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DOI 10.1007/s00467-015-3284-2
ORIGINAL ARTICLE
Received: 17 May 2015 / Revised: 19 November 2015 / Accepted: 19 November 2015 / Published online: 14 December 2015
# IPNA 2015
supra physiological erythropoiesis. Therefore, the risk of func- aimed to investigate the relationship between Ret-He and the
tional iron deficiency, defined as insufficient iron availability currently used traditional markers of iron and erythropoiesis in
to meet the demands of stimulated erythropoiesis, even though pediatric patients on chronic dialysis. We hypothesized that
the total body iron stores may not be depleted, is high [12]. Ret-He is a clinically useful tool for the evaluation of iron
Both absolute and functional iron deficiency ultimately status in this population.
limit the effectiveness of rHuEPO therapy, resulting in high
dosing and costs [13, 14]. As in adults, the appropriate iron
supplementation in the pediatric population on dialysis can Materials and methods
improve the erythropoietic response to rHuEPO [15–17]. On
the other hand, unnecessary iron treatment, especially in the Study design and settings
parenteral form, can be associated with serious immediate and
long-term side effects. Therefore, evaluation of iron status is This was a national retrospective cohort study of children with
an essential part of assessment and management of anemia in end-stage kidney disease (ESKD) on chronic dialysis under
CKD [7, 18, 19]. the care of the pediatric national renal service at Starship Chil-
The traditional biomarkers for iron availability, serum fer- dren’s Hospital in New Zealand.
ritin and transferrin saturation (TSAT), are recognized as sub-
optimal measures of iron status in patients with CKD. Serum Participants
ferritin reflects total body iron stores but is also an acute phase
reactant, making its level difficult to interpret in patients with All patients under 18 years of age on dialysis for a min-
CKD [20, 21]. In fact, rather than diagnosing an iron-limited imum of 3 months between July 1, 2007 and June 30,
anemic state, serum ferritin has been found to have an inverse 2013 were eligible. The study period commenced from
relationship with hemoglobin (Hb) in both children on dialysis the time Ret-He was routinely included in our dialysis
and with non-dialysis CKD [1, 22]. The TSAT (serum iron database. Each patient’s diagnosis history was screened
divided by total iron binding capacity) is also used as a marker for alternative causes of anemia, and any patient with
of iron availability for erythropoiesis [7]. However, TSAT such diagnoses was excluded. Participant data was cen-
levels display diurnal fluctuation [23] and can be falsely ele- sored if they received a renal transplant, died, or were
vated when transferrin synthesis is reduced in the setting of transferred to adult services. Participants were managed
malnutrition or chronic disease [20]. Despite the evidence, with rHuEPO and iron therapy according to local proto-
serum ferritin and TSAT continue to be commonly used as col, aiming to maintain Hb between 100 and 120 g/l for
the primary tools in assessment of iron status in renal anemia, children under 6 months and between 110 and 130 g/l for
partly due to a lack of accepted and available alternative those over 6 months of age. Parenteral and/or oral iron
measures. replacement was provided to target a TSAT above 0.2 and
A number of other biomarkers have been evaluated to as- serum ferritin between 200 and 500 mg/l.
sess iron availability for erythropoiesis and predict response to
iron therapy in the CKD population. These markers may not Data collection
all be widely available and their diagnostic performance is
variable [7, 18, 19, 24]. One marker, reticulocyte hemoglobin Data were collected from the department database and the
content, reflects iron availability for incorporation into reticu- hospital and laboratory electronic record systems. The da-
locytes in real time, over the preceding 2–4 days [25]. It is tabase contains clinical and laboratory data of all pediatric
measured by flow cytometry on ADVIA120 and 2120 ana- dialysis patients from inpatient and outpatient encounters.
