research paper

Renal function is independently associated with red cell

distribution width in kidney transplant recipients: a potential
new auxiliary parameter for the clinical evaluation of patients
with chronic kidney disease

Akos Ujszaszi,1,2 Miklos Z. Molnar,1,2,3 Summary

Maria E. Czira,4 Marta Novak4,5 and
Istvan Mucsi1,4,6
1
Institute of Pathophysiology, Semmelweis Uni-
versity, Budapest, Hungary, 2Harold Simmons
Center for Chronic Disease Research & Epidemi-
ology, University of California Irvine Medical
Center, Irvine, CA, USA, 3Division of Nephrol-
ogy, Department of Medicine, University Health
Network, University of Toronto, Toronto, ON,
Canada, 4Institute of Behavioral Sciences, Sem-
melweis University, Budapest, Hungary, 5Depart-
ment of Psychiatry, University Health Network,
University of Toronto, Toronto, ON, and
6
Division of Nephrology, Department of
Medicine, McGill University Health Centre,
Montreal, QC, Canada
Received 3 December 2012; accepted for
publication 26 February 2013
Correspondence: Miklos Z. Molnar, MD, PhD,
Institute of Pathophysiology, Semmelweis
University, Nagyvarad ter 4, Budapest H-1089,
Hungary.
E-mail: molnar@medformol.hu
Red cell distribution width (RDW), a measure of heterogeneity in the size
of circulating erythrocytes, reportedly predicts mortality. Similarly to RDW,
impaired renal function is also associated with inflammation and protein-
energy wasting. This study assessed if renal function is associated with
RDW independent of relevant confounders in stable kidney transplant
recipients. We examined the association between RDW and estimated
glomerular filtration rate (eGFR) in a cohort of 723 prevalent kidney trans-
planted recipients who were not receiving erythropoietin-stimulating
agents. Associations were examined in regression models adjusted for age,
sex, comorbidity, blood haemoglobin, iron indices, markers of nutritional
status and inflammation, markers of bone and mineral metabolism and the
use of immune suppressants. Lower eGFR was significantly associated with
higher RDW (r = 0
382, P < 0
001). This association remained highly
significant even after multivariate adjustments where 10 ml/min decrease in
the eGFR was significantly associated with an increase of the RDW values
(B10 ml/min decrease = 0
078; 95% confidence interval: 0
044–0
111). The
results were consistent in subgroups of patients with different levels of
haemoglobin, chronic kidney disease status and various markers of inflam-
mation and iron status. Lower eGFR is associated with higher RDW, inde-
pendent of comorbidity, iron deficiency, inflammation and nutritional
status in kidney transplant recipients.
Keywords: red cell distribution width, renal function, glomerular filtration
rate, kidney transplantation.

The red blood cell distribution width (RDW) is a quantita-
tive measure of the size variability of circulating erythrocytes.
It is generally reported as part of the standard complete
blood count (CBC) and is available in everyday clinical prac-
tice at no additional cost. Generally, higher RDW values
reflect greater variability in erythrocyte cell size, which may
indicate dysfunctional erythropoiesis or shortened erythro-
cyte lifespan. RDW was previously used as a marker of iron
deficiency anaemia (Karnad & Poskitt, 1985) but had largely
been neglected in clinical practice until it was identified as a
prognostic factor for all-cause mortality in patients with car-
diovascular (CV) disease (Felker et al, 2007). Subsequent
studies have confirmed this finding in community-dwelling
individuals, as well as in general hospital inpatients (Patel
et al, 2009; Perlstein et al, 2009), suggesting a more general-
izable association between elevated RDW and mortality.
Moreover, one study revealed that higher RDW values, even
in the normal reference range, were associated with adverse
outcome in patients with CV disease (Tonelli et al, 2008).
Although a consistent association between RDW, comorbid
conditions and mortality has repeatedly been demonstrated,
the mechanism between RDW and adverse clinical outcomes
is still largely unknown.
Given this consistent association with mortality, several
studies aimed to reveal the underlying mechanisms contrib-
uting to variability of RDW, which is closely associated

