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Therapeutic Apheresis and Dialysis 2014; ••(••):••–•• doi: 10.1111/1744-9987.12237 © 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
Acceleration of Iron Utilization After Intravenous Iron Administration During Activated Erythropoiesis in Hemodialysis Patients: A Randomized Study Tadashi Kuji,1,2 Yoshiyuki Toya,2 Tetsuya Fujikawa,2,3 Midori Kakimoto-Shino,2 Masahiro Nishihara,4 Kazuhiko Shibata,5 Kouichi Tamura,2 Nobuhito Hirawa,2 Hidehisa Satta,6 Sei-ichi Kawata,1 Naoaki Kouguchi,1 and Satoshi Umemura2 1
Yokodai Central Clinic, 2Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine and School of Medicine, 3Center for Health Service Sciences, Yokohama National University, 4Toshin Clinic, 5Yokohama Minami Clinic, 6Kasama Clinic, Yokohama, Kanagawa, Japan
Abstract: This study aimed to evaluate the effect of different timings of iron administration during erythropoiesis activated by continuous erythropoietin receptor activator (CERA) on reticulocyte iron uptake in hemodialysis patients. In total, 110 patients were randomized to receive 40 mg intravenous elemental iron doses at all three hemodialysis sessions in the first week (IW1 group: n = 57) or in the third week (IW3 group: n = 53) after CERA administration. Following CERA administration at day 0, reticulocyte count increased, peaking at day 7. At days 7 and 14, the observed changes in Ret-He were higher in the IW1 group than in the IW3 group. Increases in total reticulocyte hemoglobin at day 7 were higher in the IW1 group than in
the IW3 group. In contrast, there was only tendency toward greater total reticulocyte hemoglobin after iron administration in the third week in the IW3 group. Intravenous iron supplementation in the first week of CERA administration increases reticulocyte iron uptake; however, iron supplementation in the third week does not. The findings indicate that iron should be intravenously administered to increase the efficacy of CERA within 1 week of CERA administration during highly active erythropoiesis. Key Words: Continuous erythropoietin receptor activator, Hemodialysis, Iron utilization, Renal anemia, Reticulocyte hemoglobin equivalent.
Anemia is a common comorbidity among patients with end-stage renal disease requiring dialysis therapy and is a major cause of morbidity and mortality among hemodialysis (HD) patients (1). Recombinant human erythropoietin was first introduced to clinical practice as a treatment agent for renal anemia. This was followed by a new generation of erythropoiesis-stimulating agents (ESAs). Currently, ESAs are the first-line therapy for renal anemia in HD patients and have been shown to improve quality of life (2) and prognosis (3).
Although anemia can be effectively corrected using ESAs (4), responses to ESAs vary between individuals. ESA response is a clinically important issue because a lowered response, as well as anemia, is a risk factor for morbidity and mortality (5,6). Many factors are related to responsiveness to ESA, including iron deficiency, inflammation and malnutrition (7). In particular, iron deficiency is a major cause of resistance to ESA therapy (8). Intravenous iron supplementation has been shown to be an effective therapy in HD patients with iron deficiency (9), including those with functional iron deficiency (10,11). However, iron supplementation also has toxic effects (12). Excessive iron use could theoretically increase the risk of infectionrelated mortality (13) and cardiovascular events (12). Observational studies have linked higher iron doses with mortality (14). Iron dosing should be carefully
Received February 2014; revised June 2014. Address correspondence and reprint requests to Dr Tetsuya Fujikawa, Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine and School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 2360004, Japan. Email: [email protected]
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considered to prevent iron overload, which is associated with poor prognosis. In order to maximize advantages and minimize disadvantages of iron supplementation, further investigation of optimal iron dosing is required. Some reports have indicated that, similar to the effect of large doses, small doses of iron can increase responsiveness to therapy with ESA (15), indicating that iron supplementation can be conducted more safely in HD patients. Maintaining iron levels sufficient for erythropoiesis with minimum supplementation is desirable in order to maximize the effectiveness of ESA therapy. However, few studies have been conducted to determine the optimal timing of iron administration for ESA-induced erythropoiesis. Continuous erythropoietin receptor activator (CERA) has an active erythropoiesis phase of 4 weeks, and patients receive treatment in 4-week cycles (16). Previous studies identified specific patterns of iron metabolism marker levels during CERA treatment. A transient decline in hepcidin, Ret-He, transferrin saturation (TSAT), and ferritin, as well as an increase in reticulocytosis, has been observed following CERA administration (17,18). Hepcidin is a key regulator of iron metabolism, and reduced hepcidin levels increase iron availability (19). Longterm erythropoiesis stimulation and concomitant iron demand have been shown to increase and decrease gradually during the 4-week CERA treatment cycle (16–18). To date, although iron demand changes according to the degree of erythropoiesis activation, it is unknown if the effect of iron administration changes with iron demand in patients treated with ESA. This study aimed to evaluate the effect of different timings
of iron administration during erythropoiesis activated by CERA on reticulocyte iron uptake in HD patients. PATIENTS AND METHODS Participants Outpatients being treated at the Yokodai Central Clinic in Yokohama, Japan, who had received HD for >12 weeks and had been receiving CERA treatment for ≥2 months prior to recruitment were selected. Patients with severe congestive heart failure (New York Heart Association class III or IV), uncontrolled hypertension (defined as a pre-dialysis diastolic blood pressure >110 mm Hg), acute malignancy, major surgery within the previous 6 months, active bleeding, need for erythrocyte transfusion within 12 weeks before the study, and systemic inflammatory disease and/or C-reactive protein levels >3 mg/dL were excluded. After inclusion and exclusion assessment (Fig. 1), 110 patients were eligible for enrollment in the study. The institutional review board of Yokohama City University and the local ethics committee approved the protocol.The procedures followed were in accordance with the Helsinki Declaration. This study was registered in the UMIN Clinical Trials Registry (registration ID number: UMIN000010084). All patients provided written informed consent. Study protocol This was a randomized, controlled, parallelgroup study. At the start of the study, demographic data, comorbidity data, physical examination results and laboratory data were recorded for each patient. Eligible patients were randomized using a
FIG. 1. Flow chart of patient involvement.
