Full text of DOI:10.1053/ajkd.2002.30542

The Official Journal of the
National Kidney Foundation
VOL 39, NO 2, FEBRUARY 2002
American Journal of
Kidney Diseases
AJKD
IN-DEPTH REVIEW
Hemodialysis-Associated Hypertension:
Pathophysiology and Therapy
Matthias P. Ho¨rl, MD, and Walter H. Ho¨rl, MD, PhD, FRCP
● The majority of end-stage renal disease (ESRD) patients are hypertensive. Hypertension in the hemodialysis
patient population is multifactorial. Further, hypertension is associated with an increased risk for left ventricular
hypertrophy, coronary artery disease, congestive heart failure, cerebrovascular complications, and mortality.
Antihypertensive medications alone do not adequately control blood pressure (BP) in hemodialysis patients. There
are, however, several therapeutic options available to normalize BP in these patients, often without the need for
additional drug therapy (eg, long, slow hemodialysis; short, daily hemodialysis; nocturnal hemodialysis; or, most
effectively, dietary salt and fluid restriction in combination with reduction of dialysate sodium concentration).
Optimal BP in dialysis patients is not different from recommendations for the general population, even though
definite evidence is not yet available. Predialysis systolic and diastolic BPs are of particular importance. Left
ventricular mass correlates with predialysis systolic BP. Survival is better in hemodialysis patients with a mean
arterial pressure below 99 mm Hg as compared with those with higher BP. Low predialysis systolic BP (<110 mm
Hg) and low predialysis diastolic BP (<70 mm Hg) are associated with increased mortality, primarily because of
severe congestive heart failure or coronary artery disease. Patients that experience repeated intradialytic hypoten-
sive episodes should also be viewed with caution, and predialytic BP values should be reevaluated. A possible
treatment option for these patients may be slow, long hemodialysis; short, daily hemodialysis; or nocturnal
hemodialysis. Among the antihypertensive agents currently available, angiotensin-converting enzyme (ACE)
inhibitors appear to have the greatest ability to reduce left ventricular mass. Pressure load can be satisfactorily
determined by using the average value of predialysis BP measurements over 1 month. In selected hemodialysis
patients, interdialytic ambulatory blood pressure monitoring (ABPM) may help to determine if the patient is in fact
hypertensive. In addition, ABPM provides important information about the change in BP between day and night.
Regular home BP monitoring, yearly echocardiography, and treatment of traditional risk factors for cardiovascular
disease are recommended.
© 2002 by the National Kidney Foundation, Inc.
INDEX WORDS: Hemodialysis (HD); hypertension; left ventricular hypertrophy; erythropoietin (EPO); sodium
restriction; dialysis regimen; angiotensin-converting enzyme (ACE) inhibitors.
YPERTENSION is very common in pa-
H tients undergoing regular conventional he-
From the Department of Nephrology and Rheumatology,
University of Du¨sseldorf, Germany; and the Division of
Nephrology and Dialysis, Department of Medicine III, Uni-
versity of Vienna, Austria.
Received June 20, 2001; accepted in revised form August
modialysis treatment.1-6 Between 50% and 90%
of dialysis patients have a blood pressure (BP)
greater than 140/90 mm Hg, whereas only a mi-
nority has adequate BP control.7 Hypertension is
independently correlated with morbidity and mor-
tality in the hemodialysis population.2,8 Charra et
al9 have found reduced survival in hemodialysis
patients when predialysis mean arterial pressure
was greater than 99 mm Hg. In contrast, Salem
and Bower10 and Salem11 reported that hyperten-
31, 2001
Address reprint requests to Walter H. Ho¨rl, MD, PhD,
FRCP, Professor of Medicine, Chief, Division of Nephrology
and Dialysis, Department of Medicine III, Wa¨hringer Gu¨rtel
18-20, A-1090 Vienna, Austria.
© 2002 by the National Kidney Foundation, Inc.
0272-6386/02/3902-0001$35.00/0
doi:10.1053/ajkd.2002.30542
American Journal of Kidney Diseases, Vol 39, No 2 (February), 2002: pp 227-244
227

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228
HORL AND HORL
sion did not have an adverse effect on 1-year and
2-year mortality in a cohort of 649 hemodialysis
patients. Hemodialysis patients often do not have
the normal decrease in nocturnal BP,7,12-14 thereby
exposing them to the development of left ventric-
ular hypertrophy.15-18 Left ventricular hypertro-
phy is an independent predictor of cardiovascu-
lar disease and significantly reduces the life
expectancy of hemodialysis patients.19,20 Left
ventricular dysfunction is present in approxi-
mately 80% of end-stage renal disease (ESRD)
patients and highly predictive of future ischemic
heart disease, cardiac failure, and death.21 Car-
diac disease is the single most important risk
factor among long-term dialysis patients, account-
ing for almost 50% of deaths in the United
States.22 Data from the Canadian Organ Replace-
ment Register indicate that in 1995, 45% of the
deaths among patients on renal replacement
therapy were related to cardiovascular disease.23
Foley et al24 found that each 10 mm Hg rise in
mean arterial BP was independently associated
with a progressive increase of concentric left
ventricular hypertrophy, the development of de
novo cardiac failure, and de novo ischemic heart
disease. Very high correlations were found be-
tween both the degree of cerebral atrophy and
predialytic BP values, as well as cerebral atrophy
and the duration of hypertension in hemodialysis
patients.25 These data suggest that long-term hy-
pertension is not a harmless condition but rather
a major risk factor for cardiovascular events in
the general population and particularly in ESRD
patients. It is well known that it takes several
years for hypertension-associated complications
to become manifest.
The aims of this overview were not only to
underline the importance of hypertension as a
cardiovascular risk factor for hemodialysis pa-
tients, but also to define how to monitor and treat
hypertension in this patient population, and, fi-
nally, to evaluate the pathophysiologic factors
involved in the manifestation of high BP in
hemodialysis patients.
