Lang, Susanne M.

Schiffl, Helmut

English

Open Access LMU ( Ludwig-Maximilians-Univ. München)

Letter to the EditorNephron 1999;81:106–108Angiotensin-Converting Enzyme Inhibitors but NotAngiotensin II AT 1 Receptor Antagonists AffectErythropoiesis in Patients with Anemia of End-StageRenal DiseaseHelmut Schiffl Susanne M. LangNephrologisches Zentrum, Klinikum Innenstadt, Universität München, DeutschlandProf. Helmut SchifflNephrologisches Zentrum, Klinikum InnenstadtUniversität München, Ziemssenstrasse 1D–80336 Munich (Germany)Tel. +49 89 5160 2220, Fax +49 89 5160 4924ABCFax + 41 61 306 12 34E-Mail karger@karger.chwww.karger.com© 1999 S. Karger AG, Basel0028–2766/99/0811–0106$17.50/0Accessible online at:http://BioMedNet.com/kargerDear Sir,The origin of anemia of chronic renalfailure is multifactorial. The primary defectof this anemia is decreased erythropoiesis,but a number of other factors may play acontributory role. Virtually all patients un-dergoing renal replacement therapy treatedwith recombinant human erythropoietin(rHU-EPO) achieve a significant rise inhemoglobin concentration or hematocrit(HCT). However, certain patients with ane-mia of end-stage renal disease require higherdoses and need longer to reach stabilization.Numerous medical disorders or drugs maycause resistance to rHU-EPO therapy. He-matological changes associated with angio-tensin-converting enzyme (ACE) inhibitorsare well documented in healthy subjects, inpatients with heart failure, and in patientswith essential hypertension as well aschronic renal failure or renal transplants.Characteristically, these effects include a re-duction in HCT levels which appears to becaused by a decrease in endogenous EPOproduction or activity. In anemic dialysispatients, therapy of hypertension or heartfailure with ACE inhibitors may reduce theresponse to rHU-Epo therapy [1]. Angioten-sin II receptor antagonists are often used totreat cardiovascular disorders associatedwith end-stage renal disease, but their effectson hematological parameters are largely un-known. This prospective randomized con-trolled study was carried out to compare theeffects of these drugs on renal anemia andthe requirement of EPO therapy.Twenty-four anemic patients with end-stage renal disease receiving regular hemodi-alysis were selected from four outpatient di-alysis centers. They all gave informed con-sent to participate in the investigation. Theyall had normocytic-normochromic anemia,hypertension refractory to dialysis, andmaintenance dialysis treatment for at least 6months. The patients were matched accord-ing to demographic, biochemical, and treat-ment characteristics. The first patient ofeach pair was randomly assigned to onetreatment group (captopril or losartan), theother patient of the pair received the alterna-tive therapy. Deficiency of folic acid or vita-min B12, aluminum intoxication, severe hy-perparathyroidism, hypothyroidism, activegastrointestinal bleeding, hematological dis-eases, malignancy, or chronic inflammationwere excluded by appropriate methods inthese patients. None of the patients had hy-persplenism or a history of alcohol abuse,and they did not use immunosuppressivedrugs affecting erythropoiesis. Captopril(37.5–150 mg/day) or losartan (25–50 mg/day) were added to calcium antagonist basedantihypertensive pharmacotherapy at dosesto achieve adequate blood pressure control(!140/90 mm Hg). All patients underwentconventional hemodialysis three times perweek (4–5 h/session) using bicarbonate-buff-ered dialysate and biocompatible high-fluxpolysulfone or polyester-polymer mem-branes. Treatments were performed withvolumetrically controlled ultrafiltration; thedry weight of the patients was assessed bymeasurements of the diameter of the inferiorvena cava. The study protocol consisted of(1) a 3-month run-in period with introduc-tion of the active drugs to the antihyperten-sive pharmacotherapy without rHU-EPOtherapy; (2) a 3-month washout period with-out active drugs nor EPO replacement thera-py, and (3) final 6-month period with con-current therapy of renal hypertension by ac-tive drugs and treatment of renal anemia byrHu-EPO.The initial EPO dose (epoietin alpha)was 50 U/kg, thereafter doses were adjustedto maintain predialytic hemglobin concen-trations of 10 g/dl. Intravenous iron was giv-en to maintain serum ferritin above 400 Ìg/land transferrin saturation above 25%. HCT,endogenous EPO, ferritin, transferrin, andC-reactive protein were monitored monthly;intact parathyroid hormone and serum alu-minum were measured quarterly. Kt/Vureaaccording to Daugirdas was calculatedmonthly.There were no significant differences inage, gender, cause of end-stage renal disease,blood pressure control, main components ofantihypertensive pharmacotherapy, para-thyroid hormone or aluminum levels, andCaptoprilAngiotensin II