Effects of frequent hemodialysis on bloodpressure: Results from the randomizedfrequent hemodialysis network trials
Peter KOTANKO,1 Amit X. GARG,2,3 Tom DEPNER,4 Andreas PIERRATOS,5
Christopher T. CHAN,6,7 Nathan W. LEVIN,1 Tom GREENE,8,9 Brett LARIVE,9
Gerald J. BECK,9 Jennifer GASSMAN,9 Alan S. KLIGER,10 John B. STOKES11
the FHN Trial Group1Renal Research Institute, New York City, New York, USA; 2Department of Medicine, London HealthSciences Centre, London, Ontario, Canada; 3Western University, London, Ontario, Canada; 4Davis
Medical Center, University of California Davis, Sacramento, California, USA; 5Humber River RegionalHospital, 6Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario,Canada; 7Department of Medicine, Toronto General Hospital, Toronto, Ontario, Canada; 8Division of
Epidemiology, University of Utah, Salt Lake City, Utah, USA; 9Department of Quantitative HealthSciences, Cleveland Clinic Foundation, Cleveland, Ohio, USA; 10Department of Medicine, Hospital of
Saint Raphael, Yale University School of Medicine, New Haven, Connecticut, USA; 11University of Iowa,Iowa City, Iowa, USA
AbstractHypertension is a common complication of chronic kidney disease and persists among mostpatients with end-stage renal disease despite the provision of conventional thrice weekly hemodi-alysis (HD). We analyzed the effects of frequent HD on blood pressure in the randomized controlledFrequent Hemodialysis Network trials. The daily trial randomized 245 patients to 12 months of 6×(“frequent”) vs. 3× (“conventional”) weekly in-center hemodialysis; the nocturnal trial randomized87 patients to 12 months of 6× weekly nocturnal HD vs. 3× weekly predominantly home-basedhemodialysis. In the daily trial, compared with 3× weekly HD, 2 months of frequent HD loweredpredialysis systolic blood pressure by −7.7 mmHg [95% confidence interval (CI): −11.9 to −3.5] anddiastolic blood pressure by −3.9 mmHg [95% CI: −6.5 to −1.3]. In the nocturnal trial, compared with3× weekly HD, 2 months of frequent HD lowered systolic blood pressure by −7.3 mmHg [95% CI:−14.2 to −0.3] and diastolic blood pressure by −4.2 mmHg [95% CI: −8.3 to −0.1]. In both trials,blood pressure treatment effects were sustained until month 12. Frequent HD resulted in signifi-cantly fewer antihypertensive medications (daily: −0.36 medications [95% CI: −0.65 to −0.08];nocturnal: −0.44 mediations [95% CI: −0.89 to −0.03]). In the daily trial, the relative risk per dialysissession for intradialytic hypotension was lower with 6×/week HD but given the higher number ofsessions per week, there was a higher relative risk for intradialytic hypotensive requiring salineadministration. In summary, frequent HD reduces blood pressure and the number of prescribedantihypertensive medications.
Hypertension is diagnosed in over 80% of patients onmaintenance hemodialysis (HD).1 While there is noagreement on optimal blood pressure (BP) targets orthe therapeutic means to achieve BP goals,2 recentmeta-analyses indicate that antihypertensive therapy inpatients on maintenance HD is associated with lowermortality.3,4 Previous studies suggest that 6× weekly HDcompared with the conventional 3× weekly regimenreduces BP.5–15 Two small randomized 6-month-longtrials16,17 reported 7–23 mmHg reductions in pre-HD sys-tolic BP (SBP) and 4–12 mmHg in diastolic BP (DBP).However, there is little information about how frequentHD affects BP over time. To our knowledge, no publishedstudy has described the effects of frequent HD on epi-sodes of intradialytic hypotension, a common problemassociated with poor short-term and long-term out-comes.18 We previously reported the primary results of 2parallel year-long randomized controlled trials on theeffects of frequent HD.19,20 Here, we provide a descriptionof BP dynamics in both Frequent Hemodialysis Network(FHN) trials, the influence of baseline factors on treat-ment effects, the association between changes in pre-HDSBP and fluid status, and the effects of frequent HD onantihypertensive therapy and intradialytic hypotensiveevents.
SUBJECTS AND METHODS
Frequent Hemodialysis Network trials
The FHN daily and nocturnal trials (ClinicalTrials.gov#NCT00264758) are multicenter, randomized, pro-spective trials of in-center short daily HD and predomi-nantly home-based nocturnal HD. The designs, inclusion,and exclusion criteria of both trials were described previ-ously.21 Pertinent to this report was the less stringentexclusion criterion for residual renal function in the noc-turnal trial (average of the urea and creatinine clearances>10 mL/min/1.73m2) compared with the daily trial(>3 mL/min per 35 L urea distribution volume).22
Post-HD target weight was prescribed by the patient’sattending nephrologist. Patients were enrolled betweenMarch 2006 and May 2009 and the trials concluded inMay 2010. Both trials were conducted in accordance withthe Declaration of Helsinki and were approved by theInstitutional Review Board at each participating site. Anindependent Data Safety Monitoring Board provided over-sight of both trials.
Measurements
In the daily trial, BP was measured according to facilityprotocol by an automated device before and after HD. Pre-and post-HD BP were averaged over 1 week each month.Patients in the nocturnal study kept flow sheets for all oftheir home treatments and brought them to the clinic oncea month. Patients on home HD monitored their BP ini-tially every 30 minutes per treatment for a week and thenevery hour for 2–3 weeks. Nocturnal patients wereadvised to monitor their BP every hour during the nightfor the first month after they went home. The reason wedid this was to detect if the patient had any hypotensiveepisodes during the night. Once the investigators werecomfortable that hypotensive episodes did not occur,patients were advised to stop measuring BP every hourand just measure it before and after dialysis treatment.Caregivers were trained to measure BP and look for symp-toms when a patient was dialyzed at home or at night.