HOW TO MONITOR BLOOD PRESSURE?
Manual home BP monitoring is recommended.
Agarwal26 compared daily home BP monitoring
in chronic hemodialysis patients with the 44-
hour interdialytic ambulatory blood pressures
(ABPs) by using a Spacelab 90207 ABP monitor
(SpaceLabs Medical Inc, Redmond, WA). Ambu-
latory blood pressure monitoring (ABPM)
showed a progressive BP decrease after dialysis
and during the first night. BP rapidly reached
predialysis levels by the next morning and did
not decrease during the second night (Fig 1). The
investigator found an excellent correlation be-
tween average systolic and diastolic ABP and
respective home BPs. Predialysis diastolic (pre-
diastolic) BPs more than predialysis systolic
(presystolic) BPs were a good reflection of the
respective ABPs. Studies using ABPM in patients
undergoing regular hemodialysis therapy have
shown that casual BP measurements either under-
Fig 1. The average heart
rate and systolic BP with
ABP monitoring during the
44-hour interval. The error
bars are the standard error
of the mean and the shaded
columns represent the hours
of 10 PM to 6 AM defined as
night for the purpose of anal-
ysis of ABP. Reprinted with
permission from Agarwal.26

HEMODIALYSIS AND HYPERTENSION
229
estimate or overestimate the degree of hyperten-
sion during the interdialytic period.4,7,27-29
age.34,35 The prevalence of nondipping increases
with declining renal function. Abnormal diurnal
BP is found in approximately 80% of the dialysis
patients, in approximately 75% of the patients
with plasma creatinine greater than 6.8 mg/dL,
and in renal transplant recipients.36 The associa-
tion of altered nycthemeral BP rhythm and an
increased pulse pressure plays a major role in
the cardiovascular prognosis of ESRD patients.
Pulse-wave velocity is significantly higher in
nondippers than in dippers.37
Sorof et al30 measured interdialytic BP by
ABPM during in-patient fluid restriction in 12
children receiving chronic hemodialysis. The in-
vestigators found that sleep BP decreased from
daytime BP by 6% for systolic and 11% for
diastolic BP. One patient had a normal dip
(Ն10%) in systolic BP and 7 children had a
normal dip in diastolic BP. Sleep loads (defined
as the percentage of BPs greater than the 95th
percentile) were significantly greater than day-
time loads for systolic BP (53% versus 28%) and
diastolic BP (57% versus 27%). Casual BP corre-
lated poorly with ABPM.30
WHAT IS THE TARGET BLOOD PRESSURE
IN HYPERTENSIVE DIALYSIS PATIENTS?
The target BP in hypertensive patients should
not be different than that recommended for the
general population.38 Several studies, however,
have shown that low presystolic BP is associated
with increased mortality in hemodialysis pa-
tients.39-44 The risk of mortality is U shaped,
being higher among patients who are markedly
hypertensive (presystolic BP Ͼ180 mm Hg) or
markedly hypotensive (presystolic BP Ͻ110 mm
Hg) before dialysis or markedly hypotensive
after dialysis. The mortality risk was lowest for
patients with presystolic BP between 150 and
159 mm Hg.42 Cardiovascular complications may
contribute to this high mortality risk. Hemodialy-
sis patients with low presystolic BP also have
congestive heart failure and/or coronary artery
disease.42,44 Therefore, low predialytic BP is a
marker of severe congestive heart failure rather
Conlon et al31 found no difference between
daytime and nighttime ABP in adult hemodialy-
sis patients; however, they observed a strong
correlation between systolic ABP and presystolic
BP. Postdiastolic BP correlated better with dia-
stolic ABP than did prediastolic BP. In this group
of hemodialysis patients on stable antihyperten-
sive medications and with stable hematocrit val-
ues, left ventricular mass correlated with systolic
ABP and presystolic BP (Fig 2). Zoccali et al32
concluded that the pressure load can be satisfac-
torily approached by using the average value of
12 predialysis BP measurements over 1 month.
Normal nocturnal decline of BP in healthy
individuals results in a 15% reduction in systolic
and a 20% reduction in diastolic BP.33 ABP over
a 24-hour period correlates with end-organ dam-
Fig 2. (A) Relationship between mean predialysis systolic BP and left ventricular mass. (B) Relationship between
mean 24-hour systolic ABP and left ventricular mass. Straight line is regression line, and dotted line is 95%
confidence interval of regression line. Reprinted with permission from Conlon et al, “Predialysis systolic blood
pressure correlates strongly with mean 24-hour systolic blood pressure and left ventricular mass in stable
hemodialysis patients.” J Am Soc Nephrol 7(12):2658-2663, 1996.31

¨
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230
HORL AND HORL
than a causal risk factor for cardiovascular mor-
tality in ESRD patients.45
tion and/or cardiovascular disease in chronic
hemodialysis patients. Therefore, the investiga-
tors recommended higher target diastolic BP
levels in chronic hemodialysis patients than in
the general population. On the other hand, there
was a significant correlation between diastolic
BP and both interdialytic weight gain and per-
cent weight gain.49 Mazzuchi et al50 found that
lower predialytic BP values were predictive of
death during short observation periods. Mortality
in long-term observations was, however, less in
hemodialysis patients with normal BP as com-
pared with those with hypertension.
Presystolic hypertension is associated with
left ventricular hypertrophy,31 a main mortality
risk factor not only in ESRD patients but also in
the general population. In hemodialysis patients
without intradialytic hypotension, BP should not
differ from recommendations made for the gen-
eral population.46 In the study by Port et al,43 the
presystolic BP of the reference group was be-
tween 120 and 149 mm Hg. These investigators
found an association between low presystolic BP
and an elevated adjusted mortality risk (Fig 3).
