Narrative Review

Intensive Hemodialysis, Blood Pressure, and Antihypertensive

Medication Use
George L. Bakris, MD,1 John M. Burkart, MD,2 Eric D. Weinhandl, PhD, MS,3
Peter A. McCullough, MD, MPH,4,5,6,7 and Michael A. Kraus, MD 8

Hypertension is a cardinal feature of end-stage renal disease (ESRD). Hypertensive nephropathy is the
primary cause of ESRD for nearly 30% of patients, and the prevalence of hypertension is .85% in new pa-
tients with ESRD. In contemporary hemodialysis (HD) patients, mean predialysis systolic blood pressure
(SBP) is nearly 150 mm Hg, and about 70%, 50%, and 40% use b-blockers, calcium channel blockers, and
renin-angiotensin system inhibitors, respectively. Predialysis SBP generally exhibits a U-shaped association
with mortality risk. Interdialytic ambulatory SBP is more strongly associated with risk. Hypertension is multi-
factorial; key causes include persistent hypervolemia and elevated peripheral resistance. With 3 HD sessions
per week, blood pressure (BP) climbs during the interdialytic interval, in step with interdialytic weight gain,
particularly among elderly patients and those with higher dry weight. Elevated peripheral resistance can be
attributed to inappropriate activation of the sympathetic nervous system due to higher plasma norepinephrine
concentrations. Multiple randomized clinical trials show that intensive HD reduces BP and the need for oral
medications indicated for hypertension. In the first 2 months of the Frequent Hemodialysis Network trial, the
short daily schedule reduced predialysis SBP by 7.7 mm Hg, whereas the nocturnal schedule reduced pre-
dialysis SBP by 7.3 mm Hg, both relative to 3 sessions per week. Improvements were sustained after 12
months. Both schedules reduced antihypertensive medication use relative to 3 sessions per week. In
FREEDOM (Following Rehabilitation, Economics, and Everyday-Dialysis Outcome Measurements), a pro-
spective cohort study of short daily HD, the mean number of prescribed antihypertensive agents decreased
from 1.7 to 1.0 in 1 year, whereas the percentage of patients not prescribed antihypertensive agents increased
from 21% to 47%. Nocturnal HD appears to markedly reduce total peripheral resistance and plasma norepi-
nephrine and restore endothelium-dependent vasodilation. In conclusion, intensive HD reduces BP and the
need for antihypertensive medications.
Am J Kidney Dis. 68(5)(suppl 1):S15-S23. ª 2016 by the National Kidney Foundation, Inc.

INDEX WORDS: Antihypertensive medication; blood pressure; cardiovascular disease; chronic kidney
disease; daily dialysis; end-stage renal disease (ESRD); fluid overload; Frequent Hemodialysis Network;
home dialysis; hypertension; intensive hemodialysis; nocturnal hemodialysis; short daily hemodialysis;
ultrafiltration; review.

H ypertension is intertwined with chronic kidney

disease (CKD). As endogenous kidney function
declines, the prevalence of hypertension increases
inexorably. For example, in KEEP (Kidney Early
Evaluation Program) participants from 2000 to 2006,
prevalences of hypertension were 61%, 64%, 68%,
72%, 86%, 91%, and 94% in those with estimated
glomerular filtration rates of 90 to 99, 80 to 89, 70 to
79, 60 to 69, 50 to 59, 40 to 49, and 30 to 39 mL/min/
1.73 m2, respectively; in those with estimated
glomerular filtration rates , 30 mL/min/1.73 m2 (ie,
with either CKD stage 4 or 5), the prevalence of hy-
pertension was 96%.1 Here, hypertension was defined
as systolic blood pressure (SBP) $ 130 mm Hg or
diastolic blood pressure (DBP) $ 80 mm Hg in par-
ticipants with diabetes or self-reported kidney disease
and SBP $ 140 mm Hg or DBP $ 90 mm Hg in all
other participants. In KEEP, the degree of blood
pressure (BP) control was strongly associated with the
incidence of end-stage renal disease (ESRD).2 Anal-
ysis of concurrent NHANES (National Health and
Nutrition Examination Survey) participants revealed a

From the 1American Society of Hypertension Comprehensive
Hypertension Center, Section of Endocrinology, Diabetes, and
Metabolism, Department of Medicine, University of Chicago
Medicine, Chicago, IL; 2Wake Forest University Medical Center,
Winston-Salem, NC; 3Department of Pharmaceutical Care and
Health Systems, College of Pharmacy, University of Minnesota,
Minneapolis, MN; 4Baylor University Medical Center; 5Baylor Heart
and Vascular Institute; 6Baylor Jack and Jane Hamilton Heart and
Vascular Hospital, Dallas; 7The Heart Hospital Baylor Plano, Plano,
TX; and 8Indiana University Medical School, Indianapolis, IN.
Received February 16, 2016. Accepted in revised form May 25,
2016.
This article is part of a supplement that was developed with
funding from NxStage Medical, Inc.
Address correspondence to Eric D. Weinhandl, PhD, MS,
Department of Pharmaceutical Care and Health Systems, College
of Pharmacy, University of Minnesota, Weaver-Densford Hall, 7th
Fl, 308 Harvard St SE, Minneapolis, MN 55455. E-mail:
wein0205@umn.edu
 2016 by the National Kidney Foundation, Inc.
0272-6386
http://dx.doi.org/10.1053/j.ajkd.2016.05.026

