Transferrin Receptor Values Research Articles

Tumor cell-imposed iron restriction drives immunosuppressive polarization of tumor-associated macrophages

BackgroundTumor-associated macrophages (TAM) are immunosuppressive cells that contribute to impaired anti-cancer immunity. Iron plays a critical role in regulating macrophage function. However, it is still elusive whether it can drive the functional polarization of macrophages in the context of cancer and how tumor cells affect the iron-handing properties of TAM. In this study, using hepatocellular carcinoma (HCC) as a study model, we aimed to explore the effect and mechanism of reduced ferrous iron in TAM.MethodsTAM from HCC patients and mouse HCC tissues were collected to analyze the level of ferrous iron. Quantitative real-time PCR was used to assess M1 or M2 signature genes of macrophages treated with iron chelators. A co-culture system was established to explore the iron competition between macrophages and HCC cells. Flow cytometry analysis was performed to determine the holo-transferrin uptake of macrophages. HCC samples from The Cancer Genome Atlas (TCGA) were enrolled to evaluate the prognostic value of transferrin receptor (TFRC) and its relevance to tumor-infiltrating M2 macrophages.ResultsWe revealed that ferrous iron in M2-like TAM is lower than that in M1-like TAM. In vitro analysis showed that loss of iron-induced immunosuppressive M2 polarization of mouse macrophages. Further experiments showed that TFRC, the primary receptor for transferrin-mediated iron uptake, was overexpressed on HCC cells but not TAM. Mechanistically, HCC cells competed with macrophages for iron to upregulate the expression of M2-related genes via induction of HIF-1α, thus contributing to M2-like TAM polarization. We further clarified the oncogenic role of TFRC in HCC patients by TCGA. TFRC is significantly increased in varieties of malignancies, including HCC, and HCC patients with high TFRC levels have considerably shortened overall survival. Also, TFRC is shown to be positively related to tumor-infiltrating M2 macrophages.ConclusionsCollectively, we identified iron starvation through TFRC-mediated iron competition drives functional immunosuppressive polarization of TAM, providing new insight into the interconnection between iron metabolism and tumor immunity.

Prognostic Value of Transferrin Receptor-1 (CD71) Expression in Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is the commonest childhood cancer. Transferrin receptor 1 (CD71) is a trans-membrane glycoprotein which has important role in iron homeostasis by acting as a gatekeeper regulating iron uptake from transferrin and is an attractive target for anti-cancer agents, particularly those that aim to induce lethal iron deprivation in malignant hematopoietic cells. To assess the prognostic value of Transferrin receptor -1 (CD71) in children with newly diagnosed ALL. This study was carried out on 75 patients with newly diagnosed ALL. Transferrin receptor-1 expression was analyzed on the bone marrow blasts by flow cytometry at time of diagnosis with positive CD71 expression is considered when ≥20% of malignant cells express this marker while negative expression is considered when <20% of malignant cells express this marker. Transferrin receptor-1 positive expression was detected in 45 patients (60%) while negative expression was found in the remaining 30 patients (40%). CD71 expression was significantly higher on T- ALL patients compared with B-ALL patients. Positive CD71 expression at diagnosis was significantly associated with bad clinical and laboratory prognostic factors as lymphadenopathy, higher white blood cell count, higher hemoglobin level, lower platelets count, and higher blast cells in peripheral blood and bone marrow and higher lactate dehydrogenase levels'. There were significant differences in disease free survival (DFS) and overall survival (OS) between positive and negative CD71 expression groups with significantly shorter DFS and OS in positive CD71 expression group compared to negative group. 'Positive Transferrin receptor -1 (CD71) expression in patients with ALL is adverse prognostic factor and should be taken in consideration in designing future therapeutic strategies based on patient- specific risk factors'.

Association of Fecal Markers of Environmental Enteric Dysfunction with Zinc and Iron Status among Children at First Two Years of Life in Bangladesh.

