Blood Purif 2010;29:93–98
DOI: 10.1159/000245631
Special Considerations for
Antihypertensive Agents in
Dialysis Patients
Josep Redon a, b Fernando Martinez a Alfred K. Cheung c
a
Hypertension Clinic, Hospital Clinico, University of Valencia, Valencia, and b CIBER 06/03, Fisiopatología de la
Obesidad y Nutrición, Institute of Health Carlos III, Madrid, Spain; c University of Utah, Salt Lake City, Utah, USA
Key Words
Hypertension ⴢ Antihypertensive drugs ⴢ Dialysis ⴢ
Chronic kidney disease stage 5
Abstract
Hypertension is present in most patients with end-stage re-
nal disease and likely contributes to the premature cardio-
vascular disease in dialysis patients. Previous practice guide-
lines have recommended that, in patients on chronic dialy-
sis, blood pressure (BP) should be reduced below 130/80 mm
Hg. This is based on opinions but not strong evidence, since
no concrete information exists about which BP values should
be the parameter to follow and which should be the target
BP values. The majority of the antihypertensive agents can
be used in this population, but the pharmacokinetics altered
by the impaired kidney function and dialyzability influence
the appropriate dosage as well as the time and frequency of
administration. Combination therapy using multiple agents
is often necessary. Because of the prevalence of overactivity
of the renin-angiotensin-aldosterone system and sympa-
thetic tone as well as the high calcium influx in vascular
smooth muscle cells in dialysis patients, drugs acting in these
three specific systems may potentially have additional car-
dioprotective benefits beyond their BP-lowering effect.
© 2010 S. Karger AG, Basel
0253–5068/10/0292–0093$26.00/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
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Published online: January 8, 2010
Thus, antihypertensive regimens should preferably be based
on these classes of drugs, alone or in combination. Other an-
tihypertensive drug classes can play a complementary role.
Copyright © 2010 S. Karger AG, Basel
Introduction
Hypertension, as defined in the general population, is
present in most patients with end-stage renal disease and
probably contributes to premature cardiovascular diseas-
es in this population [1]. Consequently, control is recom-
mended in the attempt to reduce the cardiovascular dis-
ease burden, although complications associated with
these treatments are not uncommon as the pathogenesis
of hypertension in end-stage renal disease is complex and
multiple mechanisms are likely involved in the blood
pressure (BP) dysregulation. Thus, antihypertensive
treatment is sometimes not an easy task, and refractory
hypertension is common [2]. Understanding the treat-
ment targets, intra- and interdialytic BP behavior and
pharmacokinetic properties of antihypertensive drugs in
impaired kidney function and during dialysis is the key
to achieve success in BP treatment. Furthermore, poten-
tial additional cardioprotective benefits of the antihyper-
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Weizmann Inst. of Science
Josep Redon, MD, PhD
Hypertension Clinic, Internal Medicine Department
Hospital Clinico, University of Valencia
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ES–46010 Valencia (Spain)
Tel./Fax +34 963 862 647, E-Mail josep.redon @ uv.es
tensive drugs, beyond their BP-lowering effects, need also
to be considered. In the following sections, key issues
about the use of antihypertensive drugs in dialysis are
reviewed.
Beneficial Impact of Antihypertensive Drugs in
Cardiovascular Risk
Practice guideline recommendations [3–5] stated that
in patients on chronic dialysis, BP should be reduced be-
low 130/80 mm Hg. This is based largely on opinions, but
not on sound evidence, since unfortunately no solid in-
formation exists about the BP parameters that should be
followed and the target values of these parameters that
would yield the best clinical outcome.
In fact, there are very few randomized trials on the
impact of antihypertensive drugs on hard clinical out-
comes in dialysis patients, and all of them have been
pooled in two recently published meta-analyses [6, 7].