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© 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
Iron dosing timing and hemoglobin synthesis centralized allocation method such that each patient received 40 mg intravenous doses of elemental iron (Fesin, Nichi-Iko Pharmaceutical, Toyoma City, Japan) at all three HD sessions during week 1 after CERA administration (day 0, 2 and 4: IW1 group: N = 57) or at all 3 sessions during week 3 after CERA administration (day 14, 16 and 18: IW3 group: N = 53) (Mircera, Chugai Pharmaceutical, Tokyo, Japan). CERA dose was adjusted and administered after the first HD session of week 1 (day 0) to maintain the target hemoglobin (Hb) level of 10–11 g/dL, according to the 2008 Guidelines for Renal anemia in Chronic Kidney Disease (20). Hb, reticulocyte Hb equivalent (Ret-He), TSAT and ferritin levels were examined before the HD session once a week (day 0, 7, 14, 21, 28).TSAT was calculated using the following formula: TSAT (%) = serum iron (μg/dL)/total iron binding capacity (μg/dL) × 100. HD was performed regularly for 3 to 6 h, 3 times a week. The dialysate flow rate was 400 mL/min in most patients, and the blood flow rate ranged from 150 to 280 mL/min. Dry weight was determined for each patient using the pre-dialysis cardiothoracic ratio. Before the study, intravenous doses of 40 mg elemental iron per week were administered if serum ferritin level was below 100 ng/mL and transferrin saturation was less than 20%. Analytical methods Ret-He (21) is a direct indicator of iron utilization as well as reticulocyte Hb content (22). Conventional erythrocyte parameters and Ret-He were measured using an XE-5000 hematology analyzer (XE RET MASTER, Sysmex, Kobe, Japan). Ret-He was analyzed using a fluorescent flow cytometry technique. In the reticulocyte channel, using a polymethine dye, this technique also determines the mean value of forward light scatter intensity derived from mature erythrocytes and reticulocytes (21). Because blood Hb concentration is an indicator of the total amount of erythrocyte Hb, blood concentration of total reticulocyte Hb can be an index of newly synthesized Hb. According to the prior study (23), total reticulocyte Hb (reticulocyte Hb, mg/dL) was defined as Ret-He (pg) per cell multiplied by reticulocyte count (109 cells/L). Statistical analysis Sample size was estimated based on a previous report (17) with the following assumptions: α was set at 0.05, the expected power was 80%, difference between groups in changes of Ret-He at 12% and a standard deviation of 20%. Unless otherwise specified, data are presented as mean ± standard devia© 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
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tion. Differences between the two groups were analyzed using the unpaired Student’s t-test for continuous variables and the χ2 test for proportion. P-values of < 0.05 were considered to be statistically significant. Statistical analyses were performed using the SPSS software version 19.0 for Windows (SPSS, Chicago, IL, USA).
RESULTS Figure 1 is a flow chart of the study population. The baseline characteristics of the 110 patients (IW1 group: N = 57; IW3 group: N = 53) are shown in Table 1. No significant differences in baseline characteristics were evident between the two groups with the exception of serum iron level. During the evaluation period of 4 weeks, six patients in the IW1 group were withdrawn from the study because of hospital admission. Five patients in the IW3 group were withdrawn due to hospital admission (N = 2), clinic transfer (N = 1) and discontinuation of CERA (N = 2) (Fig. 1). Ninety-nine participants (IW1 group: N = 51; IW3 group: N = 48) were included in the final analysis. No significant differences in baseline characteristics were detected between the two groups included in the final analysis. Mean CERA dosages during the evaluation period were not different between the IW1 and IW3 groups (92.6 ± 50.8 μg/month vs. 95.3 ± 52.3 μg/ month, P = 0.798). Mean Hb levels during the evaluation period were 10.8 ± 0.7 g/dL in the IW1 group and 10.6 ± 0.5 g/dL in the IW3 group (P = 0.199). Concerning stability of Hb control, increases in Hb levels from day 0 at day 28 were 0.13 ± 0.76 g/dL in the IW1 group and 0.22 ± 0.90 g/dL in the IW3 group (P = 0.595). No patients required blood transfusion during the study period. TSAT and ferritin levels showed generally adequate iron status throughout the study period. Figure 2 shows changes in Hb levels, reticulocyte count, Ret-He, reticulocyte Hb, TSAT and ferritin levels from day 0. Increases in Hb at days 7, 14, 21 and 28 during the evaluation period were not significantly different between the two groups (Fig. 2a). Reticulocyte count increased, peaking at day 7 in the two groups (Fig. 2b). Increases in reticulocyte count from day 0 at days 7, 14, 21 and 28 were not significantly different between the two groups. Changes in Ret-He from day 0 at days 7 and 14 were higher in the IW1 group than in the IW3 group (2.10 ± 2.30 pg vs. –0.93 ± 2.84 pg, P < 0001; –0.67 ± 2.06 pg vs. −1.58 ± 2.22 pg, P = 0.037, respectively; Fig. 2c).
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T Kuji et al. TABLE 1.
Baseline characteristics of patients between IW1 and IW3 groups
Variables
IW1 group, N = 57
IW3 group, N = 53
P-value
67.8 ± 13.0 66.7 21.9 ± 3.8 1.24 ± 0.18 96.5 ± 44.9 91.2 66.7 47.4 78.9 21.1 17.5 10.4 ± 0.9 27.4 ± 15.2 33.1 ± 2.1 90.7 ± 50.1 77.4 ± 26.5 220.5 ± 37.1 242.8 ± 119.3 35.9 ± 14.0 0.52 ± 0.99 3.7 ± 0.3 66.7 ± 13.0 10.8 ± 2.3 198.4 ± 110.4
70.3 ± 12.3 77.4 21.4 ± 3.1 1.19 ± 0.17 90.4 ± 41.5 88.7 62.3 54.7 73.6 26.4 17.0 10.4 ± 0.8 27.9 ± 17.3 33.1 ± 2.5 93.4 ± 59.8 90.1 ± 35.8 229.1 ± 36.1 210.0 ± 143.6 40.1 ± 17.1 0.56 ± 1.42 3.6 ± 0.3 63.7 ± 13.7 10.3 ± 2.1 222.3 ± 100.4
0.314 0.213 0.413 0.123 0.464 0.656 0.630 0.441 0.508 0.508 0.938 0.604 0.869 0.994 0.804 0.037* 0.225 0.198 0.168 0.839 0.537 0.246 0.283 0.446
Age, years Male, % Body mass index, kg/m2 Double-pool Kt/V Mean CERA dose (μg/month) in a previous month Arteriovenous fistula, % Renin-angiotensin system inhibitors, % Diabetes mellitus, % Hypertension, % Cardiovascular disease, % Cancer, % Hemoglobin, g/dL Reticulocyte count, 109/L Ret-He, pg Reticulocyte hemoglobin, mg/dL Serum iron, μg/dL Total iron binding capacity, μg/dL Ferritin, ng/mL Transferrin saturation, % C-reactive protein, mg/dL Albumin, g/dL Blood urea nitrogen, mg/dL Creatinine, mg/dL Intact-parathyroid hormone, pg/mL
P-values for the difference between IW1 and IW3 groups. *P < 0.05; **P < 0.01. Data are mean ± SD. CERA, continuous erythropoietin receptor activator; IW1, iron dosing during week 1; IW3, iron dosing during week 3.
