Enhanced oxidative stress in haemodialysis patients receiving intravenous iron therapy.
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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. (+info)
Detection of acute myocardial infarction by 99mTc-labeled D-glucaric acid imaging in patients with acute chest pain.
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Definitive diagnosis of acute myocardial infarction early in the process is often difficult. An imaging agent that localized quickly and specifically in areas of acute necrosis could provide this critical diagnostic information. To determine whether imaging with 99mTc-labeled D-glucaric acid (GLA) could provide this information, we imaged a group of patients presenting with symptoms suggestive of acute infarction. METHODS: Twenty-eight patients presenting to the emergency department with symptoms highly suggestive of acute infarction were injected with 99mTC-GLA and imaged about 3 h later. RESULTS: The sensitivity of lesion detection was remarkably time dependent. Fourteen patients with acute infarction injected within 9 h of onset of chest pain had positive scans, even in the presence of persistent occlusion. The remaining 14 patients had negative scans. Nine patients with negative scans had acute infarction but were injected more than 9 h after onset of chest pain. The final diagnosis in the remaining 5 patients was unstable angina (3 injected <9 h and 2 injected >9 h after onset of chest pain). Six patients were reinjected with 99mTc-GLA 4-6 wk after their initial study to determine whether persistent positive scans occurred with this agent. All 6 had negative scans. CONCLUSION: This study suggests that 99mTc-GLA localizes in zones of acute myocardial necrosis when injected within 9 h of onset of infarction. (+info)
Different induction of gulonolactone oxidase in aromatic hydrocarbon-responsive or -unresponsive mouse strains.
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The role of aromatic hydrocarbon receptor (AhR)-mediated signal transduction pathways was investigated in the regulation of ascorbate synthesis by using Ah-responsive and Ah-unresponsive mouse strains. In vivo 3-methylcholanthrene treatment increased hepatic and plasma ascorbate concentrations only in the Ah-responsive strain. The mRNA level of gulonolactone oxidase and the microsomal ascorbate production from p-nitrophenyl glucuronide, D-glucuronic acid or gulonolactone in the liver of Ah-responsive and Ah-unresponsive mice were compared. In Ah-responsive mice, these parameters were higher originally, and they further increased upon in vivo addition of 3-methylcholanthrene, while in Ah-unresponsive mice the treatment was not effective. These results suggest that the transcription of gulonolactone oxidase gene is regulated by an Ah receptor-dependent signal transduction pathway. (+info)
A common regulator for the operons encoding the enzymes involved in D-galactarate, D-glucarate, and D-glycerate utilization in Escherichia coli.
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Genes for D-galactarate (gar) and D-glucarate (gud) metabolism in Escherichia coli are organized in three transcriptional units: garD, garPLRK, and gudPD. Two observations suggested a common regulator for the three operons. (i) Their expression was triggered by D-galactarate, D-glucarate, and D-glycerate. (ii) Metabolism of the three compounds was impaired by a single Tn5 insertion mapped in the yaeG gene (proposed name, sdaR), outside the D-galactarate and D-glucarate systems. Expression of the sdaR gene is autogenously regulated. (+info)
Catalytically active iron and bacterial growth in serum of haemodialysis patients after i.v. iron-saccharate administration.
