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*
Division of Nephrology and Hypertension, Department of Medicine, Henry
Ford Hospital, Detroit, Michigan
Department of Pharmacy, Henry Ford Hospital, Detroit, Michigan
§
Life-Chem Labs, Rockleigh, New Jersey.
Correspondence to Dr. Anatole Besarab, Division of Nephrology, Department of Medicine, University of West Virginia, Room 1264 HSS, P. O. Box 9165, Morgantown, WV. Phone: 304-293-2551; Fax: 304-293-7373; E-mail: abesarab{at}pol.net
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionConclusionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionReferences |
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In functional iron deficiency, the bone marrow's erythropoietic capacity to respond to Epoetin is limited by iron release from storage depots (8,9,10) or by a limited capacity of plasma transport. Iron stores drop precipitously when red blood cell production accelerates following initiation of Epoetin therapy in both non-azotemic as well as dialysis-dependent subjects (11,12). The National Kidney Foundation-Dialysis Outcomes Quality Initiative (NKF-DOQI) guidelines advocate aggressive detection and management of functional iron deficiency (5). Functional iron deficiency is assessed by the response to a course of parenteral iron producing either a decrease in dose of rhEPO needed to maintain the target hematocrit or an increase in hemoglobin at the same dose of Epoetin (6,9,10,13,14). Maintenance parenteral iron administration as opposed to "as-needed" strategies consistently achieve target hematocrit using lower amounts of Epoetin (13,14,15,16,17), presumably by avoiding iron-limited erythropoiesis. Analysis of such "iron restoration-maintenance" studies reveals that ferritin increases from a pretreatment mean of 209 to 447 ng/ml and mean transferrin saturation (TSAT) from 22 to 35% (18). The optimal strategy for maintenance iron administration, i.e., the frequency of and dose amount, is controversial (15,16,19).
Avoidance of iron-limited erythropoiesis anemia depends on its detection. Threshold values for iron repletion therapy in HD patients, TSAT <20% or a serum ferritin <100 ng/ml (5), are frequently inadequate to detect functional iron deficiency (20,21) because marrow iron deficiency can develop in HD patients at TSAT values approaching 30% (20,21) or ferritin levels in excess of 500 ng/ml (22,23). The key questions in managing anemia then become: (1) At what levels of TSAT and ferritin are adequate amounts of iron being supplied to support optimal erythropoietic activity? (2) Are there readily available hematopoietic parameters that can detect functional iron deficiency and be measured sequentially to guide iron therapy?
We have previously demonstrated that the use of standard intermittent need-based dosing strategy increased the amount of rhEPO needed to maintain an average hemoglobin level of 10.5 g/dl when compared with a weekly maintenance intravenous iron dextran (ivID) regimen of 41 to 66 mg (15). Maintenance patients averaged a TSAT of 34.5% compared with only 26.1% for the "need-based" subjects. We hypothesized that TSAT values of 20 to 30% in ESRD patients could be associated with limited iron delivery to the erythron because of the ESRD-associated decreased plasma iron carrying capacity. The main objective of the present study was to determine whether a maintenance iron protocol that increased TSAT from conventional levels of 20 to 30% to 30 to 50% would increase erythropoiesis and result in reductions in rhEPO doses needed to maintain a hemoglobin level of 9.5 to 12.0 g/dl when compared with a maintenance protocol that targeted TSAT levels of 20 to 30%. Secondary goals were to determine whether zinc protoporphyrin (ZPP) and reticulocyte hemoglobin content (CHr), two measures of ongoing erythropoiesis and iron deficiency in hemodialysis patients receiving Epoetin (24,25,26), could be used to assess adequacy of iron delivery for erythropoiesis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionReferences |
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9.5 g/dl; (3) stable rhEPO (Epogen®; Amgen, Thousand Oaks,
CA) dose for anemia management over the previous 3 mo (±25%), but this
baseline dose had to exceed 700 U intravenously three times per week; and
(4) no prior adverse reactions to parenteral iron. Exclusion criteria
were hemolytic anemia, known aluminum toxicity, the presence of acute
infection/inflammation, hematologic malignancies, active known acute or
chronic gastrointestinal bleeding, or moderate hyperparathyroidism
(parathyroid hormone >450 pg/dl).