Increases in reticulocyte Hb between day 0 and day 7 were higher in the IW1 group than in the IW3 group (226.1 ± 85.6 mg/dL vs. 183.5 ± 89.8 mg/dL, P = 0.018; Fig. 2d). In contrast, compared to the IW1 group, there was a tendency toward greater increases in reticulocyte Hb between day 0 and day 21 in the IW3 group (8.4 ± 37.8 mg/dL vs. 21.8 ± 38.9 mg/dL, P = 0.084; Fig. 2d). Changes in TSAT from day 0 at days 7, 14, 21 and 28 did not differ between the two groups (Fig. 2e). Changes in ferritin levels were higher between day 0 and days 7 and 14 in the IW1 group and were lower between day 0 and day 21 in the IW1 group than in the IW3 group (16.4 ± 49.8 ng/mL vs. −59.2 ± 41.2 ng/ mL, P < 0.001; −19.7 ± 57.1 ng/mL vs. −65.7 ± 61.4 ng/ mL, P < 0.001; 2.9 ± 72.1 ng/mL vs. 52.0 ± 60.2 ng/mL, P < 0.001, respectively; Fig. 2f). DISCUSSION In this study, we aimed to evaluate the effect of the timing of iron administration during CERA-induced erythropoiesis on reticulocyte iron uptake in HD patients. Our results showed that on day 7, the Ret-He was higher in the IW1 group than in the IW3 group, suggesting that iron dosing during the first week of CERA administration prevents a transient reduction
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in Ret-He. Furthermore, in the first week, the IW1 group showed a greater increase in the reticulocyte Hb than the IW3 group. However, in the third week, reticulocyte Hb in the IW3 group tended to increase after iron administration. These results indicate that iron should be intravenously administered to increase the efficacy of CERA within one week of CERA administration during highly active erythropoiesis. We used CERA, an ESA with a long half-life, to induce erythropoiesis, and used Ret-He to evaluate iron utilization due to erythropoiesis. This approach can be applied to other ESAs as well. The optimal iron-dosing pattern can vary among ESAs and depends on the type of ESA used. The Ret-He indicates the level of newly synthesized Hb in a reticulocyte (21). The total amount of newly synthesized Hb can be estimated by calculating the Hb content in all reticulocytes (23). In our study, iron dosing during active erythropoiesis increased the RetHe. It also increased the reticulocyte Hb, but not the reticulocyte count. These results suggest that iron dosing during strong ESA-induced erythropoiesis boosts iron uptake in reticulocytes and increases the total amount of newly synthesized Hb. Thus, iron supplementation is needed to maximize the efficacy of ESA treatment during strong ESA-induced erythropoiesis. © 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
Iron dosing timing and hemoglobin synthesis b 80.0
1.0
Change in reculocyte (109 /L)
Change in hemoglobin (g/dL)
a
5
0.8 0.6 0.4 0.2 0.0 -0.2
70.0 60.0 50.0 40.0 30.0 20.0 10.0 0.0 -10.0
-0.4 0
7
14 day
21
0
28
7
14 day
21
28
14
21
28
Change in Ret-He (pg)
3.0
**
2.0 1.0 0.0
*
-1.0 -2.0 -3.0 0
14 day
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28
300.0
*
250.0 200.0 150.0 100.0 50.0 0.0 -50.0 0
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day
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100.0 80.0
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Change in ferrin (ng/mL)
Change in transferrin saturaon (%)
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Change in reculocyte hemoglobin (mg/dL)
d c
0.0 -5.0 -10.0 -15.0 -20.0
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60.0 40.0
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20.0 0.0
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-20.0 -40.0 -60.0 -80.0 -100.0
-25.0 0
7
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21
28
0
7
14 day
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FIG. 2. Changes in (a) hemoglobin levels (b) reticulocyte counts (c) reticulocyte hemoglobin equivalent (Ret-He) (d) reticulocyte hemoglobin (e) transferrin saturation and (f) ferritin levels between groups that received iron administration in the first week or the third week following treatment initiation. Continuous erythropoietin receptor activator (CERA) was administered at day 0. Data are presented as , Iron means ± standard error of the mean (SEM). *P < 0.01; **P < 0.001 for comparison of changes from day 0 between the two groups. , Iron dosing during week 3 (days 14, 16, and 18). dosing during week 1 (days 0, 2, and 4);
To date, the need for iron supplementation has been evaluated by measuring the TSAT and ferritin levels as indicators of iron availability and storage. However, the TSAT is not a direct indicator of the amount of available iron. Thus, in our current study, we focused on measuring the reticulocyte Hb as it is a reliable direct indicator of iron utilization (23). The reticulocyte Hb showed that the timing of iron dosing is a key factor for iron utilization; this finding will allow further elucidation of iron metabolism in ESA treatment. Iron administration in the first week, but not the third week, showed a significant increase in the reticulocyte Hb. A previous study showed that activa© 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
tion of erythropoiesis by CERA is less effective in the third week compared with that in the first week of administration (16). For all ESAs, iron dosing may be needed during highly active erythropoiesis, especially if Ret-He decreases after ESA administration. The timing of iron dosing is clinically important for all ESAs and needs to be carefully determined in order to achieve an optimal response to the ESA and reduce excessive ESA dosing. Although most patients in this study had normal iron levels before the study and did not have functional iron deficiency, their iron uptake by reticulocytes could be improved. Compared to the iron reserved in the body, iron administered during