No association was observed between mortality
risk and presystolic hypertension, except for an
elevated risk for cerebrovascular deaths. There-
fore, low predialysis BP must to be viewed with
great concern.43 London47 recommends an opti-
mum predialysis BP of less than 140/90 mm Hg
for hemodialysis patients with classic systolic-
diastolic hypertension. For patients with isolated
systolic hypertension (commonly observed in
elderly people), he recommends presystolic BP
values of 150 to 160 mm Hg (“my personal
opinion”47), but adequate controlled studies are
not available. In the study by Grekas et al,6 only
4.5% of the hemodialysis patients had isolated
systolic hypertension. Iseki et al48 found a crude
death rate of 40% in a cohort of chronic hemodi-
alysis patients when the diastolic BP was less
than 70 mm Hg, of 35.0% at 70 to 79 mm Hg, of
25.0% at 80 to 89 mm Hg and 90 to 100 mm Hg,
and of 13.0% at greater than 100 mm Hg. Low
diastolic BP may be a manifestation of malnutri-
WHICH BLOOD PRESSURE SHOULD BE
TREATED: PREDIALYSIS OR POSTDIALYSIS?
Mittal et al5 defined hypertension for the hemo-
dialysis patient population as BP greater than
150/90 mm Hg. These investigators found presys-
tolic hypertension in 112 patients (58.9%), predi-
astolic hypertension in 49 patients (25.8%), post-
systolic hypertension in 61 patients (32.1%), and
postdiastolic hypertension in 26 patients (13.7%).
Kooman et al13 also included hypotensive pa-
tients in their analysis and found that the postdi-
alysis BP was more representative of the average
interdialytic BP in hemodialysis patients than the
predialysis BP values. On the second day, how-
ever, predialysis systolic BP was more represen-
tative of the average ABP. Systolic BP is more
strongly linked to cardiovascular risk than either
the diastolic BP or the mean arterial pressure.51,52
According to Conlon et al,31 it is essential to
control presystolic BP in hemodialysis patients.
Fig 3. Relative mortality
risk (RR) according to predi-
alysis systolic BP compared
with the reference group of
120 to 149 mm Hg (RR ؍
1.00). Three separate mod-
els are shown according
to the level of statistical ad-
justment. (}) Demographic
only; (■) noncardiovascular
added; (Œ) cardiovascular
added. Reprinted with per-
mission from Port et al.43

HEMODIALYSIS AND HYPERTENSION
231
Table 1. Reasons for Hypertension
in Hemodialysis Patients
studies have failed to show such a relation-
ship.4,7,29,54,61,62 A possible explanation for this
discrepancy can be taken from data by Luik et
al.63 In this study, a 3-L interdialytic fluid load
did not result in a BP increase in most hemodialy-
sis patients. Only 3 of 10 patients had a higher
systolic but not diastolic BP after fluid load.63
Interdialytic weight gain, systolic BP, and hemat-
ocrit independently influence the left ventricular
mass index in chronic hemodialysis patients.64
There is a correlation between loss of weight
during hemodialysis and lowering of systolic
BP.5 A reduction in postdialysis mean arterial
pressure of Ն5%, controlled by ultrafiltration,
was found in 68.5% of hypertensive but in 87.5%
of normotensive hemodialysis patients.6 Plasma
aldosterone and fluid volume removed by ultrafil-
tration are significantly correlated.65 Volume sen-
sitivity is higher in hypertensive as compared
Extracellular volume excess/volume overload
Derangements of renin-angiotensin system
Sympathetic overactivity
Impaired endothelium-dependent vasodilatation
Uremic toxins (ADMA, homocysteine)
Genetic factors
Geographic factors/influence of climate
Correction of renal anemia by rHuEPO
Secondary hyperparathyroidism
Sodium intake/dialysate sodium concentration
Hemodialysis regimen
PATHOPHYSIOLOGY OF HYPERTENSION
Potential risk factors responsible for the devel-
opment of hypertension in hemodialysis patients
are summarized in Table 1.
with normotensive hemodialysis patients.66
A
Expanded Extracellular Fluid Volume and
Renin-Angiotensin-Aldosteron System
correlation between BP and interdialytic weight
gain does not exist for normotensive patients,67
probably because of an adequate vasodilatatory
response in these patients that may be less effec-
tive or even absent in hypertensive hemodialysis
patients. Patients with uncontrolled hypertension
are more likely to have hypertension as the cause
of their ESRD as compared with normotensive
hemodialysis patients.49
Extracellular fluid expansion is the most con-
sistent finding in hypertensive ESRD patients.
Lins et al53 determined a total body water of
54.7% Ϯ 5.3% in normotensive and of 58.9% Ϯ
4.6% in hypertensive hemodialysis patients. Im-
proved dialysis survival occurs when extracellu-
lar fluid volume is controlled by long, slow
hemodialysis technique.9,54,55 Because extracellu-
lar fluid expansion in patients suffering from
nephrotic syndrome is not necessarily associated
with hypertension, pertubations in vascular auto-
regulation may occur in hypervolemic ESRD
patients. Mailloux56 recently summarized the
mechanisms involved as follows: (1) inappropri-
ate increased angiotensin II in relationship to
volume and exchangeable sodium, (2) increased
vascular sensitivity to endogenous pressors, (3)
increased cardiac output in the presence of an
inappropriately high peripheral vascular resis-
tance, and (4) failure to fully suppress vasocon-
strictor systems.
