Hypotransferrinemia of chronically hemodialyzed patients

Increasingly, the iron needs of hemodialysis patients receiving erythropoietin are being met by infusions of intravenous iron guided by laboratory tests to measure body iron availability. The interpretation of assays based on ferritin and transferrin must take into account the effect of inflammation on both proteins and malnutrition on the latter. In our chronic hemodialysis population, hypotransferrinemia was present in greater than 90% of the patients. Using statistical methods and laboratory studies, we sought to identify the principal reasons for the high prevalence of hypotransferrinemia. We observed that transferrin levels were disproportionately low relative to albumin and prealbumin and correlated inversely with ferritin levels. There was no correlation between transferrin and the soluble transferrin receptor. After the infusion of 900 mg of iron, transferrin saturation increased and total transferrin decreased so that unsaturated iron bonding capacity decreased as well. Ferritin concentrations increased significantly after iron loading. Attempts to demonstrate activation of the patients' antioxidant mechanisms associated with iron infusion were negative. We concluded that the low transferrin may be principally the result of diminished synthesis related to the chronic inflammatory status of hemodialysis patients, which favors production of ferritin, but iron and nutritional status may also influence the blood transferrin concentration. These factors make interpretation of transferrin-dependent assessment of body iron stores unreliable and can result in inadequate or overly aggressive iron-replacement therapy.     

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.     

Intravenous iron dextran and erythropoietin use in pediatric hemodialysis patients

Recombinant human erythropoietin (rHuEPO) is an effective treatment for the anemia of chronic renal failure. However, adequate availability of iron is necessary for an optimal response. We prospectively evaluated the effect of an intravenous iron protocol in a pediatric hemodialysis unit. Patients with either a serum ferritin less than 150 ng/ml or transferrin saturation (TSAT) less than 20% received intravenous iron dextran during ten consecutive dialysis sessions. The administration of rHuEPO was adjusted using a protocol designed to maintain patient hematocrit between 33% and 36%. Thirteen courses of intravenous iron were evaluated. Patients received 4 mg/kg of iron dextran (maximum of 100 mg) during each of ten consecutive dialysis sessions. In 12 cases there was a decrease in rHuEPO use 2 months after completing the course of intravenous iron. The mean rHuEPO dose decreased from 3,784 units to 2,115 units (P<0.005). Based on the criteria of response to intravenous iron, a percentage iron saturation of less than 20% had a high specificity for detecting iron deficiency. All patients who received a course of intravenous iron had a TSAT less than 20%. The measurement of serum ferritin was less useful in our patients.     

Comparison of intravenous ascorbic acid versus intravenous iron for functional iron deficiency in hemodialysis patients

The effect of intravenous ascorbic acid was compared with that of intravenous iron in the treatment of functional iron deficiency, as defined as serum ferritin levels over 300 ng/ml and serum iron levels below 50 microg/dl, in patients on chronic hemodialysis. Thirteen patients on chronic hemodialysis with functional iron deficiency received intravenous injections of ascorbic acid, 100 mg, three times a week, after hemodialysis. The therapy was continued until serum ferritin decreased to below 300 ng/ml (3 months at the maximum). The iron and control group were composed of patients who had serum iron levels below 50 microg/dl within 3 months after serum ferritin rose to over 300 ng/ml. Seven patients with the iron group received more than a total of 10 intravenous injections of saccharated ferric oxide (40 mg/dose) after hemodialysis, and seven patients with the control group received no iron preparation during the 3 months. In the ascorbic acid group, while hemoglobin did not change from 10.9 +/- 0.5 g/dl (mean +/- SE) during the three-month period, serum iron increased significantly from 37 +/- 4 microg/dl to 49 +/- 4 microg/dl after one month (p<0.01), and remained elevated until the end of the three-month period. Serum ferritin decreased significantly from 607 +/- 118 ng/ml to 354 +/- 30 ng/ml after 3 months (p<0.01). In the iron group, hemoglobin and serum iron increased significantly from the respective pre-treatment levels during the 2-month period, and serum ferritin rose significantly after 3 months. In the control group, hemoglobin, serum iron and ferritin levels decreased significantly from the respective pre-treatment levels during the 3 months. The recombinant erythropoietin dose remained stable for three months in the ascorbic acid, iron, and control groups, respectively. These results suggest that in hemodialysis patients with a functional iron deficiency, treatment with intravenous ascorbic acid can prevent iron overload due to treatment with intravenous iron, and provide a useful adjuvant means of maintaining hemoglobin and serum iron levels.     

