Association between Serum Dickkopf-1 (DKK-1) Glycoprotein and Calcific Deposits on Cardiac Valves and Carotid Intimal-Medial Thickness in Hemodialysis Patients

Abstract

Background: Cardiac valve calcification (CVC) is common in hemodialysis (HD) patients, and associated with cardiovascular and all-cause mortality. Once believed to be a passive process, it is now understood that the Wnt signaling pathway has a major role. The aim of the current study was to assess the relationship between circulating DKK-1, a negative regulator of the Wnt signaling pathway, and CVC, as well as carotid intimal-medial thickness (CIMT) in HD patients. Methods: We enrolled 74 consecutive adults on maintenance HD. Echocardiographic calcification of the mitral valve (MV) and aortic valve (AV) were detected according to Wilkins score (range 0-4), and the study of Tenenbaum et al. [Int J Cardiol. 2004 Mar; 94(1): 7-13] (range 0-4), respectively. CVC severity was calculated by a supposed score (range 0-8) that represents the sum of calcification grade of MV and AV. CVC severity was classified into absent (CVC score = 0), mild (CVC score = 1-2), moderate (CVC score = 3-4), and severe (CVC score ≥5). Demographic and biochemical data were collected in addition to serum DKK-1 levels and CIMT. Results: CVC was present in 67 patients (91.0%). There was a highly significant negative correlation between serum DKK-1 level and CVC score (r =-0.492; p ≤ 0.001), as well as CIMT (r =-0.611; p ≤ 0.001). Age and CIMT were independent determinants of CVC. Conclusions: CVC is almost present in all HD patients. DKK-1 seems to have a direct relation with CVC and CIMT in HD patients. Age is the strongest independent determinant of CVC.

Valvular Calcific Deposits and Mortality in Peritoneal Dialysis Patients: A Propensity Score-Matched Cohort Analysis

“…Consistent with previous studies [14, 15], the Kaplan-Meier test showed that patient survival was significantly lower in the CVC group than in the non-CVC group. The PSM method was applied to reduce potential confounding factors.…”

Relation of Wnt Signaling Pathway Inhibitors (Sclerostin and Dickkopf-1) to Left Ventricular Mass Index in Maintenance Hemodialysis Patients

“…It is well known that Wnt- β -catenin signaling pathway inhibition by sclerostin and Dkk-1 protects against cardiac AV and MV calcifications and both have a significant negative correlation with both valves' calcification [ 41 , 42 ]. Our study revealed that AVC and MVC had a significant negative correlation with sclerostin but a nonsignificant negative correlation with Dkk-1 which coincides with Yang et al, 2015, who reported that circulating sclerostin but not Dkk-1 is inversely associated with aortic calcifications and future cardiovascular events [ 43 ].…”

Platelets

“…Indeed, platelets release DKK-1 glycoprotein that acts as a potent antagonist to the Wnt-β-catenin signaling pathway. As a consequence, runt-related transcription factor 2 (Runx2), which is a canonical Wnt target and an osteogenic marker, gets activated ( 14 , 15 ). The upregulation of Runx2 by DKK-1 enhances the fibrotic mineralization of aortic endothelial cells under osteogenic conditions ( 13 ).…”

“…Furthermore, the inhibition of DKK-1 with a neutralizing antibody, abolished interleukin (IL)-8 and MCP-1 in human umbilical vein endothelial cells that were activated by platelets ( 16 , 17 ). Moreover, a recent clinical showed that DKK1 was associated with calcific deposits on cardiac valves in hemodialysis patients ( 15 ). In addition to the role of platelets in the blood vascular network, they mediate the formation lymphatic vessels during embryonic development and prevent the mixing of blood to the lymphatic network ( 18 ).…”