Enhanced oxidative stress in haemodialysis patients receiving intravenous iron therapy.

BACKGROUND: Iron balance is critical for adequate erythropoiesis and there remains much debate concerning the optimal timing and dosage of iron therapy for haemodialysis patients receiving recombinant human erythropoietin therapy. METHODS: In this study, we examined the influence of baseline ferritin level and intravenous infusion of 100 mg ferric saccharate on the oxidative status of the patients on maintenance haemodialysis. The levels of antioxidant enzymes and lipid peroxides were determined in erythrocytes and plasma of 50 uraemic patients on haemodialysis. These patients were divided into groups 1, 2, and 3, based on their baseline serum ferritin levels of <300, 301-600, and >601 microg/l, respectively. RESULTS: We found that the mean superoxide dismutase (SOD) activities in the erythrocytes were similar in the three groups of patients and did not differ from those of the age-matched controls. On the other hand, all the haemodialysis patients showed significantly higher plasma SOD activity as compared to controls. After intravenous iron infusion, group 3 patients showed the largest decrease in plasma SOD activity. The plasma glutathione peroxidase (GSHPx) activities of the patients in all three groups and the erythrocyte GSHPx activities of the patients in the groups 2 and 3 were lower than those of the healthy controls. In all three groups of patients, no difference in GSHPx activity was found before and after intravenous iron infusion. On the other hand, we found that the average baseline levels of plasma lipid peroxides of all three groups of patients were significantly higher than that of the controls. The patients in group 3 with the highest serum ferritin levels showed the highest levels of plasma lipid peroxides. More importantly, we found that after iron infusion, the patients in all three groups, particularly those in group 3, showed significantly elevated levels of plasma lipid peroxides. CONCLUSION: We demonstrated that increased oxidative stress in the blood circulation of the uraemic patients on haemodialysis is exacerbated by the elevated baseline serum ferritin levels and intravenous iron infusion. The resultant oxidative damage may contribute to the increased incidence of atherosclerosis in the patients with end-stage renal disease on long-term haemodialysis.     

静脉补铁对维持性血液透析患者微炎症及氧化应激状态的影响

目的探讨静脉补铁对维持性血液透析(MHD)患者微炎症及氧化应激状态的影响。方法选择MHD患者71例,随机分为静脉组(24例)、口服组(27例)和未补铁组(20例)。观察用药前后血红蛋白(Hb)浓度、红细胞压积(Hct)、血清铁(SI)、血清铁蛋白(SF)、转铁蛋白饱和度(TSAT)等疗效指标以及血清C反应蛋白(CRP)、白介素-1β(IL-1β)、白介素-6(IL-6)、白介素-10(IL-10)、肿瘤坏死因子-α(TNF-α)等炎症指标和血浆及红细胞中丙二醛(MDA)、过氧化物歧化酶(SOD)、谷胱苷肽过氧化物酶(CSH-px)、全血过氧化氢酶(CAT)等氧化应激指标,并监测不良反应。结果8周后,静脉组Hb水平及SF较治疗前明显改善(P<0.01);血浆及红细胞中MDA较治疗前显著升高(P<0.01),SOD、GSH-px和全血中的CAT均较治疗前显著降低(P<0.01或P<0.05);血清CRP、IL-1β、TNF-α均较治疗前显著升高(P<0.01或P<0.05)。相关性分析发现,8周后静脉组血浆MDA与SF呈正相关,MDA与TNF-α呈正相关(P<0.01)。结论静脉补铁可有效改善患者贫血及缺铁,但也加剧了其炎症及氧化应激状态。MHD患者体内炎症及氧化应激之间具有相关性,氧化应激似乎是形成慢性炎症的关键因素之一。     

Effect of intravenous iron sucrose on oxidative stress in peritoneal dialysis patients