Treatment of Iron Deficiency Anemia in Orthopedic Surgery with Intravenous Iron: Efficacy and Limits: A Prospective Study

Background: Preoperative anemia is frequent in patients undergoing orthopedic surgery. The purpose of this study was to assess the preoperative increase of hemoglobin in iron deficiency anemia patients treated with intravenous iron.

Methods: After obtaining written informed consent, 20 patients with iron deficiency anemia received 900 mg intravenous iron sucrose over 10 days starting 4 weeks before surgery. Changes of hemoglobin and iron status were measured over 4 weeks and at discharge. In the last 11 patients, endogenous erythropoietin was also measured. Data were analyzed using the Friedman test followed by pairwise Wilcoxon signed rank tests with Bonferroni correction.

Results: Hemoglobin increased significantly (P < 0.0001) after intravenous iron treatment. Overall, the mean maximum increase was 1.0 +/- 0.6 g/dl (range, 0.2-2.2 g/dl). Ferritin increased from 78 +/- 70 to 428 +/- 191 [mu]g/l (P = 0.0001), ferritin index decreased from 2.7 +/- 2.4 to 1.5 +/- 1.0 (P = 0.0001), and soluble transferrin receptor decreased from 4.1 +/- 2.3 mg/l to 3.7 +/- 2.3 mg/l (P = 0.049), whereas transferrin saturation (20.5 +/- 9.0 to 22.9 +/- 9.0%) and serum iron (13.3 +/- 4.6 to 13.1 +/- 4.5 [mu]m) did not change significantly after intravenous iron treatment. Endogenous erythropoietin decreased from 261 +/- 130 pg/ml to 190 +/- 49 pg/ml 2 weeks after intravenous iron treatment (P = 0.050, not significant after Bonferroni correction). No adverse events related to intravenous iron were observed. The maximum increase of hemoglobin was observed 2 weeks after the start of intravenous iron treatment, indicating that administration of intravenous iron 2-3 weeks before surgery may be optimal.     

Adverse events in chronic hemodialysis patients receiving intravenous iron dextran--a comparison of two products

BACKGROUND: Parenteral iron therapy is required in a majority of chronic dialysis patients who are receiving recombinant human erythropoietin (r-HuEPO) in order to provide adequate iron for erythropoiesis. At this time, there are only two formulations of parenteral iron dextran available for clinical use in the USA. These two preparations of iron dextran have different physical and chemical characteristics that might affect the adverse events experienced by dialysis patients receiving iron dextran. METHODS: We performed a retrospective analysis of all 665 courses of parenteral iron dextran which were administered in our hemodialysis unit from June 1992 through July 1997. An adverse event (AE) was defined as any event which led to interruption of the prescribed course of iron therapy or precluded subsequent administration of parenteral iron in the presence of documented iron deficiency. Database elements included patient age, gender, cause of renal failure, and prior history of drug allergy. The average hemoglobin value and serum iron parameters (iron, total iron binding capacity (TIBC), percent saturation of TIBC, and ferritin) were recorded both pre- and post-iron administration, when available. A course of parenteral iron dextran consisted of a 25-mg test dose, followed by four or five doses of 300 mg each. Iron dextran was infused into the venous limb of the hemodialysis blood circuit over the last 30-60 min of a dialysis treatment. The two forms of iron dextran were designated as Iron A (molecular weight = 165,000) and Iron B (molecular weight = 267,000). RESULTS: Fifty-seven percent of our patients were male, 92% were of white race, and diabetes was the most common cause of renal failure (34%). Sixty-four percent of the patients were 60 years of age or older, and 39% had a history of allergy to one or more drugs. We observed 33 AEs during the administration of parenteral iron dextran, and these AEs occurred in 21 courses of parenteral iron dextran administration. Eighteen of the AEs were gastrointestinal in nature; 7 AEs were cutaneous in nature, 6 AEs had systemic manifestations, while only 2 AEs caused respiratory problems. Two of the AEs were felt to be anaphylactoid in nature. Female gender (p = 0.06) and iron dextran product (p = 0.02) were identified as potential risk factors for the development of an AE. There were 468 courses of Iron A administered, 10 of these courses were complicated by 15 AEs (one or more AE per course). One hundred and ninety-seven courses of Iron B were administered and 11 (5.6%) courses were complicated by the development of 18 AEs (9.1 AEs per 100 courses). Serum iron rose by 22 microg/dl and TIBC saturation increased by 14% after the administration of parenteral iron. The average serum ferritin level rose by 430 microg/l and hemoglobin values rose by an average of 0.8 g/dl. There were no significant differences in the changes of iron parameters or hemoglobin levels between the two iron dextran preparations. CONCLUSIONS: The administration of parenteral iron dextran to chronic hemodialysis patients has a relatively high degree of safety. Both iron products were equally efficacious in increasing serum iron parameters and hemoglobin levels. Even when corrected for other factors, there was a significant difference in the observed AEs between the two formulations of parenteral iron dextran. Our observations, if true, may have important implications for the management of anemia in chronic hemodialysis patients. If a significant number of AEs prohibit the administration of a specific iron dextran product to a large number of chronic hemodialysis patients, then anemia management may become suboptimal. In the future, newer iron products may provide even safer alternatives for the administration of parenteral iron to chronic hemodialysis patients.     

