Dmitrieva et al.

BMC Nephrology 2013, 14:24

http://www.biomedcentral.com/1471-2369/14/24

RESEARCH ARTICLE Open Access

Association of anaemia in primary care patients

with chronic kidney disease: cross sectional study
of quality improvement in chronic kidney disease
(QICKD) trial data
Olga Dmitrieva1, Simon de Lusignan1*, Iain C Macdougall2, Hugh Gallagher3, Charles Tomson4, Kevin Harris5,
Terry Desombre1 and David Goldsmith6

Abstract
Background: Anaemia is a known risk factor for cardiovascular disease and treating anaemia in chronic kidney
disease (CKD) may improve outcomes. However, little is known about the scope to improve primary care
management of anaemia in CKD.
Methods: An observational study (N = 1,099,292) with a nationally representative sample using anonymised routine
primary care data from 127 Quality Improvement in CKD trial practices (ISRCTN5631023731). We explored variables
associated with anaemia in CKD: eGFR, haemoglobin (Hb), mean corpuscular volume (MCV), iron status,
cardiovascular comorbidities, and use of therapy which associated with gastrointestinal bleeding, oral iron and
deprivation score. We developed a linear regression model to identify variables amenable to improved primary care
management.
Results: The prevalence of Stage 35 CKD was 6.76%. Hb was lower in CKD (13.2 g/dl) than without (13.7 g/dl).
22.2% of people with CKD had World Health Organization defined anaemia; 8.6% had Hb 11 g/dl; 3% Hb 10 g/
dl; and 1% Hb 9 g/dl. Normocytic anaemia was present in 80.5% with Hb 11; 72.7% with Hb 10 g/dl; and
67.6% with Hb 9 g/dl; microcytic anaemia in 13.4% with Hb 11 g/dl; 20.8% with Hb 10 g/dl; and 24.9% where
Hb 9 g/dl. 82.7% of people with microcytic and 58.8% with normocytic anaemia (Hb 11 g/dl) had a low ferritin
(<100ug/mL). Hypertension (67.2% vs. 54%) and diabetes (30.7% vs. 15.4%) were more prevalent in CKD and
anaemia; 61% had been prescribed aspirin; 73% non-steroidal anti-inflammatory drugs (NSAIDs); 14.1% warfarin
12.4% clopidogrel; and 53.1% aspirin and NSAID. 56.3% of people with CKD and anaemia had been prescribed oral
iron. The main limitations of the study are that routine data are inevitably incomplete and definitions of anaemia
have not been standardised.
Conclusions: Medication review is needed in people with CKD and anaemia prior to considering erythropoietin or
parenteral iron. Iron stores may be depleted in over >60% of people with normocytic anaemia. Prescribing oral iron
has not corrected anaemia.
Keywords: Aspirin, Chronic, Anaemia, Data collection, Erythropoietin, Family practice, Iron-deficiency, Medical
records systems, Computerized, Renal insufficiency chronic

* Correspondence: s.lusignan@surrey.ac.uk
1
Department of Health Care Management and Policy, University of Surrey,
Guildford, Surrey GU2 7XH, UK
Full list of author information is available at the end of the article

2013 Dmitrieva et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
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reproduction in any medium, provided the original work is properly cited.
Dmitrieva et al. BMC Nephrology 2013, 14:24 Page 2 of 9
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Background with cardiovascular diseases, and assess whether practi-