AIM: Intravenous iron therapy is an accepted treatment for patients receiving hemodialysis and continuous ambulatory peritoneal dialysis (CAPD). Studies have found enhanced oxidative stress in hemodialysis patients receiving intravenous iron, but there are no clinical data for CAPD patients. The aim of the current study was to investigate the effect of 100 mg of intravenous iron-sucrose on the erythrocyte (RBC) antioxidant enzymes (namely, superoxide dismutase [SOD], catalase [CAT], and glutathione peroxidase [GSHPx]) and plasma malondialdehyde (MDA), an oxidant molecule, in CAPD patients. METHODS: Twelve CAPD patients receiving maintenance intravenous iron-sucrose were recruited. After a 12-hour fast, blood samples were taken for hemoglobin, iron, ferritin, and high-sensitivity C-reactive protein (hsCRP), and for baseline activities of erythrocyte antioxidant enzymes (i.e., SOD, CAT, GSHPx) and the plasma oxidant molecule, MDA. 100 mg iron-sucrose was infused over 30 minutes. Blood samples taken during (i.e., 15 minutes after commencement of infusion) and after (i.e., at 30 minutes, 60 minutes, and 6 hours after commencement) the infusion were taken for measurement of plasma iron, ferritin, TSAT, RBC SOD, CAT, GSHPx, and plasma MDA. RESULTS: Plasma iron and transferrin saturation elevated significantly during infusion (p < 0.05). There was no significant change in erythrocyte SOD, CAT, GSHPx, or in MDA activities. There was a reduction of GSHPx activity at the 30th minute (from 153.69 +/- 66.69 to 123.68 +/- 25.50 mU/mL), but it was not statistically significant. The patients were grouped according to baseline ferritin (100-400 and 400-800 ng/mL); 60th-minute MDA was significantly higher in the latter group (p < 0.05). There was no correlation between hsCRP and oxidant-antioxidant balance. No correlation was noted between RBC antioxidant enzymes or plasma oxidant molecule and ferritin levels. CONCLUSION: There are no acute deteriorating effects from a 100 mg of intravenous iron-sucrose in CAPD patients with optimal iron stores. This dose may be applied safely in CAPD patients.     

Vitamin E attenuates oxidative stress induced by intravenous iron in patients on hemodialysis

Intravenous iron application to anemic patients on hemodialysis leads to an "oversaturation" of transferrin. As a result, non-transferrin-bound, redox-active iron might induce lipid peroxidation. To test the hypothesis that vitamin E attenuates lipid peroxidation in patients receiving 100 mg of iron(III) hydroxide sucrose complex intravenously during a hemodialysis session, 22 patients were investigated in a randomized cross-over design, either with or without a single oral dose of 1200 IU of all-rac-alpha-tocopheryl acetate taken 6 h before the hemodialysis session. Blood was drawn before and 30, 60, 90, 135, and 180 min after the start of the iron infusion, and areas under the curve (AUC0-180 min) of ratios of plasma malondialdehyde (MDA) to cholesterol and plasma total peroxides to cholesterol (two markers of lipid peroxidation) were determined as the outcome variables. At baseline of the session without vitamin E supplementation, plasma alpha-tocopherol concentrations (27.6 +/- 1.8 micromol/L) and ratios of alpha-tocopherol to cholesterol (5.88 +/- 1.09 mmol/mol) were normal, plasma MDA concentrations were above normal (1.20 +/- 0.28 micromol/ L), and bleomycin-detectable iron (BDI), indicating the presence of redox-active iron, was not detectable. Upon iron infusion, BDI and MDA concentrations increased significantly (P < 0.001). BDI concentrations explained the increase over baseline in MDA concentrations (MDA = 1.29 +/- 0.075 x BDI). Vitamin E supplementation, leading to a 68% increase in plasma alpha-tocopherol concentrations, significantly reduced the AUC0-180 min of MDA to cholesterol (P = 0.004) and peroxides to cholesterol (P = 0.002). These data demonstrate that a single oral dose of vitamin E attenuates lipid peroxidation in patients on hemodialysis receiving intravenous iron. Given that intravenous iron is applied repeatedly to patients on hemodialysis, this therapeutic approach may protect against oxidative stress-related degenerative disease in the long term.     