Hypertension is mainly related to weight gain
during the interval between 2 dialysis sessions,
and BP may be maintained within the normal
range by correcting extracellular volume excess
with dialysis.57 However, the results obtained in
different studies in adults and children on chronic
hemodialysis therapy are contradictory. For ex-
ample, some studies found that volume status
affects interdialytic BP,30,44,49,58-60 whereas other
Role of Sympathetic Nervous System
Increased activity of the sympathetic nervous
system may contribute to hypertension in ESRD
patients.68,69 Plasma volume contraction and nega-
tive sodium balance during dialysis therapy may
induce an increase in plasma catecholamine lev-
els.70 Grekas et al65 found no difference between
pre- and postdialysis plasma adrenaline, noradren-
aline, and renin activity in normotensive and
hypertensive hemodialysis patients. These inves-
tigators suggested that sympathetic activity is not
associated with hemodialysis hypertension. In
contrast, Converse et al71 provided evidence for
chronic sympathetic overactivity in hemodialy-
sis patients. Sympathetic-nerve discharge was
2.5 times higher in maintenance hemodialysis
patients than in normal subjects. Hemodialysis
patients who had undergone bilateral nephrec-
tomy had sympathetic-nerve discharge similar to
normal subjects. The rate of sympathetic-nerve
discharge was not correlated with either plasma

¨
¨
232
HORL AND HORL
noradrenaline concentration or plasma renin ac-
tivity,71 which may explain the negative find-
ings of Grekas et al65 reported earlier. Reduced
sympathetic-nerve discharge may be 1 important
mechanism by which bilateral nephrectomy
lowers BP.71 Fluid overload of greater than 6%
of body weight results in activation of the
sympathetic nervous system and release of the
vasoconstrictor neuropeptide Y,72 whereas a 3-L
interval fluid load does not influence plasma
catecholamines.63 Angiotensin-converting en-
zyme (ACE) inhibition results in reduction of
sympathetic hyperactivity in patients with chronic
renal failure.73
renomedullin, a potent vasorelaxant. In the study
of Mallamaci et al,85 the average plasma ad-
renomedullin concentration was 2.6 times higher
in uremic patients than in healthy subjects. After
fluid subtraction by isolated ultrafiltration, ad-
renomedullin fell but remained well above the
upper limit seen in normal subjects. Systemically
administered adrenomedullin has been shown to
significantly decrease mean arterial pressure in
healthy subjects86,87 but to a much lesser extent
in patients with congestive heart failure.87
Influence of Climate and Geographic Factors
Argile´s et al88 accurately evaluated the impor-
tance of BP variations associated with seasonal
changes in maintenance hemodialysis patients.
The variations amounted to 12 mm Hg for mean
systolic BP (153 Ϯ 3 versus 141 Ϯ 3 mm Hg)
and 7 mm Hg for diastolic BP (82 Ϯ 2 versus
75 Ϯ 2 mm Hg). The patients were evaluated 3
times weekly for 31 months in the same city. The
investigators concluded that high temperature
and low humidity facilitate BP control in ESRD
patients undergoing regular hemodialysis therapy.88
Several studies have shown that geographic fac-
tors are also determinants of BP in the general
population.89-92
Impaired Vasodilatation
Endothelium-dependent vasodilatation is im-
paired in uremia.74 The vascular endothelium
produces and releases vasoactive compounds such
as nitric oxide (NO), which may cause vasodila-
tation and inhibition of vascular smooth muscle
cell proliferation.75 Morris et al76 showed reduced
vasodilatation to carbachol, an endothelium-
dependent vasodilatator, in uremic patients,
whereas the response to sodium nitroprusside, an
endothelium-independent vasodilatator, was pre-
served. Experimental NO deficiency causes hy-
pertension.77 NO deficiency occurs in ESRD
patients and may contribute to hypertension in
this population.78,79 The production of NO by the
vascular endothelium is inhibited by asymmetric
dimethylarginine (ADMA), which accumulates
in chronic renal failure patients.80 PlasmaADMA
levels are 6- to 10-fold higher in hemodialysis
patients than in healthy subjects. These ADMA
concentrations may inhibit NO synthases. Plasma
ADMA concentration can be reduced during the
dialysis procedure by 65%.79,81 Plasma ADMA
levels are also elevated in patients with atheroscle-
rotic diseases and normal kidney function82 but
are particularly enhanced in hemodialysis pa-
tients with atherosclerotic complications.81 There-
fore, high plasma ADMA levels may, at least in
part, be responsible for impaired endothelium-
dependent vasodilatation observed in uremia. No
significant correlation, however, was observed
between ADMA concentration and BP in dialysis
patients.83 Another factor that may impair endo-
thelial function in ESRD patients is hyperhomo-
cysteinemia.84
Erythropoietin and Correction of Renal Anemia
In the study by Mittal et al,5 the dose of human
recombinant erythropoietin (rHuEPO) had no
effect on the degree of hypertension. The hemo-
dialysis patients received a mean rHuEPO dose
of 5,905 Ϯ 3,854 U per treatment to maintain a
mean hematocrit of 33.3% Ϯ 3.5%. Similar data
were obtained by Coomer et al.8 In contrast,
Raine and Roger,93 as well as Grekas et al,6
observed a significant correlation between the
weekly dose of rHuEPO and BP. In the study by
Grekas et al,6 the prevalence of hypertension was
62% in rHuEPO-treated hemodialysis patients
but only 38% in those not receiving rHuEPO.
In 20% to 30% of kidney failure patients,
regular administration of rHuEPO is accompa-
nied by de novo hypertension or aggravation of
preexisting hypertension. The increase in arterial
BP does not occur immediately but rather within
a few weeks to months after initiation of rHuEPO
therapy.93-96 Hypertension associated with rHuEPO
therapy is not mediated by the increase in hemat-
ocrit. Vaziri et al97 showed a marked increase in
Hypervolemia enhances the release of ad-

HEMODIALYSIS AND HYPERTENSION
233
arterial BP of equal magnitude beginning 1 week
after initiation of rHuEPO therapy in both iron-
deficient and iron-sufficient rats with chronic
renal failure. The investigators could also show
that multiple, small, packed red blood cell trans-
fusions failed to increase arterial BP in these
animals despite hematocrit values identical to
those of iron-sufficient animals achieved by
rHuEPO treatment.97 Kaupke et al98 observed a
marked increase of hematocrit after iron reple-
tion in rHuEPO-treated dialysis patients with
preexisting iron-deficiency anemia without fur-
ther increase in BP.