Am J Kidney Dis. 2016;68(5)(suppl 1):S15-S23 S15


similar gradient of prevalence across the spectrum of
kidney function, with overwhelming prevalence (98%)
in the sample of those with CKD stage 4 or 5.1 Not
surprisingly, hypertension is an important complica-
tion in patients who progress to ESRD (ie, requiring
either dialysis therapy or kidney transplantation).
The pharmacologic armamentarium for the treat-
ment of hypertension notably includes b-blockers,
(dihydropyridine) calcium channel blockers, and
renin-angiotensin system (RAS) inhibitors. Less
commonly used classes in dialysis patients comprise
central a agonists, peripheral a antagonists, and direct
vasodilators. Diuretics constitute another antihyper-
tensive modality in patients with normal urine output
or mild oliguria, but their utility is limited in ESRD;
aside from loop diuretics (in patients with residual
kidney function), class members are infrequently
prescribed. In dialysis patients, hypertension can be
managed with agents in one or more classes; for pa-
tients who have also been diagnosed with heart fail-
ure, b-blockers and RAS inhibitors may be efficacious
through mechanisms other than BP reduction.
Antihypertensive agents lower BP by inhibiting
renin release (b-blockers and aliskiren), inhibiting the
RAS (angiotensin-converting enzyme [ACE] in-
hibitors and angiotensin II receptor blockers [ARBs]),
inhibiting the sympathetic nervous system (central a
agonists and peripheral a antagonists), dilating the
vasculature (vasodilators), or eliminating sodium
(diuretics). Thus, these agents fail to address the most
proximal cause of hypertension in dialysis patients:
excess intravascular volume. In the absence of resid-
ual kidney function (and setting aside the possibility
of limiting fluid intake), the only method by which to
lower volume is dialysis itself. If more dialysis, in the
form of either greater session frequency or duration,
can effectively address persistent hypervolemia, hy-
pertension might be more adequately addressed, as
has been observed with increasing treatment duration
on conventional in-center hemodialysis (HD).3
In this review, we examine the epidemiology of
hypertension, pathogenesis of hypertension, efficacy
and limitations of antihypertensive agents, and effects
of intensive HD on both BP and antihypertensive
agent use. We show that both short daily HD and
nocturnal HD can effectively lower BP and reduce the
use of antihypertensive agents.
EPIDEMIOLOGY OF HYPERTENSION
Prevalence at Dialysis Initiation
According to the US Renal Data System, hyper-
tension was the second leading cause of ESRD among
incident patients with ESRD in 2013.4 Specifically, in
each year since the beginning of the century, hyper-
tension has constituted the primary cause of ESRD for
S16
Bakris et al
w28% of incident patients with ESRD. The preva-
lence of hypertension as merely a comorbid condition
is much higher. As described previously, data from
KEEP and NHANES both suggest that the prevalence
is .95% in patients with estimated glomerular
filtration rates , 30 mL/min/1.73 m2.1 Because hy-
pertension is a risk factor for cardiovascular death in
non2dialysis-dependent CKD (NDD-CKD) and
because death and ESRD are competing outcomes in
NDD-CKD, the prevalence of hypertension may be
modestly lower in incident patients with ESRD (ie,
those who survived NDD-CKD). According to the
ESRD Medical Evidence Report (CMS [Centers for
Medicare & Medicaid Services] form 2728), the
prevalence of hypertension was 86% in incident pa-
tients with ESRD from 2010 to 2012.4 In an analysis
of more than 16,000 patients who initiated HD ther-
apy in a not-for-profit dialysis provider organization,
mean predialysis SBP during the second, third, and
fourth months of HD therapy was 150 6 19 (standard
deviation) mm Hg, and mean predialysis DBP was
78 6 12 mm Hg.5 In a more recent study of more
than 3,400 patients who initiated HD therapy in Renal
Research Institute facilities, the prevalence of SBP of
140 to 159 mm Hg during the first week of treatment
was 38%, whereas prevalences of SBP of 160 to
179 mm Hg and .180 mm Hg were 21% and 6%,
respectively.6
Prevalence After Dialysis Initiation
In the aforementioned study of Renal Research
Institute facilities, mean SBP declined sharply be-
tween the first and second weeks of treatment, from
150.5 to 147.7 mm Hg, before increasing during the
rest of the first 12 weeks of treatment.6 However, the
aggregate pattern belies heterogeneity in SBP trends
by initial SBP. In patients with severe hypertension
(ie, initial SBP . 180 mm Hg), mean SBP actually
increased during the second, third, and fourth weeks
of treatment, before gradually decreasing to a
plateau of w170 mm Hg by the middle of the first
year of treatment. In patients with initial SBPs of
140 to 159 mm Hg, mean SBP was very stable at
nearly 150 mm Hg during the first year. Finally,
in patients with relative hypotension (ie, initial
SBPs , 120 mm Hg), mean SBP initially decreased
further, to 110 mm Hg during the first month, before
