anaemia correction in predialysis elderly patients: influence of the antihypertensive therapy on...

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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 Darbepoietin Predialysis 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 (&) A. Baptista E. Morgado A. Iglesias H. Carrasqueira M.Faı´sca C. Soares A. P. Silva Servic ¸o de Nefrologia, Hospital Distrital de Faro, Rua Lea ˜ o Penedo, 8000 Faro, Portugal e-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 darbepoietin dose Pedro Lea ˜o Neves Alexandre Baptista Elsa Morgado Alfonso Iglesias Hermı´nio Carrasqueira Marı´liaFaı´sca Carla Soares Ana P. Silva Received: 9 April 2006 / Accepted: 9 June 2006 / Published online: 26 September 2006 Ó Springer Science+Business Media B.V. 2006

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Page 1: Anaemia correction in predialysis elderly patients: influence of the antihypertensive therapy on darbepoietin dose

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

Page 2: Anaemia correction in predialysis elderly patients: influence of the antihypertensive therapy on darbepoietin dose

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

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Page 3: Anaemia correction in predialysis elderly patients: influence of the antihypertensive therapy on darbepoietin dose

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

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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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