Alterations of the arterial system in ESRD
patients include diffuse dilatation, hypertrophy, and
stiffening of the aorta and major arteries.99-102
Increased aortic stiffness is a strong independent
predictor of all-cause and mainly cardiovascular
mortality in ESRD patients undergoing hemodi-
alysis. Age and aortic pulse-wave velocity
emerged as predictors for the mortality observed,
whereas hemoglobin and low diastolic BP inter-
fered to a smaller extent.103
Mechanisms of BP increase during rHuEPO
therapy in ESRD patients are summarized in
Table 2. Increasing the hematocrit from 20% to
30% leads to an increase in peripheral resistance
of approximately 25% (from 1,578 to 1,988
dyn ϫ s ϫ cmϪ5).104 In the study by Lebel et
al,105 systemic vascular resistance increased by
28% but was not adequately counterbalanced by
the decrease of only 6% in cardiac output, result-
ing in an increased predialysis and postdialysis
systolic and diastolic BP. Hypoxia causes a re-
active peripheral vasodilatation to improve re-
gional blood flow and thus oxygen supply.104
Roger et al106 determined forearm vascular resis-
tance and systemic BP in dialysis patients breath-
ing room air and 60% oxygen before and after
correction of anemia by rHuEPO. Those pa-
tients, who showed an increase in systemic BP
during rHuEPO therapy, also had a significant
increase in forearm vascular resistance after oxy-
gen breathing in the anemic state. If oxygen
breathing, however, did not alter vascular resis-
tance in the anemic state, systemic hemody-
namic parameters remained unchanged after cor-
rection of anemia.106
An increase in red cell mass during or after
correction of anemia leads to an increase in
whole-blood viscosity107 and thereby increases
cardiac afterload.104 Anastassiades et al108 found
a marked expansion of the red cell volume from
912 Ϯ 127 to 1,471 Ϯ 222 mL and a concomitant
contraction of the plasma volume from 3,923 Ϯ
250 to 3,178 Ϯ 326 mL, leaving the blood
volume unchanged. In this study, predialysis
patients had a similar expansion of the red cell
volume but no contraction of the plasma volume,
so that the blood volume tended to expand from
4,149 Ϯ 347 to 4,618 Ϯ 414 mL. Gradual
reduction of plasma volume may be an important
strategy for the prevention and control of
rHuEPO-induced hypertension.108 Red cell mass
increased significantly in the study by Lebel et
al105 during correction of renal anemia, but plasma
volume, extracellular fluid volume, and exchange-
able sodium decreased significantly. Therefore,
the investigators suggested that volume-indepen-
dent mechanisms contribute to rHuEPO-induced
BP increase. Because an increase in BP may
occur even before hematocrit increases, this also
argues that other mechanisms contribute to the
increase in peripheral resistance associated with
rHuEPO therapy.
Table 2. Mechanisms of BP Increase During rHuEPO
Therapy in Hemodialysis Patients
Increase in whole-blood viscosity
Activation of various neurohumoral systems
Endothelin release
Vascular endothelial dysfunction
Genetic prediction of hypertension
Preexisting hypertension
Direct vasopressor effect of rHuEPO on renal resistance
vessels
Elevation of cytosolic free calcium in vascular smooth
muscle cells
Inhibition of NO synthesis
Up-regulation of genes implicated in the regulation of
vascular functions
Low baseline hematocrit
(Too) Rapid correction of anemia
Other factors in rHuEPO-induced hyperten-
sion include activation of various neurohor-
monal systems,109,110 endothelin release,111,112
vascular endothelial dysfunction,113,114 genetic
predisposition of hypertension,115,116 preexist-
ing hypertension,117,118 elevation of cytosolic free
calcium in vascular smooth muscle cells,119,120
inhibition of NO synthesis,121-123 up-regulation
of genes implicated in the regulation of vascular

¨
¨
234
HORL AND HORL
functions,124 low baseline hematocrit levels,125
and rapid correction of renal anemia.126-128
more, infusion of physiologic doses of parathy-
roid hormone increases BP and intracellular
calcium in healthy subjects.146
Chronic administration of rHuEPO increases
intracellular calcium by facilitating cellular Ca2ϩ
uptake.97,119,129,130 Elevation of basal intracellu-
lar calcium concentration increases vascular
smooth muscle tone,131 and down-regulation of
NO production132 results in hypertension. Nor-
malization of intracellular calcium by calcium
channel blockade abrogates rHuEPO-induced hy-
pertension and reverses down-regulation of NO
production.133 Erythropoietin has synergistic ef-
fects on angiotensin II– or noradrenaline-in-
duced intracellular calcium mobilization in vas-
cular smooth muscle cells.120 Erythropoietin
enhances vascular responsiveness to norepineph-
rine, endothelin-1, and constrictor prosta-
noids.134,135 Studies on rats with chronic renal
failure, however, suggest that rHuEPO-induced
hypertension is not mediated by increased plasma
endothelin-1 levels but by an increase in blood
vessel endothelin-1 production.136
Natriuretic Factors in ESRD Patients
Circulating natriuretic peptides, particularly
␣-human atrial natriuretic peptide (␣-ANP), regu-
late volume homeostasis and control BP and
electrolyte balance.147,148 In dialysis patients, plasma
␣-ANP levels are elevated because of stimula-
tion of ␣-ANP secretion, reflecting extracellular
volume expansion. The ␣-ANP values decrease
postdialysis but are still significantly higher than
those observed in healthy volunteers. Postdia-
lytic ␣-ANP levels remain elevated in normovol-
emic patients with altered left atrial hemodynam-
ics. Therefore, ␣-ANP might only be useful as a
parameter for fluid overload when cardiac func-
tion is normal. Similar to ␣-ANP, the concentra-
tion of brain natriuretic peptide (BNP) in plasma
is higher in hemodialysis patients than in healthy
subjects. In contrast to the ␣-ANP levels, those
of BNP were lowered less efficiently by the
hemodialysis procedure,149 probably because of
the longer half-life of BNP.