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BACKGROUND: I.v. iron is commonly administered to haemodialysis patients suffering from anaemia to improve their response to erythropoietin therapy. It has been unclear whether routinely used doses of i.v. iron preparations could result in iron release into plasma in amounts exceeding the iron binding capacity of transferrin. Here, we have studied the effect of 100 mg of iron saccharate given as an i.v. injection on transferrin saturation and the appearance of potentially harmful catalytically active iron. METHODS: We followed serum iron, transferrin and transferrin-saturation before and 5-210 min after administration of iron saccharate in 12 patients on chronic haemodialysis due to end-stage renal disease. We measured catalytically active iron by the bleomycin-detectable iron (BDI) assay and transferrin iron forms by urea gel electrophoresis, and studied iron-dependent growth of Staphylococcus epidermidis inoculated into the serum samples in vitro. RESULTS: The iron saccharate injection resulted in full transferrin saturation and appearance of BDI in the serum in seven out of the 12 patients. BDI appeared more often in patients with a low serum transferrin concentration, but it was not possible to identify patients at risk based on serum transferrin or ferritin level before i.v. iron. The average transferrin saturation and BDI level increased until the end of the follow-up time of 3.5 h. The appearance of BDI resulted in loss of the ability of patient serum to resist the growth of S. epidermidis, which was restored by adding iron-free apotransferrin to the serum. Iron saccharate, added to serum in vitro, released only little iron and promoted only slow bacterial growth, but caused falsely high transferrin saturation by one routinely used serum iron assay. CONCLUSIONS: The results indicate that 100 mg of iron saccharate often leads to transferrin oversaturation and the presence of catalytically active iron within 3.5 h after i.v. injection. As catalytically active iron is potentially toxic and may promote bacterial growth, it may be recommendable to use dosage regimens for i.v. iron that would not cause transferrin oversaturation. (+info)
A randomized study of oral vs intravenous iron supplementation in patients with progressive renal insufficiency treated with erythropoietin.
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BACKGROUND: Correction of anaemia as a result of renal failure improves cardiovascular function and also provides significant cognitive and emotional benefits. The most appropriate route for iron supplementation has not been determined for patients with chronic renal failure who are not yet on dialysis. METHODS: Forty-five anaemic patients with progressive renal insufficiency (PRI) were prospectively randomized to receive oral (ferrous sulphate 200 mg tds) or intravenous (300 mg iron sucrose monthly) iron treatment. Erythropoietin (rHuEpo) was simultaneously commenced and the dose adjusted according to a pre-established protocol. RESULTS: There were no significant differences in baseline patient characteristics between the two groups. The average follow-up was 5.2 months. Three patients suffered possible allergic reactions to iron sucrose. Haemoglobin response and changes in red cell hypochromasia were similar in the two groups, but serum ferritin was significantly higher in the intravenous group. The starting dose of rHuEpo could be temporarily discontinued in 43% of patients on oral iron and 33% of patients receiving iron sucrose (NS). rHuEpo was increased after 3 months in 9% of patients on oral iron and 19% of patients receiving iron sucrose (NS). Final doses of rHuEpo were 33.5 (0-66) and 41.6 (0-124) U/kg/week respectively in the oral and intravenous groups (NS). Although gastro-intestinal symptoms were more commonly reported in patients taking oral iron, these were mild according to scores on visual analogue scales. Dietary protein and energy intake were not significantly different in the two groups at 0, 3 and 6 months. CONCLUSIONS: In pre-dialysis patients, the efficacy of monthly 300 mg iron sucrose given intravenously is not superior with regard to haemoglobin response and rHuEpo dose as compared with a daily oral dose of 600 mg of ferrous sulphate or equivalent. Where intravenous iron is preferred, lower doses may help to reduce the incidence of allergic or "free iron" reactions, especially in patients with low body mass. (+info)
Experience with a large dose (500 mg) of intravenous iron dextran and iron saccharate in peritoneal dialysis patients.
