anaemia correction in predialysis elderly patients: influence of the antihypertensive therapy on...
TRANSCRIPT
Abstract Anaemia and hypertension are com-
mon in patients with chronic renal insufficiency.
The correction of anaemia with erythropoiesis
stimulating agents (ESA) can improve survival
and decrease the decline of renal function.
Angiotensin converting-enzyme inhibitors
(ACEI) and angiotensin II receptor blockers
(AIIRA) can also slow the progression of renal
failure, but the blockade of the renin-angiotensin
system can worsen anaemia. The aim of our study
was to assess the impact of antihypertensive
therapy (ACEI plus AIIRA) in the requirements
of darbepoietin in a group of elderly predialysis
patients. We included 71 patients (m = 39,
f = 32), mean age of 76.3 years with a mean cre-
atinine clearance of 17.5 ml/min. Patients were
divided in two groups according to their antihy-
pertensive therapy: G-I patients under ACEI or
AIIRA therapy and G-II normotensive patients
or hypertensive patients under antihypertensive
drugs other than ACEI or AIIRA. The groups
were compared regarding demographic, nutri-
tional, biochemical and inflammatory parameters.
We also compared the mean darbepoietin dose.
In GI the mean dose of darbepoietin was higher
than in GII (0.543 vs. 0.325 lg/kg/week,
P = 0.032). We did not find any difference
regarding other parameters analysed. We con-
clude that ACEI and AIIRA can increase the
needs of darbepoietin in predialysis elderly pa-
tients. However, when formally indicated to treat
hypertension in a specific patient, they should not
be switched to another antihypertensive agent.
Instead, in such cases, higher doses of ESA should
be used, if necessary.
Keywords Antihypertensive drugs Æ Darbepoietin ÆPredialysis
Introduction
The ageing process is characterized, among other
things, by a decreasing kidney function. There is
also a propensity for the elderly to become more
susceptible to the diverse situations that can cause
renal failure [1, 2]. As expected, older patients
(>65 years) are the fast growing group of patients
beginning renal replacement therapy in the
Western Countries [3, 4].
With the decrease in renal function, anaemia
becomes common [5] and although it varies, when
glomerular filtration rate falls below 30 ml/min,
haemoglobin concentration usually drops below
11 g/dl [5, 6]. According to the European
P. L. Neves (&) Æ A. Baptista Æ E. Morgado ÆA. Iglesias Æ H. Carrasqueira Æ M. Faısca Æ C. Soares ÆA. P. SilvaServico de Nefrologia, Hospital Distrital de Faro,Rua Leao Penedo, 8000 Faro, Portugale-mail: [email protected]
Int Urol Nephrol (2007) 39:685–689
DOI 10.1007/s11255-006-9082-9
123
ORIGINAL PAPER
Anaemia correction in predialysis elderly patients:influence of the antihypertensive therapy on darbepoietindose
Pedro Leao Neves Æ Alexandre Baptista Æ Elsa Morgado Æ Alfonso Iglesias ÆHermınio Carrasqueira Æ Marılia Faısca Æ Carla Soares Æ Ana P. Silva
Received: 9 April 2006 / Accepted: 9 June 2006 / Published online: 26 September 2006� Springer Science+Business Media B.V. 2006
Guidelines, patients with renal insufficiency must
begin erythropoiesis-stimulating agents (ESAs)
when haemoglobin level is lower than 11 g/dl,
after other causes of anaemia have been excluded
[7].
On the other hand, with the progression of
renal disease, the prevalence of hypertension in-
creases [8] and most of the time chronic renal
failure patients need a multiple drug therapy [9].
With the exception of a recent meta analysis [10],
angiotensin converting enzyme inhibitors (ACEI)
and angiotensin II receptor antagonists (AIIRA)
have been shown to slow the progression of renal
disease more than could be expected from the
blood pressure lowering effect [11, 12]. These
results have prompted their indication as the drug
of choice to treat hypertension in most chronic
renal patients [13, 14]. However, both drugs have
been shown to worsen anaemia in uraemic pa-
tients [15, 16]. The pathogenesis of anaemia
associated with the blockade of the renin-angio-
tensin axis is multifactorial [17].
As far as we know there are not reports on the
effect of ACEI and AIIRA on darbepoietin dose
in renal patients.
The aim of our study was to assess the impact
of the antihypertensive therapy on darbepoietin
dose requirements of elderly patients followed in
a ‘‘chronic kidney disease’’ (CKD) outpatient
clinic.