Study Design
A single-center, open-label, randomized, comparative, prospective
outpatient study was conducted in HD patients. Randomization to the two groups
was performed after enrollment, at which time all oral iron was discontinued.
Patients were then variably supplemented with parenteral iron (INFeD®,
Schein Pharmaceutical, Inc., Florham Park, NJ) by slow infusion (<5 mg/min)
to maintain TSAT between 20 and 30% during the next 16- to 20-wk run-in phase.
Patients were considered to be in steady state if the maximal variation of
hemoglobin was <1.2 g/dl (and without a trend by linear regression) and if
the maximal variation in Epoetin dosage was <500 U/dose during the last 6
wk of the run-in phase. Once in steady state, patients entered one of the
following groups to which they had been previously randomly assigned:
The measured monthly TSAT, the group assignment, and the ferritin level determined the amount of iron dextran administered to each patient. The investigator and staff were blinded to the ZPP and CHr measurement results so that these would not influence the ivID dosing decisions.
Both groups received Epoetin (Epogen®; Amgen) to maintain the starting hemoglobin (9.5 to 12 g/dl). The rhEPO dose was adjusted as necessary (but no more often than monthly) to keep the hemoglobin of each patient at its baseline level (the average of four determinations before randomization for each patient, generally 10 to 12 g/dl). The algorithm for Epoetin dose adjustments was ±25% for every variation in hemoglobin of 1 g/dl within any 4-wk period (e.g., if hemoglobin increased by 1 g/dl within 4 wk, the rhEPO dose was reduced by 25%).
Blood counts and red blood cell indices were measured by standard automated counter methods. Hemoglobin (g/dl) was measured by a colorimetric method and monitored on a weekly basis. Iron indices (serum iron, TSAT, and ferritin) were evaluated monthly. If more than 100 mg of iron dextran had been given in the previous week, iron index measurements were delayed until the following week (19). If ferritin levels exceeded 1500 ng/ml, parenteral iron was withheld for at least 1 mo. Serum iron and total iron binding capacity (TIBC) were measured by a colorimetric method (Hitachi 747; Boehringer Mannheim, Indianapolis, IN). Serum ferritin (ng/ml) was measured monthly by a chemiluminescence immunoassay method (ACCESS; Beckman Instruments, Fullerton, CA) or by a heterogeneous competitive magnetic separation assay using Immuno-1 (Bayer Diagnostics, Tarry-town, NY). TSAT (%) was calculated monthly as serum iron/TIBC. Parathyroid hormone and serum aluminum levels were measured every 12 wk unless A1 containing phosphate binders were being used, in which case the frequency was increased to every 6 wk. Serum parathyroid hormone levels were measured by immunoradiometric assay at the reference laboratory (LIFE-CHEM, Rockleigh, NJ). ZPP and CHr were measured monthly beginning with month 0 (last month of the run in stabilization period). ZPP was measured fluorometrically at a reference laboratory (SmithKline Beecham, St. Louis, MO) with a normal reference range of <70 µg/dl. CHr was measured by a flow cytometric method using a Bayer H3 hematology analyzer (Bayer Diagnostic, Tarrytown, NY) with a reported normal range of 24 to 36 pg (reference range at the time of our measurements, 24.5 to 31 pg). Functional iron deficiency was defined as possibly being present if ZPP was >100 µg/dl (27) or a CHr < 26 pg (26,28).
Signs and symptoms were evaluated during and after each dialysis session, and the incidence of hospitalization, infections, and deaths was recorded. Our computerized database categorized 53 different events that could occur during dialysis.
Statistical Analyses
Sample size was based on a 40% difference in Epoetin dose at a P
value of 0.05 and power of 80%; the required number of patients was 14 in each
group. Data were collected and maintained in a computerized database. Results
are expressed as mean ± SEM unless otherwise stated. Comparisons at
baseline between groups used t test and 
2 analysis.
Monthly treatment group comparisons with respect to hemoglobin, CHr, serum
iron, ferritin, TSAT, and ZPP, as well as the change in Epoetin dose and the
change in iron dextran dose, were made using a repeated-measures ANOVA.
