BRIEF REVIEW www.jasn.

org

Assessment and Management of Hypertension in

Patients on Dialysis
Rajiv Agarwal,* Joseph Flynn,† Velvie Pogue,‡ Mahboob Rahman,§ Efrain Reisin,| and
Matthew R. Weir¶
*Division of Nephrology, Department of Medicine, Indiana University School of Medicine and Richard L. Roudebush
Veterans Affairs Medical Center, Indianapolis, Indiana; †Division of Nephrology, Seattle Children’s Hospital, University of
Washington, Seattle, Washington; ‡formerly Division of Nephrology, Harlem Hospital, Columbia University College of
Physicians & Surgeons, New York, New York; §Division of Nephrology and Hypertension, University Hospitals Case
Medical Center, Louis Stokes Cleveland Veterans Affairs Medical Center, Case Western Reserve University, Cleveland,
Ohio; |Division of Nephrology and Hypertension, Louisiana State University Health Science Center, New Orleans,
Louisiana; and ¶Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore,
Maryland

ABSTRACT
Hypertension is common, difficult to diagnose, and poorly controlled among antihypertensive drug use per se do not
patients with ESRD. However, controversy surrounds the diagnosis and treatment lead to worse BP control; in the absence
of hypertension. Here, we describe the diagnosis, epidemiology, and management of adequate volume control, increasing
of hypertension in dialysis patients, and examine the data sparking debate over antihypertensive drug use may simply re-
appropriate methods for diagnosing and treating hypertension. Furthermore, we flect difficult-to-control BP.
consider the issues uniquely related to hypertension in pediatric dialysis patients.
Future clinical trials designed to clarify the controversial results discussed here Epidemiology Using Ambulatory BP
should lead to the implementation of diagnostic and therapeutic techniques that Measurements
improve long-term cardiovascular outcomes in patients with ESRD. The prevalence of hypertension (defined
by either a 44-hour interdialytic ambula-
J Am Soc Nephrol 25: 1630–1646, 2014. doi: 10.1681/ASN.2013060601
tory BP of $135/85 mmHg or the pre-
scription of any antihypertensive agent)
was 86% among 369 chronic HD pa-
Hypertension is common among pa- Epidemiology with Routine BP tients.8 Although hypertension was being
tients with ESRD. In this review, we Measurements treated with antihypertensive drugs in
discuss the diagnosis, epidemiology, and The prevalence of hypertension (defined 89% of patients, it was adequately con-
management of hypertension among as 1-week average predialysis systolic BP trolled only in 38%. The independent de-
dialysis patients. We also review areas [SBP] measurements .150 mmHg or di- terminants of poor control were the use of
of existing controversies and briefly astolic BP [DBP].85 mmHg or the use of antihypertensive drugs and an expanded
discuss the issue of hypertension in antihypertensive medications) was 86% extracellular volume state. If patients were
pediatric dialysis patients. among 2535 clinically stable adult HD pa- volume overloaded, nearly 80% became
tients participating in a multicenter trial.1 hypertensive when medications were
Among hypertensive patients, 12% did
EPIDEMIOLOGY not receive antihypertensive drugs, 58%
were treated but not controlled, and only Published online ahead of print. Publication date
The prevalence, treatment, and control 30% were controlled. The use of antihy- available at www.jasn.org.
of hypertension among people on he- pertensive drugs has been reported to vary Correspondence: Dr. Rajiv Agarwal, Division of
modialysis (HD) have used varying from 59% to 83%.2–5 Furthermore, even Nephrology, Department of Medicine, Indiana Uni-
versity School of Medicine and Richard L.
definitions to diagnose hypertension. among children on long-term HD, similar
Roudebush Veterans Affairs Medical Center, 1481
The epidemiology differs based on findings have been reported.6 Several West 10th Street, 111N, Indianapolis, IN 46202.
how BP is measured: either before and studies have confirmed greater antihyper- Email: ragarwal@iupui.edu
after dialysis or using ambulatory BP tensive drug use to be associated with Copyright © 2014 by the American Society of
recordings. poorer control.7,8 It should be noted that Nephrology

