Administration of iron-containing drugs in non-dialyzed patients with chronic kidney disease

In the review paper an issue of the administration of iron containing drugs in the treatment of anemia in non-dialyzed patients with chronic kidney disease (CKD) is presented. Iron deficiency in patients with CKD (serum ferritin concentration below 100 ng/ml, transferrin saturation below 20%) occurs in 20-70% of cases. Prevalence of iron deficiency depends on stage of CKD and patients' gender. Among causes of iron deficiency the following reasons are mentioned: blood loss through gastrointestinal tract (17-18% of patients in pre-dialysis stage show positive results of tests on occult blood), diminished absorption (uremic gastroenteropathy, administration of drugs decreasing iron absorption), decreased delivery of food (anorexia, low protein diet), infections and inflammatory state. In the course of infections and inflammatory states body iron storage may be normal, but its utilization for erythropoesis is deteriorated (functional iron deficiency). Results of randomized controlled studies indicate greater efficiency of intravenous therapy in comparison with oral route of iron administration. In practice, the main route of administration of iron-containing drugs to non-dialyzed patients with CKD remains, however, the oral one (iron sulfate, iron fumarate, hem iron) as more convenient and seldom leading to serious side effects. Intravenous iron therapy (iron dextrose, iron polymaltose, sodium-iron gluconate, iron sucrose) is required for cases with absolute deficiency of this microelement, disturbed intestinal absorption, poor tolerance of oral iron medication or its ineffectiveness from other reasons. Administration of erythropoiesis stimulating agents in predialysis period may require intravenous iron therapy because of enhanced consumption of its stores for erythropoiesis. Attention should be paid to possible nephrotoxic effects of administration of iron containing drugs (transient proteinuria, damage of renal tubules, decrease in glomerular filtration rate).     

Erythropoiesis and iron

Iron and erythropoiesis are inextricably linked. Erythropoiesis is a dynamic process that requires 30-40 mg of iron per day. In normal circumstances this is met from red cell destruction but in anaemia this will not be the case. Reduced iron stores will limit iron supply to erythroblasts but normal or raised iron stores may not be able to supply iron fast enough. This is particularly true when the marrow is stimulated by erythropoietin therapy; the most common cause of failure to respond is "functional iron deficiency"'. This entity can only be effectively addressed by intravenous iron therapy.While haemoglobin and serum ferritin concentrations reflect the major iron pools, iron supply to erythroid cells can only be assessed by measuring effective haemoglobinization through the percentage of hypochromic red cells in the circulation.     

Anaemia in rheumatoid arthritis: pathogenesis,diagnosis and treatment

Summary The pathogenesis, diagnosis and treatment of the anaemia of chronic disorders (ACD) in rheumatoid arthritis (RA) were reviewed. Causes of anaemia other than ACD frequently present in RA. Decreased iron absorption was shown to be the result of active RA rather than a cause of ACD or iron deficiency. It has been hypothesized that bone morrow iron availability decreases due to decreased iron release by the mononuclear phagocyte system or that the anaemia in ACD is due to ineffective erythropoiesis; these remain controversial theories. Studies considering a decreased erythropoietin responsiveness have not produced consistent results. Erythroid colony growth is suppressed in vitro by interleukins and tumour necrosis factor but their role in vivo in ACD is unknown. The diagnosis of ACD is made by exclusion. Iron deficiencyis detected by transferrin, ferritin, and cellular indices after adaption of their normal values. Treatment of the anaemia consists merely of antirheumatic treatment. Iron administration is counterproductive since iron chelators or exogenous erythropoietin administration might increase erythropoiesis.     