.Environmental enteric dysfunction (EED) causes gut inflammation and increased intestinal permeability leading to deficiencies in micronutrients such as zinc and iron. Fecal markers such as myeloperoxidase (MPO), neopterin (NEO), and alpha-1-anti-trypsin (AAT) can predict EED. The aim of this study was to examine the association between fecal markers of EED with zinc and iron status among children at first 2 years of life. Malnutrition and Enteric Disease Study Bangladeshi birth cohort data were used to conduct this analysis. Multivariable analyses using generalized estimating equations were performed to test the association between individual fecal markers with zinc or iron status of the children. A total of 265 children were enrolled in the study (male:female = 1:1). Of the 627 stool samples collected (N = 222 children), 535, 511, and 577 were accompanied by zinc, ferritin, and soluble transferrin receptor values, respectively. Median (interquartile range [IQR]) values of AAT, MPO, and NEO were 0.33 (0.18–0.62) mg/g, 3,895.42 (1,563.76–8,432.82) ng/mL, and 890.81 (331.57–2,089.04) nmol/L, respectively. Overall, 60%, 71%, and 97% of samples were above the values considered normal in nontropical settings for AAT, MPO, and NEO, respectively. High AAT levels were significantly associated with low ferritin values after adjusting for age and gender (coefficient = −5.85; 95% confidence interval = −11.23 to −0.47; P value = 0.03). No such association was found between AAT and plasma zinc status. Myeloperoxidase and NEO were not associated with plasma zinc or iron status. The study results imply the importance of enteric protein loss in contributing to reduced ferritin levels at first 2 years of life.

Association between menarche and iron deficiency in non-anemic young women.

BackgroundThe prevalence of iron deficiency (ID) among non-pregnant, reproductive-age US women significantly exceeds rates among males. In clinical practice ID screening relies on hemoglobin, a late-stage indicator of ID. As a single, low-cost laboratory test to diagnose ID before anemia develops is lacking, the study objective was to improve ID screening by identifying risk factors among non-anemic, iron-deficient reproductive age women.MethodsCross-sectional data were from the National Health and Nutrition Examination Survey (NHANES) 2003–2010. Hemoglobin identified non-anemic women. ID was defined using the body iron formula, requiring ferritin and transferrin receptor values. Logistic regression assessed the association of sociodemographic, behavioral, and reproductive risk factors in an anemia-based conceptual framework with non-anemic reproductive age women (12–49 years) with ID, as well as subsets of younger (12–21 years) and older (22–49 years) women, recognizing that risks may differ by age.ResultsAmong 6216 women, 494 had ID (prevalence was 8.0%, 95% CI 7.3%, 8.6%). Among non-anemic younger women, 250 (8.7%, 95% CI 7.7%, 9.8%) had ID, compared to 244 (7.3%, 95% CI 6.4%, 8.2%) older women. Among younger women, menstruation for over 3 years was the only variable significantly associated with non-anemic ID (risk ratio 3.18, 95% CI 2.03, 4.96). No other significant risk factors were identified.ConclusionMenstrual years was the only risk factor significantly associated with ID among non-anemic younger women. The negative results suggest ID risk factors among non-anemic women may need to be considered separately from those associated with ID anemia.