1630 ISSN : 1046-6673/2508-1630 J Am Soc Nephrol 25: 1630–1646, 2014


withdrawn. Paradoxically, the more med-
ications the patients received, the more
likely they were to be hypertensive.
Epidemiology of Hypertension in
Peritoneal Dialysis
Some studies suggest that hypertension
control in patients on peritoneal dialysis
(PD) is superior compared with those on
HD.9,10 For example, among 1202 pa-
tients participating in the 1995 Perito-
neal Dialysis Core Indicators Study, the
average BP among PD patients was 139/
80 mmHg.11 This is in contrast with the
predialysis BP of 152/82 mmHg among
1238 participants in the Hemodialysis
study 3 or in another study including
414 Italian PD patients, in which the
prevalence of hypertension was 88%
based on office BP$140/90 mmHg and
69% based on BP load .30%.12 Some
have theorized that better BP control in
PD patients could be explained in part by
removal of vasopressors and sodium
pump inhibitors by PD.13
In another study, the comparison of
22 patients on HD with 24 patients on PD
with 44-hour ambulatory BP monitor-
ing showed no differences in daytime
and nighttime BP.14 Nonetheless, high-
quality head-to-head studies are sparse
and the epidemiology of hypertension
may be similar to that seen among HD
patients.15
Among PD patients, volume excess, as
assessed by tracer dilution, was common
and was related to DBP and eccentric left
ventricular hypertrophy (LVH).16 Volume
overload in PD patients may be related to
the peritoneal transport characteristics.17
High transporters tend to have a higher
BP; ultrafiltration may restore their BP
to more normotensive levels.17 In a small
study, patients on continuous cyclic PD
were reported to have a greater left ven-
tricular mass compared with those on
continuous ambulatory PD.18 This was
thought to be a result of greater volume
overload.18
DIAGNOSIS
The diagnosis of hypertension among
patients on HD is challenging and this
J Am Soc Nephrol 25: 1630–1646, 2014
may lead to overtreatment or undertreat-
ment of hypertension.19–22 Diagnosing
hypertension is difficult for several rea-
sons.23 BP in these patients is often mea-
sured without attention to technique.24
BP declines during HD with ultrafiltra-
tion. This decline in BP can be variable
and in part is related to the magnitude
and intensity of ultrafiltration.25 For ex-
ample, those patients who have a large
volume removed over a short period of
time may have a large decline in BP.
These patients may also gain the removed
volume back over the interdialytic interval
and have a large increase in BP.26 Predial-
ysis BP may therefore be hypertensive
and postdialysis BP may be hypotensive.
It therefore becomes unclear which BP
measurement to use to diagnose hyper-
tension,27 and substantial errors can oc-
cur both in detecting hypertension and
assessing its severity.28,29 Both predialysis
and postdialysis BP measurements are
highly variable such that the variability
between patients is about the same as var-
iability in an individual patient over
time.30 In addition, HD patients have sig-
nificant seasonal variability in BP; BP is
highest during winters and lowest dur-
ing summers.31 This may be related to
temperature-induced vasodilation. Al-
though significant relationships exist
between both predialysis and postdial-
ysis BP and interdialytic ambulatory
BP,32 a meta-analysis has shown that
predialysis and postdialysis BP mea-
surements agree poorly with interdia-
lytic ambulatory BP. 33 Accordingly,
among HD patients, large errors are
possible when using predialysis or
postdialysis BP to judge the magnitude
of elevation in interdialytic ambulatory
BP.
The existing, although somewhat
dated, National Kidney Foundation Kid-
ney Disease Outcomes Quality Initiative
guidelines recommend that BP measure-
ments should be ,140/90 and ,130/80
mmHg before and after HD, respec-
tively.34 Use of predialysis or postdialysis
BP measurements to make management
decisions in the interdialytic period can
be problematic. For example, in a sur-
vey in the United Kingdom, centers
that achieved better postdialysis BP
www.jasn.org BRIEF REVIEW
targets had more intradialytic hypoten-
sion.35 What is clear is that interdialytic
weight gain increases predialysis BP3,36–39
and provokes the use of antihypertensive
therapy. 36,37 However, interdialytic
weight gain does not correlate with inter-
dialytic ambulatory BP.40,41 Therefore,
whether achieving these peridialysis BP
targets would cause clinical harm (or
benefit) remains unknown.
Using all BP values measured during a
mid-week dialysis may serve as a more
useful tool to estimate interdialytic am-
bulatory BP.42 Although the mean in-
tradialytic BP serves as a useful tool to
assess hypertension, the calculation of
median intradialytic BP is computation-
ally easier than calculating the mean. It
may therefore be used as a bedside tool
to predict interdialytic ambulatory BP. A
mid-week median intradialytic BP of
$140/90 mmHg has sensitivity and
specificity that exceeds predialysis or
postdialysis measurements and can serve
as a rapid and convenient tool to assess
hypertension in long-term HD pa-
tients.42 However, this is the method of
last resort because better methods are
available to evaluate hypertension in
HD patients.
Home BP monitoring is a practical way
to diagnose and manage hypertension in
all patients with kidney disease.43,44 Home
BP monitoring is recommended by both
the American Heart Association and the
European Society of Hypertension for di-
agnosing and managing hypertension.45,46
Home BP monitoring is especially valu-
able in diagnosing and managing hyper-
tension for those on HD for the following
reasons. 47 Home BP correlates more
closely with ambulatory BP compared
with predialysis or postdialysis BP record-
ings.48 Home BP can track changes in BP
evoked by the reduction in dry weight.49
Home BP, compared with predialysis or
postdialysis BP recordings, is much more
reproducible from one week to the next.49
Home BP is superior to measurements
made in the dialysis unit, even when the
dialysis unit measurements are made us-
ing recommended techniques, in predict-
ing the presence of target organ damage
(echocardiographic LVH)50,51 or long-
term outcomes such as cardiovascular
Hypertension in ESRD 1631
 BRIEF REVIEW www.jasn.org
events52 or mortality.52–55 The association
of BP and outcomes is discussed further in