Pre-HD and post-HD weights were recorded during thesame week each month that the BP measurements weretaken. Interdialytic weight gain (IDWG) was estimatedfrom the intradialytic weight loss, calculated as pre-HDweight minus post-HD weight per dialysis session; theaverage IDWG over the recorded week was used for esti-mating associations with changes in BP. Brain natriureticpeptide (B-type natriuretic peptide; BNP) was measuredin F1 and F12.
Antihypertensive therapy
Category and dose of prescribed antihypertensive medi-cations were recorded at baseline and every 4 monthsduring the course of the trials. The quantities of medi-cations belonging to relevant drug classes were summedover a 4-week period. Adjustment of antihyper-tensive therapy was at the discretion of the attendingnephrologist.
Intradialytic hypotensiveepisodes (IDHEs)
We defined sessions associated with IDHE as those HDtreatments during which hypotensive symptoms led toeither lowering the ultrafiltration rate or to saline admin-istration. In the nocturnal trial, patients were taught togive themselves 250–500 mL of normal saline wheneverthey experienced hypotensive symptoms during the dialy-sis treatment. We analyzed relative rates as well as theabsolute counts of sessions associated with IDHE. Inci-dents of sessions associated with IDHE during a 1-week
Kotanko et al.
Hemodialysis International 2015; ••:••–••2
period were recorded monthly. A maximum of 1 IDHEwas counted per HD session.
Subgroup analyses
We defined a priori 3 baseline factors that might modifythe effect of frequent HD on the change in average pre-HDSBP during follow-up months 3 to 5 (F3–5) and 10 to 12(F10–12). The primary assessment of treatment interac-tions with quantitative subgroup factors was based on atest for linear interaction, which treated the subgroupfactor as a continuous variable; estimated treatment effectsare also provided for the subgroups defined by the indi-cated cut-offs for descriptive purposes. These 3 factorswere (a) baseline pre-HD SBP ≤ 145 or > 145 mmHg, (b)baseline IDWG ≤ 3 or > 3 kg, and (c) baseline urinevolume (daily trial: ≤ 100 or >100 mL/day; nocturnaltrial: ≤ 500 or > 500 mL/day). We also conducted a pos-teriori subgroup analyses in patients with baseline urinaryvolumes of 0, 1–400, and >400 mL/day. Exploratoryanalyses were conducted in patients whose SBP declined30 mmHg or more from baseline to F10–12.
Statistical methods
We summarized categorical variables using proportionsand continuous variables using mean ± SD or medianwith 10th and 90th percentiles where data were skewed.Descriptive summaries of changes in treatment-relatedvariables are provided for the patients with nonmissingvalues at four time points: baseline, F2, F3–5, andF10–12.
We estimated the effects of the randomized treatmentassignment on pre-HD SBP, DBP, and other continuousoutcomes with a mixed effects analysis that included atime interaction with the baseline value of each outcomefor both trials and with clinical centers for the daily trial.The mixed effects analyses incorporated baseline andmonthly measurements; we used a combined compound-symmetry first-order autoregressive covariance matrix toaccount for correlations in measurements over time.23
This analytic approach incorporated baseline BP measure-ments in cases where patients died or dropped out of thestudy during the follow-up period. We estimated treat-ment effects for the mean changes from baseline to theaverage values during F2, F3–5, and F10–12 with changeto F10–12 representing the pre-specified measure of mostinterest. While not pre-specified, we conducted an addi-tional analysis with adjustment for prescribed dialysatesodium concentration.
We obtained treatment group comparisons for thenumber of prescribed antihypertensive medications atF3–5 and F10–12 using exact permutation tests stratifiedby the baseline amounts.
For each of the 3 prespecified subgroup factors, weused linear regression analyses to relate the change inpre-HD SBP to treatment assignment, the prespecifiedbaseline covariates, and to corresponding interactionterms. The primary assessment of treatment interactionswith quantitative subgroup factors was based on a test forlinear interaction, which treated the subgroup factor as acontinuous variable. In the daily trial, we present P valuesfor the subgroup interactions without adjustment for mul-tiple comparisons. Due to its limited sample size, wetreated all subgroup analyses in the nocturnal trial asexploratory without significance testing.
To assess the relationship between changes in SBP andchanges in indicators of fluid status, we depicted theassociation of changes in pre-HD SBP with changes inother factors for individual patients using scatter plotswith separate nonparametric local regression curves foreach treatment group24 and we also computed Spearmancorrelations between the changes for each group.
We report both the absolute numbers and the relativerates of IDHE. Treatment-based differences in both out-comes were tested using generalized estimating equations.Analyses were not adjusted for baseline values of IDHEs orother covariates.
We performed all analyses using SAS version 9.2. Two-tailed P values <0.05 were considered statistically signifi-cant, unless otherwise indicated.
RESULTS
In the daily trial, 245 patients were randomized to 12months of 6× weekly HD or 3× weekly in-center HD. Inthe nocturnal trial, 87 patients were randomized to 12months of 6× weekly nocturnal HD or 3× weekly conven-tional predominantly home-based HD, 4 patients wentthrough all of follow-up being dialyzed in-center(Table 1).
Fourteen patients died in the daily trial (5 in 6× weeklyand 9 in 3× weekly cohorts) and 3 in the nocturnal trial (2in the nocturnal and 1 in the 3× weekly cohorts).
Treatment effects on BP dynamics andantihypertensive therapy
In the daily trial, compared with 3× weekly HD, 6×weekly HD resulted in a significant reduction of pre-HDSBP by 7.7 mmHg and DBP by 3.9 mmHg at month 2 of
Results are shown as mean ± standard deviation, median (10th and 90th percentiles), or frequency (%), as indicated.aHypertension defined as average predialysis systolic blood pressure >140/90, patient taking antihypertensive medication(s), or the diagnosisof hypertension from clinical records.ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCB = calcium channel blocker; COPD = chronicobstructive pulmonary disease; ESA = erythropoiesis stimulating agent; ESRD = end-stage renal disease.