Anaemia is an independent risk marker for cardiovascular tioners had attempted to treat the patients with oral iron.
morbidity and mortality and it is a common complication
in patients with chronic kidney disease (CKD) [1-3]. CKD Methods
is divided into stages 1 to 5, with stage 3 sub-divided into We used data from the Quality Improvement in Chronic
two sub-stages, 3A and 3B. Haemoglobin (Hb) levels de- Kidney Disease (QICKD - ISRCTN5631023731) trial
cline as renal function deteriorates [4]. The prevalence of [32,33]. The QICKD trial was conducted in 127 practices
anaemia (Hb less than 12 g/dl in men and 11 g/dl in drawn from localities across England and contains
women) is 1% in people with stage 3 CKD; 9% in stage 4; extracts from the records of all registered patients within
and 33% in stage 5 CKD [5]. Anaemia affects over two- these practices, a total of 1,099,296 people. The popula-
thirds (68%) of people starting dialysis [6]; and 49.6% of tion profile approximates to the national average in the
men and 51.2% of women in stage 4 and 5 CKD not re- 2001 Census with a small excess of working age people
ferred to renal specialists are anaemic [7]. Anaemia in and slightly fewer older people aged 60 to 75 years
patients with CKD and end stage renal disease (ESRD) has (Additional file 1: Figure S1). The QICKD trial practices
been associated with fatigue and reduced exercise capacity; are usual general practices with routine data expected to
poorer quality of life, higher incidences of myocardial infarc- be similar to those found in other practices. These data
tion, congestive heart failure, and increased left ventricular were collected at the trial mid-point between December
mass index (LVMI) [8-12]. Diabetes mellitus is also asso- 2009 and July 2010 using well established methods
ciated with a doubling of the prevalence of anaemia in CKD [34,35]. Our dataset included demographic details: age,
[13]; there are also concerns that angiotensin converting gender, ethnicity and deprivation score. The latter used
enzyme inhibitors (ACE-I) are associated with anaemia [14]. the index of multiple deprivation (IMD) [36]. Deprivation
Patients with CKD have a high cardiovascular risk and is a concept that overlaps with, but is not synonymous
effective anaemia management may improve outcomes with poverty. IMD is calculated across the UK based on
[15-17]. Partial correction of anaemia in CKD patients seven constituent parts to allow comparisons between
has been associated with reduced LVMI and left ven- areas. The seven domains of deprivation are: (1) income,
tricular hypertrophy [18,19], improved cardiovascular (2) employment, (3) health deprivation and disability, (4)
outcomes [20], lower rate of transfusions [21], improved education skills and training, (5) barriers to housing and
quality of life [9], and, delayed renal failure progression services, (6) crime and (7) the living environment. IMD is
in predialysis nondiabetic patients [22] and improved divided into deciles of equal sizes, where the first decile
renal function in patients with severe heart failure [23]. (IMD 5.63) is the least deprived and decile ten (IMD
In the UK the National Institute for Health and Clinical 45.33) the most deprived.
Excellence (NICE) recommends evaluation of possible We defined cases of stages 3 to 5 CKD by the estimated
causes of anaemia where Hb 11 g/dl and treatment glomerular filtration rate (eGFR), taking into account the
with intravenous iron and erthyropoiesis-stimulating requirement of three month period of chronicity for for-
agents (ESA) to maintain Hb in the range 10-12 g/dl mal diagnosis. Wherever available we used laboratory cal-
[24,25]. Anaemia treatment with ESA has been shown to culated eGFR because it is subject to a national calibration
improve clinical outcomes in non-CKD patients with scheme [37]. We describe people with eGFR 90 ml/min/
CVD [23,26,27]. However, in CKD ESA use has failed to 1.73 m2 as having a normal eGFR, those with eGFR
show a positive effects on CVD mortality and is instead 60 ml/min/1.73 m2 and <90 ml/min/1.73 m2 as having
associated with some negative clinical outcomes espe- mildly impaired renal function. We subdivide those with
cially where Hb is corrected to over 12 g/dl [3,28-30]. an eGFR <60 ml/min/1.73 m2 into stages 3A, 3B, 4 and 5
The U.S. Food and Drug Administration (FDA) recom- using conventional eGFR ranges [38]. Where we use the
mends to consider starting ESA treatment only when term CKD alone we mean stage 3 to 5 CKD. We did not
the Hb level is less than 10 g/dl for non-dialysis people include diagnostic codes for CKD as these under-report
with the CKD and anaemia [31]. the prevalence of CKD [39].
Despite advances in the use of ESA for CKD patients, We extracted a dataset that included Hb, mean cor-
there is low uptake of this therapy [16]. Although it is puscular volume (MCV) and common potential causes
suggested up to 10% of patients in Primary Care in UK of anaemia so that we could differentiate between renal
have CKD [15] and up to 6% of CKD patients have an- and other causes of anaemia. We defined anaemia as
aemia [17] little is known about the aetiology, iron store Hb 11 g/dl in line with NICE guidance [24].
status, and the extent to which family physicians may We report the prevalence of Hb measurement among
have tried to treat anaemia in practice. people with CKD and compare their Hb with those in
We carried out this cross-sectional study to report the people without CKD. We also explored what proportion
prevalence of anaemia in CKD, examine its association of people had a recent measure of Hb, which we define
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as a recording within the last two years. We classify an- outcome variable for either one unit of change, or the
aemia into micro-, normo- and macrocytic based on the presence or absence of the predictor variable. E.g. eGFR
MCV. Microcytic anaemia is defined as an MCV of has a B of 0.003, this means that for every 10 ml/min
<80 fl, normocytic as 100-80 fl, and macrocytic as rise in eGFR Hb rises by 0.03 g/dl; B Stage 3 to 5 CKD
>100 fl [40]. We also extracted ferritin values, as marker is 0.482, implying that people with stage 3 to 5 CKD
of iron stores. In CKD stage 34, iron deficiency was have an Hb 0.5 g/dl lower than those who do not. We
defined as ferritin <100ug/ml [41,42] as patients with did not include age, gender or ethnicity in our model as
depleted iron stores benefit from intravenous iron even they are already included in the equation used to esti-
where their MCV is normal; [43] though we also report mate renal function [48]. We did however include the
ferritin < 15 ug/ml as this has been proposed as a lower use of ACE-I, ACE-I and hypertension, and hypertension
limit of normal [44,45]. alone in our model to explore any influence from a
To explore the association between age and anaemia patients therapy. We then grouped our best predictive
the prevalence of anaemia by eGFR category and age variables into a single model for which we additionally
band we report the change using previously described quote R2, the correlation coefficient which gives an ef-
groupings [46]. fect size (i.e. to what extent the change seen can be
We explored any association between CVD, CKD and ascribed to the variables in the model; an R2 of 0.11 im-
anaemia. We included in our definition of cardiovascular plies that it contributes 11% of the change).
disease (CVD) diagnoses of heart failure (HF), ischaemic Ethical approval for the trial was given by the Oxford
heart disease (IHD), stroke, transient ischaemic attack Research Ethics committee and is included in our clin-
and cerebrovascular disease (CEVD), peripheral vascular ical trial registration details (ISRCTN56023731) [49].
disease (PVD), and hypertension (HT); and diabetes
mellitus.
Results
We investigated whether anaemic patients had been
Prevalence of CKD in the study population
prescribed aspirin and non-steroidal anti-inflammatory
The prevalence of CKD in the general population is
drugs (NSAIDs), clopidogrel or warfarin. These are med-
5.3% (n = 58,592); 6.76% (50,319) in people aged over
ications which are all associated with an increased risk
18 years. As renal function declines from normal to
of gastrointestinal bleeding.
stage 3B CKD the mean age of the people gets older
Finally we looked at oral iron prescriptions in order to
with each declining stage of CKD; those with stage 4
see if iron was being prescribed to correct anaemia and
and 5 CKD are slightly younger (See Additional file 2:
to assess whether its use was associated with correction
Figure S2), possibly due to survival bias.
of anaemia. As intravenous iron and ESA therapy is
largely provided via specialist renal units, information
about parenteral iron is not contained within the family Prevalence of micro- , normo-, and macrocytic anaemia in
practice computerised medical record. CKD patients
The data used in the study were extracted from pri- We found that 94% of people with CKD have had an Hb
mary care computer systems and processed using our measurement at some time, with 70% measured within
established method [34,47]. We analysed these data the last 2 years. The mean Hb value for patients without
using SPSS (Statistical Package for Social Sciences, Ver- CKD was 13.71 g/dl (median 13.7 g/dl, SD 1.6), com-
sion 18). We used simple descriptive statistics to report pared to 13.22 g/dl (median 13.3 g/dl, SD 1.6) in patients
our findings; we used Pearson chi square to test whether with CKD. Furthermore, prevalence of anaemia was
proportions were significantly different reporting the increased in the higher CKD stages (Table 1). The over-
probability and commenting if not significant (n.s.). We all prevalence of anaemia (Hb 11 g/dl) in people with
report differences in Hb between different subgroups CKD Stage 35 is 8.6% (n = 4,690). 3.0% (n = 1,648) have
using independent samples T-tests, reporting the mean Hb 10 g/dl and 1% (n = 563) Hb 9 g/dl. 22.2% of
difference and probability (p). We constructed a linear people with CKD had anaemia as defined by the World
regression model to test the extent to which the vari- Health Organization (WHO) (Hb <12 g/dl in women
ables reported in our model are predictors of any change and <13 g/dl in men).
in Hb. We observed in our data that anaemia in CKD is age-
We carried out a regression analysis initially testing independent when eGFR <45 ml/min per 1.73 m2 as
each variable separately to explore any predictive effect also found in a recent large US national cross-sectional
on our outcome variable (Hb). We then grouped our study [46]. Anaemia prevalence increases as eGFR preva-
best predictor variables into a single model reporting the lence rises in all age groups (Figure 1). Anaemia was
unstandardised coefficient (B); it standard error (E); and more common in older patients then in young patients
significance (p). B represents the unit change in the with moderately decreased eGFR (Figure 1).
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Table 1 Prevalence of anaemia in patients with CKD