the section on prognosis. A recent trial
randomized stable HD patients to home
BP-guided therapy or predialysis BP-
guided therapy.56 The primary goal was
to assess change in interdialytic ambula-
tory BP at 6 months and change in echo-
cardiographic LVH. There was no change
in ambulatory BP at 6 months in the pre-
dialysis BP-guided therapy group. A sig-
nificant decrease in ambulatory SBP (but
not DBP) was noted at 6 months in the
group treated using home BP recordings.
Between-group differences were signifi-
cant. Given the small number of patients
and variability in timing of echocardio-
graphic left ventricular mass measure-
ments, no between-groups differences
were noted. Another trial randomized 17
HD patients to usual care and 17 patients
to home BP monitoring. Significant im-
provement in average weekly SBP was seen
in the home BP group only.57 These data
support the use of home BP measurement
to manage HD patients.
Among HD patients, the timing and
frequency of home BP monitoring is of
particular importance. Home BP increases
on average at a rate of 4 mmHg every 10
hours elapsed after dialysis.58 Therefore,
measurement soon after dialysis or just
before dialysis will underestimate or over-
estimate the burden of hypertension.
Therefore, it is important to measure BP
at various intervals after dialysis. Simply
obtaining a BP measurement 20 minutes
postdialysis may not yield the most repre-
sentative interdialytic BP.59 We recom-
mend that measurements be made twice
daily (on waking up in the morning and
just before going to sleep) after a midweek
dialysis for 4 days,60 given that inter-
dialytic BP measures may more capably
predict LVH and mortality.50–55 These
measurements allow an adequate number
of measurements for diagnosing and man-
aging hypertension. For long-term follow-
up, monthly measurement (over 4 days
after a midweek dialysis as noted above)
should suffice in most patients. More fre-
quent measurements may be needed in in-
dividuals who are clinically unstable.
Ambulatory BP monitoring, among
HD patients, is held to be the gold
1632 Journal of the American Society of Nephrology
standard for diagnosing hyperten-
sion.27,61–63 Compared with peridialytic
BP recordings, it correlates better with
LVH50 and all-cause mortality.64 While
using a validated monitor, 65 we re-
commend measuring BP over the entire
interdialytic interval (44 hours). We rec-
ommend recording BP every 20 minutes
from 6 AM to 10 PM and every 30 minutes
from 10 PM to 6 AM66 As in the case of
home BP, interdialytic SBP increases, al-
beit at a slower rate of 2.5 mmHg every
10 hours.67,68 Because a much greater
number of measurements during the in-
terdialytic interval are typically available
compared with home BP, patterns of BP
can be evaluated. Figure 1 illustrates the
pattern of BP and heart rate over an in-
terdialytic interval. Among HD patients,
ambulatory BP monitoring remains a re-
search technique.
In approximately 10%–15% of pa-
tients, instead of decreasing, BP paradox-
ically increases during dialysis.69 These
patients have intradialytic hypertension.
Intradialytic hypertension is defined in
different ways. These definitions include
the following: (1) a discrete change in BP
from predialysis to postdialysis in a certain
number of dialysis treatments; (2) regres-
sion of all intradialytic BP with a slope .0;
and (3) a change of .0 mmHg from pre-
dialysis to postdialysis. Intradialytic hy-
pertension is associated with greater
short-term (6-month) mortality in HD
patients.70 In another cohort, an increase
in SBP by .10 mmHg during HD oc-
curred in approximately 10% of incident
patients. Although this increase in SBP
during HD was associated with decreased
2-year survival, these findings were lim-
ited to patients with predialysis SBP of
,120 mmHg. 71 Although the exact
mechanism of this relationship is un-
clear,72,73 a study shows that intradialytic
hypertension in HD patients using defini-
tion 2 noted above is associated with both
volume excess and interdialytic hyper-
tension.74 Another study, using definition
1, confirmed the association between in-
tradialytic hypertension and interdialytic
hypertension.75
At least two studies suggest that low-
ering dry weight may improve inter-
dialytic hypertension. Cirit et al. treated
seven hypertensive patients on HD with
marked cardiac dilation that experienced
paradoxical hypertension during dialy-
sis.76 After probing dry weight, both BP
and postdialysis weight was reduced; the
BP reduction was 46/22 mmHg and post-
dialysis weight was reduced by 6.7 kg. The
authors concluded that BP may paradoxi-
cally rise with ultrafiltration when patients
are volume overloaded. Dry weight was re-
duced progressively in the randomized
Dry-Weight Reduction in Hypertensive
Hemodialysis Patients (DRIP) trial, as dis-
cussed below.77 Those patients with intra-
dialytic hypertension who had additional
ultrafiltration and therefore a reduction in
dry weight had improvement in both intra-
dialytic and interdialytic hypertension.74
This suggests that an appropriate therapy
for this condition would be to further lower
dry weight. However, the phenomenon of
intradialytic hypertension is complex and
incompletely understood; pilot studies sug-
gest that endothelial dysfunction may be
operative in its pathogenesis.78
Home BP measurement is a practical
way to measure and manage hypertension
among HD patients. The targets of therapy
using home BP monitoring will need to be
defined in future trials. Guidelines of the
American Heart Association define hy-
pertension as home BP of at least 135/85
mmHg45; lowering BP in the interdialytic
period to at least 140/90 mmHg appears
to be a reasonable goal (Table 1).
NONPHARMACOLOGIC
TREATMENT
Once an accurate diagnosis is made, the
therapy of hypertension among HD
patients rests on nonpharmacologic
management. Although scarcely studied,
one small study lasting 6 months
showed a beneficial effect of exercise on
BP and medication requirements.79 Ex-
ercise consisted of using a stationary bi-
cycle during dialysis. 79 Besides this
promising strategy, the nonpharmaco-
logic management of hypertension is
based on four principles: dietary sodium
restriction, individualizing dialysate so-
dium, the management of dry weight,
and providing an adequate duration of
J Am Soc Nephrol 25: 1630–1646, 2014
 www.jasn.org BRIEF REVIEW

