A comparison between the soluble transferrin receptor,transferrin saturation and serum ferritin as markers of iron state in hemodialysis patients

An adequate iron management is important in the treatment of anemia and in hemodialysis (HD) patients. Serum ferritin and transferrin saturation (TS) may be influenced by the presence of inflammation. Recently, the soluble transferrin receptor (s-TfR) has been advocated as a parameter of iron status in HD patients. The aim of the present study was to assess firstly the relation between serum ferritin, TS, and s-TfR in HD patients and to predict their agreement (assessed by kappa) in the diagnosis of iron deficiency, and, secondly, to assess the influence of inflammation on the relation between the parameters of iron state. Iron deficiency by either marker was respectively defined as ferritin <100 microg/l, TS <20%, or s-TfR >2.4 microg/ml. In the overall group of patients, TS and s-TfR were significantly related (r = -0.38), whereas s-TfR and serum ferritin were not. Both serum ferritin and TS were related to CRP (r = 0.50 and -0.34; p < 0.05), whereas s-TfR was not. The kappa value for agreement between serum ferritin and TS in the diagnosis of iron deficiency was 0.24 (p = 0.07), 0.12 (p = NS) for the agreement between TS and s-TfR and 0 for that between serum ferritin and s-TfR. In patients with CRP levels 相似文献   

Serum soluble transferrin receptor reflects erythropoiesis but not iron availability in erythropoietin-treated chronic hemodialysis patients

BACKGROUND: The diagnosis of iron deficiency using the current commonly used tests is usually difficult in hemodialysis patients. Soluble transferrin receptor (sTfR) has caught the attention of physicians recently as regards its use as a parameter for the evaluation of iron status. This study was conducted in order to evaluate the correlation of serum soluble transferrin receptor (sTfR) concentration with hematological parameters and iron profiles, in the role of identifying iron deficiency among dialysis patients. METHODS: Seventy-three patients having received chronic hemodialysis and stable maintenance recombinant human erythropoietin (rHuEPO) therapy were included. Iron, total iron-binding capacity, ferritin and sTfR were measured in the first week. Following this, these patients began to receive intravenous iron dextran (2 mg/kg/week) for 4 weeks. The hematocrit (Hct), hemoglobin (Hb) levels and reticulocyte counts were evaluated weekly. At the beginning of fifth week, the sTfR level was measured again. Patients were classified as belonging to one of the following groups: serum ferritin < 100 microg/L - absolute iron-deficient group; initial ferritin level > or = 100 microg/L with an increase in hemoglobin of greater than 1 g/dL at the end of the study occult iron deficiency group; others - non iron-deficient group. RESULTS: Seventy-one patients completed the study. The concentration of sTfR was positively correlated with Hct, Hb and reticulocyte index at the beginning (r = 0.236, p = 0.047; r = 0.257, p = 0.04; r = 0.401, p < 0.01, respectively) and at the end of the study (r = 0.384, p < 0.01; r = 0.338, p < 0.01; r = 0.427, p < 0.001, respectively). After 4 weeks of iron and rHuEPO therapy, the sTfR concentration increased, rather than declined, from 21.85 +/- 8.06 nM to 23.76 +/- 7.42 nM (p = 0.04) and the change was positively correlated with the changes in Hct, Hb and reticulocyte index. The administered rHuEPO doses did not differbetween the iron deficiency group (absolute deficiency, n = 3; occult deficiency, n = 10) and non-iron deficiency group (n = 58). The sTfR levels failed to identify the occult iron deficiency group because there was no difference between occult iron-deficient and non-iron-deficient patients (24.73 +/- 9.09 nM versus 21.60 +/- 7.89 nM, p = 0.34). Instead, transferrin saturation (TS) could be a differential marker between the 2 groups (19.0 +/- 10.9% versus 30.1 +/- 12.7%, p = 0.012). CONCLUSION: The serum sTfR concentration is indeed an appropriate marker for erythropoiesis. The erythropoitic effect of administered rHuEPO could mask the effect of iron status on the sTfR concentration. This might make the sTfR concentration no longer an appropriate index to identify the presence of occult iron deficiency. Thus, TS and ferritin currently remain better methods for the evaluation of iron status in rHuEPO-treated chronic hemodialysis patients.     

Early prediction of response to intravenous iron supplementation by reticulocyte haemoglobin content and high-fluorescence reticulocyte count in haemodialysis patients.