ª 2013 John Wiley & Sons Ltd First published online 27 March 2013
British Journal of Haematology, 2013, 161, 715–725 doi:10.1111/bjh.12315
A. Ujszaszi et al
with functional iron availability and bone marrow function
(Evans & Jehle, 1991). Recently the presence of inflamma-
tion (Evans & Jehle, 1991) and malnutrition (Patel et al,
2009, 2010) were also related to higher RDW, independent
of iron or anaemia status. In addition, an observational
study in patients with chronic heart failure suggested that
kidney function is associated with RDW (Lippi et al,
2008). Similarly to RDW, impaired kidney function is
associated with higher prevalence of anaemia (Stevens &
Levin, 2003), elevated inflammatory and nutritional status
(Kopple et al, 2000; Oberg et al, 2004). We suggest that
determining the potential mechanisms linking impaired
renal function to increased RDW may further our under-
standing of the adverse effects of chronic kidney disease
(CKD).
We hypothesized that, similar to patients with CV disease,
higher RDW levels are associated with kidney function in
renal transplant recipients independent of relevant covariates.
We evaluated the association of RDW with estimated kidney
function in a cross-sectional study of stable, registered kidney
transplant recipients.
Patients and methods
Patient population, data collection and statistical
analyses
All registered kidney transplant recipients aged 18 years or
older (n = 1214), who were followed at a single transplant
outpatient clinic at the Department of Transplantation and
Surgery, Semmelweis University Faculty of Medicine, Buda-
pest, Hungary on 31 December 2006, were invited to partici-
pate in a prospective, observational study [Malnutrition-
Inflammation in Transplant - Hungary Study (MINIT-HU
Study)]. Exclusion criteria were: acute rejection within the
last 4 weeks, current hospitalization, transplantation in the
previous 3 months, acute infection or bleeding (Kovesdy
et al, 2010a,b, 2011; Molnar et al, 2010, 2011a,b,c). The
baseline assessment took place during the year of 2007
(Kovesdy et al, 2010a,b, 2011; Molnar et al, 2010, 2011a,b,c).
After 1-year follow-up, all living patients with a functioning
graft from the original cohort were re-evaluated for inclu-
sion/exclusion criteria and were subsequently invited to
continue participating in the study.
Anthropometric measurements (weight, height, abdominal
circumference), details of medical history and socio-
demographic data were collected at baseline, when informa-
tion on age, gender, menopause status, aetiology of CKD,
transplantation-related data including immunosuppressant
medication, erythropoietin-stimulating agent (ESA) use (yes/no),
and co-morbidities (the modified Charlson Comorbidity
Index (CCI)) (Jassal et al, 2005) were obtained. The esti-
mated glomerular filtration rate (eGFR) was calculated using
the CKD Epidemiology Collaboration (CKD-EPI) equation
(Levey et al, 2009).
716
The study was approved by the Ethics Committee of the
Semmelweis University (49/2006). Before enrolment, patients
received detailed written and verbal information regarding
the aims and protocol of the study and gave written consent
to participate.
Laboratory data
All laboratory data was measured during the study visits in a
fasting state and included, among others, RDW, blood hae-
moglobin concentration (Hb), serum C-reactive protein
(CRP) and creatinine, blood urea nitrogen (BUN) and serum
albumin levels. Ferritin level was determined as a marker of
total iron stores. To determine functional iron availability
transferrin levels, soluble transferrin receptor, serum iron and
total iron binding capacity were also measured. RDW was
measured as part of a standard complete blood count mea-
surement. For some of the analyses, patients were allocated
to one of three groups according to their tertile RDW levels
[1 tertile: <13
3% (n = 215); 2 tertile: 13
3–14
0% (n = 258);
3 tertile  14
1% (n = 252)].
Serum samples were also collected at the time of the base-
line assessment and stored at 70°C for future use.
Transplantation-related data and donor characteristics
Transplant-related data was extracted from the medical
records and included current medications (including current
immunosuppressive treatment), transplant history, i.e. time
elapsed since the date of transplantation, length of time on
dialysis, type of allograft, history of treated acute rejection
(s) after transplantation, human leucocyte antigen (HLA)
mismatch, panel reactive antibodies titre (PRA), cold ischae-
mia time, donor age and gender, and history of delayed
graft function. Total time with end-stage renal disease
(ESRD) was defined as the total time on any type of renal
replacement therapy (including any type of dialysis or
kidney transplant).
Immunosuppressive therapy
Standard maintenance immunosuppressive therapy consisted
of prednisolone, with either ciclosporin micro emulsion for-
mulation (CsA, Neoral; Novartis International AG, Basel,
Switzerland) or tacrolimus, combined with mycophenolate-
mofetil (MMF) or azathioprine or mammalian target of
rapamycin use (mTOR, i.e. sirolimus or everolimus).
Statistical analysis
Statistical analyses were carried out using STATA 12.1 (Stata-
Corp, College Station, TX, USA) software. Descriptive data
were summarized using proportions, means (, SD) or
medians (interquartile range) as appropriate and compared
across RDW tertiles using analysis of variance (ANOVA) test
ª 2013 John Wiley & Sons Ltd
British Journal of Haematology, 2013, 161, 715–725