Because the primary outcome was a change in Epoetin dose that could not be
immediately discerned, a modified intention-to-treat analysis was used. For
analytical purposes, the last observation was carried forward only for those
subjects who finished at least 6 wk of the experimental phase of the study. An
analysis was also performed for those who completed the entire 6 mo.
Additional analyses included regression analysis. A P value <0.05
was considered significant.
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Results |
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Thirty-seven patients (control group, 17 patients; study group, 20 patients) completed 6 wk of randomized treatment, and 32 patients (control group, 15 patients; study group, 17 patients) completed the entire 6 mo of study. Data are presented for the 37 patients who completed 6 wk of randomized treatment, using a last-observation-carried-forward approach for any patient who withdrew from the study before completion. The results were not altered by considering only those who completed the full study.
Before entry into the randomized treatment phase (last month of the run-in stabilization period or month 0), the two treatment groups were similar in age, male:female ratio, hemoglobin levels, Epoetin dose, iron indices of TIBC, TSAT, and ferritin, and iron requirements (Table 1). Hyperparathyroidism was of mild-to-moderate severity in both groups with mean/median values of 275/186 pg/ml and 262/219 pg/ml for the control and study groups, respectively. Alkaline phosphatase levels were equal at 110 ± 14 U/L and 128 ± 16, respectively. Baseline serum albumin was 3.9 ± 0.1 and 3.8 ± 0.1 in the control and study groups, respectively.
Table 2 shows changes in various parameters during the course of the experimental phase. At baseline, mean values of both ZPP and CHr were normal for both groups. Ten of the 37 patients had at baseline either a ZPP >100 µg/dl or a CHr <26 pg, indicative of possible iron-limited erythropoiesis. Mean ZPP did not change in either group during the randomized treatment phase of the study (Table 2). At baseline, seven of the 37 subjects had a CHr <26 pg (iron deficiency) despite maintenance iron administration that maintained TSAT >20% and ferritin >150 ng/ml. In three of four control group subjects, basal low CHr levels persisted throughout the experimental phase, but a TSAT <20% was seen only transiently. These subjects received the same amount of iron as those control subjects who never developed CHr <26 pg during the treatment phase. A basal CHr <26 pg was corrected in all three study group subjects during the treatment phase of the study. CHr <26 pg developed in three additional control and three study group subjects at some time during the experimental phase even though ferritin 150 ng/ml and TSAT >19% was maintained in five of the six subjects. When all available data were analyzed, there was a weak positive correlation (CHr = 26.6 + 0.031ZPP, r = 0.26, P < 0.05) between CHr and ZPP. On multivariate regression, the only significant correlation for CHr was with serum iron (HCr = 23.5 + 0.099Fe, r2 = 0.34) and previously significant univariate correlations between CHr and TSAT, and CHr and TIBC dropped out of the model. Baseline Epoetin dose was independent of CHr.
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The hemoglobin level remained unchanged in both groups during the 6-mo
randomized treatment period (Figure
1, top panel). Average hemoglobin for all measured values during
the 6 mo was 10.3 ± 0.1 in the control group and 10.6 ± 0.1 in
the study group. Repeated-measures ANOVA showed no effect of time in either
group. As shown in Figure 1
(bottom panel), the doses of Epoetin in the control group remained essentially
constant throughout the 6-mo randomized treatment period. The overall mean
Epoetin dose in the control group over this period was 3795 ± 248 U.
Within the study group, the dose of Epoetin progressively decreased over the
6-mo randomized treatment period. The reduction in dose between the study
group and the control group reached approximately 40% at each of months 4, 5,
and 6. We defined a 20% change in Epoetin dose as being clinically
significant, since it approximated our dosing algorithm. The experimental
group had more subjects with decreases in Epoetin dose (12 versus 4)
during the last 3 mo of the study compared with amount received during their 4
mo stabilization period and fewer patients with increases (2 versus
5) or no change in dose (6 versus 9). The overall effect was highly
significant (2 = 15.50, P = 0.0038). The change in
Epoetin dose at the end of the study was independent of the baseline dose in
both the Study Group (r2 = 0.022, NS) and the control
group (r2 = 0.054, NS).