Usefulness of measuring reticulocyte hemoglobin equivalent in the management of haemodialysis patients with iron deficiency

The evaluation of iron status in dialysis patients provides information essential to the planning of adequate recombinant human erythropoietin treatment. The cellular iron status of the patients can be determined from the recently available measurement of reticulocyte hemoglobin equivalent (RET-He). RET-He is measured on the basis of automated fluorescent flow cytometry which in the reticulocyte channel, using a polymethine dye, also measures the mean value of the forward light scatter intensity of mature red blood cells and reticulocytes. These values equate with reticulocyte hemoglobin content. In this study, to clarify the accuracy of RET-He in diagnosing iron deficiency in dialysis patients, we initially compared RET-He with such iron parameters as serum ferritin levels, transferrin saturation and content of reticulocyte hemoglobin (CHr) which has been established as indicators of functional iron deficiency. Secondly, we investigated the changes in RET-He during iron supplementation for iron-deficient patients to determine whether this marker is a prospective and reliable indicator of iron sufficiency. The participants in this study were 217 haemodialysis patients. Iron deficiency was defined as havsing a transferrin saturation (TSAT) < 20% or serum ferritin < 100 ng/ml. Conventional parameters of red blood cells and RET-He were measured by on a XE-2100 automated blood cell counter (Sysmex). CHr was measured on an ADVIA120 autoanalyser (Siemens). RET-He mean value was 32.4 pg and good correlation (r = 0.858) between RET-He and CHr is obtained in dialysis patients. Receiver operating characteristic curve analysis revealed, values of the area was 0.776 and at a cutoff value of 33.0 pg, a sensitivity of 74.3% and a specificity of 64.9%, were achieved. Iron supplements given to the patients with low TSAT or ferritin, RET-He responded within 2 weeks, and this seemed to be a potential advantage of using RET-He in the estimation of iron status. RET-He is a new parameter, equivalent value to CHr, and is easily measurable on the widely spread and popular blood cell counter and is a sensitive and specific marker of iron status in dialysis patients.     

Microcytic and hypochromic anemias

In the majority of cases, microcytosis is the result of impaired hemoglobin synthesis. Disorders of iron metabolism and protoporphyrin and heme synthesis, as well as impaired globin synthesis, lead to defective hemoglobin production and to the generation of microcytosis and microcytic anemia. Iron deficiency anemie, anemia of chronic diseases, thalassemias, congenital sideroblastic anemias and homozygous HbE disease are the main representatives of microcytosis and microcytic anemias. Serum iron, total iron binding capacity, transferrin saturation, serum ferritin, serum transferrin receptor, transferrin receptor-ferritin index, and zinc-protoporhyrin concentration in erythrocytes are tests used for assessment of iron deficiency. The convention laboratory test for diagnosing iron deficiency is the measurement of serum ferritin. The most precise method for evaluating body iron stores is the examination for iron on aspirated bone marrow or marrow biopsy. Increased content of Hb A2 over 3.5% is diagnostic for beta-thalassemia. Presence of ringed sideroblasts is characteristic of sideroblastic anemias. Hemoglobin electrophoresis is required for the diagnosis of hemoglobinopathy E. The optimal therapeutic regimen in iron deficiency anemia used in this country is to administer 100 mg of elemental iron twice daily separately from meals. Ferrous sulphate (Ferronat Retard tbl. or Sorbifer Dulures tbl.) which are slow-releasing iron formulations are preferred because of their low cost, high bioavailability and low side-effects. Parenteral iron therapy is justified only in patients who cannot absorb iron, who have blood losses that exceed the maximal absorptive capacity of their intestinal tract or who are totally intolerant of oral iron. However, parenteral iron therapy may be associated with serious and even fatal side-effects.     

Erythropoietin, iron, and erythropoiesis

Recent knowledge gained regarding the relationship between erythropoietin, iron, and erythropoiesis in patients with blood loss anemia, with or without recombinant human erythropoietin therapy, has implications for patient management. Under conditions of significant blood loss, erythropoietin therapy, or both, iron-restricted erythropoiesis is evident, even in the presence of storage iron and iron oral supplementation. Intravenous iron therapy in renal dialysis patients undergoing erythropoietin therapy can produce hematologic responses with serum ferritin levels up to 400 microg/L, indicating that traditional biochemical markers of storage iron in patients with anemia caused by chronic disease are unhelpful in the assessment of iron status. Newer measurements of erythrocyte and reticulocyte indices using automated counters show promise in the evaluation of iron-restricted erythropoiesis. Assays for serum erythropoietin and the transferrin receptor are valuable tools for clinical research, but their roles in routine clinical practice remain undefined. The availability of safer intravenous iron preparations allows for carefully controlled studies of their value in patients undergoing erythropoietin therapy or experiencing blood loss, or both.     