Low-dose intravenous iron administration in chronic hemodialysis patients treated with recombinant human erythropoietin

We conducted a prospective study to determine the effect of intravenous low-dose iron administration in chronic hemodialysis patients treated with recombinant human erythropoietin (rHuEPO). Sixteen hemodialysis patients (8 males and 8 females; mean age 63.1+/-9.8 years) on maintenance rHuEPO therapy were included in the study. Patients with <100 ng/ml of ferritin received 50 mg iron during every hemodialysis session. Patients with 100-200 ng/ml of ferritin were given 50 mg iron fortnightly. Iron was not supplemented in patients with ferritin levels >200 ng/ml. Mean hematocrit, serum iron levels and transferrin saturations were significantly higher at 6 and 12 months. There was a significant reduction in weekly rHuEPO doses between the start and the 6th and 12th months. Our study shows intravenous iron administration of 100 mg/month may be sufficient to achieve a satisfactory iron status in dialysis patients on maintenance rHuEPO therapy.     

The safety and efficacy of an accelerated iron sucrose dosing regimen in patients with chronic kidney disease

BACKGROUND: Provision of adequate iron to support erythropoiesis in patients with chronic kidney disease (CKD) is time consuming and may present adherence problems for patients in the outpatient setting. We studied an accelerated regimen of high-dose intravenous iron sucrose therapy in a cohort of iron-deficient, anemic CKD patients. METHODS: Intravenous iron sucrose 500 mg was infused over three hours on two consecutive days in 107 CKD patients (glomerular filtration rate, 32.3 +/- 19.6 mL/min/1.73m2, baseline hemoglobin 10.2 +/- 1.7 g/dL). Iron indices (transferrin saturation, ferritin) were measured at baseline and at two and seven days after completion of the iron regimen. Blood pressures were monitored immediately prior to, and hourly throughout the iron sucrose infusions. RESULTS: Transferrin saturation and serum ferritin increased from 18.5 +/- 8.5% and 177 +/- 123.8 ng/mL at baseline to 40.2 +/- 22.3% and 811 +/- 294.1 ng/mL in 102 evaluated patients (P < 0.015). In 55 patients with additional measurements at 7 days post-dosing, the transferrin saturation and ferritin had fallen to 26.3 +/- 10.6% and 691 +/- 261.8 ng/mL (P < 0.015 compared to two days' post-dose). Blood pressure rose slightly, but not significantly, throughout the infusions, and altering the infusion rate was not necessary. Two patients had seven adverse events that were considered related to iron sucrose. CONCLUSION: An accelerated regimen of high-dose intravenous iron sucrose therapy in CKD patients is safe and effective in restoring iron stores, and may potentially save time and improve patient adherence.     

