Serum Calcification Propensity Represents a Good Biomarker of Vascular Calcification: A Systematic Review

Abstract

Vascular calcification contributes to cardiovascular morbidity and mortality. A recently developed serum calcification propensity assay is based on the half-transformation time (T50) from primary calciprotein particles (CPPs) to secondary CPPs, reflecting the serum’s endogenous capacity to prevent calcium phosphate precipitation. We sought to identify and review the results of all published studies since the development of the T50-test by Pasch et al. in 2012 (whether performed in vitro, in animals or in the clinic) of serum calcification propensity. To this end, we searched PubMed, Elsevier EMBASE, the Cochrane Library and Google Scholar databases from 2012 onwards. At the end of the selection process, 57 studies were analyzed with regard to the study design, sample size, characteristics of the study population, the intervention and the main results concerning T50. In patients with primary aldosteronism, T50 is associated with the extent of vascular calcification in the abdominal aorta. In chronic kidney disease (CKD), T50 is associated with the severity and progression of coronary artery calcification. T50 is also associated with cardiovascular events and all-cause mortality in CKD patients, patients on dialysis and kidney transplant recipients and with cardiovascular mortality in patients on dialysis, kidney transplant recipients, patients with ischemic heart failure and reduced ejection fraction, and in the general population. Switching from acetate-acidified dialysate to citrate-acidified dialysate led to a longer T50, as did a higher dialysate magnesium concentration. Oral administration of magnesium (in CKD patients), phosphate binders, etelcalcetide and spironolactone (in hemodialysis patients) was associated with a lower serum calcification propensity. Serum calcification propensity is an overall marker of calcification associated with hard outcomes but is currently used in research projects only. This assay might be a valuable tool for screening serum calcification propensity in at-risk populations (such as CKD patients and hemodialyzed patients) and, in particular, for monitoring changes over time in T50.

Vascular Calcification: Molecular Networking, Pathological Implications and Translational Opportunities

“…T50 is currently employed in research projects only. However, T 50 is associated with cardiovascular events, mortality, and kidney disease progression, underscoring its importance as a prognostic marker, as a potentially therapeutic target, and as a management parameter of vascular calcification in patients with CKD, including those undergoing hemodialysis [ 207 ]. The presence of vascular calcification contributes significantly to increased mortality rates in patients with CKD due to cardiovascular complications, making these biomarkers of high clinical importance.…”

New therapeutic perspectives for vascular and valvular calcifications in chronic kidney disease

“…T50 is associated with cardiovascular events and all-cause mortality across CKD stages, including dialysis and transplant recipients. It is also associated with cardiovascular mortality in dialysis and kidney transplant populations [56]. Interventions such as adjusting dialysate composition from acetate-acidified to citrate-acidified, and increasing magnesium dialysate concentration led to a higher T50 [50,58,59].…”

“…Interventions such as adjusting dialysate composition from acetate-acidified to citrate-acidified, and increasing magnesium dialysate concentration led to a higher T50 [50,58,59]. Oral administration of magnesium (in CKD patients), phosphate binders, etelcalcetide and spironolactone (in hemodialysis patients) was associated with higher T50 levels [56]. While currently limited to research, T50 holds promise as a clinical tool for screening calcification propensity in CKD and monitoring changes in calcification risk over time.…”

“…The serum calcification propensity assay (T50) developed in 2012 measures the half-transformation time from primary CPP to secondary CPP, reflecting the ability of serum to resist hydroxyapatite crystal formation (the final step in vascular calcification) [55]. A systematic review of 57 publications on serum calcification propensity has recently been published [56]. T50 was not associated with the prevalence and incidence of CAC in CKD, but was associated with CAC severity and progression [57].…”

Calciprotein Particles Induce Cellular Compartment-Specific Proteome Alterations in Human Arterial Endothelial Cells

“…This, in turn, results in the conversion of amorphous and spherical primary CPPs (CPP-P) into hazardous crystalline and spindle-shaped secondary CPPs (CPP-S), ultimately provoking endothelial dysfunction [14][15][16][17][18][19] and ectopic calcification [21,22]. Biochemical indicators of calcium overload such as ionised calcium (Ca 2+ ) level measured by colorimetry or potentiometry, T 50 value defining the rate of amorphous-to-crystalline transition of CPPs (transformation of CPP-P into CPP-S) [23][24][25][26][27][28][29], optical density (OD 650 ) increment after ex vivo supersaturation of serum with Ca 2+ and PO 4 3− ions [18], and OsteoSense fluorescent-labeled bisphosphonate probe binding to CPPs and calciprotein monomers [30][31][32][33][34][35][36] have been consistently associated with major adverse cardiovascular events [18,24,26,37,38]. Taken together, these observations show the pathophysiological relevance of CPP generation in the human blood, underscoring the need to counteract its deregulation.…”