steadily increasing to almost 130 mm Hg at the end of
the first year.
As of December 2015, in the DOPPS (Dialysis
Outcomes and Practice Patterns Study), mean pre-
dialysis SBP among prevalent HD patients was
148 mm Hg, with 75th and 90th percentiles of 163 and
179 mm Hg, respectively.7 Alternatively, 32%, 21%,
and 9% had predialysis SBPs of 140 to 159, 160 to
179, and .180 mm Hg, respectively (Fig 1).7 Thus,
Am J Kidney Dis. 2016;68(5)(suppl 1):S15-S23
Blood Pressure With Intensive Hemodialysis
40
35
30
25
Percentage of patients
20
15
10
5
0
<120 120−139 140−159 160−179
Systolic blood pressure (mmHg)
Figure 1. Distribution of predialysis systolic blood pressure
in the Dialysis Outcomes and Practice Patterns Study Practice
Monitor, December 2015.7
without accounting for isolated diastolic hypertension,
the prevalence of hypertension in a large sample of US
HD patients is .60% despite the substantial use of
antihypertensive agents, as described later.
Associations With Morbidity and Mortality
The association of BP with risks for mortality and
morbidity has been studied extensively in long-term
dialysis patients. Many epidemiologic studies have
pointed toward a U-shaped or even reverse J-shaped
association between BP in the dialysis facility and
mortality risk, such that hypotensive patients have
much higher risk and hypertensive patients have
modestly higher risk relative to patients with moderate
BP (ie, with SBP of 130 to 180 mm Hg, an interval that
extends higher than BP targets for the general popu-
lation).8 Still, these patterns have been identified in
observational studies, which may experience unmea-
sured confounding. Apart from confounding, another
issue that complicates these observational studies is the
timing of BP measurement. Predialysis BP over-
estimates interdialytic ambulatory BP.9 In NDD-CKD,
ambulatory BP not at goal is a more powerful risk
predictor than clinic BP not at goal.10 In dialysis-
dependent CKD, both ambulatory and home mea-
surements of SBP are more strongly associated with
mortality risk than pre- and postdialysis measurements
are, with increasing risk along a linear gradient
beginning at w120 mm Hg.11-14 In addition, ran-
domized clinical trials of BP-lowering interventions in
dialysis patients suggest that addressing hypertension
Am J Kidney Dis. 2016;68(5)(suppl 1):S15-S23
can lower the risk for cardiovascular mortality and
morbidity. In a meta-analysis of 8 randomized clinical
trials that collectively included 1,679 patients and 495
cardiovascular events, mean SBP was 4.5 mm Hg
lower and mean DBP was 2.3 mm Hg lower in actively
treated patients versus controls.15 Moreover, BP-
lowering treatment was associated with lower risks
for both cardiovascular mortality (relative risk, 0.71;
95% confidence interval [CI], 0.50-0.99) and cardio-
vascular morbidity (relative risk, 0.71; 95% CI, 0.55-
0.92).
PATHOGENESIS OF HYPERTENSION
The pathogenesis of hypertension in dialysis pa-
tients is exceedingly complex. The NKF-KDOQI
(National Kidney Foundation2Kidney Disease Out-
comes Quality Initiative) guideline regarding cardio-
vascular disease in dialysis patients lists a wide
≥180 variety of factors, including sodium and volume
excess; increased activity of vasoconstrictors, such as
the renin-angiotensin-aldosterone and sympathetic
nervous systems; decreased activity of vasodilators,
such as nitric oxide and kinins; pathologic changes in
the arterial and venous vasculature; and use of
exogenous erythropoietin.16 Complicating the matter
in dialysis patients is the difficulty assessing and
determining dry weight.17
The role of excessive intravascular volume in the
pathogenesis of hypertension is especially important.
Clearly, volume expansion increases BP. In adjusted
analyses of Crit-Line Intradialytic Monitoring Benefit
(CLIMB) Study participants, each 1-point increment
in relative interdialytic weight gain was associated
with a 1.002mm Hg increase in predialysis SBP and
a 1.082mm Hg increase in change in SBP (ie, pre-
dialysis SBP 2 postdialysis SBP).18 These associa-
tions were pronounced in elderly patients and those
with higher dry weight. However, the HD procedure
tends to lower BP. In a post hoc analysis of one he-
modialysis session in a subset (n 5 468) of HEMO
(Hemodialysis) Study participants, HD treatment
reduced body weight by 3.1 kg because plasma vol-
ume was reduced by 10.1%. In adjusted analyses,
each 5-point increment in the percentage reduction of
plasma volume during dialysis was associated with
2.562 and 1.122mm Hg decrements in postdialysis
SBP and DBP, respectively, both of which were
significant.19 Increased peripheral vascular resistance
is itself multifactorial. Key causes include excessive
activity of the sympathetic nervous system due to
higher plasma norepinephrine concentrations, and in
the long run, stiffening of the vasculature due to
calcification.20,21 Exogenous erythropoietin may
induce hypersensitivity to angiotensin II and norepi-
nephrine and increase circulating endothelin 1
concentrations.22
S17