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active erythropoiesis may be more effectively absorbed into the bone marrow and used to synthesize Hb. Intravenous iron dosing has been shown to ameliorate the response to recombinant human erythropoietin in patients with iron repletion (10,11). Iron dosing during the first week of the treatment cycle both increased Ret-He and inhibited a decrease in ferritin levels. The ferritin level did not decrease from day 7 to day 28, indicating no decrease in the iron storage. The ferritin level is usually overestimated when measured within one week of iron administration (24); however, it is accurately estimated when measured 4 weeks after administration. Our findings suggest that lower iron doses may improve erythropoiesis to some extent and not hinder utilization of stored iron. Furthermore, determining the iron supplementation dose that does not disrupt iron utilization may facilitate the enhancement of Hb synthesis without additional iron storage in patients with iron repletion. Each individual’s response to ESA varies depending on several factors such as the presence of iron deficiency, inflammation, or malnutrition (7). Our baseline data showed that there was no difference in the factors related to ESA resistance between the two groups. Hence, it is unlikely that the results obtained in this study were affected by any confounding factors. The randomized design seemed to have effectively suppressed these factors from complicating or concealing the effectiveness of iron administration in the first week. One limitation of our study was that the dose range of CERA used may have been low. According to a previous report (17), high doses of CERA could decrease the Ret-He to a greater extent than small doses. In patients showing a drastic decrease in RetHe, iron utilization needs to be improved. Iron administration in the first week may be more effective for patients who require treatment with larger doses of CERA. The serum iron level at baseline was lower in the IW1 group than in the IW3 group, but the Ret-He increased notably by iron supplementation in the IW1 group. Hence, if the serum iron level in the IW1 group was higher than the currently observed baseline level, the Ret-He may have increased further. This finding supports the reliability of the efficacy of iron dosing within the first week of CERA administration. Further study is needed to determine a more appropriate dosage and timing of iron administration in order to successfully promote iron utilization and avoid excessive iron storage. Furthermore, determining the optimal iron dosage could contribute to improving the prognosis of HD patients.
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CONCLUSIONS Intravenous iron supplementation in the first week of continuous erythropoietin receptor activator administration increases reticulocyte iron uptake; however, iron supplementation in the third week does not cause such elevation. Thus, iron should be administered to increase the efficacy of CERA within one week of CERA administration during highly active erythropoiesis. Conflict of interest: none declared.
REFERENCES 1. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE. The impact of anemia on cardiomyopathy, morbidity and mortality in end-stage renal disease. Am J Kidney Dis 1996;28:53–61. 2. Moreno F, Aracil FJ, Perez R, Valderrabano F. Controlled study on the improvement of quality of life in elderly hemodialysis patients after correcting end-stage renal diseaserelated anemia with erythropoietin. Am J Kidney Dis 1996;27:548–56. 3. Mocks J, Franke W, Ehmer B, Scigalla P, Quarder O. Analysis of safety database for long-term epoetin-beta treatment. A metaanalysis covering 3697 patients. In: Koch KM, Stein G, eds. Pathogenetic and Therapeutic Aspects of Chronic Renal Failure. New York: Marcel Dekker, 1997; 163–79. 4. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the anemia of end stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med 1987;316:73–8. 5. López-Gómez JM, Portolés JM, Aljama P. Factors that condition the response to erythropoietin in patients on hemodialysis and their relation to mortality. Kidney Int Suppl 2008;111:S75– 81. 6. Fujikawa T, Ikeda Y, Fukuhara S et al. Time-dependent resistance to erythropoiesis-stimulating agent and mortality in hemodialysis patients in the Japan dialysis outcomes and practice patterns study. Nephron Clin Pract 2012;122:24–32. 7. Richardson D. Clinical factors influencing sensitivity and response to epoetin. Nephrol Dial Transplant 2002;l7(Suppl): 53–9. 8. Drüeke T. Hyporesponsiveness to recombinant human erythropoietin. Nephrol Dial Transplant 2001;16:25–8. 9. Macdougall IC, Chandler G, Elston O, Harchowal J. Beneficial effects of adopting an aggressive intravenous iron policy in a hemodialysis unit. Am J Kidney Dis 1999;34:S40–6. 10. Macdougall IC, Hörl WH, Jacobs C et al. European best practice guidelines 6–8: assessing and optimizing iron stores. Nephrol Dial Transplant 2000;15(Suppl 4):20–32. 11. Coyne DW, Kapoian T, Suki W et al. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) Study. J Am Soc Nephrol 2007;18:975–94. 12. Brewster UC. Intravenous iron therapy in endstage renal disease. Semin Dial 2006;19:285–90. 13. Bullen JJ, Rogers HJ, Spalding PB, Ward CG. Iron and infection: the heart of the matter. FEMS Immunol Med Microbiol 2005;43:325–30. 14. Feldman HI, Santanna J, Guo W et al. Iron administration and clinical outcomes in hemodialysis patients. J Am Soc Nephrol 2002;13:734–44. 15. Goldstein SL, Morris D, Warady BA. Comparison of the safety and efficacy of 3 iron sucrose iron maintenance regimens © 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
Iron dosing timing and hemoglobin synthesis in children, adolescents, and young adults with CKD: a randomized controlled trial. Am J Kidney Dis 2013;61:588–97. 16. Chanu P, Gieschke R, Charoin JE, Pannier A, Reigner B. Population pharmacokinetic/pharmacodynamic model for C.E.R.A. in both ESA-naive and ESA-treated chronic kidney disease patients with renal anemia. J Clin Pharmacol 2010;50: 507–20. 17. Jonckheere S, Dierick J, Vanhouteghem H, Devleeschouwer M, Stove V. Erythrocyte indices in the assessment of iron status in dialysis-dependent patients with end-stage renal disease on continuous erythropoietin receptor activator versus epoetin beta therapy. Acta Haematol 2010;124:27–33. 18. Kakimoto-Shino M, Toya Y, Kuji T, Fujikawa T, Umemura S. Changes in hepcidin and reticulocyte hemoglobin equivalent levels in response to continuous erythropoietin receptor activator administration in hemodialysis patients:a randomized study. Ther Apher Dial 2014; doi: 10.1111/17449987.12161.