BACKGROUND: Optimal response to recombinant human erythropoietin (rHuEpo) in haemodialysis (HD) patients requires provision of sufficient available iron. However, a balance between iron requirements and supplements remains a challenge in clinical practice. Reticulocyte parameters, i.e. reticulocyte haemoglobin content (CHr) and reticulocytes in a high-fluorescence intensity region (HFR), have been shown to be accurate predictors of iron-deficient erythropoiesis as compared with traditional markers. Therefore, the aim of this study was to appraise the diagnostic power of these two parameters in the early prediction of response to intravenous iron (IVFE) medications in HD patients receiving rHuEpo. METHODS: Sixty-five HD patients with a serum ferritin level of <500 microg/l and on rHuEpo therapy for >6 months were enrolled for IVFE supplementation (100 mg iron saccharate three times a week for 4 weeks, then 100 mg every 2 weeks for 5 months). Haemoglobin, haematocrit, serum ferritin, transferrin saturation, reticulocyte count, percentage of hypochromic red cells, CHr and HFR were measured before and following iron supplementation. Response was defined as a rise in haematocrit of >3% and/or a reduction in rHuEpo dose of >30% over the baseline values at the end of the study. RESULTS: Forty-two patients had a dramatic response to IVFE therapy with a 13.5% increase in mean haematocrit and a 38% reduction in rHuEpo dose at the end of the study (P<0.001). This paralleled a statistically significant rise in CHr and HFR (P<0.001). Univariate analyses showed that ferritin (P<0.010) and CHr (P<0.001) at baseline, changes in CHr (DeltaCHr(2W), P<0.001) and HFR (DeltaHFR(2W), P<0.010) at 2 weeks, as well as changes in CHr (DeltaCHr(4W), P<0.001) and HFR (DeltaHFR(4W), P<0.001) at 4 weeks, strongly correlated with response to IVFE supplementation. Stepwise discriminant analysis disclosed that DeltaCHr(4W) in conjunction with DeltaHFR(4W) exhibited an r(2) value of 0.531 (P<0.001) to predict response to IVFE therapy. Analyses by receiver operating characteristic curves and logistic regression further revealed that DeltaCHr(4W) at a cut-off value of >1.2 pg and DeltaHFR(4W) of >500/microl were more specific to the status of iron-deficient erythropoiesis following IVFE medications. Combined use of the two cut-off values allowed for the highest accuracy in the early prediction of the response to IVFE therapy, with a sensitivity of 96% and a specificity of 100%. CONCLUSIONS: Our study shows that changes in CHr and HFR at either 2 or 4 weeks are superior to the conventional erythrocyte and iron metabolism indices and may serve as reliable parameters to detect iron-deficient erythropoiesis in HD patients undergoing rHuEpo therapy. During aggressive IVFE treatment, early identification of non-responsiveness and subsequent discontinuation of treatment can avoid the inadvertent iron-related toxicity due to over-treatment.     

Factors determining the percentage of hypochromic red blood cells in hemodialysis patients.

Factors determining the percentage of hypochromic red blood cells determines iron status in hemodialysis patients. BACKGROUND: Determination of the percentage of hypochromic red blood cells (RBC; %HYPO) has been advocated as a sensitive index of functional iron deficiency during erythropoietin (EPO) therapy in hemodialyzed patients. METHODS: The significance of %HYPO in chronic renal failure was evaluated in 64 chronically hemodialyzed patients. The linear correlation was determined between %HYPO and 13 variables, including age, sex, weight, C-reactive protein (CRP), ferritin, transferrin (Tf), Tf saturation, soluble Tf receptor (sTfR), serum iron (SI), urea, parathormone, dialysis dose (Kt/V), dose of EPO administered (EPO), and absolute reticulocyte count. Multiple regression analyses were then performed to select the parameters that jointly provide the best prediction of %HYPO. RESULTS: Univariate analysis showed significant correlations between %HYPO and iron parameters (sTfR, Tf saturation, SI, and ferritin, in decreasing order), EPO, reticulocyte count, and CRP. Multivariate analysis yielded an equation showing that the variation of %HYPO is essentially associated with the combined changes in sTfR, CRP, and EPO dosage. CONCLUSIONS: %HYPO is a meaningful and inexpensive parameter that reflects the integrated effects of iron stores, inflammation, and erythropoietic stimulation on iron availability in hemodialyzed patients. Among iron exchange parameters, sTfR is the best predictor of %HYPO, followed by Tf saturation, SI, and ferritin.     

