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International Journal of Laboratory Hematology

The Official journal of the International Society for Laboratory Hematology

ORIGINAL ARTICLE INTERNAT IONAL JOURNAL OF LABORATO RY HEMATO LOGY

Percentage of hypochromic erythrocytes and reticulocyte


hemoglobin equivalent predictors of response to intravenous iron
in hemodialysis patients
~ ‡ , I. GALLARDO ‡ ,
E. URRECHAGA*, O. BOVEDA*, F. J. AGUAYO † , P. DE LA HERA † , R. I. MU NOZ
J. F. ESCANERO §

*Hematology Laboratory, S U M M A RY
Hospital Galdakao – Usansolo,
Galdakao, Vizcaya, Spain Introduction: Reticulocyte hemoglobin content and percentage of

Laboratory, Hospital hypochromic red cells are incorporated into the European best
Universitario Basurto, Bilbao,
Vizcaya, Spain practice guidelines on anemia management in chronic kidney

Nephrology. HD Unit. Hospital disease. Sysmex XN analyzer (Sysmex Corporation, Kobe, Japan)
Galdakao – Usansolo, Galdakao, reports reticulocyte hemoglobin equivalent (Ret-He) and the hypo-
Vizcaya, Spain
§ chromic fraction of erythrocytes (%Hypo-He). Our aim was to
Department of Pharmacology
and Physiology, Faculty of assess the value of these parameters, in terms of the sensitivity and
Medicine, University of specificity for detecting functional iron deficiency, in hemodialysis
Zaragoza, Zaragoza, Spain (HD) patients.
Methods: Forty HD patients in the maintenance phase of erythropoi-
Correspondence:
Eloısa Urrechaga, Hematology etin therapy were included. Intravenous iron supplementation was
Laboratory, Hospital Galdakao – interrupted at least 3 weeks before recruitment. Two samples were
Usansolo, 48960 Galdakao, analyzed for each patient: the baseline after the iron-free period and
Vizcaya, Spain.
the second sample after 4 weeks of IV iron administration. Hemo-
Tel.:+ 34 94 400 7102;
Fax: + 34 94 400 7128; gram and biochemical parameters of the iron status were measured.
E-mail: eloisa.urrechagaigartua@ Patients were classified as responders or nonresponders to an iron
osakidetza.net load; responders had an increase in Hb of at least 10 g/L after iron
administration, compared to the baseline. To identify the efficiency
doi:10.1111/ijlh.12496 of the test for predicting the response to iron administration,
receiver operating characteristic analysis (ROC) was performed.
Received 16 September 2015; Results: According to the established criteria, 21 patients were
accepted for publication 8 responders and 19 nonresponders. ROC analysis results: Ret-He
March 2016 area under curve (AUC) was 0.84 (95% CI 0.64–0.93), at cutoff
30.8 pg, sensitivity 78.7%, and specificity 87.2%. % Hypo-He AUC
Keywords
was 0.78 (95% CI 0.64–0.91), at cutoff 2.4%, sensitivity 72.2%,
Iron availability, hemodialysis,
reticulocyte hemoglobin con- and specificity 88.1%.
tent, hypochromic erythrocytes, Conclusions: % Hypo-He and Ret-He are reliable parameters for the
Erythropoiesis study of erythropoiesis status in HD patients.

