| Abstract|| |
We attempt in this study to evaluate the effect of intravenous iron saccharate (i.v. Sach) on the erythropoietin (EPO) requirements during the initial phase of replacement therapy with recombinant human erythropoietin (r-HuEPO) in adult chronic hemodialysis (HD) patients. We evaluated 96 study patients who completed 12 weeks of treatment with EPO. There were 69 (72%) males and 27 (28%) females with a mean age of 44 ± 10 years (range 24 to74 years). The patients were initiated on EPO at 50 units/kg body weight subcutaneously post-dialysis two to three times weekly. Intravenous iron was administered to maintain the ferritin levels and transferrin saturation ratio within normal range. There were 36 (37.5%) patients who received i.v. Sach at doses of 100 mg at the end of dialysis two or three times per week during the whole study period (total dose 2400-3600 mg). Of the 96 study patients, 91 (94.8%) responded to the EPO. The mean hemoglobin (Hb) at entry to the study was 72 ± 84 g/L (range 52-88 g/L). There was a significant increase of the mean Hb to 108 ± 10 g/L (range 70-120 grams/L) at the end of the study (P<0.0001). The mean total weekly dose per kg per patient per week of EPO was 149 ± 11 (range 100-225) units/kg/week and decreased significantly to 141 ± 24 units/kg/week at the end of the study (P<0.0006). The study patients were stratified by the baseline ferritin and transferrin saturation (TSAT) into three sub-groups: group I: patients with TSAT <0.2 and ferritin <100 ng/ml; group II: patients with TSAT >0.2 and ferritin <100 ng/ml; group III: patients with TSAT >0.2 and ferritin >100 ng/ml. There were 19 patients in group I (13 received i.v. Sach), 26 in group II (16 received i.v. Sach) and 44 in group III (seven received i.v. Sach). There was a group of seven patients who had TSAT <0.2 and ferritin >100 ng/ml, however, none received i.v. Sach and they were not included in the stratification. There was no significant difference in the mean Hb between patients who received and those who did not receive i.v. Sach in the sub-groups studied. However, there was a significant decrease in the mean weekly dose of EPO in the patients who received i.v. Sach. We conclude that routine use of i.v. iron supplementation in chronic HD patients receiving recombinant EPO may be beneficial in the initial phase of treatment in attaining the target Hb with lower doses of EPO, regardless of the status of the iron indices.
Keywords: Hemodialysis, Erythropoietin, Iron, Ferritin, Iron stores, Transferrin saturation.
|How to cite this article:|
Shaheen FA, Souqiyyeh MZ, Akeel N. Effect of Intravenous Iron Saccharate on the Requirements of Erythropoietin in Hemodialysis Patients. Saudi J Kidney Dis Transpl 2002;13:131-40
|How to cite this URL:|
Shaheen FA, Souqiyyeh MZ, Akeel N. Effect of Intravenous Iron Saccharate on the Requirements of Erythropoietin in Hemodialysis Patients. Saudi J Kidney Dis Transpl [serial online] 2002 [cited 2020 Jan 23];13:131-40. Available from: http://www.sjkdt.org/text.asp?2002/13/2/131/33124
| Introduction|| |
The primary cause of anemia in patients with chronic renal failure (CRF) is insufficient production of erythropoietin (EPO) by the diseased kidneys.  The use of various hematinics such as iron, folic acid and vitamin B12, is important in promoting eryth ropoiesis. ,, Iron deficiency  in these patients results from blood loss due to repeated laboratory testing, needle punctures, blood retention in the dialyzer and tubing and/or gastrointestinal bleeding. Effective erythropoiesis requires both iron and EPO in CRF patients; and lack of an adequate supply of either one or both, results in anemia. 
Normal body iron stores are 800 to 1200 mg.  Of this, approximately 400 mg of iron are needed simply to replace iron losses during three months of hemodialysis (HD). The other 600 mg of iron are required to support production of sufficient numbers of red blood cells to achieve the target hematocrit/hemoglobin (Hct/Hb).
The distinction between absolute and functional iron deficiency is crucial to understanding what constitutes adequate transferrin saturation (TSAT) and serum ferritin levels in EPO treated patients. In otherwise healthy subjects, iron deficiency is considered "absolute" when iron stores are depleted, as indicated by serum ferritin levels <12 ng/mL,  and iron delivery to the erythroid marrow is impaired, as evidenced by TSAT levels below 15%.  Absolute iron deficiency in CRF patients has been defined as serum ferritin levels <100 ng/mL and TSAT levels <20 percent. 