Percentage of hypochromic red blood cells as predictor of erythropoietic and iron response after i.v. iron supplementation in maintenance haemodialysis patients

Background. The percentage of hypochromic red blood cells (RBC), defined as those with a cellular haemoglobin <28 g/dl has been suggested to be a sensitive marker of functional iron deficiency in maintenance haemodialysis (HD) patients. Thus, during rHuEpo therapy an increase in hypochromic RBC to >10% would indicate that more intensive iron supplementation may be required. Methods. We investigated 70 HD patients 57.1±15.3 years old and on maintenance HD for 66.3±47.9 months without blood loss from gastrointestinal bleeding or from the vascular access, without surgery and without infectious disease or malignancy. During the study period of 12 weeks, each patient received an i.v. dose of 800 mg ferrogluconate. Haemoglobin, haematocrit, and the percentage of hypochromic RBC were measured before and every 4 weeks after the start of the study; serum ferritin, zinc protoporphyrin (ZPP) and C-reactive protein (CRP) were measured at the beginning (baseline) and end of the study. Results. At baseline the percentage of hypochromic RBC was ⩽5.0% in 28 patients, >5.0 and ⩽10.0% in 25 patients and >10.0% in 17 patients, suggesting functional iron deficiency in at least 42 patients, suggesting functional iron deficiency in at least 42 patients. Nine patients had serum ferritin values <100 &mgr;g/l; nonetheless in these patients the median percentage of hypochromic RBC was 5.9% (range 0.9-14.3%), indicating that an absolute iron deficiency can occur in the presence of normal amounts of hypochromic RBC. There was a significant correlation between serum ferritin levels and hypochromic RBC at the end, but not at the beginning, of the study. However, there was no correlation between ZPP and hypochromic RBC at any time during the study. During i.v. iron supplementation the rHuEpo dose could be reduced by 8.5% in patients with hypochromic RBC ⩽5.0%, by 11.3% in patients with hypochromic RBC>5.0 and ⩽10.0% and by 23.4% in patients with hypochromic RBC>10.0%, demonstrating the benefit of i.v. iron in patients with functional iron deficiency. In HD patients in whom serum ferritin levels remained below 290 &mgr;g/l until the end of the study, a significant reduction of the rHuEpo dosage could be obtained during i.v. iron therapy. This was not the case in patients with serum ferritin >290 &mgr;g/l after iron supplementation. We found that the percentage of hypochromic RBC is the most sensitive parameter for predicting hyporesponsiveness in CPR-positive patients. Finally our data indicate that HD patients with hypochromic RBC>6% and low to moderate increases in serum ferritin levels after i.v. iron supplementation significantly benefit from i.v. iron therapy. Conclusions. Two different aspectsshould be taken into consideration in HD patients treated with rHuEpo and concomitant i.v. iron therapy: (1) response of the erythropoietic system to rHuEpo, and (2) adequate delivery of the supplemented iron to the erythropoietic system. The patient's percentage of hypochromic RBC and increase in serum ferritin after i.v. iron supplementation should be used to decide whether or no i.v. iron should be given and to monitor this type of therapy in HD patients.     

The relationship between reticulocyte hemoglobin content with C-reactive protein and conventional iron parameters in dialysis patients

Adequate iron stores are a prerequisite for successful erythropoietin (EPO) therapy in hemodialysis (HD) patients. Nevertheless, iron status estimation in HD patients remains problematic, as most parameters are influenced by inflammation. The reticulocyte hemoglobin content (CHr) has recently been proposed as a useful tool in iron status assessment. However, the effect of inflammation on CHr remains unstudied. This study aimed to assess the relationship between CHr with other parameters of iron status as well as with C-reactive protein (CRP). This relationship was studied in all the patients (n=61) at our dialysis unit. CHr was significantly and positively related to transferrin saturation (TS) (rho=0.26; p<0.05) and inversely to the percentage of hypochromic red blood cells (%Hypo) (rho=-0.63; p<0.0001), but not to serum ferritin. CHr was strongly and inversely related to log CRP (rho=-0.50; p<0.0001). Despite the use of maintenance intravenous (i.v.) iron doses and relatively high serum ferritin levels, a large percentage of patients were in a state of functional iron deficiency (%Hypo > or = 6 in 41% of patients and CHr < or = 29 pg in 13% of patients). This percentage was far lower in patients with CRP levels below the detection limit (2 mg/L) (26% and 0%, respectively). In conclusion, CHr is related to both TS and %Hypo, but not to serum ferritin, and is strongly influenced by the presence of inflammation (as determined by CRP). In patients with elevated CRP levels, it is very difficult to reach target iron status levels without exceeding the upper limits for serum ferritin.     

High blood soluble receptor p80 for tumour necrosis factor-alpha is associated with erythropoietin resistance in haemodialysis patients.

