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Brief Review

Intradialysis Hypertension in End-Stage Renal


Disease Patients
Clinical Epidemiology, Pathogenesis, and Treatment
Panagiotis I. Georgianos, Pantelis A. Sarafidis, Carmine Zoccali

Online Data Supplement

I ntradialytic hypotension is an established, common, and


risky complication of hemodialysis.1 However, hypotension
is only 1 component of the abnormal hemodynamic response
hypertension. This is important because, although several
patients may experience 1 episodes of BP rise during a
single dialysis session, only few of them may have persistent
to ultrafiltration dialysis; the opposite phenomenon, that is, intradialytic hypertension. No study until now has attempted
paradoxical rise in blood pressure (BP) during or immediately to differentiate asymptomatic BP increases during dialysis
after dialysis, intradialytic hypertension is equally common from hypertensive emergencies, that is, rapid increases in
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and associates with adverse cardiovascular outcomes.2 BP that may cause severe organ damage in a matter of hours.
Intradialytic hypertension has a prevalence of 5% to 15% However, true hypertensive emergencies during dialysis are
and predicts cardiovascular mortality.2,3 The BP rise during considered as rare events and the issue will not be discussed
dialysis has a complex mechanistic background and is multi- in the present review.
factorial in nature.2,4 Herein, we provide a systematic review
of the epidemiology and pathogenesis of intradialytic hyper- Clinical Epidemiology of Intradialytic
tension and key recommendations for the management of this Hypertension: From Prevalence to Prognosis
neglected dialysis-related complication. The search strategy Seminal observations in the 1990s suggested that hyperten-
and selection criteria used for this review are reported in Table sion during dialysis occurs in 5% to 15% of patients.10 As
S1 in the online-only Data Supplement and Figure S1. shown in Table1, a more accurate estimate of the prevalence
of intradialytic hypertension was provided by an analysis of
Epidemiology of Intradialytic Hypertension 438 dialysis patients participating in the Crit-Line Intradialytic
Monitoring Benefit (CLIMB) study, in which 13.2% of par-
Definition ticipants exhibited intradialytic rise in systolic BP (SBP) >10
Although the phenomenon of BP rise during hemodialysis is mmHg.5 Patients with intradialytic hypertension tended to
recognized for several years, there are no accepted criteria to be older, received more antihypertensive drugs, had lower
define intradialytic hypertension. In some studies, intradia- dry weight and lower interdialytic weight gain as compared
lytic hypertension was defined as rise in mean arterial pressure with those without intradialytic hypertension.5 In a subsequent
>15 mmHg within or immediately post dialysis.2 In others, a analysis from the US Renal Data System Dialysis Morbidity
lower threshold was applied (>10 mmHg increase in systolic and Mortality Wave II cohort, Inrig et al3 showed that 213 of
pressure)3,5 and in some an inclusive definition was adopted 1718 patients (12.2%) experienced intradialytic hyperten-
(BP rise of any degree during the second or third intradia- sion, defined as increase in SBP >10 mmHg from pre to post
lytic hour).6 Other definitions include increasing intradialytic dialysis. Again, patients with intradialytic hypertension were
BP that remains unresponsive to volume withdrawal7 and older, had lower dry weight, lower serum creatinine and albu-
worsening of pre-existing hypertension or new-onset hyper- min, and were receiving more antihypertensive medications
tension after administration of erythropoietic-stimulating than those with SBP that remained unchanged or decreased
agents (ESAs).8 Consistency is a fundamental criterion in during dialysis. Another recent retrospective study, including
the analysis of biological and clinical phenomena.9 However, data from 22995 dialysis treatments for a 6-month follow-
none of the aforementioned definitions considered reproduc- up, showed that 22.3% of dialysis sessions were complicated
ibility as criterion for adjudicating the diagnosis intradialysis by intradialytic increase in SBP >10 mmHg.11 However, in

Received May 15, 2015; first decision May 29, 2015; revision accepted June 13, 2015.
From the Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital (P.I.G.) and Department of Nephrology, Hippokration
Hospital (P.A.S.), Aristotle University of Thessaloniki, Thessaloniki, Greece; and CNR-IFC, Clinical Epidemiology and Pathophysiology of Hypertension
and Renal Diseases, Ospedali Riuniti, Reggio Calabria, Italy (C.Z.).
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.
115.05858/-/DC1.
Correspondence to Panagiotis I. Georgianos, Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital, Aristotle
University of Thessaloniki, St Kyriakidi 1, Thessaloniki, Greece. E-mail pangeorgi@yahoo.gr
(Hypertension. 2015;66:456-463. DOI: 10.1161/HYPERTENSIONAHA.115.05858.)
2015 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.115.05858