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During the 4-mo run-in period, the amount of iron administered to the two groups was similar: 203 ± 32 mg/mo in the control group and 157 ± 29 mg/mo in the study group. The iron dextran administered to patients in the control group to maintain a TSAT of 20 to 30% (mean ± SEM TSAT = 26.4 ± 0.8% over months 1 to 6) remained unchanged, averaging 191 ± 15 mg/mo over the 6 mo (Figure 2, middle panel). The monthly doses during months 1 to 6 were not associated with any progressive increases in ferritin (Table 2; Figure 2, bottom panel) or any temporal changes in ZPP or CHr (Figure 3).
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The mean dose of iron dextran in the study group increased nearly fourfold during the first treatment month to 610 ± 39 mg (Figure 2, middle panel), in part due to the four to six 100-mg doses administered during consecutive hemodialysis to achieve an initial TSAT >30%. The monthly iron dextran dose required by the study group over the next 5-mo randomized treatment period to maintain the target TSAT level >30% (TSAT = 32.8 ± 1.2% over months 2 to 6) remained high at 504 ± 21 mg/mo and essentially constant. Administration of these doses was associated with progressive increases in mean ferritin as shown in Figure 2 (from 272 ng/ml at month 0 to 730 ng/ml at month 6). Mean CHr increased from 28.5 pg at month 0 to a peak of 30.1 pg at month 5 (Figure 3).
Because of the large difference in ferritin levels between month 6 and month 0 in the control group (24 ± 37 ng/ml) compared to the study group (435 ± 73 ng/ml), we performed a stepwise regression to determine which factors influenced the change in ferritin level between month 6 and month 0 during the randomized treatment phase of the study (all 37 randomized patients). Only the monthly dose of iron (F = 20.3) and the presence/absence of an inflammatory state in the last 3 mo of the study (vida infra, Safety) (F = 12.3) were statistically significant factors (both P < 0.01), whereas the change in hemoglobin, the baseline TSAT value, and the change in TSAT from baseline, iron dextran dose, Epoetin dose, ferritin, baseline CHr, and the change in CHr were not. When only the patients who finished all 6 mo of study were analyzed, baseline CHr also became a significant predictor.
The relationship between change in Epoetin dose and CHr is shown in Figure 4. Epoetin dose was averaged over the last 3 mo of the randomized experimental treatment phase and factored by the dose at month 0 to provide an Epoetin dose ratio. In both groups, there was an inverse relationship between the Epoetin ratio and the change in CHr best fit by an inverse exponential relationship. Comparison of the relationships indicates a significant change in intercept but not slope for the two groups. In the control group, there was no change from baseline in CHr during months 4 to 6 of the study: 0.23 ± 0.67 pg compared with an increase of 1.41 ± 0.65 pg in the study group (P < 0.05). The CHr increased in 15 of the 20 study group patients.
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Alkaline phosphatase and parathyroid hormone were unchanged and similar for both treatment groups (Figure 5) at all time points. The aluminum levels were low (averages <10 µg/L with a range of 5 to 31 µg/L) and remained unchanged in both groups (data not shown).
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Safety
Three patients died during this study. Two patients in the control group
died as a result of underlying disease during the third (cerebrovascular
accident [CVA]) and fifth (post-laminectomy surgery) months of the randomized
treatment period. One patient in the study group died in the fifth month as a
result of catheter-associated sepsis. This elderly patient on hemodialysis for
8 yr had a medical history of hypertension, insulin-dependent diabetes
mellitus, CVA, and multiple lacunar infarcts, bilateral above the knee
amputation, multiple sacral decubiti, and three permanent accesses that had
required five salvage procedures. Because of the latter complications, the
patient had had 12 central vein catheters and four previous catheter-related
sepsis episodes before entry into the study. She required four catheters
during the 5 mo in the study. Late in the third month of the treatment phase,
her catheter malfunctioned and was replaced. Ferritin was 450 ng/ml, TSAT 28%,
and albumin 3.8 g/dl. Only femoral vein access remained available. Over the
course of the next 6 wk, the patient had multiple debridements of her sacral
decubiti, developed hypoalbuminemia (3.3 g/dl), and had a preterminal episode
of line-related sepsis that did not clear even with line removal and
vancomycin. Ferritin was 714 ng/dl, TSAT 37% just before the event. Death
followed a massive CVA.