BACKGROUND: Inflammation is one of the major causes of resistance to erythropoietin (rHuEpo) treatment. Tumour necrosis factor-alpha (TNF-alpha), one of the most potent proinflammatory cytokines, is known to inhibit human erythropoiesis directly in vitro. Although blood levels of soluble receptors for TNF-alpha (sTNFRs) are elevated in haemodialysis (HD) patients, the role of sTNFR for rHuEpo responsiveness in HD patients remains to be clarified. METHODS: We measured serum sTNFR (p55 and p80) levels in 83 stable outpatients undergoing regular HD (age 62+/-1, HD duration 15+/-1 years). After dividing the patients into three groups according to rHuEpo dose: (low (L) <60, n=31; moderate (M) > or =60 to <120, n=31; high (H) > or =120 U/kg/week rHuEpo, n=21), we examined the relationship between serum sTNFR levels and the degree of renal anaemia and rHuEpo dosage. RESULTS: Haemoglobin was significantly higher in patients receiving low rHuEpo dosage (L, 10.5+/-0.2; M, 9.7+/-0.1; H, 9.5+/-0.2 g/dl, P<0.01 vs M and H groups). There were no differences in blood TNF-alpha, sTNFR p55, C-reactive protein, albumin, ferritin, or intact parathyroid hormone levels among the three groups. Body mass index and creatinine generation rate, a marker of whole-body muscle volume, were significantly reduced in group H (P<0.01). Serum sTNFR p80 levels were significantly higher in group H (4.88+/-0.45 ng/ml) than in L (3.73+/-0.14 ng/ml) and M (3.67+/-0.21 ng/ml) groups (P<0.05). The blood interleukin (IL)-6 level was also increased in patients requiring high rHuEpo doses (L, 5.5+/-0.5; M, 6.4+/-0.5; H, 10.2+/-2.0 pg/ml, P<0.05 vs L and H groups). A stepwise regression analysis revealed that gender and sTNFR p80 were significant predictors of rHuEpo dosage. A significant direct relationship was found between rHuEpo dose and sTNFR p80 (r=0.499) and IL-6 (r=0.439) values in women (P<0.01) but not in men. CONCLUSIONS: These findings suggest that high blood sTNFR p80 may contribute to the development of rHuEpo resistance in female patients undergoing long-term HD.     

Importance of iron supply for erythropoietin therapy

BACKGROUND.: rHuEpo and iron therapy corrects renal anaemia. However, dosage,route of administration, and monitoring of iron and rHuEpo therapyin uraemic patients remains controversial. METHODS.: Therefore a 22-month i.v. iron substitution trial, subdividedinto four study periods, was initiated in 64 iron-depleted chronichaemodialysis (HD) patients receiving i.v. rHuEpo therapy. Withinthe first period (6 months) patients were treated with high-doseiron (100mg at the end of HD treatment, mean cumulative i.v.iron saccharate dosage was 2538±810 mg per patient) inorder to replete the iron stores. During the 2nd period (6 months)the available iron pool was maintained with low-dose iron byadministration of 10, 20, or 40 mg iron at each HD, dependingon haemoglobin, serum ferritin and transferrin saturation levels.During the 3rd period (4 months), the iron-replete patientswere randomized to i.v. or s.c. route of rHuEpo administration.During the 4th period (3 months) iron substitution was omittedto exclude severe iron overload. RESULTS.: In the first study period, high-dose iron therapy dramaticallyreduced the weekly rHuEpo requirement by 70% of the initialdose (from 217±179 to 62.6±70.2 U/kg/week). Inthe 2nd period iron storage pools were easily maintained. Serumferritin and transferrin saturation levels remained stable duringthis study period. Randomization for thrice-weekly i.v. or s.c.administration of rHuEpo in the 3rd study period revealed comparableefficacy for both administration routes in iron-replete patients.In well-nourished patients (serum albumin >40 g/1) withouthyperparathyroidism (parathyroid hormone levels < 100 pg/ml),50–60 U/kg/week rHuEpo were required in contrast to >100 U/kg/week in patients with hyperparathyroidism. In the 4thstudy period, withdrawal of iron administration led to a rapiddecrease of serum ferritin and transferrin saturation levels,indicating the absence of severe iron overload. CONCLUSIONS.: Long-term thrice-weekly i.v. low-dose iron therapy (10–20mg per HD treatment) proved to be a very effective, economicaland safe treatment schedule for iron-replete HD patients. Intravenousand s.c. rHuEpo therapy was equally efficacious in iron-replete,well-nourished patients. HD patients with increased parathyroidhormone levels require significantly more rHuEpo than HD patientswith parathyroid hormone levels values <100 pg/ml).     

Body mass index and resistance to recombinant human erythropoietin therapy in maintenance hemodialysis patients