456
Georgianos et al Intradialytic Hypertension 457

Table 1. Prevalence of Intradialytic Hypertension Among Hemodialysis Patients


Study ID Patients Definition Prevalence Estimates
Inrig et al5 438 hemodialysis patients participating in the Rise in SBP 10 mmHg from pre to post dialysis 13.2% of patients met the definition
Kidney Int 2009 CLIMB study of intradialytic hypertension
Inrig et al3 1748 hemodialysis patients participating in the Rise in SBP >10 mmHg from pre to post dialysis, 12.2% of patients were classified as
AJKD 2009 USRDS Dialysis Morbidity and Mortality Wave II averaged from 3 consecutive dialysis sessions intradialytic hypertensives
study
Van Buren et al11 362 hemodialysis patients receiving treatment Rise in SBP >10 mmHg from pre to post dialysis, 22.3% of dialysis treatments
Int J Artific Organs 2012 in the USA averaged for the total number of dialysis were complicated by intradialysis
treatments performed during 6 months of hypertension. Persistent intradialytic
follow-up hypertension was noted in 8% study
participants
CLIMB indicates Critic-Line Intradialytic Monitoring Benefit study; SBP, systolic blood pressure; and USRDS, US Renal Data System.

this study, persistent (ie, consistent over time) intradialytic receiving hemodialysis in 580 centers in the United States
hypertension was observed only in 8% of participants.11 The during 2001 to 2006,13 a U-shaped association between BP
phenomenon of intradialytic hypertension gained momentum changes during dialysis and survival was evident. Large intra-
after the publication of cohort studies linking this hemody- dialytic drops in SBP (ie, >30 mmHg) and any elevation in
namic alteration with increased risk of mortality (Table2). SBP during dialysis were both associated with increased mor-
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In the CLIMB study, intradialytic hypertension was associ- tality risk.13 In contrast to the US Renal Data System data,3
ated with 2.17-fold increased risk for a combined end-point the association of intradialytic hypertension with mortality
including all-cause mortality and nonvascular access-related was stronger for patients with predialysis SBP >120 mmHg.13
hospitalization (odds ratio, 2.17; 95% confidence intervals In the study by Inrig et al,13 general linear modeling was
[CI], 1.134.15).5 Subsequently, analyses performed in the US applied,3 whereas in the second Cox regression with restricted
Renal Data System Dialysis Morbidity and Mortality Wave II cubic splines was used, which is considered a more appropri-
cohort reported that each 10mmHg rise in SBP from pre to ate approach to detect nonlinear associations. In general, the
post dialysis underlies a 12% excess risk for all-cause mortal- adjusted HR associated with intradialytic rises in BP is of just
ity during a mean follow-up of 2 years (hazard ratio [HR], moderate degree (up to 1.6 for a 30mmHg rise in SBP in
1.06; 95% CI, 1.011.12).3 When the analysis was stratified the largest study to date).13 To add sufficient discrimination
according to predialysis SBP levels, the relationship between power over other risk factors for the identification of patients
intradialytic hypotension and mortality attenuated, whereas who will develop future events and to improve risk classifica-
intradialytic hypertension remained an independent predic- tion at individual level, risk factors should have a high HR
tor of all-cause death in patients with predialysis SBP <120 for the outcome of interest.14 Thus, it is highly unlikely that
mmHg (HR, 1.12; 95% CI, 1.051.21 for each 10mmHg rise intradialysis hypertension per se adds meaningful predictive
in SBP during dialysis).3 power to standard risk factors in dialysis patients.
In a study by Yang et al12 in 115 hemodialysis patients, a
mean rise in SBP >5 mmHg from pre to post dialysis for 25 Ambulatory Blood Pressure Monitoring Phenotype
consecutive dialysis sessions was associated with 3.9 higher in Patients With Intradialysis Hypertension
risk of all-cause mortality for a 3.4-year follow-up (HR, Peridialytic BP recordings exhibit high variability, poor repro-
3.93; 95% CI, 1.4210.85).12 In a cohort of 113255 patients ducibility and provide inaccurate estimates of interdialytic

