Quantitative assessment of erythropoiesis in haemodialysis patients demonstrates gradual expansion of erythroblasts during constant reatment with recombinant human erythropoietin

Béguin, Yves; Loo, Martine; R'Zik, Samir; Sautois, Brieuc; Lejeune, Françoise; Rorive, Georges; Fillet, Georges

doi:10.1111/j.1365-2141.1995.tb08916.x

Cited by 31 publications

(13 citation statements)

References 10 publications

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“…Serum soluble transferrin receptor, a truncated monomer of cell surface-expressed transferrin receptor, is primarily released from erythroblasts, and its serum level reflects the erythropoietic activity of BM and spleen. 26,27 We also observed multilobed polymorphonuclear neutrophils in the PCFT Ϫ/Ϫ blood smears and giant metamyelocytes in the PCFT Ϫ/Ϫ BM, consistent with abnormal myelopoiesis often observed in patients with folate deficiencyinduced anemia. Internal bleeding in the cerebral vasculature and bloody stools were also noted in PCFT Ϫ/Ϫ mice, which too is often associated with folate deficiency-induced anemia.…”

Section: Discussionmentioning

confidence: 64%

A mouse model of hereditary folate malabsorption: deletion of the PCFT gene leads to systemic folate deficiency

Salojin

Cabrera²,

Sun

et al. 2011

Blood

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IntroductionFolate is an essential cosubstrate of many biochemical reactions, such as the de novo synthesis of purines and pyrimidines, methionine, and deoxythymidylate monophosphate. 1,2 Mammals cannot synthesize folate; therefore, inadequate dietary supply or folate malabsorption results in defective DNA synthesis. One of the first manifestations of a folate deficiency is in the rapidly proliferating cells of the hematopoietic system, leading to pancytopenia and anemia of the megaloblastic type. Patients with megaloblastic anemia demonstrate ineffective erythropoiesis by harboring large immature red blood cell (RBC) precursors that fail to survive to the postmitotic, terminal stages, undergoing premature apoptosis. 2 Three mammalian folate transporter systems have been described to date in a variety of tissues: (1) the bidirectional reduced folate carrier 1 (RFC1), also known as SLC19A1, 3,4 (2) the glycosyl-phosphatidylinositol-anchored folate receptors (FOLR1, FOLR2, and FOLR4) and one secreted receptor in humans without a mouse homolog (FOLR3), 5 and (3) the human proton coupled folate transporter (PCFT). 6-8 The RFC1 transporter is expressed ubiquitously, including the brush-border membrane of epithelial cells in the small intestine. 9 Although RFC1 is necessary for folate transport in erythroid cells, its involvement in intestinal folate uptake has not been confirmed. 6 Inactivation of RFC1 in mice by homologous recombination led to either embryonic lethality or defective erythropoiesis in pups born to mothers who were supplemented with 1 mg daily subcutaneous doses of folic acid. 10,11 Because this transporter functions at a neutral pH optimum whereas the majority of intestinal folate transport occurs in an acidic luminal milieu, RFC1 is an unlikely candidate for an intestinal folate transporter. 7 The role of FOLR1 in folate absorption and transport has also been demonstrated, where a 60% to 70% reduction was observed in plasma folate of FOLR1 Ϫ/Ϫ mice fed low folate and normal chow. 12 FOLR1 also regulates folate homeostasis via endocytotic mechanisms during embryonic development, and mice rendered null for this receptor display severe morphogenetic abnormalities and die in utero unless provided supraphysiologic concentrations of either folinic acid or 5-methyltetrahydrofolate. 5,13 The PCFT transporter is highly expressed in tissues involved in folate and heme transport, including the duodenum and liver. 6,14 Initially, PCFT was identified as a low-affinity, pHindependent heme transporter 14 and then later described to function as a low pH-dependent folate transporter in intestinal cells. 6 The latter role of the transporter was confirmed by the identification of loss-of-function mutations in the human PCFT gene in persons diagnosed with hereditary folate malabsorption syndrome. 6 Studies have also indicated that PCFT facilitates folate transport during folate receptor-mediated endocytosis, where FOLR1 binds folate, and its export into the cytosol is driven by PCFT activity as the vesicle undergoes en...