Sodium exposure also plays an important part in the
pathogenesis of hypertension because plasma osmo-
lality drives thirst and resultant fluid intake.23 Dietary
salt restriction is effective for BP control and left
ventricular hypertrophy regression.24,25 According to a
recent systematic review of 23 studies of dialysate
sodium concentrations, BP was not markedly affected
by high versus low concentrations, although both
randomized clinical trials with ambulatory BP moni-
toring detected lower SBP and DBP with low con-
centrations.26 Most studies identified a correlation
between high dialysate sodium concentration and
significantly higher interdialytic weight gain.26
PHARMACOLOGIC TREATMENT OF
HYPERTENSION
Available Therapies
The dominant pharmacologic interventions for the
treatment of hypertension in dialysis patients are b-
blockers, (dihydropyridine) calcium channel blockers,
and RAS inhibitors, including ACE inhibitors and
ARBs. In the DOPPS surveillance population, as of
December 2015, the prevalence of use of b-blockers
was 68%; calcium channel blockers, 51%; and RAS
inhibitors, 38%.7 Thus, simple arithmetic shows that
prevalent HD patients typically use agents in more
than one of these classes. In an older analysis of
incident dialysis patients in a not-for-profit dialysis
organization, the prevalence of use after 6 months of
HD (peritoneal dialysis) treatment was 59% (55%) for
b-blockers, 49% (50%) for calcium channel blockers,
and 45% (52%) for RAS inhibitors.27 The use of other
classes was also assessed. Because the study cohort
comprised incident dialysis patients in whom residual
kidney function is not uncommon, 28% of HD and
41% of peritoneal dialysis (PD) patients used a
diuretic after 6 months of dialysis treatment; most
used loop diuretics, which are more effective in pa-
tients with limited kidney function but may induce
hypokalemia. In addition, in HD (peritoneal dialysis)
patients, 19% (15%) used central a agonists, primar-
ily clonidine, with higher use in black patients; 7%
(10%) used peripheral a antagonists; and 12% (6%)
used direct vasodilators. In total, incident HD patients
used 2.3 antihypertensive agents in the first month of
dialysis treatment and 2.5 agents in the sixth month,
whereas incident peritoneal dialysis patients used 2.8
antihypertensive agents in the first month and 2.5
agents in the sixth month. Thus, polypharmacy is
common, even in the subset of oral medications
indicated for the treatment of hypertension.
Adherence
In light of polypharmacy, the pill burden associated
with antihypertensive agents is high. In a 3-center
S18
Bakris et al
study of prevalent HD patients, mean pill burden
across all oral medications was 19 pills per day, with
tremendous positive skew (ie, standard deviation, 12
pills per day).28 Approximately 18% of the pill
burden was attributable to antihypertensive agents.
Although the most widely used antihypertensive
agents (eg, metoprolol, amlodipine, lisinopril, val-
sartan, and furosemide) are typically taken once daily,
the combined pill burden of antihypertensive agents
and other medications, notably phosphate binders,
may encourage nonadherence, resulting in inade-
quately controlled hypertension. Poor adherence to
oral medications is common. Moreover, medication
regimen complexity appears to be linked with
adherence. In a survey of more than 1,200 dialysis
patients in Italy, the number of prescribed tablets per
day was significantly associated with self-reported
adherence, after adjustment for putative confounding
factors.29 Other factors associated with poor adher-
ence include younger age, male sex, elevated number
of comorbid conditions, and depression.30
Dialyzability
Another challenge with antihypertensive agents
concerns the pharmacokinetics of these agents. Some
antihypertensive agents are cleared by HD, whereas
others are not. In general, agents with molecular
weight . 500 Da, not highly protein bound, and
water soluble are dialyzable. In the class of b-
blockers, atenolol and metoprolol are cleared effec-
tively by HD, whereas carvedilol is not.31 None of the
calcium channel blockers are cleared by HD.32 In the
class of RAS inhibitors, all ACE inhibitors except
fosinopril and trandolapril are cleared by HD,
whereas ARBs are not.32,33 A recent pharmacoepi-
demiologic study suggested that exposure to high-
dialyzability versus low-dialyzability b-blockers was
associated with increased risk for death and arrhyth-
mias in elderly HD patients.34 In patients with heart
failure, the removal of b-blockers and ACE inhibitors
from a steady-state level may be tantamount to
medication withdrawal of either class of agent, which
has been associated in the general population with
increased risks for heart failure hospitalization and
death.35,36 Due to low dialyzability, calcium channel
blockers and direct vasodilators are withheld on the
morning of HD in some patients (eg, those with
autonomic dysfunction secondary to diabetes, those
who are prone to hypotension, and those who are
adherent to a low-sodium diet).
Comparative Effectiveness
Data regarding the comparative effectiveness of
medication classes are sparse. The NKF-KDOQI
guidelines suggest that RAS inhibitors should be
preferred because they cause greater regression of left
Am J Kidney Dis. 2016;68(5)(suppl 1):S15-S23