Iron stores in regular blood donors in Lagos, Nigeria

BackgroundApart from challenging the bone marrow to increase its red cell production, thereby producing more blood for the donor, regular blood donation has been shown to have several benefits, one of which is preventing accumulation of body iron which can cause free radical formation in the body. This study was carried out to assess body iron stores in regular blood donors.MethodsA total of 52 regular (study) and 30 first-time (control) volunteer blood donors were studied prospectively. Twenty milliliters of venous blood was drawn from each subject, 5 mL of which was put into sodium ethylenediamine tetra-acetic acid specimen bottles for a full blood count, including red blood cell indices. The remaining sample was allowed to clot in a plain container, and the serum was then retrieved for serum ferritin, serum iron, and serum transferrin receptor measurement by enzyme-linked immunosorbent assay.ResultsMean hemoglobin and packed cell volume in the study group (13.47 ± 2.36 g/dL and 42.00 ± 7.10, respectively, P = 0.303) were not significantly higher than in the control group (12.98 ± 1.30 g/dL and 39.76 ± 4.41, respectively, P = 0.119). Mean serum ferritin was 102.46 ± 80.26 ng/mL in the control group and 41.46 ± 40.33 ng/mL in the study group (P = 0.001). Mean serum ferritin for women in the study group (28.02 ± 25.00 ng/mL) was significantly lower than for women in the control group (56.35 ± 34.03 ng/mL, P = 0.014). Similarly, men in the study group had a lower mean serum ferritin (48.57 ± 45.17 ng/mL) than men in the control group (145.49 ± 87.74 ng/mL, P = 0.00). The mean serum transferrin receptor value was higher in the study group (1.56 ± 0.88 μg/mL) than in the control group (1.19 ± 0.38 μg/mL, P = 0.033).ConclusionThese findings suggest that hemoglobin concentration, packed cell volume, and serum iron levels are not significantly affected by regular blood donation and that regular blood donors appear to have reduced iron stores compared with controls.

Iron deficiency and susceptibility to infections: evaluation of the clinical evidence

Iron is a fundamental nutrient for human and microbial life. We sought to examine the association of iron deficiency versus normal iron status with the susceptibility to infections. A systematic search in the PubMed and Scopus databases was performed to identify relevant clinical studies. Six studies (including a total of 1,422 participants) met the inclusion criteria: four prospective cohort (859 participants), one retrospective case-control (115 participants), and one retrospective cohort study (448 participants). Intensive care unit (ICU)-acquired and postoperative infections were more common in patients with iron deficiency than among those with normal iron status in two studies, while no difference was reported in another study. In one study examining pregnant women with normal mean iron values, higher soluble transferrin receptor values independently predicted vaginosis-like microflora. Iron deficiency anemia was an independent predictor of respiratory tract infections in one study, and postoperative urinary tract infections were more common in patients with iron deficiency anemia in another. The limited available evidence suggests that individuals with iron deficiency and those with iron deficiency anemia may be more susceptible to infections than patients with normal iron status. Future studies should elucidate further these findings.

The “Thomas Plot”: Its Usefulness in the Assessment of Iron Status in Anemia.

A diagnostic plot to assess iron status in anemia of chronic disorders (ACD) has recently been developed (Thomas C, Thomas L. Lab Hematol 2005). The plot is based on the relation between the ratio of the soluble transferrin receptor value to the logarithm of the ferritin value (sTfR/log sFt) and the RET-He parameter -reticulocyte hemoglobin equivalent-. A different cut-off point for sTfR/log sFt is proposed for patients with a CRP ≤5mg/L or with a CRP >5mg/L. The main aim of our study was to validate the usefulness of the “Thomas Plot” in assessing iron status. We also ascertained whether a modification on the sTfR/log sFt cut-off point improved the results. CRP was determined in 306 patients, 198 with iron deficiency (ID) and 108 with ACD. All of them were anemia cases studied in accordance with our standard protocol. RET-He, sTfR and sTfR/log sFt were calculated in all samples. The Thomas Plot was applied to all the cases and the results were compared. A discrepancy was considered relevant when it implied a change in patient treatment. Using logistic regression analysis, we investigated the optimum cut-off point of sTfR/log sFt in our series. Overall, the Thomas Plot correctly classified 223/306 patients (73%). There were clinically relevant discrepancies in 29 patients (9.5%), in 5 patients with CRP ≤5mg/L (5%) and in 24 patients with CRP >5mg/L (12%). It failed to identify ID in 12/198 patients (6%) but classified 17 cases with ACD (16%) as latent ID or IDA. The optimum sTfR/log sFt cut-off point in our series was 2.4 for patients with CRP ≤5mg/L and 2.39 for patients with CRP>5mg/L. As a consequence, we investigated a modified “Thomas Plot” using a sTfR/log sFt cut-off point of 2.4 for all the patients. The modified algorithm correctly classified 77% of the patients. There were clinical relevant discrepancies only in 17 patients (5%). It failed to identify ID in 12/198 patients (6%) and only classified 5 cases with ACD as latent ID or IDA (4.6%). The sensitivity of the Thomas Plot to identify ID was very high but the specificity was lower. A cut-off point of 2.4 for sTfR/log sFt is useful for patients with or without inflammatory traits and yields more accurate results.