Short-term small-dose intravenous iron trial to detect functional iron deficiency in dialysis patients

BACKGROUND/AIM: Management of renal anemia in end-stage renal disease requires careful evaluation of the iron status before and in particular during erythropoietin treatment. However, there is no simple and practical iron index accurately predictive of functional iron deficiency in these patients till now. The purpose of this prospective study, therefore, is to evaluate whether a short course of low-dose intravenous iron challenge can detect functional iron deficiency in hemodialysis patients. METHODS: Twenty-four patients with baseline serum ferritin levels between 100 and 500 ng/ml were treated with intravenous saccharated ferric oxide, 960 mg over 24 hemodialysis treatments, and the hemoglobin level was checked every week. RESULTS: Patients whose hemoglobin value increased at least by 1 g/dl within the 8-week period were classified as having functional iron deficiency or as responders (n = 26; 81.2%). All other subjects were classified as having adequate iron levels or as nonresponders (n = 6; 18.8%). There were no significant differences in age, sex, dialysis years, Kt/V, dialyzers, hemoglobin, and basal and final transferrin saturation and ferritin between responders and nonresponders. In addition, there were no iron indices with acceptable levels of sensitivity and specificity. On the contrary, the cutoff value of increments of hemoglobin of at least 0.2 g/dl after a 2-week intravenous iron trial had a sensitivity of 96.2% and a specificity of 100% in all patients (n = 32) and a sensitivity of 100% and a specificity of 100% after patients with transferrin saturation <20% were excluded (n = 24). These values had the greatest utility of the tests studied in this work. CONCLUSION: A 240-mg intravenous iron challenge during a 2-week period may be a simple, accurate, and straightforward method to detect a functional iron deficiency status in hemodialysis patients undergoing erythropoietin therapy.     

Vitamin B(6) therapy does not improve hematocrit in hemodialysis patients supplemented with iron and erythropoietin

BACKGROUND/AIM: Pyridoxine deficiency may be the cause of failure to respond appropriately to iron and erythropoietin (EPO) administration in hemodialysis patients. METHOD: We studied 36 patients on chronic hemodialysis amply supplemented with iron and EPO, who failed to raise hematocrit levels >33%. Patients were divided into three equal groups and evaluated for 6 months as follows: Group A -- no additional therapy; group B -- supplemented with oral pyridoxine 50 mg/day, and group C received 100 mg/day pyridoxine orally. RESULTS: In all our patients, erythrocyte pyridoxine levels were initially within reference range for a healthy population and did not vary significantly during the study period. Likewise, ferritin levels and iron saturation values remained normal and constant. Hemoglobin and/or hematocrit levels remained practically unchanged in all three groups. CONCLUSIONS: The results indicate that in hemodialysis patients with normal pyridoxine status who, despite appropriate supplementation of iron and EPO, fail to reach optimal hematocrit levels, additional pyridoxine treatment does not produce any hematocrit elevation.     

A prospective crossover trial comparing intermittent intravenous and continuous oral iron supplements in peritoneal dialysis patients.

BACKGROUND: Concomitant iron supplementation is required in the great majority of erythropoietin (Epo)-treated patients with end-stage renal failure. Intravenous (i.v.) iron supplementation has been demonstrated to be superior to oral iron therapy in Epo-treated haemodialysis patients, but comparative data in iron-replete peritoneal dialysis (PD) patients are lacking. METHODS: A 12-month, prospective, crossover trial comparing oral and i.v. iron supplementation was conducted in all Princess Alexandra Hospital PD patients who were on a stable dose of Epo, had no identifiable cause of impaired haemopoiesis other than uraemia, and had normal iron stores (transferrin saturation >20% and serum ferritin 100-500 mg/l). Patients received daily oral iron supplements (210 mg elemental iron per day) for 4 months followed by intermittent, outpatient i.v. iron infusions (200 mg every 2 months) for 4 months, followed by a further 4 months of oral iron. Haemoglobin levels and body iron stores were measured monthly. RESULTS: Twenty-eight individuals were entered into the study and 16 patients completed 12 months of follow-up. Using repeated-measures analysis of variance, haemoglobin concentrations increased significantly during the i.v. phase (108+/-3 to 114+/-3 g/l) compared with each of the oral phases (109+/-3 to 108+/-3 g/l and 114+/-3 to 107+/-4 g/l, P<0.05). Similar patterns were seen for both percentage transferrin saturation (23.8+/-2.3 to 30.8+/-3.0%, 24.8+/-2.1 to 23.8+/-2.3%, and 30.8+/-3.0 to 26.8+/-2.1%, respectively, P<0.05) and ferritin (385+/-47 to 544+/-103 mg/l, 317+/-46 to 385+/-47 mg/l, 544+/-103 to 463+/-50 mg/l, respectively, P=0.10). No significant changes in Epo dosages were observed throughout the study. I.v. iron supplementation was associated with a much lower incidence of gastrointestinal disturbances (11 vs 46%, P<0.05), but exceeded the cost of oral iron treatment by 6.5-fold. CONCLUSIONS: Two-monthly i.v. iron infusions represent a practical alternative to oral iron and can be safely administered to PD patients in an outpatient setting. Compared with daily oral therapy, 2-monthly i.v. iron supplementation in PD patients was better tolerated and resulted in superior haemoglobin levels and body iron stores.     