Low Hemoglobin Density as a Measure of Iron Status

Iron deficiency anemia is the commonest cause of anemia in the developing countries. Iron status is the result of the balance between the rate of erythropoiesis and the amount of iron stored in the body. Various biochemical parameters have been used to assess iron status such as iron levels, transferrin, transferrin saturation and ferritin, and all of them may be influenced by acute phase response and are also expensive tests 1–4. In our situation where patients cannot afford exhaustive tests to document iron deficiency we utilized the LHD values as a predictor of iron status based on the formula provided by Urrechaga 5.     

Aproximación al diagnóstico y tratamiento de la anemia crónica secundaria a causas digestivas

Iron deficiency anemia is the most common type of anemia and can cause asthenia, cognitive and functional impairment, and decompensation of underlying diseases. Iron deficiency anemia is not a disease but is the result of a potentially serious medical problem. Consequently, patients should always undergo investigation of the underlying cause. In men and postmenopausal women, the condition is caused by gastrointestinal loss and malabsorption of iron. In this group, recommended procedures are gastroscopy, colonoscopy and serological testing for celiac disease. If the results of these tests are negative, repeat examinations and iron therapy should be considered. In treatment-refractory or recurrent anemia, the small intestine should be investigated. In this case, the procedure of choice is capsule endoscopy. Iron deficiency anemia should always be treated until iron deposits have returned to normal levels. A wide variety of preparations are available, in both oral and parental formulations.     

Evaluation of reticulocyte haemoglobin content as marker of iron deficiency and predictor of response to intravenous iron in haemodialysis patients

Because serum ferritin and transferrin saturation (TS) have a limitation in estimating iron status in haemodialysis patients, the reticulocyte haemoglobin content (CHr) has been proposed as a new tool. We investigate the accuracy of CHr in comparison with conventional tests and the relationship between changes in CHr and haemoglobin levels after therapy. We selected 140 haemodialysis patients receiving rHuEPO and intravenous iron supplementation and measured their complete blood count, CHr and iron parameters. Iron deficiency was defined as a ferritin <100 microg/l and/or a TS <20%. Hb, CHr, ferritin and TS levels were determined 1 month after therapy. Fifty-three patients were iron deficient. CHr were distributed with 33.7 +/- 1.4 pg in the iron sufficient group and with 29.9 +/- 1.9 pg in the iron deficient group (P = 0.001). The cutoff value of CHr for detecting iron deficiency was <32.4 pg. In iron deficient patients, a significant correlation was found between CHr and TS. The change in CHr after therapy was significantly larger in iron-deficient patients, and a lower baseline CHr is associated with a greater haemoglobin change. CHr is useful in screening iron status in dialysis patients, and a CHr cut-off value of 32 pg is appropriate for the assessment of iron deficiency. Moreover, CHr may serve as a predictor of the response to anaemia treatment.     

Blood viscosity and its relationship to iron deficiency, symptoms, and exercise capacity in adults with cyanotic congenital heart disease.