Subjects and methods
We have studied only elderly patients (age
>65 years) followed in our CKD clinic. Most of
them were followed in our Nephrology Unit
previously and they were referred to the CKD
clinic when their creatinine clearance (CrCl) fell
below 25 ml /min.
During the first visit, patients had a full clinical
history and clinical examination and also a com-
plete biochemical and nutritional assessment. The
presence of hypertension was considered when
blood pressure was higher than 140/90 mmHg or
whenever the patient was receiving antihyperten-
sive therapy. Data concerning antihypertensive
therapy was gathered from patient’s file. CrCl
was estimated according to the Cockroft–Gault
equation [18]. Biochemical evaluation included:
complete blood count, serum iron, serum ferritin,
serum creatinine, blood urea nitrogen, calcium,
phosphorous, PTH (intact molecule—RIA), ser-
um lipid profile, albumin, prealbumin and
inflammatory parameters (hs PCR, IL-6, TNF-a).
For nutritional evaluation, we used a modified
subjective general assessment (SGA) [19], as well
anthropometric measurements, including mid-
arm circumference (MAC), triceps skinfold
thickness (TSF), mid-arm muscle circumference
(MAMC) and body mass index (BMI). The TSF
was measured with a conventional skin-fold cali-
per. The MAC was measured using a metal tape-
measure. The MAMC was derived according to
the formula: MAMC = MAC – (3.1415 · TSF).
Patients were divided into two groups accord-
ing to their antihypertensive therapy: G-I patients
under ACEI or AIIRA therapy and G-II nor-
motensive patients or hypertensive patients under
antihypertensive drugs other than ACEI or AI-
IRA. The groups were compared regarding
demographic, nutritional and biochemical
parameters. We also compared mean darbepoie-
tin dose (lg/kg/week). Darbepoietin was given
subcutaneously in all patients. All patients on
darbepoietin were on oral iron therapy. Data are
expressed as mean ± SD values. For comparison
between groups, Student’s t-test and the v2-test
were used. The null hypothesis was rejected be-
low the 5% level.
Results
We studied 71 (32 females and 39 males) elderly
(>65 years) patients. Their age ranged from 65 to
96 years (76.3 ± 6.6 years). Mean calculated CrCl
[20] of the entire population was 17.5 ± 7.2 ml/
min/1.73 m2 BSA. Hypertension was present in 55
patients (77.5%). Original disease was unknown
in 26.8% (n = 19), 32.4% had diabetic nephrop-
athy (n = 23), 19.7% had hypertensive nephro-
sclerosis (n = 14), 19.7% had chronic interstitial
disease (n = 14) and only one patient (1.4%) had
chronic glomerulonephritis.
There were no differences between groups
regarding demographic and anthropometric
parameters and the modified SGA (Table 1).
686 Int Urol Nephrol (2007) 39:685–689
123
There was also no difference regarding the time
the patient was followed at our Nephrology Unit.
Table 2 compares the darbepoietin dose, as
well as several biochemical and inflammatory
parameters between the two groups. In group I
(patients under ACEI or AIIRA therapy), the
mean darbepoietin dose was higher than in group
II (0.543 vs. 0.325 lg/kg/week, P = 0.032). The
proportion of patients in group I who were using
darbepoietin was 76.4%, and in G-II was 72.9%
(P = ns). When we compared the dose of darbe-
poietin only in patients who were on this eryth-
ropoiesis-stimulating agent, the dose was still
significantly higher in GI (0.685 ± 0.45 vs.
0.446 ± 0.20 lg/kg/week, P = 0.016). With re-
gards to all other parameters, there were no sta-
tistically significant differences between the two
groups.
Discussion
In the last years, the number of older people
reaching dialysis programs increased in the Wes-
tern countries [3, 14]. The number of elderly pa-
tients with renal insufficiency, followed in
nephrology units is unknown, but certainly this
group constitutes a large part of all renal patients.
The ageing of the renal population is a conse-
quence of the ageing of the general population,
and in areas where resources are limited some
ethical questions have emerged [21, 22]. We be-
lieve, like others, that physiological rather than
chronological age must be taken into consider-
ation, when we treat such patients [1, 23, 24].
In this study, we assessed the impact of anti-
hypertensive therapy on darbepoietin dose in a
selected predialysis population.