Table 2. Prospective Observational Studies Associating Intradialytic Hypertension With Increased Risk of Mortality
Study ID Patients Follow-Up Predictor Outcome Risk
Inrig et al5 438 dialysis patients 6 mo SBP from pre to post Combined end point of OR, 2.17; 95% CI, 1.134.15
Kidney Int 2009 participating in the CLIMB dialysis 10 mmHg nondialysis-related
study hospitalization or all-cause
mortality
Inrig et al3 1748 hemodialysis patients 2y SBP from pre to post All-cause mortality HR, 1.12; 95% CI, 1.051.21 per 10 mmHg
AJKD 2009 participating in the USRDS dialysis increase in SBP during dialysis
Dialysis Morbidity and
Mortality Wave II study
Yang et al12 115 prevalent dialysis patients 4y SBP >5 mmHg from All-cause mortality HR, 3.925; 95% CI, 1.41010.846
BMC Nephrol 2012 pre to post dialysis
Park et al13 113255 prevalent dialysis 2.2 yr SBP from pre to post All cause mortality Intradialytic reduction in SBP >30 mmHg
Kidney Int 2013 patients dialysis Cardiovascular mortality and any rise in SBP during dialysis were both
associated with increased risk of all-cause
and cardiovascular mortality
SBP indicates change in systolic blood pressure; CI, confidence interval; CLIMB, Critic-Line Intradialytic Monitoring Benefit study; HR, hazard ratio; OR, odds ratio;
and USRDS, US Renal Data System.
458HypertensionSeptember 2015

BP and poor association with cardiovascular outcomes.15 In parameters.7 The notion that volume overload maybe a pos-
contrast, elevated home BP and high ambulatory BP predict sible pathogenic mechanism of intradialytic hypertension is
cardiovascular morbidity and mortality independently of other supported by a post hoc analysis of the Dry weight Reduction
risk factors in dialysis patients.16 It is therefore of importance in Hypertensive Hemodialysis Patients (DRIP) trial.18 In this
to clarify whether any paradoxical rise in BP during dialy- study, 100 patients were randomized to intensive ultrafiltra-
sis associates with BP patterns during the interdialytic period tion during dialysis for 8 weeks and another 50 to a control
or whether intradialysis hypertension is a phenomenon unre- group who did not have their dry-weight probed. This analysis
lated to systemic hypertension as measured during the dialysis showed that probing of dry weight in the ultrafiltration group
interval, that is, during the ideal period for estimating the BP resulted into a steepening of the slopes of intradialytic SBP
burden in the dialysis population. during the course of the trial, whereas intradialytic SBP slopes
In a casecontrol study, Van Buren et al17 compared the in the control group remained unchanged. Each percent per
ambulatory BP profile of 25 patients with well-defined intra- hour steepening of the intradialytic SBP slope was associated
dialytic hypertension (>10 mmHg rise in SBP during dialysis with 0.71 mmHg fall in 44-hour interdialytic SBP.18 Although
in 4 of 6 consecutive dialysis sessions), with that of 25 age-, extracellular volume was not directly assessed in the DRIP
sex-, and diabetic status-matched patients without intradia- trial and no cause-and-effect associations between volume
lytic hypertension. Patients with intradialytic hypertension had expansion and intradialytic hypertension can be drawn, these
higher mean 44-hour ambulatory SBP and diastolic BP than findings support that dry-weight probing may be an effective
controls (155.414.2 versus 142.416.5 mmHg; P=0.005 for tool to achieve normal intradialytic BP reduction and improve
SBP and 82.410.8 versus 76.98.6 mmHg; P<0.05 for dia-
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BP profile during the out-of-dialysis period in patients with