The analysis performed by Heerspink et al. [6] included
8 randomized trials, 1 published only in abstract form, 5
of which examined renin-angiotensin-aldosterone sys-
tem (RAAS) blockade, 2 examined ␤-blockers (␤Bs) and
1 examined a calcium channel blocker (CCB). Data for
1,679 patients and 495 cardiovascular events were pro-
vided. BP-lowering treatment was associated with a sig-
nificant reduction of cardiovascular events (29%), all-
cause mortality (20%) and cardiovascular mortality
(29%), for a systolic/diastolic BP difference versus control
(not using these antihypertensive agents) of –4.5/–2.3
mm Hg. Regretfully, no information was provided about
the absolute BP values achieved with treatment, although
the fact that statistically significant beneficial effects were
observed only in the subgroup of patients with hyperten-
sion and not in the normotensive subgroup may suggest
that BP values achieved by treatment were not particu-
larly low.
The analysis performed by Agarwal and Sinha [7] in-
cluded 5 randomized trials, which were a subset of the
one performed by Heerspink et al. [6]. Although the main
results are similar to the previous one, these latter authors
stressed that beneficial effects of antihypertensive medi-
cations were markedly diminished and became statisti-
cally nonsignificant when normotensive subjects were in-
cluded. The matter is further complicated by the exten-
sive use in these studies of RAAS blockers, which are
thought to possess specific cardioprotective and renopro-
tective properties that make the effect attributable to BP
reductions more difficult to unravel.
94 Blood Purif 2010;29:93–98
The results of these meta-analyses need to be inter-
preted with caution. Beside limitations such as heteroge-
neity of individual study designs and publication bias,
causality cannot be inferred from the association be-
tween the decrease in BP and beneficial clinical effects,
in part because no BP goals were predefined in these tri-
als. Adequately powered randomized trials specifically
designed to compare the effects of different BP goals on
clinical outcomes are necessary to guide clinical manage-
ment decisions. However, the inherent difficulties to
these large randomized studies and the complexity in di-
alysis patients, including the large variations in inter- and
intradialytic BP values, make this a difficult task. In the
meantime, inference from studies performed on hyper-
tensive patients in earlier stages of chronic kidney disease
(CKD) or the non-CKD population with individualized
clinical assessment is a reasonable approach.
BP-Lowering Effect
While important, nonpharmacological treatments,
such as fluid removal, are often insufficient to achieve the
presumed target BP levels in dialysis patients. Multiple
antihypertensive drugs are often necessary [2]. Because
of this, emphasis on a single first line of drugs to be used
is not very useful. Nevertheless, there are many condi-
tions for which evidence supports the use of one drug
over others, either as initial treatment or as a part of a
combination.
Four major classes of antihypertensive agents are suit-
able for the initiation and maintenance of antihyperten-
sive treatment, alone or in combination. These are CCBs,
angiotensin-converting enzyme inhibitors (ACEIs), an-
giotensin receptor blockers and ␤Bs. In addition, ␣-ad-
renergic blockers, central-acting agents and direct vaso-
dilatory drugs can also be useful. Loop diuretics can be
used in subjects with residual kidney function, with more
than 300 ml daily of urinary output, usually a short pe-
riod of time after starting hemodialysis. Finally, the re-
cently introduced direct renin inhibitors are also of inter-
est although no information on this class of drugs has
been available for patients on dialysis up to now [8].
Whether or not one class of drug results in greater BP re-
duction compared to other classes in dialysis patients has
not been fully explored.
The Task Force for the Management of Arterial Hy-
pertension of the European Society of Hypertension and
of the European Society of Cardiology (ESH/ESC) has
provided recommendations for the use of combination
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Loop diuretics
␤Bs ARBs
␣-Blockers CCBs
ACEIs
Fig. 1. Recommendations for combining antihypertensive drugs
according to the ESH/ESC guidelines [5]. The most recommend-
ed are those connected by solid lines. For dialysis patients who do
not respond to diuretics, dialytic fluid removal should substitute
loop diuretics. Caution should be exercised when combining
CCBs and ␤Bs in patients who are prone to develop bradycardia
or heart block. ARBs = Angiotensin receptor blockers.
drug therapy [5]. This schema is presented in figure 1.
The unique characteristics and the complexity of treat-
ment in dialysis patients do not favor the use of single-pill
combination drugs.