Abstract

The aim of this work was to contribute to a better understanding of the relationship between resistance to recombinant human erythropoietin (rhEPO) therapy and body mass index (BMI) in hemodialysis (HD) patients. We evaluated 191 HD patients and 25 healthy individuals. Complete blood count, reticulocyte count, and circulating levels of ferritin, transferrin, iron, soluble transferrin receptor (sTfR), transferrin saturation, hepcidin, C-reactive protein (CRP), interleukin 6 (IL-6), albumin, and adiponectin were measured in all patients and controls. Non-responder patients (n?=?16), as compared with responder patients (n?=?175), showed statistically significant lower BMI values, an enhanced inflammatory and higher adiponectin levels, associated with disturbances in iron metabolism. Analyzing the results according to BMI, we found that underweight patients required higher rhEPO doses than normal, overweight, and obese patients, and a higher percentage of non-responders patients were found within the underweight group of HD patients. Moreover, underweight patients presented lower levels of transferrin and higher levels of adiponectin compared to overweight and obese patients, and lower levels of iron compared with normal weight patients. Multiple regression analysis identified the sTfR, hemoglobin, BMI, and albumin as independent variables associated with rhEPO doses. In conclusion, our work showed that HD patients resistant to rhEPO therapy present a functional iron deficiency and a higher degree of inflammation, despite their lower BMI values and higher levels of adiponectin. Actually, BMI is poorly related with markers of systemic inflammation, such as IL-6 and CRP, while adiponectin works a fairly good indirect marker of adiposity within HD patients.     

Intravenous ascorbic acid as an adjuvant therapy for recombinant erythropoietin in hemodialysis patients with hyperferritinemia.

BACKGROUND: Inadequate iron mobilization and defective iron utilization may cause recombinant erythropoietin (rEPO) hyporesponsiveness in hemodialysis (HD) patients with iron overload. We have demonstrated that intravenous ascorbic acid (IVAA), but not intravenous iron medication, can effectively circumvent the functional iron-deficient erythropoiesis associated with iron overload in HD patients. However, it is uncertain whether all HD patients with hyperferritinemia will consistently respond to IVAA and which index may indicate functional iron deficiency in the special entity. Therefore, a prospective study was conducted to establish the guidelines for IVAA adjuvant therapy. METHODS: Sixty-five HD patients with serum ferritin levels of more than 500 microgram/liter were recruited and divided into the control (N = 19) and IVAA (N = 46) groups. IVAA patients with a hematocrit (Hct) of less than 30% received 300 mg of ascorbic acid three times per week for eight weeks. Controls had a Hct of more than 30% and did not receive the adjuvant therapy. Red blood cell and reticulocyte counts, iron metabolism indices, erythrocyte zinc protoporphyrin (E-ZPP), and the concentrations of plasma ascorbate and oxalate were examined before and following the therapy. RESULTS: Thirteen patients (four controls and nine IVAA patients) withdrew by the end of the study. Eighteen patients had a dramatic response to IVAA with a significant increase in their hemoglobin and reticulocyte index and a concomitant 24% reduction in rEPO dose after eight weeks. This paralleled a significant rise in serum iron and transferrin saturation (TS) and a fall in E-ZPP and serum ferritin (baselines vs. 8 weeks, serum iron 68 +/- 37 vs. 124 +/- 64 microgram/dl, TS 27 +/- 10 vs. 48 +/- 19%, E-ZPP 123 +/- 44 vs. 70 +/- 13 micromol/mol heme, and serum ferritin 816 +/- 435 vs. 587 +/- 323 microgram/liter, P < 0. 05). Compared with responders, mean values of hemoglobin, rEPO dose, iron metabolism parameters, and E-ZPP showed no significant changes in controls (N = 15) and in non-responders (N = 19). Thirty-seven patients (18 responders and 19 non-responders) were further analyzed by receiver operating characteristic curves to seek the criteria for prediction of a response to IVAA treatment. The results showed that E-ZPP at a cut-off level of more than 105 micromol/mol heme and TS at a level of less than 25% were more specific to confirm the status of functional iron deficiency in iron-overloaded patients. The two criterion values had the highest accuracy to predict a response to treatment. CONCLUSIONS: Functional iron-deficient erythropoiesis plays a role in rEPO-hyporesponsive anemia in HD patients with hyperferritinemia. IVAA may be an adjuvant therapy for rEPO in these patients, and E-ZPP of more than 105 micromol/mol heme and TS of less than 25% should be used to guide the IVAA treatment.     

Recombinant human erythropoietin independence in chronic hemodialysis patients: clinical features, iron homeostasis and erythropoiesis