Diagnostic value of iron indices in hemodialysis patients receiving epoetin.

BACKGROUND: Iron deficiency remains a common cause of hyporesponsiveness to epoetin in hemodialysis patients. However, considerable controversy exists regarding the best strategies for diagnosis and treatment. METHODS: As part of a multicenter randomized clinical trial of intravenous versus subcutaneous administration of epoetin, we made monthly determinations of serum iron, total iron binding capacity, percentage transferrin saturation, and serum ferritin. If a patient had serum ferritin <100 ng/mL or the combination of serum ferritin <400 ng/mL and a transferrin saturation <20%, he/she received parenteral iron, given as iron dextran 100 mg at ten consecutive dialysis sessions. We analyzed parenteral iron use during the trial, the effect of its administration on iron indices and epoetin dose, and the ability of the iron indices to predict a reduction in epoetin dose in response to parenteral iron administration. RESULTS: Eighty-seven percent of the 208 patients required parenteral iron to maintain adequate iron stores at an average dose of 1516 mg over 41.7 weeks, or 36 mg/week. Only two of 180 patients experienced serious reactions to intravenous iron administration. Two thirds of the patients receiving parenteral iron had a decrease in their epoetin requirement of at least 30 U/kg/week compared with 29% of patients who did not receive iron (P = 0.004). The average dose decrease 12 weeks after initiating iron therapy was 1763 U/week. A serum ferritin <200 ng/mL had the best positive predictive value (76%) for predicting a response to parenteral iron administration, but it still had limited clinical utility. CONCLUSIONS: Iron deficiency commonly develops during epoetin therapy, and parenteral iron administration may result in a clinically significant reduction in epoetin dose. The use of transferrin saturation or serum ferritin as an indicator for parenteral iron administration has limited utility.     

A parallel, comparative study of intravenous iron versus intravenous ascorbic acid for erythropoietin-hyporesponsive anaemia in haemodialysis patients with iron overload

Background: Functional iron deficiency may develop and cause erythropoietin resistance in haemodialysis patients with iron overload. Controversy remains as to whether intravenous iron medication can improve this hyporesponsiveness due to decreased iron availability, or whether iron therapy will aggravate haemosiderosis. Intravenous administration of ascorbic acid has been shown to effectively circumvent resistant anaemia associated with iron overload in a small preliminary study. To elucidate further the possible mechanisms of this resistance, a parallel, comparative study was conducted to compare the effects of intravenous iron and ascorbate therapies in iron-overloaded haemodialysis patients. Methods: Fifty haemodialysis patients with serum ferritin of >500 &mgr;g/l were randomly divided into two protocols. They were further stratified into controls (Control I, n=11) and intravenous iron group (IVFE, n=15) in protocol I; and into controls (Control II, n=12) and intravenous ascorbic acid group (IVAA, n=12) in protocol II. Controls had a haematocrit of >30% and did not receive any adjuvant therapy. IVFE and IVAA patients were hyporesponsive to erythropoietin and functionally iron deficient. Ferric saccharate (100 mg dose) was administered intravenously post-dialysis on five consecutive dialysis sessions in the first 2 weeks; and ascorbic acid (300 mg dose) thrice a week for 8 weeks. Red cell and iron metabolism indices were examined before and following therapy. Results: Mean values of haematocrit and transferrin saturation were significantly lower, and erythropoietin dose was higher in IVFE and IVAA patients compared to controls. Intravenous iron therapy neither improved erythropoiesis nor reduced erythropoietin dose during 12 weeks. Iron metabolism indices significantly increased at 2 and 6 weeks, but decreased at 12 weeks returning to the baselines. In contrast, mean haematocrit significantly increased from 25.8±0.5 to 30.6±0.6% with a concomitant reduction of 20% in erythropoietin dose after 8 weeks of ascorbate therapy. Serum ferritin modestly fell but with no statistical significance. The enhanced erythropoiesis paralleled a rise in transferrin saturation from 27±3 to 48±6% and serum iron from 70±11 to 107±19 &mgr;g/dl (P<0.05). Conclusions: Short term intravenous iron therapy cannot resolve the issue of functional iron deficiency in haemodialysis patients with iron overload. Intravenous administration of ascorbic acid not only facilitates iron release from storage sites, but also increases iron utilization in the erythron. Our study draws attention to a potential adjuvant therapy, intravenous ascorbic acid, to treat erythropoietin-hyporesponsive anaemia in iron-overloaded patients.     