stolic BP). Furthermore, patients with intradialytic hyperten- intradialytic hypertension.
sion had a gradual BP decline during the first 24 hours after A similar effect of extracellular volume expansion was
dialysis, which contrasted with the (typical) gradual increase explored in a recent cross-sectional analysis of 531 preva-
from postdialysis onwards in patients without intradialytic
lent hemodialysis patients, who had their body composition
hypertension.17 This study suggests that intradialytic hyper-
assessed with bioelectrical impedance analysis before and
tension is the exacerbation of a background hypertensive
after a midweek dialysis session.19 When patients were strati-
condition rather than a phenomenon restricted to the dialysis
fied into 3 categories according to the type of intradialytic
session. Thus, elevated interdialytic BP, rather than intradialy-
hemodynamic response, those with intradialytic rise in SBP
sis BP per se, may be a prominent contributor to the increased
>10 mmHg had higher extracellular water/total body water
risk of cardiovascular mortality associated with intradialytic
ratio predialysis, lower weight loss within dialysis, and higher
hypertension. In other words, from a pathogenic point of view,
extracellular water/total body water ratio post dialysis than
it remains undefined whether the excess risk for mortality in
those with SBP fall or stable SBP during dialysis.19 Notably,
patients with intradialysis hypertension depends on the BP rise
although volume expansion is suggested as a major patho-
during dialysis per se or on background systemic hypertension
as measured by ambulatory blood pressure monitoring. The genic mechanism of intradialytic hypertension, not all patients
issue can be approached by modeling the risk of intradialysis presenting this phenomenon are volume overloaded.
hypertension in analyses adjusting for 24 or 44-hour ambula-
Endothelial Dysfunction
tory blood pressure monitoring during the days offdialysis. If
the predictive power of intradialysis hypertension for death and In response to volume withdrawal and other mechanical and
cardiovascular complications either attenuates or disappears hormonal stimuli during dialysis, the endothelium releases
after such an adjustment, systemic background hypertension, various factors regulating vasomotor function and intradia-
rather than intradialysis hypertension, would be the factor actu- lytic hemodynamic response.20 Among patients with intradia-
ally responsible for the apparent excessive risk of this condi- lytic hypertension, endothelial dysfunction is hypothesized to
tion. No such analyses have been performed until now. generate an imbalance between endothelial-derived vasocon-
strictors and vasodilators in favor of the former, resulting in
Pathogenesis of Intradialytic Hypertension increased peripheral vascular resistance and hypertension.6
The mechanistic background of intradialytic hypertension is In a casecontrol study, Chou et al21 compared the circulat-
complex and not yet fully elucidated. Several factors, besides ing levels of endothelin-1 and NO pre and post dialysis in 30
increased cardiac output and peripheral vascular resistance, patients with and another 30 age- and sex-matched controls
have been proposed to be implicated into this phenomenon.2 without intradialytic hypertension. Among patients with intra-
These factors are summarized in the Figure and discussed in dialytic hypertension, a significant increase in endothelin-1
detail below. release and a parallel decrease in endothelial-derived NO dur-
ing dialysis were evident. NO/endothelin-1 ratio, although
Volume Overload depressed in both groups post dialysis, was significantly
Earlier uncontrolled observations suggested that among hemo- lower among patients with intradialytic hypertension.21 In a
dialysis patients with left ventricular dilatation and intradialytic subsequent study of 45 hemodialysis patients stratified into
hypertension, intensified ultrafiltration produced remarkable 3 groups according to the pattern of hemodynamic response
BP reductions of 46/22 mmHg, disappearance of the phe- during dialysis, El-Shafey et al22 showed that endothelin-1
nomenon of intradialytic BP elevation, and improvement in levels were significantly increased from pre to post dialysis in
cardiothoracic index and several other echacardiographic patients with intradialytic hypertension, decreased in patients
Georgianos et al Intradialytic Hypertension 459
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Figure. Pathogenic mechanisms of intradialysis hypertension. The dimension of circles reflects the relative relevance of individual risk
factors (see text). The sympathetic system stimulates renin release and may increase endothelin-1 (arrows). ESA indicates erythropoietic-
stimulating agent; i.v., intravenous; and SNS, sympathetic nervous system.