lyzers (called CHr) and on the widely used XE-2100 Sysmex Data obtained from the database were verified for accura-
analyzer (called Ret-He) [26–28]. Ret-He has been found to cy with the hospital and laboratory electronic systems and
be a marker of iron availability for erythropoiesis in adults on were entered into an Excel data spreadsheet in de-
hemodialysis, although the cut-off values, specificity, and sen- identified form. The data included demographic variables,
sitivity vary [27, 29, 30]. While reticulocyte hemoglobin con- type of renal disease (as defined by the European Renal
tent can be a reliable screening tool for iron deficiency in Association-European Dialysis Transplant Association
otherwise healthy infants and children [31, 32], evidence re- (ERA-EDTA) [33]), anthropometric data, the mode, dura-
garding the utility of Ret-He to assess iron availability in chil- tion, and outcome of dialysis and episodes of peritonitis.
dren on chronic dialysis is not available. Anemia and iron status indices included paired data of
The Ret-He parameter has been available in our laboratory Ret-He with Hb, reticulocyte count, serum iron, ferritin,
since 2005. The national pediatric renal service at Starship total iron binding capacity, TSAT, and dose of rHuEPO at
Children’s Hospital has been monitoring this parameter in all multiple observations from each patient. The observations
children on chronic dialysis since July 2007. In this study, we were determined by Ret-He data. Missing height data at
Pediatr Nephrol (2016) 31:819–826 821
observations were determined by extrapolation using the Table 1 Demographic and clinical characteristics of study population
most recent preceding and succeeding height percentile Characteristic n (%)
from WHO growth charts.
Female patients 24 (53 %)
Statistical analysis Previous renal transplant 4 (9 %)
Primary renal diagnosis
Statistical analysis was conducted with the use of statistical Congenital 16 (36 %)
software JMP 10.0 (SAS Inc). Descriptive statistical analysis Glomerulopathy 15 (33 %)
was performed and normally distributed data were reported as Vasculitis 4 (9 %)
mean and standard deviation. Skewed data were reported as Metabolic 1 (2 %)
median and interquartile range (IQR). To allow for the non- Ischemia 5 (11 %)
independence of the repeated observations from each patient, Other 4 (9 %)
Bland–Altman multiple linear regression was used to deter- Native kidneys in situ at study enrolment 41 (91 %)
mine the within-patient correlation between Ret-He and tradi- Dialysis modality during study
tional markers of iron deficiency (ferritin and TSAT), Hb, and PD only 26 (58 %)
reticulocyte count within each patient [34]. Receiver operating HD only 4 (9 %)
characteristic (ROC) analysis was utilized to determine the PD and HD 15 (33 %)
performance of Ret-He in diagnosing absolute iron deficiency Age (years) at start of dialysis in years 6.7 [1.6–12.6]
anemia. The presence of absolute iron deficiency anemia was (median [IQR])
defined as Hb less than 100 g/l in children younger than <1 year 6 (13 %)
6 months or less than 110 g/l in children over 6 months, with 1–<5 years 12 (27 %)
ferritin less than 100 mcg/l, and TSAT less than 0.2. Addition- 5–<12 years 15 (33 %)
ally, we analyzed those with apparent “functional iron defi- 12–18 years 12 (27 %)
ciency” anemia, defined by Hb less than 100 g/l under Age (years) at study enrolment (median [IQR]) 7.6 [1.8–12.7]
6 months of age or 110 g/l older than 6 months of age with <1 year 5 (11 %)
TSAT of less than 0.2 and ferritin >200 mcg/l. The Ret-He cut- 1–<5 years 11 (24 %)
off was established based on the optimal combination of sen- 5–<12 years 18 (40 %)
sitivity and specificity. 12–18 years 11 (24 %)
Outcome of dialysis
Renal transplant 26 (58 %)
Results Death 4 (9 %)
Transfer to adult service on ongoing dialysis 8 (18 %)
Patient characteristics Ongoing dialysis under pediatric care 7 (16 %)