Evaluation of oxidative stress after fractures. A preliminary study

In a preliminary attempt to see if oxidative stress occurs after major fractures, we evaluated two groups of patients sustaining a single fracture (Group A) and multiple fractures (Group B), and compared them with healthy controls (Group C). Indirect evaluation using plasma was done, as serial samples directly from bone could not be taken in humans. We measured plasma levels of malonyldialdehyde (MDA), which depicts the lipid peroxide content, and the unstable nitric Acid (indirectly through measuring reactive nitrogen intermediates and citrulline), serially over a four-week period. The endogenous ferric reducing anti-oxidant power assay (FRAP) was also done. All these have been proven to be representative of oxidative stress in other situations. We noted significant changes in these values, peaking by the 2nd and 3rd weeks post fracture, and coming down by the 4th week. This implies that oxidative stress does occur after a fracture; the initial few days are eventless, probably because the fracture causes a local region of ischaemia. Oxidant levels rise by the 2nd and 3rd week, perhaps due to callus formation and angiogenesis, which results in reperfusion at the fracture site. Oxidative stress may also be proportional to the number of bones fractured, as Group B, with multiple fractures had more elevated values. The antioxidant levels also behave similarly to combat the detrimental effect. The pro and antioxidants values then gradually decline by the 4th week, probably because by then the bone starts to organize. A better understanding of these mechanisms may help in defining the role of oxidative stresses after fracture and perhaps better define the role of antioxidants in helping fracture healing.     

静脉补铁与口服补铁治疗非透析慢性肾功能不全患者贫血效果比较的Meta分析

目的通过系统评价评估静脉补铁与口服补铁两种补铁方法对治疗非透析慢性肾功能不全(ND-CKD)患者贫血的疗效。 方法通过计算机并结合手工检索,检索EMBASE、PUBMED、Cochrane Library,检索时间截止到2017年12月1日,查找所有关于静脉补铁与口服补铁治疗ND-CKD患者贫血疗效的全部外文随机对照试验(RCT)。所得数据采用Rev Man 5.0软件进行Meta分析。 结果共纳入11项外文RCT研究,合计共1 707例患者,其中静脉补铁852例,口服补铁855例。分析结果示,与口服补铁相比,静脉补铁可显著提高血红蛋白(WMD 0.39 g/dl,95%CI,0.26～0.52;P<0.0001)、转铁蛋白饱和度(TSAT)(WMD 3.97%; 95%CI,2.24～5.7;P<0.0001)及铁蛋白水平(WMD,244.51 ng/ml,95%CI,185.51～303.52; P<0.0001);两种补铁方法的不良事件发生率无明显差别(RR,0.79; 95%CI,0.44～1.44;P＝0.45)。 结论通过系统评价得出：与口服补铁相比,静脉补铁对治疗非透析慢性肾功能不全患者的贫血疗效较好。     

The effect of different doses and types of intravenous iron on oxidative stress and inflammation in hemodialysis patients

Background: Although intravenous iron (IVI) is thought to have potential inflammatory and atherogenic effects, there are not enough studies comparing these effects in chronic hemodialysis (HD) patients. In this study, different doses and types of IVI were examined for effects on inflammation and oxidative stress. Methods: Chronic HD patients (n=101) were grouped into those not receiving IVI (group 1, n=29), those getting intermittent iron sucrose (group 2, n=25), those receiving intermittent iron dextran (group 3, n=24) and those getting a once monthly total dose of iron dextran (group 4, n=23). Malondialdehyde (MDA), advanced oxidation protein product (AOPP), C-reactive protein (CRP) and TNF-alpha levels were measured on days 0, 2, 7 and 28. Results: Groups were similar regarding age, sex, hemoglobin, iron indices and total amount of IVI given monthly. Although MDA levels at days 7 and 28, AOPP levels at days 0 and 28, CRP levels at day 28 and TNF-alpha level at day 7 were higher than at other days, there were no significant differences between the IVI groups on statistical analysis. Conclusion: The different types and doses (intermittent or once monthly total dose) of IVI treatments are well tolerated without negative effects on the markers of lipid and protein oxidation and inflammatory indices in chronic HD patients.     

