Phosphorylated fetuin-A-containing calciprotein particles are associated with aortic stiffness and a procalcific milieu in patients with pre-dialysis CKD

Abstract

Vascular stiffening occurs in normal ageing and is accelerated in chronic kidney disease (CKD). Vascular calcification contributes to this stiffening and to the high incidence of vascular morbidity and mortality in this population. A network of inhibitors work in concert to reduce mineralization risk in extra-osseous tissue. Fetuin-A is an important systemic inhibitor of ectopic calcification. A fraction of the total circulating fetuin-A interacts with mineral ions to form stable colloidal complexes, calciprotein particles (CPP), preventing deposition. We sought to assess whether CPP fetuin-A levels were associated with procalcific factors and aortic stiffness in a cohort of patients with Stages 3 and 4 CKD. We measured fetuin-A CPP levels, serum inflammatory markers [C-reactive protein (CRP), interleukin-6, tumour necrosis factor-α], oxidized low-density lipoprotein (oxLDL), bone morphogenetic protein-2 (BMP-2) and -7 (BMP-7) and aortic pulse wave velocity (APWV) in a cohort of 200 CKD patients. Serum measurements were also made in 78 healthy controls. CPP fetuin-A phosphorylation was characterized by phosphate-affinity gel chromatography. Fetuin-A-containing CPPs were only detectable in the serum of CKD patients. Inflammatory markers, oxLDL and BMP-2 levels were all significantly higher in the CKD than control subjects. CPP fetuin-A levels were independently associated with serum phosphate, high-sensitivity C-reactive protein, oxLDL, BMP-2/7 ratio and inversely with estimated glomerular filtration rate (model R(2) = 0.51). After adjusting for confounders, CPP fetuin-A levels were independently associated with APWV. Only phosphorylated fetuin-A was present in serum CPP. Increased CPP fetuin-A levels reflect an increasingly procalcific milieu and are associated with increased aortic stiffness in patients with pre-dialysis CKD.