Duration of dialysis in months 15.5 [10.9–38.6]
Forty-five patients satisfied inclusion criteria. Patient charac- (median [IQR])
teristics are summarized in Table 1. Patients were followed up <6 months 5 (11 %)
for a median of 14.8 months (IQR 10.9–29.6 months). 6–<12 months 9 (20 %)
Follow-up was discontinued during the study period in 38 12 mo–<24 months 14 (31 %)
patients (84 %) due to renal transplant, death, or transfer to 24 mo–<48 months 10 (22 %)
the adult services. Fifty-eight percent of patients were on peri- >48 months 7 (16 %)
toneal dialysis, however only a third of patients required at Duration of follow-up in months (median [IQR]) 14.8 [10.9–29.6]
least one change of dialysis modality. rHuEPO was used con- Peritonitis during study 27 (60 %)
tinuously throughout the observation period in 25 patients Episodes of peritonitis per patient (median [IQR]) 1 [0–3]
(56 %), intermittently in 18 patients (40 %), and not at all in ACE inhibitor treatment 22 (49 %)
two patients (4 %). rHuEPO treatment 43 (96 %)
IQR interquartile range, Ret-He reticulocyte hemoglobin content, HD hemodialysis, PD peritoneal dialysis,
rHuEPO recombinant human erythropoietin, TSAT transferrin saturation, BSA body surface area
Anemia and iron status characteristics are given in Table 2. episode of peritonitis, minimizing the confounding effect of
The median Ret-He was 31.2 pg (IQR 28.6–32.9). The mean acute inflammation on ferritin and transferrin.
Hb in patients under 6 months of age was 108 g/l, and 17 % of
patients in this age group were classified as anemic. In chil- Association of Ret-He with anemia and traditional
dren over 6 months of age, the mean Hb was 111 g/l; the markers of iron status
proportion of anemia in this group was 45 %. The majority
of observations were measured while receiving rHuEPO. The In the multiple linear regression analysis, there was a modest
median weekly dose of rHuEPO, where the body surface area relationship between Ret-He and TSAT in 544 observations
(BSA) could be calculated, was 6365 IU/m2. The majority of on 45 patients (r=0.34, p<0.001). The correlation between
observations (94 %) were obtained at least 1 month after an Ret-He and TSAT was stronger in patients on hemodialysis
Fig. 1 a Correlation between serum ferritin and hemoglobin (r=−0.14, The average regression lines for each individual are shown (observations
p value=0.002). The average regression lines for each individual are = 538, individuals = 45). c Correlation between Ret-He and hemoglobin
shown (observations = 539, individuals = 45). b Correlation between (r = 0.22, p value <0.001). The average regression lines for each
transferrin saturation (TSAT) and hemoglobin (r=0.12, p value=0.007). individual are shown (observations = 599, individuals = 45)
Pediatr Nephrol (2016) 31:819–826 823
Acknowledgments We would like to acknowledge Jane Ronaldson, during r-huEPO therapy—a consensus report. Nephrol Dial
renal nurse specialist at Starship Hospital for her continued data collection Transplant 11:246–250
efforts and exemplary care provided to our children needing dialysis. 15. Ruiz-Jaramillo M, Guízar-Mendoza JM, Gutiérrez-Navarro MJ,
Dubey-Ortega LA, Amador-Licona N (2004) Intermittent versus
Study approval Institutional ethical approval was obtained from the maintenance iron therapy in children on hemodialysis: a random-
Auckland District Health Board research review office with a waiver of ized study. Pediatr Nephrol 19:77–81
patient informed consent requirement due to the retrospective nature of 16. Warady BA, Kausz A, Lerner G, Brewer ED, Chadha V, Brugnara
the study. C, Dahl NV, Watkins SL (2004) Iron therapy in the pediatric hemo-
dialysis population. Pediatr Nephrol 19:655–661
Compliance with ethical standards 17. Warady BA, Zobrist RH, Wu J, Finan E (2005) Sodium ferric glu-
conate complex therapy in anemic children on hemodialysis.
