calcification inhibitors, fetuin-A, osteoprotegerin and Matrix Gla-protein, may influence an individual patients’ susceptibility to calcify, and but have not been described in children. I found that these levels influenced vascular stiffness and calcification, and that there may be a protective upregulation of fetuin-A in the early stages of exposure to a pro-calcific and pro-inflammatory uraemic environment. In a subsequent translational study I have sought to find direct evidence of vascular damage and calcification in the vessels. Using intact human arteries removed at the time of routine surgery, I have shown that calcium accumulation begins pre-dialysis, but dialysis induced vascular smooth muscle cell apoptosis coupled with osteo/chondrocytic transformation and a loss of the normal calcification inhibitors leads to overt calcification. Our currently available clinical measures are not sensitive enough to detect the earliest stages of calcification. On in vitro culture in calcifying media, dialysis but not control vessels showed accelerated time-dependent calcification, suggesting that these vessels had lost their smooth muscle cell defence mechanisms and were primed to undergo rapid calcification. Apoptotic cell death was a key event that triggerred calcification, and this was a vesicle mediated process, possibly involving oxidative DNA damage. This thesis investigates the role of modifiable risk factors in uraemic vascular damage and calcification in children with CKD and explores the earliest changes in the pathophysiology of uraemic medial calcification in intact human vessels.
|Title:||Uraemic vascular damage and calcification in children with chronic kidney disease|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health > Department of Cardiorespiratory Sciences > ICH - Cardiac Unit|
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