dialysis. These principles are further dis-

cussed.

Dietary Sodium Restriction

Dietary sodium restriction limits inter-
dialytic weight gain and improves the
feasibility of achieving dry weight.80,81
Instead of restricting dietary sodium, pa-
tients on HD are sometimes prescribed
fluid-restricted diets. With the exception
of treating hyponatremia, there is no scien-
tific basis for prescribing a fluid-restricted
diet in these patients.82
Recent guidelines suggest that elderly
persons and individuals with CKD are
most likely to derive the greatest benefits
from dietary sodium restriction.83 These
guidelines are even stricter on sodium in-
take than those advocated earlier (2 g/d).
Dietary sodium restriction to no more
than 1.5 g sodium (or approximately
65 mmol) per day is now recommended.
Although no randomized trials have
been performed among patients with
ESRD, observational studies among
long-term HD patients suggest that re-
stricting dietary sodium and achieving dry
weight can improve LVH.84

Individualizing Dialysate Sodium

High sodium dialysis was initially pre-
scribed to provide hemodynamic stability,
fewer disequilibrium symptoms, and fewer
muscle cramps.85 Early studies found that
high sodium dialysate among normoten-
sive patients reduced dialysis-induced hy-
potension and was not associated with
long-term hypertension.86 However, its ef-
fect among those with hypertension was
less clear.86 A double-blind crossover trial
in seven dialysis patients found that com-
pared with dialysate sodium of 135 mEq/L,
both dialysate sodium of 143 mEq/L or
sodium gradient dialysate of 160–133
mEq/L were associated with greater inter-
dialytic weight gain (2.2, 2.6, and 2.8 kg
respectively).87 Another study showed
that interdialytic weight gain and thirst
can be provoked with the prescription of
hypertonic dialysate.88 These findings are
now being recognized as important treat-
Figure 1. Modeled trended cosinor BP and pulse rate in HD patients. Notice the linear ment targets.89 The prescription of high
trend in SBP, DBP, and pulse pressure but the lack thereof in heart rate. Reprinted from sodium dialysate allows increased fluid
reference 67, with permission. volume removal and better hemodynamic
stability. However, it provokes increased

J Am Soc Nephrol 25: 1630–1646, 2014 Hypertension in ESRD 1633

 BRIEF REVIEW www.jasn.org
Table 1. Diagnosis and epidemiology
of hypertension
Summary Statements
1. Diagnosing hypertension in dialysis patients
is challenging.
2. Compared with predialysis and postdialysis
BP measurements, diagnosis of
hypertension is better made by using home
BP recordings or interdialytic ambulatory BP
recordings.
3. Hypertension is frequently treated with
antihypertensive drugs, but remains
adequately controlled in only a minority of
the patients.
4. Hypertension in children on dialysis is as
prevalent as in adults and given the life-time
risk needs to be controlled.
thirst, increased interdialytic weight gain,
and more fluid removal with next dialysis.
It may therefore provoke hemodynamic
instability and prescription of even a
higher dialysate sodium, perpetuating a vi-
cious cycle.90 In some patients, worsening
of BP control may ensue.86 The vicious
cycle can be interrupted by individualizing
dialysate sodium concentration,91 which
may improve BP control.92 In a pilot study
of 16 patients, dialysate sodium was pro-
gressively decreased in four phases from
137.8 to 135.6 mmol.93 As a result of this
maneuver, the net sodium loss increased
nearly 100 mmol from 383 to 480 mmol
per treatment; this was associated with re-
duced interdialytic weight gain and BP.93
Thus, facilitating diffusive sodium losses in
addition to convective loss can increase net
sodium removal and therefore lower BP.
Sodium ramping that is prescribed to off-
set intradialytic hemodynamic instability
is associated with fewer hypotensive epi-
sodes on dialysis but greater interdialytic
fatigue and thirst, greater interdialytic
weight gain, and hypertension.94 Interdia-
lytic 24-hour ambulatory BP increased
when the time-averaged concentration of
sodium was extremely elevated at 147
mEq/dl.95 Therefore, one sodium pre-
scription may not fit all patients.
In a nonrandomized trial, improve-
ment in nocturnal mean arterial pressure
was found among PD patients who were
prescribed a low dialysate sodium. 96
However, if the low dialysate sodium
was not accompanied by a reduction in
1634 Journal of the American Society of Nephrology
dry weight, BP did not change. Prescrib-
ing both low dialysate sodium and chal-
lenging dry weight may improve BP
control over and above one strategy
alone. In addition, BP increments pro-
voked by higher sodium dialysate can be
adequately controlled by the adjustment
of dry weight.97
Management of Dry Weight
The management of dry weight poses
several challenges. First and foremost,
there is no universally agreed-upon defi-
nition of dry weight. Sinha and Agarwal
define dry weight as the lowest tolerated
post dialysis weight achieved via gradual
change in postdialysis weight at which
there are minimal signs or symptoms of
either hypovolemia or hypervolemia.98
Assessment of Dry Weight
The physical examination is notoriously
unreliable in excluding volume overload.
For example, pedal edema does not cor-
relate with dry weight very well. In a case-
control study, Agarwal et al. found that
inferior vena cava diameter, blood volume
monitoring, plasma volume markers, and
inflammation markers were not determi-
nants of edema.99 For the most part, the
assessment and achievement of dry weight
is an iterative process that often provokes
uncomfortable intradialytic symptoms
such as hypotension, dizziness, cramps,
nausea, and vomiting. These symptoms
often lead to interventions such as cessa-
tion of ultrafiltration, administration of
saline, premature cessation of dialysis, or
placing the patient in the head-down
(Trendelenburg) position. Interestingly,
placing the patient in the head-down po-
sition does little to protect the BP and this
practice is questionable100; raising the leg
passively without lowering the head can,
however, be effective to raise ventricular
filling pressure.101 Often physicians will
respond to these distressing symptoms
by raising dry weight, and then adding
more antihypertensive medication. Para-
doxically, this may make subsequent
achievement of dry weight even more dif-
ficult. However, if dry weight is reduced
gently either by setting the ultrafiltra-
tion goal to just a little above the previous
achieved postdialysis weight (e.g., by
0.2–0.3 kg in an adult) either without
changing the dialysis time or better still
by prolonging the dialysis time to allow
for slower ultrafiltration with dialysis, dry
weight can then be successfully achieved.
Benefits of Probing Dry Weight
Dry weight was probed without changing
the dialysis time in a randomized con-
trolled trial of hypertensive HD patients.77
Notably, in this study, patients with obvi-
ous volume overload were excluded. Thus,
the study tested the hypothesis that hyper-
tension among HD patients who do not
manifest overt signs of volume overload is
mediated by excess volume. Interdialytic
ambulatory BP monitoring was per-
formed three times (at baseline, 4 weeks,
and 8 weeks) in 50 patients randomized
to a control group and 100 patients ran-
domized to ultrafiltration group. Ambula-
tory BP was reduced within 4 weeks by
11/6 mmHg77 (Figure 2). This level of
BP reduction was achieved despite stable
concurrent use of 2.7 antihypertensive
drugs. The magnitude of reduction in BP
is therefore much larger than what would
be expected by adding an additional anti-
hypertensive agent. Because the control
group had a placebo effect, subtracting
this effect from the intervention group re-
sulted in still a significant ambulatory BP
reduction of 7/3 mmHg. This antihyper-
tensive effect was sustained for 8 weeks of
observation. Despite provoking occa-
sional uncomfortable intradialytic symp-
toms, the quality of life was not impaired.
Even in this randomized trial, the presence
or absence of edema, which is often taken
as a reliable sign of volume overload, had
no predictive value in separating the res-
ponders from nonresponders. Further-
more, 10% of the patients in the control
group developed accelerated hyperten-
sion, defined as BP $175/105 mmHg by
interdialytic ambulatory monitoring. This
study provides strong support for the hy-
pothesis that among HD patients, dry
weight reduction is an effective strategy
for reducing BP.
Observational studies also support the
practice of probing dry weight. In 1969,
Vertes et al. reported that 35 of 40 patients
became “normotensive” by achieving dry
weight.102 In a more recent report from
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primary strategy had the following bene-