Iron supplementation in haemodialysis - practical clinical guidelines

Background. The aim of this prospective study was to test a new protocol for iron supplementation in haemodialysis patients, as well as to assess the utility of different iron metabolism markers in common use and their 'target' values for the correction of iron deficiency. Methods. Thirty-three of 56 chronic haemodialysis patients were selected for long-term (6 months) i.v. iron therapy at 20 mg three times per week post-dialysis based on the presence of at least one of the following iron metabolism markers: percentage of transferrin saturation (%TSAT) <20%; percentage of hypochromic erythrocytes (%HypoE) >10% and serum ferritin (SF) <400 &mgr;g/l. Reasons for patient exclusion were active inflammatory or infectious diseases, haematological diseases, psychosis, probable iron overload (SF ⩾400 &mgr;g/l) and/or acute need of blood transfusion mostly due to haemorrhage and change in renal replacement treatment. Results. More than half (51.8%) of the patients of our dialysis centre proved to have some degree of iron deficiency in spite of their regular oral iron supplementation. At the start of the study the mean haemoglobin was 10.8 g/dl and increased after the 6 months of iron treatment to 12.8 g/dl (P<0.0001). The use of erythropoietin decreased from 188 units/kg/week to 84 units/kg/week. The criterion for iron supplementation with the best sensitivity/specificity relationship (100/87.9%) was ferritin <400 &mgr;g/l. Patients with ferritin <100 &mgr;g/l and those with ferritin between 100 &mgr;g/l and 400 &mgr;g/l had the same increase in haemoglobin but other parameters of iron metabolism were different between the two groups. Conclusions. Routine supplementation of iron in haemodialysis patients should be performed intravenously. Target ferritin values should be considered individually and the best mean haemoglobin values were achieved at 6 months with a mean ferritin of 456 &mgr;g/l (variation from to 919 &mgr;g/l). The percentage of transferrin saturation, percentage of hypochromic erythrocytes and ferritin <100 &mgr;/l, were not considered useful parameters to monitor routine iron supplementation in haemodialysis patients. No significant adverse reactions to iron therapy were observed. Keywords: erythropoietin; ferritin; haemodialysis; iron; intravenous      

Reduction in erythropoietin doses by the use of chronic intravenous iron supplementation in iron-replete hemodialysis patients

BACKGROUND: Iron deficiency is the most common cause of suboptimal response to recombinant human erythropoietin (rHuEPO) in chronic hemodialysis (HD) patients. Iron supply can correct this situation, however, optimal dosage, route of administration, and monitoring of iron status during rHuEPO therapy in maintenance HD patients remains controversial. METHODS: We conducted a 12-month intravenous iron substitution trial in 149 iron-replete chronic HD patients receiving subcutaneous rHuEPO therapy. The available iron pool was maintained with 100 mg iron every 2 weeks or 1 month depending on serum ferritin and transferrin saturation levels, the rHuEPO dosage titrated depending on hematocrit (Hct) levels. RESULTS: After 12-month protocol, the Hct increased (28.7 +/- 4.1 vs 27.7 +/- 2.6, p = 0.003), rHuEPO requirement reduced 25% (46.1 +/- 28.9 vs 61.5 +/- 67.8 U/kg/week, p = 0.006), serum ferritin increased (1,383 +/- 727 vs 930 +/- 857 ng/ml, p < 0.001), so did the transferrin saturation (36.1 +/- 12.7 vs 27.5 +/- 12.8%, p < 0.001). The serum albumin decreased slightly but reached statistical significance (4.1 +/- 0.48 vs 4.2 +/- 0.36 g/dl, p = 0.006), so did the cholesterol levels (166 +/- 41 vs 173 +/- 38 mg/dl, p = 0.044) and pre-dialysis creatinine (11.3 +/- 2.3 vs 11.5 +/- 2.4 mg/dl, p = 0.015). Besides, the iPTH levels did not interfere with the rHuEPO dosage reduction and Hct increment in our patients. CONCLUSION: We conclude that maintaining high levels of serum ferritin and transferrin saturation could further reduce the requirement of rHuEPO in chronic HD patients, but the long-term effect of iron overloading to patients' nutritional status must be further evaluated in contrast to the economic saving.     