for homogeneity, to evaluate differences across groups, and
test for trend, to evaluate if the linear trend or ordering
increased or decreased across groups. For continuous vari-
ables, Pearson’s or Spearman correlations were used based
on the distribution of the data to report correlation of with
RDW. Linear regression models were used to analyse the
association between RDW and eGFR. Logistic regression
models were used to identify markers associated with ele-
vated RDW (>14
0%). The association between RDW values
and eGFR was evaluated by multivariate-adjusted regression
models. In all statistics, two-sided tests were used and the
results were considered statistically significant if the P-value
was <0
05.
The variables entered in the multivariate-adjusted models
were selected based on theoretical considerations; we
included predictors in the models that were known to be
associated with RDW levels based on external evidence and
clinical experience, and were available in our database. For
analyses, five models were examined depending on the level
of multivariate adjustment:
1 unadjusted model (only eGFR);
2 model 1 plus case-mix: [(age, gender, underlying disease
of ESRD, CCI, ESRD time, tacrolimus and mTOR use,
and use of angiotensin-converting enzyme inhibitor
[ACEi] or angiotensin-receptor blocker [( ARB)]];
3 model 2 plus anaemia and iron markers: (ferritin, soluble
transferrin receptor, haemoglobin, endogenous erythro-
poietin level, iron supplementation);
4 model 3 plus malnutrition and inflammatory markers:
(abdominal circumference white blood cell count, lym-
phocyte %, albumin, C-reactive protein,)
5 model 4 plus bone, mineral metabolism markers: [(Ca, P,
intact parathyroid hormone iPTH)].
Our principal analyses were restricted to patients who
were not receiving ESA therapy. Additionally, as a sensitivity
analysis, the association between RDW and eGFR was analy-
sed in a sample that also included ESA-treated patients
(n = 805).
Subgroup analyses were also performed in relevant
subgroups of patients based on: age, gender, presence of dia-
betes, CKD stage, body mass index (BMI) categories, Hb,
soluble transferrin receptor, serum erythropoietin, serum
albumin, CRP levels, tacrolimus and mTOR use. For these
analyses, we restricted adjustment to eGFR, age, gender, CCI,
total ESRD time, Hb, soluble transferrin receptor, endoge-
nous erythropoietin level, CRP, serum albumin, abdominal
circumference, tacrolimus and mTOR use, in order to com-
ply with the general rule of having at least 10 observations
patients/covariate included in the model.
Variance inflation factors (VIF) were used to assess
collinearity between independent variables. Model selection
was guided by minimization of Akaike Information Criterion
(AIC). Less than1% of our data were missing for all vari-
ables, thus we used a complete-case analysis approach.
ª 2013 John Wiley & Sons Ltd
British Journal of Haematology, 2013, 161, 715–725
RDW and Renal Function
Results
Demographics and baseline characteristics
Patient selection processes are shown in Figure S1. Of the
potential 1214 patients invited to participate, 205 (17%)
refused to participate at the baseline data collection and
16 (1%) patients were excluded based on exclusion criteria,
hence the baseline study sample therefore included 993 patients.
After 1 year of follow-up, an additional 71 (7%) patients
refused to continue participation or were lost to follow-up.
one-hundred and fifteen patients were excluded from the
analysis because they had had an outcome event during the
first year and 82 (10%) were not included in the primary
analyses because they were receiving ESA therapy. Finally,
RDW was missing for two patients, resulting in a cohort of
723 ESA untreated patients for our primary analyses.
Baseline patient characteristics are shown in Table I by
RDW tertile. Patients in the 3rd tertile (highest RDW values)
had the worst kidney function (63
9  19
3 vs. 53
6  18
9
vs. 47
1  18
6 ml/min; P < 0
001), were older (46  14 vs.
52  12 vs. 55  11 years; P < 0
001), had more time
elapsed since ESRD diagnosis (110 (73) vs. 121 (79) vs.
126 (103) months; P = 0
005) and had more comorbid con-
ditions (Table I). Patients with the highest RDW values also
had lower Hb levels (142  14 vs. 140  14 vs. 139  16 g/l;
P = 0
016) and more iron deficiency (Table I). They seemed
to have higher BMI values (26
4  4
6 vs. 27
9  5
0 vs.
27
7  4
7 kg/m2; P = 0
006) and significantly higher
measure of central obesity (abdominal circumference) (96  13
vs. 100  14 vs. 102  13 cm; P < 0
001). Additionally,
patients with highest RDW had worse nutritional and
inflammatory profiles, as indicated by lower serum albumin
(41
5  3
6 vs. 41
2  3
6 vs. 39  3
9 g/l; P<0
001) and
higher CRP levels (2
4 (2
8) vs. 2
8 (3
8) vs. 4
0 (6
2) mg/l;
P < 0
001) (Table I). Furthermore, serum phosphate levels
(1
01  0
19 vs. 1
05  0
21 vs. 1
06  0
22 mmol/l;
P = 0
038) and iPTH levels (68
1 (29
4) vs. 78
6 (54
5) vs.
90
5 (82
0) pg/ml; P < 0
001) were higher in the highest
RDW tertile (Table I). Correlations with RDW values are
shown in Table SI.
Erythropoietin-stimulating agent treated patients, who
were excluded from our principal analyses, were older, the
proportion of females were higher, were more anaemic, had
higher RDW values and worse the kidney function
(Table SII).
Figure 1 shows unadjusted and multivariate-adjusted
associations of CKD stages with predicted RDW level,
indicating a linear and significant association of lower
eGFR categories with higher RDW values. We also per-
formed an additional analysis that included quadratic
terms of eGFR, which was not significant and this further
confirmed the linear association between RDW and eGFR.
Table SIII shows the association of kidney function with
RDW levels in 723 ESA untreated kidney transplant
717
A. Ujszaszi et al

Table I. Baseline characteristics of the study sample.