Although erythropoietin deficiency is the main
factor [5, 6], the pathogenesis of the renal anae-
mia is multifactorial [5, 25]. The association be-
tween the use of ACEI or AIIRA and an
increased need of erythropoietin has been de-
scribed by several authors [15, 16]. However, we
are not aware of any work describing the associ-
ation between the use of these antihypertensive
drugs and the increased requirements of darbe-
poietin.
Darbepoietin alpha stimulates erythropoeisis
like recombinant human erythropoietin (rHu-
EPO), with the only difference that it has a longer
half-life due to an additional sialic acid-containing
carbohydrate [26].
In this study, we observed that in the group of
elderly patients under ACEI or AIIRA drugs, the
dose of darbepoietin required to obtain a com-
parable haemoglobin level, was statistically sig.-
nificantly higher (Table 2). The mean haemoglobin
level of both groups of patients was above the
recommended level of 11 g/dl [7]. Regarding
other factors that could influence the darbe-
poietin dose, like renal function, iron stores,
hyperparathyroidism, nutritional status, and
inflammatory parameters, we did not find any
difference between the two groups. The high
prevalence of hypertension (77.5% of our
Table 1 Demographic, anthropometric parameters andmodified SGA
G-I (n = 34) G-II (n = 37) P
Age (years) 77 ± 6.8 75.6 ± 6.5 nsSex (f/m) 16/18 16/21 nsTime on unit (m) 25.3 ± 29.2 40.4 ± 52.9 nsBMI (kg/m2) 24.1 ± 4.8 25.4 ± 5.0 nsMAC (cm) 25.8 ± 3.7 27.2 ± 3.8 nsMAMC (cm) 21.8 ± 2.7 22.8 ± 2.7 nsTSF (cm) 1.33 ± 0.63 1.42 ± 0.63 nsMSGA 13.3 ± 3.8 12.2 ± 3.0 ns
Table 2 Darbepoietin dose, biochemical andinflammatory parameters in the two groups of patientsGroup I = patients on ACEIs or AIIRA GroupII = patients on other antihypertensives or normotensives
G-I(n = 34)
G-II(n = 37)
P
Darbepoietindose (lg/kg/week)
0.524 ± 0.49 0.330 ± 0.26 0.036
Creatinineclearance (ml/min)
17.8 ± 7.1 17.3 ± 7.4 ns
Hb (g/dl) 11.4 ± 1.6 11.9 ± 1.4 nsIron (lg/dl) 58 ± 32 71 ± 36 nsFerritin (ng/ml) 128 ± 115 136 ± 160 nsCa (mg/dl) 9.8 ± 0.9 9.9 ± 0.6 nsPi (mg/dl) 4.7 ± 1.7 4.4 ± 1.2 nsPTH (ng/ml) 272 ± 241 327 ± 261 nsAlbumin (g/dl) 4.2 ± 0.6 4.3 ± 0.3 nsPrealbumin (mg/dl) 28.6 ± 1.2 32.2 ± 1.5 nsIL-6 (pg/ml) 6.2 ± 7.4 4.6 ± 3.0 nsTNF-a (pg/ml) 10.0 ± 6.1 10.1 ± 4.7 nshs-PCR (mg/dl) 1.03 ± 1.3 1.0 ± 2.9 ns
Int Urol Nephrol (2007) 39:685–689 687
123
patients) was expected in patients at stages 4 and
5 of CKD. Of our hypertensive patients, 34
(47.9%) were treated with ACEI or AIIRA.
These two groups of antihypertensive agents are
particularly recommended in patients with
chronic renal insufficiency [11–14], but the
blockade of the renin-angiotensin axis that they
produce can worsen anaemia. Several mecha-
nisms have been described in the literature: pre-
vention of the stimulatory effect of angiotensin II
on the synthesis of erythropoietin; increase renal
plasma flow, reducing the hypoxic stimulus for
erythropoietin formation; diminished precursors
of erythropoietin; direct effect on red blood stem
cells [17]. These drugs are particularly indicated
in CKD patients because, with one exception [10],
all other studies have been shown them to delay
the progression of renal disease [11, 12]. There-
fore, it is not surprising that almost half of our
patients were under ACEI or AIIRA. On the
other hand, it has been described that the cor-
rection of anaemia in CKD patients can slow the
progression of renal insufficiency [20]. Despite
the fact that the use of ACEI or AIIRA can in-
crease the required dose of ESA, raising the costs
of the therapy, we believe that, when there is
need to treat hypertension in CKD patients, they
should not be replaced to other antihypertensive
drugs, and if necessary we should increase the
dose of ESA, to achieve the same haemoglobin
level.
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