In contrast to absolute iron deficiency, functional iron deficiency results when there is a need for a greater amount of iron to support hemoglobin synthesis than can be released from iron stores (reticuloendothelial cells). This situation, which can be caused by pharmacological stimulation of erythropoiesis by EPO, can occur in the presence of adequate iron stores. As a result, the percent TSAT decreases to levels consistent with iron deficiency despite a normal or elevated serum ferritin. ,,, Patients with this condition do not meet the traditional laboratory criteria for absolute iron deficiency, but may demonstrate an increase in Hct/Hb when intravenous (i.v.) iron is administered.
We attempt in this study to evaluate the effect of iron saccharate (i.v. Sach) on the requirements of the recombinant human erythropoietin (r-HuEPO) during the initial phase of replacement therapy with this hormone in chronic HD patients.
| Materials and Methods|| |
This is a 12-week open-label prospective study of the adult chronic HD patients with anemia, on treatment with EPO at the King Fahd Hospital in Jeddah, Saudi Arabia.
The patients who fulfilled the following inclusion criteria at the time of entry to the study were accepted for the study. Patients who were maintained on regular HD (2 or 3 times weekly) for at least six weeks and who were optimally dialyzed as judged by usual dialysis and serum chemistry parameters. The accepted entry hemoglobin was less than 90 g/L. The patients' age was between 15 and 75 years. Females were accepted if they were not at risk of pregnancy during the study period. Exclsuion criteria were: anemia not related to renal failure (especially folate and/or vitamin B12 deficiency), uncontrolled hypertension postdialysis, clinically relevant liver disease, severe secondary hyperparathyroidism, signs of aluminum toxicity, androgen use, uncontrolled diabetes or any acute illnesses. The investigators informed the patients of all the risks and benefits of the study and obtained the informed consent. Also, none of the patients was currently participating in any other therapeutic trial.
On entry to the study, each patient had history and physical examination including detailed history of anemia and renal disease in addition to the current therapies. Base-line laboratory investigations included complete blood count, hepatitis screen (C and B types), p-human chorionic gonadotrophin of pregnancy where applicable as well as serum levels for electrolytes, calcium, phosphate, liver function tests, ferritin, iron, total iron binding capacity, transferrin saturation, glucose, urea, creatinine, cholesterol, folate and vitamin B12.
The patients received Epotec®, a recombinant human EPO manufactured by the Saudi Pharmaceutical Industries and Medical Appliances Corporation (SPIMACO), Riyadh, Saudi Arabia, which has an identical formulation and composition to Epogen® (r-HuEPO manufactured by Amgen Inc., Thousand Oaks, CA; USA).
The plan of the dosing of EPO included an initial dose of 50 units/kg body weight subcutaneously (S.C.) post-dialysis two to three times weekly. This dose was maintained for four weeks and response was assessed. In case of inadequate response, the dose was increased by 25 U/kg/dose and maintained for four other weeks. Increments of EPO at 25 U/kg/dose, at four weekly intervals were continued until the target Hb of 100-120 g/L was achieved. The maximum allowed dose was 200 U/kg given three times a week. If the Hb value exceeded 120 g/L, the EPO was discontinued until the Hb level returned to values between 100-120 g/L and then, restarted at a dose which was reduced by 25 U/kg over the previous dose. Reduction of the dose frequency of EPO from thrice to twice a week was considered after the patient's Hb concentration was stable (100-120 g/L).
The follow-up data documented included the dose of EPO and the pre- and post dialysis body weight, temperature and blood pressure of the patient at each dialysis session. Complete blood count, platelet count and reticulocytes were obtained at the end of each week of the study. Serum electrolytes, calcium, phosphorus, liver function tests, iron, ferritin, total iron binding capacity, transferrin saturation, urea and creatinine were done at the end of each four weeks of the study.
Intravenous iron supplements were administered to maintain the ferritin levels and transferrin saturation ratio within the normal ranges. There were 36 patients who received intravenous iron saccharate (i.v. Sach) (Ferosac® by SPIMACO) at doses of 100 mg at the end of dialysis two or three times per week during the whole study period (total dose 2400-3600 mg). Some patients received i.v. iron, even if they had normal ferritin level and/or normal transferrin saturation.
The study patients were stratified by the baseline ferritin and transferrin saturation into sub-groups to evaluate the significance of these parameters in modifying the response to the treatment with i.v. Sach and EPO. The mean Hb and the dose of EPO were used as end-points for comparison. The sub-groups included group I: patients with TSAT <0.2 and ferritin <100 ng/ml; group II: patients with TSAT >0.2 and ferritin <100 ng/ml; group III: the patients with TSAT >0.2 and ferritin >100 ng/ml. Some patients in each of these sub-groups received i.v. Sach. There was a group of seven patients who had TSAT <0.2 and ferritin >100 ng/ml. None of these patients received i.v. Sach and they were not included in the stratification.
| Statistical Methods|| |
We used the descriptive statistics and the analysis of variance (ANOVA) to compare the equality of means for any three or more groups of quantitative variables. The two sample independent and paired t-test was used to compare the equality of the means of groups where appropriate. The P value was set as significant if below 0.05.