Conflict of interest No funding source was required for the preparation Pediatr Nephrol 20:1320–1327
of this work. 18. Locatelli F, Aljama P, Bárány P, Canaud B, Carrera F, Eckardt KU,
The authors have no financial or ethical conflicts of interest as relate to Hörl WH, Macdougal IC, Macleod A, Wiecek A, Cameron S,
this manuscript. European Best Practice Guidelines Working Group (2004)
Revised European best practice guidelines for the management of
anemia in patients with chronic renal failure. Nephrol Dial
Transplant 19(Suppl 2):ii1–ii47
19. Padhi S, Glen J, Pordes BA (2015) Management of anaemia in
chronic kidney disease: summary of updated NICE guidance.
References BMJ; 350:h2258. doi:10.1136/bmj.h2258.
20. Kalantar-Zadeh K, Rodriguez RA, Humphreys MH (2004)
Association between serum ferritin and measures of inflammation,
1. Borzych-Duzalka D, Bilginer Y, Ha S, Bak M, Rees L, Cano F, nutrition and iron in haemodialysis patients. Nephrol Dial
Munarriz RL, Chua A, Pesle S, Emre S, Urzykowska A, Quiroz L, Transplant 19:141–149
Ruscasso JD, White C, Pape L, Ramela V, Printza N, Vogel A, 21. Rambod M, Kovesdy CP, Kalantar-Zadeh K (2008) Combined high
Kuzmanovska D, Simkova E, Muller-Wiefel DE, Snader A, serum ferritin and low iron saturation in hemodialysis patients: The
Warady BA, Schaefer F (2013) Management of anemia in children role of inflammation. Clin J Am Soc Nephrol 3:1691–1701
receiving chronic peritoneal dialysis. J Am Soc Nephrol 24:665– 22. Atkinson MA, Pierce CB, Fadrowski JJ, Benador NM, White CT,
676 Turman MA, Pan CG, Abraham AG, Warady BA, Furth SL (2012)
2. Chavers BM, Roberts TL, Herzog CA, Collins AJ, St Peter WL Association between common iron store markers and hemoglobin in
(2004) Prevalence of anemia in erythropoietin-treated pediatric as children with chronic kidney disease. Pediatr Nephrol 27:2275–2283
compared to adult chronic dialysis patients. Kidney Int 65:266–273 23. Dale JC, Burritt MF, Zinsmeister AR (2002) Diurnal variation of
3. Van Stralen KJ, Krischock L, Schaefer F, Verrina E, Groothoff JW, serum iron, iron-binding capacity, transferrin saturation, and ferritin
Evans J, Heaf J, Ivanov D, Kostic M, Maringhini S, Podracka L, Levels. Am J Clin Pathol 117:802–808
Printza N, Pundziene B, Reusz GS Vondrak K, Jager KJ, Tizard EJ 24. KDOQI, National Kidney Foundation (2006) III Clinical practice
(2012) Prevalence and predictors of the sub-target Hb level in chil- recommendations for anemia in chronic kidney disease in children.