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19. Nemeth E, Tuttle MS, Powelson J et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004;306:2090–3. 20. Tsubakihara Y, Nishi S, Akiba T et al. 2008 Japanese Society for Dialysis Therapy: guidelines for renal anemia in chronic kidney disease. Ther Apher Dial 2010;14:240–75. 21. Thomas L, Franck S, Messinger M, Linssen J, Thome M, Thomas C. Reticulocyte hemoglobin measurement— comparison of two methods in the diagnosis of iron-restricted erythropoiesis. Clin Chem Lab Med 2005;43:1193–202. 22. Fishbane S, Galgano C, Langley RC Jr, Canfield W, Maesaka JK. Reticulocyte hemoglobin content in the evaluation of iron status of hemodialysis patients. Kidney Int 1997;52:217–22. 23. Goodnough LT, Skikne B, Brugnara C. Erythropoietin, iron, and erythropoiesis. Blood 2000;96:823–33. 24. Besarab A, Kaiser JW, Frinak S. A study of parenteral iron regimens in hemodialysis patients. Am J Kidney Dis 1999;34: 21–8.
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Therapeutic Apheresis and Dialysis 2014; ••(••):••–•• doi: 10.1111/1744-9987.12237 © 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
Acceleration of Iron Utilization After Intravenous Iron Administration During Activated Erythropoiesis in Hemodialysis Patients: A Randomized Study Tadashi Kuji,1,2 Yoshiyuki Toya,2 Tetsuya Fujikawa,2,3 Midori Kakimoto-Shino,2 Masahiro Nishihara,4 Kazuhiko Shibata,5 Kouichi Tamura,2 Nobuhito Hirawa,2 Hidehisa Satta,6 Sei-ichi Kawata,1 Naoaki Kouguchi,1 and Satoshi Umemura2 1
Yokodai Central Clinic, 2Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine and School of Medicine, 3Center for Health Service Sciences, Yokohama National University, 4Toshin Clinic, 5Yokohama Minami Clinic, 6Kasama Clinic, Yokohama, Kanagawa, Japan
Abstract: This study aimed to evaluate the effect of different timings of iron administration during erythropoiesis activated by continuous erythropoietin receptor activator (CERA) on reticulocyte iron uptake in hemodialysis patients. In total, 110 patients were randomized to receive 40 mg intravenous elemental iron doses at all three hemodialysis sessions in the first week (IW1 group: n = 57) or in the third week (IW3 group: n = 53) after CERA administration. Following CERA administration at day 0, reticulocyte count increased, peaking at day 7. At days 7 and 14, the observed changes in Ret-He were higher in the IW1 group than in the IW3 group. Increases in total reticulocyte hemoglobin at day 7 were higher in the IW1 group than in
the IW3 group. In contrast, there was only tendency toward greater total reticulocyte hemoglobin after iron administration in the third week in the IW3 group. Intravenous iron supplementation in the first week of CERA administration increases reticulocyte iron uptake; however, iron supplementation in the third week does not. The findings indicate that iron should be intravenously administered to increase the efficacy of CERA within 1 week of CERA administration during highly active erythropoiesis. Key Words: Continuous erythropoietin receptor activator, Hemodialysis, Iron utilization, Renal anemia, Reticulocyte hemoglobin equivalent.
Anemia is a common comorbidity among patients with end-stage renal disease requiring dialysis therapy and is a major cause of morbidity and mortality among hemodialysis (HD) patients (1). Recombinant human erythropoietin was first introduced to clinical practice as a treatment agent for renal anemia. This was followed by a new generation of erythropoiesis-stimulating agents (ESAs). Currently, ESAs are the first-line therapy for renal anemia in HD patients and have been shown to improve quality of life (2) and prognosis (3).
Although anemia can be effectively corrected using ESAs (4), responses to ESAs vary between individuals. ESA response is a clinically important issue because a lowered response, as well as anemia, is a risk factor for morbidity and mortality (5,6). Many factors are related to responsiveness to ESA, including iron deficiency, inflammation and malnutrition (7). In particular, iron deficiency is a major cause of resistance to ESA therapy (8). Intravenous iron supplementation has been shown to be an effective therapy in HD patients with iron deficiency (9), including those with functional iron deficiency (10,11). However, iron supplementation also has toxic effects (12). Excessive iron use could theoretically increase the risk of infectionrelated mortality (13) and cardiovascular events (12). Observational studies have linked higher iron doses with mortality (14). Iron dosing should be carefully
Received February 2014; revised June 2014. Address correspondence and reprint requests to Dr Tetsuya Fujikawa, Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine and School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 2360004, Japan. Email: [email protected]
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considered to prevent iron overload, which is associated with poor prognosis. In order to maximize advantages and minimize disadvantages of iron supplementation, further investigation of optimal iron dosing is required. Some reports have indicated that, similar to the effect of large doses, small doses of iron can increase responsiveness to therapy with ESA (15), indicating that iron supplementation can be conducted more safely in HD patients. Maintaining iron levels sufficient for erythropoiesis with minimum supplementation is desirable in order to maximize the effectiveness of ESA therapy. However, few studies have been conducted to determine the optimal timing of iron administration for ESA-induced erythropoiesis. Continuous erythropoietin receptor activator (CERA) has an active erythropoiesis phase of 4 weeks, and patients receive treatment in 4-week cycles (16). Previous studies identified specific patterns of iron metabolism marker levels during CERA treatment. A transient decline in hepcidin, Ret-He, transferrin saturation (TSAT), and ferritin, as well as an increase in reticulocytosis, has been observed following CERA administration (17,18). Hepcidin is a key regulator of iron metabolism, and reduced hepcidin levels increase iron availability (19). Longterm erythropoiesis stimulation and concomitant iron demand have been shown to increase and decrease gradually during the 4-week CERA treatment cycle (16–18). To date, although iron demand changes according to the degree of erythropoiesis activation, it is unknown if the effect of iron administration changes with iron demand in patients treated with ESA. This study aimed to evaluate the effect of different timings
of iron administration during erythropoiesis activated by CERA on reticulocyte iron uptake in HD patients. PATIENTS AND METHODS Participants Outpatients being treated at the Yokodai Central Clinic in Yokohama, Japan, who had received HD for >12 weeks and had been receiving CERA treatment for ≥2 months prior to recruitment were selected. Patients with severe congestive heart failure (New York Heart Association class III or IV), uncontrolled hypertension (defined as a pre-dialysis diastolic blood pressure >110 mm Hg), acute malignancy, major surgery within the previous 6 months, active bleeding, need for erythrocyte transfusion within 12 weeks before the study, and systemic inflammatory disease and/or C-reactive protein levels >3 mg/dL were excluded. After inclusion and exclusion assessment (Fig. 1), 110 patients were eligible for enrollment in the study. The institutional review board of Yokohama City University and the local ethics committee approved the protocol.The procedures followed were in accordance with the Helsinki Declaration. This study was registered in the UMIN Clinical Trials Registry (registration ID number: UMIN000010084). All patients provided written informed consent. Study protocol This was a randomized, controlled, parallelgroup study. At the start of the study, demographic data, comorbidity data, physical examination results and laboratory data were recorded for each patient. Eligible patients were randomized using a
FIG. 1. Flow chart of patient involvement.
