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a report by

Cri stoph Hassl acher


St. Josefskrankenhaus Heidelberg, Academic Teaching Hospital, University of Heidelberg
The prognosis for diabetics with renal insufficiency is still unfavourable
even today. The five-year survival of dialysis patients with type 2 diabetes
is approximately 30% and as such resembles the life expectancy resulting
from a malignant gastrointestinal tumour. The poor prognosis is based on
the excessively high cardiovascular morbidity and mortality of these
patients whose cause cannot be explained merely by a cluster of
conventional risk factors for atherosclerosis.
1,2
Over the last years the role
of anaemia, which can be demonstrated in the majority of patients with
terminal renal insufficiency,
3,4
has been closely examined as a possible
partial cause for cardiovascular complications.
Anaemia can lead to defects in the cardiovascular system through
various mechanisms.
5,6
Functional adaptations, such as an increase in
cardiac output to ensure an adequate supply of oxygen to the tissues,
first occur upon falling haemoglobin levels. If this hyperdynamic
situation persists, structural modifications of the heart muscle occur
that are mediated via various growth factors, cytokines and other
mediators: development of a left ventricular hypertrophy (LVH) and
enlargement of the heart cavities (eccentric hypertrophy). It is known
that LVH is associated with a higher risk for ischaemic events, cardiac
insufficiency or even death.
3,4
The presence of anaemia represents a
pre-disposing factor for the appearance of ischaemias, arrhythmias or
formation of fibroses through further reductions in the coronary
reserves. Several studies have been able to show an association
between anaemia and the appearance of cardiovascular complications
in renal-insufficient or cardiac-insufficient patients.
79
The treatment of
anaemia with erythropoietin, for example, led to a partial regeneration
of the left ventricular muscular mass, an improvement in performance
and an improvement in prognosis.
10,11
Up to now it was considered that a renal anaemia appears only with
severe renal insufficiency, i.e. creatinine-clearance <30ml/min.
However, more recent studies have shown that the haemoglobin
concentration starts to decline at a creatinine-clearance of
<60ml/min.
12
Patients with diabetes in particular seem to have a higher
risk of developing anaemia when kidney function is impaired.
13,14
While the initially published studies only reported on small collectives
without a precise definition of the stage of the renal insufficiency, the
DiaNe project recently conducted a broad screening of the prevalence
of anaemia in Germany and its relationship to kidney function in
undialysed diabetics.
Prevalence of Anaemia in Diabetic Nephropathy
The DiaNe Project
In practices specialised in diabetology, 120,034 patients with known
diabetes were screened for the presence of renal insufficiency, defined
as a serum creatinine >1.3mg/dl. Three thousand, three hundred and
seven patients were identified (2,069 men, average age 67.7 years and
1,438 women, average age 71.2 years). Haemoglobin concentration
was determined and creatinine-clearance was calculated according to
the Cockgroft-Gault procedure. Details of the study were published
elsewhere.
15
According to World Health Organization (WHO) criteria,
anaemia was diagnosed among men with a haemoglobin level of
<13g/dl and among women with a level of <12g/dl. A therapy-
obligatory anaemia was defined gender-independently as a
haemoglobin level of <11g/dl.
The average haemoglobin level of all patients amounted in women to
12.12.11g/dl and in men to 13.072.43g/dl. In both sexes the
average haemoglobin levels decreased with decreasing kidney function
(coefficient of correlation according to Pearson 0.305; p<0.01).
According to WHO criteria, 44% of the women and 40% of the men
with renal insufficiency revealed anaemia. A severe anaemia, i.e.
haemoglobin values <11g/dl, was determined in 26% (female) and
17% (male) of the patients.
Figure 1 shows gender-specificity of the prevalence of anaemia according
to stage of renal insufficiency. Already, at a creatinine-clearance of
Anaemia in Patients with Diabetic Nephropathy
Prevalence, Causes and Clinical Consequences
T O U C H B R I E F I N G S 2 0 0 7
Cristoph Hasslacher is the Head Physician of the Medical
Clinic of St Josefs Hospital, Heidelberg. He is the speaker
for numerous professional societies and the Diabetes
and Kidney working group of the German Diabetes
Society and is a former Vice President of the European
Diabetic Nephropathy Study Group. His main research