Blood Pressure With Intensive Hemodialysis
ventricular hypertrophy and reduce sympathetic nerve
activity.16 Recently, in HDPAL (Hypertension in
Hemodialysis Patients Treated With Atenolol or
Lisinopril), an open-label randomized clinical trial of
atenolol versus lisinopril in 200 in-center HD patients,
the effects of atenolol (vs lisinopril) on interdialytic
ambulatory SBP, postdialysis weight, and left ven-
tricular mass index were 23.6 mm Hg
(P . 0.05), 22.4 kg (P , 0.05), and 26.4 g/m2
(P . 0.05) respectively, after 12 months.37 The ratio
of cardiovascular event incidence rates for atenolol
versus lisinopril was 0.42 (95% CI, 0.24-0.74).
EFFECTS OF INTENSIVE HD
Interdialytic Interval
In the Frequent Hemodialysis Network (FHN) tri-
als, patients were randomly assigned to short daily or
conventional HD in the Daily Trial (n 5 245) and to
nocturnal or conventional HD in the Nocturnal Trial
(n 5 87).38,39 For patients assigned to short daily HD,
mean hours between sessions declined from 54 hours
at baseline to 32 hours after 3 to 5 months of follow-
up and to 35 hours after 10 to 12 months. For patients
assigned to nocturnal HD, mean hours between ses-
sions declined from 53 hours at baseline to 41 hours
after 3 to 5 months of follow-up and 44 hours after 10
to 12 months.
Ultrafiltration
Ayus et al40 reported a single-center prospective
cohort study of 77 patients, all of whom were offered
and 26 of whom chose short daily HD; the other 51
patients chose conventional HD. Mean ultrafiltration
decreased sharply with short daily HD, from 3.32 kg
per treatment at baseline to 2.81 and 2.67 kg per
treatment after 6 and 12 months of follow-up,
respectively. Meanwhile, with conventional HD,
mean ultrafiltration volume per treatment steadily
climbed from 3.38 kg per treatment at baseline to
3.62 kg per treatment after 12 months.
Kraus et al41 performed a feasibility study of short
daily HD with the NxStage System One, a portable
low-dialysate-volume machine. The study enrolled 32
individuals who had previously received HD for at
least 3 months. The design included 8-week phases of
in-center treatment and home treatment, with a 2-
week transition phase between the longer phases.
Patients were prescribed 6 HD sessions per week for
the entirety of the study; in practice, patients received
on average 5.8 sessions per week. Relative to the
retrospective period (ie, concurrent with conventional
HD treatment), interdialytic weight gain was cut by
w60% and amounted to w1.0 kg at the end of the
study.
In the FHN Daily Trial, ultrafiltration per session
was 3.06 L with conventional HD, but only 2.12 L
Am J Kidney Dis. 2016;68(5)(suppl 1):S15-S23
with short daily HD.38 However, due to the higher
number of sessions per week with short daily HD,
cumulative ultrafiltration per week was 8.99 L with
conventional HD and 10.58 L with short-daily HD
(an increase of 18% with short daily HD). As a per-
centage of postdialysis weight, ultrafiltration per ses-
sion was 3.99% and 2.83% with conventional and
short daily HD, respectively. Likewise, in the FHN
Nocturnal Trial, ultrafiltration per session was 2.52 L
with conventional HD and 1.95 L with nocturnal HD,
but ultrafiltration per week was 7.41 L with conven-
tional HD and 9.13 L with nocturnal HD (an increase
of 23% with nocturnal HD).39 As a percentage of
postdialysis weight, ultrafiltration per session was
3.10% and 2.29% with conventional and nocturnal
HD, respectively.
BP With Short Daily HD
In the previously described study of 26 patients
who chose short daily HD and 51 patients who chose
conventional HD, mean SBP declined significantly
with short daily HD, from 145 mm Hg at baseline to
139 mm Hg after 6 months of follow-up (before
increasing slightly to 142 mm Hg after 12 months of
follow-up).40 In contrast, mean SBP was unchanged
with conventional HD. In the feasibility study for the
NxStage System One, relative to the retrospective
period, mean SBP was 17.6 mm Hg lower during the
in-center phase and 23.9 mm Hg lower during the
home phase.41 DBP declined similarly and was 3.6
and 6.9 mm Hg lower during the in-center and home
phases, respectively, relative to the retrospective
period.
In the FHN Daily Trial, predialysis SBP decreased
with intensive HD from 147 mm Hg at baseline to
139 mm Hg at month 2 and decreased further to
137 mm Hg at months 10 to 12.42 Concurrently,
predialysis SBP remained at 147 mm Hg with con-
ventional HD. The treatment effect of intensive HD
on predialysis SBP (210 mm Hg) was significant
(Fig 2), as were treatment effects on postdialysis SBP
(28 mm Hg), predialysis DBP (25 mm Hg), and
postdialysis DBP (23 mm Hg). Interdialytic weight
gain was 1 kg lower with intensive HD versus con-
ventional HD. Fourteen (11%) patients on intensive
HD therapy had decreases . 30 mm Hg in predialysis
SBP from the beginning to the end of the study. In
contrast, only 2 (2%) patients on conventional HD
therapy had such decreases. Notably, the treatment
effect on predialysis SBP was larger in anuric patients
than in those with urine output.
In a series of small studies, Buoncristiani et al43
evaluated changes in left ventricular structure with
short daily HD. In particular, the studies identified
positive correlations in left ventricular end-diastolic
diameter reduction (after 6-12 months of short daily
S19
 Bakris et al