Assessment of iron status by erythrocyte ferritin in uremic patients with or without recombinant human erythropoietin therapy.

Erythrocyte ferritin may be a better estimator of iron bioavailability than the conventional markers of iron stores (serum ferritin and transferrin saturation). To investigate the accuracy of these conventional markers in uremic patients compared with erythrocyte ferritin, we studied 29 chronic hemodialysis patients on erythropoietin (EPO) therapy, 18 without EPO therapy, and 22 healthy control subjects. Apart from the red blood cell indices, serum ferritin, transferrin saturation, and erythrocyte ferritin, the analytical study included red blood cell protoporphyrin and plasma aluminum levels. The control group showed erythrocyte ferritin concentrations between 8.3 and 12.5 attograms/cell (95% confidence interval). In the EPO group, red blood cell protoporphyrin correlated negatively with erythrocyte ferritin, but not with serum ferritin or transferrin saturation. In the non-EPO group, serum ferritin, erythrocyte ferritin, and transferrin saturation did not correlate with red blood cell protoporphyrin. Even though erythrocyte ferritin correlated well with serum ferritin in the EPO group (r = 0.61, P = 0.0003), the sensitivity of normal serum ferritin levels (30 to 300 ng/mL) to discard a low erythrocyte ferritin concentration (erythrocyte ferritin less than 7 ag/cell) was 0.53, while the sensitivity of serum ferritin at levels less than 30 ng/mL to indicate an absolute iron deficiency expressed as a low erythrocyte ferritin concentration was 0.28. Only values of serum ferritin and transferrin saturation greater than 300 ng/mL and 35%, respectively, could rule out a relative iron deficiency expressed as a low erythrocyte ferritin and high red blood cell protoporphyrin concentration. Plasma aluminum levels did not correlate with red blood cell protoporphyrin or erythrocyte ferritin levels in either uremic group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Time-dependent associations between iron and mortality in hemodialysis patients

The independent association between the indices of iron stores or administered intravenous iron, both of which vary over time, and survival in patients who are on maintenance hemodialysis (MHD) is not clear. It was hypothesized that the observed associations between moderately high levels of three iron markers (serum ferritin, iron, and iron saturation ratio) or administered intravenous iron and all-cause and cardiovascular death is due to the time-varying confounding effect of malnutrition-inflammation-cachexia syndrome (MICS). Time-dependent Cox regression models were examined using prospectively collected data of the 2-yr (July 2001 to June 2003) historical cohort of 58,058 MHD patients from virtually all DaVita dialysis clinics in the United States. After time-dependent and multivariate adjustment for case mix, administered intravenous iron and erythropoietin doses, and available surrogates of MICS, serum ferritin levels between 200 and 1200 ng/ml (reference 100 to 199 ng/ml), serum iron levels between 60 and 120 microg/ml (reference 50 to 59 microg/ml), and iron saturation ratio between 30 and 50% (reference 45 to 50%) were associated with the lowest all-cause and cardiovascular death risks. Compared with those who did not receive intravenous iron, administered intravenous iron up to 400 mg/mo was associated with improved survival, whereas doses >400 mg/mo tended to be associated with higher death rates. The association between serum ferritin levels >800 ng/ml and mortality in MHD patients seems to be due mostly to the confounding effects of MICS. For ascertaining whether the observed associations between moderate doses of administered intravenous iron and improved survival are causal or due to selection bias by indication, clinical trials are warranted.     