Class CKD Hb < 13 g/dl(M)* Hb > 11 g/dl Hb 11 g/dl** Hb 10 g/dl*** Hb 9 g/dl
Hb < 12 g/dl(F)
N % N % N % N % N %
eGFR > 90 F 11545 18.5% 61287 92.8% 4732 7.2% 1523 2.3% 536 0.8%
M 3552 6.3% 54902 98.6% 790 1.4% 340 0.6% 142 0.3%
eGFR 60-89 F 16032 11.1% 132285 96.0% 5455 4.0% 1747 1.3% 612 0.4%
M 7228 6.0% 106310 98.8% 1281 1.2% 541 0.5% 235 0.2%
Stage 3A F 4542 14.3% 28205 94.5% 1654 5.5% 508 1.7% 173 0.6%
M 2997 20.4% 12760 95.1% 657 4.9% 254 1.9% 101 0.8%
Stage 3B F 2340 36.4% 5065 82.6% 1065 17.4% 329 5.4% 96 1.6%
M 1616 48.7% 2654 83.5% 523 16.5% 207 6.5% 86 2.7%
Stage 4 F 663 59.8% 680 63.6% 389 36.4% 167 15.6% 35 3.3%
M 553 71.3% 516 69.2% 230 30.8% 102 13.7% 38 5.1%
Stage 5 F 128 61.2% 108 55.1% 88 44.9% 43 21.9% 16 8.2%
M 176 81.5% 123 59.4% 84 40.6% 38 18.4% 18 8.7%
CKD stage 3-5 F 7673 19.4% 34058 91.4% 3196 8.6% 1047 2.8% 320 0.9%
M 5342 28.1% 16053 91.5% 1494 8.5% 601 3.4% 243 1.4%
Total CKD 3-5 13015 22.2% 50111 91.4% 4690 8.6% 1648 3.0% 563 1.0%
*WHO anaemia definition. **NICE UK guidelines ***FDA recommended level for anaemia correction.