AIMS: Recombinant human erythropoietin (r-HuEPO) is widely used to correct renal anemia in uremic patients. Interestingly, some chronic hemodialysis (HD) patients can maintain high hemoglobin level without the need of r-HuEPO. The aim of this study is to investigate clinical features, iron metabolism and erythropoiesis of these r-HuEPO-independent HD patients. METHODS: r-HuEPO independence was defined in dialysis patients as hemoglobin greater than 12 g/dl and no use of r-HuEPO for at least 6 months. An age- and sex-matched group was selected for comparison. Their underlying diseases, duration of hemodialysis therapy, efficacy of dialysis (Kt/V), normalized protein catabolic rate (nPCR) and body mass index (BMI) were recorded. Laboratory data including: hemoglobin, albumin, high sensitivity C-reactive protein, serum iron, total iron binding capacity, transferrin saturation, ferritin, intact parathyroid hormone, soluble transferrin receptor (sTfR), serum EPO, cortisol, testosterone, aluminum and leptin levels were measured. Renal sonography was also performed in each patient to evaluate renal cyst formation. RESULTS: About 2.3% of all HD patients (21/888; M : F = 18 : 3) were r-HuEPO-independent. These patients had significantly longer HD duration and higher serum EPO and sTfR levels, and lower transferrin saturation rate than dependent groups. Correlation analysis revealed that hemoglobin level strongly correlated with HD duration, serum sTfR and EPO levels. Levels of sTfR were positively related with serum EPO levels and BMI. Multivariate regression analysis showed that level of sTfR was the only independent factor related to r-HuEPO independence. CONCLUSION: R-HuEPO independence is rare among chronic hemodialysis patients. Factors contributing to this dependence are complex and multiple. Level of serum sTfR parallels erythropoiesis and is the most significant factor associated with r-HuEPO independence in chronic HD patients.     

血液透析红细胞生成素抵抗患者pro-hepcidin与炎性反应和铁代谢的关系

目的 研究维持性血液透析(MHD)红细胞生成素(EPO)抵抗患者pro-hepcidin与炎性反应和铁代谢的关系.方法 40例MHD患者为研究对象,其中20例EPO低反应和20例EPO正常反应.20例健康体检者为对照组.检测参试者的血红细胞计数(RBC)、血红蛋白(Hb)、网织红细胞计数(Ret)、红细胞比容(Hct)、血清铁蛋白(SF)、转铁蛋白(TF)、血清铁和总铁结合力、转铁蛋白饱和度(TSAT)(TSAT=血清铁/总铁结合力)、血清pro-hepcidin、血清超敏C反应蛋白(hs-CRP),并比较组间差异.Pearson相关法分析pro-hepcidin的影响因素.ROC曲线预测pro-hepcidin对EPO抵抗的价值.结果 MHD患者SF、血清pro-hepcidin、hs-CRP显著高于健康对照者(P＜0.01),TF显著低于健康对照者(P＜0.05).EPO抵抗患者血清铁蛋白、血清pro-hepcidin、hs-CRP明显高于反应正常的患者(P＜0.01).Pearson相关分析显示MHD EPO抵抗患者血清pro-hepcidin水平与血清铁蛋白(r=0.843,P=0.000)和hs-CRP(r=0.695,P=0.001)呈正相关.预测EPO抵抗的ROC曲线显示,pro-hepcidin、SF、hs-CRP曲线下面积分别为0.713、0.769和0.958.结论 EPO抵抗与炎性反应和铁代谢相关.血清pro-hepcidin、SF、hs-CRP有可能成为EPO抵抗的标志.     

A serial study of the erythropoietic response to thermal injury.

OBJECTIVE: Since controversy exists over whether erythropoietin levels are increased or decreased after thermal injury, a prospective study was performed to answer this question as well as to characterize the erythropoietic response to thermal injury. SUMMARY BACKGROUND DATA: The concept of using erythropoietin to reduce the need for blood transfusions after thermal injury is attractive. However, since the etiology of burn anemia is both unclear and multifocal, prior to initiating a trial of erythropoietin therapy, it will be necessary to better define the erythropoietic response to thermal injury. METHODS: Twenty-four burn patients with a mean burn size of 31 +/- 18% had serial measurements of serum iron, total iron binding capacity (TIBC), ferritin, erythropoietin, transferrin saturation, hemoglobin, and reticulocyte counts performed on burn days 1, 3, 5, 7, 10, 14, and then weekly. RESULTS: The erythropoietic response was characterized by a decrease in hemoglobin levels as well as serum iron, TIBC, and transferrin saturation (p < 0.05). Ferritin and erythropoietin levels increased as did the reticulocyte count. The erythropoietin response to anemia appeared to be at least grossly intact, since there was an appropriate inverse relationship between the degree of anemia and the magnitude of the erythropoietin response (r2 = .61, p < 0.00001). CONCLUSIONS: Since the erythropoietin levels of these anemic burn victims reached supranormal levels and they manifested a moderate reticulocytosis, the role of replacement erythropoietin therapy after thermal injury requires further study.     