When using antihypertensive agents in the dialysis pa-
tient, recommendations for antihypertensive treatment
in the non-CKD population generally apply [4, 5]. Long-
acting antihypertensive drugs which cover the 24 h with
once-a-day administration are recommended to improve
adherence to treatment [9]. In addition, several questions
should be addressed: can the full dose of the drug be used
or does it need to be reduced because of impaired kidney
clearance of the drug? Is the drug removable by hemodi-
alysis or peritoneal dialysis? Is a supplemental dose nec-
essary after dialysis? Finally, are there special conditions
that favor one drug or another? These questions have
been discussed in detail in recent publications [10, 11].
Dose Reduction
The necessity or not to reduce the dose of the drug in
dialysis patients largely depends on the metabolism and
excretion route and capacity of the drug (fig. 2). Not only
do drug classes differ in their pharmacokinetic patterns
from each other, clinically relevant intraclass differences
also exist. All loop diuretics, CCBs, angiotensin receptor
blockers and ␣-adrenergic blockers can be administered
Antihypertensive Agents and Dialysis
at full dose and at time intervals as in the non-CKD pop-
ulation. This generalization is based on considerations of
plasma drug levels. However, considerations for efficacy
may necessitate the change in dose. For example, a much
larger dose of loop diuretics may be required to achieve
diuresis in the dialysis patients. In contrast, the dose
should be reduced by at least 50%, or the dosing interval
should be at least doubled, for the majority of the ACEIs.
Only fosinopril and benazepril allow use with a modest
reduction of dose of approximately 25%, because they are
largely metabolized in the liver.
The situation of the other antihypertensive classes is
more heterogeneous. Consider, for example, ␤Bs, 1 of the
4 main antihypertensive classes. While the doses of ace-
butolol, atenolol, betaxolol, carvedilol, nadolol and so-
talol need to be reduced at least by half, all the others can
maintain the full dose. Among the central-acting agents,
in contrast to clonidine and guanabenz, the doses of gua-
nethidine and methyldopa need to be reduced, while re-
serpine should be avoided. Hydralazine is the only direct
vasodilatory drug that requires dose reduction. The us-
age and dosing of direct renin inhibitors should await
specific data on this drug in dialysis patients.
Removal and Supplement for Dialysis
The extent to which a drug is affected by dialysis is de-
termined by several physicochemical characteristics of the
drugs. These include molecular weight, plasma protein
binding, volume of distribution and intercompartmental
transfer, water solubility and plasma clearance by the body,
besides the technical aspects of the dialysis procedure such
as characteristics of the dialysis membrane, blood and di-
alysate flow rates, convective versus diffusive mode of sol-
ute transport, and treatment time [10]. The removal of
drugs during dialysis is the result of this complex interplay
of conditions. The extent of this removal, in turn, deter-
mines whether supplemental dosing is necessary during
or following dialysis. Interactions of a specific hemodialy-
sis membrane, the AN69 membrane, with coagulation
proteins in the presence of ACEIs can produce anaphylac-
toid reactions, as a result of the generation and accumula-
tion of vasoactive bradykinin in the plasma [12].
In general, antihypertensive drugs are not removed
significantly by hemodialysis, with the exception of
ACEIs, some ␤Bs (acebutolol, atenolol, nadolol, sotalol),
methyldopa and hydralazine (fig. 3). In these cases, the
use of long-acting drugs 3 times a week after each hemo-
dialysis session is a good option for promoting drug ad-
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Blood Purif 2010;29:93–98 95
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 ACEIs ␤Bs Vasodilators Central ARBs CCBs ␣-Blockers
agents
bisoprolol diazoxide clonidine candesartan all doxazosine
esmolol minoxidil guanabenz eprosartan dihydropyridines prazosine
labetalol nitroprusside irbesartan terazosine
metoprolol losartan verapamil
pindolol olmesartan diltiazem
timolol telmisartan
valsartan Full dose

fosinopril
acebutolol
benazepril betaxolol 25% dose reduction
atenolol hydralazine guanethidine
carvedilol methyldopa 50% dose reduction
captopril nadolol
enalapril sotalol
lisinopril
Fig. 2. Dose recommendations for the an- perindopril
tihypertensive drugs used in dialysis pa- quinapril
ramipril
tients. ARBs = Angiotensin receptor block-
trandolapril 50–75% dose reduction
ers.

