Shroff RC, Shah V, Hiorns MP, et al. 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: 3.58). 06/2008; 23(10):3263-71. DOI: 10.1093/ndt/gfn226
Source: PubMed


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.

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Available from: Leon J Schurgers, Oct 14, 2015
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    • "It should be noted that in the latter study, patients had fetuin-A levels comparable with controls and low levels of inflammatory activity. Finally, the studies by Schroff et al. [12] in children and by Porażko et al. [24] in adult HD patients, are in agreement with our findings. The above discrepant results may, at least partially, reflect differences in methodology and patient population. "
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    ABSTRACT: Background Cardiovascular morbidity and mortality remains excessive in patients with chronic kidney disease. The association of vascular changes with regulators of extraosseous calcification in this patient population is still under investigation. The aim of the present study was to investigate the associations of the calcification inhibitor fetuin-A, and the anti-osteoclastic factor osteoprotegerin (OPG) with vascular pathology in chronic hemodialysis patients. Methods In this cross-sectional study including 81 stable chronic hemodialysis patients, we measured carotid-to-femoral pulse wave velocity (cfPWV) with applanation tonometry, reflecting arterial stiffness, and common carotid intima-media thickness (ccIMT), a surrogate of early atherosclerosis, as well as serum levels of fetuin-A and OPG. Co-morbidities, traditional cardiovascular risk factors, inflammatory markers and mineral-bone disease serology parameters were also recorded. Results cfPWV correlated inversely with fetuin-A (r=−0.355, p=0.001) and positively with OPG (r=0.584, p<0.001). In multilinear regression analysis including age, gender, diabetes, cardiovascular disease, hypertension, pulse pressure, LDL, logCRP, both fetuin-A and OPG were independently associated with cfPWV (p=0.024 and p=0.041 respectively). ccIMT was negatively associated with fetuin-A (r=−0.312, p=0.005) and positively with OPG (r=0.521, p<0.0001); however these associations lost statistical significance after adjustment for age. Conclusion In chronic hemodialysis patients both fetuin-A and OPG levels are independently associated with arterial stiffness but not with early atherosclerotic vascular changes.
    BMC Nephrology 06/2013; 14(1):122. DOI:10.1186/1471-2369-14-122 · 1.69 Impact Factor
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    • "In in vitro studies, fetuin-A contributes about 50% of the calcification-inhibitory capacity of human plasma [22]. Recently, several studies have reported a protective role of fetuin-A against arterial stiffness and cardiovascular mortality in patients with ESRD; our results are consistent with these findings [24-27]. "
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    ABSTRACT: We assessed changes in hemodynamic and arterial stiffness parameters following reductions of dialysate calcium concentrations in patients undergoing hemodialysis. In this prospective study, 20 patients on maintenance hemodialysis (10 females, 10 males) with dialysate calcium concentrations of 1.75 mmol/L were enrolled. At the start of the study, the dialysate calcium level was lowered to 1.50 mmol/L. Serial changes in biochemical, hemodynamic, and arterial stiffness parameters, including pulse wave velocity (PWV) and augmentation index (AIx), were assessed every 2 months for 6 months. We also examined changes in the calcification-inhibitory protein, serum fetuin-A. During the 6-month study period, serum total calcium and ionized calcium decreased consistently (9.5 ± 1.0 to 9.0 ± 0.7, p = 0.002 vs. 1.3 ± 0.1 to 1.1 ± 0.1, p = 0.035). Although no apparent changes in blood pressure were observed, heart-femoral PWW (hf-PWV) and AIx showed significant improvement (p = 0.012, 0.043, respectively). Repeated-measures ANOVA indicated a significant effect of lowering dialysate calcium on hf-PWV (F = 4.58, p = 0.004) and AIx (F = 2.55, p = 0.049). Accompanying the change in serum calcium, serum fetuin-A levels significantly increased (95.8 ± 45.8 pmol/mL at baseline to 124.9 ± 82.2 pmol/mL at 6 months, p = 0.043). Lowering dialysate calcium concentration significantly improved arterial stiffness parameters, which may have been associated with upregulation of serum fetuin-A.
    The Korean Journal of Internal Medicine 09/2011; 26(3):320-7. DOI:10.3904/kjim.2011.26.3.320 · 1.43 Impact Factor
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    • "Even though some studies suggested higher fetuin-A levels in PD than hemodialysis patients [51], lower serum fetuin-A was linked to an increased risk of all-cause mortality and cardiovascular death in both hemodialysis [48] and PD patients [49]. Lower fetuin-A was associated with more inflammation and valvular calcification in PD patients [49] and was inversely related to more aortic calcification in pediatric dialysis patients [52]. All these data lent supporting evidence that fetuin-A may be involved in inhibiting vascular and valvular calcification. "
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    ABSTRACT: Cardiovascular disease accounts over half of the total mortality in peritoneal dialysis (PD) patients. In addition, there is an increasing recognition of a high prevalence of vascular and valvular calcification that may contribute to the increased all-cause and cardiovascular mortality in the PD patients. Disturbed mineral metabolism in association with chronic kidney disease has been suggested as one of the major contributing factors to the increased vascular/valvular calcification in this population. In this paper, we provide an overview of the prevalence and importance of this complication in the PD patients. In addition, we review the contributing factors and some emerging mechanisms for this complication. Furthermore, we discuss some therapeutic strategies that may be useful in limiting the progression of vascular/valvular calcification in the PD population.
    08/2011; 2011:198045. DOI:10.4061/2011/198045
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