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American
Journal of
Nephrology
Am J Nephrol 2014;39:171182
DOI: 10.1159/000358603
Abstract
To test the hypothesis that thiazide-type diuretics effectively lower blood pressure (BP) in moderate to advanced chronic kidney disease (CKD; estimated GFR 2045 ml/min/
1.73 m2), after confirming poorly controlled hypertension
with 24-hour ambulatory BP monitoring, chlorthalidone was
added to existing medications in a dose of 25 mg/day, and
the dose doubled every 4 weeks if the BP remained elevated.
The average age of the 14 subjects was 67.5 years, a median
of 4 antihypertensive drugs were used and estimated GFR
was 26.8 8.8 ml/min/1.73 m2. Twelve subjects completed
the 12-week treatment phase, and the 24-hour BP, which
was 143.1/75.1 mm Hg at baseline, was reduced by 10.5/
3.1 mm Hg (p = 0.01/p = 0.17). Home BP prior to initiating
chlorthalidone was 152.4/82.6 mm Hg and fell at 4, 8, and 12
weeks by 10.2/4.8, 13.4/6.0, and 9.4/3.7 mm Hg (all p < 0.05).
Maximal reduction in body weight and total body volume
(measured by air displacement plethysmography) was seen
at 8 weeks, concurrent with the maximal elevation in serum
creatinine concentration and plasma renin activity. Albu-
Introduction
It is estimated that in the United States there are approximately 8 million individuals with moderate to severe chronic kidney disease (CKD) not on dialysis [1].
Among these patients, volume expansion plays an important role in the pathogenesis of hypertension [2].
According to the most recent guidelines, diuretics
should be used to treat hypertension in most patients with
CKD [3]. For those with estimated GFR 30 ml/min/
Rajiv Agarwal, MD, Professor of Medicine
Indiana University and VAMC
1481 West 10th Street
Indianapolis, IN 46202 (USA)
E-Mail ragarwal@iu.edu
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Key Words
Chronic kidney disease Blood pressure Estimated GFR
Chlorthalidone
Methods
Study Design
A single-center pilot study of chlorthalidone in patients with
poorly controlled hypertension and CKD was designed as outlined
in the supplementary figure 1 (for all supplementary material, see
www.karger.com/doi/10.1159/000358603). The study protocol
was approved by the Institutional Review Board and the VA Research and Development Committee, and all subjects provided
written informed consent. The study was registered at clinicaltrials.gov (NCT01750294).
Inclusion and Exclusion Criteria
Eligible subjects were at least 18 years of age and at the time of
recruitment had an estimated GFR 45 ml/min/1.73 m2 but >20
ml/min/1.73 m2 using an IDMS-calibrated creatinine assay [6].
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DOI: 10.1159/000358603
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1.73 m2, thiazide diuretics given once daily are recommended. However, loop diuretics are recommended for
those with estimated GFR <30 ml/min/1.73 m2. Loop diuretics given once or twice daily, in combination with thiazide diuretics, can be used for patients with extracellular
fluid volume expansion and edema. All these recommendations have an A level of evidence. Joint National Commission 7 guidelines [4] state, with advanced renal disease (estimated GFR <30 ml/min 1.73 m2, corresponding
to a serum creatinine of 2.53 mg/dl), increasing doses of
loop diuretics are usually needed in combination with
other drug classes. Furthermore, the guidelines state,
most patients with CKD should receive an ACEI or an
ARB in combination with a diuretic, and that many will
require a loop diuretic rather than a thiazide.
Prior to conducting this pilot study, we conducted a
systematic review and found 7 studies evaluating the use
of thiazide diuretics in advanced CKD either alone or in
combination with loop diuretics [5]. Of these, 3 studies
were observational, 2 were single-blind, crossover studies, and 2 were double-blind crossover trials. We concluded that whether thiazides can lower blood pressure (BP)
in patients with more advanced CKD remains unclear.
Given the central role of volume excess in the pathogenesis of hypertension in CKD, and the low cost of thiazide
diuretics, there is a need to study the use of these drugs to
lower BP among patients with uncontrolled hypertension
and moderately advanced CKD.
Accordingly, we hypothesized that among patients
with moderate to severe CKD, chlorthalidone will result
in improved 24-hour ambulatory BP over 12 weeks. The
sample size was chosen to provide preliminary data to inform design of a randomized controlled trial to improve
control rates of hypertension in the CKD population.