interests lie in diabetic nephropathy, hypertension and
biomarkers of diabetic micro and macro-angiopathy.
Professor Hasslacher studied medicine at the universities
of Bonn and Heidelberg. He subsequently became Senior
Physician then Full Professor in the Endocrinology and
Metabolism Department of the Medical Clinic of the
University of Heidelberg.
Nephropathy
80
Patients with diabetes in particular
seem to have a higher risk of
developing anaemia when kidney
function is impaired.
Hasslacher_book.qxp 16/6/07 4:21 pm Page 80
81 E U R O P E A N C A R D I O V A S C U L A R D I S E A S E 2 0 0 7
Anaemia in Patients with Diabetic Nephropathy Prevalence, Causes and Clinical Consequences
6089ml/min, 35% of the women and 25% of the men showed
anaemia. The prevalence of a therapy-obligatory anaemia (haemoglobin
<11g/dl) in these patients already lay at 18% (female) and 11% (male).
With increasing renal insufficiency the anaemia rate increased as
expected. With pre-terminal renal insufficiency, about 65% of the female
and 83% of the male patients showed anaemia according to WHO
criteria; the corresponding prevalence of therapy-obligatory anaemia was
41% and 43%, respectively.
Figure 2 shows the prevalence of anaemia among diabetics of the
DiaNe collective compared with a population study from the US
(National Health and Nutrition Examination Survey NHANES III).
12
It
shows that anaemia occurs 610 times more frequently in diabetic
patients than in the average population at slight restriction of renal
function. When comparing this with patients suffering from renal
insufficiency of a non-diabetic origin, a similar result is apparent (see
Figure 3). The prevalence of anaemia at a serum creatinine level below
3mg/dl was approximately 210-fold higher amongst the diabetics of
the DiaNe collective than in patients with a non-diabetic nephropathy.
16
The DiaNe project therefore confirms the initial findings
13,14
that
among diabetic patients with renal dysfunction anaemia occurs earlier
than in non-diabetic patients. Similar findings were recently published
from 800 diabetic patients with and without nephropathy by Thomas
et al.
17
in an Australian study. In comparison with NHANES III, these
authors found a 35-fold higher anaemia prevalence in the creatinine-
clearance range of 9030ml/min. With more severe impairment of
renal function, no difference could be found in comparison with non-
diabetics with severe renal insufficiency in the DiaNe collective. This
corresponds to the findings of the Predialysis Survey of Anaemia
Management (PRESAM), which also found no difference in the
anaemia prevalence amongst pre-terminal kidney-insufficient patients
with and without diabetes.
18
Causes Underlying Early Anaemia Development
The causes underlying the frequent occurrence of anaemia among
diabetics have not yet been clarified completely. Thomas et al.
17
recently showed that about half of their diabetic patients with
anaemia had inadequate iron stores. Similar results were obtained
from another study in South Korea.
19
Transferrinuria, chronic
inflammation, an autoimmune gastritis or infections with Helicobacter
pylori with the latter occurring more frequently in diabetics have
been discussed as possible causes of the iron deficiency. Blood loss due
to frequent blood withdrawal or blood sugar self-checks might also
come into consideration as possible causes for an iron deficit, although
Thomas et al. could not find any relationship between the number of
blood withdrawals and the degree of the anaemia.
17
Changed eating
habits, e.g. a decreased protein intake with kidney insufficiency, may
also play a role.
Apart from an inadequate iron supply, a disturbed regulation of EPO
synthesis represents a significant factor in anaemia development
among diabetics with renal dysfunction. It has been shown that EPO
synthesis is not increased appropriately when haemoglobin levels fall
off.
13,14
This leads to a so-called renal anaemia that is both
normochromic and normocytic. The pathogenesis of the disturbed
erythropoietin response remains to be clarified in detail. Damage of
the tubulointerstitial tissue (seen more often in diabetics), an
autonomous neuropathy, chronic inflammation and various other
factors are discussed.
17,20
The authors group was able to show
recently that renally-insufficient diabetics with poor metabolic control
show lower haemoglobin and EPO levels than patients with better
adjusted metabolic regulation.
21
Figure 1: Prevalence of Anaemia According to Various
Definitions in Relation to Renal Function Among Male and
Female Diabetic Patients
0
6089 3059
Creatinine clearance (ml/min)
Male patients
<30
20
40
60
80
100