Anemia of Chronic Disease: Pathophysiology and Laboratory Diagnosis

Classic iron deficiency (ID) does not represent a challenge for the laboratory and physicians. The anemia that accompanies infection, inflammation, and cancer, commonly termed anemia of chronic disease (ACD), features apparently normal or increased iron stores. However, 20% of these patients have iron-restricted erythropoiesis (functional ID), an imbalance between the iron requirements of the erythroid marrow and the actual iron supply. Functional ID leads to a reduction in red cell hemoglobiniza-tion, causing hypochromic microcytic anemia. The diagnosis of functional ID in real time is based on measuring the hemoglobin content of reticulocytes. An examination of the biochemical markers of iron metabolism demonstrates weaknesses in the diagnosis of functional ID. We developed a diagnostic plot for the assessment of iron status in ACD and the detection of advancing ID in patients with ID, ACD, and the combined state of functional ID and ACD. The plot indicates the correlation between a marker of the iron supply for erythropoiesis (ie, the ratio of the soluble transferrin receptor value to the logarithm of the ferritin value) and the reticulocyte hemoglobin content and functions as a marker of iron demand. The diagnostic plot shows good selectivity for assessing the iron status of disease-specific anemias such as classic ID, end-stage renal failure, cancer-related anemia, and the anemia of infection and inflammation. The therapeutic implications of the diagnostic plot are to differentiate patients who should be administered oral iron supplements, recombinant human erythropoietin (r-HuEPO), or a combination of r-HuEPO and iron. The response of erythropoiesis to r-HuEPO depends on the iron supply and the proliferation of erythropoiesis. The lack of an increase or a decrease in reticulocyte hemoglobin levels indicates a nonresponder to r-HuEPO or functional ID.

Iron transporters in rat mammary gland: effects of different stages of lactation and maternal iron status

Mechanisms regulating iron transfer from maternal circulation into milk are yet unknown. Whether intestinal iron transporters, divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1), are present in the mammary gland and are involved in iron transfer into milk are unknown. The objective was to examine DMT1 and FPN1 in rat mammary gland at different stages of lactation and to evaluate the effects of maternal iron status. Rats were fed either 35 mg Fe (control rats) or 8 mg Fe (low-iron rats) per kg diet for 3 wk and were fed the same diet throughout pregnancy and lactation. Mammary gland DMT1, FPN1, transferrin receptor, and ferritin were examined in control rats on days 1, 5, 10, and 20 of lactation and in low-iron rats on days 10 and 20 of lactation. Tissue and milk iron were measured. Milk iron, DMT1, and FPN1 decreased throughout lactation. Iron status was compromised in low-iron rats, whereas milk iron was maintained. On day 10 of lactation, mammary gland iron and ferritin were lower in the low-iron rats. DMT1, FPN1, and transferrin receptor values were unchanged; however, a smaller-size DMT1 protein was observed in the low-iron rats. On day 20, transferrin receptor increased in the low-iron rats, whereas mammary gland iron, ferritin, DMT1, and FPN1 were unchanged. The results show that DMT1 and FPN1 concentrations are higher during early lactation and are possibly involved in iron transfer into milk. Mammary gland regulation of DMT and FPN1 during low iron status appears to be different from that in the intestine.

Serum Transferrin Receptor Value as a Universal Indicator of Erythropoietic Activity.