OBJECTIVES: This study sought to determine the relationship between blood viscosity and iron deficiency and their impact on symptoms and exercise function in adults with cyanotic congenital heart disease. BACKGROUND: Iron deficiency is believed to raise whole blood viscosity in cyanotic congenital heart disease, although available data are inconsistent. METHODS: Thirty-nine cyanotic adults were prospectively assessed for iron deficiency (transferrin saturation < or =5%), hyperviscosity symptoms, and exercise capacity. Same-day measurement of whole blood viscosity and hematocrit (Hct) adjusted viscosity (cells resuspended in autologous plasma to Hct of 45%) was performed at shear rates ranging from 0.277 s(-1) to 128.5 s(-1). RESULTS: Viscosity did not differ between patients with iron deficiency (n = 14) and those without (n = 25). Whole blood viscosity correlated with Hct (r = 0.63, p < 0.001 at low shear and r = 0.84, p < 0.001 at high shear) but not with red blood cell size or iron indices. Hyperviscosity symptoms were independent of iron indices but directly correlated with increased Hct-adjusted viscosity (r = 0.41, p = 0.01). Exercise capacity did not differ in iron-deficient patients. However, peak oxygen consumption was higher in those with Hct > or = 65% (12.6 +/- 3.4 ml/kg/m2 vs. 9.8 +/- 2.6 ml/kg/m2, mean +/- SD, p = 0.036) despite higher whole blood viscosity in these same individuals (p < 0.01 for all shear rates). CONCLUSIONS: Iron deficiency is common in cyanotic adults but does not alter viscosity. Hyperviscosity symptoms are associated with a higher Hct-adjusted viscosity independent of cell size or iron stores. Higher Hct is associated with better exercise capacity. Further work to understand the origin of hyperviscosity symptoms is warranted.     

Anemia in critically ill patients

Anemia is common in acute critically ill patients. Although blood loss, either by trauma, surgery, phlebotomies or gastrointestinal bleeding, may play a role, the anemia in these patients bears many similarities to the anemia characteristic of chronic disease. Serum iron is low with a high concentration of ferritin and low-to-normal transferrin and serum transferrin receptor levels. Several mechanisms may be involved, with inflammation playing a crucial role. Although the exact nature of the inflammatory response and the role of various cytokines need further elucidation, it is known that inflammation blunts the responsiveness of the hormone erythropoietin and induces functional iron deficiency. Iron is trapped in cells of the mononuclear phagocytic system and its release is temporarily blocked. The bone marrow is still capable of incorporating iron and of responding to treatment with recombinant human erythropoietin (rh-EPO). The duration of the anemia is related to the persistence of the inflammation. Although the effects of anemia on morbidity and mortality in the critically ill are poorly defined, a restrictive transfusion policy, in which hemoglobin concentration is maintained between 7.0 and 9.0 g/dl, proves to be at least as effective as, if not superior to, a more liberal regimen. In individual situations, such as in cardiovascular and cancer patients, higher thresholds may be appropriate. The administration of rh-EPO is an alternative to reduce the need for red blood cell transfusions and to avoid transfusion-related complications. Although its efficacy has been shown, questions regarding cost-benefit, dose regimen and clinical outcomes need to be answered before its large-scale use can be recommended.     

Treatment of iron deficiency anemia in pediatric inflammatory bowel disease

Opinion statement Anemia is a frequent extraintestinal manifestation of inflammatory bowel disease (IBD) that is commonly overlooked, despite its significant impact on quality of life. Characteristic symptoms include chronic fatigue, headache, and subtle impairment of cognitive function, although some less common symptoms include dyspnea, dizziness, pica, angular stomatitis, shortened attention span, and esophageal webs. Several types of anemia are associated with IBD, but iron deficiency anemia (IDA) accounts for the majority of cases and others include anemia of chronic disease, anemia associated with vitamin deficiency (vitamin B₁₂ and folate), autoimmune anemia, and anemia caused by medication used to treat IBD. The diagnosis of IDA relies on laboratory blood tests. Therefore, these tests should be obtained on a regular basis because characteristic symptoms may be absent or not readily recognized by patients and their clinicians. Complete blood count may suffice; however, iron studies and serum vitamin levels may be necessary to differentiate between specific types of anemia. During the diagnostic process, it is important to consider coexistence of different types of anemia, especially if no response to therapy is noted. The therapy for anemia is directed towards treatment of the underlying inflammatory process and supplemental therapy, depending on the type of deficiency. Iron deficiency anemia is treated with iron preparations, first orally, and if unresponsive or if associated with untoward adverse events leading to decrease in adherence with the therapeutic regimen, with intravenous preparations. Intramuscular therapy has been abandoned due to high rate of complications. Intravenous therapy may be administered as a multiple-dose regimen (intravenous iron sucrose and gluconate) or as a single intravenous dose (iron dextran), which is associated with a higher risk of allergic infusion reactions and requires obligatory test dose administration. Treatment with erythropoietin is reserved for a select subgroup of patients with anemia of chronic disease. With appropriate treatment, the majority of patients with IBD will have significant improvement or resolution of anemia, which can lead to a better quality of life. However, a high index of suspicion should be maintained in order to identify the precise cause of anemia and to prescribe the appropriate therapy.     

