Journal of the American Society of Hypertension 6(6) (2012) 439442

Debate from the American Society of Hypertension Annual Meeting

Debate from the 2012 ASH Annual Scientific Sessions: should blood
pressure be reduced in hemodialysis patients? pro position
Rajiv L. Agarwal, MD
Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN
Manuscript received August 16, 2012 and accepted August 26, 2012

Abstract

Among chronic hemodialysis patients with hypertension, blood pressure should be lowered. Blood pressure reduction with
antihypertensive drugs does not increase mortality; in contrast, meta-analysis of randomized trials suggests that treatment
of hypertension in this high-risk population may, in fact, improve cardiovascular outcomes. The association of low blood
pressure with increased mortality in longitudinal studies should not be considered as evidence against lowering blood pres-
sure. Lowering blood pressure among hypertensive patients should primarily be done by sodium restriction and dry-weight
reduction. Treatment is perhaps better directed to home blood pressure than pre- or post-dialysis blood pressure recordings.
Although no firm data are available, it appears that treating home blood pressure to <140/90 mm Hg appears reasonable.
Nonetheless, all blood pressure recordings during dialysis are important to ensure patient safety. Adequately designed
and powered randomized trials are needed to examine the notion that blood pressure lowering and, if so, to what level of
blood pressure will improve clinically meaningful outcomes among chronic dialysis patients. J Am Soc Hypertens
2012;6(6):439442. Published by Elsevier Inc on behalf of American Society of Hypertension.

