RESUMO
BACKGROUND: Hemodialysis patients have a markedly increased risk of cardiovascular (CV) morbidity and mortality. Oxidative stress plays a pathogenic role in the progression of atherosclerosis and CV disease among chronic hemodialysis patients. The 8-hydroxy-2'-deoxyguanosine (8-OHdG) content in leukocyte deoxyribonucleic acid (DNA) has been shown as a sensitive and well-known biomarker of oxidant-induced DNA damage in chronic hemodialysis patients. METHODS: We conducted a retrospective cohort study to investigate the association of leukocyte 8-OHdG and CV events and deaths in patients of chronic hemodialysis. In this study, 217 chronic hemodialysis patients were recruited from 2016 to 2021. The 8-OHdG content of leukocyte DNA was measured by a high-performance liquid chromatography electrochemical detection method. Study outcomes were CV events as well as CV and all-cause deaths. The patients were followed until May 2021. RESULTS: The median follow-up period was 34.8 months. At the end of May 2021, 57 first CV events and 89 all-CV events occurred. Among the first and all CV events, 17 (29.8%) and 32 (36.0%) were fatal, respectively. Multivariate Cox regression analysis showed per 1/10 5 dG increment in leukocyte 8-OHdG values increased risk of CV events (adjusted hazard ratio [aHR], 1.19; 95% CI, 1.10-1.41; p < 0.001), CV death (aHR, 1.27; 95% CI, 1.03-1.72; p = 0.034), and all-cause death (aHR, 1.11; 95% CI, 1.01-1.30; p = 0.038). CONCLUSION: This is the first study to demonstrate that oxidative stress assessed by 8-OHdG levels of leukocyte DNA predicted CV events as well as CV and all-cause deaths among chronic hemodialysis patients.
RESUMO
BACKGROUND: The association between intravenous (IV) iron administration and outcomes in hemodialysis (HD) patients is still debated. Therefore, this study was aimed to assess the relationship between the IV administration of ferric chloride hexahydrate (Atofen®) and cardiovascular (CV) outcome and the interaction between iron-induced oxidative stress and endothelial dysfunction in chronic HD patients. METHODOLOGY/PRINCIPAL FINDINGS: A cohort of 1239 chronic HD patients was recruited. In a follow-up of 12 months, Kaplan-Meier survival curves showed that higher doses of IV Atofen associated with higher risks for CV events and deaths in HD patients. In multivariate Cox models, compared to no iron supplementation, IV Atofen administration was an independent predictor for CV events and overall mortality. However, the nature of the observational cohort study possibly bears selection bias. We further found that IV Atofen enhanced the superoxide production of mononuclear cells (MNCs), the levels of circulating soluble adhesion molecules, and the adhesion of MNCs to human aortic endothelial cells (HAECs). In vitro experiments showed that Atofen increased the expression of intracellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 in HAECs and aggravated the endothelial adhesiveness in a dose-dependent manner. These iron-induced changes were significantly attenuated by the co-treatment of HAECs with N-acetylcysteine and inhibitors of NADPH oxidase, nuclear factor κB, and activator protein-1. CONCLUSION: A cumulative dose of IV Atofen >800 mg within 6 months was associated with an adverse CV outcome and a higher mortality among chronic HD patients. The detrimental effects of IV iron supplementation were partly due to the increased oxidative stress and induction of MNC adhesion to endothelial cells, a pivotal index of early atherogenesis.