fits: lower antihypertensive drug use (7%
versus 42%), lower interdialytic weight
gain, lower left ventricular mass, better di-
astolic and systolic left ventricular func-
tion, and fewer episodes of intradialytic
hypotension. These observations are im-
portant and of clinical relevance; they
suggest that probing for dry weight as op-
posed to adding more antihypertensive
drugs perhaps diminishes the risk for car-
diac remodeling and mitigates LVH, and
preserves systolic and diastolic left ven-
tricular function. Although a case-control
study cannot assert causation, the results
of this study support the use of nonphar-
macologic therapies in the management
of patients with ESRD.

Dry Weight and Outcomes

Studies among HD patients in both
adults and children suggest that manag-
ing intradialytic relative plasma volume
(RPV) may reduce the number of hos-
pital admissions caused by fluid over-
load,104,105 may improve BP control, and
may decrease hypotension-associated
dialysis symptoms.106 It is possible that
the latter benefit is, in part, related to
diminished use of antihypertensive
medication. Accordingly, monthly mon-
itoring of RPV and home BP may offer
an attractive way to assess the adequacy
of volume control among HD patients.
To note, the multicenter randomized
Figure 2. The effect of dry weight reduction on interdialytic ambulatory SBP and DBP in Crit-Line Intradialytic Monitoring Ben-
hypertensive HD patients. The mean SBPs (A) and DBPs (B) are shown for the baseline efit (CLIMB) trial107 demonstrated that
control and ultrafiltration groups. The mean changes in BP are shown for weeks 4 and 8 after RPV-guided therapy was associated with
randomization (solid arrows), and the mean differences in BPs (dotted arrows) between the worse outcomes, contrary to the original
two groups at each 4-week interval. The numbers next to the dotted lines connecting the hypothesis. The CLIMB trial random-
data points are the mean changes in BP between groups at 4 and 8 weeks after random- ized 227 HD patients to RPV monitoring
ization. The 95% confidence intervals (95% CIs) are given in parentheses. Significant dif- and 216 to conventional monitoring for
ferences between groups or within groups are as indicated as follows: *P,0.05; †P,0.01; 6 months to test the hypothesis that
‡
P,0.001. The ultrafiltration-attributable change in SBP was 26.9 mmHg (95% CI, 212.4
RPV-guided monitoring would result
to 21.3 mmHg; P=0.02) at 4 weeks and 26.6 mmHg (95% CI, 212.2 to 21.0 mmHg;
in reduced hospitalization rates. Com-
P=0.02) at 8 weeks. The ultrafiltration-attributable change in DBP was 23.1 mmHg (95% CI,
26.2 to 20.02 mmHg; P=0.05) at 4 weeks and 23.3 mmHg (95% CI, 26.4 to 20.2 mmHg; pared with the conventional group, the
P=0.04) at 8 weeks. Reprinted from reference 77, with permission. adjusted risk ratios (RR) were 1.61 (95%
confidence interval [95% CI], 1.15 to
2.25; P=0.01) for nonaccess hospitaliza-
Turkey, Kayikcioglu et al. compared the salt restriction and dry weight reduction tion and 1.52 for access-related hospital-
benefit of nonpharmacologic therapy ver- were compared with patients at another ization (P=0.04) in the RPV-guided
sus pharmacologic therapy for control of center where antihypertensive-based ther- monitoring group. Mortality was 8.7%
left ventricular mass among HD pa- apy was the primary method for manage- and 3.3% (95% CI, 1.02 to 2.28;
tients.103 In a case-control study, patients ment of hypertension. The center using P=0.021) in the RPV-guided monitoring
who had been treated at one center with dry weight and salt restriction as a and conventional monitoring groups,