Normocytic anaemia is the most common form of an- Prevalence of Iron deficiency anaemia in CKD patients
aemia in patients with CKD (Figure 2). 80.5% (n = 3,744) of Approximately one third (31%, n = 18,157) of people with
patients with CKD and Hb 11 g/dl have normocytic an- CKD have had their ferritin measured. In two-thirds (63.7%,
aemia. The proportion falls to three quarters (72.7%, n = n = 11,570) of these patients the ferritin is <100ug/mL and
1,057) for Hb 10 g/dl and to two thirds (67.6%, n = 375) 2.7% (n = 1,569) had a ferritin level <15ug/mL; suggesting
where Hb 9 g/dl. As Hb falls so the proportion of people that they had reduced iron stores. Over three-quarters
with microcytic anaemia increases: from 13.4% (n = 625) (82.7%) of people with CKD and microcytic anaemia (Hb
where Hb 11 g/dl, to 20.8% (n = 302) where Hb 10 g/dl, 11 g/dl) have a ferritin less than 100 ug/mL (Chi-square,
to a quarter of those with Hb 9 g/dl (n = 138). The pro- p = 0.017), compared with 58.8% of those with normocytic
portion of macrocytic anaemia only slightly rises as Hb falls (Chi-square p < 0.001) and 45.5% of those with macrocytic
in CKD: 6.0% (n = 280) of people with Hb 11 g/dl rising anaemia (Chi-square p = 0.8, n.s.). Furthermore, 39%
to 7.6% (n = 42) of people with Hb 9 g/dl (Table 2). patients with CKD and microcytic anaemia have ferritin
level below 15 ug/mL (Table 3).