Influence of intravenous vitamin E supplementation in cardiac surgery on oxidative stress: a double-blinded,randomized, controlled study

Background. I.V. infusions of vitamin E emulsion (all-rac-     

Sperm quality improvement after date seed oil in Vitro supplementation in spontaneous and induced oxidative stress

In vitro supplementation with date seed oil （DSO） can protect spermatozoa against hydrogen peroxide （HiO2）- mediated damage and can improve sperm function, possibly owing to antioxidant properties. We tested the antioxidant effects of DSO on human sperm motility, sperm viability, reacted acrosome and lipid peroxidation assessed in vitro after H202-mediated oxidative damage in spermatozoa. Sixteen patients （mean age： 35 years; range： 25-45 years） referred to the Histology-Embryology Laboratory of the Medicine Faculty of Sfax for semen analysis after 12-24 months of sexual intercourse without conception were selected. After spermiogram, sperm selection by twointerface discontinuous Sill Select gradient was performed, and selected spermatozoa were used in four experimental assays： control; incubation with 100um H2O2; incubation with 0.1% DSO; and co-incubation with 0.1% DSO and 100 um H2O2. Motility and viability were determined using World Health Organization criteria. Acrosome reaction and lipid peroxidation were assessed by staining with fluorescein isothiocyanate-Pisum sativum and spectrophotometric measurement of malondialdehyde, respectively. Results showed that incubation with H2O2 alone led to a significant increase in lipid peroxidation （57.83%, P 〈 0.05） associated with a significant decrease in sperm motility, sperm viability （after 30 min and 24 h） and percentage of reacted acrosome （P 〈 0.05）. Date seed oil im- proved sperm motility after 24 h of incubation （P 〈 0.05） and protected spermatozoa against the deleterious effects of H2O2 on motility, viability, acrosome reaction and lipid peroxidation. We conclude that supplementation with DSO may have a function in antioxidant protection against male infertility.     

Carbonyl stress induced by intravenous iron during haemodialysis.

BACKGROUND: Anaemic haemodialysis (HD) patients are treated with erythropoietin and intravenous iron for effective erythropoiesis. Since iron is a potent inducer and aggravator of pre-existing oxidative processes in HD patients, this study was aimed to evaluate the acute in vivo effect of two recommended iron doses on protein oxidation during the HD session. METHODS: Iron gluconate was intravenously administered to HD patients in doses of 62.5 or 125 mg per session. A dialysis session without iron administration served as a control for each patient. Carbonylated fibrinogen and iron profile parameters were monitored before and after each session. Plasma carbonylated fibrinogen levels from healthy subjects and HD patients before dialysis were compared. Protein associated carbonyls were identified in plasma by derivatization with 2,4-dinitrophenylhydrazine followed by western analysis and were quantified by densitometry. RESULTS: HD patients on maintenance iron showed elevated carbonylated fibrinogen compared with healthy subjects. During a HD session, carbonyls on fibrinogen further increased when 125 mg iron gluconate was administered, but no changes were detected with 62.5 mg iron gluconate or in the absence of iron. The changes in carbonylated fibrinogen during dialysis showed a significant linear correlation with the calculated values of transferrin saturation and free transferrin. CONCLUSIONS: The significant acute increase in carbonylated fibrinogen with 125 mg iron gluconate suggests that this iron dose should be used with caution. As fibrinogen is highly susceptible to iron-induced oxidation in vivo, it may serve as a marker reflecting acute iron oxidative damage and as a tool in refinement of the existing clinical dose guidelines for intravenous iron therapy.     

Drug insight: Safety of intravenous iron supplementation with sodium ferric gluconate complex

Intravenous iron is necessary for optimal management of anemia in patients receiving hemodialysis and is utilized in the majority of these patients in the US. The availability of nondextran formulations of intravenous iron has significantly improved the safety of its use. The nondextran iron formulation sodium ferric gluconate complex (SFGC) has been extensively studied in the hemodialysis population, with two large phase IV trials documenting its safety. SFGC is efficacious and, at recommended doses, is associated with a low incidence of adverse events. There have been few comparative studies of the nondextran intravenous iron preparations; however, they are known to have different pharmacokinetic characteristics. There is also evidence to indicate that these compounds differ in terms of their cytotoxic and proinflammatory properties, and their propensity to induce oxidative stress. This paper reviews the current literature on the safety of SFGC and examines the emerging safety issues surrounding the use of intravenous iron.     