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Iron dosing timing and hemoglobin synthesis centralized allocation method such that each patient received 40 mg intravenous doses of elemental iron (Fesin, Nichi-Iko Pharmaceutical, Toyoma City, Japan) at all three HD sessions during week 1 after CERA administration (day 0, 2 and 4: IW1 group: N = 57) or at all 3 sessions during week 3 after CERA administration (day 14, 16 and 18: IW3 group: N = 53) (Mircera, Chugai Pharmaceutical, Tokyo, Japan). CERA dose was adjusted and administered after the first HD session of week 1 (day 0) to maintain the target hemoglobin (Hb) level of 10–11 g/dL, according to the 2008 Guidelines for Renal anemia in Chronic Kidney Disease (20). Hb, reticulocyte Hb equivalent (Ret-He), TSAT and ferritin levels were examined before the HD session once a week (day 0, 7, 14, 21, 28).TSAT was calculated using the following formula: TSAT (%) = serum iron (μg/dL)/total iron binding capacity (μg/dL) × 100. HD was performed regularly for 3 to 6 h, 3 times a week. The dialysate flow rate was 400 mL/min in most patients, and the blood flow rate ranged from 150 to 280 mL/min. Dry weight was determined for each patient using the pre-dialysis cardiothoracic ratio. Before the study, intravenous doses of 40 mg elemental iron per week were administered if serum ferritin level was below 100 ng/mL and transferrin saturation was less than 20%. Analytical methods Ret-He (21) is a direct indicator of iron utilization as well as reticulocyte Hb content (22). Conventional erythrocyte parameters and Ret-He were measured using an XE-5000 hematology analyzer (XE RET MASTER, Sysmex, Kobe, Japan). Ret-He was analyzed using a fluorescent flow cytometry technique. In the reticulocyte channel, using a polymethine dye, this technique also determines the mean value of forward light scatter intensity derived from mature erythrocytes and reticulocytes (21). Because blood Hb concentration is an indicator of the total amount of erythrocyte Hb, blood concentration of total reticulocyte Hb can be an index of newly synthesized Hb. According to the prior study (23), total reticulocyte Hb (reticulocyte Hb, mg/dL) was defined as Ret-He (pg) per cell multiplied by reticulocyte count (109 cells/L). Statistical analysis Sample size was estimated based on a previous report (17) with the following assumptions: α was set at 0.05, the expected power was 80%, difference between groups in changes of Ret-He at 12% and a standard deviation of 20%. Unless otherwise specified, data are presented as mean ± standard devia© 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
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tion. Differences between the two groups were analyzed using the unpaired Student’s t-test for continuous variables and the χ2 test for proportion. P-values of < 0.05 were considered to be statistically significant. Statistical analyses were performed using the SPSS software version 19.0 for Windows (SPSS, Chicago, IL, USA).
RESULTS Figure 1 is a flow chart of the study population. The baseline characteristics of the 110 patients (IW1 group: N = 57; IW3 group: N = 53) are shown in Table 1. No significant differences in baseline characteristics were evident between the two groups with the exception of serum iron level. During the evaluation period of 4 weeks, six patients in the IW1 group were withdrawn from the study because of hospital admission. Five patients in the IW3 group were withdrawn due to hospital admission (N = 2), clinic transfer (N = 1) and discontinuation of CERA (N = 2) (Fig. 1). Ninety-nine participants (IW1 group: N = 51; IW3 group: N = 48) were included in the final analysis. No significant differences in baseline characteristics were detected between the two groups included in the final analysis. Mean CERA dosages during the evaluation period were not different between the IW1 and IW3 groups (92.6 ± 50.8 μg/month vs. 95.3 ± 52.3 μg/ month, P = 0.798). Mean Hb levels during the evaluation period were 10.8 ± 0.7 g/dL in the IW1 group and 10.6 ± 0.5 g/dL in the IW3 group (P = 0.199). Concerning stability of Hb control, increases in Hb levels from day 0 at day 28 were 0.13 ± 0.76 g/dL in the IW1 group and 0.22 ± 0.90 g/dL in the IW3 group (P = 0.595). No patients required blood transfusion during the study period. TSAT and ferritin levels showed generally adequate iron status throughout the study period. Figure 2 shows changes in Hb levels, reticulocyte count, Ret-He, reticulocyte Hb, TSAT and ferritin levels from day 0. Increases in Hb at days 7, 14, 21 and 28 during the evaluation period were not significantly different between the two groups (Fig. 2a). Reticulocyte count increased, peaking at day 7 in the two groups (Fig. 2b). Increases in reticulocyte count from day 0 at days 7, 14, 21 and 28 were not significantly different between the two groups. Changes in Ret-He from day 0 at days 7 and 14 were higher in the IW1 group than in the IW3 group (2.10 ± 2.30 pg vs. –0.93 ± 2.84 pg, P < 0001; –0.67 ± 2.06 pg vs. −1.58 ± 2.22 pg, P = 0.037, respectively; Fig. 2c).
