Worsening calcification propensity precedes all-cause and cardiovascular mortality in haemodialyzed patients

Abstract

A novel in-vitro test (T₅₀-test) assesses ex-vivo serum calcification propensity which predicts mortality in HD patients. The association of longitudinal changes of T₅₀ with all-cause and cardiovascular mortality has not been investigated. We assessed T₅₀ in paired sera collected at baseline and at 24 months in 188 prevalent European HD patients from the ISAR cohort, most of whom were Caucasians. Patients were followed for another 19 [interquartile range: 11-37] months. Serum T₅₀ exhibited a significant decline between baseline and 24 months (246 ± 64 to 190 ± 68 minutes; p < 0.001). With serum Δ-phosphate showing the strongest independent association with declining T₅₀ (r = -0.39; p < 0.001) in multivariable linear regression. The rate of decline of T₅₀ over 24 months was a significant predictor of all-cause (HR = 1.51 per 1SD decline, 95% CI: 1.04 to 2.2; p = 0.03) and cardiovascular mortality (HR = 2.15; 95% CI: 1.15 to 3.97; p = 0.02) in Kaplan Meier and multivariable Cox-regression analysis, while cross-sectional T₅₀ at inclusion and 24 months were not. Worsening serum calcification propensity was an independent predictor of mortality in this small cohort of prevalent HD patients. Prospective larger scaled studies are needed to assess the value of calcification propensity as a longitudinal parameter for risk stratification and monitoring of therapeutic interventions.

Figure 1

Observation schedule, endpoints and selection of the study population; Patients were selected per predefined criteria stated in “methods”. Dotted arrows indicate patients not selected or leaving the study. Sera were collected at inclusion and after 24 [23–25] months of observation. Patients were then followed up for mortality for an average of 19 [11; 37] months.

Figure 2

Absolute T₅₀ at baseline and FU and percentage decline of T₅₀; (A) Absolute T₅₀ values at baseline (white boxplot) and at 24 months FU (grey boxplot). (B) Histogram stating the frequencies of T₅₀ ^Change ((=T₅₀ ^{Follow up} − T₅₀ ^Baseline)/(T₅₀ ^Baseline)) of n = 188 Patients. (C) Individual patients were sorted in descending order per their T₅₀ ^Change values. Patients displaying a decline in T₅₀ (defined by T₅₀ ^Change < −5.1%; 5,1% was the inter-assay coefficient for T₅₀ standards at 260 min in the EVOLVE cohort) were stained red. Absolute number of patients and (percent of total) are reported with dashed rectangles. The same colour code was used to stain the histogram in B.

Figure 3

Relation of serum phosphate and T₅₀ ^Change; (A) Left: Absolute phosphate levels at baseline (broadest white boxplot) and FU (broadest grey box plot) in the total cohort (n = 188). This cohort was split per T₅₀ decliners versus T₅₀ non-decliners Middle: Absolute phosphate levels at baseline (white boxplot) and FU (grey boxplot) in those that declined in T₅₀ between baseline and FU (T₅₀ ^Change  <  −5.1%); n = 139. Right: Absolute phosphate levels at baseline (small white boxplot) and FU (small grey boxplot) in those that had stable or increasing T₅₀ (T₅₀ ^Change ≥ −5.1%); n = 49. Differences among groups regarding absolute phosphate levels were tested using paired and unpaired t-test as appropriate. (B) Dot plot depicting the correlation of T₅₀ ^Change with ∆ phosphate (=phosphate ^{Follow up}−phosphate ^Baseline). T₅₀ decliners and non-decliners were coloured red and blue, respectively. Pearson correlation was used to quantify the relation.

Figure 4

Univariate correlation of T₅₀ ^Change and absolute T₅₀ ^Change. (A) Overall cumulative incidence functions stratified by median T₅₀ ^Change (=−22.7%). (B) Overall cumulative incidence functions stratified by median T₅₀ ^{Follow up} (=192.5 min). Patients at risk and total events per group are reported below the graphs. (C) Predicted cardiovascular death incidence functions stratified by median T₅₀ ^Change. (D) Predicted cardiovascular death incidence functions stratified by median T₅₀ ^{Follow up}. Number of lethal cardiovascular events are reported below the graphs. Log-rank statistics was used for comparison of incidence functions. p-values are reported in the upper right corner of each graph.