Markers of Thrombogenesis Activation and Endothelial Dysfunction in End Stage Renal Disease

The pathogenesis of ESRD is complex involving inflammatory, thrombotic, and calcification processes. The leading cause of morbidity and mortality in ESRD is cardiovascular disease (CVD), accounting for 50% of all deaths. Current studies suggest that chronic inflammation is a major risk factor in ESRD. This investigation profiles markers of inflammation, thrombogenesis, and vascular dysfunction in patients with ESRD. METHODS Samples from ESRD patients (n=117) over the age of 18 on maintenance hemodialysis for at least 3 months and aged matched control samples (n=50) obtained from healthy volunteers were included in the study. The Randox Evidence Investigator (Antrim, United Kingdom) was used to measure IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, Vascular Endothelial Growth Factor (VEGF), Interferon-γ (INF-γ), Tumor Necrosis Factor-α (TNF-α), Monocyte Chemotactic Protein-1 (MCP-1), Epidermal Growth Factor (EGF), C-Reactive Protein (CRP), D-Dimer, and Thrombomodulin (TM). Plasminogen Activator Inhibitor -1 (PAI-1) and Asymmetric Dimethylarginine (ADMA) were measured using ELISA kits from Diagnostica Stago (Paris, France) and DLD Diagnostika GmbH (Hamburg, Germany), respectively. RESULTS IL-6 levels in ESRD were 4.3 times the controls. VEGF and INF-γ were both elevated at 2.6 times the controls. MCP-1, IL-8, IL-10, EGF, TNF-α, and IL-1α were elevated at 2.0, 1.6, 1.4, 1.4, 1.3, 1.2 times the controls, respectively. IL-4, IL-2, and IL-1 β levels were reduced at 0.9, 0.9, and 0.5 times the controls. TM, CRP, DDMER, PAI-1, and ADMA were increased at 5.9, 4.4, 3.0, 1.4, and 1.6 times the controls, respectively, each demonstrating statistically significant p-values. DISCUSSION The elevation of the interleukins, INF-γ, TNF-α and MCP-1 reveals intense inflammatory activation of leukocytes. The increase in these cytokines also demonstrates the vascular and tissue damage that occurs in ESRD. VEGF and EGF are both elevated in the ESRD samples indicating a state of cellular proliferation, possibly in an attempt to replace damaged tissue caused by the heightened inflammatory state. These results also demonstrate that ESRD patients have a significant upregulation in markers of thrombogenesis and endothelial dysfunction. The upregulation of the nitric oxide inhibitor ADMA points to disturbances in vascular lumen size regulation while CRP and TM suggest significant endothelial damage. Additionally, the upregulation of PAI-1 and D-Dimer indicates an activation of coagulation in ESRD. The combined disruption of endothelial regulation and endothelial damage along with the upregulation of thrombogenic and inflammatory markers helps to explain the significant prevalence of DVT, PE and CVD in ESRD. These markers should be evaluated for their roles in kidney disease risk stratification and prognosis.

No relevant conflicts of interest to declare.