Evaluation of reticulocyte hemoglobin content,percentage of hypochromic red blood cells,and ratio of serum transferrin receptor level/serum iron level as markers of iron-deficiency erythropoiesis in patients undergoing hemodialysis

Reticulocyte hemoglobin content(CHr), percentage of hypochromic red blood cells(%HRC, level of serum transferrin receptor(sTfR), and sTfR/serum iron ratio(sTfR/Fe) were measured in 132 hemodialysis patients. On univariate analysis, CHr was positively correlated with serum amyloid A(SAA) and negatively correlated with Kt/V. %HRC showed a positive correlation with the recombinant human erythropoietin(rHuEPO) dosage. The dependency of each iron-status index on 5 variables, SAA, sFt, TS, KtN, and dose of rHuEPO administered, was determined by stepwise multiple regression analysis. CHr was influenced only by TS, while %HRC, sTfR and sTfR/Fe were influenced by both logrHuEPO dosage and TS. Patients whose hemoglobin concentration increased by more than 1 g/dl following iron supplementation were defined as Iron-Responders, and the remaining patients were defined as Iron-Nonresponders. Fifteen out of 20 patients responded to 10 consecutive intravenous administrations of 80 mg of saccharated ferric oxide at each dialysis session, while five did not. The baseline CHr was significantly lower in Iron-Responders than Iron-Nonresponders. The baseline %HRC, sTfR, and sTfR/Fe were significantly higher in Iron-Responders than Iron-Nonresponders. The baseline CHr, %HRC, and sTfR/Fe were correlated with the degree of change in Hb concentration at 4 weeks of iron supplementation. The absolute change in CHr at 2 weeks of iron supplementation was positively correlated with the absolute change in Hb concentration over the first 4 weeks. CONCLUSION: (1) In assessing the iron metabolic status of dialysis patients, CHr, %HRC, and sTfR/Fe were unique indices compared with the ordinary indices, particularly in diagnosing the functional iron deficiency state. (2) CHr was a valuable marker of iron deficiency anemia and could predict the degree of increase in Hb level following iron supplementation. (3) The %HRC and sTfR/Fe seemed to reflect both erythropoiesis induced by rHuEPO and the iron supply to erythropoietic cells.     

多囊卵巢综合征合并妊娠期糖尿病患者铁代谢与胰岛素抵抗的关系

目的分析多囊卵巢综合征(polycystic ovary syndrome,PCOS)合并妊娠期糖尿病(gestational diabetes mellitus,GDM)患者铁代谢改变及与胰岛素抵抗(insulin resistance,IR)的关系。方法选择2017年1月至2018年2月在烟台毓璜顶医院常规产检,妊娠24~28周的孕妇为筛查对象。确诊为GDM的孕妇60例为GDM组,既往诊断为PCOS且合并GDM的孕妇60例为多囊卵巢合并妊娠期糖尿病(polycystic ovary syndrome with gestational diabetes mellitus,PGDM)组,同时按年龄段进行1∶1∶1匹配,选择正常孕妇60例为正常对照(NC)组。检测3组患者血糖、胰岛素、血红蛋白(Hb)、铁代谢(血清铁、铁蛋白、转铁蛋白饱和度)水平,并评估患者氧化应激损伤及炎症水平的改变,利用多元线性回归法分析铁代谢指标与炎症指标及IR的关系。结果与NC组相比,PGDM组Hb水平降低,铁蛋白(SF)、转铁蛋白饱和度(TS)升高(F=3.55、8.24、5.10,均P<0.05);丙二醛(MDA)水平升高,超氧化物歧化酶(SOD)水平降低(F=11.11、7.24,均P<0.01);肿瘤坏死因子-α(TNF-α)、白介素-6(IL-6)水平升高(F=4.02、19.06,均P<0.05);与GDM组相比,PGDM组Hb水平降低,SF、TS升高,HOMA-IR、MDA、TNF-α、IL-6水平均升高(均P<0.05)。MDA、TNF-α、IL-6与SF呈正相关(r=0.42、0.43、0.56,均P<0.05),与TS呈正相关(r=0.61、0.42、0.52,均P<0.01);SF、TS与胰岛素抵抗指数呈正相关(r=0.39、0.41,均P<0.01)。结论PGDM患者铁沉积状况导致机体氧化应激损伤程度升高,炎症反应增加,从而加重了IR程度。铁代谢紊乱可能与PGDM患者血糖升高机制有关。     

Very low doses of direct intravenous iron in each session as maintenance therapy in hemodialysis patients

Background: Intravenous (IV) iron supplementation is widely used in hemodialysis (HD) patients to treat their periodic losses. However, the ideal dose and frequency is unknown. The goal of the study is to see if a 20?mg dose of iron IV at the end of each session of HD as iron maintenance is better than the iron prior therapy. We analyze the erythropoiesis activity (EA) and functional iron (FI) after four weeks of treatment.

Methods: In 36 patients, we measure reticulocyte count and content of hemoglobin reticulocyte (CHr) as EA and FI markers, respectively, before and after the treatment. Before the study, 23 patients received another different therapy with IV iron as maintenance therapy.