and Erythropoiesis Nephron 1999;81:106–108 107Kt/Vurea values between the two treatmentgroups (table 1). There was also no signifi-cant difference in mean HCT, ferritin, ortransferrin saturation at the start of studyperiod A. Captopril but not losartan caused astatistically significant decrease in circulat-ing endogenous EPO concentrations andcorresponding HCT values. During the 3-month run-in period, none of the patientshad intercurrent diseases or signs of fluidoverload; all patients had ferritin levels andtransferrin saturation levels above minimumlevels. To maintain a similar HCT duringconcomitant therapy of hypertension andanemia, the captopril group required a statis-tically significantly higher rHU-EPO dose(expressed as dose per patient and per ses-sion) than the losartan group (table 2).This study in 24 matched patients withend-stage renal disease indicates that capto-pril aggravated anemia of chronic renal fail-ure and decreased endogenous EPO produc-tion or activity. The ACE inhibitor also im-paired the response to rHU-EPO therapy. Areview of the literature showed no similarstudy assessing in detail the hematologicaleffects of losartan. Our results confirm clini-cal observations in patients with essentialhypertension showing no adverse effects oflosartan on erythropoiesis [2]. The exactcause of the effects induced by ACE inhibi-tors on the erythropoietic activity is un-known, but it is clear that these drugs pro-duce not only changes in erythropoietic regu-latory factors, but alter control of erythropoi-esis with reduced sensitivity to rHU-EPO.There is considerable evidence, includingthis study, that ACE inhibitors may reduceerythropoietic activity presumably by de-creasing the angiotensin II concentrationwhich in turn lowers EPO production and/oractivity. Furthermore, recent data havedemonstrated that factors other than EPO,such as insulin like growth factor 1 can pro-mote erythropoiesis and correct anemia.Morrone et al. [3] found that therapy withACE inhibitors significantly reduced circu-lating insulin like growth factor 1 and HCTin patients with posttransplant erythrocyto-sis without modifying serum EPO levels.Thirdly, it has been shown that ACE inhibi-tors increased the plasma levels of the natu-ral stem cell regulator N-acetyl-seryl-aspar-Table 1. Demographic characteristics, biochemical data, and treat-ment parameters at recruitment (mean B SD where appropriate)CaptoprilgroupLosartangroupNumber of patients 12 12Age, years 56B12 58B13Male/female ratio 7/5 6/6Cause of renal failureChronic glomerulonephritis 7 6Chronic interstitial nephritis 4 5Hypertensive nephropathy 1 1Time on hemodialysis, months 34B22 36B27Weight, kg 65B15 66B14Blood pressure, mm HgSystolic 142B12 138B14Diastolic 84B8 85B10Antihypertensive drugsCalcium antagonists 8 7Beta blockers 7 7Parathyroid hormone, pg/ml 85B45 98B35Serum aluminum, Ìg/l 25B25 20B10Kt/Vurea 1.3B0.3 1.4B0.3Table 2. Effects of captopril or losartanon endogenous EPO concentrations andon response to rHU-EPO treatment(mean B SD)Study AEPOconcentrationpg/mlHCT%Study BEPO dose/6 monthsU/sessionHCT%Before treatment 17.4B2.5 27B1 – 27B2After treatment 11.3B1.5* 24B1* 2,413B157 32B1*LosartanBefore treatment 18.4B2.5 28B1 – 28B2After treatment 17.9B1.4 29B1 1,685B212* 33B2** p ! 0.05 compared to pretreatment value or to corresponding captopril treatmentvalue.108 Nephron 1999;81:106–108 Schiffl/Langtyl-lysyl-proline which prevents the recruit-ment of pluripotent hematopoietic stem cells[4].The notion of a partial resistance to rHU-EPO in end-stage renal disease patientstreated with ACE inhibitors has clinical im-plications, because higher doses of EPO notonly cause higher costs but may be associat-ed with an increased incidence of side ef-fects. Thus, ACE inhibitors should be re-served for hypertension or heart failure resis-tant to other medications in patients withend-stage renal disease.References1 Albitar S, Genin R, Fen-Chong M, ServeauxMO, Bourgeon B: High dose enalapril impairsthe response to erythropoietin treatment in he-modialysis patients. Nephrol Dial Transplant1998;13:1206–1210.2 Shand BI, Gilchrist NL, Nicholls MG, BaileyRR: Effect of losartan on haematology and hae-morheology in elderly patients with essentialhypertension: A pilot study. J Hum Hypertens1995;9:233–235.3 Morrone LF, Di Paolo S, Logoluso F, SchenaA, Stallone G, Giorgino F, Schena FP: Interfer-ence of angiotensin-converting enzyme inhibi-tors on erythropoiesis in kidney transplant re-cipients: Role of growth factors and cytokines.Transplantation 1997;64:913–918.4 Azizi M, Rousseau A, Ezan E, Guyene TT,Michelet S, Grognet JM, Lenfant M, Corvol P,Menard J: Acute angiotensin-converting en-zyme inhibition increases the plasma level ofthe natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline. J Clin Invest 1996;97:839–844.