Systolic blood pressure (mmHg)

110 120 130 140 150 160

Intensive
FHN Daily Trial
Conventional

Intensive
FHN Nocturnal Trial
Conventional

Intensive
Canadian Trial At baseline
At end of study
Conventional

FHN Daily Trial

FHN Nocturnal Trial
Canadian Trial

−25 −20 −15 −10 −5 0 5

Treatment effect (mmHg, intensive versus conventional)

Figure 2. Effects of intensive versus conventional hemodialysis on predialysis systolic blood pressure in the Frequent Hemodial-
ysis Network (FHN) Daily Trial,42 FHN Nocturnal Trial,42 and Canadian trial of nocturnal hemodialysis.46 Estimated treatment effects
(solid dots) and associated 95% confidence intervals (solid lines) are displayed at the bottom.

HD) with reductions in mean arterial pressure, mean
SBP, and extracellular water.43
BP With Nocturnal HD
Chan et al44 described the experience of 28 patients
who began daily nocturnal HD treatment at a single
center, as well as the experience of 13 conventional
HD patients who were otherwise eligible for nocturnal
HD treatment. Mean SBP decreased significantly with
nocturnal HD, from 146 to 122 mm Hg, whereas
mean DBP decreased from 84 to 74 mm Hg. With
conventional HD, mean SBP and DBP decreased only
trivially. In nocturnal HD patients, there was a strong
correlation between left ventricular mass index and
SBP (Pearson coefficient, 0.6). Lockridge et al45
described the experience of 40 patients who con-
verted to daily nocturnal HD therapy. In that cohort,
mean SBP declined from 159 to 134 mm Hg and
mean DBP declined from 90 to 74 mm Hg.45
In a randomized clinical trial of daily nocturnal HD
(n 5 26) versus conventional HD (n 5 25) in Canada,
mean SBP decreased from 129 mm Hg at baseline to
122 mm Hg after 6 months of nocturnal HD, whereas
mean SBP increased from 135 mm Hg at baseline to
139 mm Hg after 6 months of conventional HD
therapy.46 The treatment effect on SBP (211 mm Hg,
in favor of intensive HD) was slightly shy of signif-
icance (Fig 2). Similarly, mean DBP decreased from
75 mm Hg at baseline to 68 mm Hg after 6 months of
nocturnal HD, whereas mean SBP decreased from
77 mm Hg at baseline to 75 mm Hg after 6 months of
conventional HD. That treatment effect (25 mm Hg,
again in favor of intensive HD) was also slightly shy
of significance.
In the FHN Nocturnal Trial, predialysis SBP
decreased with intensive HD, from 145 to 142 mm Hg
at month 2, and steadily declined to 137 mm Hg at
months 10 to 12.42 Concurrently, predialysis SBP

S20 Am J Kidney Dis. 2016;68(5)(suppl 1):S15-S23

Blood Pressure With Intensive Hemodialysis

decreased only slightly with conventional HD, from the FHN Nocturnal Trial, the number of antihyper-
153 mm Hg at baseline to 151 mm Hg at the end of the tensive medications per patient decreased from 1.9 to
study. The adjusted treatment effect on predialysis 1.1 with intensive HD and remained at 1.6 with
SBP (28 mm Hg) was significant (Fig 2), as was the conventional HD (Fig 4).42 The treatment effect of
effect on predialysis DBP (25 mm Hg); the adjusted 0.44 fewer agents per patient, in favor of intensive
treatment effects on postdialysis SBP and DBP were HD, was also significant.
not significant, although they also favored intensive In an earlier trial of nocturnal versus conventional
HD. Interdialytic weight gain was w0.5 kg lower with HD, 16 of 26 (62%) patients assigned to nocturnal
intensive versus conventional HD. HD reduced or discontinued antihypertensive medi-
cation use during follow-up, whereas only 3 of 25
Antihypertensive Medication Use (12%) patients assigned to conventional HD reduced
In the feasibility study for the NxStage System or discontinued antihypertensive medication use.46
One, antihypertensive medication use declined. In the In the series of 28 nocturnal HD patients and 13
retrospective phase, 20 patients took a cumulative 50 conventional HD controls described by Chan et al,44
agents (agents per treated patient, 2.5). At the end of the mean number of antihypertensive medications
the study, 7 of these patients had discontinued anti- was reduced from 1.8 to 0.3 agents with nocturnal
hypertensive medication use, and among the remain- HD, but remained stable at 1.5 agents with conven-
ing 13 users, agents per treated patient were 1.45.41 In tional HD. Similarly, in the series of 40 nocturnal HD
an interim analysis of 57 patients who completed patients described by Lockridge et al,45 the mean
FREEDOM (Following Rehabilitation, Economics, number of antihypertensive medications decreased
and Everyday-Dialysis Outcome Measurements), a significantly, from 2.15 to 0.73 agents per day.
prospective study of short daily HD, the mean number
of prescribed antihypertensive agents decreased from CONCLUSIONS
1.7 to 1.0 in 1 year, whereas the percentage of patients Hypertension is an ongoing challenge in the care of
prescribed no agents increased from 21% to 47%.47 dialysis patients. Antihypertensive medications are
In the FHN Daily Trial, the number of antihyper- widely used and polypharmacy is common, but
tensive medications per patient decreased from 2.2 to pharmacologic intervention is typically unsuccessful
1.4 with intensive HD and from 2.3 to 2.0 with at lowering BP to normotensive levels, partially due
conventional HD (Fig 3).42 The treatment effect of to poor adherence to prescribed therapy and partially
0.36 fewer antihypertensive agents per patient, in due to poor volume control on the parts of patients
favor of intensive HD, was significant. Meanwhile, in and dialysis delivery. Even in the case of high
4

4
Number of prescribed antihypertensive agents

Number of prescribed antihypertensive agents

3

3
2

2
1

1
0

Baseline Month 4 Month 12 Baseline Month 4 Month 12 Baseline Month 4 Month 12 Baseline Month 4 Month 12
Intensive Conventional Intensive Conventional

Figure 3. Mean number of prescribed antihypertensive med- Figure 4. Mean number of prescribed antihypertensive med-
ications at baseline, month 4, and month 12 of the Frequent He- ications at baseline, month 4, and month 12 of the Frequent He-
modialysis Network (FHN) Daily Trial.42 Dashed bars span 1 modialysis Network (FHN) Nocturnal Trial.42 Dashed bars span
standard deviation above and below the mean. 1 standard deviation above and below the mean.