Deficiência de Ferro na Insuficiência Cardíaca com Fração de Ejeção Reduzida: Fisiopatologia,Diagnóstico e Tratamento

Iron deficiency (ID) is an important comorbidity in heart failure with reduced ejection (HFrEF) and is highly prevalent in both anemic and non-anemic patients. In HFrEF, iron deficiency should be investigated by measurements of transferrin saturation and ferritin. There are two types of ID: absolute deficiency, with depletion of iron stores; and functional ID, where iron supply is not sufficient despite normal stores. ID is associated with worse functional class and higher risk of death in patients with HFrEF, and scientific evidence has indicated improvement of symptoms and quality of life of these patients with treatment with parenteral iron in the form of ferric carboxymaltose. Iron plays vital roles such as oxygen transportation (hemoglobin) and storage (myoblogin), and is crucial for adequate functioning of mitochondria, which are composed of iron-based proteins and the place of energy generation by oxidative metabolism at the electron transport chain. An insufficient generation and abnormal uptake of iron by skeletal and cardiac muscle cells contribute to the pathophysiology of HF. The present review aims to increase the knowledge of the pathophysiology of ID in HFrEF, and to address available tools for its diagnosis and current scientific evidence on iron replacement therapy.     

Erythropoietin test methods.

Recombinant human erythropoietin (rhEPO), which increases red cell mass, is one of the most abused substances in sport. Abuse is currently undetectable by the only direct routine method, immunoassay, since blood and urine rhEPO are immunologically indistinguishable from endogenous EPO. Elevated EPO levels are only detectable several days after rhEPO administration. Indirect parameters have therefore been introduced, primarily the haematocrit level, but also markers of functional iron deficiency during or after rhEPO administration (hypochromic red cells and reticulocytes, serum transferrin receptors, ferritin levels) and, in the urine, fibrin degradation products. Although iron status indices have yielded promising results, athletes are currently banned solely on the basis of their haematocrit. Yet various factors can cause false positive haematocrit results with potentially fatal consequences to athletes' careers. Until new direct assays such as liquid chromatography-mass spectrometry have been evaluated and introduced, efforts must be directed at using a battery of tests to increase the sensitivity and specificity and reduce the number of false positives and false negatives.     

Pathogenesis and treatment of anaemia of chronic disease

Anaemia of chronic disease (ACD), the most frequent anaemia among hospitalized patients, develops under chronic inflammatory disorders such as chronic infections, cancer or autoimmune diseases. A number of different pathways contribute to ACD, such as diversion of iron traffic, a diminished erythropoiesis, a blunted response to erythropoietin, erythrophagocytosis and bone marrow invasion by tumour cells and pathogens. Nevertheless, ACD is a reflection of an activated immune system and possibly results from an innovative defence strategy of the body in order to withdraw the essential growth factor iron from invading pathogens and to increase the efficacy of cell-mediated immunity. Diagnosis of ACD can be assessed by examination of chances in serum iron parameters with low to normal serum iron, transferrin saturation and transferrin concentrations on the one hand and normal to increased ferritin, zinc protoporphyrin IX and cytokine levels on the other side. Therapy of ACD includes the cure of the underlying the disease. Apart from this transfusions for rapid correction of haemoglobin levels, and human recombinant erythropoietin for prolonged therapy are used. However, response rates to recombinant erythropoietin are sometimes low. Iron alone should be strictly avoided due to its growth-promoting effect towards micro-organisms and tumour cells and because of it capacity to inhibit T-cell-mediated immune effector pathways. We urgently need prospective clinical trials to gain knowledge about the effects of anaemia correction and/or the use of erythropoietin towards the course of the underlying disease, to find out if a combination therapy with erythropoietin and iron may be beneficial in ACD and to define therapeutic end-points.     