Acute angiotensin-converting enzyme inhibition increases the plasma level of the natural stem cell regulator N-acetyl-serylaspartyl-lysyl-proline.

High dose enalapril impairs the response to erythropoietin treatment in hemodialysis patients.

RR: Effect of losartan on haematology and haemorheology in elderly patients with essential hypertension: A pilot study.

Schena FP: Interference of angiotensin-converting enzyme inhibitors on erythropoiesis in kidney transplant recipients: Role of growth factors and cytokines. Transplantation

Angiotensin-converting enzyme inhibitors but not angiotensin II AT 1 receptor antagonists affect erythropoiesis in patients with anemia of end-stage renal disease

Universität München: Elektronischen Publikationen

Letter to the Editor
Nephron 1999;81:106–108
Angiotensin-Converting Enzyme Inhibitors but Not
Angiotensin II AT 1 Receptor Antagonists Affect
Erythropoiesis in Patients with Anemia of End-Stage
Renal Disease
Helmut Schiffl Susanne M. Lang
Nephrologisches Zentrum, Klinikum Innenstadt, Universität München, Deutschland
Prof. Helmut Schiffl
Nephrologisches Zentrum, Klinikum Innenstadt
Universität München, Ziemssenstrasse 1
D–80336 Munich (Germany)
Tel. +49 89 5160 2220, Fax +49 89 5160 4924
ABC
Fax + 41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
© 1999 S. Karger AG, Basel
0028–2766/99/0811–0106$17.50/0
Accessible online at:
http://BioMedNet.com/karger
Dear Sir,
The origin of anemia of chronic renal
failure is multifactorial. The primary defect
of this anemia is decreased erythropoiesis,
but a number of other factors may play a
contributory role. Virtually all patients un-
dergoing renal replacement therapy treated
with recombinant human erythropoietin
(rHU-EPO) achieve a significant rise in
hemoglobin concentration or hematocrit
(HCT). However, certain patients with ane-
mia of end-stage renal disease require higher
doses and need longer to reach stabilization.
Numerous medical disorders or drugs may
cause resistance to rHU-EPO therapy. He-
matological changes associated with angio-
tensin-converting enzyme (ACE) inhibitors
are well documented in healthy subjects, in
patients with heart failure, and in patients
with essential hypertension as well as
chronic renal failure or renal transplants.
Characteristically, these effects include a re-
duction in HCT levels which appears to be
caused by a decrease in endogenous EPO
production or activity. In anemic dialysis
patients, therapy of hypertension or heart
failure with ACE inhibitors may reduce the
response to rHU-Epo therapy [1]. Angioten-
sin II receptor antagonists are often used to
treat cardiovascular disorders associated
with end-stage renal disease, but their effects
on hematological parameters are largely un-
known. This prospective randomized con-
trolled study was carried out to compare the
effects of these drugs on renal anemia and
the requirement of EPO therapy.
Twenty-four anemic patients with end-
stage renal disease receiving regular hemodi-
alysis were selected from four outpatient di-
alysis centers. They all gave informed con-
sent to participate in the investigation. They
all had normocytic-normochromic anemia,
hypertension refractory to dialysis, and
maintenance dialysis treatment for at least 6
months. The patients were matched accord-
ing to demographic, biochemical, and treat-
ment characteristics. The first patient of
each pair was randomly assigned to one
treatment group (captopril or losartan), the
other patient of the pair received the alterna-
tive therapy. Deficiency of folic acid or vita-
min B12, aluminum intoxication, severe hy-