P-ANOVA
RDW tertile 1 RDW tertile 2 RDW tertile 3 (test for
All patients (<13
3%) (13
3–14
0) (  14
1%) heterogeneity/
(n = 723) (n = 215)) (n = 258) (n = 252) P-for Trend homogeneity)

RDW (%) 13
8  1
0 12
9  0
3 13
6  0
2 14
9  0
9 <0
001 <0
001
eGFR (CKD-EPI) 54
3  20
0 63
9  19
3 53
6  18
9 47
1  18
6 <0
001 <0
001
(ml/min/1
73 m²)
Demographics
Age (years) 51  13 46  14 52  12 55  11 <0
001 <0
001
Gender, female (%) 41 41 48 34 0
089 0
008
History
Presence of anaemia (%) 14 6 12 22 <0
001 <0
001
Presence of hypertension (%) 93 89 93 95 0
008 0
027
Presence of diabetes (%) 21 13 22 26 <0
001 0
013
Presence of coronary 8 4 7 13 <0
001 0
001
heart disease (%)
CCI 2 (1) 2 (1) 2 (1) 2 (2) <0
001 <0
001
Smoking (%) 19 20 19 20 0
958 0
683
Time since last 84 (75) 78 (63) 87 (81) 90 (74) 0
049 0
069
transplant (month)
Previous time on 19 (29) 18 (28) 20 (30) 22 (29) 0
074 0
092
dialysis (month)
Total ESRD time (month) 119 (87) 110 (73) 121 (79) 126 (103) 0
005 0
003
Primary cause of ESRD (%) 0
490 0
919
Chronic GN 24 26 23 23
Chronic TIN 13 15 13 11
PKD 17 13 18 21
Diabetic nephropathy 5 3 5 6
Hypertensive nephropathy 6 6 8 5
Others or unknown 35 37 33 34
Haematological parameters
White blood cell count (109/l) 7
9  2
3 7
5  2
0 7
7  2
1 8
5  2
6 <0
001 <0
001
Hb (g/l) 140  15 142  14 140  14 139  16 0
016 0
038
MCV (fl) 87  5 87  4 87  5 87  7 0
077 0
304
Erythropoietic and iron markers
Ferritin (ng/ml) 120 (195) 131 (246) 120 (203) 117 (175) 0
005 0
004
Transferrin (g/l) 2
37  0
44 2
35  0
42 2
37  0
41 2
38  0
48 0
404 0
731
Sol. transferrin 3
42  1
41 2
83  0
90 3
28  1
19 4
04  1
68 <0
001 <0
001
receptor (mg/l)
Serum iron (lmol/l) 17
4  9
2 19
7  10
2 18
3  9
6 14
6  6
8 <0
001 <0
001
Total iron binding 51
8  12
2 50
7  12
5 51
4  12
0 53
1  12
1 0
047 0
091
capacity (lmol/l)
Erythropoietin level (l/l) 10
3 (7
1) 9
4 (5
2) 10
0 (6
3) 12
0 (10
3) <0
001 <0
001
Iron or folic acid 23 25 21 22 0
450 0
619
supplementation (%)
Use of ACE inhibitor 31 25 33 34 0
047 0
085
or ARB (%)
Nutritional and inflammatory markers
BMI (kg/m²) 27
4  4
8 26
4  4
6 27
9  5
0 27
7  4
7 0
006 0
002
Abdominal circumference (cm) 99  14 96  13 100  14 102  13 <0
001 <0
001
Serum albumin (g/l) 40
9  3
7 41
5  3
6 41
2  3
6 39  3
9 <0
001 <0
001
Total protein (g/l) 72
3  5
3 73
2  4
7 72
7  5
2 71
1  5
8 <0
001 <0
001
Total cholesterol (mmol/l) 5
1  1
1 4
9  1
0 5
2  1
1 5
1  1
0 0
065 0
013
Triglyceride(mmol/l) 1
7 (1
4) 1
5 (1
2) 1
7 (1
4) 1
8 (1
4) 0
001 0
003
CRP (mg/l) 2
9 (4
2) 2
4 (2
8) 2
8 (3
8) 4
0 (6
2) <0
001 <0
001
Markers of bone and mineral metabolism

718 ª 2013 John Wiley & Sons Ltd

British Journal of Haematology, 2013, 161, 715–725
 RDW and Renal Function

Table I. (Continued)

P-ANOVA
RDW tertile 1 RDW tertile 2 RDW tertile 3 (test for
All patients (<13
3%) (13
3–14
0) (  14
1%) heterogeneity/
(n = 723) (n = 215)) (n = 258) (n = 252) P-for Trend homogeneity)