| Results|| |
There were 96 patients who fulfilled the inclusion criteria and completed the 12week trial. There were 69 (72%) males and 27 (28%) females with a mean age of 44 ± 10 years (range 24 to74 years). There were 71 (74%) patients on three dialysis sessions per week and 25 (26%) on two sessions per week. They all completed 12.2 ± 14.5 months (range of 3 to 111.3 months) on dialysis at the time of study. There were 43 patients without history of blood transfusion, 35 with one unit transfused, 14 with two units transfused, three patients with three units transfused and one patient with five units transfused. There were 58 (60.4%) patients who had renal failure of unknown etiology and 21 (21.9%) patients who had renal failure secondary to diabetes mellitus, which constituted the largest group with identifiable etiology.
All the patients were prescribed calcium carbonate, 1-a vitamin D 3 , vitamin B-complex, folic acid and oral iron preparations. A total of 62 (64.6%) patients were not on any antihypertensive medications at the time of entry to the study, while 28 (29%) patients were on one drug only.
[Table - 1] shows the characteristics of the study patients. There were 25 patients on two doses of EPO per week versus 71 patients on three doses per week at the start of the study. The number of patients on two doses increased at the end of the study to 39, while the number of those on three doses decreased to 57. The mean total weekly dose per kg per patient decreased significantly at the end of the study. There was a significant increase of the means of Hb and Hct in 91 (94.8%) patients. Also, there was a significant decrease of the mean serum ferritin, serum iron and transferrin saturation (serum iron/serum total iron binding capacity) at the end of the study. The mean serum folate was 19 ± 39 and the mean serum vitamin B12 was 500 ± 154 pg/ml at the entry to the study (both within normal limits).
A total of 36 (37.5%) patients received i.v. Sach during the study period. There were no significant differences in the mean Hb level between the whole study group and those treated with i.v. Sach. However, the patients treated with i.v. Sach required significantly lower mean weekly doses of erythropoietin, 8677 ± 222 versus 9493 ± 179 units/week, respectively, P<0.0001.
[Table - 2] shows the effect of the i.v. Sach administration on the mean ferritin level and TSAT in comparison with those who did not receive it. The levels decreased significantly at the end of the study in those not treated with i.v. Sach, while they remained unchanged in those patients treated by i.v. Sach.
Of the 19 patients in group I, (stratified according to both the TSAT and ferritin status and treatment with i.v. Sach), 13 received i.v. Sach; of the 26 patients in group II, 16 received i.v. Sach; and of the 44 patients in group III, seven received i.v. Sach. There was no significant difference in the mean Hb between the mean of the whole study group and any of the sub-groups. However, there was a significant difference in the mean weekly dose of EPO between the patients who received and those who did not receive i.v. Sach in all three groups. In group I, the patients who received i.v. Sach received a mean dose of EPO, 9598 ± 320 units/week versus 9963 ± 35 in patients not receiving i.v. Sach (P<0.0007). In group II, the respective doses of EPO were 8114 ± 185 units/week and 8878 ± 44 (P<0.0001). In group III, the respective doses of EPO were 8239 ± 270 units/week and 9725 ± 236 (P<0.0001).
[Figure - 1] shows that there was higher mean Hb in the patients who received i.v. Sach, in comparison with those who did not receive it, in all the groups and during the whole study period, although it did not reach a statistically significant difference.
[Figure - 2] shows that there was a statistically significant decrease in the mean weekly dose of EPO in the patients who received i.v. Sach compared to those who did not receive it, in all the groups during the study period.
There were no major adverse effects encountered with administration of i.v. iron saccharate or EPO during the study period.
The frequency of administration of i.v. Sach did not influence the mean Hb, TSAT and ferritin levels as well as dose of EPO.
| Discussion|| |
The patients of this study were selected because of their anemia secondary to renal failure and EPO deficiency. The patients showed a remarkable response to the EPO and all reached their target Hb. There was an increase in the mean Hct to 33%, which was compatible with the recommended level of 33-36% required to decrease morbidity and mortality  and achieve better quality of life. 
When EPO is given S.C. to adult patients, the recommended dose is 80-120 units/kg/ week in two or three doses per week.  When selecting the initial dose of EPO, the goal is to achieve the target Hb within a 2 to 4 months period (corresponding to the lifespan of red blood cells in CRF) through the induction of a slow, steady increase of the Hb. Ideally, that dose will also be the dose necessary to maintain the Hb at the target value.  With the recommended doses of EPO and with optimal iron stores, the absolute rise in Hct can be expected to be about 1 percentage point per week (a typical response ranges 0.5 to 1.5 percentage point per week) in CRF patients, ,,,, though the dose-response range is wide. Ninety-six percent of patients usually respond to EPO at 300 units/kg/wk administered S.C. within 4 to 6 months, provided there are adequate iron stores.  Most of our study patients responded very well to a mean dose of EPO of 150 units/kg/week, which is compatible with the experience of others.  There were five (5.2%) slow responders with less than 0.5 percentage point rise of Hct per week.