perparathyroidism, hypothyroidism, active
gastrointestinal bleeding, hematological dis-
eases, malignancy, or chronic inflammation
were excluded by appropriate methods in
these patients. None of the patients had hy-
persplenism or a history of alcohol abuse,
and they did not use immunosuppressive
drugs affecting erythropoiesis. Captopril
(37.5–150 mg/day) or losartan (25–50 mg/
day) were added to calcium antagonist based
antihypertensive pharmacotherapy at doses
to achieve adequate blood pressure control
(!140/90 mm Hg). All patients underwent
conventional hemodialysis three times per
week (4–5 h/session) using bicarbonate-buff-
ered dialysate and biocompatible high-flux
polysulfone or polyester-polymer mem-
branes. Treatments were performed with
volumetrically controlled ultrafiltration; the
dry weight of the patients was assessed by
measurements of the diameter of the inferior
vena cava. The study protocol consisted of
(1) a 3-month run-in period with introduc-
tion of the active drugs to the antihyperten-
sive pharmacotherapy without rHU-EPO
therapy; (2) a 3-month washout period with-
out active drugs nor EPO replacement thera-
py, and (3) final 6-month period with con-
current therapy of renal hypertension by ac-
tive drugs and treatment of renal anemia by
rHu-EPO.
The initial EPO dose (epoietin alpha)
was 50 U/kg, thereafter doses were adjusted
to maintain predialytic hemglobin concen-
trations of 10 g/dl. Intravenous iron was giv-
en to maintain serum ferritin above 400 Ìg/l
and transferrin saturation above 25%. HCT,
endogenous EPO, ferritin, transferrin, and
C-reactive protein were monitored monthly;
intact parathyroid hormone and serum alu-
minum were measured quarterly. Kt/Vurea
according to Daugirdas was calculated
monthly.
There were no significant differences in
age, gender, cause of end-stage renal disease,
blood pressure control, main components of
antihypertensive pharmacotherapy, para-
thyroid hormone or aluminum levels, and
Captopril
Angiotensin II and Erythropoiesis Nephron 1999;81:106–108 107
Kt/Vurea values between the two treatment
groups (table 1). There was also no signifi-
cant difference in mean HCT, ferritin, or
transferrin saturation at the start of study
period A. Captopril but not losartan caused a
statistically significant decrease in circulat-
ing endogenous EPO concentrations and
corresponding HCT values. During the 3-
month run-in period, none of the patients
had intercurrent diseases or signs of fluid
overload; all patients had ferritin levels and
transferrin saturation levels above minimum
levels. To maintain a similar HCT during
concomitant therapy of hypertension and
anemia, the captopril group required a statis-
tically significantly higher rHU-EPO dose
(expressed as dose per patient and per ses-
sion) than the losartan group (table 2).
This study in 24 matched patients with
end-stage renal disease indicates that capto-
pril aggravated anemia of chronic renal fail-
ure and decreased endogenous EPO produc-
tion or activity. The ACE inhibitor also im-
paired the response to rHU-EPO therapy. A
review of the literature showed no similar
study assessing in detail the hematological
effects of losartan. Our results confirm clini-
cal observations in patients with essential
hypertension showing no adverse effects of
losartan on erythropoiesis [2]. The exact
cause of the effects induced by ACE inhibi-
tors on the erythropoietic activity is un-
known, but it is clear that these drugs pro-
duce not only changes in erythropoietic regu-
latory factors, but alter control of erythropoi-
esis with reduced sensitivity to rHU-EPO.