Hypertension is frequently associated with
elevated proANP and ␣-ANP concentrations.
Circulating concentrations of proANP(1-30),
proANP(31-67), proANP(79-98), and ␣-ANP in-
crease in patients with high BP in an apparent
attempt to overcome the constriction of blood
vessels.150 Winters and Vesely151 reported a de-
crease of ␣-ANP during the hemodialysis ses-
sion but proANP(1-98) and proANP(31-67) in-
creased. We studied 122 ESRD patients on
maintenance hemodialysis.152,153 ProANP(1-98)
levels increased 98-fold, proANP(1-30) levels
increased 35-fold, and proANP(31-67) increased
56-fold as compared with healthy subjects. Be-
fore hemodialysis, ␣-ANP was 217-fold elevated
as compared with controls. The interdialytic
weight gain ranged between 0 and 5.6 kg with a
mean value (ϮSD) of 2.3 Ϯ 1.0 kg. There was no
significant correlation between predialytic plasma
levels of ␣-ANP, proANP(1-30), proANP(31-
67), proANP(1-98), and interdialytic weight gain,
or between the respective plasma concentrations
and volume removal during hemodialysis. The
diameter of the vena cava inferior as a possible
parameter for volume overload, normovolemia,
or underhydration also did not correlate with
Heidenreich et al137 found a direct vasopressor
effect of rHuEPO on renal resistance vessels. On
the other hand, longer-term exposure of human
endothelial cells in culture with rHuEPO had a
vasodilatory effect.138 Administration of rHuEPO
is not associated with an instantaneous increase
in BP.139 A single intravenous infusion of 100 U
rHuEPO/kg body weight increases mean arterial
pressure. This effect, however, does not occur if
the rHuEPO dose is given subcutaneously.140
Correction of hematocrit to normal with rHuEPO
in chronic hemodialysis patients with cardiac
disease does not cause increased interdialytic BP
or predialysis and postdialysis BPs.141
Role of Secondary Hyperparathyroidism
Secondary hyperparathyroidism may also re-
sult in hypertension in ESRD patients by encour-
aging entry of calcium into vessel wall smooth
muscle cells.142 Ifudu et al143 compared predialy-
sis blood pressure, weight, and dose of antihyper-
tensive medications prescribed in 19 hemodialy-
sis patients before and after total parathyroidectomy.
Parathyroidectomy failed to correct hypertension
in patients on maintenance hemodialysis.143 In
contrast, treatment of secondary hyperparathy-
roidism by alfacalcidol resulted in significant
decreases in parathyroid hormone, platelet intra-
cellular calcium, and mean BP.144,145 Further-

HEMODIALYSIS AND HYPERTENSION
235
proANP(1-30), proANP(31-67), proANP(1-98), or
␣-ANP.152 Hemodialysis treatment using cellulose
triacetate dialyzer membranes lowered the plasma
concentrations of proANP(1-30), proANP(31-67),
and proANP(1-98) significantly more than using
polysulfone dialyzer membranes, whereas ␣-ANP
was not concentration affected.153 Hemodialysis
patients with moderate or severe hypertension
had higher concentrations of proANP fragments
and ␣-ANP than patients with normal BP or
patients with only mild hypertension.152 These
data indicate that circulating ␣-ANP and proANP
fragments are influenced by a variety of factors
such as ESRD, hemodialysis treatment, dialyzer
membrane material, cardiac dysfunction, and hy-
pertension. Therefore, ␣-ANP and proANP frag-
ments are not useful markers to accurately esti-
mate volume status in hemodialysis patients.
Cardiac natriuretic peptides are related to left
ventricular mass and function in dialysis pa-
tients, and predict overall and cardiovascular
mortality.154
function also by the urinary excretion of sodium
and chloride.
In Tassin (France), 95% of the patients ob-
tained normal BP without medication in the first
weeks of long dialysis therapy because of so-
dium and volume control.160 Dietary salt restric-
tion and reduction in dialysate sodium may also
control hypertension without lengthening dialy-
sis time.161,162 Dialysate sodium concentration
was gradually lowered from 140 to 135 mmol/L
at a rate of 1 mmol/L every 3 to 4 weeks in
combination with a NaCl-restricted diet of no
more than 6 g/day.160 In a pilot study, Kooman et
al163 decreased dialysate sodium concentration
from 140 to 136 mmol/L during a 6-week time
period, but did not find significant changes in
predialytic systolic or diastolic BP. These pa-
tients, however, were maintained on a sodium-
restricted diet, which may explain the failure of a
further BP decrease by reduction of dialysate
sodium concentration.163 Sodium overload in-
creases intracellular sodium and calcium concen-
tration and thereby increases the tone of vascular
smooth muscle cells. On the other hand, sodium
reduction may reverse this mechanism, resulting
in BP decrease.164
Sodium Restriction
The most effective way to control hyperten-
sion in dialysis patients is with the use of a
salt-restricted diet.155 There is an initial reduction
in extracellular volume that corresponds to the
volume and weight-loss correction. After a lag
period of several weeks to months,156 BP con-
tinues to decrease without a further decrease in
extracellular volume.157 This BP reduction is
associated with a decrease in peripheral vascular
resistance.158 Noninvasive assessments of dry
weight include radiologic features on chest radio-
graph such as heart size and intrapulmonary fluid
retention, echocardiography, sonography of the
inferior caval vein diameter, conductivity mea-
surements such as bioimpedance spectroscopy or
multiple-frequency bioelectric impedance, and
determination of several biochemical markers
such as plasma levels of natriuretic peptides,
cyclic guanosine 3Ј5Ј-monophosphate, or calcito-
nine-gene–related peptide. There is, however, no
single parameter to define adequate dry body
weight of a hemodialysis patient.159 Therefore,
volume expansion may persist in several patients
after the clinician has thought the patient reached
dry weight.56 Dialysis patients ingesting a low-
sodium (chloride) diet are monitored by follow-
ing body weight and in those with residual renal
Several studies on dietary salt intake have
¨
been performed in dialysis patients. Ozkahya et
al162 reemphasized salt restriction, stopped all
antihypertensive medication, and intensified ul-
trafiltration during hemodialysis. Interdialytic
weight gain decreased from 2.8 Ϯ 1.4 kg to
1.6 Ϯ 0.8 kg. During the total follow-up of 37 Ϯ
15 months, there was not only a significant
reduction in BP but also in wall thickness of the
left ventricle. In a further study,165 these investi-
gators restricted sodium chloride intake to less
than 100 mmol/day (Ͻ6 g/day) in 67 mainte-
nance hemodialysis patients. Average BP de-
creased from 173 Ϯ 17/102 Ϯ 9 to 139 Ϯ
18/86 Ϯ 11 mm Hg after 6 months and to 118 Ϯ
12/73 Ϯ 6 mm Hg after 36 months despite
discontinuation of antihypertensive drugs at the
beginning of treatment.
