Download High dose enalapril impairs the response to erythropoietin treatment

Nephrol Dial Transplant (1998) 13: 1206–1210
Nephrology
Dialysis
Transplantation
Original Article
High dose enalapril impairs the response to erythropoietin treatment in
haemodialysis patients
Sami Albitar, Robert Genin, Michel Fen-Chong, Marie-Odile Serveaux and Bruno Bourgeon
Department of Nephrology, Felix Guyon Hospital and AURAR, St Denis, France
Abstract
Background. The resistance to recombinant human
erythropoietin (rHuEpo) therapy in haemodialysis
(HD) patients has multifactorial aetiologies: erythropoietin insufficiency, dialysis insufficiency, iron
deficiency, and secondary hyperparathyroidism.
Angiotensin-converting enzyme (ACE) inhibitors
induce anaemia in patients with essential hypertension,
congestive heart failure, chronic renal insufficiency,
and renal transplants. Data exist suggesting that ACE
inhibitors impair erythropoiesis in HD patients.
Therefore the aim of this study was to investigate the
impact of enalapril on rHuEpo requirement.
Methods. In the present prospective non-randomized
study of 12 months, we compared the effects of enalapril and nifedipine on rHuEpo requirement in 40 hypertensive patients receiving rHuEpo for more than 6
months on maintenance haemodialysis. Twenty normotensive rHuEpo-dependent patients served as a control
group. All patients with severe hyperparathyroidism
or iron deficiency were excluded.
Results. The mean (±SD) haemoglobin concentration
was >10 g/dl in all groups. The mean weekly rHuEpo
dose increased in the enalapril group (P<0.0001 vs
before) and remained constant in the nifedipine and
control groups (P=NS vs before). Statistically, there
was no differences with regard to iPTH levels, dialysis
parameters, iron status, and underlying renal diseases
among all groups.
Conclusion. High-dose enalapril increases rHuEpo
requirement and should be reserved for dialysis patients
with hypertension uncontrollable with other antihypertensive medications or dialysis patients with cardiac
failure.
Key words: anaemia; enalapril; erythropoietin requirement; haemodialysis
Introduction
Anaemia, a consistent clinical feature of end-stage
renal disease, is efficiently treated with recombinant
Correspondence and offprint requests to: Dr Sami Albitar,
Haemodialysis Centre, AURAR, 6 Av. Stanislas Gimart, F-97490
Ste Clotilde, France.
human erythropoietin (rHuEpo) [1–4]. Development
and aggravation of hypertension has been documented
as the most relevant side-effect of rHuEpo treatment
with an incidence of up to 30 to 40% of treated patients
[1,2]. Risk factors for hypertension include pre-existing
hypertension, severe anaemia at initiation, rapid increment in haematocrit levels, high intravenous rHuEpo
doses, and the presence of native kidneys [2]. The
mechanisms involved in the development of hypertension secondary to rHuEpo include loss of hypoxic
dilatation and increases in blood viscosity, blood
volume, activation of the renin–angiotensin system,
endothelin levels, vascular calcium uptake, or plateletdependent mitogenic action [2]. In the majority of
haemodialysis patients, rHuEpo-induced hypertension
is successfully controlled by water and sodium removal
during dialysis, subcutaneous administration of
rHuEpo, lower target haemoglobin levels and progressive attainment of this target, or conventional antihypertensive therapy [1–4].
Enalapril maleate, a non-sulph-hydryl angiotensinconverting-enzyme (ACE) inhibitor, is a pro-drug
whose pharmacological activity is dependent on its
de-esterification in the liver to its active diacid metabolite, enalaprilat. Enalaprilat excretion occurs primarily
via the urine and secondarily via the bile. The mean
peak serum concentrations of enalapril and enalaprilat
are greater and delayed in patients with chronic renal
insufficiency. Steady-state enalaprilat serum levels are
not achieved in haemodialysis (HD) patients because
HD effectively reduces enalaprilat serum levels with a
dialysis clearance of enalaprilat amounting to more
than 50 ml/min [5]. A strong link exists between enalapril serum levels and ACE inhibition, but not with the
haemodynamic effects. Thus the optimum dosage of
enalapril has not been determined [5]. However,
2.5 mg/day, 5 mg/day, or 5–40 mg/day of enalapril
were successfully used to reduce blood pressure in HD
patients without significant untoward events [5,6 ].