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OBJECTIVE: To compare efficacy in anemia correction and side effects of large doses of intravenous (IV) iron dextran and iron saccharate preparations in peritoneal dialysis (PD) patients. SETTING: Tertiary-care teaching hospital of University of Toronto. DESIGN: Retrospective analysis of 379 PD patients who attended PD clinics in past 5 years. Of these 379 patients, 62 were selected to receive IV iron based on ferrokinetic markers of iron deficiency, noncompliance to or ineffectiveness of oral iron, or increased erythropoietin (EPO) requirement. INTERVENTION: Sixty-one patients received two IV iron injections of 500 mg each, 1 week apart, 33 patients received iron dextran, 23 received iron saccharate, and 5 received both iron dextran and iron saccharate. One patient developed anaphylaxis to a test dose of iron dextran and was excluded from further therapy. Blood samples were collected before and 3 and 6 months after iron infusions. RESULTS: At 3 months, the group's average hemoglobin rose from 98.3+/-18.3 g/L to 110.6+/-16.4 g/L (p < 0.0001). Ferritin rose from 104.9+/-115.4 microg/L to 391.5+/-294.1 microg/L (p < 0.0001), and transferrin saturation from 0.17+/-0.07 to 0.26+/-0.19 (p < 0.0001). Erythropoietin requirements fell from 7278.7 IU/week to 5900 IU/week (p < 0.01). Five of the 34 patients who received iron dextran developed minor side effects and 1 patient had anaphylaxis to the test dose. Of the 23 patients who received iron saccharate, 1 had an anaphylactic reaction and 2 had transient chest pain, which subsided without therapy. Overall, there were more side effects with iron dextran (7.4% of injections) compared to the iron saccharate group (4.3% of injections), but this difference was statistically insignificant. Although statistically insignificant, there was an increase in the number of peritonitis episodes during the 6 months after IV iron infusion, especially with iron dextran, compared to the peritonitis episodes during the 6 months before iron infusions. CONCLUSION: Our study indicates that IV iron in PD patients is effective in restoring iron stores and in decreasing EPO requirements. One anaphylactic reaction occurred in each group. Our data suggest that as much caution be exercised with iron saccharate as with iron dextran. The slight trend toward increased peritonitis rates after iron infusions needs to be investigated in a larger group of patients. (+info)
Efficacy of a low-dose intravenous iron sucrose regimen in peritoneal dialysis patients.
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OBJECTIVE: Sufficient iron substitution leads to a decrease in the required recombinant human erythropoietin (rHuEPO) dose and/or an increased hematocrit in dialysis patients. Intravenous (i.v.) application of larger doses of iron sucrose may be associated with hyperferritinemia, appearance of catalytically free iron, and impaired phagocyte function. Therefore, we investigated the effectiveness of a low-dose i.v. iron regimen in peritoneal dialysis (PD) patients. PATIENTS AND INTERVENTIONS: Forty-five PD patients were followed over a period of 1 year. Serum ferritin, serum transferrin saturation, and hemoglobin were measured monthly. In cases of absolute iron deficiency (serum ferritin < 100 microg/L), 50 mg iron sucrose was given i.v. every second week. In cases of functional iron deficiency (ferritin > or = 100 microg/L and transferrin saturation < 20%) and in iron repleted patients (ferritin > or = 100 microg/L and transferrin saturation > or = 20%), 50 mg i.v. iron sucrose was applied monthly. Iron therapy was stopped in cases of acute infection (until complete recovery) and when serum ferritin level was > or = 600 microg/L. RESULTS: To analyze the influence of iron substitution on erythropoiesis and rHuEPO requirements, the EPO resistance index (ERI; quotient of rHuEPO dose in units/kilogram/week and hemoglobin in grams per deciliter) was calculated every 3 months. The ERI decreased significantly during the course of the study in the whole patient group (p = 0.009) as well as in the subgroup of 21 patients with absolute iron deficiency (p = 0.01). A nonsignificant decrease in the ERI was observed within the group of 14 iron repleted patients (p = 0.5). There was no significant change in the ERI in 10 patients with functional iron deficiency (p = 0.6). CONCLUSION: The low-dose i.v. iron regimen used in this study substantially decreased rHuEPO requirements in patients with absolute iron deficiency and was effective in maintaining iron stores in iron repleted patients. However, in the absence of significant hyperparathyroidism, aluminum toxicity, or inadequate dialysis, it did not improve the ERI in patients with functional iron deficiency. (+info)