ACEIs ␤Bs Vasodilators Central ARBs CCBs ␣-Blockers

agents
fosinopril bisoprolol diazoxide clonidine candesartan all doxazosine
benazepril esmolol minoxidil guanabenz eprosartan dihydropyridines prazosine
labetalol nitroprusside guanethidine irbesartan terazosine
metoptrolol losartan verapamil
pindolol olmesartan diltiazem
timolol telmisartan
acebutolol valsartan
betaxolol No removal
quinapril
Fig. 3. Removal of antihypertensive drugs ramipril
by hemodialysis. Drugs in the shaded ar- trandolapril 30% removal
eas require a supplementary dose after di-
alysis. The magnitude of removal varies captopril atenolol hydralazine methyldopa
depending on the efficiency and duration enalapril carvedilol
lisinopril
of the dialysis session. Removal also oc- nadolol
perindopril
curs on peritoneal dialysis. ARBs = Angio- sotalol
50% removal
tensin receptor blockers.

herence. In peritoneal dialysis, only methyldopa and hy-
dralazine are the major drugs that are dialyzable. These
drugs, especially methyldopa, are not commonly used
nowadays.
Special Conditions
Clinical characteristics of individual patients can af-
fect the choice of the antihypertensive drugs, either fa-
voring or discouraging their use, as in the case of hyper-
tensive patients not on chronic dialysis. For example, the
presence of coronary heart disease or congestive heart
failure is a compelling indication for ␤Bs, while concom-
itant peripheral vascular disease or bronchial hyperreac-
tivity discourages their use. The venodilatory property
of furosemide can be beneficial in congestive heart fail-
ure. Persistent hyperkalemia can limit the use of drugs
that block the RAAS or the ␤Bs, even in dialysis pa-
tients.
A complete list of reasons for favoring or for avoiding
the use of each antihypertensive class was listed in the
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ESH/ESC guidelines published in 2007 [5]. Recommen-
dations of specific drug classes for the treatment of car-
diovascular diseases should be taken with caution in di-
alysis patients [13–15], because of the paucity of solid ev-
idence-based data supporting their efficacies.
Potential Effects beyond BP Reduction
A large burden of cardiovascular disease exists in the
dialysis patients. End-stage renal disease is associated
with a 10- to 20-fold increased risk of cardiovascular
mortality, compared with age- and sex-matched controls
without CKD [1]. Cardiac deaths are extremely common
in dialysis patients and account for the majority of car-
diovascular deaths [16]. Coronary heart disease, vascular
calcification and uremic cardiomyopathy probably un-
derlie the majority of these cardiac deaths [17]. Thus, car-
dioprotective properties of antihypertensive drugs, be-
yond their BP-lowering effect, should be taken into ac-
count. Drugs blocking the RAAS and ␤Bs and CCBs may
confer potential additional benefits, since overactivity of
the RAAS (as reflected by increased plasma renin activ-
ity), increased levels of sympathetic activity (as reflected
by elevated plasma levels of norepinephrine and neuro-
peptide Y and reduced heart rate variability) and intra-
cellular calcium overload are common in dialysis pa-
tients. Furthermore, sympathetic overactivity has been
associated with increased cardiovascular mortality in he-
modialysis patients [18, 19].
Antihypertensive drugs also have effects on other pu-
tative cardiovascular risk factors that are frequently pres-
ent in dialysis patients. Hypertriglyceridemia and glu-
cose intolerance can be worsened by the use of ␤Bs, while
CCBs [20] and drugs blocking the RAAS [21] exert a ben-
eficial or at least a neutral effect.
However, the potential additional benefits of these
classes of drugs are inferior to their BP-lowering effects
in hypertensive subjects not on dialysis [22–24]. In con-
trast, subjects with BP values in the ‘normal range’ can
gain benefits with the use of these antihypertensive drugs,
but excessive BP reduction should be avoided in frail pa-
tients in which a ‘J curve’ relationship between BP and
mortality is observed. Drug-induced electrolyte disorder
is an additional concern in dialysis subjects who are prone
to develop hyperkalemia.