P
r
e
v
a
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c
e

o
f

a
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a

(
%
)
0
6089 3059
Creatinine clearance (ml/min)
Female patients
<30
20
40
60
80
100

P
r
e
v
a
l
e
n
c
e

o
f

a
n
a
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m
i
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(
%
)
Hb<13g/d
Hb<11g/d
Hb<12g/d
Hb<11g/d
Figure 2: Prevalence of Anaemia in Male and Female Diabetic
Patients Among the DiaNe Collective Compared with a Population
Study US National Health and Nutrition Examination Survey III
0
6089
Creatinine clearance (ml/min)
Creatinine clearance (ml/min)
3059 <30
10
20
30
40
50
60
70
80
90
100
Male patients
Female patients
P
r
e
v
a
l
e
n
c
e

o
f

a
n
a
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(
%
)
0
6089 3059 <30
10
20
30
40
50
60
70
80
90
100
P
r
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v
a
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a
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(
%
)
DiaNe 2002
NHANSES
DiaNe 2002
NHANSES
Definition of anaemia: in males HB <13g/dl; in females HB <12g/dl.
Hasslacher_book.qxp 22/6/07 2:54 pm Page 81
82 E U R O P E A N C A R D I O V A S C U L A R D I S E A S E 2 0 0 7
Nephropathy
Clinical Consequences
An early diagnosis of anaemia in proteinuric diabetics is important
since a reduction in haemoglobin coincides with the development of
cardiovascular complications even before the dialysis stage is reached.
Levin et al.
22
were able to show in a large prospective study that
one-third of patients with a creatinine-clearance of between 75 and
25ml/min show an LVH. After a follow-up period of one year the
increase in muscle mass was basically determined by two factors that
could both be influenced by therapy: systolic blood pressure and
haemoglobin level. The authors showed that within this patient
collective a decrease in haemoglobin of 0.5g/dl correlates with a
significant increase in LVH.
Early recognition and treatment of anaemia might therefore represent
an important component in the cardiovascular protection of renally-
insufficient patients. The final results of prospective studies remain to
be published. More recent studies assume that the progression of the
nephropathy is promoted by the anaemia too. In a follow-up study of
type 1 and type 2 diabetics with nephropathy, Hasslacher et al.
23
were
able to show that patients with anaemia showed a more rapid decline
of kidney function than patients without anaemia. Similar findings
were also acquired in the Reduction of Endpoints in Non-Insulin-
Dependent Diabetes Mellitus with the Angiotensin II Antagonist
Losartan (RENAAL) study.
24
Kuriyama et al.
25
found that an increase in
haemoglobin caused by erythropoietin among anaemic patients with
renal insufficiency of varying origin was associated with a slower
progression of nephropathy.
Amongst diabetics with nephropathy, the appearance of anaemia
therefore identifies a group with an excessively high cardiovascular
and renal risk. The DiaNe study shows that mild forms of anaemia can
often be detected among patients with minor renal insufficiency.
Consistent monitoring of the frequently taken blood counts, further
characterisation of an (accidentally) detected anaemia and, where
necessary, introduction of therapy represent important new tasks in
the everyday treatment of diabetic patients.
Acknowledgements
The study was supported by ORTHO BIOTEC, a division of Janssen Cilag,
Neuss, Germany
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18. Valderrabano F, Anaemia management in chronic kidney
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on development of anemia and erythropoietin levels in Type 1
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2006;23(Suppl 4):93.
22. Levin A, Thompson CR, Ethier J, et al., Left ventricular mass
index increase in early renal disease: impact of decline in
haemoglobin, Am J Ki d Di s, 1999;34:25056.
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Type 2 diabetic patients, Di abetol ogi a, 2002;45(Suppl. 2):A363.
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Figure 3: Prevalence of Anaemia (Hb <11g/dl) Among
Diabetic and Non-diabetic Patients with Renal Insufficiency
0
1.32 23
Serum creatinine (mg/dl)
34 >4
10
20
30
40
50
60
70
P
r
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v
a
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o
f

a
n
a
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m
i
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(
%
)
Diabetics (DiaNe 2002)
Nondiabetics (Jungers*)
*Jungers et al., Nephrol Dial Transplant, 2002;17:1621.
An early diagnosis of anaemia in
proteinuric diabetics is important since
a reduction in haemoglobin coincides
with the development of cardiovascular
complications even before the dialysis
stage is reached.
Hasslacher_book.qxp 16/6/07 4:26 pm Page 82

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