Figure 2 Micro-, normo-, and macrocytic anaemia for each

Figure 1 Age-specific prevalence of anaemia in CKD. stage CKD.
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Table 2 Normocytic anaemia is the most common in Table 4 Anaemia is associated with CVD in CKD patients
patients with CKD Population CKD
MCV range Microcytic Normocytic Macrocytic Hb > 11 g/dl Hb 11 g/dl
Hb (g/dl) N % N % N % Female N % N % N %
Female Hb > 11 810 2.4% 32267 95.1% 842 2.5% HT 71811 16.4% 17591 51.7% 2140 67.0%
Hb 11 481 15.1% 2536 79.7% 164 5.2% Diabetes 19909 4.6% 4299 12.6% 923 28.9%
Hb 10 230 24.8% 647 69.7% 51 5.5% IHD 12309 2.8% 4329 12.7% 715 22.4%
Hb 9 103 32.5% 195 61.5% 19 6.0% HF 3659 0.8% 1642 4.8% 409 12.8%
Male Hb > 11 398 2.5% 14955 93.8% 589 3.7% PVD 2642 0.6% 851 2.5% 161 5.0%
Hb 11 144 9.8% 1208 82.3% 116 7.9% CVA 9903 2.3% 3114 9.1% 534 16.7%
Hb 10 72 13.7% 410 77.9% 44 8.4% Male
Hb 9 35 14.7% 180 75.6% 23 9.7% HT 60758 14.2% 9458 58.9% 1014 67.9%
Total Hb > 11 1208 2.4% 47222 94.7% 1431 2.9% Diabetes 24322 5.7% 3427 21.4% 519 34.7%
Hb 11 625 13.4% 3744 80.5% 280 6.0% IHD 19729 4.6% 4251 26.5% 561 37.6%
Hb 10 302 20.8% 1057 72.7% 95 6.5% HF 3927 0.9% 1407 8.8% 273 18.3%
Hb 9 138 24.9% 375 67.6% 42 7.6% PVD 3925 0.9% 952 5.9% 165 11.0%
CVA 9754 2.3% 2129 13.3% 319 21.4%
Anaemia as a risk factor for CVD in patients with CKD Total
Analysis of cardiovascular co-morbidities and diabetes HT 132569 15.4% 27049 54.0% 3154 67.2%
showed that these conditions are more prevalent among Diabetes 44231 5.1% 7726 15.4% 1442 30.7%
people with anaemia and CKD than those with CKD and IHD 32038 3.7% 8580 17.1% 1276 27.2%
a normal Hb. The prevalence of ischaemic heart disease
HF 7586 0.9% 3049 6.1% 682 14.5%
(IHD), heart failure (HF), stroke and transient ischaemic
PVD 6567 0.8% 1803 3.6% 326 7.0%
attack grouped as cerebrovascular disease (CEVD), per-
CVA 19657 2.3% 5243 10.5% 853 18.2%
ipheral vascular disease (PVD) and diabetes is approxi-
Test of proportion (Chi-square) for all rows (p < 0.001) in favour of an
mately twice that of CKD patients without anaemia increased prevalence of anaemia with CKD.
(Table 4). In addition, 67.2% of patients with CKD and
anaemia have hypertension as compared with 54% quarters (73%, n = 3,422) NSAID, 14.1% (n = 662) were
patients with CKD only (Chi-square p < 0.001). taking warfarin and 12.4% (n = 581) clopidogrel. Further-
more, more than half (55.6%, n = 999) of patients with iron
deficiency anaemia and CKD stage 35 were concurrently
Drug prescription in patients with CKD and anaemia prescribed NSAIDs and aspirin (Table 5).
Two-thirds of patients (62%) in our study receive one or
more drugs causing anaemia in the last two years, 84.7% Oral Iron prescription
ever. Nearly half of people with CKD and anaemia have Over half (62.6%) of people with anaemia in the general
been prescribed aspirin and non-steroidal anti-inflamma- population had been prescribed oral iron therapy (Table 6)
tory drugs (NSAID) (49.1%, n = 2,301 and 46.2%, n = 2166 with prescriptions issued to a slightly lower proportion
respectively), 8.1% (n = 378) received clopidogrel and (56.3%) of people with anaemia and CKD. The common-
10.3% (n = 485) warfarin in the last two years. Analysis of est prescribed iron preparations were ferrous fumarate
medication history showed that 61% (n = 2,862) of people (322 mg bd) and ferrous sulphate (200 mg tid); with the
with CKD and Hb 11 g/dl had taken aspirin, three- prescriptions intended to provide 200 mg or 195 mg elem-
ental iron, respectively; in line with current recommenda-
Table 3 Low ferritin level in CKD patients is associated
tions [50].
with microcytic anaemia Two-thirds (67.6%) of people with anaemia and CKD
Ferritin Microcytic Normocytic Macrocytic All
and a low ferritin level were taking oral iron. The mean
Hb in the iron treated group was 10.0 g/dl (n = 582) com-
ug/mL n % n % n % n %
pared with 10.3 g/dl (n = 1214) in the non-iron treated
<15 171 39.0% 236 10.3% 4 2.3% 411 14.1
(t-test p < 0.001).
15-99 192 43.7% 1117 48.5% 76 43.2% 1385 47.5
100-199 36 8.2% 469 20.4% 34 19.3% 539 18.5
Regression analysis
200 40 9.1% 480 20.9% 62 35.2% 582 20.0
Stage 35 CKD was associated with a reduction in Hb,
Total 439 100% 2302 100% 176 100% 2917 100.0 0.712 g/dL (SE 0.017 g/dL, p < 0.001, R2 = 0.9%). The
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Table 5 Prescribing in patients with CKD and anaemia

CKD CKD & anaemia CKD, anaemia, ferritin < 100ug/ml CKD, anaemia, ferritin < 15ug/mL
N % N % N % N %
Aspirin 25218 43.1% 2862 61.0% 1133 63.1% 225 54.7%
Clopidogrel 4149 7.1% 581 12.4% 231 12.9% 44 10.7%
Warfarin 5697 9.7% 662 14.1% 248 13.8% 40 9.7%
NSAID 40121 68.5% 3422 73.0% 1363 75.9% 304 74.0%
Aspirin + NSAID 21614 36.9% 2490 53.1% 999 55.6% 194 47.2%
Aspirin + Clopidogrel 3453 5.9% 491 10.5% 198 11.0% 36 8.8%
Aspirin + Warfar 3461 5.9% 412 8.8% 160 8.9% 21 5.1%
NSAID + Clopidogrel 3350 5.7% 497 10.6% 206 11.5% 39 9.5%
NSAID + Warfarin 4047 6.9% 482 10.3% 182 10.1% 29 7.1%
Aspirin + NSAID + Clopidogrel 3006 5.1% 454 9.7% 188 10.5% 34 8.3%
Aspirin + NSAID + Warfarin 2992 5.1% 367 7.8% 142 7.9% 21 5.1%
Aspirin + NSAID + Clopid + Warfarin 495 0.8% 73 1.6% 26 1.4% 4 1.0%