360 © 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38, 360–365
E. URRECHAGA ET AL. | PERCENTAGE OF HYPOCHROMIC ERYTHROCYTES AND RETICULOCYTE HEMOGLOBIN 361

by increasing the total erythroblast mass, could also


INTRODUCTION
increase the sTfR [9].
Chronic kidney disease is defined as a reduced glomeru- The direct consequence of an imbalance between
lar filtration rate, increased urinary albumin excretion, the erythroid marrow iron requirements and the
or both and is an increasing public health issue. Preva- actual supply is a reduction in red cell hemoglobin
lence is estimated to be 8–16% worldwide [1]. content, which first causes hypochromic reticulocytes
A common complication of CKD is anemia, which and later hypochromic mature red cells.
results from inadequate erythropoietin or from iron Reticulocyte hemoglobin content (CHr) and the per-
deficiency as a result of inadequate absorption or mobi- centage of hypochromic red blood cells (%Hypo) reflect
lization. The management of anemia in CKD patients current iron availability to the erythropoietic system
must strike an appropriate balance between stimulating and are reliable markers of functional iron deficiency
erythropoiesis and maintaining sufficient iron levels for [11, 12]. First reported by the then Technicon manufac-
optimum hemoglobin (Hb) production [2]. turer, in their H*1 and H*3 analyzers, now Advia
Erythropoietic stimulating agents (ESAs) mobilize (Siemens Diagnostic, Deerfield, IL, USA), CHr and %
iron stores in promoting erythropoiesis; however, Hypo are incorporated into National Kidney Founda-
decreased iron stores or iron availability is the most tion (NKF-K/DOQI) guidelines for the monitoring of
common reasons for resistance to the effect of ESAs. recombinant human erythropoietin therapy [13, 14].
Thus, most patients who receive ESA treatment will Sysmex Corporation (Kobe, Japan) has produced
require supplemental (oral or intravenous) iron to comparable indices, the so-called reticulocyte hemo-
ensure an adequate response with erythropoietic globin equivalent (Ret-He) and %Hypo-He (fraction
agents. Iron management (iron status assessment and of erythrocytes with Hb content <17 pg), reported by
iron treatment), therefore, is an essential part of the the Sysmex XE series analyzers. Measurements of
treatment of anemia associated with CKD, as there Ret-He provide useful information in diagnosing ane-
remain outstanding concerns regarding the adverse mia, iron-restricted erythropoiesis, functional iron
effects associated with elevated doses of ESAs [3] and deficiency, and response to iron therapy.
supplemental iron [4]. Twenty-nine picograms is the cutoff value that
Guidelines on monitoring iron status stipulate that defines deficient erythropoiesis [15–17]. Ret-He corre-
hemodialysis (HD) patients receiving erythropoietin lates with CHr with the same clinical meaning [18, 19].
should have their iron status monitored every Data already published about %Hypo-He include
3 months, and maintain transferrin saturation (TSAT) reference ranges [20] and the reliability in the diagno-
>20% and a serum ferritin level >100 lg/L (>200 lg/ sis of iron deficiency in patients on dialysis and ACD
L for CKD patients on HD) [5, 6]. [21–23].
Although widely used, classical laboratory biomark- The XN Modular analyzer, launched in 2011, pro-
ers of iron status are not without drawbacks when used duces the same RBC extended parameters [24]. The
in CKD patients: CKD is a pro-inflammatory state, and aim of the study was to assess their performance in
the biological variability of serum iron, transferrin satu- the detection of functional iron deficiency in terms of
ration, and ferritin is known to be large in the context sensitivity and specificity in hemodialysis (HD)
of underlying inflammation [7, 8]. patients and to verify the optimal cutoffs to predict an
New markers for iron status have been introduced adequate response to iron supplement.
that may be useful when serum ferritin and transferrin
saturation are insufficient. These tests include reticulo-
M AT E R I A L S A N D M E T H O D S
cyte hemoglobin content, percentage of hypochromic
red cells, and soluble transferrin receptor (sTfR) [9].
Patient selection and study design
sTfR is not affected by inflammation [10] and the
test is based on the fact that erythroblasts in the bone The study was approved by the Regional Ethics Com-
marrow will increase the expression level of mem- mission of the Basque Country. Forty HD patients (23
brane transferrin receptor in the setting of iron defi- male, 17 female, 43–81 years, mean age 70.3 years)
ciency, but the treatment of a patient with an ESA, were managed according to the recommendations of

© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38, 360–365
362 E. URRECHAGA ET AL. | PERCENTAGE OF HYPOCHROMIC ERYTHROCYTES AND RETICULOCYTE HEMOGLOBIN

the NKF-K/DOQI (National Kidney Foundation, Kid- Serum iron, transferrin, ferritin, and sTfR were
ney Disease Outcomes Quality Initiative) guidelines. assayed in a chemical analyzer Cobas c 711 (Roche
All of them were treated with intermittent in center Diagnostics, Mannheim, Germany).
hemodialysis (standard 4-h bicarbonate dialysis, three
times per week), receiving erythropoietin (rHuEPO) for
Statistical analysis
at least 3 months, and were in the maintenance phase
of their treatment, with stable doses (2000 U/week) for Statistical software package SPSS (SPSS; Chicago, IL,
at least 4 weeks. Patients were receiving folate (5 mg USA) version 19.0 for windows was applied for statis-
orally twice a week) and vitamin B12 (1000 lg three tical analysis of the results.
times a week) supplement and iron therapy (intra- The differences between responders and nonre-
venous iron sucrose), to maintain the iron availability sponders were evaluated using Student’s t-test; P val-
and TSAT > 20%. IV iron administration was inter- ues less than 0.05 were considered to be statistically
rupted at least 3 weeks before recruitment. The study significant.
began at the end of the washout iron-free period: At To identify the efficiency of the test and the opti-
this point, hematological and iron monitoring parame- mal cutoff for predicting the response to iron adminis-
ters were measured (baseline). tration, receiver operating characteristic analysis
The second sample for each patient was analyzed (ROC) was performed.
after 4 weeks of the IV iron administration, 100 mg
iron sucrose at each dialysis session for 4 weeks.
R E S U LT S
Patients were classified as responders or nonrespon-
ders to iron load according to their Hb increment. According to the established criteria, 21 patients were
Those who had an increase in Hb of at least 10 g/L at responders and 19 nonresponders. Their clinical and
the end of iron loading compared to the baseline were pharmacological conditions are listed in Table 1 and
considered responders, while nonresponders presented mean values together with standard deviation for ana-
a difference in Hb of <10 g/L. lytical data in Table 2.
Hb, RBC, Ret-He, and % Hypo-He were statistically
different in responders and nonresponders,
Laboratory methods
P < 0.0001, while ferritin and TSAT had no differ-
Samples were obtained in the course of routine analy- ences (P = 0.888 and 0.522 respectively).
sis, collected in EDTA anticoagulant tubes (Vacu- Changes after administration of IV iron were
tainerTM Becton-Dickinson, Rutherford, NJ, USA), recorded. In the responders group, Hb mean incre-
and were run in the Sysmex XN analyzer Sysmex ment was 15 g/L. The change in parameters related to
Corporation, Kobe, Japan) within 6 h of collection. Hb content is summarized in Table 3.

Table 1. Baseline characteristic of patients. Values are reported as mean (standard deviation)

Responders mean (SD) Nonresponders mean (SD) P

Age (years) 58.7 (12.9) 53.6 (13.7) 0.091


Dialysis vintage (months) 105.1 (76.9) 116.0 (73.6) 0.056
Body mass index (Kg/m2) 21.1 (2.4) 20.5 (2.8) 0.42
Systolic blood pressure (mmHg) 143.9 (24.6) 140.3 (21.7) 0.142
Diabetes mellitus (%) 20 10 0.191
Cardiovascular disease (%) 42.3 42.6 0.981
ACEI and/or ARB (%) 40.7 42.1 0.882
rHuEPO (UI/Kg/week) 183 (75) 189 (113) 0.134

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; rHuEPO, recombinant human
erythropoietin.

© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38, 360–365
E. URRECHAGA ET AL. | PERCENTAGE OF HYPOCHROMIC ERYTHROCYTES AND RETICULOCYTE HEMOGLOBIN 363

specificity 87.2%; % Hypo-He AUC was 0.78 (95% CI


Table 2. Baseline data of 40 patients on HD. Patients
were classified as responders or nonresponders to an 0.64–0.9), at cutoff 2.4%, sensitivity 72.2%, and
iron load of 100 mg iron sucrose at each dialysis specificity 88.1%
session for 4 weeks, according to whether their Hb AUC for erythrocyte indices MCH was 0.723 (95%
increased by>10 g/L at the end of iron loading. CI 0.583–0.899) and MCHC 0.703 (95% CI 0.576–
Values are reported as mean (standard deviation). 0.86).
The differences between responders and
ROC analysis was recalculated leaving out the
nonresponders were evaluated using Student’s t-test;
P values less than 0.05 were considered to be patients with Hb 115 g/L; results for Ret-He were sim-
statistically significant ilar to the results obtained previously, while the best
cutoff for % Hypo-He was found to be 3.5%, AUC
Responders Nonresponders 0.75 (95% CI 0.663–0.865), sensitivity 73.8%, and
mean (SD) mean (SD) P
specificity 78.1%.
RBC, 1012/L 3.56 (0.58) 3.90 (0.87) <0.0001
Hb, g/L 109 (9) 116 (4) <0.0001
MCV, fL 96.9 (4.8) 95.9 (3.7) 0.042 DISCUSSION
MCH, pg 30.8 (1.8) 32.2 (1.7) 0.031
MCHC, g/L 323 (15) 327 (13) 0.543 Functional iron deficiency, defined as a positive
Ret-He, pg 29.5 (1.7) 31.2 (1.9) <0.0001 response to further intravenous iron supplementation
%Hypo-He 3.6 (2.3) 1.6 (1.8) <0.0001 in the absence of absolute iron deficiency, remains a
Ferritin, lg/L 576 (230) 507 (235) 0.888 daily challenge for nephrologists.
Saturation % 23 (5) 25 (8) 0.522 The diagnosis and monitoring of the response to
sTfR mg/L 4.0 (2.2) 1.9 (1.1) 0.01
therapy presumes the use of highly specific and sensi-
RBC, red blood cells; Hb, hemoglobin; MCV, mean cell tive tests, which can be useful to prevent iron over-
volume; MCH, mean cell hemoglobin; %Hypo-He, per- load and its accumulation-associated complications;
centage of hypochromic red cells; Ret-He, reticulocyte along with the safety of new iron preparations, the
hemoglobin content; sTfR, soluble transferrin receptor.
evidence of iron overload in long-term HD patients is
increasing [25–28].
Results from the multinational Dialysis Outcomes
Table 3. Changes in parameters reflecting Hb content and Practice Patterns Study add important new infor-
in responders and nonresponders groups 1 month mation in that they show an increase in mortality as
after iron supplementation well as hospitalization rates in patients whose
monthly IV iron dose was higher than 300 mg. High
Responders Nonresponders
doses are associated with an increased risk for
mean (SD) mean (SD) P
all-cause mortality in patients with hemoglobin
D Hb g/L 15 (6) 8 (6) 0.007 100–120 g/L and ≥120 g/L. [29].
D MCH pg 1.1 (0.5) 0.9 (0.6) 0.411 The present study evaluates Ret-He and % Hypo-
D MCHC g/L 5 (2) 3 (2) 0.003
He reported by the Sysmex XN analyzer to verify
D Ret-He pg 3.1 (0.3) 1.1 (0.2) <0.0001
D Hypo-He % 2.6 (2.1) 2.0 (1.0) 0.163 whether these parameters could help the correct clas-
sification of patients suffering functional iron defi-
D, difference between the tests value after iron supple- ciency, who will benefit from therapy, and other
ments and the baseline value; Hb, hemoglobin; MCV,
patients at risk of iron overload.
mean cell volume; MCH, mean cell hemoglobin; %Hypo-
He, percentage of hypochromic red cells; Ret-He, reticu- As shown in Table 2, the nonresponders group pre-
locyte hemoglobin content. sented Hb and red cell indices near reference ranges,
so it could be suspected that the iron supply was ade-
quate to maintain the erythropoiesis and no further
increment in Hb should be expected. The conclusion
ROC analysis results
then is that iron supplementation is not recom-
Ret-He area under curve (AUC) was 0.84 (95% CI mended in this group, and Ret-He and %Hypo-He can
0.64–0.93), at cutoff 30.8 pg, sensitivity 78.7%, and be used to avoid exposure to excess of iron.

© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38, 360–365
364 E. URRECHAGA ET AL. | PERCENTAGE OF HYPOCHROMIC ERYTHROCYTES AND RETICULOCYTE HEMOGLOBIN

The cutoffs obtained correlate with those published needed to detect significant descent after iron admin-
for the RBC extended parameters reported by the Sys- istration [33].
mex XE series analyzers. TSAT is currently used to monitor IV iron therapy,
The cutoff obtained for Ret-He, 30.8 pg, is around as a marker of iron functionally available for erythro-
the value currently accepted for the detection of func- poiesis [13, 14]; our results show that, based on TSAT
tional iron deficiency, not only for Sysmex XE series values, the clinician cannot recognize a responder
analyzers, but also for Siemens and Abbott counters patient.
[17, 18, 21, 30]. The combined use of TSAT <20% and sTfR
Kim et al. evaluated the same Siemens parameter >1.5 mg/L has been proposed to improve functional
as a marker of iron deficiency and predictor of iron deficiency detection in dialysis patients suspected
response to intravenous iron in hemodialysis patients of having inflammatory conditions [34], but this is an
[31]; Miwa et al., the Ret-He responses postiron sup- expensive test; for this reason, the new parameters of
plementation [32]; and both studies found more the hemogram reported with no additional cost seem
marked differences than traditional measurements promising.
after iron supplements; our results show similar XN analyzer has been recently launched, so we
trends. tried to verify that the clinical decision limits of its
The cutoff 2.7% has been proposed for %Hypo-He markers of hypochromia are in concordance with
in HD patients, in correlation with %Hypo reported those of XE 5000.
by Siemens analyzers [21], and 3.6% when the com- A limitation of the study is that we have focused on
parison was made with soluble transferrin receptor parameters of iron status, but factors other than low
[22]. iron stores have been recognized to hamper the efficacy
The efficiency of %Hypo-He was better than that of ESA therapy, that is high turnover bone disease and
obtained for MCH and MCHC. These indices are the hyperparathyroidism [35], so prospective studies are
mean values of the global red cell population; the needed, including more variables, to verify these results
contribution to the hypochromic subset is diluted by in dialyzed patients in different clinical situations.
the majority of normochromic population. The % The conclusion is that Ret-He and %Hypo-He
Hypo-He presents the advantage to directly quantify reported by Sysmex XN analyzer seems to be an
hypochromic erythrocytes, so the changes in this preferable alternative in the routine practice. Both
important subset can be detected and evaluated could be useful in assessing functional iron deficiency
accordingly. and therefore improve anemia management in
Nevertheless, %Hypo-He in the group of responder patients receiving HD and could help to guide clini-
patients presented no significant differences between cians in their iron management decisions. In conjunc-
the baseline and the second sample. The explanation tion with standard parameters, it could enable the
could be that the gap between both samples was only diagnosis of the patients who will benefit from ther-
4 weeks, but due to red cell lifespan, 6 to 8 weeks are apy rapidly and accurately.

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Hemoglobin Equivalent: an indicator of Efficacy and safety of intravenous iron

© 2016 John Wiley & Sons Ltd, Int. Jnl. Lab. Hem. 2016, 38, 360–365

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