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 BRIEF REVIEW www.jasn.org
respectively. An elaborate protocol was
available to guide fluid management
based on RPV-guided monitoring; al-
gorithm use was encouraged but not
mandated. Furthermore, highly variable
implementation of the monitoring and
interventional algorithm occurred
within and across dialysis units. At base-
line, as determined by RPV slope pat-
terns, patients in the conventional group
appeared to be more volume overloaded
compared with the RPV-guided group.
At 6 months, both groups had similar
RPV slopes. Thus, the conventional
group appeared to have had greater vol-
ume challenge than the intervention
group. Although this was a randomized
trial, the findings should be interpreted
with caution for the above reasons.
To study the effect of volume status on
mortality, Wizemann et al. followed 269
prevalent HD patients for several
years.108 They measured hydration state
using a body composition analyzer. If
there was .15% excess of extracellular
water (2.5 L volume excess), they classi-
fied such patients as volume overloaded;
25% of the patients had excess extracel-
lular fluid (ECF) volume. In a multivar-
iate adjusted analysis, they found that
excess volume was associated with high
mortality. Compared with those without
excess ECF volume, the hazard ratio of
mortality with excess fluid volume was
2.1 (95% CI, 1.39 to 3.18; P=0.003). Al-
though the study did not examine the
effect of reduction in ECF volume on
subsequent outcomes, such studies
need to be performed in the future.
Inrig et al. compared the change in
pulse pressure during dialysis as a risk
factor for hospitalization and mortality
among prevalent HD patients participat-
ing in a randomized controlled trial.109
They found that patients who had the
least change in pulse pressure from be-
fore to after dialysis had clinical charac-
teristics indicating volume overload.
Among these patients, lowering of the
pulse pressure from before to after dial-
ysis was associated with lower hospitali-
zation and mortality outcomes. Because
pulse pressure is largely driven by SBP, it
is likely that lowering of pulse pressure
with dialysis reflects more volume loss
1636 Journal of the American Society of Nephrology
and a lower ECF volume state, and may
provide better cardiovascular outcomes,
perhaps through less pressure/volume
stress on the heart.
Potential Hazards of Probing Dry Weight
There are potential hazards related to
probing dry weight, none of which have
been adequately examined.77 These in-
clude the following: (1) increased risk
of clotted angioaccess, (2) increased
rate of attrition in residual renal func-
tion, and (3) complications related to
intradialytic hypotension. Intradialytic
hypotension, besides requiring more
nursing interventions, can be complicated
by cerebral hypoperfusion, seizures, myo-
cardial dysfunction, and mesenteric ische-
mia. Furthermore, it has been associated
with mortality.110 The relative risks and
benefits of probing dry weight need to
be examined in long-term randomized
trials.
Providing Adequate Duration of
Dialysis
The European Best Practice Guidelines
recommend that dialysis should be de-
livered at least three times a week and the
total duration should be at least 12 hours
per week, unless substantial residual re-
nal function is present.111 An increase in
treatment time and or frequency should
be considered in patients who experi-
ence hemodynamic instability or remain
hypertensive despite maximal possible
fluid removal.
In the United States, a recent study
reported that the average duration of
dialysis among 32,065 participants in the
ESRD Clinical Performance Measures
Project was 217 minutes.112 The inter-
quartile range was 195–240 minutes.
This means that one-quarter of the pa-
tients were receiving ,3 hours and 15
minutes of dialysis and only one-quarter
of the patients were receiving .4 hours
of dialysis.
Although what constitutes an ade-
quate dialysis is still debated, it is clear
that patients who shorten treatment have
hypertension that is more difficult to
control.5 Patients who dialyze 8 hours
three times a week have excellent BP
control, minimal requirement for
antihypertensive drugs, and excellent
long-term survival.41,113 In a random-
ized crossover trial of 38 patients, the
effects of 4-hour dialysis to 5-hour dial-
ysis were evaluated.114 Hemodynamic
stability and hypotensive episodes were
fewer with longer dialysis, especially
among older patients (aged .65 years).
However, these data are difficult to gen-
eralize because treatment was evaluated
only over 2 weeks and those requiring
.4 L ultrafiltration were excluded. Lon-
ger or more frequent dialysis sessions, in
general, are associated with less hemo-
dynamic instability, better achievement
of postdialysis dry weight, better control
of BP, and the reduced need for antihy-
pertensive drugs.
FREQUENT DIALYSIS AND ITS
EFFECT ON BP
Observational studies suggest that con-
version of patients from three times a
week conventional dialysis to nocturnal
dialysis may improve BP and left ven-
tricular mass.115 In a cumulative analysis
of 72 patients from nine centers it was
noted that predialysis SBP and DBP fell
within 1 month of dialysis by 13/7
mmHg from 163/94 mmHg.116 This re-
duction was accompanied by a 1% de-
cline in postdialysis weight. Although BP
did not change after 1 month, the num-
ber of antihypertensive agents declined
significantly. At baseline, 54% of patients
were not taking antihypertensive drugs,
whereas at 12 months after switching to
daily dialysis, 75% were not taking anti-
hypertensive agents.
Several observations have suggested
improvements in BP and left ventricular
mass among patients undergoing more
frequent dialysis. For example, Chan
et al. reported an improvement in both
SBP and DBP, a reduction in antihyper-
tensive drugs and doses, and a reduction
in left ventricular mass in patients un-
dergoing nocturnal dialysis. 115 This
group also reported an improvement in
pharyngeal size among nocturnally dia-
lyzed patients. 117 This may improve
sleep apnea and consequently ambula-
tory BP. Another mechanism of BP
J Am Soc Nephrol 25: 1630–1646, 2014

