Individuals with beta-thalassemia develop progressive systemic iron overload, resulting in high morbidity and mortality. These complications are caused by labile plasma iron, which is taken up by parenchymal cells in a dysregulated manner; in contrast, erythropoiesis depends on transferrin-bound iron uptake via the transferrin receptor. We hypothesized that the ineffective erythropoiesis and anemia observed in beta-thalassemia might be ameliorated by increasing the amount of circulating transferrin. We tested the ability of transferrin injections to modulate iron metabolism and erythropoiesis in Hbb(th1/th1) mice, an experimental model of beta-thalassemia. Injected transferrin reversed or markedly improved the thalassemia phenotype in these mice. Specifically, transferrin injections normalized labile plasma iron concentrations, increased hepcidin expression, normalized red blood cell survival and increased hemoglobin production; this treatment concomitantly decreased reticulocytosis, erythropoietin abundance and splenomegaly. These results indicate that transferrin is a limiting factor contributing to anemia in these mice and suggest that transferrin therapy might be beneficial in human beta-thalassemia.

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.

Summary. Hydroxyl radical formation catalysed by nontransferrin-bound iron (NTBI) might contribute to transplantation-related complications. The occurrence of NTBI in 10 adult allogeneic stem cell transplantation (SCT) patients was followed for 20 d. The transferrin saturation reached 99% on d 24 and remained . 80% thereafter. NTBI, measured as bleomycin-detectable iron, was detected for 6±18 d in all patients with a peak on d 24. High transferrin saturation levels were associated with the appearance of NTBI with a threshold at 80% saturation. Prevention of the potential deleterious effects of NTBI might reduce transplantation-related morbidity.Keywords: NTBI, iron, transferrin saturation, stem cell transplantation, bleomycin-detectable iron.Erythropoiesis, the main route of iron utilization, is temporarily halted by the myeloablative conditioning given before stem cell transplantation (SCT). The toxicity of the conditioning often affects not only haematopoiesis but also other organs, including the liver from which stored iron may be liberated as a result of hepatocellular injury (McDonald et al, 1986). Liver damage may also disturb transferrin synthesis. Thus, increasing saturation of serum transferrin results both from iron accumulation and a decline in the transferrin concentration, which, together, may lead to the appearance of potentially toxic nontransferrin-bound iron (NTBI) in the circulation. PATIENTS AND METHODSTen consecutive adult patients undergoing allogeneic SCT with cyclophosphamide/total body irradiation (CY/TBI) were enrolled in the study. The conditioning consisted of CY 60 mg/kg/d on d 26 and 25 (in relation to the SCT on d 0), and TBI 12 Grays fractionated in six doses from d 24 to d 0. The immunosuppressive prophylaxis consisted of i.v. cyclosporin, a short course of methotrexate and oral methylprednisolone (Ruutu et al, 2000).The baseline samples were collected on d 210 to 26, daily samples until d 114. The transferrin saturation was calculated using the formula: serum iron (mmol/l)/serum transferrin (g/l) Â 3´98. NTBI in serum was determined using the bleomycin-detectable iron (BDI) assay (Evans & Halliwell, 1994) modified for small serum volumes. The samples were measured in parallel with a corresponding blank without the addition of bleomycin. The absorbance value of the blank was deducted from that of each sample. The reagent blank value was deducted from the absorbance values of the standards, and a standard curve between 0´1 and 3 mmol/l was calculated by linear regression from each series. According to a validation study (unpublished observations), samples with BDI levels $ 0´1 mmol/l were considered positive for NTBI. RESULTSAt baseline, the mean serum total iron and mean transferrin levels were within the reference ranges. The mean transferrin saturation was 56%, but the variation was wide (Fig 1). NTBI was present in three of the nine evaluable patients; they also had transferrin saturation . 80%.The mean serum transferrin level decreased throughout the study period. During the f...

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Redox-active iron is released into the circulation in the course of renal I/R. Reducing the amount of circulating redox-active iron by treatment with apotransferrin protects against renal I/R injury, inhibiting oxidative stress, inflammation, and loss of function. Apotransferrin could be used in the treatment of acute renal failure, as seen after transplantation of ischemically damaged organs.