Phosphate (mmol/l) 1
04  0
21 1
01  0
19 1
05  0
21 1
06  0
22 0
038 0
047
Calcium (mmol/l) 2
35  0
14 2
36  0
14 2
36  0
14 2
36  0
14 0
071 0
060
Parathyroid hormone (pg/ml) 77
8 (59
8) 68
1 (29
4) 78
6 (54
5) 90
5 (82
0) <0
001 <0
001
Transplantation related data
Cold ischaemic time (minute) 1235  356 1201  378 1235  362 1262  329 0
135 0
185
History of delayed 25 24 24 26 0
529 0
775
graft function (%)
History of acute rejection (%) 32 26 35 33 0
156 0
145
HLA mismatches (%) 0
812 0
945
0 1 2 1 1
1 6 6 6 4
2 22 22 21 21
3 45 39 46 50
4 21 25 20 20
5 4 3 5 3
6 1 3 1 1
Immunsuppression
Steroid use (%) 79 70 79 85 <0
001 <0
001
Ciclosporin use (%) 43 41 49 39 0
522 0
062
Tacrolimus use (%) 47 54 43 44 0
038 0
029
Azathioprine use (%) 3 1 4 3 0
408 0
268
MMF use (%) 82 87 87 73 <0
001 <0
001
mTOR use (%) 9 3 6 16 <0
001 <0
001

RDW, red blood cell distribution width; ESRD, end stage renal disease; eGFR, estimated GFR; CKD-EPI, Chronic Kidney Disease – Epidemiology
Collaboration; CCI, Charlson Comorbidity Index; Hb, haemoglobin; CRP, C-reactive protein; ACE, angiotensin-converting enzyme; ARB, angio-
tensin-receptor blocker; GN, glomerulonephritis; TIN, tubulo-interstitialis nephritis; PKD, polycystic kidney disease; HLA, human leucocyte
antigen; MMF, mycophenolat mofetil; mammalian target of rapamycin (mTOR, i.e. sirolimus or everolimus) use.
Values are in median with interquartile range or in mean  SD.

recipients. In unadjusted linear regression analyses a 10 ml/ Subgroup analysis

min decrease in the eGFR was significantly associated with
Figure 3 shows adjusted regression coefficients of eGFR asso-
an increase of RDW values (B10 ml/min decrease = 0
151; 95%
ciated with a 1% higher RDW level in various patient
confidence interval [CI]: 0
116–0
186). This association
subgroups. The association with estimated kidney function
remained significant after adjusting for age, gender, cause
was similar in almost all examined subgroups. However,
and duration of ESRD, comorbidities and immunosuppres-
ESA-treated patients showed interaction (Pinteraction = 0
013)
sive medications (B10 ml/min decrease = 0
123; 95% CI: 0
088–
with RDW. All other tests of interactions were not statisti-
0
157), as well as iron markers (B10 ml/min decrease = 0
087;
cally significant, indicating no effect modification by the
95% CI: 0
054–0
120). The association remained significant
examined characteristics (age, gender, presence of diabetes,
after additional adjustment for nutritional and inflamma-
BMI categories, CKD stage, Hb level, soluble transferrin level,
tory markers (B10 ml/min decrease = 0
087; 95% CI: 0
055–
endogenous erythropoietin level, CRP level, albumin level,
0
119). Moreover, additional adjustment for indicators of
mTOR and tacrolimus use).
bone and mineral metabolism in the final model did not
weaken this association (B10 ml/min decrease = 0
078; 95% CI:
0
044–0
111). The association of RDW showed an inverse,
Predictors of elevated RDW values
graded association with eGFR when it was modelled using
linear regression in both unadjusted (Fig 2) and fully To identify potential risk factors of elevated RDW, we
adjusted models. We found qualitatively similar linear performed logistic regression analyses on relevant markers
association between eGFR and RDW when the 82 patients modelling risk of elevated RDW values (i.e., RDW >14%,
who received ESA treatment were included in the sensitiv- reference is  14%). In the fully adjusted models, the risk
ity analyses (Figure S2). of elevated RDW was associated with each 10 ml/min