ACE inhibitors are widely used in the treatment of
hypertension, left ventricular dysfunction, diabetic
nephropathy, and renal post-transplant erythrocytosis,
and in preventing the progression of established renal
disease of diverse causes [7–23]. Anaemia has been
reported as a side-effect of ACE inhibitors in normal
© 1998 European Renal Association–European Dialysis and Transplant Association
Erythropoietin and enalapril
1207
volunteers and in patients with essential hypertension
[7], heart failure [8], chronic renal insufficiency [9],
ESRD on maintenance HD [10], or renal transplants
[14].
However, little is known about the impact of highdose enalapril on rHuEpo requirement in HD patients
with anaemia. Therefore, the present prospective,
unblinded, non-randomized study was designed to
evaluate rHuEpo dosing in rHuEpo-dependent HD
patients with hypertension treated with enalapril or
nifedipine, compared to normotensive patients treated
with rHuEpo who served as a control group for 12
months of follow-up.
quarterly. Kt/V (urea) according to Daugirdas [26 ] and
protein catabolic rate (PCR) according to Gotch and Sargent
[27] were calculated monthly.
Subjects and methods
Results
We evaluated patients from five haemodialysis centres who
had been on maintenance haemodialysis for more than 6
months and who were treated with antihypertensive drugs
and rHuEpo for more than two months with a haemoglobin
concentration 10 g/dl.
We excluded all patients with folate or vitamin B defi12
ciency, serum aluminium >40 mg/l, serum ferritin <200 mg/l,
intact parathyroid hormone (iPTH ) >300 pg/ml, active
bleeding lesions, haematological diseases, active untreated
infections, malignancies or other causes of inflammation,
and those taking bone-marrow suppression medications. All
patients were matched with respect to age, sex, subjacent
renal disease, duration on HD, dialysis parameters, intact
parathyroid hormone levels, haemoglobin concentrations,
iron status, and rHuEpo dose before starting this study.
Forty hypertensive patients fulfilled these criteria, and 20
rHuEpo-dependent patients without hypertension served as
a control group. Patients were divided into one of three
classifications based on treatment regimen: those who had
enalapril plus rHuEpo (n=20, enalapril group); nifedipine
plus rHuEpo (n=20, nifedipine group); and rHuEpo (n=
20, control group ). The initial doses of enalapril and slowrelease nifedipine were 5 and 20 mg/day respectively. The
doses of enalapril and nifedipine were increased to adequately
control the (BP <140/90 mmHg). When maximal doses
(20 mg/day for enalapril or 40 mg/day for nifedipine) of
initial medications were reached, atenolol was added in order
to control the high blood pressure more adequately.
Intravenous iron infusion (average dosage 50–
100 mg/week) was used to maintain serum ferritin 400 mg/l
and transferrin saturation 25%, and the rHuEpo dose was
adjusted monthly to maintain haemoglobin >10 g/dl.
Patient characteristics and laboratory data are summarized in Tables 1 and 2. The majority of patients in
all groups had ESRD secondary to diabetic nephropathy, hypertensive nephropathy, or glomerular
nephropathy ( Table 1). One patient in the enalapril
group was omitted due to cough attributed to ACE
inhibitor therapy, and two patients in the nifedipine
group were excluded because of pitting oedema of the
lower extremities attributed to nifedipine in the first
case and a severe inflammatory syndrome in the
second. Two patients in the control group received
renal grafts and were also excluded.
Fifteen patients were treated with 20 mg of enalapril;
four patients with 10 mg of enalapril, and 18 patients
were on 40 mg of nifedipine. Four patients in the
enalapril group and five patients in the nifedipine
group also received atenolol to maintain blood pressure
within the normal range.
There was no statistically significant difference
among the three groups in terms of age, sex, duration
on haemodialysis, blood pressure, Kt/V, PCR, serum
albumin, iPTH, iron status, absolute reticulocyte
count, or haemoglobin values. Average haemoglobin
concentrations were 10.6±0.4 g/dl, 10.7±0.2 g/dl,
and 10.8±0.3 g/dl before and 10.5±0.3 g/dl,
Statistical analysis
The end-point of the study was the effect of enalapril or
nifedipine on rHuEpo requirements in haemodialysis patients
over time. Statistical analysis was performed with Chi-square
or Fisher’s test as appropriate. All data are presented as
means±standard deviation. Univariate analysis was used to
identify differences among the three group. All P values were
two-tailed and a P value ∏0.05 was considered statistically
significant.
