Elastin Degradation Is Associated With Progressive Aortic Stiffening and All-Cause Mortality in Predialysis Chronic Kidney Disease

Abstract

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 increaseϭ1.78; Pϭ0.021). In predialysis chronic kidney disease, elastin degradation is an important determinant of arterial stiffness and is associated with all-cause mortality. 1 Loss of elastin leads to an increase in the collagen:elastin ratio and augmented mechanical loading of stiffer collagen fibers. With age, vascular smooth muscle cells (VSMCs) become less contractile, and there are increased rates of cellular senescence and death.2 Together, these changes contribute to the loss of intrinsic elasticity and progressive stiffening of the arterial wall.3 In addition to promoting arteriosclerosis, elastin degradation also stimulates intimal VSMC invasion, neointima formation, and plaque destabilization and, thus, may also be an important factor in the pathogenesis of atherosclerotic disease. Age-associated arterial remodeling is accelerated in patients with chronic kidney disease (CKD), who have a vastly elevated cardiovascular risk compared with the general population. 5 Although not a universal finding, arterial stiffness, as measured by various methods, has been associated with decline in renal function in patients with CKD 6-8 and is a strong predictor of cardiovascular risk and all-cause mortality in patients with end-stage renal failure 9 and in non-CKD populations. 10Extracellular matrix turnover is mediated by a number of elastolytic proteinases, including Zn 2ϩ /Ca 2ϩ -dependent matrix metalloproteinases (MMPs; eg, MMP-2) and cathepsin cysteine proteases, such as cathepsin S. These proteases are mainly secreted by activated macrophage, resident myofibroblasts, or VSMCs but are also expressed intracellularly in a wide range of cell types. 4 The activities of MMP-2 and cathepsin S are partly regulated by the concentration of endog...

Serum Calcification Propensity Predicts All-Cause Mortality in Predialysis CKD

“…28,29 A detailed study description with inclusion and exclusion criteria is provided in Supplemental Material. These patients were recruited from nephrology outpatient clinics at Brighton and Sussex University Hospitals National Health Service Trust, United Kingdom, between March of 2006 and September of 2009.…”

Elastin-Derived Peptides Are New Regulators of Thrombosis

“…Generation of EDP is a typical feature of inflamm-aging 8 and correlates with occurrence of vascular stiffness, calcification, and lipid deposits. [9][10][11]21,22 A growing body of evidences now suggests that these extracellular matrix degradation products can also affect adjacent/circulating cells and contribute to the progression of age-associated vascular diseases. 21,23 In this context, we recently demonstrated that chronic injection of EDP in mice potentiates atherosclerosis development and promotes insulin resistance, 14,24 2 events that mainly occur during aging.…”

“…[25][26][27][28] However, blood EDP production has been shown to increase with the progression of various vascular diseases, such as in atherosclerosis, aneurysms, and chronic kidney disease. 22,26,28 For instance, serum EDP concentration in patients with chronic kidney disease at stages 3 and 4 has been measured at 57 μg/mL ranging from 43 to 78 μg/mL. 22 In wild-type C57Bl/6J male mice, blood EDP concentration was estimated at 7.7±1.1 mg/kg culminating at 14.2±1.1 mg/kg in high fat diet mice and 15.2±1.2 mg/kg in diabetic (db/db) mice.…”

Neurocritical Care for Patients with Kidney Dysfunction

“…Peptides derived from elastin degradation can also drive osteogenic transformation of VSMC via binding to elastin laminin receptors on VSMC [49]. In CKD patients, increased serum levels of elastinderived peptides are associated with higher aortic pulsewave velocity and overall mortality risk [50]. Elastolytic enzymes are elevated in the uremic milieu and further contribute to impaired vascular function: the matrix metalloproteinases MMP-2 and MMP-9 are elevated in the arteries from CKD patients and correlate with vascular stiffness and impaired angiogenesis [51].…”