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Hemodialysis International 2015; ••:••–••4
the trial (F2) (Figure 1; Table 2a). The SBP reductionremained relatively stable for the subsequent 10 months;the mean reduction of pre-HD SBP at F10–12 was10 mmHg (Figure 1; Table 2a). Comparable dynamicswere observed for pre-HD DBP, post-HD SBP, andpost-HD DBP (Table 2a). Sixteen patients (7%) experi-enced a decline in pre-HD SBP of ≥30 mmHg betweenbaseline and F10–12 (13 in the 6× weekly group; 3 in the3× weekly arm; Table 3). The most prominent clinicalcharacteristic among these patients was a relatively highbaseline SBP (164 ± 17.8 mmHg).
In the nocturnal trial at F2, the pre-HD SBP treatmenteffect was 7.3 mmHg and 4.2 mmHg for pre-HD DBP.These relative BP changes remained stable thereafter(Figure 2; Table 2b). No significant treatment effects wereobserved on post-HD SBP and DBP (Table 2b). In 7 sub-jects (8%), pre-HD SBP fell by ≥30 mmHg between base-line and F10–12 (4 in the 6× weekly nocturnal arm; 3 inthe conventional arm; Table 4). Older age (60.6 ± 13.3years) and a higher pre-HD SBP (166 ± 14.7 mmHg) atbaseline distinguished these patients.
The number of prescribed antihypertensive drugs wassignificantly lower among 6× weekly subjects by F3–5both in the daily trial (−0.38 [95% confidence interval(CI): −0.70 to −0.008]; Table 2a) and in the nocturnal trial(−0.46 [95% CI: −0.98 to −0.004]; Table 2b).
We also conducted a not prespecified analysis withadjustment for prescribed dialysate sodium concentra-tions. This additional analysis indicated a significant treat-ment effect for pre-HD SBP in the daily trial but not in thenocturnal trial (Supporting Information Table S1).
Treatment effects on indicators offluid volume
In the daily trial, in the 6× weekly group, post-HD weightat F2 was relatively lower compared with the 3× weeklycontrol group. The difference was not significant later inthe trial (Table 2a). In the nocturnal trial, there was notreatment effect on post-HD weight at any time point(Table 2b). In contrast, pre-HD weight decreased by 1.3–1.6 kg more among daily 6× weekly subjects in the first2–5 months compared with conventional HD (P < 0.001).However, by F10–12, this difference was no longer sig-nificant (Table 2a). In the nocturnal trial, there were nosignificant changes in either the pre- or the post-HDweights by treatment group (Table 2b).
In the daily trial, in both treatment groups, changes inIDWG from baseline remained remarkably constantthroughout the study (3× weekly: ∼3.1 kg; 6× weekly:∼1.0 kg) (Table 2a). In the nocturnal trial, the overall
IDWG was ∼2.4 kg in the 3× weekly group and ∼1.9 kg inthe 6× weekly group with a significant difference of ∼0.5 kgbetween the two treatment arms from F2 onward(Table 2b).
In the daily trial, there was a trend for a lower percentageof sessions associated with IDHEs relative to the numberof sampled HD sessions in the 6× weekly group comparedwith the 3× weekly group (P = 0.056). However, withmore HD sessions in the 6× weekly group, the absolutenumber of sessions associated with IDHE episodes requir-ing saline administration was also greater, resulting in arelative risk of 1.53 (95% CI: 1.11–2.09) for 6× weeklypatients in the daily trial.
In the nocturnal trial, the relative frequency of sessionsassociated with IDHE was significantly lower in the 6×weekly group (P < 0.001). The relative risk for sessionsassociated with IDHE requiring saline administration for6× weekly subjects was 0.35 (95% CI: 0.18–0.69) com-pared with 3× weekly subjects.
Baseline predictors of pre-HD SBPresponse to frequent dialysis
Neither baseline pre-HD SBP nor the baseline IDWG sig-nificantly influenced the treatment effect on BP in bothtrials (data not shown). However, the effect of frequentHD on pre-HD SBP was significantly greater among dailytrial patients who were anuric at baseline, when comparedto those who produced any urine (interaction P = 0.05)(Figure 3). A comparable modification of urine volume onthe treatment effect was not seen in the nocturnal trial(interaction P = 0.73) (Figure 4).
Correlational analyses
In the daily trial, changes in pre-HD SBP between baselineand F2 were modestly correlated with changes in IDWGin the 3× weekly group (Spearman’s rho = 0.21,P = 0.035), but not in the 6× weekly groups (Figure 5).This lack of correlation was also true at F10–12. In thenocturnal trial, there was no correlation between thechange in pre-HD SBP and the change in IDWG in F2(Figure 6). There was also no correlation between thechange in post-HD weight and the change in pre-HD BP ineither trial (data not shown). In both trials, changes inBNP between F1 and F12 and changes in pre-HD SBPwere not correlated (data not shown).
Blood pressure in frequent dialysis
Hemodialysis International 2015; ••:••–•• 5
(a)
(b)
Figure 1 (a) Monthly predialysis systolic blood pressure (SBP) in the daily trial. Patients in the 6× weekly group (open squares)had significantly lower values than the 3× weekly group (closed circles) at F1 (P < 0.001) and thereafter (mixed effectsanalysis adjusting for baseline value of outcome and clinical center). (b) Monthly mean changes of predialysis SBP frombaseline in the daily trial. Patients in the 6× weekly group (open squares) had significantly lower values than the 3× weeklygroup (closed circles) at F1 (P < 0.001) and thereafter (mixed effects analysis adjusting for baseline value of outcome andclinical center).
Kotanko et al.
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Tab
le2a
Dai
lytr
ial—
Trea
tmen
tef
fect
son
outc
ome
vari
able
s
Out
com
eTr
eatm
ent
Obs
erve
dda
tam
ean
(SD
)a6×
vs.
3×tr
eatm
ent
com
pari
son:
Mea
nch
ange
sfr
omba
selin
e(9
5%C
I)b
Base
line
F2F3
–5F1
0–12
F2F3
–5F1
0–12
Pre-
HD
SBP
(mm
Hg)
3×w
eekl
y14
6.6
(17.
8)14
5.5
(22.
3)14
4.8
(17.