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British Journal of Haematology, 2013, 161, 715–725
A. Ujszaszi et al
Fig 1. Predicted red blood cell distribution width (RDW) values
(and 95% confidence intervals) using unadjusted and multivariate-
adjusted regression model in patients divided according to chronic
kidney disease stage. Multivariate models were adjusted for estimated
Glomerular Filtration Rate (eGFR), age, gender, underlying disease
of end-stage renal disease (ESRD), Charlson Comorbidity Index,
ESRD duration, tacrolimus and mammalian target of rapamycin use,
angiotensin converting enzyme inhibitor or angiotensin receptor
blocker use, ferritin, soluble transferrin receptor, haemoglobin, iron
supplementation, albumin, abdominal circumference, white blood
cell count, C-reactive protein, calcium, phosphate, intact parathyroid
hormone.
Fig 2. Unadjusted association between eGFR and RDW in 723
ESA-untreated kidney transplant recipients with additional distribu-
tional histogram of the eGFR. eGFR, estimated Glomerular Filtration
Rate; RDW, red blood cell distribution width.
decrease of eGFR (Odds Ratio [OR]10 ml/min decrease: 1
267;
95% CI: 1
121–1
431; P < 0
001). Patients with CKD stage
3 had an almost two times higher odds of having elevated
RDW values (OReGFR 30–60 ml/min: 1
995; 95% CI: 1
271–
3
131; P = 0
002), when compared with patients who had
eGFR levels higher than 60 ml/min. Moreover, patients with
CKD stage 4 or 5 had an even higher risk of having elevated
RDW values (OReGFR <30 ml/min: 3
334; 95% CI: 1
557–7
138;
P < 0
001). In addition, older age, male gender, longer ESRD
history, use of mTOR, lower serum albumin and higher
720
inflammatory markers, as surrogates of protein-energy wast-
ing/inflammation, were all predictors of elevated RDW levels
(Table II).
Discussion
In this cross-sectional study of 723 registered ESA untreated
kidney transplant recipients we found a strong, consistent
and independent association between RDW and estimated
kidney function. We demonstrated that each 10 ml/min
decrease of eGFR was associated with a 0
1% increase of the
RDW. Moreover, each 10 ml/min decrease of eGFR was
associated with a 27% increase in the odds of having an
elevated RDW value (>14%), independent of known con-
founders. In addition, patients with CKD stage 3 had two
times higher, and patients with CKD stage 4 or 5 had more
than three times higher odds of having an elevated RDW
value even after adjustment for potential confounders. These
associations were not specific to any particular subgroup in
the study sample. Hence, we believe that our study in kidney
transplant recipients corroborates previous findings where
renal function was associated with the elevation in RDW
values Lippi et al, 2008; (Afonso et al, 2011. To the best of
our knowledge this study is the first to show this association
in renal transplant recipients.
Preliminary alterations in RDW values had been demon-
strated in CKD patients Docci et al (1989), who found that
maintenance haemodialysis patients had higher RDW values
than normal individuals. Recent data advocate that kidney
function is closely associated with RDW. More recently,
Lippi et al (2008) reported an inverse, graded association
between renal function and RDW in a large sample of
unselected outpatients. Furthermore, a subsequent study
showed that higher RDW values were associated not only
with renal function, but also with the presence of micro-
albuminuria, an early indicator of kidney injury (Afonso
et al, 2011). It is important to note that the association
remained significant after adjustment for kidney function
and markers related to higher inflammatory, worse nutri-
tional or iron status in a large unselected patient popula-
tion. In addition, a recent study among critically ill
patients with acute kidney injury showed an additional pre-
dictive ability of RDW levels for mortality (Oh et al, 2012).
Similar to patients with acute kidney injury, we also
observed a strong association between elevated RDW values
and adverse outcomes in our study population, validating
the association of RDW with mortality in kidney transplant
recipients (Mucsi et al, 2012).
Although there is an inverse, graded correlation between
RDW and eGFR, we have to consider the fact that comor-
bid conditions related to an increased RDW are also asso-
ciated with impaired kidney function. Impaired renal
function, similarly to elevated RDW, is associated with
increased CV risk, higher prevalence of anaemia in patients
with CKD, malnutrition and inflammation, presence of
ª 2013 John Wiley & Sons Ltd
British Journal of Haematology, 2013, 161, 715–725
 RDW and Renal Function

Fig 3. Forest plot of regression coefficients (beta) [95% confidence intervals] of the association of eGFR (10 ml/min decrease) and red cell distri-
bution width using a multivariate-adjusted linear regression model in 723 ESA-untreated kidney transplant recipient in various subgroups of
patients. Models were adjusted for age, gender, Charlson Comorbidity Index, total end-stage renal disease duration, haemoglobin level, STFR,
endogenous erythropoietin level, CRP, serum albumin, abdominal circumference, tacrolimus and mTOR use. ESA, erythropoiesis-stimulating
agent; eGFR, estimated Glomerular Filtration Rate; BMI, body mass index; EPO, erythropoietin; STFR, soluble transferrin receptor; CRP,
C-reactive protein; mTOR, mammalian target of rapamycin.

hypertension, and disturbances of bone and mineral metab-
olism and adverse outcome in non-transplant populations
(Buckalew et al, 1996; Kopple et al, 2000; Sarnak et al,
2003; Stevens & Levin, 2003; Oberg et al, 2004). It is
known that impaired renal function is associated with
higher inflammatory state and elevated cytokine levels
(Oberg et al, 2004). Inflammation is associated with
dysfunctional erythropoiesis not only via iron metabolism,
but also through direct impact on bone marrow function
of cytokines (Chiari et al, 1995; Pierce & Larson, 2005).
Moreover, inflammatory cytokines and malnutrition are
known to be associated with erythropoietin responsiveness

