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Osteoprotegerin predicts cardiovascular events in patients treated with haemodialysis
Ping-Hsun Wu1,2,3, Rie Io Glerup4, My Hanna Sofia Svensson5,6
1Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Insights
Osteoprotegerin (OPG) is linked to cardiovascular events (CVEs) in hemodialysis patients, independent of inflammation. Other bone biomarkers
Area of Science:
- Bone mineral metabolism
- Cardiovascular disease biomarkers
- Proteomics
Background:
- Disturbances in bone metabolism are linked to mortality and cardiovascular events (CVEs).
- The independent association of bone-associated protein biomarkers with mortality and CVEs, separate from cytokine activation, is not well understood.
- This study investigates bone-associated proteins, inflammatory cytokines, and cardiovascular outcomes.
Purpose of the Study:
- To examine nine bone-associated proteins in hemodialysis patients.
- To assess the association of these proteins with all-cause death, cardiovascular death, and CVEs.
- To determine if these associations are independent of inflammatory cytokines.
Main Methods:
- Prospective study of 331 hemodialysis patients.
- Proximity extension proteomics assay used to measure nine bone-associated proteins.
- Random forest algorithm evaluated marker importance; Cox models analyzed associations with outcomes, adjusting for confounders and inflammatory proteins.
Main Results:
- Cathepsin L1 (CTSL1) remained associated with all-cause death; four biomarkers were linked to CVEs after initial adjustment.
- Associations between most bone markers and outcomes were attenuated after adjusting for inflammatory proteins.
- Osteoprotegerin (OPG) was the most important marker for CVEs and improved prediction models, independent of cytokine activity.
Conclusions:
- Osteoprotegerin (OPG) is associated with cardiovascular events (CVEs) independently of cytokine activity.
- The association of TRAIL receptor 2 (TRAIL-R2), cathepsin D (CTSD), and cathepsin L1 (CTSL1) with CVEs is influenced by inflammatory cytokine activity.
Background:
Disturbances in bone mineral metabolism are associated with increased mortality and cardiovascular events (CVEs). However, the association between bone-associated protein biomarkers, mortality and CVEs independent of cytokine activation remains unknown. This study aimed to investigate bone-associated protein biomarkers and the association with inflammatory cytokines and cardiovascular (CV) outcomes.
Methods:
This prospective study enrolled haemodialysis patients in Denmark between December 2010 and March 2011. Using a proximity extension proteomics assay, nine bone-associated proteins were examined: cathepsin D (CTSD), cathepsin L1 (CTSL1), dickkopf-related protein 1, fibroblast growth factor 23, leptin, osteoprotegerin (OPG), receptor activator of nuclear factor kappa-Β ligand, TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptor 2 (TRAIL-R2). The importance of the bone-associated protein markers was evaluated by a random forest (RF) algorithm. The association between bone-associated proteins with all-cause death, CV death and CVEs was analysed in multivariable Cox models adjusted for age, gender, comorbidities, laboratory data and dialysis duration.
Results:
We enrolled 331 patients [63.7% men; mean age, 65 years (standard deviation 14.6)] in a prospective cohort study with 5 years of follow-up. When adjusting for confounders, CTSL1 remained associated with all-cause death and four biomarkers were associated with CVEs. However, the association between bone markers and the outcomes was attenuated after adjusting for inflammatory proteins and only OPG remained associated with CVEs in the adjusted model. Evaluating the importance of bone markers by RF, OPG was the most important marker related to CVEs. OPG also improved the prediction of CVEs in integrated discrimination improvement and net reclassification improvement analyses.
Conclusions:
OPG, a well-known bone biomarker, was associated with CVEs independent of cytokine activity. In contrast, the association between CVEs and the remaining three bone-associated proteins (TRAIL-R2, CTSD and CTSL1) was affected by cytokine inflammation activity.
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