Whether blood pressure should be lowered among dialysis
patients is a matter of controversy because epidemiological
studies nearly uniformly suggest that lower blood pressure
among hemodialysis patients is associated with greater
mortality.1 The first study in the United States that convinc-
ingly demonstrated that lower blood pressure is associated
with an increased mortality was performed in a cohort of
patients dialyzed at facilities managed by a nonprofit dialysis
provider.2 In this observational study involving several thou-
sand patients, Zager et al demonstrated that the relative death
rate was not changed with increasing levels of blood pressure
measured post-dialysis.2 However, if post-dialysis blood pres-
sure was modeled as a time-dependent covariate, then it was
found that a lower blood pressure was associated with
increased mortality.2 A post-dialysis systolic blood pressure
of <110 mm Hg was associated with a risk ratio of 2.04 for
death compared with a reference blood pressure post dialysis
of 140149 mm Hg.2 Cause-specific death rates showed an
even more remarkable relationship. For instance, post-
dialysis blood pressure of <110 mm Hg was associated with
Funding: NIH 2R01-DK062030-08.
Corresponding author: Rajiv L. Agarwal, MD, Professor of
Medicine, Indiana University and VAMC, 1481 West 10th Street,
Indianapolis, IN 46202. Tel: (317) 988-2241.
E-mail: ragarwal@iupui.edu
1933-1711/$ - see front matter Published by Elsevier Inc on behalf of American Society of Hypertension.
http://dx.doi.org/10.1016/j.jash.2012.08.009
a risk ratio of 2.62 compared with a reference blood pressure
of 140149 mm Hg.2 In contrast, noncardiac-related cause
of death was associated with a risk ratio of 1.55 when the
systolic blood pressure was <110 mm Hg compared with
a reference range of 140149 mm Hg.2
The next study, published in 1999, the United States Renal
Data System case mix adequacy study, demonstrated that
a pre-dialysis blood pressure of <109 mm Hg systolic was
associated with a risk ratio of cardiovascular death of 1.86
and a blood pressure of 110119 mm Hg was associated
with a risk ratio of 1.27.3 The reference pre-dialysis systolic
blood pressure (with risk ratio of 1) was 120 to 149 mm
Hg.3 In 2005, Kalantar-Zadeh et al confirmed the inverse rela-
tionship of cardiovascular death and blood pressure in the
hemodialysis population, which they described as the reverse
epidemiology of hypertension.4 Using the database of a dial-
ysis provider (DaVita), the authors demonstrated a J-shaped
relationship of cardiovascular death even after adjustments
for several risk factors.4 Cardiovascular death was similarly
strongly and inversely associated with post-dialysis systolic
blood pressure.4 Post-dialysis systolic blood pressure of
<120 mm Hg was associated with an increased mortality.
The following year, Li et al confirmed these observations in
yet another analysis of a dialysis provider (Fresenius).5 Pre-
dialysis systolic blood pressure <120 mm Hg was associated
with a hazard ratio of 3.5 (reference predialysis systolic blood
440 R.L. Agarwal / Journal of the American Society of Hypertension 6(6) (2012) 439442
pressure <180 mm Hg) for all-cause mortality.5 The time-
varying model for death yielded estimates of hazards of 67.5
These observations can perhaps be explained by the high
comorbidity that exists in dialysis patients. For example, in
a low-risk population (such as those with uncomplicated
hypertension, absence of diabetes, and heart failure), a direct
relationship would be anticipated between increasing blood
pressure and mortality.6 However, in a high-risk population
(such as the patients who have presence of heart failure and
systemic inflammation), this relationship could be hypothe-
sized to be inverted. This occurs because blood pressures in
these patients the severity of the underlying illness.
Compared with those with essential hypertension, dialysis
patients have a much higher proportion of patients with
the heart failure and systemic inflammation; therefore,
a U-shaped relationship could be anticipated.6
These observational, cohort studies did not lower blood
pressure; in fact, none of these studies had any information
on antihypertensive medications. The fall in blood pressure
was spontaneous and may have been related to disease
states. Accordingly, one has to be cautious in extrapolating
these studies. Cohort studies examine association but not
causality.
The distinction between achieving a lower blood pressure
and targeting a lower blood pressure can be demonstrated
through a clever analysis of the African American Study
of Kidney disease. In that study, target mean arterial pressure
for the two randomized groups was <92 mm Hg or
<115 mm Hg.7 The primary end point was the rate of decline
in the measured glomerular filtration rate (GFR), which was
not different over 4 years between the two groups. The
composite end point of 50% decline in GFR, a decline of at
least 25 mL/min/1.73 m2 in GFR, end-stage renal disease,
or death was also no different between the randomized
groups.7 This leads to the conclusion that targeting blood
pressure more aggressively does not reduce the risk of
progression of kidney disease for hard outcomes in such pop-
ulations.7 Achieved blood pressure analysis, however,
yielded results that were quite different. For example, the
mean GFR slope was higher in patients who had a mean
follow-up mean arterial pressure of 113 mm Hg as compared
with those with a mean achieved pressure of 86 mm Hg.7 The
hazard ratio of the primary end point was also increased in
those patients who were in the highest quartile of mean
>113 mm Hg. Accordingly, analyses based on achieved
blood pressure led to markedly different inferences than the
intention-to-treat analysis.7 This may be attributed to con-
founding of achieved blood pressure by comorbidities,
disease severity, or nonadherence.7 As a result, the authors
concluded that clinicians and policy makers should exercise
caution when making treatment recommendations based on
analyses relating outcomes to achieved blood pressures.7
Although adequately powered randomized trials among
dialysis patients are not yet available, meta-analyses of
randomized controlled trials of antihypertensive drugs in
hemodialysis patients suggest a benefit of blood pressure
lowering. In a meta-analysis of eight trials, the overall reduc-
tion in cardiovascular events was 36% (P < .05).8 In further
examination of these studies, it was noted that when normo-
tensive patients were included, the risk reduction for adverse
cardiovascular events was only 12% in contrast to a 55% risk
reduction when hypertensive patients were treated with anti-