Five patients were prematurely discontinued from study. In the control group, one arose from a massive cerebrovascular event on last day of study and the other from loss to follow-up after 5 mo. Within the study group, one patient was discontinued due to development of acute gastrointestinal bleeding, one patient due to mastectomy complicated by a cerebrovascular event, and one patient due to kidney transplant.
No differences in hospitalizations or infection rate were noted. Ten of the 17 control group subjects were hospitalized for non-transplant-related causes on 15 occasions compared with 10 of the 19 study group patients on 15 occasions. Each group had one admission for an infectious etiology (pneumonia in the control group, line-related sepsis in the study group). Infection of inflammation (foot ulcer, inflammatory bowel disease, leukocytosis of unclear cause, chronic bronchitis, arthritis with joint effusion, persistent gastritis) occurred during the last 3 mo of the study in seven of 17 control and six of 19 study patients. Our computerized database categorizes 53 different events occurring during dialysis. None of these differed between the two groups, including the frequency of hypotension, shortness of breath, chest pain, and arthralgia.
Cost Effectiveness
Comparative treatment costs were determined by comparing monthly and
average wholesale price total costs of supplying the two groups with
INFeD® and rhEPO. During weekly maintenance therapy, costs for syringes,
saline diluent, and iv administration sets are identical in both groups.
Similarly, since our unit policy is to measure iron indices monthly, the cost
of these is equal in the two groups. The individual monthly costs, as well as
the total costs for months 2 through 6, were lower for the study regimen
compared with the control regimen. The cost difference reached statistical
significance by the third month and remained so for the remainder of the study
(P < 0.02). Overall cost analysis revealed a potential savings of
$109/mo or $1308/yr per patient with maintenance of the TSAT between 30 and
50%.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionReferences |
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Our findings suggest that decreased transferrin levels associated with ESRD limit the delivery of iron to the erythron at TSAT levels in the 20 to 30% range. We believe that the overall effect of reducing Epoetin dose in the experimental group reflects the increase in iron delivery to tissues when higher TSAT were achieved by intensive iron therapy. Classical studies by Cazzola et al. (27) showed that delivery of iron to tissues increases as the amount of iron bound to transferrin also increases, but the number of transferrin molecules that leave the plasma per unit time does not. In plasma, transferrin exists as a mixture of unsaturated, partially saturated monoferric, and fully saturated diferric transferrin. Diferric transferrin has a 4.2-fold greater advantage over monoferric transferrin (28) in delivering iron to the developing red blood cell. Erythroid transferrin uptake in turn depends on the activity of the bone marrow, increasing when erythropoiesis is stimulated (29). For the same target hemoglobin, if the limitation to effective erythropoiesis is due to inadequate iron delivery due to decreased transferrin, then less Epoetin is needed if iron delivery can be maximized.
Changes in Epoetin dose following deliberate increases in TSAT were not uniform. Changes in Epoetin dose and in CHr in response to parenteral iron were quite variable despite the intent to make the groups as homogeneous as possible. As shown in Figure 5, there was significant dispersion in the change in CHr from baseline in both groups, with CHr serving as an indicator for iron availability to the erythron. These findings reflected the development of intercurrent events such as unsuspected blood losses as well as inflammatory processes. The latter occurred in one-third of the patients but was of equal frequency in the two groups.
We used CHr retrospectively to determine the effectiveness of iron incorporation at the level of the bone marrow. Mittman et al. (26) demonstrated that a CHr value of <28 pg is a more sensitive marker of functional iron deficiency in Epoetin-treated hemodialysis than transferrin saturation and ferritin. Fishbane et al. (25) found a slightly lower value of 26 pg as the best discriminator for the presence of functional iron deficiency but used a larger 1000-mg dose. Our baseline mean CHr values of 28 to 28.5 pg are comparable to those obtained by others for HD patients (43,45), although higher mean baseline values of 31 to 33 pg have been observed in adult normal volunteers (30,31). In our study, changes in Epoetin doses correlated with the change in HCr for both the control and experimental groups (Figure 5). The curve is shifted downward for patients maintained at a higher TSAT, i.e., loading transferrin with iron alters the response to Epoetin, but the absolute effect achieved depends on the directional change in CHr, which was not under the control of the investigator. The best predictor of CHr is the serum iron and not the TSAT or ferritin.