ª 2013 John Wiley & Sons Ltd 721

British Journal of Haematology, 2013, 161, 715–725
A. Ujszaszi et al

Table II. Multivariate-adjusted logistic regression of RDW >14% in Table II. (Continued)
723 ESA-untreated kidney transplant recipients. (A). The results of
eGFR as a continuous variable. (B). The results of eGFR as a categor- 95%
ical variable, according to CKD stages. confidence
interval
95%
confidence Variables Odds Ratio Lower Upper P value
interval
Use of Iron supplement 1
038 0
634 1
701 0
881
Variables Odds Ratio Lower Upper P value medication
Haemoglobin level 0
980 0
964 0
996 0
018
A (1 g/l increase)
eGFR (10 ml/min 1
267 1
121 1
431 <0
001 log[Ferritin level] 0
782 0
643 0
951 0
014
decrease) (1 increase)
Covariates Sol. Transferrin receptor 1
521 1
287 1
797 <0
001
Age (1 year increase) 1
030 1
011 1
049 0
002 (1 mg/l increase)
Gender (female) 0
277 0
170 0
450 <0
001 log[endogenous EPO 1
709 1
090 2
678 0
019
CCI (1 increase) 1
117 0
996 1
253 0
058 level] (1 increase)
Total ESRD time 1
005 1
001 1
008 0
004 Abdominal circumference 0
992 0
976 1
009 0
360
(1 month increase) (1 cm increase)
Use of tacrolimus 1
361 0
897 2
066 0
147 Serum Albumin level 0
939 0
882 0
999 0
048
Use of mTOR 3
646 1
811 7
340 <0
001 (1 g/l increase)
Use of ACEi or ARB 0
986 0
649 1
496 0
946 WBC (1 x 106/l increase) 1
229 1
115 1
354 <0
001
Use of Iron supplement 0
987 0
602 1
619 0
960 Lymphocyte% (1% 0
999 0
972 1
027 0
942
medication increase)
Haemoglobin level 0
981 0
965 0
998 0
025 log[CRP] level (1 1
380 1
119 1
702 0
003
(1 g/l increase) increase)
log[Ferritin level] 0
779 0
640 0
948 0
013 Ca (1 mmol/l increase) 0
930 0
199 4
352 0
927
(1 increase) P (1 mmol/l increase) 1
505 0
539 4
205 0
436
Sol. Transferrin receptor 1
498 1
269 1
768 <0
001 log[iPTH] (1 increase) 1
282 0
934 1
759 0
124
(1 mg/l increase)
log[endogenous EPO 1
731 1
106 2
709 0
016 eGFR, estimated Glomerular Filtration Rate; ESRD, end stage renal
level] (1 increase) disease; mTOR, mammalian target of rapamycin; ACEi, angiotensin
Abdominal circumference 0
993 0
977 1
010 0
430 converting enzyme inhibitor; ARB, angiotensin receptor blocker;
(1 cm increase) EPO, erythropoietin, WBC, white blood cell count;; Ca, calcium;
Serum Albumin level 0
938 0
882 0
998 0
044 P, phosphate; iPTH, intact parathyroid hormone.
(1 g/l increase)
WBC (1 9 106/l 1
232 1
118 1
357 <0
001 in maintenance haemodialysis patients (Goicoechea et al,
increase) 1998) and pre-dialysis patients (De Lurdes Agostinho
Lymphocyte% (1% 1
002 0
975 1
029 0
908 Cabrita et al, 2011). Prior studies have confirmed in patients
increase) with CV disease that RDW is independently associated
log[CRP] level (1 1
364 1
106 1
682 0
004 with inflammation (Lappe et al, 2011) and an early
increase) increase in RDW is detectable, even before the Hb falls to
Ca (1 mmol/l increase) 0
932 0
199 4
371 0
929 anaemic levels (Pascual-Figal et al, 2011). The above find-
P (1 mmol/l increase) 1
408 0
509 3
895 0
509
ings may suggest a possible link between renal function
log[iPTH] (1 increase) 1
200 0
868 1
660 0
269
and RDW through the direct and indirect effect of
B
eGFR (<30 ml/min) 3
334 1
557 7
138 0
002
impaired kidney function to erythropoiesis. It is important
eGFR (30–60 ml/min) 1
995 1
271 3
131 0
003 to emphasize that the above-mentioned co-morbidities,
eGFR (>60 ml/min, 1
000 1
000 1
000 1
000 malnutrition, and higher inflammatory state are prevalent
reference) in kidney transplant recipients(Molnar et al, 2011b). It
Covariates should also be noted that side effects of frequently utilized
Age (1 year increase) 1
032 1
013 1
051 <0
001 medications, such as renin-angiotensin blockade (Vanren-
Gender (female) 0
264 0
162 0
431 <0
001 terghem et al, 2003) or certain immunosuppressant medi-
CCI (1 increase) 1
114 0
995 1
249 0
062 cations, are associated with suboptimal bone marrow
Total ESRD time 1
005 1
001 1
008 0
005 function in renal transplant recipients, which may lead to
(1 month increase)
higher RDW (Afzali et al, 2006). While there is a complex
Use of tacrolimus 1
327 0
875 2
013 0
184
association between co-morbid conditions, impaired renal
Use of mTOR 3
601 1
808 7
173 <0
001
Use of ACEi or ARB 0
962 0
634 1
461 0
856
function and RDW, it is possible that the inverse relation-
ship between RDW and kidney function in these patients