Anemia in Crohn's disease

Intestinal blood loss as well as chronic inflammation are regarded as the most important mechanisms in the pathogenesis of anemia in Crohn's disease. In addition, cytokines such as interleukin-6 can suppress erythropoietin production. This study was performed to investigate the importance of iron status, inflammatory activity, and endogenous erythropoietin concentrations for the development of anemia in Crohn's disease. In 49 consecutive patients with Crohn's disease, hemoglobin, inflammatory activity (Crohn's disease activity index, C-reactive protein, α₁-acid glycoprotein), iron status (serum iron, transferrin, transferrin saturation, ferritin), and serum erythropoietin levels were studied. Anemic (Hb<12.0 g/dl;N=16) vs nonanemic patients (Hb≥12 g/dl;N=33) showed reduced iron compartments (eg, ferritin 28.7±12.9 µg/liter vs 63.2±15.0 µg/liter, transferrin saturation 6.2±1.4% vs 11.5±1.3%,P<0.01) but no differences in inflammatory activity. An inverse correlation between erythropoietin and hemoglobin concentrations was found (r=-0.62;P<0.001), but the increase in erythropoietin levels was inadequate to the degree of anemia. There was no correlation between erythropoietin and interleukin-6 serum levels. Four of five anemic patients with hemoglobin below 10.5 g/dl and erythropoietin levels within the normal range were treated with parenteral iron (200 mg iron saccharate in 250 ml NaCl, weekly, intravenously). Two of them additionally received recombinant human erythropoietin (150 units/kg, 3× weekly, subcutaneously). After five weeks all patients had a marked increase in hemoglobin. However, the mean increase in erythropoietin-treated patients was 5.0 g/dl compared to 2.0 g/dl in the patients with iron therapy only. No side effects were seen. Our data demonstrate that inadequate erythropoietin production and iron deficiency are pathogenetic factors of anemia in Crohn's disease. The therapeutic management using recombinant human erythropoietin and parenteral iron is reasonable and effective.     

Diagnosis of iron deficiency: evaluation of the "soluble transferrin receptor/transferrin" ratio

OBJECTIVE: This study was aimed at determining the diagnostic value of conventional laboratory tests regarding the iron status and serum transferrin receptor in hospitalized patients. METHODS: Patients who had to undergo bone marrow aspirate examination were included in this 8-month prospective study. Iron deficiency was defined as the absence of stainable iron on bone marrow examination. Patients with stainable iron were included in the control group. The higher value of diagnostic efficacy determined the cut-off value for each parameter of the iron status. RESULTS: Twenty-one patients (17 females, four males) (mean age: 52 years) with iron deficiency and 33 control subjects (20 females, 13 males) (mean age: 60 years) were included in the study. The ratio serum transferrin receptor/serum ferritin had the best diagnostic efficiency (78%) with a sensitivity of 81% and a specificity of 97%. Serum ferritin alone with a cut-off value of 60 micrograms/L had the same specificity (97%) but a lower sensitivity (76%). The diagnostic value of all other analyzed tests was below 66% (transferrin alone, mean corpuscular volume, transferrin saturation, iron, serum transferrin receptor alone, red cell distribution width). CONCLUSION: Among in-patients, ferritin remains the first intention test to diagnose iron deficiency, but the cut-off value should be increased (60 micrograms/L in this study). The ratio "serum transferrin receptor to serum ferritin" provides the highest specificity with a higher cost and should be used only in doubtful cases.     