However, in these patients the initial doses were not increased. Furthermore, most of the patients in our study were started on EPO as three divided doses per week. The mean weekly dose and the frequency of the dosing were decreased significantly towards the end of the study because many patients could reach the target Hb.
If the initial Hct is 25% and the target Hct is 35%, the magnitude of supplemental iron required by the patients during the first three months of EPO therapy is approximately 1000 mg. Once the target Hct/Hgb is achieved, approximately 400 to 500 mg of supplemental iron will be needed every three months to replace iron losses and maintain adequate iron stores. ,
Traditionally, a TSAT of <20% in HD patients has been considered to be indicative of iron deficiency. However, several studies ,, have demonstrated that a TSAT of <20% versus >20% is not an accurate discriminator between patients who are and who are not, iron deficient. Although the vast majority of patients who have a TSAT <20% are iron deficient, there are some patients who have a TSAT <20% who are able to achieve a Hct of 33 to 36% and/or do not respond to higher doses of iron. In our study 26 (27%) patients had TSAT <20% and could attain the target Hb and administration of i.v. Sach did not make any difference.
There are also many patients who have a TSAT >20 percent, but are functionally iron deficient (i.e, they respond to higher doses of iron with either an increase in their Hct or maintenance of their Hct at a reduced dose of EPO). ,, Whereas TSAT reflects iron that is readily available for erythropoiesis, serum ferritin reflects storage iron, i.e, iron that is stored in liver, spleen, and the bone marrow reticuloendothelial cells. As is the case with the TSAT, the serum ferritin level is the most accurate predictor of iron level status. However, serum ferritin is neither sensitive nor specific. This is partly due to the fact that, in addition to reflecting body iron stores, serum ferritin also is an acute phase reactant. Thus, it can increase in the setting of either acute or chronic inflammation. While no single value of TSAT or serum ferritin accurately discriminates between CRF patients who are, or are not, functionally iron deficient, available data demonstrate that the lower the TSAT and ferritin, the higher the likelihood that a patient is iron deficient, and vice versa. ,
Other tests of iron status, such as zinc protoporphyrin and RBC ferritin, are less widely available and do not appear to offer any increase in diagnostic sensitivity or specificity over serum ferritin and TSAT.  The percent of hypochromic red cells does appear to be a sensitive and reliable indicator for iron deficiency and has been shown to be helpful in the diagnosis of functional iron deficiency. , Normally, there are less than 2.5% of red cells with individual cell hemoglobin levels of less than 28 g/dL. Values exceeding 10% are compatible with functional iron deficiency in the erythropoietin-treated patients. This measurement is presently performed as part of a routine full blood count sample that requires a Technicon H-1, H-2, or H-3 automated cell counter, which is a specialized equipment (Bayer Diagnostics) available in parts of Europe, but presently not available in most medical centers in the United States.
Currently, the serum iron, total iron binding capacity, and serum ferritin are the best indicators of iron available for erythropoiesis as well as iron stores, but do not provide absolute criteria of either iron deficiency or iron overload. Serum ferritin should be maintained at greater than 100 ng/mL, but no upper limit has been set.
Transferrin saturation should be maintained at greater than 20%. , In our study, the mean serum ferritin and transferrin saturation were maintained at levels more than 100 ng/ml and 20%, respectively during the whole study period, with iron supplementation in the study patients. The comparison of Hb levels between the patients on i.v. iron and patients not on it showed no significant difference. However, the mean dose of the EPO was lower in those patients receiving i.v. iron. Moreover, the patients treated with i.v. Sach benefited from the supplementation by maintaining higher levels of ferritin and TSAT. Other workers have reported similar findings. ,,,,, We believe that those patients with functional iron deficiency would have benefited as the other groups, if they had received i.v. iron.
Furthermore, we found that twice a week i.v. Sach during the induction phase of EPO therapy was as effective as three times. Others have used variable frequencies of maintenance i.v. iron therapy, such as thrice weekly (with every HD),  twice weekly,  weekly,  or every other week  to provide 1,000-2000 mg of iron within 10 weeks.
We conclude that routine use of i.v. iron supplementation in chronic HD patients receiving recombinant EPO may be beneficial in the initial phase of treatment in attaining the target Hb with lower doses of this hormone, regardless of the status of the iron indices.
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Faissal AM Shaheen
Saudi Center for Organ Transplantation, P.O. Box 27049, Riyadh 11417
[Figure - 1], [Figure - 2]
[Table - 1], [Table - 2]