with intradialytic hypotension, and remained unchanged resistance and BP elevation. An uncontrolled study showed
among patients with stable hemodynamics during dialysis. that administration of 50 mg of the angiotensin-converting
A recent study comparing circulating markers of endo- enzyme inhibitor (ACEI) captopril just before dialysis in 6
thelial function between 11 patients with and 10 controls patients with intradialytic hypertension was associated with
without intradialytic hypertension confirmed that the former achievement of adequate BP control and cessation of intradia-
had significantly higher postdialysis levels of endothelin-1 lytic hypertensive episodes.26 In another study, plasma renin
and higher peripheral vascular resistance than the latter.23 In concentration remained unchanged during dialysis among
addition, Inrig et al24 showed that the number of peripheral patients prone to intradialytic hypertension, while exhibited
endothelial progenitor cells in 25 hemodialysis patients with a slight increase in hemodynamically stable patients.21 In
intradialytic hypertension is by 50% higher than in 25 age- theory, positive intradialytic sodium balance in patents prone
and sex-matched controls with normal intradialytic BP profile, to intradialytic hypertension may blunt ultrafiltration-induced
an alteration accompanied by reduced endothelium-dependent renninangiotensin activation. Sympathetic overactivity is a
vasodilatation. Thus, patients with intradialytic hypertension likely player in intradialysis hypertension (see below) and a
display severely impaired endothelial repair capacity and powerful stimulus of renin release. Therefore, activation of
diminished endothelial response to shear stress. Endothelial the RAS remains a likely player in this disturbance. Further
dysfunction is a plausible mechanism contributing to the high studies are needed to better ascertain the role of this system in
cardiovascular risk of these patients.25 intradialysis hypertension.

ReninAngiotensin System Sympathetic Nervous System


Rapid intravascular volume reduction with ultrafiltration may Seminal sympathetic microneurography studies in hemodi-
act as a stimulus for the reninangiotensin system (RAS) dur- alysis patients in the 1990s documented a doubling in sym-
ing dialysis, inducing sudden increase in peripheral vascular pathetic nerve firing in patients with intact native kidneys,
460HypertensionSeptember 2015

whereas no such alteration was present in patients with bilat- Arterial Stiffness
eral nephrectomy.27 Bilateral nephrectomy has a dramatic In 47 hemodialysis patients without history of cardiovascu-
effect in hemodialysis patients with resistant hypertension lar disease, Mourad et al39 showed that patients in whom BP
and reduced sympathetic nerve discharge is considered as the remained unchanged or decreased during dialysis had sig-
major factor responsible for the profound hypotensive effect nificantly lower aortic pulse wave velocity than those with
of this intervention.27 Accordingly, renal denervation produces intradialytic hypertension.39 Arterial stiffness goes along with
a relevant BP reduction and a substantial decrease in sympa- endothelial function in end-stage renal disease patients40 and
thetic nerve discharge in hemodialysis patients with severe therefore this association may be the expression of the under-
hypertension resistant to drug treatment and ultrafiltration lying link between endothelial dysfunction (discussed above)
intensification.28 About three-fourth of intradialytic hyperten- and arterial stiffness. The major consequence of increased
sive episodes, rather than evoking baroreceptor-mediated bra- arterial stiffness is premature arrival of the reflected pulse
dycardia, are accompanied by synchronous increases in heart wave from the periphery to the aorta during systole rather than
rate, a phenomenon underlying sympathovagal imbalance and diastole, raising aortic SBP and left ventricular afterload.41
sympathetic overactivity.29 Studies using the gold-standard Thus, elevated wave reflections might be another factor trig-
method of microneurography will shed further light into the gering intradialytic hypertension in some patients. However,
role of sympathetic nervous system (SNS) overactivity in the it is not yet clarified whether arterial stiffness is directly
pathogenesis of intradialytic hypertension. involved in the causal pathway of this phenomenon or is sim-
ply a marker of accelerated end-organ damage among patients
Dialysis-Related Electrolyte Disorders
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with intradialytic hypertension.


