Associations of serum sclerostin and Dickkopf-related protein-1 proteins with future cardiovascular events and mortality in haemodialysis patients: a prospective cohort study.

BACKGROUND: Sclerostin and Dickkopf-related protein-1 (Dkk-1) proteins are inhibitors of the canonical Wnt/β-catenin bone pathway. Sclerostin but not Dkk-1 is associated with increased arterial stiffness. This study examined the prognostic significance of sclerostin and Dkk-1 levels for cardiovascular outcomes and mortality in haemodialysis (HD) patients. METHODS: Serum sclerostin and Dkk-1 levels were measured with enzyme-linked immunosorbent assay in 80 HD patients that were followed-up for a median of 45 months. Factors that could interfere with the association of sclerostin and Dkk-1 with outcomes [including carotid-femoral pulse wave velocity (PWV), parathyroid hormone (PTH), calcium-phosphate product and others] were assessed at baseline. The primary endpoint was a combination of all-cause death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, hospitalization for decompensated heart failure and new-onset atrial fibrillation. Secondary endpoints included cardiovascular and all-cause mortality. RESULTS: Cumulative freedom from the primary endpoint was significantly lower for higher tertiles of sclerostin (77.8, 69.2 and 40.7%; Tertiles 1-3, respectively; log-rank P = 0.004). The risk for the primary outcome gradually increased for higher sclerostin tertiles [Tertile 3: hazard ratio (HR) = 3.847, 95% confidence interval (CI) 1.502-9.851]. No significant association was evident between sclerostin and all-cause mortality, whereas higher sclerostin levels presented a trend towards higher risk for cardiovascular mortality. Dkk-1 levels exhibited no association with the risk of the primary or secondary endpoints. In stepwise Cox regression modelled analysis, sclerostin levels were associated with the primary outcome, independently of PTH, calcium-phosphate product, serum albumin, C-reactive protein and PWV levels (HR = 2.921, 95% CI 1.401-6.090; P = 0.004). CONCLUSIONS: High sclerostin levels are associated with lower cumulative freedom and higher risk for a composite endpoint of cardiovascular events and mortality. Dkk-1 exhibited no association with the future risk of adverse outcomes.