%D 2009
%A R. Shroff
%I UCL (University College London)
%T Uraemic vascular damage and calcification in children with
chronic kidney disease
%L discovery14730
%X 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.