Table 1. Clinical data (mean±SD)
Enalapril
group
Nifedipine
group
Control
group
46.3±21.7
11/9
48.2±23.1
10/10
52.1±14.7
10/10
9
8
1
2
34±29
56.9±31.2
56.4±31.3
177±14
132±19
91±15
80±13
8
7
2
3
36±27
55.3±25.1
55.1±25.6
172±16
130±17
92±14
78±14
10
3
2
5
29±41
57.3±35.8
57.8±31.9
125±13
124±8
77±5
78±4
Dialysis programme
All patients underwent conventional haemodialysis three
times a week (range 4–5 h/session), using bicarbonatebuffered dialysate and cellulosic membrane, and were managed to maintain their Kt/V (urea) >1 and protein catabolic
rate (PCR) at 1–1.2 g/kg/day (Table 2).
Measurements
Haemoglobin level, haematocrit, absolute reticulocyte count,
serum ferritin, and transferrin saturation were monitored
monthly. Intact parathyroid hormone (iPTH ), serum albumin by nephelometry, and serum aluminium were measured
Age (years)
Gender (M/F )
Cause of renal failure
Diabetes mellitus
Hypertension
Glomerulonephritis
Unknown
Duration on HD (months)
Pretrial weight (kg)
12-month weight (kg)
Pretrial SBP (mmHg)
12-month SBP (mmHg)
Pretrial DBP (mmHg)
12-month DBP (mmHg)
1208
S. Albitar et al.
Table 2. Basic biological data and dialysis parameters (mean±SD)
Pretrial haemoglobin (g/dl )
12-month haemoglobin (g/dl )
Pretrial serum ferritin (mg/l )
12-month serum ferritin (mg/l )
Pretrial transferrin saturation (%)
12-month trasferrin saturation (%)
Pretrial parathyroid hormone (pg/ml )
12-month parathyroid hormone (pg/ml )
Pretrial serum albumin (g/l )
12-month serum albumin (g/l )
Pretrial Kt/V (urea)
12-month Kt/V
Protein catabolic rate (g/kg)
12-month protein catabolic rate (g/kg)
Enalapril group
Nifedipine group
Control group
10.6±0.4
10.5±0.3
480±356
671±381
32.1±6.2
31.4±9.5
245±147
234±121
41.1±3.2
42.3±5.4
1.31±0.24
1.32±0.29
1.29±0.19
1.26±0.21
10.7±0.2
10.4±0.2
457±321
680±346
33.2±9.5
29.7±5.6
286±110
216±132
40.2±3.4
41.4±4.1
1.39±0.21
1.35±0.23
1.24±0.21
1.23±0.18
10.8±0.3
10.3±0.2
386±184
450±178
30.7±8.3
29.1±6.3
296±137
245±178
42.4±5.1
42.3±6.2
1.28±0.19
1.29±0.23
1.19±0.11
1.17±0.02
10.4±0.2 g/dl, and 10.3±0.2 g/dl at 1 year in the
enalapril, nifedipine, and control groups respectively.
Figure 1 compares the mean weekly rHuEpo dose
subcutaneously administered to the three groups. To
maintain a similar haemoglobin level, the enalapril
group received 84±14 IU/kg/week before and 138±10
U/kg/week at 1 year (P<0.0001 vs before), 86±7
U/kg/week before and 77±5 U/kg/week at 1 year in
the nifedipine group (P<0.0001 vs enalapril at 1 year),
and 79±11 U/kg/week before and 80±9 U/kg/week
in the control group (P<0.0001 vs enalapril at 1 year).
However, there were no statistically significant differences between the nifedipine group and control group
(P=NS).
The mean monthly individual intravenous ferric
hydroxide polymaltose dose was 212±61 mg in the
enalapril group, 194±53 mg in the nifedipine group,
and 197±47 mg in the control group. Again, there
were no statistically significant differences among the
three groups (P=NS ). None of the patients received
transfusions during the study.
Discussion
Fig. 1. Mean (±SD) erythropoietin dose for each group.
In this study we have shown that high-dose enalapril
can lead to substantial and sustained increase in
rHuEpo requirement of haemodialysis populations.
The mean rHuEpo dose increased significantly after 1
year of treatment with ACE inhibitors (P<0.0001).