5)14
7.3
(18.
5)−7
.7(−
11.9
,−3.
5)**
*−6
.6(−
10.3
,−2.
9)**
*−1
0.0
(−13
.9,−
6.0)
***
6×w
eekl
y14
7.0
(18.
9)13
8.7
(20.
7)13
7.7
(19.
7)13
7.4
(20.
5)Pr
e-H
DD
BP(m
mH
g)3×
wee
kly
78.2
(11.
6)79
.4(1
3.6)
78.2
(12.
6)79
.6(1
2.0)
−3.9
(−6.
5,−1
.3)*
*−3
.4(−
5.6,
−1.2
)**
−5.1
(−7.
4,−2
.8)*
**6×
wee
kly
81.5
(11.
7)76
.7(1
1.8)
76.5
(11.
7)76
.0(1
1.5)
Post
-HD
SBP
(mm
Hg)
3×w
eekl
y13
4.6
(18.
3)13
5.8
(22.
7)13
3.6
(19.
4)13
4.2
(18.
9)−8
.7(−
12.9
,−4.
6)**
*−8
.4(−
12.0
,−4.
8)**
*−7
.9(−
11.8
,−3.
9)**
*6×
wee
kly
132.
6(1
9.0)
125.
7(1
7.2)
124.
4(1
5.9)
125.
2(1
6.0)
Post
-HD
DBP
(mm
Hg)
3×w
eekl
y71
.9(1
1.1)
73.4
(12.
4)76
.5(1
0.4)
74.1
(12.
1)−3
.4(−
5.9,
−1.0
)**
−3.1
(−5.
2,−1
.1)*
*−3
.4(−
5.6,
−1.2
)**
6×w
eekl
y72
.9(1
1.7)
70.2
(10.
0)73
.9(1
3.1)
72.4
(13.
4)Pr
e-H
Dw
eigh
t(k
g)3×
wee
kly
81.8
(20.
3)82
.1(2
0.7)
81.9
(20.
5)82
.0(2
0.4)
−1.6
(−2.
2,−1
.1)*
**−1
.3(−
2.0,
−0.6
)***
−0.2
(−1.
1,0.
7)6×
wee
kly
80.2
(21.
3)78
.9(2
1.4)
79.3
(21.
5)80
.3(2
1.5)
Post
-HD
wei
ght
(kg)
3×w
eekl
y78
.9(1
9.8)
79.5
(20.
3)79
.1(1
9.9)
79.2
(19.
9)−0
.6(−
1.1,
−0.1
)*−0
.36
(−1.
07,0
.34)
0.79
(−0.
1,1.
68)
6×w
eekl
y77
.0(2
0.8)
78.0
(20.
5)77
.1(2
1.2)
78.2
(21.
2)In
terd
ialy
tic
wei
ght
gain
(kg)
3×w
eekl
y3.
14(0
.96)
3.15
(1.1
1)3.
11(1
.08)
3.10
(1.0
4)−1
.1(−
1.2,
−0.9
)***
−0.9
2(−
1.08
,−.7
6)**
*−1
.0(−
1.1,
−0.8
)***
6×w
eekl
y3.
16(0
.99)
2.08
(0.8
9)2.
15(0
.77)
2.11
(0.8
6)U
ltra
filtr
atio
nra
te(m
L/m
in)
3×w
eekl
y14
.8(4
.1)
14.6
(4.6
)14
.6(4
.7)
14.5
(4.3
)−1
.1(−
2.1,
−0.1
)*−0
.4(−
1.3,
0.4)
−0.6
(−1.
5,0.
3)6×
wee
kly
15.0
(5.5
)13
.7(4
.6)
14.3
(4.1
)13
.9(4
.7)
Trea
tmen
tti
me
(min
/ses
sion
)3×
wee
kly
214
(27.
8)21
3(2
9.9)
215
(31.
5)21
7(3
0.3)
−64.
6(−
69.1
,−60
.2)*
**−6
3.2
(−67
.9,−
58.6
)***
−63.
8(−
68.7
,−58
.9)*
**6×
wee
kly
219
(27.
2)15
0(2
4.5)
153
(26.
6)15
4(2
9.5)
Num
ber
ofpr
escr
ibed
anti
hype
rten
sive
drug
s(p
erpa
tien
t)
3×w
eekl
y2.
3(1
.4)
—2.
1(1
.4)
2.0
(1.4
)—
−0.3
8(−
0.70
to−0
.08)
*−0
.36
(−0.
65to
−0.0
8)*
6×w
eekl
y2.
2(1
.6)
—1.
6(1
.5)
1.4
(1.3
)
a For
pati
ents
wit
hno
nmis
sing
base
line,
4-m
oan
d12
-mo
valu
es(3
×w
eekl
yN
=92
–93,
6×w
eekl
yN
=10
3–10
4).
b Res
ults
cont
rolli
ngfo
rba
selin
eva
lue
and
clin
ical
cent
er.
—=
not
avai
labl
e;C
I=
confi
denc
ein
terv
al;
DBP
=di
asto
licbl
ood
pres
sure
;H
D=
hem
odia
lysi
s;SB
P=
syst
olic
bloo
dpr
essu
re.
*P<
0.05
,**
P<
0.01
,**
*P<
0.00
1.
Blood pressure in frequent dialysis
Hemodialysis International 2015; ••:••–•• 7
Tab
le2b
Noc
turn
altr
ial—
Trea
tmen
tef
fect
son
outc
ome
vari
able
s
Out
com
eTr
eatm
ent
Obs
erve
dda
tam
ean
(SD
)a6×
vs.
3×tr
eatm
ent
com
pari
son:
Mea
nch
ange
sfr
omba
selin
e(9
5%C
I)b
Base
line
F2F3
–5F1
0–12
F2F3
–5F1
0–12
Pre-
HD
SBP
(mm
Hg)
3×w
eekl
y15
2.6
(22.
2)15
5.7
(23.
4)15
5.0
(20.
6)15
0.7
(18.
6)−7
.3(−
14.2
,−0.