Sodium
Although potentially useful for the prevention of intradialytic
Medications
hypotension, high time-averaged concentration of dialysate Removal of Antihypertensive Drugs During Dialysis
sodium during sodium-profiled hemodialysis is associated with Removal of antihypertensive drugs by dialysis may in theory
positive sodium balance and higher interdialytic weight gain.30 contribute to raise BP during the session. ACEIs (with the
Sodium gain may arise even at standard dialysate sodium (ie, exception of fosinopril) and -blockers (particularly ateno-
140 mEq/L) when patients start dialysis with a lower serum lol and metoprolol) are the antihypertensive drug classes that
sodium concentration (ie, <140 mEq/L).31 Apart from raising are more extensively removed during dialysis (Table S2).42
interdialytic weight gain and BP, this positive sodium gradient In contrast, blood concentrations of most calcium-channel
may be of particular importance in pathogenesis of intradia- blockers and angiotensin-receptor blockers (ARBs) are not
lytic hypertension. A direct association between the dialysate- substantially influenced by dialysis.42
to-serum sodium gradient and change in SBP during dialysis
Erythropoietin-Stimulating Agents
was observed in 206 hemodialysis patients.32 Volume-related
ESAs are associated with new-onset hypertension or worsen-
implications of intradialytic sodium load apart, in vitro studies
ing of pre-existing hypertension in hemodialysis patients.43
suggest that high sodium concentrations may blunt endothe-
ESAs may trigger an acute vasoconstrictor effect mediated by
lial release of NO,33 causing vasoconstriction and increased
endothelin-1. Intravenous human recombinant erythropoietin
peripheral vascular resistance.
causes a clinically important (20 mmHg) increase in mean
Potassium arterial pressure after 30 minutes of injection and such an
In a study of 11 hemodialysis patients, Dolson et al34 evalu- increase lasts 3 hours.44 In contrast, subcutaneous admin-
ated the effect of 3 different dialysate potassium concentra- istration of ESAs, particularly long-acting, do not raise BP.
tions (1, 2, and 3 mmol/L) on BP levels recorded predialysis, Intravenous ESAs are usually administered after dialysis and
immediately postdialysis and 1-hour after dialysis. Low dialy- therefore they may hardly contribute to the intradialysis BP
sate potassium was associated with rebound elevation of BP profile.
1-hour after dialysis. At currently applied dialysate potassium
concentrations (2.03.5 mmol/L) it is unlikely that hypokale- Recommendations for the Management of
mia-triggered vasoconstriction plays a relevant role in intra- or Intradialytic Hypertension
postdialysis hypertension. Low dialysate potassium, however, Because patients with intradialytic hypertension have mark-
has a strong arrhythmogenic effect.35 edly elevated BP load during the out-of-dialysis period,17
therapy should aim at controlling hypertension globally rather
Calcium than focus on the dialysis session time. In this respect, appro-
Changes in levels of ionized calcium acutely affect myocar- priate treatment of background hypertension along current
dial contractility and vascular tone.36 Clinical studies have guidelines15 cannot be overemphasized. Some specific mecha-
associated increased calcium concentrations in the dialysate nistic pathways may be additional targets of therapy in these
with improvement in intradialytic hemodynamic instability.37 individuals (Table3).
Other studies have reported that increased calcium in dialysate
acutely worsens arterial compliance and minimizes intradia- Volume and Sodium Control
lytic BP reduction.38 At least in theory, high calcium dialy- A major therapeutic target in individuals with intradialytic
sate may worsen the hemodynamic response to ultrafiltration hypertension is adequate volume control. The DRIP trial
dialysis in patients with intradialytic hypertension. showed that probing of dry weight is an important part of the
Georgianos et al Intradialytic Hypertension 461

Table 3. Recommendations for Management of Intradialytic which was accompanied by reduced occurrence of intradialytic
Hypertension hypertensive episodes during follow-up and with a significant
Volume and sodium control fall (7 mmHg) in 44-hour ambulatory SBP.4 Therefore, antihy-
Probing of dry weight pertensive agents exerting beneficial actions on endothelium,
such vasodilating -blockers, may be of benefit for patients
Tapering of antihypertensive drugs to facilitate dry-weight achievement
with intradialytic hypertension. Older antihypertensive drugs
Individualized prescription of sodium concentration in the dialysate
causing direct vasodilation (ie, minoxidil) were also formerly
Avoid shortly delivered dialysis used for intradialysis hypertension with good results.52
Treatment of endothelial dysfunction
Administration of newer vasodilating -blockers RAS Inhibition
Reninangiotensinaldosterone system inhibition Excess activation of the reninangiotensin response to rapid
Treatment of sympathetic nervous system overactivity intravascular volume reduction during dialysis is another
Prolong the duration of dialysis therapy
mechanism of intradialytic hypertension.2 In this context,
long-acting ACEIs and ARBs should be considered as a tool
Adrenergic blockade with - and -blockers
to compensate peaks of intradialytic BP. Of note, these anti-
Consider renal sympathetic denervation in cases of drug-resistant hypertensive classes have pleiotropic effects on the vascula-
hypertension
ture. Observational and clinical data suggest that ACEIs and
Background antihypertensive regimen and erythropoietin treatment ARBs may reduce cardiovascular morbidity and mortality in
Highly dialyzable antihypertensive agents should be administered post end-stage renal disease patients;53 ACEIs and ARBs seem well
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dialysis suited for the treatment of hemodialysis patients with systolic