regression analysis testing each variable separately compared with those with a normal Hb and CKD. Over
showed a small but significant effect of eGFR and CKD three-quarters of people with anaemia and CKD are on
on the outcome variable, haemoglobin (B of 0.003, SE one or more medications which may exacerbate an-
0.000, p < 0.001, R2 = 0.2%). Our best model included: aemia; over three quarters have been prescribed aspirin
CKD stages 35, significant proteinuria, heart failure, as some time, over two-thirds in the last two years.
diabetes, hypertension, stroke, deprivation score and Nearly three quarters of anaemic people with CKD have
NSAID within last 2 years, R2 = 7.4% (p < 0.001). After been prescribed an NSAIDs. Three quarters of people
adding other elements to the model the CKD remained a with microcytic anaemia and over half of those with nor-
significant contributor to the final effect (Table 7); though mocytic anaemia have been prescribed oral iron, how-
overall the combined predictive effect of the model on an- ever despite this their anaemia remains uncorrected.
aemia is small (R2 = 7.7%). We excluded ACE-I from our Stage 35 CKD and reduction in eGFR are weak but sig-
final model. The unstandardised coefficient (B) was smaller nificant predictors of reduced haemoglobin.
than that for hypertension and the overall model performed The prevalence of anaemia increased with reduction of
less well with ACE-I and hypertension included. eGFR levels in all age groups and this observation corre-
sponds, and appears to validate, in an independent sam-
ple findings in the National Health and Nutrition
Discussion Examination Survey (NHANES) population [4,5]. How-
In this study we found that anaemia is common in CKD ever, this prevalence is less than half that found in the
and usually normocytic. Anaemia in CKD is associated more targeted National Kidney Foundation Kidney Early
with a reduced ferritin in over half, suggesting depleted Evaluation Program (KEEP) [51].
iron stores. Microcytic anaemia is less common, though Stage 35 CKD is an independent predictor variable of
over three-quarters of people with this type of anaemia reduced haemoglobin. The current focus of UK National
have a reduced ferritin. All cardiovascular diseases are guidance on anaemia management in CKD needs to be
more prevalent among those with anaemia and CKD reviewed. We recommend a shift from early referral to

Table 6 Oral iron prescription in patients with anaemia

Anaemia CKD & anaemia CKD anaemia & ferritin < 100ug/mL CKD anaemia & ferritin < 15ug/mL
Gender Therapy N % Hb mean N % Hb mean N % Hb mean N % Hb mean
Female None 7212 34.5% 10.32 1341 42.0% 10.31 444 33.0% 10.31 70 21.0% 9.94
Oral Iron 13693 65.5% 10.09 1855 58.0% 10.04 902 67.0% 10.05 264 79.0% 9.92
Male None 2248 51.4% 9.91 707 47.3% 10.07 138 30.7% 10.09 15 19.5% 9.51
Oral Iron 2122 48.6% 9.89 787 52.7% 9.91 312 69.3% 9.81 62 80.5% 9.47
Total None 9460 37.4% 10.22 2048 43.7% 10.23 582 32.4% 10.26 85 20.7% 9.86
Oral Iron 15815 62.6% 10.07 2642 56.3% 10 1214 67.6% 9.99 326 79.3% 9.83
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Table 7 Multiple regression model, predictor variables effect on the outcome variable (haemoglobin level)
Dependent variable - Haemoglobin level
Predictor variables Unstandardised coefficients Standardised coefficients
B Std. Error Beta T
(Constant) 14.146 0.021 682.905
CKD stages3-5 0.712 0.017 0.204* 42.385
Significant proteinuria 0.501 0.033 0.068* 15.064
Heart failure 0.368 0.033 0.051* 11.255
Diabetes 0.078 0.016 0.023* 4.94
Hypertension 0.144 0.015 0.043* 9.315
CEBVD or Stroke 0.236 0.025 0.042* 9.309
Deprivation score 0.01 0.001 0.086* 19.138
NSAID within last 2 years 0.132 0.015 0.04* 8.955
R2 for the model = 7.4% significance for the model <0.001 (*p < 0.001).