Evaluation of oxidative stress in laparoscopic cholecystectomy

Purpose: We conducted a prospective study to evaluate the effect of CO₂ pneumoperitoneum and increased intra-abdominal pressure on arterial blood gases, end-tidal CO₂ (ETCO₂), nitric oxide (NO), blood and tissue malondialdehyde (MDA), and total antioxidant (TAOx) levels during laparoscopic cholecystectomy. Methods: Fifty selected patients with cholelithiasis were randomized to undergo either laparoscopic or open surgery. Blood samples were taken pre-, mid-, and postinsufflation, and 24 h postoperatively. To determine the tissue MDA level, tissue samples were taken from the gallbladder just after removal. Results: The increased levels of ETCO₂ and PCO₂, caused by CO₂ pneumoperitoneum resulted in a minimal decrease in blood pH during the laparoscopic surgery. Although low levels of blood MDA were seen 30 min after the start of laparoscopy, due to less oxidative stress response and tissue trauma, increased levels of tissue MDA levels indicated that the gallbladder was more traumatized during laparoscopic dissection and handling. NO levels were slightly lower in the laparoscopic cholecystectomy (LC) group, but there were no significant differences compared with the open cholecystectomy group (OC). TAOx levels were similar in both groups 30 min after the start the procedure, but were much lower in the LC group 24 h postoperatively. Conclusions: These findings suggest that the antioxidant defense system is stimulated less with less oxidative stress, providing further evidence to support the opinion that LC is a safe technique. Received: June 13, 2001 / Accepted: March 5, 2002     

Markers of oxidative stress after renal transplantation

Abstract An increased degree of oxidative stress (OS) in chronic renal failure (CRF) and a possible role of free radicals in CRF have already been described. However, data on OS after renal transplantation are scarce. The aim of the present study was to estimate the degree of OS in renal transplant patients. The study included four groups: 1) 15 haemodialysis patients (HD group), 2) 11 renal transplant patients with stable function (SF group), 3) 12 renal transplant patients with chronic biopsy-proven rejection (CR group), and 4) 10 healthy controls (C group). Markers of OS (malondialdehyde and thiol group levels) and antioxidant activity (glutathione peroxidase and Cu, Zn-su-peroxide dismutase) were determined in plasma and in red blood cells of all examined individuals. After successful renal transplantation a significant improvement, but not normalization, of antioxidant enzyme activities accompanied by significantly reduced lipid peroxidation were found. In the CR group the degree of OS was increased, and our results suggest that OS may be a relevant pathophysiological factor for CR development.     

静脉输注瑞芬太尼诱发大鼠心肌氧化应激水平的效应

目的 评价静脉输注瑞芬太尼诱发大鼠心肌氧化应激水平的效应.方法 健康雄性SD大鼠180只,体重250 ～ 300 g,5～6月龄,采用随机数字表法,将其随机分为15组(n=12):对照组(C组)、缺血预处理组(IPC组)、瑞芬太尼预处理组(RPC组)及静脉输注瑞芬太尼组,静脉输注瑞芬太尼组速率分别为1、5、10、20 μg·kg-1·min-1,输注时间分为15、60、120 min,分别为R1-15组、R1-60组、R1-120组、R5-15组、R5-60组、R5-120组、R10-15组、R10-60组、R10-120组、R20-15组、R20-120组和R20-120组.在动脉圆锥与左心耳之间左冠状动脉前降支下穿线,15 min后进行分组处理.采用结扎左冠状动脉前降支进行心肌缺血,IPC组心肌缺血5 min,再灌注5 min,共3个循环；RPC组静脉输注瑞芬太尼5μg·kg-1·min-15 min,暂停5 min,共3个循环.每组取6只大鼠,于分组处理30 min时进行心肌缺血30 min,再灌注120 min时取心肌组织,测定心肌梗死面积.每组取另外6只大鼠,于分组处理结束后取心肌组织,测定氧自由基、丙二醛和硝基酪氨酸的水平.结果 与C组比较,IPC组、RPC组、R1-120组、R5-60组、R5-120组和R10-60组心肌梗死面积缩小,R1-120组、R5-60组、R5-120组、R10-60组、R10-120组、R20-15组、R20-60组和R20-120组心肌组织氧自由基表达上调,R20-15组、R20-60组和R20-120组心肌组织丙二醛和硝基酪氨酸的含量升高(P＜0.05或0.01).结论 高速率和长时间输注瑞芬太尼可诱发大鼠心肌氧化应激反应.     