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Section: Discussionmentioning

confidence: 64%

A mouse model of hereditary folate malabsorption: deletion of the PCFT gene leads to systemic folate deficiency

Salojin

Cabrera²,

Sun

et al. 2011

Blood

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“…Soluble TfR is of particular interest in assessing response to recombinant human erythropoietin (rHuEpo) in patients with chronic renal failure [32,33], aplastic anemia [34], pure red cell aplasia [35], thalassemia intermedia [36], cancer [37 -39], myelodysplastic syndrome (MDS) [37,40], rheumatoid arthritis [41], genetic hemochromatosis [42] or in intensive care [43], as well as in normal subjects [44], autologous blood donors [45] and premature infants [46] or after stem cell transplantation [47,48]. Similarly, sTfR levels can be used to monitor how erythropoiesis subside after cessation of rHuEpo therapy [49].…”

Section: Main Characteristicsmentioning

confidence: 99%

“…In response to rHuEpo, the erythroblast compartment is very slow to respond, expanding over a period of 6 weeks before reaching a steady state during which the Hb continue to rise [32]. The dose of rHuEpo needed to achieve response is highly variable because of such interfering factors as functional iron deficiency or inflammation.…”

Section: Main Characteristicsmentioning

confidence: 99%

“…If sTfR was mostly a marker of functional iron deficiency induced by rHuEpo, it should increase more consistently in nonresponders (primary cause of failure is functional iron deficiency) than in responders: in fact the reverse is true [33,118]. In addition, sTfR increments correlate well with later hematocrit increases [32], whereas levels are not different in patients with low or high ferritin [119] and correction of iron deficiency with oral iron is associated with little changes [118,120]. Furthermore, the elevation of sTfR in response to rHuEpo is larger in iron overloaded rats than in normal animals who develop functional iron deficiency [121].…”

Section: Soluble Tfr: a Marker Of Iron Status And/or Erythropoiesis?mentioning

confidence: 99%

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Soluble transferrin receptor for the evaluation of erythropoiesis and iron status

Béguin

2003

Clinica Chimica Acta

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398

316

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Iron transport in the plasma is carried out by transferrin, which donates iron to cells through its interaction with a specific membrane receptor, the transferrin receptor (TfR). A soluble form of the TfR (sTfR) has been identified in animal and human serum. Soluble TfR is a truncated monomer of tissue receptor, lacking its first 100 amino acids, which circulates in the form of a complex of transferrin and its receptor. The erythroblasts rather than reticulocytes are the main source of serum sTfR. Serum sTfR levels average 5.0 F 1.0 mg/l in normal subjects but the various commercial assays give disparate values because of the lack of an international standard. The most important determinant of sTfR levels appears to be marrow erythropoietic activity which can cause variations up to 8 times below and up to 20 times above average normal values. Soluble TfR levels are decreased in situations characterized by diminished erythropoietic activity, and are increased when erythropoiesis is stimulated by hemolysis or ineffective erythropoiesis. Measurements of sTfR are very helpful to investigate the pathophysiology of anemia, quantitatively evaluating the absolute rate of erythropoiesis and the adequacy of marrow proliferative capacity for any given degree of anemia, and to monitor the erythropoietic response to various forms of therapy, in particular allowing to predict response early when changes in hemoglobin are not yet apparent. Iron status also influences sTfR levels, which are considerably elevated in iron deficiency anemia but remain normal in the anemia of inflammation, and thus may be of considerable help in the differential diagnosis of microcytic anemia. This is particularly useful to identify concomitant iron deficiency in a patient with inflammation because ferritin values are then generally normal. Elevated sTfR levels are also the characteristic feature of functional iron deficiency, a situation defined by tissue iron deficiency despite adequate iron stores. The sTfR/ferritin ratio can thus describe iron availability over a wide range of iron stores. With the exception of chronic lymphocytic leukemia (CLL) and high-grade non-Hodgkin's lymphoma and possibly hepatocellular carcinoma, sTfR levels are not increased in patients with malignancies. We conclude that soluble TfR represents a valuable quantitative assay of marrow erythropoietic activity as well as a marker of tissue iron deficiency. D