The serum transferrin receptor (sTfR) is thought a sensitive and quantitative parameter of tissue iron deficiency as well as an indicator of erythropoietic activity. This study was aimed at the verification of a hypothesis that sTfR is a general indicator of erythropoiesis regardless whatever the cause is. A total of 173 patients in heterogeneous diseases who underwent bone marrow study as a workup for anemia were measured for sTfR, reticulocyte maturity index (RMI), erythroid element proportion of bone marrow cells, and other hematologic parameters (hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration, red cell distribution width, absolute reticulocyte count). By immunoenzymometric method sTfR was measured using IDeATMcTfR kids (Orion Diagnostica, Orion, Finland). Reticulocyte count and proportion was measured manually by one expert examiner after standard blood smear and stain. Reticulocyte subpopulation was automatically analyzed by flow cytometry using R-3000 TM (Sysmex, TOA, Japan). RMI was calculated from the equation of (medium fluorescent reticulocyte fraction + high fluorescent reticulocyte fraction) X 100 / low fluorescent reticulocyte fraction. Correlation analysis was done among the variables including sTfR, RMI, erythroid element proportion of bone marrow cells, and other hematologic parameters using SAS 6.12 soft ware. The analysis was carried out for the whole 173 patients to see the general trends and repeated for 4 groups of disease category, arbitrarily divided to group 1 (n=33, iron deficiency or or disease with no predisposition to anemia of chronic disease), group 2 (n=53, hematologic malignancies), group 3 (n=44, solid tumors), and group 4 (n=43, chronic or infectious disease) to see if the trends may be affected by specific diseases. The results showed a solid correlation of sTfR with RMI as well as erythroid precursors in bone marrow, not only in the whole patient population (e.g. sTfR vs RMI, R=0.587, p=0.0001) but also in individual groups (e.g. sTfR vs RMI, R=0.48, p=0.005 in group 1, R=0.69, p=0.0001 in group 2, R=0.58, p=0.0001 in group 3, R=0.81, p=0.0001 in group 4). These findings indicated the significance of sTfR is valid under any clinical setting as a universal indicator of hematopoietic activity. The sTfR can be used as a useful parameter for monitoring of erythropoiesis in a variety disease.

In patients who have stainable iron in the bone marrow an elevated plasma transferrin receptor value may reflect functional iron deficiency.

Elevated transferrin receptor (TfR) concentration may be either because of iron deficiency or an increased rate of erythropoiesis. We have studied the relationship between elevated TfR and advanced RBC and reticulocyte indices in an unselected population of hospitalized patients. The iron status in 95 consecutive hospitalized patients was assessed using bone marrow aspirate examination and analysis of the RBC and reticulocyte indices was performed using the Advia 120 haematology system. Of the 95 patients, a total of 17 had no stainable iron in the bone marrow and most of them also had an elevated TfR. Of the 78 patients with stainable iron stores, 15 also had an elevated TfR concentration (> or =2.4 mg/l). Six of them also had an elevated %HYPOm (> or =3.4%), and therefore were regarded as having functional iron deficiency. We evaluated the possible causes of elevated TfR concentrations in patients having stainable iron in the bone marrow, and this study suggests that functional iron deficiency explains a considerable proportion of these cases.

Receptor sérico de transferrina en niños sanos. Valor diagnóstico en la anemia infecciosa y en la ferropénica

