Compensatory Vascular Remodeling in Stage 5 Chronic Kidney Disease in Response to Chronic Inflammation: An Interplay between Platelets and Lymphocytes

Abstract

INTRODUCTION: Widespread chronic inflammation in patients with stage 5 chronic kidney disease on hemodialysis (CKD5-HD) has been demonstrated by elevated levels of circulating inflammatory biomarkers, including CD40 ligand (CD40L), angiopoietin-1 (Ang-1), and angiopoietin-2 (Ang-2). As CD40L and Ang-2 are indicators of damage due to inflammation, Ang-1 demonstrates protective vascular effects, such as inflammation reduction and vascular remodeling. In CKD5-HD patients, renal death increases levels of circulating inflammatory mediators, which may be damaging to endothelial cells throughout the vascular system. Despite this chronic inflammation, complex activation of the immune system may be involved in upregulated Ang-1-mediated compensatory mechanisms to maintain vascular integrity and counter the Ang-2 response.METHODS: Plasma levels of CD40L, Ang-2, Ang-1, and PAI-1 in CKD5-HD patients (n=97) and commercially acquired controls (n=17-50) were measured using sandwich ELISA technique. Complete blood counts (CBC) and electronic medical records (EMR) were reviewed for blood values. WBC count between 4-11 K/UL and platelet count between 150-450 K/UL were considered within normal range. GraphPad Prism software was used for Mann-Whitney t-tests, Kruskal-Wallis nonparametric ANOVAs and Spearman r statistical analyses.RESULTS: CD40L (0.32 ± 0.04 ng/mL), Ang-2 (10.46 ± 0.67 ng/mL), and Ang-1 (0.62 ± 0.08 ng/mL) levels were significantly increased in CKD5-HD patients compared to controls (p<0.0001), although there was no significant difference between PAI-1 levels (p=0.9764). WBC count (6.798 ± 0.244 K/UL) was normal in 87.63% of CKD5-HD patients, and platelet count (199.1 ± 7.51 K/UL) was normal in 73.20% of patients. Correlation between platelet and WBC counts revealed strong statistical significance (r=0.5331; p<0.0001). Correlation between CD40L and Ang-1 was also significant (r=0.209; p=0.040).SUMMARY AND CONCLUSION: Elevated levels of CD40L and Ang-2 are suggestive of chronic inflammation related to CKD5-HD. As inflammatory mediators, such as these, are continually elevated in this condition, Ang-1 may be upregulated as a compensatory mechanism to dampen the inflammatory response and promote vascular remodeling of damaged vessels. Strong correlation between CD40L and Ang-1 may be indirectly related to platelet activation. Besides activating lymphocytes, CD40L activates platelets, which, in turn, release Ang-1. This may be another tactic to limit inflammation. Within the endothelium, Ang-1 reduces recruitment of lymphocytes to damaged tissue by downregulating adhesion molecules and reducing vascular leak. Additionally, Ang-1 has been demonstrated to enhance HSC quiescence in bone marrow niches. These combined effects of Ang-1 activation of the Tie2 signaling pathway may counteract chronic inflammation-mediated stress signals to help maintain homeostatic WBC and platelet counts seen in most of these patients. The overall increase in CD40L, Ang-1, and Ang-2 in CKD5-HD suggests the homeostatic role of Ang-1 in maintaining the vasculature damaged by chronic inflammation, participation in maintaining normal levels of WBC and platelets, and demonstrates its potential to be utilized for therapeutic management of CKD5-HD patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.