Intravenous Iron Exacerbates Oxidative DNA Damage in Peripheral Blood Lymphocytes in Chronic Hemodialysis Patients

Abstract

Patients undergoing maintenance hemodialysis have elevated markers of oxidative stress, but the reasons for this are not fully understood. Intravenous administration of iron, which many of these patients receive, may provoke the generation of bioactive iron, which enhances oxidative stress and lipid peroxidation. In this study, 110 hemodialysis patients were randomly assigned to five groups that were administered single intravenous doses of iron sucrose, ranging from 20 to 500 mg. A time-and dosage-dependent rise in lymphocyte 8-hydroxy-2Ј-deoxyguanosine (8-OHdG) levels in lymphocyte DNA, a marker of oxidative DNA damage, with a significant increase at 2 h after intravenous iron of Ն200 mg (P Ͻ 0.05). Four weeks later, patients were randomly assigned to weekly iron sucrose (100 mg of elemental iron) or saline for 12 wk, and 89 patients completed the study. Mean lymphocyte 8-OHdG content was significantly higher in patients receiving intravenous iron compared with control subjects (P Ͻ 0.05), especially in those with ferritin levels Ͼ500 g/L. In addition, flow cytometric techniques revealed increased production of reactive oxygen species in lymphocytes among those treated with intravenous iron. Treatment with intravenous iron but not saline was also associated with decreased plasma ascorbate and ␣-tocopherol levels and increased oxidized glutathione/reduced glutathione ratio (P Ͻ 0.05). In summary, intravenous iron sucrose provokes oxidative damage to peripheral blood lymphocyte DNA in hemodialysis patients, especially among those with high levels of ferritin. 19: 181719: -182619: , 200819: . doi: 10.1681 Cumulative evidence indicates that oxidative stress frequently occurs in patients undergoing maintenance hemodialysis (HD) as a result of a decrease of antioxidant defenses and an overproduction of reactive oxygen species (ROS), such as superoxide anion, hydrogen peroxide, hydroxyl radical, and hypochlorous acid. 1-4 Direct measurement of ROS is difficult because of its lower plasma levels and shorter half-life; however, measurement of oxidative byproducts combined with the assessment of antioxidant levels become more feasible. Oxidative damage to cellular constituents, such as membrane lipids, protein, and DNA, are fingerprints of oxidative byproducts. Recently, investigators disclosed that 8-hydroxy 2Ј-deoxyguanosine (8-OHdG) is one of the most abundant oxidative DNA products and a sensitive DNA damage marker because it can be detected by a HPLC electrochemical detection method in the femtomole range. 5,6 Our previous J Am Soc Nephrol

GST M1 Polymorphism Associates with DNA Oxidative Damage and Mortality among Hemodialysis Patients

“…The observed difference cannot be completely accounted for by the differences in the major confounders that may affect the levels of 8-OHdG, such as age, smoking status, diabetes status, and iron overload. 2,30,31 Moreover, multivariate regression analysis validated the independent effect of the GST M1(Ϫ) genotype on leukocyte 8-OHdG content (Table 3). Our findings confirm similar results presented in the previous reports in which, in human leukocytes and lung tissue, GST M1 null individuals showed detectable DNA adducts, whereas GST M1 active individuals did not.…”

Considerations and Challenges in Defining Optimal Iron Utilization in Hemodialysis

“…78,82 Despite clear clinical ramifications, data remain insufficient to make firm recommendations regarding the maximum single, weekly, or cumulative dose of IVI or to support a particular limit of iron indices above which iron administration is clearly contraindicated. Given current levels of exposure to IVI, these data raise the possibility of large-scale harm to dialysis patients from current practices.…”

New Options for Iron Supplementation in Maintenance Hemodialysis Patients

“…Although IV iron preparations are effective, their indiscriminate use can have serious adverse consequences that may go undetected in short-term clinical trials. As described in a recent review, 9 use of IV iron preparations can increase the risk for infection, 10,11 cause oxidative stress, [12][13][14][15][16][17][18][19] promote cardiovascular disease, 11,[20][21][22][23][24] and lead to iron overload. [25][26][27][28] In addition, some IV iron preparations cause life-threatening anaphylactic reactions in susceptible individuals.…”