The serum transferrin receptor (TfR) presents certain advantages over other parameters of cellular iron status because it does not vary in acute or chronic diseases. To establish reference ranges of TfR in healthy children for our laboratory, to define the distribution of this variable in children with acute illness and in those with iron deficiency, and to evaluate the diagnostic yield of TfR, the transferrin-receptor/ferritin ratio (TfR/F) and the transferrin-receptor-ferritin index (TfR-F) in distinguishing ferropenic from infectious anemia. A descriptive, cross-sectional analysis was conducted in 132 children aged from 6 months to 16 years for a period of 18 months. The subjects were classified in three groups: healthy children, children with acute illness, and children with iron deficiency. The distribution of TfR and its diagnostic yield were evaluated. Of the 132 subjects, 30 were excluded because they lacked one or more of the parameters under analysis and 19 were excluded because they showed a thalassemic trait. In the 30 healthy children, the mean TfR concentration was 1.2 mg/l (SD 0.36) and the median was 1.02 (IQR 0.7-1.7). In the 32 children with acute illness, with or without anemia, TfR values were similar to those found in healthy children (p > 0.05). TfR values were higher in children with iron deficiency (21 patients; mean TfR value: 1.67 mg/l SD 0:98) than in healthy children but this difference was not statistically significant (p 0.08). The highest TfR values were found in the group with ferropenic anemia (mean TfR value: 2.13 mg/l SD 1.14) with a statistically significant difference between healthy children (p 0.04) and those with iron deficiency without anemia (p 0.01). The TfR/F ratio showed an optimal diagnostic yield in distinguishing ferropenic from acute disease anemia. If this ratio is higher than 80.7 ferropenia can be suspected as the cause of the anemia with a global value of the test of 100 % (95 % CI: 75.91-99.42). TfR could be useful in evaluating intracellular iron status in children. Acute disease does not alter TfR values and, in combination with ferritin, TfR offers an optimal diagnostical yield in distinguishing ferropenic from acute illness anemia.

Soluble transferrin receptor and immature reticulocytes are not useful for distinguishing iron-deficiency anemia from heterozygous beta-thalassemia.

Iron deficiency and heterozygous beta-thalassemia are important causes of hypochromic-microcytic anemia. Two laboratory parameters are suggested for the differentiation of such anemia. High-fluorescence reticulocyte counts and soluble transferrin receptor levels were determined in iron-deficiency anemia patients (n = 49) and heterozygous beta-thalassemia patients (n = 43). There was no significant difference in high-fluorescence reticulocyte and soluble transferrin receptor values between the two groups, but a correlation was observed between high-fluorescence reticulocytes and soluble transferrin receptors in iron-deficiency anemia, probably due to increased receptor synthesis as a response to decreased iron content in erythrocytes.

Erythroblast Iron Metabolism in Sideroblastic and Sideropenic States

Iron appears to exert self-regulatory control over erythroblast iron uptake, iron storage and its incorporation into haem. It does this via iron regulatory proteins (IRPs) which bind reversibly to the iron responsive elements (IREs) on the mRNA of transferrin receptor (TfR), erythroid 5-aminolaevulinic acid synthase (ALA-S2) and ferritin. Iron deficiency leads to the binding of IRP to IRE. This binding inhibits the translation of mRNA for ALA-S2 and ferritin but stabilizes mRNA for TfR expression.Sideroblastic erythropoiesis is highly ineffective and characterized by mitochondrial iron loading. The study of X-linked sideroblastic anaemia has shown that the entry of iron into the mitochondria is poorly controlled and able to occur when protoporphyrin production is reduced, as is seen with the ALA-S2 mutations, or when it is increased as has been seen with ABC7 transporter mutations.Sideropenia characterises both iron deficiency anaemia (IDA) and the anaemia of chronic disease (ACD). Erythroblasts in ACD seem doubly equipped to protect their iron supply with their ability to increase the efficiency of transferrin-iron uptake as well as to activate the IRP/IRE system to increase surface TfR production. This increase in efficiency restricts the need to increase surface TfR production and maintains serum soluble TfR (sTfR) values within the normal range in iron replete ACD. The coexistence of iron deficiency with chronic disease, however, is associated with an increase in both the efficiency and number and a highly significant rise in sTfR values.

Transthyretin values correlate with mucosal recovery in patients with coeliac disease taking a gluten free diet.