reduction with frequent dialysis is sug-
gested to be an increase in arterial com-
pliance and consequently improvement
in baroreflex sensitivity.118 Other mech-
anisms may be better volume and toxin
removal.119
A randomized controlled trial as-
signed 52 HD patients to either frequent
dialysis, six nights per week, or conven-
tional three times a week treatment. In
the frequent dialysis group, the results
showed an improvement in cardiac mag-
netic resonance–imaged left ventricular
mass and a reduction in the need for an-
tihypertensive medications.120 The Fre-
quent Hemodialysis Network (FHN)
study randomized HD patients to either
conventional dialysis three times weekly
or more frequent in-center dialysis; the
primary endpoint was an improvement
in joint composite end points of either
(1) death or LVH or (2) death or physical
health composite. The primary end
point was met, but perhaps the most no-
table findings were an improvement in
SBP, a reduction in antihypertensive
drug use, and an improvement in left
ventricular mass.121 These findings sug-
gest better achievement of dry weight in
these patients.122 Improvement in SBP
was also noted in the companion FHN
Nocturnal trial.123 Increasing the treat-
ment duration may improve hemody-
namic stability of dialysis and make the
procedure more tolerable, but it is not a
requirement for improvement in left
ventricular mass. Shortening the pro-
cedure to tailor dialysis to a minimum
Kt/V may provoke intradialytic symptoms,
postdialysis fatigue, and nonadherence
to therapy; thus, this is not recommen-
ded.124 Normotension can be achieved
independently of the duration of dialysis
if the control of volume is adequate.125 In
fact, left ventricular mass index was also
improved to a comparable degree in
DRIP trial participants, in which the du-
ration of dialysis was not altered but the
dry weight was challenged.126
PHARMACOLOGIC TREATMENT
All classes of antihypertensive drugs,
except diuretics, are useful for managing
J Am Soc Nephrol 25: 1630–1646, 2014
hypertension in HD patients.127 Diuret-
ics are generally ineffective at very low
GFR. There is no role of loop diuretics
even when given in a high dose (e.g., as
high as 250 mg intravenously of furose-
mide) among anuric HD patients. 128
Tissue Doppler imaging revealed that
central cardiac hemodynamics were un-
altered when anuric HD patients were
given even such high doses of loop di-
uretics. Given the ototoxicity associated
with high doses of loop diuretics, their
use, especially in high doses, is not rec-
ommended. Further research is needed
to clarify the role of loop diuretics
among patients with substantial residual
renal function (e.g., patients new to
long-term dialysis). Consideration of
pharmacokinetics is important when
prescribing these drugs.129 In general, if
patients are volume overloaded, antihy-
pertensive medications are less effective.
Paradoxically, among HD patients, a
greater use of antihypertensive medica-
tions is associated with a higher BP.130
However, causality must not be as-
sumed. It is more likely that excessive
antihypertensive medication may inter-
fere with achievement of dry weight.
Drugs that block the renin-angiotensin
system are often recommended as first-
line therapy for HD patients because of
their tolerability and extrapolated cardio-
vascular benefits in the general population
with heart and kidney disease. Only one
prospective trial compared an angiotensin-
converting enzyme inhibitor (fosinopril)
versus placebo in HD patients, all of which
had LVH. Although hypertension was
not an inclusion criterion, all patients
underwent a single-blind run-in period
with 5 mg of fosinopril, and those who
experienced symptomatic hypotension
or had a SBP ,95 mmHg 4–6 hours after
test dose were excluded. Subsequently, in
the Fosinopril and Dialysis Trial, 400 HD
patients received 20 mg of fosinopril ver-
sus placebo in an equal ratio. After 4 years
of follow-up, there were no differences
between the two treatment groups in
the primary end point of cardiovascular
events that included cardiovascular
death.131 Another smaller trial compared
candesartan versus placebo in HD pa-
tients, but noted a nearly 3-fold reduction
www.jasn.org BRIEF REVIEW
in cardiovascular events with active treat-
ment versus placebo.132 These conflicting
results indicate the need for larger studies.
There are no studies in PD patients, nor
are there any studies in HD patients with
diabetes.
b-Blockers may be an effective thera-
peutic strategy in HD patients with re-
duced ejection fraction (,35%). One
study randomized 114 (not necessarily
hypertensive) patients with dilated car-
diomyopathy to 25 mg of carvedilol twice
daily or placebo for 2 years. b-Blocker
treatment reduced hospitalizations (RR,
0.44) and all-cause death (RR, 0.51).133
Regrettably, the reduction in all-cause
mortality with antihypertensive drug ther-
apy in HD patients has not been realized
with adequately powered randomized
controlled trials. This may be due to mul-
tiple reasons, including the low numbers
of patients. Nonetheless, meta-analyses
of these trials show improvement in the
cardiovascular event rate.134,135 These
benefits are especially seen among individ-
uals who have hypertension.135
The recently reported Hypertension in
HemoDialysis Patients Treated with Ate-
nolol or Lisinopril (HDPAL) trial ran-
domly assigned 200 patients to either
open-label lisinopril (n=100) or atenolol
(n=100) each administered three times
per week after dialysis. The HDPAL trial
aimed to determine whether angiotensin-
converting enzyme inhibitor–based an-
tihypertensive therapy causes a greater
regression of LVH compared with
b-blocker–based antihypertensive ther-
apy among maintenance HD patients
with echocardiographic LVH and hyper-
tension.136 Monthly monitored home BP
was controlled to ,140/90 mmHg with
medications, dry weight adjustment, and
sodium restriction. The primary outcome
was the change in the left ventricular mass
index from baseline to 12 months. At
baseline, 44-hour ambulatory BP was
similar in the atenolol (151.5/87.1
mmHg) and lisinopril groups, and im-
proved similarly over time in both groups.
However, monthly measured home BP
was consistently higher in the lisinopril
group despite needing a greater number
of antihypertensive agents and a greater
reduction in dry weight. An independent
Hypertension in ESRD 1637
 BRIEF REVIEW www.jasn.org
data safety monitoring board recommen-
ded early termination of the trial because of
cardiovascular safety. Serious cardiovascu-
lar events occurred in 16 participants in the
atenolol group who had 20 events and in 28
participants in the lisinopril group who
had 43 events (incidence rate ratio [IRR],
2.36; 95% confidence interval, 1.36 to 4.23;
P=0.001). Combined serious adverse
events of myocardial infarction, stroke,
hospitalization for heart failure, or cardio-
vascular death occurred in 10 participants
in the atenolol group who had 11 events
and in 17 participants in the lisinopril
group who had 23 events (IRR, 2.29;
95% CI, 1.07 to 5.21; P=0.02). Hospital-
izations for heart failure were worse in the
lisinopril group (IRR 3.13; 95% CI, 1.08 to
10.99; P=0.02). All-cause hospitalizations
were higher in the lisinopril group (IRR,
1.61; 95% confidence interval, 1.18 to 2.19;
P=0.002). The left ventricular mass index
improved with time; no difference be-
tween drugs was noted. These data appear
to suggest that among maintenance dial-
ysis patients with hypertension and LVH,
atenolol-based antihypertensive therapy
may be superior to lisinopril-based ther-
apy in preventing cardiovascular morbid-
ity and all-cause hospitalizations. Larger
multicenter trials should be performed
to confirm these provocative data from a
single center.
NONVOLUME-DEPENDENT
CAUSES OF HYPERTENSION IN
DIALYSIS PATIENTS
An increase in BP is a well recognized
complication of erythropoietin therapy in
HD patients.137 Hypertension is common
with erythropoietin therapy, with approx-
imately 30% of patients either developing
hypertension or requiring an adjustment
in antihypertensive medications.138,139
The etiology of hypertension with erythro-
poietin therapy is not clear. The incidence
of erythropoietin-induced hypertension
correlates with the erythropoietin dose
but appears to be independent of its ef-
fect on red blood cell mass and viscos-
ity.140,141 Available data suggest that the
most likely mechanisms involve either an
increase in production or an enhanced
1638 Journal of the American Society of Nephrology
response to the effect of various vasoac-
tive substances. 142,143 Several studies
have found that erythropoietin-induced
hypertension in hemodialyzed patients is
associated with either a significantly in-
creased circulating endothelin-1 concentra-
tion or enhanced vasoconstrictive response
to endothelin-1.144–146 Erythropoietin
treatment has also been shown to be as-
sociated with an accentuated increase in
the BP response to angiotensin II infusion
compared with the BP response before
erythropoietin therapy.147 This apparent
increased sensitivity to angiotensin II cor-
related with the erythropoietin-induced
increase in BP. Studies have also shown
noradrenergic hypersensitivity in hemo-
dialyzed patients with erythropoietin-
induced hypertension.148
The effect of erythropoietin on BP can
be missed because of variability in BP from
predialysis to postdialysis and the lack of
home or ambulatory BP measurements.
Studies that failed to detect increases in BP
with erythropoietin therapy may have
managed hypertension more aggressively
through the prescription of antihyperten-
sive drugs or closer attention to dry weight.
Erythropoietin therapy was an indepen-
dent predictor of hypertension diagnosed
by ambulatory BP monitoring.8 Some
studies show an association of erythropoi-
etin use with nondipping.149 Increase in
BP with erythropoietin occurs more com-
monly in individuals with preexisting hy-
pertension150,151 or a family history of
hypertension.152
Prevention of erythropoietin-induced
hypertension, and other complications,
is a clinical challenge with several possible
management strategies. Recommended
strategies, with little good evidence to
support these practices, have included the
following: changing the route of admin-
istration (subcutaneous versus intrave-
nous), reducing the goal hemoglobin level
(especially in patients who are unrespon-
sive to erythropoietin therapy), starting
with a low erythropoietin dose and in-
creasing the dose slowly, and avoiding the
use of erythropoietin altogether.
Sleep apnea is very common in dialysis
patients and is often associated with vol-
ume overload. Hypopneic spells during
the night lead to nocturnal hypoxemia and
provoke intense sympathetic arousal and
an increase in nocturnal BP.153 Table 2
summarizes the key points in the manage-
ment of hypertension.
Hypoxemia that characterizes sleep
apnea in patients with ESRD may cause
hypertension. 154 Patients with ESRD
with sleep apnea have shown a 7-fold
higher prevalence of resistant hyperten-
sion than individuals in the general hyper-
tension population.155 In the recumbent
position, the volume overload is redis-
tributed from the legs to the chest and
neck areas and may induce a periphar-
yngeal and upper airway resistance.156
Volume overload and the specific redis-
tribution described in patients with
ESRD may be not only a consequence
but also an important cause of obstruc-
tive sleep apnea.157
RELATIONSHIP OF BP AND
MORTALITY
Among HD patients, the relationship of BP
with cardiovascular outcomes is a subject of
much controversy.158–164 As previously
discussed, controversy relates to the spe-
cific relationship between the BP measure-
ment times and technique (predialytic,
postdialytic, or intradialytic BP measure-
ments or interdialytic ambulatory BP) and
morbidity and mortality. Some studies
suggest an association of high BP with
strokes,165,166 cerebral atrophy,167 cardiovas-
cular events,168 complex cardiac arrhyth-
mias,169 the development of congestive
heart failure,161 and all-cause mortal-
ity.170 Other studies suggest that low BP
measured either predialysis or postdialy-
sis is associated with increased mortal-
ity.164,171–173 This association of low BP
and mortality is further magnified when
BP is considered as a time-dependent co-
variate.173 High BP measured either be-
fore dialysis or after dialysis are either not
associated or minimally associated with
increased mortality. The phenomenon of
lower BP being associated with increased
mortality has been labeled as reverse ep-
idemiology of hypertension. This has
raised concerns regarding lowering of
BP among hypertensive HD patients.174,175
Other studies have demonstrated a direct
J Am Soc Nephrol 25: 1630–1646, 2014