Functional erythropoietin deficiency in patients with Type 2 diabetes and anaemia.

AIMS: Anaemia is a common finding in patients with diabetic nephropathy. Impaired production of erythropoietin is thought to be the predominant cause, as a result of renal microvascular disease. This study aims to determine the prevalence of functional erythropoietin deficiency in a cross-sectional survey of patients with Type 2 diabetes. METHODS: Clinical data on 604 patients with Type 2 diabetes were obtained, including a full blood count, iron indices and detailed history of diabetic complications. Erythropoietin levels were correlated with the presence of anaemia, iron deficiency and renal dysfunction. Functional erythropoietin deficiency was defined by erythropoietin levels in the normal range despite the presence of anaemia. RESULTS: Nineteen per cent of patients (n = 112) were anaemic, among whom erythropoietin deficiency (76%) and reduced iron availability (58%) were common findings. Over 90% of patients had erythropoietin deficiency, once those with reduced iron stores or availability were excluded. Most of these patients had moderate renal impairment (60%, n = 67). However, even in the absence of renal impairment, 71% of anaemic patients (n = 32/45) had functional erythropoietin deficiency, although most had other evidence of nephropathy. In addition, two-thirds of patients with reduced iron availability were unable to increase erythropoietin above the normal range. CONCLUSIONS: These findings confirm the failure of the kidney to produce erythropoietin in response to a falling haemoglobin is a key component to anaemia in diabetes. The likelihood of functional erythropoietin deficiency as a cause of anaemia is not dependent on the severity of renal impairment or excluded in diabetic patients with reduced iron stores or availability.     

Iron metabolism in patients with the anaemia of end-stage renal disease during treatment with recombinant human erythropoietin

Iron metabolism was studied in 21 patients with the anaemia of end-stage renal disease during 40 weeks of treatment with recombinant human erythropoietin (rhEPO). Oral iron was prescribed to all patients. Initial serum iron concentrations and transferrin saturation levels were subnormal, decreased during the correction period of treatment, and increased thereafter. In 81% of patients in whom pretreatment transferrin saturation was below 0.25, transferrin saturation decreased below 0.16, despite sufficiently high serum ferritin levels. Serum ferritin concentrations decreased significantly. There was no correlation between serum ferritin levels and serum iron or transferrin saturation. Ferrokinetic studies, performed before and during treatment, showed an increase in plasma iron turnover, in erythron transferrin uptake, and in the flux of iron binding sites through the plasma. The rhEPO dose needed to keep the haematocrit at the target level during the maintenance period of treatment was significantly correlated with transferrin saturation, and iron binding capacity, but not with serum ferritin concentrations. This suggests that the functional availability of iron in plasma, rather than the size of body iron stores, is a major factor in the determination of the response to rhEPO treatment in end-stage renal disease.     

Current data on iron metabolism]

Iron is required for cellular life. However, abnormalities of its metabolism may lead to iron deficiency or iron overload, both conditions which are deleterious. Therefore, stock and distribution of iron in the body must be very stable. Classically, four major proteins are involved in iron metabolism: (a) transferrin which is implicated in its plasmatic transport, (b) transferrin receptor which regulates iron-transferrin uptake, (c) ferritin, the major iron storage protein, and (d) IRP (Iron Regulatory Protein) which regulates both the entry and storage of iron by linking to the IRE (Iron Responsive Element), a nucleotidic sequence found on transferrin receptor and ferritin mRNA. Thus, IRP adapts gene expression to the iron cellular status. Recent data give informations about new proteins involved in iron metabolism: HFE whose gene is mutated in genetic hemochromatosis, ceruloplasmin which permits cellular iron egress and frataxin which is implicated in the exit of iron from mitochondria.