3)*
−9.4
(−15
.5,−
3.2)
**−8
.0(−
14.5
,−1.
6)*
6×w
eekl
y14
4.9
(13.
7)14
1.7
(22.
8)14
0.1
(18.
9)13
7.0
(20.
5)Pr
e-H
DD
BP(m
mH
g)3×
wee
kly
82.9
(13.
9)84
.4(1
3.1)
83.8
(11.
8)83
.0(1
2.7)
−4.2
(−8.
3,−0
.1)*
−4.9
(−8.
5,−1
.3)*
*−4
.5(−
8.3,
−0.7
)*6×
wee
kly
79.5
(11.
0)77
.8(1
3.6)
76.7
(11.
5)76
.0(1
3.9)
Post
-HD
SBP
(mm
Hg)
3×w
eekl
y13
9.2
(21.
2)14
0.8
(22.
2)14
0.4
(21.
6)13
2.3
(2.8
)−1
.2(−
9.0,
6.5)
−6.3
(−13
.0,0
.5)
−2.0
(−9.
2,5.
2)6×
wee
kly
136.
1(1
8.5)
137.
6(2
5.5)
133.
0(2
2.6)
129.
3(2
0.3)
Post
-HD
DBP
(mm
Hg)
3×w
eekl
y76
.3(1
4.9)
78.4
(13.
3)76
.5(1
0.4)
74.1
(12.
1)−1
.4(−
5.7,
2.9)
−2.4
(−6.
1,1.
3)−1
.3(−
5.2,
2.6)
6×w
eekl
y75
.1(1
1.9)
77.0
(14.
4)73
.9(1
3.1)
72.4
(13.
4)Pr
e-H
Dw
eigh
t(k
g)3×
wee
kly
85.7
(25.
1)85
.3(2
4.9)
85.7
(25.
7)86
.6(2
6.3)
−0.5
(−1.
5,0.
5)−0
.4(−
2.0,
1.1)
0.2
(−2.
4,2.
9)6×
wee
kly
90.8
(29.
0)89
.0(2
9.2)
89.7
(28.
8)91
.1(2
8.9)
Post
-HD
wei
ght
(kg)
3×w
eekl
y83
.5(2
4.1)
82.9
(24.
4)83
.3(2
5.0)
84.1
(25.
6)0.
1(−
0.9,
1.0)
0.0
(−1.
4,1.
4)0.
6(−
1.9,
3.1)
6×w
eekl
y88
.6(2
8.2)
88.6
(29.
0)87
.8(2
8.6)
89.1
(28.
6)In
terd
ialy
tic
wei
ght
gain
(kg)
3×w
eekl
y2.
42(1
.24)
2.36
(1.2
4)2.
43(1
.14)
2.55
(1.0
2)−0
.6(−
1.0,
−0.3
)***
−0.4
4(−
0.76
,−0.
17)*
*−0
.46
(−0.
77,−
0.15
)**
6×w
eekl
y1.
72(0
.77)
1.69
(0.8
2)1.
91(0
.65)
2.04
(0.8
7)U
ltra
filtr
atio
nra
te(m
L/m
in)
3×w
eekl
y10
.9(6
.2)
9.2
(4.1
)9.
6(4
.02)
10.4
(3.8
)−4
.2(−
5.7,
−2.7
)***
−3.9
(−5.
2,−2
.7)*
**−4
.1(−
5.4,
−2.8
)***
6×w
eekl
y10
.1(6
.4)
4.7
(2.8
)5.
6(2
.9)
6.0
(3.6
3)Tr
eatm
ent
tim
e(m
in/s
essi
on)
3×w
eekl
y22
9(3
2.9)
261
(78.
2)26
0(7
9.7)
258
(74.
8)12
0(9
6.4,
143.
6)**
*12
8(1
06,1
49)*
**11
2(8
9,13
4)**
*6×
wee
kly
230
(31.
9)38
1(6
9.4)
382
(60.
7)37
2(8
5.1)
Num
ber
ofpr
escr
ibed
anti
hype
rten
sive
drug
s(p
erpa
tien
t)
3×w
eekl
y1.
6(1
.1)
—1.
6(1
.2)
1.6
(1.2
)—
−0.4
6(−
0.98
to−0
.004
)*−0
.44
(−0.
89to
−0.0
3)*
6×w
eekl
y1.
9(1
.3)
—1.
3(1
.6)
1.1
(1.6
)
a For
pati
ents
wit
hno
nmis
sing
base
line,
4m
onth
and
12m
onth
valu
es(3
×w
eekl
yN
=93
,6×
wee
kly
N=
41).
b Res
ults
cont
rolli
ngfo
rba
selin
eva
lue.
—=
not
avai
labl
e;C
I=
confi
denc
ein
terv
al;
DBP
=di
asto
licbl
ood
pres
sure
;H
D=
hem
odia
lysi
s;SB
P=
syst
olic
bloo
dpr
essu
re.
*P<
0.05
;**
P<
0.01
,**
*P<
0.00
1.
Kotanko et al.
Hemodialysis International 2015; ••:••–••8
Tab
le3
Dai
lytr
ial—
Dem
ogra
phic
and
clin
ical
char
acte
rist
ics
for
subj
ects
wit
h12
-mo
SBP
decl
ines
ofat
leas
t30
mm
Hg
Pati
ent
No.
Arm
Pre-
HD
SBP
(mm
Hg)
No.
ofan
tihy
pert
ensi
vedr
ugs
Age
(y)
Vin
tage
(y)
IDW
G(k
g)Pr
e-H
Dw
eigh
t(k
g)
BLΔ
BLΔ
BLΔ
BLΔ
16×
wee
kly
191
−63.
93
045
.83.
22.
4−0
.94
73.5
2.0
23×
wee
kly
196
−49.
81
153
4.9
5.2
−1.7
610
3.4
−9.1
36×
wee
kly
177
−49.
64
−455
.26.
74.
4−1
.86
95.9
2.3
46×
wee
kly
160
−42.
84
041
.96.
05.
2−1
.97
79.3
−2.2
56×
wee
kly
155
−41.