722 ª 2013 John Wiley & Sons Ltd

British Journal of Haematology, 2013, 161, 715–725

reflect the complex relationship of the above-mentioned
co-morbid conditions. Although we have extensively
adjusted for several markers related to the presence of
potential co-morbid conditions, iron deficiency and anae-
mia, inflammation and malnutrition, indicators of bone
and mineral metabolism, as well as for medications, the
effect of residual confounding related to these conditions
cannot be excluded. Of note is the fact, however, that
adjusting for these comorbid conditions in our analysis did
not abrogate the association between RDW and renal func-
tion. The complex pathophysiological pathways linking
elevated RDW levels to impaired kidney function are still
not known and merit further investigation.
According to Bion(2000), RDW may reflect the amount of
the patient’s physiological reserve. Generally, the physiologi-
cal reserve represents a cellular response to stress. To main-
tain stable homeostasis, the bone marrow buffers the effect
of stress by producing and releasing mature red cells. When
the physiological reserve is reduced or already exhausted,
anisocytotic, immature red cells appear in the circulation,
which results in an elevated RDW and indicates decreased
response to stress. However, this reserve theory was evaluated
in acute illnesses; patients with a chronic disease, such as
CKD, might also have disparities in physiological reserve.
This explanation may elucidate our findings as to why
patients with elevated RDW had only marginal differences,
mostly within normal range either in markers of iron status
or nutritional and inflammatory parameters. It is possible
that, in patients with CKD, even small changes in the
patients’ health status may lead to an early increase in RDW
values and adverse outcomes.
Why might the close association between RDW and
eGFR be clinically useful? Decisions about timing of dialysis
initiation in ESRD patients and re-initiation in kidney
transplant patients are still controversial. Guidelines for tim-
ing of dialysis initiation are based mainly on eGFR, in the
range of 6–15 ml/min but, surprisingly, observational stud-
ies and also a recently published randomized, controlled
trial (Cooper et al, 2010) failed to justify the “early start”
hypothesis. Based on the previously mentioned physiological
reserve theory, we propose that RDW might be a useful
additional parameter in the classification of patients to early
or late dialysis initiation. This hypothesis could only be
tested in future studies.
Our study is remarkable for its large sample size and low
number of missing data. However, as any observational
study with a cross-sectional design, our study has certain
limitations. A study such as ours cannot prove causal associ-
ation between RDW values and eGFR. Because the patients
were followed in a single centre, our results may not be
readily generalizable to other populations. Despite large
numbers of potential predictors that might affect RDW
values and eGFR levels, we cannot exclude the possibility of
residual confounding. Single measurement of RDW levels
could have reflected acute changes in RDW despite the fact
ª 2013 John Wiley & Sons Ltd
British Journal of Haematology, 2013, 161, 715–725
RDW and Renal Function
that we excluded all patients with recent bleeding or hospi-
talization; we did not measure changes in RDW levels, thus
we could not adjust for the possible changes over time. In
addition, the accuracy of GFR estimation based on creatinine
is limited and can be affected by dietary intake, muscle mass
or even after exercise. In agreement with recent findings
(Lippi et al, 2008; Afonso et al, 2011), we believe that
elevated RDW is associated with renal function. Future stud-
ies investigating the association of higher RDW levels with
mortality, particularly CV mortality, might lead to new
knowledge regarding the high prevalence of CV death in
kidney transplant recipients.
Conclusions
In summary, we demonstrated that impaired kidney function
is a significant predictor of elevated RDW in kidney trans-
plant recipients. Further studies to determine the potential
mechanisms linking impaired renal function to increased
RDW may yield new knowledge about the mechanisms link-
ing CKD to adverse outcomes.
Acknowledgements
The authors thank the patients and the staff in the Depart-
ment of Transplantation and Surgery, Semmelweis University
Budapest.
Author contributions
Akos Ujszaszi contributed to analysing and interpretation of
data and writing the manuscript. Miklos Z Molnar designed,
organized and coordinated the study, organized and super-
vised data management, contributed to data analysis and
interpretation of data and wrote the manuscript. Maria E.
Czira contributed to organizing and supervising data collec-
tion and entry, analysis and interpretation of data. Marta
Novak contributed designing and organizing the study, to
the analysis and interpretation of data. Istvan Mucsi
designed, organized the study, contributed to the analysis
and interpretation of data and writing the manuscript.
Funding source
This study was supported by grants from the Hungarian
Kidney Foundation, Hungarian Society of Hypertension,
Hungarian Society of Nephrology and the Foundation for
Prevention in Medicine. MZ. Molnar is recipient of the
Hungarian E€ otv€ €
os Scholarship (MOB/77-2/2012). A. Ujszaszi
is recipient of the Hungarian E€ otv€ €
os Scholarship (MOB/77-
3/2012).
Conflict of interest
None.
723
A. Ujszaszi et al

Table SI. Correlation table of RDW in 723 ESA-untreated

Supporting Information
kidney transplant recipients.
Additional Supporting Information may be found in the Table SII. Comparison of ESA treated and untreated kid-
online version of this article: ney transplant recipients.
Fig S1. Flow chart of patients’ selection. Table SIII. Associations of RDW and 10 ml/min decrease
Fig S2. Unadjusted association of eGFR with RDW in all in eGFR of 725 ESA-untreated kidney transplant recipients
(805) kidney transplant recipients. estimated with multilevel adjusted linear regression.

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