specialist centres for administration of parenteral iron or Organization (WHO) define anaemia as <12 g/dl in women
ESA to more effective medication management in primary and <13 g/dl in men [57]. Whilst prescription of oral iron
care, with improved access to parenteral iron. Family phy- was not associated with correction of anaemia; we cannot
sicians should carefully balance the risk benefit ratio of conclude that it is ineffective as we dont know the pre-
prescribing aspirin in cardiovascular disease and of treatment Hb levels. Although generally 200 mg of elemen-
NSAIDs in people with CKD. The concurrent use of acid tal iron is the default prescription in UK family practice, we
suppressant therapy may help reduce the risk of gastro- know that it is common practice in primary care to advise
intestinal blood loss. patients to reduce the iron dose if they experience gastro-
Our findings are consistent with a systematic review and intestinal side effects. We also only have evidence a pre-
meta-analysis that showed little benefit from oral iron in scription was issued, and nothing about what was actually
people with CKD. Interestingly, the rise in Hb reported dispensed.
using parenteral iron (0.83 g/dL) is similar to the decline Serum ferritin <100 ng/mL is used in this paper as a
seen in people with CKD (0.72 g/dL) [52]. surrogate for iron deficiency; this is an expert consensus,
In USA the Third National Health & Nutrition Examin- used in UK national guidance [58] though many normal
ation Survey Public health (NHANES III) reported a high individuals having levels beneath this threshold [59].
prevalence of anaemia, and a low ferritin in people with Prospective studies are needed to assess whether more
heart failure and CKD, which is also compatible with our effective anaemia management strategies might reduce
results [53]. Likewise, NHANES found 42.2% (95% confi- the incidence of CVD in people with CKD. Tools and
dence interval 28.3-56.0%) of people with eGFR <40 ml/min algorithms are needed to help family doctors asses the
were anaemic compared with 34% in this study. Antihyper- relative risk of stopping NSAIDs, aspirin and other ther-
tensive medication, including angiotensin-converting en- apy against the potential benefits of correcting anaemia.
zyme inhibitors are also associated with anaemia [14,54].
We included hypertension, not anti-hypertensive therapy
in our regression model. It is possible that the small reduc- Conclusion
tion in haemoglobin associated with hypertension might Anaemia is common among CKD patients in the UK and
be related to therapy. associated with cardiovascular diseases and prescription of
Our approach is limited by the inevitable incomplete- drugs which may cause anaemia. Having stage 35 CKD is
ness of the routine data, though their strengths and weak- a predictor variable of a decline in haemoglobin. Primary
nesses are well known [55]. The associations reported in care management should start with a careful medication
this paper do not prove or imply a causative link; and review and assessment prior to referral for replacement of
paradoxically agents that might cause gastrointestinal depleted iron stores with parenteral iron.
haemorrhage were not associated with greater degrees of
iron deficiency. Additional files
A further difficulty is that definitions of anaemia are
not completely standardised. The European guidelines Additional file 1: Figure S1. Age sex profile of study population
compared to census data.
define anaemia as <11 g/dl [56], which is marginally
Additional file 2: Figure S2. Patients by stage CKD, age and sex.
different from guidance in England. The World Health
Dmitrieva et al. BMC Nephrology 2013, 14:24 Page 8 of 9
http://www.biomedcentral.com/1471-2369/14/24

Abbreviations 3. Eckardt KU: Managing a fateful alliance: anaemia and cardiovascular