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“…Several lines of evidence have indicated that the direct relationship to the number of erythroid precursors makes soluble TfR assay the method of choice for evaluation of erythroid marrow activity in clinical settings. Indeed, serial measurements of TfR are useful for the quantitative assessment of erythropoietic activity in hemodialysis (HD) patients who are treated with recombinant human erythropoietin (rHuEPO) (2,3) and for monitoring the hemoglobin response to rHuEPO therapy (4). The body iron status is the second major determinant of soluble TfR, and circulating receptor levels rise in the iron-depleted status as a result of the posttranscriptional modification of TfR mRNA expression in the erythroid precursors (5).…”

mentioning

confidence: 99%

Effect of Intravenous Ascorbic Acid Medication on Serum Levels of Soluble Transferrin Receptor in Hemodialysis Patients

Tarng

Hung

Huang

2004

Journal of the American Society of Nephrology

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Abstract. Intravenous ascorbic acid (IVAA) medication has been shown to facilitate iron release from inert depots and subsequently circumvent the defective iron utilization in chronic hemodialysis (HD) patients who are treated with recombinant human erythropoietin (rHuEPO). This study focuses on the effects of IVAA supplementation on serum concentrations of soluble transferrin receptors (TfR) on the basis of the hypothesis that an increase of labile iron in the cytosol will lead to inhibition of TfR expression. First, 138 HD patients were studied to evaluate the interrelation between serum TfR and iron status. In a stepwise multivariate analysis, serum EPO and transferrin saturation (TSAT) were the two independent predictors for serum TfR in HD patients (r 2 ϭ 0.510, P Ͻ 0.001). Further analyses showed that the lower the serum EPO and the higher the TSAT, the lower the serum TfR in HD patients who are on maintenance rHuEPO treatment. Second, 36 HD patients were recruited in a randomized, controlled study to receive IVAA (total dose of 2000 mg) or normal saline (placebo) medication. Serum levels of TfR, EPO, and ferritin and TSAT were measured at baseline and within 7 d after starting IVAA or placebo. There were no significant changes in serum EPO and ferritin levels in patients who received either IVAA (n ϭ 18) or placebo (n ϭ 18). Serum TfR levels (P Ͻ 0.001) significantly declined with a parallel rise in TSAT (P Ͻ 0.05) as compared with presupplemental values within 7 d in IVAA patients before any apparent alteration in hematocrit values, but the changes were not observed in the placebo group. The trend of decreased serum TfR and increased TSAT was similar in IVAA patients with ferritin of Ͻ500 g/L or Ͼ500 g/L. It is concluded that ascorbic acid status can significantly decrease serum TfR concentrations and increase percentage of TSAT, probably through alterations in intracellular iron metabolism.

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Quantitative assessment of erythropoiesis in haemodialysis patients demonstrates gradual expansion of erythroblasts during constant reatment with recombinant human erythropoietin

Cited by 31 publications

References 10 publications

A mouse model of hereditary folate malabsorption: deletion of the PCFT gene leads to systemic folate deficiency

A mouse model of hereditary folate malabsorption: deletion of the PCFT gene leads to systemic folate deficiency

Soluble transferrin receptor for the evaluation of erythropoiesis and iron status

Effect of Intravenous Ascorbic Acid Medication on Serum Levels of Soluble Transferrin Receptor in Hemodialysis Patients

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