Paradoxically, inflammatory lipids and cytokines that promote VC have been shown to inhibit normal skeletal
mineralization. Indeed, VC has been associated with loss of mineral from bone in patients with CKD and in post-menopausal women,[36, 37] and occurs simultaneously in some rodent models of arterial mineralization. It is therefore possible to theorize that loss of bone-buffering check details capacity and increased flux of mineral through the bone-remodelling compartment and extracellular fluids may induce a state of mineral stress leading to increased CPP formation. This is consistent with our previous observation of a strong association between serum CPP fetuin-A levels and β-isomerized C-terminal telopeptides (a marker of bone turnover), independent of eGFR. Although fetuin-A is widely regarded selleckchem as negative acute phase reactant,
with hepatic synthesis being suppressed by pro-inflammatory cytokines, we did not find a significant inverse relationship with serum CRP concentrations (r = −0.190, P = 0.084). This is consistent with previous reports in patients with pre-dialysis CKD, but may reflect the fact that ‘total’ serum Fet-A concentrations are a heterogenous signal comprising free and complexed species that may be regulated differently. Moreover, while serum Fet-A RR (i.e. CPP), were strongly and positively correlated with CRP concentrations (r = 0.338, P = 0.002) supernatant Fet-A concentrations (i.e. free Fet-A) were strongly but inversely correlated with CRP (r = −0.409, P < 0.001) and weakly with albumin concentrations (r = 0.264, P = 0.032). Nintedanib (BIBF 1120) Given the aforementioned putative vasculo-protective effects of free Fet-A, downregulation of hepatic production by inflammation is likely to potentiate the propensity for ectopic mineralization. Exceptionally high Fet-A RR were found in patients with CUA, implying a very severe perturbation of mineral regulation. Interestingly the fetuin-A knockout mouse develops lesions similar to those seen in CUA, suggesting that
if free Fet-A levels are depleted by the production of CPP we might see an acquired Fet-A deficiency. Such a description was suggested by Brandenburg and colleagues when they described Fet-A concentrations reducing precipitately as CRP increased in a patient who developed CUA. Consistent with some reports,[43, 44] but not others, we observed significant reductions in serum total Fet-A concentrations during dialysis (mean 24% decrease). Somewhat unexpectedly, we also recorded reductions in CRP concentrations and serum Fet-A RR. Interestingly while the changes in serum CRP and total Fet-A were convincingly correlated (rho = 0.434, P = 0.008), there was no significant relationship between changes in CRP and Fet-A RR (rho = 0.050, P = 0.789). Given the size of CPP (50–200 nm), it seems unlikely that they would be removed by ultrafiltration; however, it is possible that particles may be retained by the membrane.