Chlorthalidone in CKD
Results
173
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the Spacelabs 90207 monitor (see online suppl. appendix for details) [7].
Home BP measurements were performed with a home digital
sphygmomanometer with an automatic inflator and printer for
recording (Model HEM790IT, Omron Healthcare Inc., Bannockburn, Ill., USA) with a cuff size appropriate for arm size.
Subjects were asked to record their BP after 5 min of seated rest
in triplicate twice daily for 1 week prior to clinic visit. All subjects
were instructed in use of the monitor prior to participation in the
study.
Clinic BP measurements were obtained in triplicate in both
arms, with the arm and the forearm supported at the level of the
heart (mid-sternal level), by a trained observer after a 5-min rest
using a digital sphygmomanometer (Model HEM-907, Omron
Healthcare) with an appropriate cuff size using oscillometric
methodology as stated in the European Society of Hypertension
recommendations for BP measurement [8]. Oscillometric BP averaged over three readings was used as that clinic visit BP. After
the first visit, the arm with the higher systolic BP was designated
the BP arm for the duration of the study.
Concentration of urinary albumin and creatinine concentration was determined using clinical assays in the hospital laboratory. Measurements were made in 24-hour urine collected during
sleep and wake states in separate aliquots.
Body volume was measured using air displacement plethysmography (ADP) using the BOD POD Gold Standard Body Composition Tracking System (Life Measurement Inc., Concord, Calif.,
USA). The ADP system consisted of the air plethysmograph, a digital scale, and computer software (BOD POD version 4.2+). Each
participant was asked to change into compression shorts and a
swim cap and to remove any jewelry. Body mass was measured to
the nearest 0.001 kg using the electronic scale prior to the body
volume measurement. Height was measured using a Seca 222 measuring rod (Seca Group, Hamburg, Germany).
Pulse wave shape and velocity were measured via the SphygmoCor EM3. Central aortic pressure and larger artery stiffness were
recorded.
Chlorthalidone Dosing
At baseline, all subjects (n = 14) were prescribed 25
mg/day of chlorthalidone. At 4 weeks, 2 subjects were no
longer taking the drug; in 1, the dose was lowered to thrice
weekly, in 6 it was not escalated, and in 5 it was titrated to
50 mg/day. At 8 weeks, 1 subject had quit all medications,
1 was continued on chlorthalidone 25 mg thrice weekly,
2 subjects on 25 mg/day, 5 subjects on 50 mg/day, and 3
were escalated to 100 mg/day. At the final visit, 1 subject
was continued on 25 mg thrice weekly, 2 on 25 mg/day, 6
on 50 mg/day, and 2 on 100 mg/day. Mixed modeled
mean prescribed chlorthalidone dosage at 4 weeks was 34
mg, at 8 weeks 55 mg, and at final visit 51 mg/day.
Ambulatory BP Response
Figure 1 shows the individual level and the mean 24hour, awake, and sleep systolic and diastolic BP in all participants. One subject stopped taking most antihypertensive medications including the study drug and had an increase in BP. The change from baseline in mean 24-hour
systolic BP was significant (10.5 mm Hg decline, p = 0.01)
whether the analysis was performed for 14 subjects or
limited to 12 subjects who had paired measurements (decline 8.5 mm Hg, p = 0.05). Similar declines were seen in
awake and sleep systolic BP, but the dipping ratio was not
altered. Diastolic BP did not decline significantly.
Home BP Response
The time course of home BP is shown in figure 2. Week
2 represents the baseline BP after which the usual medi-
shows 24-hour, middle panel awake, and lower panel sleep systolic (left) and diastolic (right) BP. Each line represents an individual subject. Black triangles show the individual level of baseline
BP in 2 subjects who did not have subsequent BP. Mean level of BP
is shown by the circle, and whiskers represent one standard error
of the mean. The table below the graph shows the number of participants at each time point (n), the duration (Durtn) of recording
in minutes, the number of hours with at least one valid BP record-
174
Am J Nephrol 2014;39:171182
DOI: 10.1159/000358603
cations were adjusted to a standard antihypertensive regimen. Two weeks after adjustment, at week 0, chlorthalidone was initiated in a dose of 25 mg once daily. All
changes in either systolic or diastolic BP were statistically
significant when measured either as change from baseline
or change after drug initiation.