Table 2. Management of hypertension
Summary Statements
1. Volume overload is often an overlooked
factor in managing hypertension.
Erythropoietin-induced hypertension and
untreated sleep apnea are other important
causes.
2. Volume overload is associated with
increased mortality in HD patients.
3. The iterative trial-and-error method of dry
weight assessment remains the current
clinical standard in assessing volume status.
4. Dietary salt restriction and individualizing
dialysate sodium prescription may improve
the feasibility of achieving dry weight.
5. Probing dry weight can improve BP among
hypertensive HD patients. The long-term
risks and benefits of probing dry weight
need to be examined in future trials.
6. Delivery of dialysis of at least 4 hours
duration three times a week may facilitate
volume and hypertension control.
7. Antihypertensive drugs are frequently
needed to control hypertension but are an
adjunct to facilitate volume control.
Diuretics have little to no role in patients
with ESRD. b-blockers may be preferred to
other agents.
relationship between BP and mortal-
ity.170,176 Consideration of the patient
characteristics, dialysis practices, and
BP measurement techniques is useful
when evaluating these outcomes.
Consideration of the level of illness and
the vintage of the patient are also instructive
to ascertain the value of hypertension as a
risk factor among HD patients. Examining
the outcomes of 2770 patients on PD
provides such insights.15 These patients
were studied between 1997 and 2004 and
had been on PD for at least 180 days in
England and Wales. In a fully adjusted
analysis, greater SBP, DBP, mean arterial,
and pulse pressure were associated with de-
creased mortality among patients who had
been on dialysis for ,1 year. However,
greater SBP and pulse pressure (but not
mean arterial pressure and DBP) were as-
sociated with increased mortality among
patients who had been on PD for $6 years.
In a subgroup of patients who were placed
on the transplant waitlist within 6 months
of starting RRT and were presumably
healthier, greater SBP, DBP, mean arterial
or pulse pressure were not associated with
J Am Soc Nephrol 25: 1630–1646, 2014
decreased mortality in the first year. Simi-
larly, among 16,959 dialysis patients in the
United States, low SBP (,120 mmHg) was
associated with increased mortality in years
1 and 2.177 However, high SBP ($150
mmHg) was associated with increased
mortality among patients who survived at
least 3 years.177
Regional differences in mortality are
unlikely to be caused by patient-specific
characteristics alone. Forexample, a center
in Tassin, France, reported a mortality rate
of 45 per 1000 patient-years.176 By con-
trast, Degoulet et al., also from France,
reported a mortality rate of 96 per 1000
patient-years.178 Differences in outcomes
may be the result of center-specific prac-
tices. Patients reported by Charra et al. in
Tassin, France, are dialyzed long hours
with low sodium dialysate and are given
low-sodium bread from the dialysis
unit.176 The vast majority of these patients
become normotensive without needing
antihypertensive drugs.
BP measurement technique is also
quite likely to contribute to variation in
the relationship between BP and out-
comes. For example, Amar et al. were
the first to discover the strong relationship
between ambulatory BP and mortality.53
These authors reported that nocturnal
SBP was directly related to mortality.
Agarwal et al. have used ambulatory BP
to detect its relationship with mortality.
In a cohort of approximately 150 patients,
the authors found a direct and statistically
significant relationship of both home and
ambulatory BP with mortality.54 No such
relationship was detectable using predial-
ysis and postdialysis BP recordings. In a
larger cohort followed for a longer time,
the authors found a W-shaped relation-
ship between both ambulatory BP and
home BP and all-cause mortality64 At ex-
tremes of BP, mortality was noted to be
high. Compared with ambulatory BP, the
optimal BP ranges for home BP were ap-
proximately 10 mmHg higher.
HYPERTENSION IN PEDIATRIC
DIALYSIS PATIENTS
Young adults with childhood-onset ESRD
have significantly elevated cardiovascular
www.jasn.org BRIEF REVIEW
risk compared with the general popula-
tion. Data from the Late Effects of Renal
Insufficiency in Children cohort study of
249 Dutch adult patients with onset of
ESRD between 0 and 14 years of age
demonstrated that the overall mortality
risk of the patients with ESRD was 31 times
that of age-matched Dutch citizens.179
Cardiovascular disease accounted for
41% of all mortalities, with cardiac death
becoming the most common cause of
mortality after 10 years of receiving
RRT.179 Similarly, among 1380 patients
with childhood-onset ESRD who died be-
fore aged 30 years, 23% of deaths were
cardiovascular in origin; the cardiovascu-
lar death rate was 1000 times higher
among children with ESRD than in the
general population, and was 100 times
higher among young adults with ESRD
than in the general population.180 Al-
though the number of patients with
childhood-onset ESRD is small compared
with the overall adult ESRD population,
they constitute a unique group in whom
control of cardiovascular risk factors is key
to ensuring long-term survival.
As in adult ESRD patients, hyperten-
sion is the most common modifiable
cardiovascular risk factor in children on
dialysis. Mitsnefes et al.181 reported that
approximately 60% of pediatric dialysis
patients had uncontrolled hypertension,
defined as measured BP$95th percen-
tile. Young age, recent dialysis initiation,
and HD modality were identified as risk
factors for having uncontrolled BP. Sim-
ilar poor control of hypertension using
predialysis and postdialysis BP measure-
ments in American dialysis patients has
been reported by Chavers et al.6 for HD
patients and Halbach et al.182 for both
HD and PD patients. In the latter study,
demographic factors such as young age
and black race and treatment factors
such as prescription of antihypertensive
medications were also identified as risk
factors for poorly controlled hyperten-
sion. More recent data from the Euro-
pean Registry for Children on Renal
Replacement Therapy on BP control
among pediatric ESRD patients in
Europe, including patients receiving
HD, PD, and postrenal transplant, con-
firmed the high rate of hypertension in
Hypertension in ESRD 1639
 BRIEF REVIEW www.jasn.org
pediatric ESRD. Hypertension was pres-
ent in 69.4% of HD patients (using BP
recordings in the peridialytic period),
68.6% of PD patients, and 66.9% of
transplant recipients.183 Among dialysis
patients, younger age, recent dialysis ini-
tiation, and HD modality were the most
important risk factors for hyperten-
sion.183 Of note, all of these studies are
notable for their reliance upon registry
data; thus, there is limited information
available on the technique and/or fre-
quency of BP measurement, or the goals
of hypertension management.
LVH is the best-studied complication
of hypertension in pediatric dialysis pa-
tients. A study by Mitsnefes et al. dem-
onstrated increased left ventricular mass
at the start of dialysis, and also showed
that this increase persisted over a mean
follow-up of 10 months.184 Risk factors
for LVH included anemia, longer du-
ration of renal disease before start of
dialysis, and higher SBP. In a recent mul-
ticenter study from the International
Pediatric Peritoneal Dialysis Network,
LVH was present in 48% of hypertensive
PD patients, with fluid overload, high
body mass index, and hyperparathyroid-
ism being the primary determinants of
LVH. 185 Studies comparing the fre-
quency of LVH in children on PD or
HD have had variable results. An Amer-
ican study showed that children on HD
had LVH more often (85%) than chil-
dren on PD (68%).186 Similarly, a Finnish
study found that 45% of children on PD
had LVH; LVH in this study was highly
correlated with the severity of hyperten-
sion (pressure overload) and with hyper-
volemia as reflected by the plasma atrial
natriuretic peptide level.187 On the con-
trary, the results from a German study
showed similar left ventricular mass index
with both modes of treatment.188 It is
therefore likely that the prevalence of left
ventricular in pediatric dialysis patients is
more dependent on the overall control of
BP and on volume status than on dialysis
modality.
Diagnosis of hypertension and achieve-
ment of BP control pose some unique
challenges in pediatric dialysis patients.
With respect to diagnosis, age-appropriate
normative values as published by the
1640 Journal of the American Society of Nephrology
National High Blood Pressure Education
Program (NHBPEP) must be used, and BP
cuffs appropriate for the child’s upper arm
must be selected.189 Normal BP in chil-
dren is defined as a BP value below the
90th percentile for age, sex, and height,
and hypertension is defined as BP values
repeatedly at or above the 95th percen-
tile.190 Thus, the clinician must consult
tables of normative BP values in order to
correctly categorize a child’s BP as normal
or elevated. It should also be noted that
there are no existing consensus recom-
mendations that specifically address the
optimal BP treatment goal for children
on dialysis. Both the NHBPEP and the
Kidney Disease Outcomes Quality Initia-
tive have recommended that hypertensive
children with CKD should be treated to a
BP below the 90th percentile,189,190 but
pediatric dialysis patients were not specif-
ically mentioned in either of these reports.
Given that normalization of BP has been
shown to lead to regression of LVH in at
least one study of pediatric HD pa-
tients,191 recommendations to achieve a
BP value below the 90th percentile would
seem appropriate until further evidence
can be generated. Among pediatric pa-
tients on dialysis, further studies are
needed to define the accuracy of peridia-
lytic BP monitoring in determining inter-
dialytic ambulatory BP.
Strategies to control hypertension in
pediatric dialysis patients are similar to
those used in adults, and include dietary
sodium restriction and control of volume
status. Vasodilating antihypertensive med-
ications are generally avoided so as not to
compromise fluid removal. A unique and
vexing issue in the treatment of hyperten-
sive pediatric dialysis patients is how to
accurately assess and achieve dry weight.
Infants and young children in particular
are expected to demonstrate progressive
weight gain and linear growth, a process
that does not proceed in a predictable
linear manner.192 Thus, it is unreasonable
to expect that pediatric patients can
achieve and maintain a stable dry weight.
Two potential approaches to this problem
have been studied: bioimpedance analysis
and blood volume monitoring. In a recent
single-center study, use of bioimpedance
analysis to determine dry weight in a small
group of pediatric HD patients was asso-
ciated with fewer episodes of pulmonary
edema and decreased prevalence of LVH
compared with a group of historical con-
trols.193 A blood volume monitoring pro-
tocol in a multicenter study demonstrated
improved control of hypertension with
decreased need for antihypertensive med-
ications, although no significant change in
postdialysis weight was seen.106 In pediat-
ric PD patients, a plasma atrial natriuretic
peptide level .3.0 nmol/L was felt to re-
flect hypervolemia on one study,187 but
this finding has not yet been replicated.
Clearly, further refinement of how to es-
tablish dry weight in pediatric dialysis pa-
tients is required.
Hypertension is an important clinical
problem in HD patients.Often medication-
directed approaches are utilized due to
its perceived simplicity, as in the general
population. However, nonpharmacologic
and dialytic approaches are more likely to
be successful and may target one of the
major factors that contribute to the de-
velopment of congestive heart failure:
central pressure/volume overload. Use of
antihypertensive drugs may improve car-
diovascular outcomes; b-blockers may
be a preferred drug class. More clinical
trials are needed to evaluate optimal indi-
vidualized strategies for defining targets
for BP and controlling BP using pharma-
cologic and nonpharmacologic strategies
in HD patients.
ACKNOWLEDGMENTS
Review of an earlier version of this work by the
publication committee of the American So-
ciety of Hypertension and the Hypertension
Advisory Group of the American Society of
Nephrology is gratefully acknowledged. We
thank Tia A. Paul, University of Maryland
School of Medicine, Baltimore, for expert
secretarial support.
This work was supported, in part, by a
grant from the National Institutes of Health
(2R01-DK6203010) to R.A.
DISCLOSURES
None.
J Am Soc Nephrol 25: 1630–1646, 2014

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