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T Kuji et al. TABLE 1.
Baseline characteristics of patients between IW1 and IW3 groups
Variables
IW1 group, N = 57
IW3 group, N = 53
P-value
67.8 ± 13.0 66.7 21.9 ± 3.8 1.24 ± 0.18 96.5 ± 44.9 91.2 66.7 47.4 78.9 21.1 17.5 10.4 ± 0.9 27.4 ± 15.2 33.1 ± 2.1 90.7 ± 50.1 77.4 ± 26.5 220.5 ± 37.1 242.8 ± 119.3 35.9 ± 14.0 0.52 ± 0.99 3.7 ± 0.3 66.7 ± 13.0 10.8 ± 2.3 198.4 ± 110.4
70.3 ± 12.3 77.4 21.4 ± 3.1 1.19 ± 0.17 90.4 ± 41.5 88.7 62.3 54.7 73.6 26.4 17.0 10.4 ± 0.8 27.9 ± 17.3 33.1 ± 2.5 93.4 ± 59.8 90.1 ± 35.8 229.1 ± 36.1 210.0 ± 143.6 40.1 ± 17.1 0.56 ± 1.42 3.6 ± 0.3 63.7 ± 13.7 10.3 ± 2.1 222.3 ± 100.4
0.314 0.213 0.413 0.123 0.464 0.656 0.630 0.441 0.508 0.508 0.938 0.604 0.869 0.994 0.804 0.037* 0.225 0.198 0.168 0.839 0.537 0.246 0.283 0.446
Age, years Male, % Body mass index, kg/m2 Double-pool Kt/V Mean CERA dose (μg/month) in a previous month Arteriovenous fistula, % Renin-angiotensin system inhibitors, % Diabetes mellitus, % Hypertension, % Cardiovascular disease, % Cancer, % Hemoglobin, g/dL Reticulocyte count, 109/L Ret-He, pg Reticulocyte hemoglobin, mg/dL Serum iron, μg/dL Total iron binding capacity, μg/dL Ferritin, ng/mL Transferrin saturation, % C-reactive protein, mg/dL Albumin, g/dL Blood urea nitrogen, mg/dL Creatinine, mg/dL Intact-parathyroid hormone, pg/mL
P-values for the difference between IW1 and IW3 groups. *P < 0.05; **P < 0.01. Data are mean ± SD. CERA, continuous erythropoietin receptor activator; IW1, iron dosing during week 1; IW3, iron dosing during week 3.
Increases in reticulocyte Hb between day 0 and day 7 were higher in the IW1 group than in the IW3 group (226.1 ± 85.6 mg/dL vs. 183.5 ± 89.8 mg/dL, P = 0.018; Fig. 2d). In contrast, compared to the IW1 group, there was a tendency toward greater increases in reticulocyte Hb between day 0 and day 21 in the IW3 group (8.4 ± 37.8 mg/dL vs. 21.8 ± 38.9 mg/dL, P = 0.084; Fig. 2d). Changes in TSAT from day 0 at days 7, 14, 21 and 28 did not differ between the two groups (Fig. 2e). Changes in ferritin levels were higher between day 0 and days 7 and 14 in the IW1 group and were lower between day 0 and day 21 in the IW1 group than in the IW3 group (16.4 ± 49.8 ng/mL vs. −59.2 ± 41.2 ng/ mL, P < 0.001; −19.7 ± 57.1 ng/mL vs. −65.7 ± 61.4 ng/ mL, P < 0.001; 2.9 ± 72.1 ng/mL vs. 52.0 ± 60.2 ng/mL, P < 0.001, respectively; Fig. 2f). DISCUSSION In this study, we aimed to evaluate the effect of the timing of iron administration during CERA-induced erythropoiesis on reticulocyte iron uptake in HD patients. Our results showed that on day 7, the Ret-He was higher in the IW1 group than in the IW3 group, suggesting that iron dosing during the first week of CERA administration prevents a transient reduction
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in Ret-He. Furthermore, in the first week, the IW1 group showed a greater increase in the reticulocyte Hb than the IW3 group. However, in the third week, reticulocyte Hb in the IW3 group tended to increase after iron administration. These results indicate that iron should be intravenously administered to increase the efficacy of CERA within one week of CERA administration during highly active erythropoiesis. We used CERA, an ESA with a long half-life, to induce erythropoiesis, and used Ret-He to evaluate iron utilization due to erythropoiesis. This approach can be applied to other ESAs as well. The optimal iron-dosing pattern can vary among ESAs and depends on the type of ESA used. The Ret-He indicates the level of newly synthesized Hb in a reticulocyte (21). The total amount of newly synthesized Hb can be estimated by calculating the Hb content in all reticulocytes (23). In our study, iron dosing during active erythropoiesis increased the RetHe. It also increased the reticulocyte Hb, but not the reticulocyte count. These results suggest that iron dosing during strong ESA-induced erythropoiesis boosts iron uptake in reticulocytes and increases the total amount of newly synthesized Hb. Thus, iron supplementation is needed to maximize the efficacy of ESA treatment during strong ESA-induced erythropoiesis. © 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
Iron dosing timing and hemoglobin synthesis b 80.0
1.0
Change in reculocyte (109 /L)
Change in hemoglobin (g/dL)
a
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0.8 0.6 0.4 0.2 0.0 -0.2
70.0 60.0 50.0 40.0 30.0 20.0 10.0 0.0 -10.0
-0.4 0
7
14 day
21
0
28
7
14 day
21
28
14
21
28
Change in Ret-He (pg)
3.0
**
2.0 1.0 0.0
*
-1.0 -2.0 -3.0 0
14 day
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28
300.0
*
250.0 200.0 150.0 100.0 50.0 0.0 -50.0 0
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day
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10.0
100.0 80.0
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Change in ferrin (ng/mL)
Change in transferrin saturaon (%)
e
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Change in reculocyte hemoglobin (mg/dL)
d c
0.0 -5.0 -10.0 -15.0 -20.0
**
60.0 40.0
**
20.0 0.0
**
-20.0 -40.0 -60.0 -80.0 -100.0
-25.0 0
7
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21
28
0
7
14 day
21
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FIG. 2. Changes in (a) hemoglobin levels (b) reticulocyte counts (c) reticulocyte hemoglobin equivalent (Ret-He) (d) reticulocyte hemoglobin (e) transferrin saturation and (f) ferritin levels between groups that received iron administration in the first week or the third week following treatment initiation. Continuous erythropoietin receptor activator (CERA) was administered at day 0. Data are presented as , Iron means ± standard error of the mean (SEM). *P < 0.01; **P < 0.001 for comparison of changes from day 0 between the two groups. , Iron dosing during week 3 (days 14, 16, and 18). dosing during week 1 (days 0, 2, and 4);
To date, the need for iron supplementation has been evaluated by measuring the TSAT and ferritin levels as indicators of iron availability and storage. However, the TSAT is not a direct indicator of the amount of available iron. Thus, in our current study, we focused on measuring the reticulocyte Hb as it is a reliable direct indicator of iron utilization (23). The reticulocyte Hb showed that the timing of iron dosing is a key factor for iron utilization; this finding will allow further elucidation of iron metabolism in ESA treatment. Iron administration in the first week, but not the third week, showed a significant increase in the reticulocyte Hb. A previous study showed that activa© 2014 The Authors Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis
tion of erythropoiesis by CERA is less effective in the third week compared with that in the first week of administration (16). For all ESAs, iron dosing may be needed during highly active erythropoiesis, especially if Ret-He decreases after ESA administration. The timing of iron dosing is clinically important for all ESAs and needs to be carefully determined in order to achieve an optimal response to the ESA and reduce excessive ESA dosing. Although most patients in this study had normal iron levels before the study and did not have functional iron deficiency, their iron uptake by reticulocytes could be improved. Compared to the iron reserved in the body, iron administered during
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active erythropoiesis may be more effectively absorbed into the bone marrow and used to synthesize Hb. Intravenous iron dosing has been shown to ameliorate the response to recombinant human erythropoietin in patients with iron repletion (10,11). Iron dosing during the first week of the treatment cycle both increased Ret-He and inhibited a decrease in ferritin levels. The ferritin level did not decrease from day 7 to day 28, indicating no decrease in the iron storage. The ferritin level is usually overestimated when measured within one week of iron administration (24); however, it is accurately estimated when measured 4 weeks after administration. Our findings suggest that lower iron doses may improve erythropoiesis to some extent and not hinder utilization of stored iron. Furthermore, determining the iron supplementation dose that does not disrupt iron utilization may facilitate the enhancement of Hb synthesis without additional iron storage in patients with iron repletion. Each individual’s response to ESA varies depending on several factors such as the presence of iron deficiency, inflammation, or malnutrition (7). Our baseline data showed that there was no difference in the factors related to ESA resistance between the two groups. Hence, it is unlikely that the results obtained in this study were affected by any confounding factors. The randomized design seemed to have effectively suppressed these factors from complicating or concealing the effectiveness of iron administration in the first week. One limitation of our study was that the dose range of CERA used may have been low. According to a previous report (17), high doses of CERA could decrease the Ret-He to a greater extent than small doses. In patients showing a drastic decrease in RetHe, iron utilization needs to be improved. Iron administration in the first week may be more effective for patients who require treatment with larger doses of CERA. The serum iron level at baseline was lower in the IW1 group than in the IW3 group, but the Ret-He increased notably by iron supplementation in the IW1 group. Hence, if the serum iron level in the IW1 group was higher than the currently observed baseline level, the Ret-He may have increased further. This finding supports the reliability of the efficacy of iron dosing within the first week of CERA administration. Further study is needed to determine a more appropriate dosage and timing of iron administration in order to successfully promote iron utilization and avoid excessive iron storage. Furthermore, determining the optimal iron dosage could contribute to improving the prognosis of HD patients.
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CONCLUSIONS Intravenous iron supplementation in the first week of continuous erythropoietin receptor activator administration increases reticulocyte iron uptake; however, iron supplementation in the third week does not cause such elevation. Thus, iron should be administered to increase the efficacy of CERA within one week of CERA administration during highly active erythropoiesis. Conflict of interest: none declared.
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Iron dosing timing and hemoglobin synthesis in children, adolescents, and young adults with CKD: a randomized controlled trial. Am J Kidney Dis 2013;61:588–97. 16. Chanu P, Gieschke R, Charoin JE, Pannier A, Reigner B. Population pharmacokinetic/pharmacodynamic model for C.E.R.A. in both ESA-naive and ESA-treated chronic kidney disease patients with renal anemia. J Clin Pharmacol 2010;50: 507–20. 17. Jonckheere S, Dierick J, Vanhouteghem H, Devleeschouwer M, Stove V. Erythrocyte indices in the assessment of iron status in dialysis-dependent patients with end-stage renal disease on continuous erythropoietin receptor activator versus epoetin beta therapy. Acta Haematol 2010;124:27–33. 18. Kakimoto-Shino M, Toya Y, Kuji T, Fujikawa T, Umemura S. Changes in hepcidin and reticulocyte hemoglobin equivalent levels in response to continuous erythropoietin receptor activator administration in hemodialysis patients:a randomized study. Ther Apher Dial 2014; doi: 10.1111/17449987.12161.
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19. Nemeth E, Tuttle MS, Powelson J et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004;306:2090–3. 20. Tsubakihara Y, Nishi S, Akiba T et al. 2008 Japanese Society for Dialysis Therapy: guidelines for renal anemia in chronic kidney disease. Ther Apher Dial 2010;14:240–75. 21. Thomas L, Franck S, Messinger M, Linssen J, Thome M, Thomas C. Reticulocyte hemoglobin measurement— comparison of two methods in the diagnosis of iron-restricted erythropoiesis. Clin Chem Lab Med 2005;43:1193–202. 22. Fishbane S, Galgano C, Langley RC Jr, Canfield W, Maesaka JK. Reticulocyte hemoglobin content in the evaluation of iron status of hemodialysis patients. Kidney Int 1997;52:217–22. 23. Goodnough LT, Skikne B, Brugnara C. Erythropoietin, iron, and erythropoiesis. Blood 2000;96:823–33. 24. Besarab A, Kaiser JW, Frinak S. A study of parenteral iron regimens in hemodialysis patients. Am J Kidney Dis 1999;34: 21–8.
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