To assess changes in indicators of nutrition and iron deficiency as possible non-invasive markers of mucosal recovery in patients with coeliac disease on a gluten free diet. Concentrations of transthyretin, retinol binding protein, soluble transferrin receptor, IgA anti-gliadin, and IgA anti-transglutaminase, and titres of IgA anti-endomysial antibody were measured in 36 newly diagnosed adult patients with coeliac disease and duodenal villous atrophy before (T0) and after one year (T1) on a gluten free diet. Duodenal biopsies taken at T0 and T1 were compared and graded as no improvement (no change in initial grade of villous atrophy) or improvement. Twenty two patients showed histological improvement and 14 showed no improvement. Transthyretin values increased in all patients with mucosal improvement and decreased in all patients showing no improvement. However, transthyretin values did not correlate with the degree of villous atrophy at T0 and T1 when assessed separately. Changes in retinol binding protein and soluble transferrin receptor values did not correlate with mucosal improvement. Coeliac disease associated antibodies (to gliadin, endomysium, and transglutaminase) decreased in most patients between T0 and T1, irrespective of mucosal recovery. Serial but not single measurements of transthyretin may be used as a non-invasive test to monitor mucosal recovery and therefore reduce the need for, or frequency of, follow up biopsies in treated patients with coeliac disease.

THE SERUM TRANSFERRIN RECEPTOR CONCENTRATION IN SEVEN FETUSES WITH HEMOLYTIC DISEASE

Six pregnant women who received intrauterine transfusions and their seven fetuses were followed during gestation. Hemoglobin concentration, hematocrit value, serum ferritin, and serum transferrin receptor (TfR) concentrations were measured. In the fetal samples, there was a tendency for the TfR concentration to decrease during gestation and after the intrauterine transfusions. Serum TfR values varied between 0.7 and 5.2 mg/L, which is near the postnatal level measured in premature infants. On the contrary, one would have expected to find highly elevated values due to the active fetal erythropoiesis. The fetal regulation of TfR production may differ from that described postnatally.

Evaluation of an ELISA test for determination of the serum transferrin receptor. Demonstration of discordance between results obtained with two methods

We undertook this study to evaluate a recently introduced ELISA kit for determining serum transferrin receptor (TfR) concentration (TfR®, Ramco Laboratories, Inc.), to produce reference values for healthy adults, and to compare the results with another commercially available reagent system. The mean (SD) recovery of added TfR was 88% (6%). In dilution studies, the ratio between the measured and expected values was 0.98 (0.11). The intra-assay and interassay coefficients of variation were from 5% to 7% and from 6% to 9% in a physiological and a supraphysiological concentration range, respectively, and from 13% to 16% in a subnormal concentration range. In healthy adults between 20 and 60 years of age, we observed no age- or sex-related differences in TfR values. Thus, the same reference interval, 3.0-8.2 mg l-1, may be used for this population. The correlation between the results obtained with the Ramco TfR® test and the Amgen Diagnostics ClinigenTM test was satisfactory (r=0.79). The Ramco TfR® test produced higher values (TfR®=0.40 (-0.45-1.25)+1.46 (1.16-1.75)* ClinigenTM). The number of samples that fell within the same concentration interval with both methods (low, normal or high in relation to the respective reference interval) was only 45% (27/60). The Ramco TfR® test had fewer values falsely suggesting iron deficiency than the ClinigenTM test. Serum TfR methods need to be uniformly standardized.

Oral iron is sufficient for erythropoietin treatment of very low-birth-weight infants. † 1285

In recombinant human erythropoietin (rHuEPO) -treated very low-birth-weight(VLBW) infants, evaluation of iron status and the need of excess iron may be complicated. The aims of this study were 1) to compare two different doses and means of administration of iron in rHuEPO-treated VLBW infants, and 2) to study the changes in serum transferrin receptor concentrations in VLBW infants with and without rHuEPO treatment. Forty-one VLBW infants were randomized to three groups. Fourteen infants were treated with rHuEPO (300 IU/kg three times a week s.c.) and oral ferrofumarate (6 mg of iron/kg/d). An additional 14 infants received the same rHuEPO treatment and a weekly injection of intramuscular ferroxypolymaltose (12 mg of iron/kg). Finally, thirteen infants were treated with the same dose of intramuscular iron without any rHuEPO. The response of erythropoiesis to rHuEPO treatment was similar in the patients receiving oral and intramuscular iron, and in both groups the transferrin receptor concentration increased from 6.7-7.2 mg/L to 10.1-11.3 mg/L. We conclude that in rHuEPO-treated VLBW infants the iron need for erythropoiesis can be met by oral administration of iron and that elevated serum transferrin receptor values are reflections of increased rates of erythropoiesis rather than evidence of rHuEPO-induced iron deficiency. We thank Cilag A.G.(Schaffhausen, Switzerland) for supplying the erythropoietin and Vifor International Incl. (St. Gallen, Switzerland) for the parenteral iron preparation.