There is considerable evidence, including
this study, that ACE inhibitors may reduce
erythropoietic activity presumably by de-
creasing the angiotensin II concentration
which in turn lowers EPO production and/or
activity. Furthermore, recent data have
demonstrated that factors other than EPO,
such as insulin like growth factor 1 can pro-
mote erythropoiesis and correct anemia.
Morrone et al. [3] found that therapy with
ACE inhibitors significantly reduced circu-
lating insulin like growth factor 1 and HCT
in patients with posttransplant erythrocyto-
sis without modifying serum EPO levels.
Thirdly, it has been shown that ACE inhibi-
tors increased the plasma levels of the natu-
ral stem cell regulator N-acetyl-seryl-aspar-
Table 1. Demographic characteristics, biochemical data, and treat-
ment parameters at recruitment (mean B SD where appropriate)
Captopril
group
Losartan
group
Number of patients 12 12
Age, years 56B12 58B13
Male/female ratio 7/5 6/6
Cause of renal failure
Chronic glomerulonephritis 7 6
Chronic interstitial nephritis 4 5
Hypertensive nephropathy 1 1
Time on hemodialysis, months 34B22 36B27
Weight, kg 65B15 66B14
Blood pressure, mm Hg
Systolic 142B12 138B14
Diastolic 84B8 85B10
Antihypertensive drugs
Calcium antagonists 8 7
Beta blockers 7 7
Parathyroid hormone, pg/ml 85B45 98B35
Serum aluminum, Ìg/l 25B25 20B10
Kt/Vurea 1.3B0.3 1.4B0.3
Table 2. Effects of captopril or losartan
on endogenous EPO concentrations and
on response to rHU-EPO treatment
(mean B SD)
Study A
EPO
concentration
pg/ml
HCT
%
Study B
EPO dose/
6 months
U/session
HCT
%
Before treatment 17.4B2.5 27B1 – 27B2
After treatment 11.3B1.5* 24B1* 2,413B157 32B1*
Losartan
Before treatment 18.4B2.5 28B1 – 28B2
After treatment 17.9B1.4 29B1 1,685B212* 33B2*
* p ! 0.05 compared to pretreatment value or to corresponding captopril treatment
value.
108 Nephron 1999;81:106–108 Schiffl/Lang
tyl-lysyl-proline which prevents the recruit-
ment of pluripotent hematopoietic stem cells
[4].
The notion of a partial resistance to rHU-
EPO in end-stage renal disease patients
treated with ACE inhibitors has clinical im-
plications, because higher doses of EPO not
only cause higher costs but may be associat-
ed with an increased incidence of side ef-
fects. Thus, ACE inhibitors should be re-
served for hypertension or heart failure resis-
tant to other medications in patients with
end-stage renal disease.
References
1 Albitar S, Genin R, Fen-Chong M, Serveaux
MO, Bourgeon B: High dose enalapril impairs
the response to erythropoietin treatment in he-
modialysis patients. Nephrol Dial Transplant
1998;13:1206–1210.
2 Shand BI, Gilchrist NL, Nicholls MG, Bailey
RR: Effect of losartan on haematology and hae-
morheology in elderly patients with essential
hypertension: A pilot study. J Hum Hypertens
1995;9:233–235.
3 Morrone LF, Di Paolo S, Logoluso F, Schena
A, Stallone G, Giorgino F, Schena FP: Interfer-
ence of angiotensin-converting enzyme inhibi-
tors on erythropoiesis in kidney transplant re-
cipients: Role of growth factors and cytokines.
Transplantation 1997;64:913–918.
4 Azizi M, Rousseau A, Ezan E, Guyene TT,
Michelet S, Grognet JM, Lenfant M, Corvol P,
Menard J: Acute angiotensin-converting en-
zyme inhibition increases the plasma level of
the natural stem cell regulator N-acetyl-seryl-
aspartyl-lysyl-proline. J Clin Invest 1996;97:
839–844.


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Angiotensin-converting enzyme inhibitors but not angiotensin II AT 1 receptor antagonists affect erythropoiesis in patients with anemia of end-stage renal disease

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