The circulating calcification inhibitors, fetuin-A and osteoprotegerin, but not Matrix Gla protein, are associated with vascular stiffness and calcification in children on dialysis

Nephrourology Unit, Great Ormond Street Hospital & UCL Institute of Child Health, London WC1N 1EH, UK.
Nephrology Dialysis Transplantation (Impact Factor: 3.49). 06/2008; 23(10):3263-71. DOI: 10.1093/ndt/gfn226
Source: PubMed

ABSTRACT Vascular calcification occurs in the majority of patients with chronic kidney disease, but a subset of patients does not develop calcification despite exposure to a similar uraemic environment. Physiological inhibitors of calcification, fetuin-A, osteoprotegerin (OPG) and undercarboxylated-matrix Gla protein (uc-MGP) may play a role in preventing the development and progression of ectopic calcification, but there are scarce and conflicting data from clinical studies.
We measured fetuin-A, OPG and uc-MGP in 61 children on dialysis and studied their associations with clinical, biochemical and vascular measures.
Fetuin-A and OPG were higher and uc-MGP lower in dialysis patients than controls. In controls, fetuin-A and OPG increased with age. Fetuin-A showed an inverse correlation with dialysis vintage (P = 0.0013), time-averaged serum phosphate (P = 0.03) and hs-CRP (P = 0.001). Aortic pulse wave velocity (PWV) and augmentation index showed a negative correlation with fetuin-A while a positive correlation was seen with PWV and OPG. Patients with calcification had lower fetuin-A and higher OPG than those without calcification. On multiple linear regression analysis Fetuin-A independently predicted aortic PWV (P = 0.004, beta = -0.45, model R(2) = 48%) and fetuin-A and OPG predicted cardiac calcification (P = 0.02, beta = -0.29 and P = 0.014, ss = 0.33, respectively, model R(2) = 32%).
This is the first study to define normal levels of the calcification inhibitors in children and show that fetuin-A and OPG are associated with increased vascular stiffness and calcification in children on dialysis. Higher levels of fetuin-A in children suggest a possible protective upregulation of fetuin-A in the early stages of exposure to the pro-calcific and pro-inflammatory uraemic environment.

Download full-text


Available from: Leon J Schurgers, Jul 07, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Vascular calcification is frequently observed and is closely associated with cardiovascular mortality in patients with chronic kidney disease (CKD). Vascular calcification is largely divided into two types. One is atherosclerotic intimal layer calcification and the other is medial layer calcification (Monckeberg's calcification). The latter is more common in patients with CKD than in general population. Evidence is growing that vascular calcification is a regulated active process as well as a passive process resulting from elevated serum phosphate (P) and an increase in the calcium phosphate (Ca x P) product leading to oversaturated plasma. Proving the active process, in vitro studies have demonstrated that the transformation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells is a crucial mechanism in the progression of vascular calcification. Reduction of the activity of systemic and local inhibitors has also been recognized to be important. The link between vitamin D and vascular calcification is complex. Experimental and clinical researches have revealed that both vitamin D excess and vitamin D deficiency have been shown to be associated with vascular calcification in uremic milieu. On the other hand, although there are some biases, recent large observational studies have demonstrated that vitamin D has beneficial effects on the mortality of patients with CKD independent of serum Ca, P, and parathyroid hormone levels, likely due to its activation of the vitamin D receptor in vasculature and cardiac myocytes. Further prospective studies are necessary to evaluate the direct effect of vitamin D on vascular calcification in order to improve the cardiovascular health of patients with CKD.
    Bone 07/2009; 45 Suppl 1:S26-9. DOI:10.1016/j.bone.2009.01.011 · 4.46 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the association between fetuin-A level (AHSG), its encoding gene (Thr256Ser) and arterial function in subjects with normal kidney function. The aortic pulse wave velocity (aPWV) is a predictor for cardiovascular mortality. Fetuin-A is a calcification inhibitor and correlates negatively with increased vascular stiffness in dialysis patients. The fetuin-A polymorphism (Thr256Ser) is associated with reduced fetuin levels and accelerated vascular calcification in dialysis patients. Little is known about the role of fetuin-A as an independent predictor for the development of arterial stiffness in healthy subjects. We studied 116 subjects with normal kidney function (age 47+/-12 years, 50 females and 66 males) of the FLEMENGHO study. Calcium measurements, plasma fetuin-A, its encoding gene (Thr256Ser) and indexes of arterial stiffness, such as aPWV and arterial distensibility, were determined. Fetuin-A levels were negatively correlated with aPWV (r=-0.21, p=0.029). After an adjustment for multiple covariables, fetuin-A levels were independently associated with aPWV (r=-0.30, p=0.022) in males but not in females. Male fetuin-A SerSer carrier had lower fetuin-A levels and higher aPWV (fetuin-A: 61.9+/-29.0 microg/ml; aPWV: 14.3+/-0.9 m/s) as compared to ThrThr (fetuin-A: 109.9+/-54.9 microg/ml; aPWV: 6.4+/-1.3 m/s) and ThrSer carrier (fetuin-A: 100.8+/-52.5 microg/ml; aPWV: 6.6+/-1.3 m/s). Other calcium variables were not significantly associated with arterial stiffness. With respect to common calcium variables, only fetuin-A level showed an inverse relation with aPWV in men with normal renal function. Male fetuin-A SerSer carriers demonstrate particularly high aortic stiffness, possibly implying a status of increased cardiovascular risk.
    Regulatory Peptides 04/2009; 154(1-3):39-43. DOI:10.1016/j.regpep.2008.12.001 · 2.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.