hypertensive agents.9
To date, no randomized trial with hard outcomes in dialysis
patients has focused on blood pressures measured outside the
dialysis unit. It is important to recognize that dialysis unit
blood pressures are poor estimates of inter-dialytic ambula-
tory blood pressure.10 For example, a meta-analysis demon-
strated that the pre-dialysis systolic blood pressure
overestimated ambulatory blood pressure by 16.7 mm Hg
and post-dialysis values underestimated by 1.6 mm Hg.11
However, the standard deviations of the estimated difference
between dialysis unit blood pressure recordings and ambula-
tory blood pressure measurements in individual studies are
wide. Accordingly, in individual patients, post-dialysis or
pre-dialysis systolic blood pressures cannot reliably predict
ambulatory blood pressure.11 In contrast, home blood pres-
sure greater than 150 mm Hg has a sensitivity of 80% and
specificity of 84% in diagnosing interdialytic ambulatory
hypertension.12 Furthermore, systolic home blood pressure
is similar to ambulatory blood pressure in predicting echocar-
diographic left ventricular hypertrophy.13 This is not so for
dialysis unit blood pressurerecorded values. In fact, out-
of-dialysis unit blood pressures are of greater prognostic
value compared with those obtained within the dialysis
unit.14 In a hemodialysis cohort of 150 patients followed
for 2 years, 31% of the patients died.14 Quartiles of systolic
blood pressure were associated with mortality in a Cox
model. For the pre-dialysis or post-dialysis blood pressure,
no statistical significance was seen. However, home blood
pressure of 125145 mm Hg was associated with the best
prognosis, as was an ambulatory blood pressure of
115125 mm Hg.14 Both home blood pressure and ambula-
tory blood pressure were statistically significant for predict-
ing prognosis.14 In a larger cohort of more than 320 patients,
pre- and post-dialysis blood pressures were not found to be of
prognostic significance for all-cause mortality.15 In contrast,
ambulatory blood pressure quartiles were highly associated
with death, as were home blood pressure recordings.15
Finally, in a trial designed to treat hypertension using home
blood pressure versus dialysis unit blood pressure, it was
noted that over a 6-month period in patients randomized to
dialysis unit obtained blood pressure treatment, systolic in-
terdialytic ambulatory blood pressure changed from 149 to
150 mm Hg (P NS).16 In those patients in whom treatment
was guided using home blood pressure, blood pressure
changed from 149 to 142, which was statistically signifi-
cant.16 Although the study failed to find improvement in
left ventricular hypertrophy, it was underpowered to detect
this difference. Given the various benefits of home blood
 R.L. Agarwal / Journal of the American Society of Hypertension 6(6) (2012) 439442
pressure monitoring emphasized in the United States17,18 and
European guidelines,19,20 it appears that this should be the
basis for the treatment of hypertension for most dialysis
patients.
How to get the blood pressure down has been an important
conundrum among nephrologists. The first-line management
should be through volume reduction. In fact, Dr. Belding
Scribner, a pioneer in dialysis treatment in the United States
remarked that In the case of dialysis patients, the slow
normal level of extracellular volume is maintained by
a powerful tool, ultrafiltration, which is, if properly used
along with dietary sodium restriction, the only proven
method of controlling blood pressure in the hemodialysis
populations. In my view, the answer to the question can anti-
hypertensive medications control blood pressure in hemodi-
alysis patients is no.21 Therefore additional volume
reduction through probing dry weight can serve as an impor-
tant tool to control hypertension in these patients. In the only
randomized trial that has examined this issuethe Dry
weight Reduction In hypertensive hemodialysis Patients
(DRIP) randomized trialit was found that interdialytic
ambulatory blood pressure was reduced 6.9 mm Hg systolic
within 4 weeks and 3.1 mm diastolic in the same period.22
This was not associated with deterioration in quality of life
but may have been associated with a slight increase in
adverse events that were not statistically significant.22
Clearly, further studies are needed to examine this notion
further, but for now it appears that volume reduction should
be attempted as first-line therapy to control hypertension in
most chronic hemodialysis patients.
Because few techniques are available to assess volemia,
relative plasma volume slopes during the dialysis procedure
measured through commercially available equipment can be
used along with the overall clinical scenario to judge volume
status.23 In fact, in the DRIP trial, participants who had dry
weight probed had steepening of relative plasma volume
slopes.24 Furthermore, those with the flattest slopes at base-
line experienced the greatest reduction in blood pressure.
In contrast, on probing dry weight the bottom quartile had
no reduction in blood pressure. Preliminary data suggest
that in comparison to flatter slopes, steeper relative plasma
volume slopes are associated with lower mortality.25 This
mortality benefit persists after multifactorial adjustments.
Taken together, these data suggest that lowering volume
may be an effective strategy to improve cardiovascular
outcomes in these patients.
In summary, the current evidence suggests that among
chronic hemodialysis patients with hypertension, blood pres-
sure should be lowered. Although no firm data are available,
it appears that treating home blood pressure to <140/90 mm
Hg appears reasonable. Blood pressure lowering does not
increase mortality; in contrast, meta-analysis of randomized
trials suggests that treatment of hypertension in this high-risk
population may in fact improve cardiovascular outcomes.
The association of low blood pressure with increased
441
mortality in longitudinal studies should not be considered
as evidence against lowering blood pressure. Blood pressure
reduction among hypertensive patients should primarily be
accomplished by sodium restriction and dry-weight reduc-
tion. Treatment is perhaps best directed to home blood
pressure rather than pre- or post-dialysis blood pressure
recordings. Nonetheless, all blood pressures measured
during dialysis are important to ensure patient safety. Finally,
adequately designed and well-powered randomized trials are
needed to examine the notion whether blood pressure
lowering will improve clinically meaningful outcomes
among chronic dialysis patients.
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