title: Elastin degradation is associated with progressive aortic stiffening and all-cause mortality in predialysis chronic kidney disease.
abstract: In the large conduit arteries, elastin is important in maintaining vascular compliance. Studies in animal models suggest that elastin degradation may promote arteriosclerotic vascular changes. There is already a well-established link between aortic stiffening and mortality in the general population and in patients undergoing dialysis. Elastin degradation is mediated by several proteases, including matrix metalloproteinase 2 and cathepsin S. Elastin turnover may be inferred by measuring serum levels of elastin-derived peptides. We analyzed the serum concentration of these biomarkers, their endogenous inhibitors, and aortic pulse wave velocity in 200 patients with stages 3 and 4 chronic kidney disease and then serially in a subgroup of 65 patients over 36 months. Serum matrix metalloproteinase 2, cathepsin S, and elastin-derived peptide levels were independently associated with baseline aortic pulse wave velocity and changes in stiffness over the follow-up period. Higher matrix metalloproteinase 2 and elastin-derived peptide levels were also independently associated with preexisting cardiovascular disease. In multivariable Cox regression, higher serum elastin-derived peptide levels were independently associated with increased all-cause mortality (hazard ratio per SD increase=1.78; P=0.021). In predialysis chronic kidney disease, elastin degradation is an important determinant of arterial stiffness and is associated with all-cause mortality.
authors.affiliation: Brighton and Sussex University Hospitals National Health Service Trust, Brighton, United Kingdom. ed.smith@monash.edu
authors.forename: Edward R
authors.initials: ER
authors.lastname: Smith
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Tomlinson
authors.forename: Martin L
authors.initials: ML
authors.lastname: Ford
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: McMahon
authors.forename: Chakravarthi
authors.initials: C
authors.lastname: Rajkumar
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Holt
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood; D001774:Blood Chemical Analysis; D001783:Blood Flow Velocity / Q000502:physiology; D001794:Blood Pressure; D002403:Cathepsins / Q000097:blood; D002423:Cause of Death; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007676:Kidney Failure, Chronic / Q000175:diagnosis* / Q000401:mortality* / Q000628:therapy; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000378:metabolism*; D006435:Renal Dialysis / Q000009:adverse effects / Q000401:mortality; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D059289:Vascular Stiffness
chemical_list: D014408:Biomarkers, Tumor; D011956:Receptors, Cell Surface; C054901:elastin-binding proteins; D002403:Cathepsins; C028217:cathepsin S; D020778:Matrix Metalloproteinase 2