维生素E对维持性血液透析患者静脉补铁诱导的氧化应激及脂代谢紊乱的影响

目的 探讨口服维生素E对静脉补铁诱导的氧化应激及脂质代谢紊乱的影响.方法 选择维持性血液透析合并肾性贫血患者40例,按随机数字表法分为静脉补铁组及静脉补铁+维生素E组,每组20例.健康对照组20名.静脉补铁组所有患者行血液透析治疗时由静脉输入100 mg蔗糖铁注射液,起始为每周2～3次,完成总剂量1000 mg后改为每周或2周1次,使患者的铁蛋白维持在100～300μg/L之间.静脉补铁+维生素E组:除按上述方法补铁外同时口服维生素E 200 mg,每日2次.两组患者同时每周使用促红素治疗(每周100～150 U/kg)并检测三组治疗前和补铁组、补铁+维生素E组治疗1、6个月血脂及氧化应激指标.结果 治疗1个月后,补铁组丙二醛(MDA)、终末氧化蛋白产物(AOPP)、总胆固醇(TCH),脂蛋白Lp(a)、载脂蛋白B(ApoB)含量与治疗前比较差异有统计学意义(P＜0.05);超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)、ApoAl含量比较差异也有统计学意义(P＜0.05);而甘油三脂(TG)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)、极低密度脂蛋白(VLDL)比较则无明显变化.补铁+维生素E组TCH水平与补铁组比较差异有统计学意义(P＜0.05);而SOD、GSH-Px、AOPP、MDA、TG、LDL、HDL、VLDL载脂蛋白Al(ApoAl)、ApoB、Lp(a)比较差异均无统计学意义(P＞0.05).治疗6个月后,补铁+维生素E组SOD、GSH-Px、ApoAl与补铁组比较比较差异有统计学意义(P＜0.05);AOPP、MDA、TCH、Lp(a)、ApoB比较差异也有统计学意义(P＜0.05);而TG、LDL、HDL、VLDL则无明显变化(P＞0.05).结论 静脉补铁可以加重维持性血液透析患者体内的氧化应激水平及脂代谢紊乱.长时间口服维生素E可以改善维持性血液透析患者静脉补铁诱导的氧化应激及脂代谢紊乱.     

Erythropoietin and oxidative stress in haemodialysis: beneficial effects of vitamin E supplementation

Oxidative stress can produce profound alterations to cellular membrane lipids, impairing cell metabolism and viability. This phenomenon, previously observed in haemodialysis patients, had been proposed as a significant factor in regard to haemodialysis-related shortened red blood cells (RBC) survival. In the present study, several parameters associated with oxidative stress were evaluated in a group of haemodialysis patients either receiving erythropoietin therapy (n=12, mean erythropoietin dose 88±24 U/kg/week) or not receiving such therapy (n=20), and in 38 controls. Malonyldialdehyde (MDA, nmol/ml), an end-product of lipid peroxidation, and RBC anti-oxidant systems were measured, including RBC &agr;-tocopherol (RBC vitamin E, mg/l), RBC glutathione (GSH, nmol/mgHb), and RBC superoxide dismutase activity (SOD, U/mgHb). Plasma vitamin E concentrations were also evaluated. Finally, oral vitamin E supplementation (500 mg daily), an exogenous antioxidant, was administered for 6 months to seven patients from the dialysis group receiving erythropoietin while oxidative parameters were repeatedly evaluated and erythropoietin requirements monitored, in order to appreciate the therapeutic relevance of an antioxidant supplementation. An elevation of serum MDA was observed in all haemodialysis patients and a significant decrease in RBC vitamin E, despite normal serum vitamin E levels. Furthermore, the reduction in RBC vitamin E was more important in patients treated with erythropoietin. Vitamin E supplementation resulted in a significant increase in RBC vitamin E (from 0.3±0.1 to 1.2±0.2 mg/l of pellet) and a reduction in erythropoietin dose (from 93±24 to 74±26 U/kg/week) while maintaining stable haemoglobin concentrations. These results suggest that the oxidative stress could be one of the resistance factors to erythropoietin response in haemodialysis and that vitamin E supplementation could have a sparing effect on erythropoietin dosage requirement. Key words: antioxidant; erythropoietin; haemodiafiltration; lipid peroxidation; oxidative stress; vitamin E