Am J Kidney Dis. 2016;68(5)(suppl 1):S15-S23 S21


adherence, antihypertensive agents do not directly
address the root cause of intermittent hypervolemia,
which accompanies the conventional HD schedule. In
contrast, intensive HD therapy lessens the duration of
the interdialytic interval, limiting interdialytic weight
gain. Importantly, intensive HD significantly lowers
BP and reduces the need for antihypertensive medi-
cations. By way of lowering BP, intensive HD may
improve cardiovascular outcomes.
ACKNOWLEDGEMENTS
Support: The publication costs associated with this journal
supplement were paid by NxStage Medical Inc. NxStage specified
neither expectations nor restrictions regarding the content of this
review. Furthermore, no employee of NxStage was involved in its
writing. Dr Weinhandl has received compensation as an epide-
miologist consultant to NxStage and his consulting agreement
included an expectation of research and writing directed toward a
journal supplement regarding intensive HD.
Financial Disclosure: All authors except Dr Weinhandl are
members of the Chronic Therapy Scientific Advisory Board at
NxStage and receive nominal compensation for their service. Drs
Bakris and McCullough report no other financial relationships
with a commercial entity producing health care–related products
and/or services. Drs Burkart and Kraus have received compensa-
tion as physician consultants to NxStage.
Peer Review: Evaluated by 2 external peer reviewers, the
Deputy Editor, and the Editor-in-Chief.
REFERENCES
1. Rao MV, Qiu Y, Wang C, Bakris G. Hypertension and
CKD: Kidney Early Evaluation Program (KEEP) and National
Health and Nutrition Examination Survey (NHANES), 1999-2004.
Am J Kidney Dis. 2008;51(4)(suppl 2):S30-S37.
2. Peralta CA, Norris KC, Li S, et al. Blood pressure compo-
nents and end-stage renal disease in persons with chronic kidney
disease: the Kidney Early Evaluation Program (KEEP). Arch
Intern Med. 2012;172(1):41-47.
3. Tandon T, Sinha AD, Agarwal R. Shorter delivered dialysis
times associate with a higher and more difficult to treat blood
pressure. Nephrol Dial Transplant. 2013;28(6):1562-1568.
4. Saran R, Li Y, Robinson B, et al. US Renal Data System
2014 Annual Data Report: epidemiology of kidney disease in the
United States. Am J Kidney Dis. 2015;66(1)(suppl 1):Svii. S1-
S305.
5. Myers OB, Adams C, Rohrscheib MR, et al. Age, race,
diabetes, blood pressure, and mortality among hemodialysis pa-
tients. J Am Soc Nephrol. 2010;21(11):1970-1978.
6. Sipahioglu MH, Usvyat L, Liu L, et al. Early systolic blood
pressure changes in incident hemodialysis patients are associated
with mortality in the first year. Kidney Blood Press Res.
2012;35(6):663-670.
7. Arbor Research Collaborative for Health. The DOPPS
Practice Monitor. http://www.dopps.org/DPM/. Accessed May
20, 2015.
8. Chang TI. Systolic blood pressure and mortality in patients
on hemodialysis. Curr Hypertens Rep. 2011;13(5):362-369.
9. Agarwal R, Peixoto AJ, Santos SFF, Zoccali C. Pre- and
postdialysis blood pressures are imprecise estimates of inter-
dialytic ambulatory blood pressure. Clin J Am Soc Nephrol.
2006;1(3):389-398.
10. Minutolo R, Gabbai FB, Agarwal R, et al. Assessment of
achieved clinic and ambulatory blood pressure recordings and
S22
Bakris et al
outcomes during treatment in hypertensive patients with CKD: a
multicenter prospective cohort study. Am J Kidney Dis.
2014;64(5):744-752.
11. Alborzi P, Patel N, Agarwal R. Home blood pressures are
of greater prognostic value than hemodialysis unit recordings. Clin
J Am Soc Nephrol. 2007;2(6):1228-1234.
12. Agarwal R. Blood pressure and mortality among hemodi-
alysis patients. Hypertension. 2010;55(3):762-768.
13. Agarwal R. The controversies of diagnosing and treating
hypertension among hemodialysis patients. Semin Dial.
2012;25(4):370-376.
14. Agarwal R. Pro: Ambulatory blood pressure should be used
in all patients on hemodialysis. Nephrol Dial Transplant.
2015;30(9):1432-1437.
15. Heerspink HJL, Ninomiya T, Zoungas S, et al. Effect of
lowering blood pressure on cardiovascular events and mortality
in patients on dialysis: a systematic review and meta-analysis
of randomised controlled trials. Lancet. 2009;373(9668):
1009-1015.
16. National Kidney Foundation. K/DOQI clinical practice
guidelines for cardiovascular disease in dialysis patients. Am J
Kidney Dis. 2005;45(4)(suppl 3):S1-S153.
17. Jaeger JQ, Mehta RL. Assessment of dry weight
in hemodialysis an overview. J Am Soc Nephrol. 1999;10(2):
392-403.
18. Inrig JK, Patel UD, Gillespie BS, et al. Relationship be-
tween interdialytic weight gain and blood pressure among preva-
lent hemodialysis patients. Am J Kidney Dis. 2007;50(1):108-118.
118.e1-e4.
19. Leypoldt JK, Cheung AK, Delmez JA, et al. Relationship
between volume status and blood pressure during chronic hemo-
dialysis. Kidney Int. 2002;61(1):266-275.
20. Mayet J, Hughes A. Cardiac and vascular pathophysiology
in hypertension. Heart. 2003;89(9):1104-1109.
21. Demer LL, Tintut Y. Vascular calcification: pathobiology