41
−134
.38.
14.
4−3
.77
76.2
−8.8
66×
wee
kly
171
−40.
41
079
.61.
73.
0−1
.99
70.1
1.6
76×
wee
kly
164
−37.
03
−241
.57.
23.
6−1
.31
75.7
2.5
86×
wee
kly
157
−34.
64
−235
.64.
01.
4−0
.82
103.
92.
59
6×w
eekl
y13
0−3
3.7
2−2
59.7
6.6
2.2
−0.7
645
.1−0
.110
6×w
eekl
y19
0−3
2.9
00
64.2
3.8
3.2
−0.8
196
.1−2
.611
6×w
eekl
y16
8−3
2.5
2−1
58.8
1.0
3.4
−1.2
079
.21.
512
3×w
eekl
y16
0−3
0.9
01
373.
04.
8−0
.05
101.
5−2
.313
6×w
eekl
y15
9−3
0.7
3−2
42.4
5.2
4.2
−1.7
110
6.9
−0.9
146×
wee
kly
152
−30.
70
053
.93.
61.
80.
7971
.18.
215
6×w
eekl
y14
8−3
0.2
6−4
51.1
19.3
2.4
−0.7
792
.9−4
.316
6×w
eekl
y14
6−3
0.1
1−1
77.4
0.6
2.8
−1.4
675
.6−2
.6R
emai
nder
3×w
eekl
ya14
5[1
7.1]
1.6
[15.
3]2.
2[1
.4]
−0.3
[1.1
]52
.2[1
4.1]
5.1
[5.3
]3.
1[0
.91]
−0.0
2[0
.76]
81.5
[20.
9]0.
37[3
.21]
Rem
aind
er6×
wee
klya
145
[17.
8]−5
.3[1
5.0]
2.2
[1.6
]−0
.7[1
.6]
48.3
[13.
5]6.
4[6
.9]
3.1
[0.9
9]−1
.01
[0.8
1]80
.7[2
1.6]
0.14
[4.0
0]
Cha
nges
(Δ)
are
calc
ulat
edas
F10–
12m
inus
base
line
(BL)
.a St
atis
tics
for
subj
ects
wit
hva
lues
atbo
thba
selin
ean
dF1
0−12
.H
D=
hem
odia
lysi
s;ID
WG
=in
terd
ialy
tic
wei
ght
gain
;SB
P=
syst
olic
bloo
dpr
essu
re.
Blood pressure in frequent dialysis
Hemodialysis International 2015; ••:••–•• 9
(a)
(b)
Figure 2 (a) Monthly predialysis systolic blood pressure (SBP) in the nocturnal trial. Patients in the 6× weekly group(open squares) had significantly lower values than the 3× weekly group (closed circles) at F3–5 (P = 0.003) andthereafter (mixed effects analysis adjusting for baseline value of outcome). (b) Monthly mean changes of predialysis SBPfrom baseline in the nocturnal trial. Patients in the 6× weekly group (open squares) had significantly lower values than the3× weekly group (closed circles) at F3–5 (P = 0.003) and thereafter (mixed effects analysis adjusting for baseline value ofoutcome).
Kotanko et al.
Hemodialysis International 2015; ••:••–••10
Tab
le4
Noc
turn
altr
ial—
Dem
ogra
phic
and
clin
ical
char
acte
rist
ics
for
subj
ects
wit
h12
-mo
SBP
decl
ines
ofat
leas
t30
mm
Hg
Pati
ent
No.
Arm
Pre-
HD
SBP
(mm
Hg)
No.
ofan
tihy
pert
ensi
vedr
ugs
Age
(y)
Vin
tage
(y)
IDW
G(k
g)Pr
e-H
DW
eigh
t(k
g)
BLΔ
BLΔ
BLΔ
BLΔ
16×
wee
kly
155
−43.
12
−266
.719
.01.
8−0
.55
89.5
−0.3
26×
wee
kly
160
−41.
92
−277
.92.
42.
6−1
.27
90.6
−6.7
36×
wee
kly
156
−40.
71
048
.40.
92.
8−1
.89
94.0
−0.6
43×
wee
kly
194
−37.
71
276
.41.
32.
20.
4987
.5−1
.35
3×w
eekl
y17
7−3
4.2
22
51.3
0.6
3.0
−1.0
656
.21.
16
6×w
eekl
y15
4−3
3.8
3−3
58.4
0.6
3.0
−0.7
610
3.0
−12.
47
3×w
eekl
y16
6−3
3.4
3−3
45.1
3.6
2.0
0.13
97.3
−2.7
Rem
aind
er3×
wee
klya
151
[21.
4]0.
9[1
3.2]
1.6
[1.1
]0.
0[1
.0]
53.8
[12.
8]3.
4[7
.5]
2.4
[1.5
]0.
2[1
.1]
86.1
[25.
1]0.
9[7
.2]
Rem
aind
er6×
wee
klya
144
[13.
5]−4
.1[1
5.5]
1.9
[1.3
]−0
.8[1
.7]
50.6
[14.
2]3.
3[4
.9]
2.2
[1.4
]−0
.1[1
.5]
89.5
[29.
0]0.
9[6
.4]
Cha
nges
(Δ)
are
calc
ulat
edas
F10–
12m
inus
base
line
(BL)
.a St
atis
tics
for
subj
ects
wit
hva
lues
atbo
thba
selin
ean
dF1
0–12
.H
D=
hem
odia
lysi
s;ID
WG
=in
terd
ialy
tic
wei
ght
gain
;SB
P=
syst
olic
bloo
dpr
essu
re.
Tab
le5
Freq
uenc
yof
sess
ions
asso
ciat
edw
ith
intr
adia
lyti
chy
pote
nsiv
eep
isod
es(I
DH
Es)
Tria
lTy
peof
IDH
E
Cou
ntof
sam
pled
dial
ysis
sess
ions
aw
ith
and
wit
hout
IDH
E
Rel
ativ
eri
sk(9
5%C
I)P
valu
eb3×
wee
kly
grou
p6×
wee
kly
grou
p
Dai
lyN
osy
mpt
oms
ofhy
pote
nsio
n29
7359
451)
Sym
ptom
sof
hypo
tens
ion
led
tolo
wer
ing
ofU
Fra
teor
redu
ced
bloo
dflo
w21
829
31.