Iron deficiency in patients with chronic kidney disease: potential role for intravenous iron therapy independent of erythropoietin

The prevalence of iron deficiency and its contribution to the anemia of end stage renal disease has been extensively studied, but much less is known about the role of iron deficiency in the pathogenesis of the anemia of chronic kidney disease in predialysis patients. All new hemodialysis patients entering a single hemodialysis unit between July 1999 and April 2002 were included in the study. The admission laboratory tests and the Health Care Financing Administration (HCFA) 2728 form were examined to determine the prevalence of erythropoietin use, anemia (Hb < 11 g/dl), and iron deficiency (ferritin < 100 ng/ml and transferrin saturation % < 20%). In a second part of the study, the effect of intravenous iron gluconate replacement in patients with stage III & IV chronic kidney disease was examined. Anemia was present in 68% of all patients starting hemodialysis. Iron deficiency was a common feature occurring in 29% of patients taking erythropoietin (49% of all patients) and 26% of patients without erythropoietin (51% of all patients). Following the administration of intravenous iron gluconate to four patients, there was a significant rise in hemoglobin levels from 10.6 ± 0.19 to 11.7 ± g/dl (p = 0.02). Conclusion: Iron deficiency is common in predialysis patients. Replenishing iron stores in anemic patients with chronic kidney disease significantly increases hemoglobin levels and should be considered as an integral part of the therapy for treating anemia in the predialysis population.     

Comparing the efficacy of intravenous iron and oral iron in nondialysis patients with chronic kidney disease

This Practice Point commentary discusses the findings and limitations of a phase III trial by Spinowitz et al. that compared oral and intravenous iron therapies in nondialysis patients with chronic kidney disease. In total, 304 patients were randomly assigned in a 3:1 ratio to receive either two 510 mg doses of intravenous ferumoxytol within 5+/-3 days or 200mg of elemental oral iron daily for 21 days. At day 35, hemoglobin levels had increased significantly more in patients who had received intravenous ferumoxytol than in those who had received oral iron therapy. Ferumoxytol was well tolerated. The superiority of ferumoxytol over other intravenous iron preparations, however, needs to be investigated, and optimal serum ferritin levels for the nondialysis CKD population need to be defined.     

The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin.

BACKGROUND: Iron deficiency (ID) is the main cause of hyporesponsiveness to erythropoietin in haemodialysis patients and its detection is of value since it is easily corrected by intravenous iron. Markers of iron supply to the erythron, including erythrocyte zinc protoporphyrin (Er-ZPP), percentage of hypochromic erythrocytes (Hypo), reticulocyte haemoglobin content (CHr) and soluble transferrin receptor (sTfR), may be more accurate predictors of ID than ferritin (Fer) and transferrin saturation (TSat), but relative diagnostic power and best threshold values are not yet established. METHODS: In 125 haemodialysis patients on maintenance erythropoietin, the diagnostic power of the above parameters was evaluated by ROC curve, multivariate regression, and stepwise discriminant analyses. Diagnosis of ID was based on haemoglobin response to intravenous iron (992 mg as sodium ferric gluconate complex over an 8-week period). RESULTS: Fifty-one patients were considered iron deficient (haemoglobin increase by 1.9+/-0.5 g/dl) and 74 as iron replete (haemoglobin increase by 0.4+/-0.3 g/dl). ROC curve analysis showed that all tests had discriminative ability with the following hierarchy: Hypo (area under curve W=0.930, efficiency 89.6% at cut-off >6%), CHr (W=0.798, efficiency 78.4% at cut-off < or =29 pg), sTfR (W=0.783, efficiency 72.4% at cut-off >1.5 mg/l), Er-ZPP (W=0.773, efficiency 73.0% at cut-off >52 micromol/mol haem), TSat (W=0.758, efficiency 70.4% at cut-off <19%) and ferritin (W=0.633, efficiency 64.0% at cut-off <50 ng/ml). Stepwise discriminant analysis identified Hypo as the only variable with independent diagnostic value, able to classify 87.2% of patients correctly. Additional tests did not substantially improve diagnostic efficiency of Hypo >6% alone. CONCLUSIONS: In haemodialysis patients on maintenance erythropoietin, Hypo >6% is the best currently available marker to identify those who will improve their response after intravenous iron. Cost-effectiveness suggests that this parameter should be a first-line tool to monitor iron requirements in clinical practice.