The Determination of Plasma Transferrin Receptor as Good Index of Erythropoietic Activity in Renal Anemia and after Renal Transplantation

Both the plasma determinations of erythropoietic (EPO) and transferrin receptor (TfR) would provide a good characterization of anemia especially when mixed erythron disorders underlie, such as in renal failure. Immunologic assays of EPO and TfR, as well as standard hematologic determinations (hematocrit, reticulocyte count, serum iron, transferrin, ferritin) were performed in patients with chronic renal failure (CRF), in regular dialysis treatment (RDT) and in transplanted (TX) patients. In nonanemic TX patients both EPO and TfR ranged normally, whereas in anemic TX ones (Hct < 40%) both values were increased suggesting the physiologic response both of the kidney and of the erythron to decreased red cell mass. In transitory posttransplant erythrocytosis the increased values of TfR, with normal EPO values, would hypothesize a defective feedback to EPO release. Both EPO and TfR values were found increased in TX patients with adult polycystic kidney disease with persistent erythrocytosis (Hct > 50%), thus confirming previous observations. In CRF and RDT patients, all anemic, both EPO and TfR were normal, even though significantly low with respect to the degree of anemia. In RDT seriously anemic patients, the administration of recombinant human EPO induced different patterns of bone marrow response. We conclude that the determination of TfR would provide further information on renal anemia since the receptor increase mostly preceded the rise of Hct, evidencing those patients who will not have an effective bone marrow response to the therapy.

THE SERUM TRANSFERRIN RECEPTOR AS INDICATOR OF IRON DEFICIENCY IN INFANTS

Objective: Serum transferrin receptor is now well established in adults as index of iron status. It increases with tissue iron need and is more sensitive than other parameters to mild iron deficiency. The purpose of this study was to test its value in infants, a population especially susceptible to iron deficiency. Methods and setting: We measured hemoglobin, serum ferritin (RIAgnost, Behring) and the serum transferrin receptor (CLINIGEN EIA, Amgen Diagnostics) in 71 healthy infants at 12 months of age from 5 centers of the Euro-Growth Study (Vienna, Salzburg, Budapest, Bilbao, Porto, Dublin). Results: Intra- and interassay variances of the transferrin receptor (TIR) measurements were 3.5% and 7.75%, respectively. Infants with hemoglobin (Hb) levels < 11 g/dl, indicating anemia, had significantly higher TfR values than infants with Hb values >11g/dl (3.46±0.99 vs 2.66±1.04 μg/ml; p<0.05. Wilcoxon rank test). In infants with Hb >11 g/dl and s-ferritin <12, between 12-20, and >20 ng/ml, TfR values were 3.04±1.13*, 2,54±0.93 and 2,18±0.64* μg/ml, respectively (*p<0.05, Duncans Multiple Range test). Regression analysis did not reveal a negative correlation between TfR and either Hb or s-ferritin. Conclusions: Serum transferrin receptor is significantly increased in infants with iron deficiency anemia. In infants with no anemia (Hb > 11 g/dl) but low iron stores (s-ferritin < 20) elevated transferrin receptor values already indicate iron deficient erythropoeisis. Although our data are limited the combination of serum ferritin and serum transferrin receptor appears promising as a screening tool for mild iron deliciency in infants.