Unlike our previous experience with maintenance iron (15), we had considerably more difficulty in this study in achieving and then maintaining a TSAT of 30 to 50%. In our previous study, once a mini-loading iron dose had been administered we were able to maintain the higher TSAT at a stable ferritin level with much lower ivID doses (232 mg/mo) than in the current study. However, unlike the design of the current study, no predetermined TSAT level determined the iron dosing in that study. Also, the patients in the current study were much more heterogeneous with considerably greater comorbidity.
How much these differences in design and population characteristics contributed to the progressive increase in ferritin is unclear. Certainly, the administration of about 500 mg/mo of ivID to the study group far exceeds the average estimated losses of about 150 to 250 mg that we noted in both groups before randomization and in the control group throughout the 6-mo experimental period. Although parenteral iron in this study was well-tolerated over the 6-mo randomized treatment period without any discernible evidence of toxicity as measured by morbidity, hospitalization, and clinical events during dialysis, the sample size is small and the period of observation is short. Because of the potential toxicity of elevated iron burdens, a patient who demonstrates a progressive increase in ferritin during iron therapy without a hematopoietic response should not continue to receive iron.
Higher than expected iron dosages in the study group resulted from several unexpected differing processes. First, three of 19 study group patients (and almost 20% of the entire cohort) had baseline CHr of <26 pg, values indicative of functional iron deficiency at study entry, although TSAT was >20% and ferritin >150 ng/dl. These individuals needed more iron than iron-replete patients to correct their baseline deficiency. Second, seven of 19 study patients had baseline CHr >30 and were unlikely to benefit from additional iron loading. Six of these seven had enrollment TSAT <30%, and in four of them a TSAT >30% was difficult to achieve despite large amounts of iron. On retrospective review, all four developed some degree of reticuloendothelial blockade because of a foot ulcer, bronchitis, arthritis with effusion, and a flare of inflammatory bowel disease, respectively. Our protocol did not withhold iron during such events. In these patients, iron loading driven by the TSAT target that could not be attained led to large increases in ferritin without an increase in CHr. A rising ferritin level after iron administration may be a marker for patients with reticuloendothelial blockade. The largest increases in ferritin did occur in patients with infection or inflammation. During the experimental phase, one patient's CHr decreased from 27.9 to 24.6 pg despite administration of 4.5 g of iron over the 6-mo period. This patient had increased blood losses. Finally, because of the poor correlation between CHr and TSAT, a CHr >30 pg was achieved in some patients, yet fluctuations in TSAT led to continued high iron dosing.
ZPP was not useful in the evaluation or serial evaluation of iron delivery to the erythron in this study. We concur with the observations of Braun et al. (32) that ZPP cannot be used to predict the response to iron supplementation in patients receiving maintenance intravenous iron. Overall, the changes in CHr in this study were modest, which may be related to the fact that the great majority of patients in this study were not in a state of "absolute" iron deficiency, having received sufficient iron in the 4-mo run-in period to maintain serum ferritin >200 ng/ml and TSAT >20%. Averaged over the last 3 mo of the study, administration of large amounts of ivID increased the mean CHr by 1.41 ± 0.65 pg compared with baseline. This modest increase did lead to a 40% reduction in Epoetin dose, similar to the results of Fishbane et al. (14), who were able to lower the mean rhEPO dose by 46%.
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Footnotes |
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References |
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I. C. Macdougall Intravenous administration of iron in epoetin-treated haemodialysis patients--which drugs, which regimen? Nephrol. Dial. Transplant., November 1, 2000; 15(11): 1743 - 1745. [Full Text] [PDF]
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) at a TSAT of 30 to 50%. Erythropoietin (EPO) dosage
was adjusted every 4 wk to maintain hemoglobin at the same value as at month 0
(top panel). Iron loading with iron dextran (middle panel) decreased EPO dose
requirements (bottom panel).
CHr is the average value for each patient during the last
3 mo of study. EPO dose ratio represents the average dose of Epoetin during
the last 3 mo of study divided by the dose at month 0 (entry into study).
[UNK], control patients; 
, study patients.