of a multifaceted disease. Circulation. 2008;117(22):2938-2948.
22. Vaziri ND. Mechanism of erythropoietin-induced hyper-
tension. Am J Kidney Dis. 1999;33(5):821-828.
23. Tomson CR. Advising dialysis patients to restrict fluid
intake without restricting sodium intake is not based on evidence
and is a waste of time. Nephrol Dial Transplant. 2001;16(8):
1538-1542.
24. Ozkahya M, Ok E, Cirit M, et al. Regression of left ven-
tricular hypertrophy in haemodialysis patients by ultrafiltration and
reduced salt intake without antihypertensive drugs. Nephrol Dial
Transplant. 1998;13(6):1489-1493.
25. Kayikcioglu M, Tumuklu M, Ozkahya M, et al. The
benefit of salt restriction in the treatment of end-stage renal dis-
ease by haemodialysis. Nephrol Dial Transplant. 2009;24(3):
956-962.
26. Basile C, Pisano A, Lisi P, Rossi L, Lomonte C,
Bolignano D. High versus low dialysate sodium concentration in
chronic haemodialysis patients: a systematic review of 23 studies.
Nephrol Dial Transplant. 2016;31(4):548-563.
27. St Peter WL, Sozio SM, Shafi T, et al. Patterns in blood
pressure medication use in US incident dialysis patients over the
first 6 months. BMC Nephrol. 2013;14:249.
28. Chiu Y-W, Teitelbaum I, Misra M, de Leon EM, Adzize T,
Mehrotra R. Pill burden, adherence, hyperphosphatemia, and
quality of life in maintenance dialysis patients. Clin J Am Soc
Nephrol. 2009;4(6):1089-1096.
29. Neri L, Martini A, Andreucci VE, et al. Regimen
complexity and prescription adherence in dialysis patients. Am J
Nephrol. 2011;34(1):71-76.
Am J Kidney Dis. 2016;68(5)(suppl 1):S15-S23
Blood Pressure With Intensive Hemodialysis
30. Burnier M, Pruijm M, Wuerzner G, Santschi V. Drug
adherence in chronic kidney diseases and dialysis. Nephrol Dial
Transplant. 2015;30(1):39-44.
31. Bakris GL, Hart P, Ritz E. Beta blockers in the manage-
ment of chronic kidney disease. Kidney Int. 2006;70(11):1905-
1913.
32. Inrig JK. Antihypertensive agents in hemodialysis patients:
a current perspective. Semin Dial. 2010;23(3):290-297.
33. White CM. Pharmacologic, pharmacokinetic, and thera-
peutic differences among ACE inhibitors. Pharmacotherapy.
1998;18(3):588-599.
34. Weir MA, Dixon SN, Fleet JL, et al. b-Blocker dialyz-
ability and mortality in older patients receiving hemodialysis. J Am
Soc Nephrol. 2015;26(4):987-996.
35. Fonarow GC, Abraham WT, Albert NM, et al. Influence of
beta-blocker continuation or withdrawal on outcomes in patients
hospitalized with heart failure: findings from the OPTIMIZE-HF
program. J Am Coll Cardiol. 2008;52(3):190-199.
36. Prins KW, Neill JM, Tyler JO, Eckman PM, Duval S. Ef-
fects of beta-blocker withdrawal in acute decompensated heart
failure: a systematic review and meta-analysis. JACC Heart Fail.
2015;3(8):647-653.
37. Agarwal R, Sinha AD, Pappas MK, Abraham TN,
Tegegne GG. Hypertension in hemodialysis patients treated with
atenolol or lisinopril: a randomized controlled trial. Nephrol Dial
Transplant. 2014;29(3):672-681.
38. FHN Trial Group; Chertow GM, Levin NW, Beck GJ, et al.
In-center hemodialysis six times per week versus three times per
week. N Engl J Med. 2010;363(24):2287-2300.
39. Rocco MV, Lockridge RS, Beck GJ, et al. The effects of
frequent nocturnal home hemodialysis: the Frequent Hemodialysis
Network Nocturnal Trial. Kidney Int. 2011;80(10):1080-1091.
Am J Kidney Dis. 2016;68(5)(suppl 1):S15-S23
40. Ayus JC, Mizani MR, Achinger SG, Thadhani R, Go AS,
Lee S. Effects of short daily versus conventional hemodialysis on
left ventricular hypertrophy and inflammatory markers: a pro-
spective, controlled study. J Am Soc Nephrol. 2005;16(9):2778-
2788.
41. Kraus M, Burkart J, Hegeman R, Solomon R, Coplon N,
Moran J. A comparison of center-based vs. home-based daily
hemodialysis for patients with end-stage renal disease. Hemodial
Int. 2007;11(4):468-477.
42. Kotanko P, Garg AX, Depner T, et al. Effects of frequent
hemodialysis on blood pressure: results from the randomized
Frequent Hemodialysis Network trials. Hemodial Int. 2015;19(3):
386-401.
43. Buoncristiani U, Fagugli R, Ciao G, et al. Left ventricular
hypertrophy in daily dialysis. Miner Electrolyte Metab. 1999;25(1-
2):90-94.
44. Chan CT, Floras JS, Miller JA, Richardson RM,
Pierratos A. Regression of left ventricular hypertrophy after con-
version to nocturnal hemodialysis. Kidney Int. 2002;61(6):2235-
2239.
45. Lockridge RS, Spencer M, Craft V, et al. Nightly home
hemodialysis: five and one-half years of experience in Lynchburg,
Virginia. Hemodial Int. 2004;8(1):61-69.
46. Culleton BF, Walsh M, Klarenbach SW, et al. Effect of
frequent nocturnal hemodialysis vs conventional hemodialysis on
left ventricular mass and quality of life: a randomized controlled
trial. JAMA. 2007;298(11):1291-1299.
47. Jaber BL, Collins AJ, Finkelstein FO, et al. Daily hemo-
dialysis reduces the need for anti-hypertensive medications.
October 2009. https://www.asn-online.org/api/download/?file5/
education/kidneyweek/archives/RW09Abstracts.pdf. Accessed
May 20, 2015.
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