Despite the uncertainty about the additional non-BP-
related benefits, RAAS blockers, ␤Bs and CCBs, either
used alone or in combination, should be strongly consid-
ered as antihypertensive agents in dialysis subjects.
Conclusions
Antihypertensive drugs are commonly used in dialy-
sis patients, often based on the belief that lowering BP
reduces morbidity and improves survival, despite the
fact that no solid information is available about when an-
tihypertensive treatment should be initiated and what
the goals of treatment should be. Nonpharmacological
treatments, although important, are usually insufficient
to control BP in dialysis patients, and multiple antihy-
pertensive drugs are often necessary. The majority of the
antihypertensive agents can be used in dialysis patients,
but their pharmacokinetics and dialyzability should be
considered. Combination drug therapy offers additive
antihypertensive activity and often reduction in side ef-
fects, but a single-pill combination is ideal because of the
complexity of dialysis patients. The potential benefits of
some antihypertensive drugs beyond their BP-lowering
effect should be considered, although many uncertain-
ties still exist concerning dialysis patients. Balancing the
potential benefits and risks in individual patients is war-
ranted.

References 1 Foley RN, Collins AJ: End-stage renal dis-
ease in the United States: an update from the
United States Renal Data System. J Am Soc
Nephrol 2007; 18:2644–2648.
2 Ram CV, Fenves AZ: Management of hyper-
tension in hemodialysis patients. Curr Hy-
pertens Rep 2009;11:292–298.
3 Kidney Disease Outcome Quality Initiative:
Clinical practice guidelines for chronic kid-
ney disease: evaluation, classification and
stratification. Am J Kidney Dis 2002;39(sup-
pl 2):S1–S246.
4 Chobanian AV, Bakris GL, Black HR, Cush-
man WC, Green LA, Izzo JL Jr, Jones DW,
Materson BJ, Oparil S, Wright JT Jr, Roccella
EJ; Joint National Committee on Prevention,
Detection, Evaluation and Treatment of
High Blood Pressure, National Heart, Lung,
and Blood Institute; National High Blood
Pressure Education Program Coordinating
Committee: Seventh report of the Joint Na-
tional Committee on Prevention, Detection,
Evaluation and Treatment of High Blood
Pressure. Hypertension 2003;42:1206–1252.
149.126.78.33 - 1/27/2016 5:47:11 AM
Weizmann Inst. of Science

Antihypertensive Agents and Dialysis Blood Purif 2010;29:93–98 97

Downloaded by:
5 Mancia G, De Backer G, Dominiczak A,
Cifkova R, Fagard R, Germano G, Grassi G,
Heagerty AM, Kjeldsen SE, Laurent S, Nar-
kiewicz K, Ruilope L, Rynkiewicz A, Schmie-
der RE, Boudier HA, Zanchetti A, Vahanian
A, Camm J, De Caterina R, Dean V, Dick-
stein K, Filippatos G, Funck-Brentano C,
Hellemans I, Kristensen SD, McGregor K,
Sechtem U, Silber S, Tendera M, Widimsky
P, Zamorano JL, Erdine S, Kiowski W, Agabi-
ti-Rosei E, Ambrosioni E, Lindholm LH, Vi-
igimaa M, Adamopoulos S, Agabiti-Rosei E,
Ambrosioni E, Bertomeu V, Clement D, Er-
dine S, Farsang C, Gaita D, Lip G, Mallion
JM, Manolis AJ, Nilsson PM, O’Brien E, Po-
nikowski P, Redon J, Ruschitzka F, Tamargo
J, van Zwieten P, Waeber B, Williams B: The
Task Force for the Management of Arterial
Hypertension of the European Society of
Hypertension (ESH) and of the European
Society of Cardiology (ESC). J Hypertens
2007;25:1105–1187.
6 Heerspink HJ, Ninomiya T, Zoungas S, de
Zeeuw D, Grobbee DE, Jardine MJ, Gallagh-
er M, Roberts MA, Cass A, Neal B, Perkovic
V: Effect of lowering blood pressure on car-
diovascular events and mortality in patients
on dialysis: a systematic review and meta-
analysis of randomised controlled trials.
Lancet 2009;373:1009–1015.