26(0
.89,
1.77
)0.
182a
)Sy
mpt
oms
ofhy
pote
nsio
nle
dto
adm
inis
trat
ion
ofsa
line
129
209
1.53
(1.1
1,2.
09)
0.00
862b
)Sy
mpt
oms
ofhy
pote
nsio
nle
dto
low
erin
gof
UF
rate
and
adm
inis
trat
ion
ofsa
line
120
220
Noc
turn
alN
osy
mpt
oms
ofhy
pote
nsio
n12
6121
591)
Sym
ptom
sof
hypo
tens
ion
led
tolo
wer
ing
ofU
Fra
teor
redu
ced
bloo
dflo
w43
380.
85(0
.33,
2.17
)0.
742a
)Sy
mpt
oms
ofhy
pote
nsio
nle
dto
adm
inis
trat
ion
ofsa
line
5111
0.35
(0.1
8,0.
69)
0.00
242b
)Sy
mpt
oms
ofhy
pote
nsio
nle
dto
low
erin
gof
UF
rate
and
adm
inis
trat
ion
ofsa
line
3719
a Dia
lysi
sse
ssio
nda
tare
cord
edov
erpe
riod
sof
1w
kea
chm
onth
.b To
pre
lati
veri
skst
atis
tics
and
Pva
lues
refle
ctte
sts
for
whe
ther
pati
ents
in1
trea
tmen
tgr
oup
wer
em
ore
likel
yto
expe
rien
cese
ssio
nsas
soci
ated
wit
hID
HE
s,w
hich
wer
etr
eate
dby
redu
cing
the
UF
rate
only
(ID
HE
cate
gory
1).
Bott
omst
atis
tics
refle
ctte
sts
for
whe
ther
pati
ents
in1
trea
tmen
tgr
oup
wer
em
ore
likel
yto
expe
rien
cese
ssio
nsas
soci
ated
wit
hID
HE
s,w
hich
wer
etr
eate
dw
ith
salin
e(I
DH
Eca
tego
ries
2aan
d2b
).C
I=
confi
denc
ein
terv
al;
UF
=ul
trafi
ltra
tion
.
Blood pressure in frequent dialysis
Hemodialysis International 2015; ••:••–•• 11
DISCUSSION
Frequent HD reduces BP and the number of prescribedantihypertensive medications whether it is given in
shorter duration daily or in longer nocturnal sessions. Ourresults are comparable to those seen in observationalstudies and randomized trials of daily in-center HD, inwhich reductions in pre-HD SBP of 7–23 mmHg and inDBP of 4–12 mmHg have been reported.5–13,16 In additionto greater declines in BP, patients who received frequentHD were also prescribed significantly fewer antihyperten-sive medications, a finding in keeping with previousstudies.5–8,11,17
Blood pressure dynamics appeared to differ slightlybetween daily and nocturnal 6× weekly HD (Table 2). Wespeculate that shorter dialysis vintage and larger urinevolumes in the nocturnal trial may have attenuated theimpact of frequent dialysis compared with the daily trial.Subgroup analysis in the daily trial indicated a significantinteraction between daily urine volume at baseline and BPresponse, so that anuric patients had greatest relativedecline in BP with frequent HD. These findings suggestthat the larger residual urinary volume in the nocturnaltrial at baseline may have tempered BP lowering in thisgroup.
Intradialytic hypotensive episodes (IDHEs) are a majorconcern for HD patients. While in patients in the frequentHD arms of both FHN trials, pre-HD SBP and DBP werelower than at baseline, there was a lower percentage ofsessions associated with IDHE relative to the total numberof sampled HD sessions in the 6× weekly groups com-pared with the 3× weekly groups in both trials. Thereasons for the lower rates of sessions associated withIDHE are not completely clear, but the lower ultrafiltra-tion rate observed with more frequent HD is a reasonablepossibility (Table 2a,b). However, while the relative fre-quency of sessions associated with IDHE decreased in the6× weekly group in the daily trial, the absolute number ofIDHE per patient over a given time increased, resulting ina significantly higher relative risk for sessions associatedwith IDHE requiring the administration of saline(Table 5). In the nocturnal trial, the relative risk of ses-sions associated with IDHE was decreased in the 6×weekly arm. The smaller number of sessions associatedwith IDHE among 6× weekly patients in the nocturnaltrial may be related to differences in monitoring; it isconceivable that in a sleeping patient, it would be lesslikely that ultrafiltration rate would be adjusted or salinebe given.
While these trials were not designed to study themechanisms responsible for BP reductions with more fre-quent HD, we speculate that several pathways may beresponsible. A reduction in interdialytic fluid gain with 6×weekly dialysis may lead to a reduction in BP. Our dataappear to support prior studies that frequent dialysis
Figure 3 Estimated treatment effect on predialysis systolicblood pressure (SBP) by magnitude of daily urine volume atbaseline in the daily trial. Tests were performed on the con-tinuous form of urine volume but results were representedusing urine volume categories, simply for illustrative pur-poses. Patients who had no urine output at baseline had agreater reduction in SBP in the frequent dialysis group com-pared with the conventional 3× weekly group (P for interac-tion = 0.05).
Figure 4 Estimated treatment effect on predialysis systolicblood pressure (SBP) by magnitude of daily urine volume atbaseline in the nocturnal trial. Tests were performed on thecontinuous form of urine volume but results were repre-sented using urine volume categories, simply for illustrativepurposes. Urine output at baseline had no modifying effecton the reduction in SBP in the frequent dialysis group com-pared with the conventional 3× weekly group.
Kotanko et al.
Hemodialysis International 2015; ••:••–••12
Figure 5 Daily trial: Association between change in predialysis systolic blood pressure and change in interdialytic weight gainbetween baseline and F2. There was a modest correlation in the 3× weekly group (Spearman’s rho = 0.21, P = 0.035), but notin the 6× weekly group.
