Elevated Circulating Osteoprotegerin Levels in the Plasma of Hemodialyzed Patients With Severe Artery Calcification

Abstract

We studied the correlations between circulating osteoprotegerin (OPG) level and radial artery calcification (RAC) assessed histologically and carotid artery intima-media thickness (CCA-IMT). Moreover, we studied the relationship between OPG levels and all-cause and cardiovascular (CV) mortality during a 5-year observation period. The study comprised 59 CKD patients (36 hemodialyzed (HD), 23 predialysis). The biochemical parameters included: creatinine, calcium, phosphate, intact parathormone, C-reactive protein, interleukin-6, tumor necrosis factor receptor II (TNFRII), transforming growth factor-β, hepatocyte growth factor, fibroblast growth factor 23, osteonectin (ON), osteopontin, osteoprotegerin, and osteocalcin. CCA-IMT and the presence of atherosclerotic plaques was assessed by ultrasound. Fragments of radial artery obtained during creation of HD access were prepared for microscopy and stained for calcifications with alizarin red. RAC was detected in 34 patients (58%). In multiple regression adjusted for dialysis status, TNFRII, ON and Framingham risk score (FRS) were identified as the independent predictors of OPG. Serum OPG above the median value of 7.55 pmol/L significantly predicted the presence of RAC in simple logistic regression (OR 5.33; 95%CI 1.39-20.4; P = 0.012) and in multiple logistic regression adjusted for FRS, dialysis status and CCA-IMT values (OR 6.56; 95%CI 1.06-40.6; P = 0.036). OPG levels above the median were associated with higher CCA-IMT values (1.02 ± 0.10 vs. 0.86 ± 0.13; P < 0.001) and predicted the presence of atherosclerotic plaques in carotid artery (OR 14.4; 95%CI 2.84-72.9; P < 0.001), independently of FRS, dialysis status and RAC. In this study, elevated serum OPG levels correlated with higher CCA-IMT, the presence of atherosclerotic plaques and the severity of the RAC independently of each other. During follow-up, 25 patients (42%) died, including 21 due to CV causes. In multiple Cox regression, OPG above the median predicted overall survival independently of dialysis status, Framingham risk score, CCA-IMT above the median value, and the presence of atherosclerotic plaques in CCA, but not independently of RAC. We postulate that circulating OPG may play a dual role as a marker for both medial arterial calcification and atherosclerosis, hence it seems to be a valuable tool for assessing CV risk in patients with CKD. OPG might be an early indicator of all-cause mortality in CKD patients with advanced medial arterial calcification.

The relationship between malnutrition risk and inflammatory biomarkers in outpatient geriatric population

“…It is also known that high level of cytokines TNFα, IL-6, and IL-2 are associated with a decrease in food intake and may contribute to anorexia. Other studies have demonstrated the relationship between malnutrition and inflammatory markers in specific population groups, including in children [24,25], dialysis patients [14,15,18,[26][27][28][29][30], patients with neoplasms [19,31,32], and patients with autoimmune diseases [33,34].…”

“…The role and significance of OPG seems to be broad and not fully understood. Krzanowski et al postulated that OPG might be an early indicator of all-cause mortality in patients with chronic kidney disease and advanced medial arterial calcification [14]. Janda et al found that elevated serum OPG levels may be useful as a prognostic marker of cardiovascular risk in dialyzed patients [15].…”

“…Increased levels of high sensitive C-reactive protein (hsCRP), TNFα and its soluble receptors, IL-6, IL-1, IL-8, IL-18 were found in different chronic conditions such as atherosclerosis, cardiovascular disease, chronic heart failure (CHF), diabetes, chronic obstructive pulmonary disease, chronic kidney disease, and cancer. Also osteoprotegerin (OPG), a member of TNFα receptor superfamily turned out to be a predictor of complications, cardiovascular risk, and of poor prognosis in many chronic conditions [14][15][16][17]. Increased level of OPG was predictive of hospitalization for heart failure in patients with advanced systolic CHF and ischemic heart disease independently of conventional risk markers [16].…”

Regulation of fibroblast growth factor 23 (FGF23) in health and disease

“…Inflammation is a common ground of many of the diseases associated with elevated FGF23 levels. Indeed, enhanced inflammation in CKD or in some other diseases have been independently associated with an increase in FGF23 levels. These results suggest that inflammation could be a trigger of FGF23 production.…”

Loss of PKCα increases arterial medial calcification in a uremic mouse model of chronic kidney disease

“…The pattern and localization of calcification detected in this study are consistent with that observed in previous studies using this uremic DBA/2 mouse model of arterial medial calcification 26,[43][44][45] ; that is, calcification was focally distributed and 'patchy'. In human specimens where larger calcified deposits have been observed, 'patchy' or focally distributed calcifications have also been detected 5,[46][47][48] . Therefore, the similar patterns of calcification observed in both mouse models and humans validates the translational validity to the human condition of advanced CKD.…”