7 Agarwal R, Sinha AD: Cardiovascular pro-
tection with antihypertensive drugs in dialy-
sis patients: systematic review and meta-
analysis. Hypertension 2009;53:860–866.
8 Schmieder RE: Renin inhibitors: optimal
strategy for renal protection. Curr Hyper-
tens Rep 2007;9:415–421.
98 Blood Purif 2010;29:93–98
9 Schmid H, Hartmann B, Schiffl H: Adher-
ence to prescribed oral medication in adult
patients undergoing chronic hemodialysis: a
critical review of the literature. Eur J Med
Res 2009;14:185–190.
10 Johnson CA: 2007 Dialysis of Drugs. Verona,
Nephrology Pharmacy Associates, 2007.
11 Levin N, Kotanko P, Eckardt KV, Kasiske B,
Chazot C, Cheung AK, Redon J, Wheeler
DC, Zoccali C, London G: Blood Pressure in
Chronic Kidney Disease Stage 5D – A Posi-
tion Statement from Kidney Disease: Im-
proving Global Outcomes. New York, Kid-
ney Disease: Improving Global Outcomes,
submitted.
12 Ebo DG, Bosmans JL, Couttenye MM, Ste-
vens WJ: Haemodialysis-associated anaphy-
lactic and anaphylactoid reactions. Allergy
2006;61:211–220.
13 Kaisar MO, Isbel NM, Johnson DW: Recent
clinical trials of pharmacologic cardiovascu-
lar interventions in patients with chronic
kidney disease. Rev Recent Clin Trials 2008;
3:79–88.
14 Leidig M, Bambauer R, Kirchertz EJ, Szabã
T, Handrock R, Leinung D, Baier M, Schmie-
der RE: Efficacy, safety and tolerability of
valsartan 80 mg compared to irbesartan 150
mg in hypertensive patients on long-term he-
modialysis (VALID study). Clin Nephrol
2008;69:425–432.
15 Suzuki H, Kanno Y, Sugahara S, Ikeda N,
Shoda J, Takenaka T, Inoue T, Araki R: Effect
of angiotensin receptor blockers on cardio-
vascular events in patients undergoing he-
modialysis: an open-label randomized con-
trolled trial. Am J Kidney Dis 2008; 52:
501–506.
16 Herzog CA, Mangrum JM, Passman R: Sud-
den cardiac death and dialysis patients.
Semin Dial 2008;21:300–307.
17 Remppis A, Ritz E: Cardiac problems in the
dialysis patient: beyond coronary disease.
Semin Dial 2008;21:319–325.
18 Tong YQ, Hou HM: Alteration of heart rate
variability parameters in nondiabetic hemo-
dialysis patients. Am J Nephrol 2007; 27:63–
69.
19 Vonend O, Rump LC, Ritz E: Sympathetic
overactivity – the Cinderella of cardiovascu-
lar risk factors in dialysis patients. Semin
Dial 2008;21:326–330.
20 Zanos S, Mitsopoulos E, Sakellariou G: Para-
thyroid hormone levels, calcium-channel
blockers, and the dyslipidemia of nondiabet-
ic hemodialysis patients. Ren Fail 2005; 27:
163–169.
21 Mancia G, Grassi G, Zanchetti A: New-onset
diabetes and antihypertensive drugs. J Hy-
pertens 2006;24:3–10.
22 Blood Pressure Lowering Treatment Trial-
ists’ Collaboration: Effects of different blood
pressure-lowering regimens on major car-
diovascular events in individuals with and
without diabetes mellitus. Arch Intern Med
2005;165:1410–1419.
23 Staessen JA, Li Y, Thijs L, Wang J-G: Blood
pressure reduction and cardiovascular pre-
vention: an update including the 2003–2004
secondary prevention trials. Hypertens Res
2005;28:385–407.
24 Law MR, Morris JK, Wald NJ: Use of blood
pressure lowering drugs in the prevention of
cardiovascular disease: meta-analysis of 147
randomised trials in the context of expecta-
tions from prospective epidemiological
studies. BMJ 2009;338:b1665.
149.126.78.33 - 1/27/2016 5:47:11 AM
Weizmann Inst. of Science
Redon /Martinez /Cheung
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