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drugs; NICE: National Institute for Health and Clinical Excellence; NHANES 2003, 41(1):112.
III: Third National Health & Nutrition Examination Survey Public health; 6. Valderrabano F, Horl WH, Macdougall IC, Rossert J, Rutkowski B, Wauters JP:
PVD: Peripheral vascular disease; SPSS: Statistical Package for Social Sciences PRE-dialysis survey on anaemia management. Nephrol Dial Transplant
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Competing interests 8. Canadian Erythropoietin Study Group: Association between recombinant
OD: None. SdeL: Involved in development of the pay-for-performance human erythropoietin and quality of life and exercise capacity of
indicator for UK practice; lead author for Department of Health Frequently patients receiving haemodialysis. Canadian Erythropoietin Study Group.
Asked Questions about chronic kidney disease. www.nhsemployers.org/ Bmj 1990, 300(6724):573578.
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honoraria from several companies involved in the manufacture of ESAs and chronic kidney disease patients. Clin J Am Soc Nephrol 2009, 4(1):3338.
IV iron products, and is a current Work Group member of the KDIGO Anemia 10. Harnett JD, Foley RN, Kent GM, Barre PE, Murray D, Parfrey PS: Congestive
Guidelines Group. HG: None. CT: None. KH: Kevin Harris has received funding heart failure in dialysis patients: prevalence, incidence, prognosis and
from several pharmaceutical companies, Edith Murphy Foundation risk factors. Kidney Int 1995, 47(3):884890.
20072010: Quality Improvement in CKD due to diabetes and LNR CLAHRC 11. Walker AM, Schneider G, Yeaw J, Nordstrom B, Robbins S, Pettitt D: Anemia
for Prevention of Chronic Disease and its Associated Co-Morbidity theme. as a predictor of cardiovascular events in patients with elevated serum
TD: None. DG: Honoraria and Speaker Fees from Takeda, Roche, Sandoz, creatinine. J Am Soc Nephrol 2006, 17(8):22932298.
Amgen. 12. Levin A, Thompson CR, Ethier J, Carlisle EJ, Tobe S, Mendelssohn D, Burgess
E, Jindal K, Barrett B, Singer J, et al: Left ventricular mass index increase in
Authors contributions early renal disease: impact of decline in hemoglobin. Am J Kidney Dis
OD, SdeL, ICM and DG conceived and designed the study; OD wrote the first 1999, 34(1):125134.
draft of the manuscript, which SDEL developed. OD and SDEL performed the 13. El-Achkar TM, Ohmit SE, McCullough PA, Crook ED, Brown WW, Grimm R,
analysis. OD, SdeL, ICM, HG, CT, KH, TD and DG. All authors contributed to Bakris GL, Keane WF, Flack JM: Higher prevalence of anemia with diabetes
editing the paper, and approved the final version of the paper. mellitus in moderate kidney insufficiency: The Kidney Early Evaluation
Program. Kidney Int 2005, 67(4):14831488.
Acknowledgments 14. Ishani A, Weinhandl E, Zhao Z, Gilbertson DT, Collins AJ, Yusuf S, Herzog CA:
Patients, clinicians and staff of the data contributing practices. Health Angiotensin-converting enzyme inhibitor as a risk factor for the
Foundation for funding the QICKD trial. Collaborators in the QICKD trial development of anemia, and the impact of incident anemia on mortality
include Kidney Research UK. Antonios Ntasioudis, Jeremy van Vlymen, in patients with left ventricular dysfunction. J Am Coll Cardiol 2005,
University of Surrey, and Andre Ring, St. Georges. Georgios Michalakidis and 45(3):391399.
Nigel Mehdi for assistance with the data repository. Tara Bader for initial 15. de Lusignan S: An educational intervention, involving feedback of
analysis contributing to Figure 2 and Chris Pearce for his comments on the routinely collected computer data, to improve cardiovascular disease
manuscript. management in UK primary care. Methods Inf Med 2007, 46(1):5762.
16. Maddux FW, Shetty S, del Aguila MA, Nelson MA, Murray BM: Effect of
Financial disclosure erythropoiesis-stimulating agents on healthcare utilization, costs, and
Health Foundation - funding of travel related to the study. The funders had outcomes in chronic kidney disease. Ann Pharmacother 2007,
no role in study design, data collection and analysis, decision to publish, or 41(11):17611769.
preparation of the manuscript. 17. Anderson J, Glynn LG, Newell J, Iglesias AA, Reddan D, Murphy AW: The
impact of renal insufficiency and anaemia on survival in patients with
Author details cardiovascular disease: a cohort study. BMC Cardiovasc Disord 2009, 9:51.
1
Department of Health Care Management and Policy, University of Surrey, 18. Parfrey PS, Lauve M, Latremouille-Viau D, Lefebvre P: Erythropoietin
Guildford, Surrey GU2 7XH, UK. 2Renal Medicine, Cheyne Wing, Kings College therapy and left ventricular mass index in CKD and ESRD patients: a
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Trust SW Thames Renal Unit, St. Helier Hospital, Wrythe Lane, Carshalton, 19. Goldberg N, Lundin AP, Delano B, Friedman EA, Stein RA: Changes in left
Surrey SM5 1AA, UK. 4Southmead Hospital, Southmead Road, ventricular size, wall thickness, and function in anemic patients treated with
Westbury-on-Trym, Bristol BS10 5NB, UK. 5University Hospitals of Leicester, recombinant human erythropoietin. Am Heart J 1992, 124(2):424427.
Gwendolen Road, Leicester LE5 4PW, UK. 6Renal and Transplantation 20. Wish JB, Nassar GM, Schulman K, del Aguila M, Provenzano R: Postdialysis
Department, Guy's Hospital, 6th Floor, Borough Wing, Great Maze Pond, outcomes associated with consistent anemia treatment in predialysis
London SE1 9RT, UK. patients with chronic kidney disease. Clin Nephrol 2008, 69(4):251259.
21. Foley RN, Curtis BM, Parfrey PS: Hemoglobin targets and blood
Received: 4 September 2012 Accepted: 21 January 2013 transfusions in hemodialysis patients without symptomatic cardiac
Published: 25 January 2013 disease receiving erythropoietin therapy. Clin J Am Soc Nephrol 2008,
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