Avoid intravenous erythropoietin administration within dialysis dysfunction54 and seem a reasonable option for patients with
Adjustment of the dialysis regimen intradialytic hypertension and end-organ damage. In addition,
Consider enhanced-frequency and extended-time hemodialysis direct renin inhibition may attenuate change in intradialytic
BP slopes through a more rapid suppression of RAS overac-
tivity; pilot studies have suggested that aliskiren is effective
puzzle of adequate volume management.18 A factor that may in reducing predialytic and home BP in dialysis patients with
interfere with achievement of volume control is excessive refractory hypertension.55
use of antihypertensive medications.45 Paradoxically, clinical
studies have shown that the higher the number of antihyper- Treatment of Sympathetic Overactivity
tensive drugs the patients receive, the less likely they are to Ultrafiltration during dialysis is a powerful activator of the
reach goal BP.46 In patients with volume excess, tapering of SNS.56 Reducing the ultrafiltration rate and diluting vol-
antihypertensive medications may facilitate achievement of ume removal over a longer dialysis treatment may attenu-
dry weight, resulting in better control of intradialytic hyper- ate SNS activation.56 Background adrenergic blockade with
tension. Another therapeutic strategy is to eliminate intradia- - and -blockers may improve intradialytic hypertension.2
lytic sodium load.47 In a recent crossover study of 16 patients -blockers may reduce cardiovascular morbidity and mortal-
with intradialytic hypertension, Inrig et al48 compared the ity in hemodialysis patients.53 In the recent Hypertension in
effect of low versus high sodium dialysate concentration Hemodialysis treated with Atenolol or Lisinopril (HDPAL)
(5 mEq/L lower or higher than serum sodium, respectively) trial, the occurrence of serious cardiovascular events, includ-
on intradialytic BP. Prescription of low dialysate sodium for ing myocardial infarction, stroke, and cardiovascular death,
a 3-week period was associated with a significant reduction was higher in the lisinopril than in the atenolol group (inci-
of 9.9 mmHg in the weekly average of intradialytic SBP. dence rate ratio, 2.36; 95% CI, 1.364.23; P=0.001), resulting
Another approach to enhance sodium removal and achieve in premature termination of the trial owing to safety issues.57
neutral or negative sodium balance is to extend the duration At variance with -blockers, -blockers seem to modulate
and the frequency of dialysis sessions. Short dialysis may rather than evenly downregulate sympathetic activity. In
promote sodium and volume excess, resulting in difficult-to- patients with heart failure on ACEIs, -blockers do not reduce
control hypertension.49 background sympathetic nerve discharge but restore low- and
high-frequency harmonic oscillations in sympathetic nerve
Treatment of Endothelial Dysfunction activity.58 Therefore, treatment with a long acting -blocker
Given the potential role of endothelin in intradialysis hyperten- may afford background cardiovascular protection, an issue of
sion, this autacoid may be targeted in these patients. Until now, paramount relevance in a condition like intradialysis hyper-
there is no study on the application of endothelin antagonists tension, characterized by background systemic hypertension.
to attenuate intradialysis hypertension. Other agents that can Case reports59 and a recent safety and proof-of-concept
interfere with the endothelin-1 pathway should be considered study28 showed that sympathetic renal denervation was feasible
as alternative options. For example, carvedilol, a -blocker with in 9 of 12 hemodialysis patients with uncontrolled predialysis
vasodilating properties, was shown to improve endothelial dys- BP (>140/90 mmHg), despite current use of at least 3 different
function in vivo50 and block endothelin-1 release in vitro.51 In antihypertensive agents and was associated with significant BP
an uncontrolled study,4 in 25 patients with intradialytic hyper- reductions of 28/10 mmHg that persisted for a 12-month fol-
tension, carvedilol treatment was associated with an improve- low-up period. Because background, persistent hypertension
ment in endothelium-dependent flow-mediated vasodilatation,4 is a hallmark in patients with intradialysis hypertension, these
462HypertensionSeptember 2015