Dialysis sodium concentration influences post-
dialysis thirst, interdialytic weight gain, and BP,
as well as intradialytic morbidity. Hemodiafiltra-
tion treatments were compared with high (143
mmol/L) and low (138 mmol/L) dialysate so-
dium concentration. Low sodium level in dialy-
sate resulted in significantly lower intra- and

¨
¨
236
HORL AND HORL
interdialytic plasma sodium and potassium con-
centration as compared with high dialysate so-
dium. Even moderate hypertonicity at the end of
dialysis treatment contributes to the increase of
plasma potassium throughout the whole interdia-
lytic period by redistribution of water and potas-
sium from the intracellular to the extracellular
compartment.166 Thus, patients on low dialysate
sodium concentration benefit not only from BP
reduction but also from lower plasma potassium
during the interdialytic period. Flanigan et al167
compared dialysis by using a dialysate sodium
concentration of 140 mEq/L with dialysis by
using a programmed exponential decrease of
dialysis sodium from 155 mEq/L to 135 mEq/L.
Programmed variable sodium dialysis resulted in
a reduction in antihypertensive drug use without
alterations in predialysis BP, interdialytic weight
gain, ultrafiltration tolerance, or the frequency of
symptomatic dialysis cramps or hypotension.167
Linear sodium ramping from 155 mEq/L to 140
mEq/L or stepwise ramping can decrease intradia-
lytic side effects but increases interdialytic symp-
toms, weight gain, and hypertension.168 Profiled
dialysate sodium and ultrafiltration may lower
symptoms in both the intradialytic and the inter-
dialytic periods as compared with constant dialy-
sate sodium and ultrafiltration. Predialysis weight
was significantly greater during profiled treat-
ments, but there were no differences in postdia-
lytic weight, BP, or thirst.169 The use of sodium
and conductivity kinetic models guarantees ad-
equate sodium removal in each patient with each
treatment.170
sions report excellent BP control with dialysis
alone.54,59,172 Good BP control is the principal
reason for the low rate of cardiovascular compli-
cations in the hemodialysis patient population in
Tassin.9 In the study by Luik et al,172 73% of the
patients on short dialysis were using antihyperten-
sive medication, but none of the patients on long
dialysis were using antihypertensive medication.
Adequate BP control of patients on long dialysis
is caused by low total peripheral resistance. In
another study, only 2 of 24 patients on home
hemodialysis (dialyzed for 7.2 Ϯ 1.1 hr 3 times
weekly) were taking antihypertensive drugs.173
The mean 24-hour BP was 129 Ϯ 17 mm Hg
(systolic) and 83 Ϯ 14 mm Hg (diastolic). Six
patients (25%) had a normal circadian BP
rhythm.173 Normotension can be achieved inde-
pendently of the duration of hemodialysis if the
control of postdialysis extracellular volume is
adequate.174 This is, however, more difficult to
obtain with short than with more prolonged he-
modialysis procedures. Intradialytic hypotension
may occur during short dialysis sessions, particu-
larly in type II diabetic patients. Koch et al175
found that 2 or 3 hypotensive episodes per week
increased the risk for cardiac death by a factor of 3.
Frequent, short hemodialysis sessions can
achieve greater urea removal than 3 times per
week hemodialysis.176,177 Pinciaroli178 reported
BP control in 12 hypertensive patients on daily
hemodialysis after a few months. By achieving
and maintaining true dry body weight, 8 patients
were without antihypertensive drugs, and medi-
cation was reduced in the other 4 hemodialysis
patients. Mean BP decreased from 174/94 mm
Hg to 141/82 mm Hg in these patients. The
cardiothoracic index declined from 0.52 to 0.46
after 1 year.178 BP normalized in all patients on
daily dialysis in the study conducted by Buoncris-
tiani et al,179 whether they were initially hyperten-
sive or hypotensive. Woods et al180 described
patient outcomes after increasing hemodialysis
frequency from 3 to 6 times per week in a cohort
of 72 patients treated at 9 centers during 1972 to
1996. Presystolic and prediastolic BPs fell by 7
and 4 mm Hg, respectively, after starting fre-
quent hemodialysis. BP reductions were greatest
among patients being treated with antihyperten-
sive medications, despite reduction in their dos-
age of medications. In the study by Kooistra et
al,181 ABPM showed a systolic BP of 141.1 Ϯ
Effects of Dialysis Regimen
Velasquez et al171 compared the status of hyper-
tension and adequacy of BP control in ESRD
patients treated with different hemodialysis, mo-
dalities. The percentage of patients taking antihy-
pertensive medication was less, and control of
hypertension was better in patients treated with
high-efficiency hemodialysis by using a cu-
prophane membrane, high-flux hemodialysis, or
high-flux hemodiafiltration as compared with
patients on conventional hemodialysis.