To maintain the same level of haemoglobin, the group
of patients treated with enalapril needed a higher dose
of rHuEpo than the group of patients treated with
nifedipine and the control group over the 1-year study
period (P<0.0001). rHuEpo requirement did not significantly differ between the nifedipine group and control
group. Further, the mean rHuEpo dose in enalapril
group returned to the baseline value 4 months after
discontinuing enalapril (results not shown).
There are many causes for rHuEpo resistance in HD
patients, such as functional iron deficiency, secondary
hyperparathyroidism, aluminium overload, dialysis
insufficiency, blood loss, or inflammatory syndrome
[5,6 ]. In our study we excluded all patients with any
one of these conditions. Good iron status was assessed
by transferrin saturation >25% and serum ferritin
>400 mg/l, aluminium overload was avoided by using
calcium carbonate as the only phosphate chelator, and
adequate dialysis was defined by Kt/V >1, PCR >1,
and serum albumin >35 g/l. In addition, there was no
statistical differences regarding iPTH levels, iron status
parameters (hypochromic RBC not measured ), haemoglobin levels, and indicators of adequate dialysis
among the three groups throughout the trial.
Erythropoietin and enalapril
The target haemoglobin level for anaemia treatment
was 10–11 g/dl which is the case for the majority of
European studies [4,30], while in the USA the upper
target haemoglobin limit has been extended to more
than 12 g/dl [2]. Adequate dialysis parameters may
improve renal failure anaemia and consequently reduce
rHuEpo need in HD patients, explaining the relatively
low rHuEpo dose of the control and nifedipine groups,
similar to that reported by others [31].
We acknowledge that this study has several limitations. First, we studied a relatively small number of
patients without randomization, but all patients were
matched before beginning the study, the data were all
registered prospectively and analysed in comparison
with the other groups during the treatment time of 12
months, and factors affecting erythropoiesis other than
enalapril were excluded before and during the study.
Secondly, it could be argued that the detrimental effect
of enalapril therapy on erythropoiesis is related to a
high-dose regimen of this agent. To the best of our
knowledge, the enalapril dose in the main previous
studies in HD patients was within a range of 2.5 to
40 mg/day [7,9,13,23,25]. Although unlikely, this may
partially explain the discrepancies between other
reports using a relatively lower dose of enalapril [23,25]
and our results. However, we cannot rule out the
possibility that higher doses of enalapril might have
had a harmful effect on red blood cell production in
our subjects. Thirdly, the negative effect on erythropoiesis may be specific to enalapril and may not apply
to other types of ACE inhibitors. Therefore it is
necessary to conduct additional studies with other
ACE inhibitors.
The mechanism by which ACE inhibitors alter erythropoiesis remains a subject of debate. In rat studies,
angiotensin II infusion produces an increment in
plasma erythropoietin levels [28] which is abolished by
ACE inhibitors [29]. Angiotensin II may directly or
indirectly, via renal hypoxia caused by the vasoconstriction, increase erythropoietin release [15]. However,
other studies showed that ACE inhibitors could lower
haemoglobin concentrations regardless of plasma
erythropoietin levels [16,17,21]. Additionally, Perazella
et al. [16 ] found that erythrocyte survival and plasma
volume are not influenced by ACE inhibitors; excluding
haemolysis or haemodilution as causing ACE-inhibitor-associated anaemia.
To explain the negative effect of ACE inhibitors on
erythrocyte production, one may speculate that ACE
inhibitors produce, either an alteration in the control
of erythropoiesis with reduced sensitivity to rHuEpo,
or an alteration in erythropoietic regulatory factors
other than erythropoietin [15]. Recently it has been
shown that captopril massively increases the tetrapeptide n-acetyl-seryl-aspartyl-lysyl-proline (Ac-SKDP)
plasma levels, which prevents the recruitment of pluripotent haematopoietic stem cells and normal early
progenitors into S-phase of the cell cycle by maintaining the Go-phase [32]. Unfortunately we did not
measure this tetrapeptide in our patients.
In our subjects one may posit that high-dose enalap-
1209
ril enhances the plasma level of Ac-SKDP and/or
lowers renal and extrarenal endogenous erythropoietin
production; explaining the refractoriness to rHuEpo
therapy.
We conclude that high-dose enalapril increases
rHuEpo requirement and should be reserved for HD
patients with high blood pressure resistant to other
antihypertensive medications or those with congestive
heart failure, unless there are specific indications to
the contrary.
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Received for publication: 25.6.97
Accepted in revised form: 1.12.97