observations suggest that in severe cases, resistant to drug Disclosures


treatment and dialysis treatment optimization, renal denerva- None.
tion may be an option to consider. However, the issue deserves
further study in larger series and in specifically designed trials. References
1. Agarwal R. How can we prevent intradialytic hypotension?
Background Antihypertensive Regimen and Curr Opin Nephrol Hypertens. 2012;21:593599. doi: 10.1097/
MNH.0b013e3283588f3c.
Erythropoietin Treatment 2. Inrig JK. Intradialytic hypertension: a less-recognized cardiovascu-
As alluded to before, ACEIs and most of conventional lar complication of hemodialysis. Am J Kidney Dis. 2010;55:580589.
-blockers are removed by dialysis. Therefore, these drugs doi: 10.1053/j.ajkd.2009.08.013.
3. Inrig JK, Patel UD, Toto RD, Szczech LA. Association of blood pres-
should be administered post rather than pre dialysis. As dis-
sure increases during hemodialysis with 2-year mortality in incident
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lisinopril administered 3 a week post dialysis allow adequate and Mortality Wave 2 Study. Am J Kidney Dis. 2009;54:881890.
home BP control during the dialysis interval (ie, reduce the doi: 10.1053/j.ajkd.2009.05.012.
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Intradialysis Hypertension in End-Stage Renal Disease Patients: Clinical Epidemiology,
Pathogenesis, and Treatment
Panagiotis I. Georgianos, Pantelis A. Sarafidis and Carmine Zoccali

Hypertension. 2015;66:456-463; originally published online July 6, 2015;


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doi: 10.1161/HYPERTENSIONAHA.115.05858
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2015 American Heart Association, Inc. All rights reserved.
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ONLINE SUPPLEMENT

TITLE PAGE

Title: INTRADIALYSIS HYPERTENSION IN END-STAGE RENAL DISEASE

PATIENTS: CLINICAL EPIDEMIOLOGY, PATHOGENESIS AND TREATMENT

Running title: Intradialytic hypertension

Authors: Panagiotis I. Georgianos,1 MD, PhD, Pantelis A. Sarafidis,2 MD, MSc,

PhD, Carmine Zoccali,3 MD, PhD

Affiliations:

1) Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA

Hospital, Aristotle University of Thessaloniki, Greece

2) Department of Nephrology, Hippokration Hospital, Aristotle University of

Thessaloniki, Greece

3) CNR-IFC, Clinical Epidemiology and Pathophysiology of Hypertension and Renal

Diseases, Ospedali Riuniti, 89124 Reggio Calabria, Italy.

Manuscript number: HYPE201505858R1

Correspondence: Panagiotis I. Georgianos, MD, PhD, Section of Nephrology and

Hypertension, 1st Department of Medicine, AHEPA Hospital, Aristotle University of

Thessaloniki, St. Kyriakidi 1, Thessaloniki, Greece. Tel: +30 2310-993-844, Fax: +30

2310-993-844. Email: pangeorgi@yahoo.gr


References

1. K/DOQI clinical practice guidelines on hypertension and antihypertensive

agents in chronic kidney disease. Am J Kidney Dis. 2004;43 (5 Suppl 1):S1-

290.
Online supplement Table S1. Literature search strategy

Search strategy (1)


Set Search
1 blood pressure tw
2 increase tw
3 hemodialysis tw
4 review tw
5 #1 AND #2 AND #3 NOT #4
Search Strategy (2)
Set Search
1 hypertension tw
2 hemodialysis tw
3 intradialytic tw
4 review tw
5 #1 AND #2 AND #3 NOT #4
Search strategy (3)
Set Search
1 hypertension tw
2 hemodialysis tw
3 during tw
4 review tw
5 #1 AND #2 AND #3 NOT #4
Online Supplement Table S2: Removal of antihypertensive drugs during the

hemodialysis procedure

Antihypertensive drug Removal (%)


Angiotensin converting enzyme inhibitors
Benazepril <30
Enalapril 35
Fosinopril 2
Lisinopril 50
Ramipril <30
Angiotensin receptor blockers
Losartan None
Candesartan None
Irbesartan None
Valsartan None
Telmisartan None
Eprosartan None
Beta-blockers
Atenolol 75
Metoprolol High
Labetalol 1
Carvedilol None
Calcium channel blockers
Amlodipine None
Nifedipine Low
Felodipine None
Diltiazem <30
Verapamil Low
Other agents
Clonidine 5
Minoxidil High
Hydralazine None

Adapted from: National Kidney Foundation. K/DOQI Clinical Practice Guidelines for
Cardiovascular Disease in Dialysis Patients.1
Online Supplement Figure S1: Search strategy (flow diagram).