Figure 6 Nocturnal trial: Association between change in prehemodialysis systolic BP and change in interdialytic weight gainbetween baseline and F2. There was no statistically significant correlation in either the 3× weekly (closed circles) and 6× weekly(open squares) groups.
Blood pressure in frequent dialysis
Hemodialysis International 2015; ••:••–•• 13
reduced predialysis BP and the number of antihyperten-sive agents. Blood pressure rises in the interdialytic periodat a rate that depends on the IDWG. This has been con-firmed using ambulatory and home BP measurements.Patients who had daily dialysis had weight excursions in anarrower range than those in conventional dialysis group,and in both trials, the weekly average IDWG was lower inthe frequent HD arms. Thus, one could hypothesize thatreduction in BP may simply reflect lower weight excur-sions, lower IDWG, and therefore lower predialysis BP. Inorder to further explore the association between changesin IDWG and pre-HD SBP, we analyzed this in individualpatients in each group. We focused on the changes 2months after randomization, reasoning that these earlierchanges would be less confounded by other factorssuch as physiological adjustments to a lower BP, changingmedications, provider adjustments to the prescribed targetweight, differences in diet, and changes in body compo-sition that might occur later in the trials. When the rela-tionship between change in IDWG and change in pre-HDSBP was examined at the individual patient level, theassociation was modest in the 3× weekly arm in the dailytrial (Spearman’s rho = 0.21, P = 0.035) and not signifi-cant in the 6× weekly groups in both trials (Figures 5and 6). In addition, correlational analysis of changes inpre-HD SBP and changes in BNP, an indicator of volumestatus, showed no relationship in both trials. These resultscall into question a direct effect of interdialytic fluid intakeon pre-HD SBP. While not excluding the role of extracel-lular volume differences, other factors, including reducedsympathetic tone,25 improved endothelial function, andmore efficient removal of pressor substances26 may play arole in the decline in BP with frequent HD. In a notpre-specified analysis, we adjusted for the effect of pre-scribed dialysate levels on pre-HD SBP. In this analysis, thetreatment effect of frequent HD on pre-HD SBP remainedsignificant in the daily but not in the nocturnal trial.Notwithstanding the fact that no data on actually deliv-ered dialysate sodium concentrations are available, webelieve that this observation deserves future research intothe relationship between actually delivered dialysatesodium and BP.
The daily and nocturnal trials are the largest publishedrandomized trials of frequent HD, permitting robustevaluations of these interventions on BP. However, thereare important limitations to the data. First, actual antihy-pertensive drug dose was not recorded; only the prescribedantihypertensive drug dose could be relied on as an indi-cator of antihypertensive therapy. Second, despite ran-domization in the nocturnal trial, average pre-HD SBP atbaseline was 7.7 mmHg higher in the 3× weekly arm
(152.6 ± 22.2 mmHg vs. 144.9 ± 13.7 mmHg; Table 2b).This baseline difference would be expected to favor amore pronounced BP decline in the 3× weekly arm.However, BP reduction was actually more pronounced inthe 6× weekly nocturnal arm. Third, we did not rigorouslystandardize methods for measuring BP and IDHE.However, this limitation should have been mitigated byour focus on changes over time since the center-specificmodes of BP measurement probably remained fixedduring the study; in addition, any differences would havebeen expected to be balanced by randomization. Fourth,ambulatory BP monitoring was not performed in eithertrial, and home BP measurements were required only atbaseline but not at the end of study. Ambulatory BP moni-toring would have facilitated to investigate in greaterdetail the time course and mechanistic concepts related tothe BP dynamics. Fifth, there is a potential for ascertain-ment bias because of the unmasked design. However, it isalmost inconceivable that an intervention such as frequentHD can be delivered in a masked fashion. Finally, addi-tional measures of extracellular (e.g., bioimpedance spec-troscopy) and/or intravascular volume (e.g., diameter ofinferior vena cava) would be very useful. Unfortunately,measurements of fluid status by means of bioimpedancespectroscopy are available only in certain selected patientsubsets. In conclusion, compared with 3× weekly HD, 6×weekly HD produced a comparable reduction of BP inboth the daily and nocturnal trials, indicating that fre-quent HD reduces BP in both frequent in-center HD andwith frequent nocturnal HD sessions at home. The BPreduction was accompanied by fewer prescribed antihy-pertensive drugs. Favorable reductions in BP should beconsidered when balancing the relative risks and benefitsof frequent HD in selected patients with end-stage renaldisease.
ACKNOWLEDGMENT
The authors wish to dedicate this manuscript to Dr JohnStokes, our colleague and collaborator who untimely leftus. John’s insight, focus, and scholarship served as aguiding light for us all. The whole FHN family is foreverindebted to Dr Stokes, and we will miss his keen obser-vations, his dedication, and his friendship.
FUNDING SOURCE
This work was supported by the National Institutes ofHealth (NIH), National Institutes of Diabetes and Diges-tive and Kidney Diseases, the Center for Medicareand Medical Services, and the NIH Research Foundation.
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Contributors to the NIH Foundation in support of theFHN trials included Amgen, Baxter, and Dialysis Clinics.Additional support was provided by DaVita, DialysisClinics, Fresenius Medical Care, Renal Advantage, RenalResearch Institute, and Satellite Healthcare.
Conflict of interest: Drs Peter Kotanko and Nathan W.Levin are full time employees of the Renal Research Insti-tute, a wholly owned subsidiary of Fresenius Medical CareHoldings, Inc., which may be considered an entity with afinancial interest in providing dialysis services anddevices; Drs. Peter Kotanko and Nathan W. Levin holdstock in Fresenius Medical Care. The other authorsdeclare no conflict of interest.
Manuscript received October 2013; revised October2014.
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SUPPORTING INFORMATION
Additional Supporting Information may be found in theonline version of this article at the publisher’s web-site:
Table S1. Treatment effects on pre-dialysis systolic bloodpressure with adjustment for effects of dialysate sodium.