dren on dialysis. Nephrol Dial Transplant 27:3950–3957 Am J Kidney Dis 47:86–108
4. Gerson A, Hwang W, Fiorenza J, Barth K, Kaskel F, Weiss L, 25. Mast AE, Blinder MA, Dietzen DJ (2008) Reticulocyte hemoglobin
Zelikovsky N, Fivush B, Furth S (2004) Anemia and health- content. Am J Hematol 83:307–310
related quality of life in adolescents with chronic kidney disease. 26. Maconi M, Cavalca L, Danise P, Cardarelli F, Brini M (2009)
Am J Kidney Dis 44:1017–1023 Erythrocyte and reticulocyte indices in iron deficiency in chronic
5. Mitsnefes MM, Daniels SR, Schwarts SM, Meyer RM, Khoury P, kidney disease: comparison of two methods. Scand J Clin Lab
Strife CF (2000) Severe left ventricular hypertrophy in pediatric Invest 69:365–370
dialysis: prevalence and predictors. Pediatr Nephrol 14:898–902 27. Miwa N, Akiba T, Kimata N, Hamaguchi Y, Arakawa Y, Tamura T,
6. Warady BA, Ho M (2003) Morbidity and mortality in children with Nitta K, Tsuchiya K (2010) Usefulness of measuring reticulocyte
anemia at initiation of dialysis. Pediatr Nephrol 18:1055–1062 hemoglobin equivalent in the management of haemodialysis pa-
7. KDIGO, National Kidney Foundation (2012) KDIGO clinical prac- tients with iron deficiency. Int J Lab Hematol 32:248–255
tice guideline for anemia in chronic kidney disease. Kidney Int 28. Thomas L, Franck S, Messinger M, Linnsen J, Thomme M,
Suppl 2:1–64 Thomas C (2005) Reticulocyte hemoglobin measurement—com-
8. Ly J, Marticorena R, Donnelly S (2004) Red blood cell survival in parison of two methods in the diagnosis of iron-restricted erythro-
chronic renal failure. Am J Kidney Dis 44:715–719 poiesis. Clin Chem Lab Med 43:1193–1202
29. Buttarello M, Pajola R, Novello E, Rebechini M, Cantaro S, Oliosi
9. Vos FE, Schollum JB, Coulter CV, Doyle TCA, Duffull SB, Walker
F, Naso A, Plebani M (2010) Diagnosis of iron deficiency in pa-
RJ (2011) Red blood cell survival in long-term dialysis patients.
tients undergoing hemodialysis. Am J Clin Pathol 133:949–954
Am J Kidney Dis 58:591–598
30. Eckhardt A, Freiberg MA, de la Fuente J, Douthat W, Capra R
10. Koshy SM, Geary DF (2008) Anemia in children with chronic (2011) Clinical usefulness of the reticulocyte hemoglobin equiva-
kidney disease. Pediatr Nephrol 23:209–219 lent in chronic hemodialysis patients. Rev Fac Cien Med Univ Nac
11. Wish JB (2006) Assessing iron status: beyond serum ferritin and Cordoba 68:51–55
transferrin saturation. Clin J Am Soc Nephrol 1:S4–S8 31. Bakr AF, Sarette G (2006) Measurement of reticulocyte hemoglo-
12. Macdougall IC (1995) Poor response to erythropoietin. BMJ 310: bin content to diagnose iron deficiency in Saudi children. Eur J
1424–1425 Pediatr 165:442–445
13. Sunder-Plassmann G, Hörl WH (1995) Importance of iron supply 32. Ullrich C, Wu A, Armsby C, Rieber S, Wingerter S, Brugnara C,
for erythropoietin therapy. Nephrol Dial Transplant 10:2070–2076 Shapiro D, Bernstein H (2005) Screening healthy infants for iron
14. Hörl WH, Cavill I, Macdougall IC, Schaefer RM, Sunder- deficiency using reticulocyte hemoglobin content. JAMA 294:924–
Plassmann G (1996) How to diagnose and correct iron deficiency 930
826 Pediatr Nephrol (2016) 31:819–826
33. ERA-EDTA Registry Annual Report 2007, Academic Medical 35. Brugnara C, Schiller B, Moran J (2006) Reticulocyte hemoglobin
Center, Department of Medical Informatics, Amsterdam, equivalent (Ret He) and assessment of iron-deficient states. Clin
The Netherlands, 2009. www.era-edta-reg.org/files/annualreports/ Lab Haematol 28:303–308
pdf/AnnRep2007.pdf 36. Chuang CL, Liu RS, Wei YH, Huang TP, Tarng DC (2003) Early
34. Bland MJ, Altman DG (1995) Calculating correlation coefficients prediction of response to intravenous iron supplementation by retic-
with repeated observations: Part 1-correlation within subjects. BMJ ulocyte haemoglobin content and high-fluorescence reticulocyte
310:446–447 count in haemodialysis patients. Nephrol Dial Transplant 18:370–377