Results: Reticulocyte count: 49.7?±?23.8?×?10³ before and 47.2?±?17.2?×?10³ after the treatment (p=?0.51). The CHr: 34.8?±?3.7?pg and 34.4?±?3.5?pg, respectively, (p=?0.35), showing an excellent correlation with the other FI markers (serum iron r?=?0.6; p?=?0.001; saturation transferrin r?=?0.49; p?=?0.004); that is not shown with the serum ferritin (r?=?0.23; p?=?0.192) or the hepcidin levels (r?=?0.22; p?=?0.251). There was not a correlation between the C-Reactive Protein, reticulocyte count, and CHr. The 13 patients who did not receive the iron prior to the study showed high FI levels, but not an increased of the serum ferritin or the serum hepcidin levels.

Conclusions: The administration of a small quantity of iron at the end of every HD session keeps the EA and the FI levels and allows reducing the iron overload administered and/or decreasing the iron stores markers in some patients.     

Increased visfatin in hemodialysis patients is associated with decreased demands for recombinant human erythropoietin

Abstract

Background: Studies detected an association between visfatin and markers of iron metabolism in patients with insulin resistance. In this study, such a relation was evaluated in hemodialysis (HD) patients. Also relations between visfatin and hepcidin, demands for recombinant human erythropoietin (rHuEpo), inflammation, and situations characterized by insulin resistance were evaluated. Methods: After a four-week washout period from iron treatment, 33 HD patients and 20 healthy volunteers enrolled in the study. Serum visfatin, hepcidin, and interleukin-6 (IL-6) were assessed by means of enzyme-linked immunosorbent assay. Hemoglobin, serum iron, ferritin, and transferrin saturation (TSAT) were also measured. Results: Visfatin was markedly increased in HD patients. Visfatin levels did not differ between diabetics and non-diabetics. No relation was detected between visfatin and body mass index or IL-6 in HD patients. From the markers of iron metabolism, the hepcidin included, visfatin was related only to TSAT. A strong positive relation was revealed between visfatin and hemoglobin, whereas visfatin was inversely related to rHuEpo dose. Resistance to rHuEpo index was inversely and independently of TSAT related to visfatin. Conclusion: Visfatin is increased in HD patients and it is associated with decreased demands for rHuEpo.     

Role of prohepcidin, inflammatory markers and iron status in resistance to rhEPO therapy in hemodialysis patients

The aim of our study was to assess possible relations between prohepcidin, iron status and inflammatory markers in hemodialysis (HD) patients, as well as its association with resistance to recombinant human erythropoietin (rhEPO) therapy. Fifty HD patients and 25 healthy controls were enrolled in the study. Among HD patients, 25 were non-responders and 25 were responders to rhEPO therapy. Complete blood cell count, reticulocyte count, and circulating levels of ferritin, iron, transferrin saturation, C-reactive protein (CRP), soluble interleukin (IL)-2 receptor (s-IL2R), soluble transferrin receptor (s-TfR), IL-6 and prohepcidin were measured in all patients and controls. HD patients showed higher circulating levels of ferritin, s-TfR, CRP, IL-6, s-IL2R and prohepcidin, and lower levels of transferrin compared to healthy controls. Higher levels of s-TfR, CRP and lower levels prohepcidin were observed among non-responders compared to responders. Prohepcidin levels correlated negatively with s-TfR and reticulocyte count. The weekly rhEPO/kg dose was found to be positively correlated with CRP, hemoglobin and s-TfR. In conclusion, our data show that a close interaction exists between inflammation, iron status and prohepcidin serum levels that ultimately regulate intracellular iron availability. Prohepcidin and s-TfR, together with CRP, may prove to be good markers of resistance to rhEPO therapy in HD patients.     

Ferroportin in monocytes of hemodialysis patients and its associations with hepcidin,inflammation, markers of iron status and resistance to erythropoietin

Purpose

Disturbed iron homeostasis contributes to resistance to recombinant human erythropoietin (rHuEpo) in hemodialysis (HD) patients. Increased hepcidin, which downregulates the iron exporter ferroportin, has been incriminated. However, other factors also control ferroportin expression in mononuclear phagocyte system. Ferroportin in monocytes, as well as serum hepcidin, interleukin-6 (IL-6) and common markers of iron status were measured and correlations with rHuEpo resistance index (ERI) were evaluated.

Methods

After a 4-week washout period from iron treatment, 34 HD patients and 20 healthy volunteers enrolled in the study. Ferroportin was assessed by means of western blotting, whereas hepcidin and IL-6 with enzyme-linked immunosorbent assay. Hemoglobin, serum iron, ferritin and transferrin saturation (TSAT) were also measured.

Results

Ferroportin in monocytes of HD patients was decreased. Serum hepcidin and IL-6 were increased, whereas serum iron and TSAT were decreased. ERI was negatively correlated with ferroportin and all the markers of iron adequacy, but not with hepcidin.

Conclusion

Decreased ferroportin in monocytes of HD patients accompanies increased hepcidin, inflammation, decreased iron availability and is correlated with resistance to rHuEpo treatment.