Low compliance with the dialysis regimen is
associated with hypertension. Patients skipping
or shortening 1 or more dialysis treatments have
higher BPs than compliant patients.44 Studies
from centers that use 8-hour hemodialysis ses-

HEMODIALYSIS AND HYPERTENSION
237
17.2 mm Hg before, and 130.9 Ϯ 19.2 mm Hg
during daily home hemodialysis. Diastolic BP
remained constant but mean arterial pressure
decreased from 102.2 Ϯ 9.5 to 94.9 Ϯ 1.4 mm
Hg. BP decreased mainly in previously hyperten-
sive hemodialysis patients. The amount of antihy-
pertensive drugs was reduced from 1.88 Ϯ 0.35
to 0.75 Ϯ 0.17. A recent prospective cross-over
study confirmed that daily hemodialysis allows
optimal BP control, reduction of left ventricular
mass, and withdrawal of antihypertensive treat-
ment.182
Sleep disorders are common in ESRD pa-
tients. Nocturnal hemodialysis enables patients
to undergo hemodialysis 7 nights per week at
home while sleeping.183 This procedure corrects
sleep apnea associated with chronic kidney fail-
ure.184 Nocturnal hemodialysis improves BP con-
trol by decreasing the volume of extracellular
fluid.185 Such a decrease in the airway may have
a salutary effect on the pathophysiology of sleep
apnea. Sleep-disordered breathing is likely to be
a risk factor for hypertension and cardiovascular
morbidity.186
2-fold over the duration of the study reported by
Agarwal.192 Atenolol was administered 3 times
weekly after dialysis, and effectively controlled
hypertension.
Left ventricular hypertrophy can be reversed
in dialysis patients.193,194 Among the antihyperten-
sive agents, ACE inhibitors appear to have the
greatest ability to reduce left ventricular mass in
renal failure patients with left ventricular hyper-
trophy.194,195 Antihypertensive monotherapy with
ACE inhibitors in chronic renal failure patients
resulted in regression of left ventricular mass
index and was associated with a significant im-
provement in the diastolic function of the left
ventricle.196 In ESRD patients with an increased
left ventricular mass index in the face of a
normal or reduced left ventricular volume, ACE
inhibitors or AT1-receptor antagonists were rec-
ommended, whereas in patients with elevated
left ventricular volume, reduction of hypovole-
mia should be the main therapeutic option.197
Hemodialysis patients with congestive heart fail-
ure, ischemic heart disease, or intradialytic BP
increase may benefit from the use of ACE inhibi-
tors and ␤-blockers.198,199 Dorhout Mees,200 how-
ever, suggests that hypotensive drugs do not
allow adequate BP control for long periods in
hemodialysis patients. In contrast, this goal can
be achieved by salt restriction and volume con-
trol.201 If dialysis fails to ensure adequate salt
and water removal, hypertension will persist
despite the use of antihypertensive medica-
tion.202 Antihypertensive medications alone can-
not control BP in hemodialysis patients.203 Malig-
nant or treatment-resistant hypertension with
hypertensive crises may be an indication for
bilateral nephrectomy with BP normalization in
the majority of patients.204
Long, slow, home hemodialysis or frequent,
short hemodialysis sessions or nocturnal hemodi-
alysis result in reduction of BP and left ventricu-
lar hypertrophy in ESRD patients.182,185,187-189
ANTIHYPERTENSIVE DRUGS
In the study byAgarwal,190 85% of the mainte-
nance hemodialysis patients were hypertensive
with BPs of 154 Ϯ 23/83 Ϯ 14 mm Hg and
137 Ϯ 23/74 Ϯ 14 mm Hg pre- and postdialysis,
respectively. At 3-year follow-up, a BP reduction
of 9.4/6.7 mm Hg was obtained by increasing the
number of antihypertensive medications from
0.91 Ϯ 0.86 to 1.41 Ϯ 1.16, but keeping body
weight and volume status unchanged. Most pa-
tients were treated with calcium channel block-
ers (39%), whereas 27% received ␤-blockers and
14% received ACE inhibitors.5 Calcium antago-
nists were also the most frequently administered
antihypertensive drugs (71%) by Zazgornik et
al,191 followed byACE inhibitors (57%), ␣-block-
ers (31%), ␤-blockers (26%), or centrally acting
drugs (16%). Patients with mild or moderate
hypertension received on average 1.5 antihyper-
tensive drugs, whereas those with severe hyper-
tension received on average 3.3 antihypertensive
drugs. The use of adrenergic blockers increased
CONCLUSIONS
The high mortality rate seen in hemodialysis
patients is related to long-standing high BP and
the presence of other risk factors for cardiovascu-
lar disease.205,206 High BP is frequent and diffi-
cult to control in this patient population. Patients
requiring total ultrafiltration volume greater than
2.5 kg may have an elevation in presystolic and
prediastolic BPs. Diabetes mellitus, older age, or
an increased number of prescribed antihyperten-
sive medications are risk factors for higher pre-
and postsystolic BPs.207 Long-term observations

¨
¨
238
HORL AND HORL
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favor normal BP values not only for the general
population but also for the hemodialysis patients.
Maintenance of normal BPs has been largely
attributed to optimal volume control, but a low-
salt diet is an important aspect of this therapy.208
Left ventricular hypertrophy and sympathetic
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and ␤-blocker therapy. Monitoring of BP, both
home and predialysis, is of particular impor-
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