Clinic BP and Orthostatic Response
The time course of clinic BP is shown in figure 3. The
top row shows seated clinic systolic and diastolic BP over
time; the middle row the standing systolic BP and standing pulse rate, and the bottom row the orthostatic change
in systolic BP and pulse rate. Change after chlorthalidone
initiation was significant for seated and standing systolic
BP only. At no time point was change statistically significant for diastolic BP, pulse rate, or orthostatic change in
systolic BP or pulse rate. Orthostatic hypotension defined
as systolic BP drop of 20 mm Hg or more upon standing
was seen in 5 subjects on 8 occasions. Five episodes occurred prior to starting chlorthalidone in 4 subjects.
Among 3 subjects who each had one episode of orthostatic hypotension, 2 had orthostatic hypotension prior to
starting chlorthalidone. In only 1 was orthostatic drop in
BP accompanied by dizziness.
Changes in volume, target organs and laboratory tests
are shown in figures 4 and 5 and table1, respectively, and
detailed in the online supplementary appendix.
Adverse and Serious Adverse Events
Adverse events were seen following administration of
chlorthalidone in 7 subjects; 3 subjects had adverse events
in the run-in period. After administration of chlorthalidone, 18 events were noted: hypokalemia (n = 4), hyperuricemia (4), hyponatremia (3), transient elevations in
serum creatinine (3), dizziness (2), hyperglycemia (1),
and constipation (1). Before the administration of
chlorthalidone, 3 events were noted: dizziness (1), urinary tract infection (1), and anemia requiring treatment
with an erythropoietin-stimulating agent (1). In the case
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110
160
155
150
145
140
135
148.7
143.1
138.6
137.5
132.6
130
126.5
125
120
n
14
Durtn 1370 35
Hrs
23 1
SBP 143.1 2.9
CFB14
CFB14(p)
CFB12
CFB12(p)
12
1279 38
22 1
132.6 3.1
-10.5 4.2
0.01
-8.5 4.3
0.05
wk 4
Systolic awake ambulatory BP (mmHg)
155
145
135
85
80
75
70
79.9
75.1
70.3
148.8
143.3
140.4
137.9
134.6
130
128.7
125
120
n
14
Hrs 14 1
sbp 143.3 2.8
cfb14
Cfb14 (p)
cfb12
Cfb12 (p)
wk 4
77.0
72.0
66.9
65
60
55
50
n
14
Durtn 1370 35
Hrs
23 1
DBP 75.1 2.4
CFB14
CFB14(p)
CFB12
CFB12(p)
wk 4
165
140
95
90
12
14 1
134.6 3
-8.8 4.1
0.03
-7.9 4.4
0.07
12
1279 38
22 1
72 2.6
-3.1 2.3
0.17
-3.3 2.3
0.15
wk 12
Week of study
110
160
150
105
100
wk 12
Week of study
170
165
170
105
100
95
90
85
80
75
70
80.7
76.1
71.6
78.4
73.6
68.8
65
60
55
50
14
n
Hrs 14 1
dbp 76.1 2.3
cfb14
Cfb14 (p)
cfb12
Cfb12 (p)
wk 12
wk 4
Week of study
12
14 1
73.6 2.5
-2.6 2.4
0.28
-3.1 2.4
0.20
wk 12
Week of study
160
155
150
149.0
145
140
135
141.8
138.4
134.6
130.7
130
125
123.0
120
14
n
Hrs 10 1
sbp 141.8 3.7
cfb14
Cfb14 (p)
cfb12
Cfb12 (p)
wk 4
12
81
130.7 3.9
-11.1 4.4
0.01
-9.1 4.3
0.03
wk 12
Week of study
105
100
95
90
85
80
75
70
65
78.8
75.6
72.9
69.5
67.0
63.3
60
55
50
12
81
69.5 3.1
-3.4 2.5
0.17
-3.4 2.6
0.19
14
n
Hrs 10 1
dbp 72.9 3
cfb14
Cfb14 (p)
cfb12
Cfb12 (p)
wk 4
wk 12
Week of study
1
Chlorthalidone in CKD
Am J Nephrol 2014;39:171182
DOI: 10.1159/000358603
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165
110
170
170
165
162.4
160
155
152.4
150
145
143.0
142.2
140
139.0
135
n
CFB ( SE)
CFB (p)
CAD (SE)
CAD (p)
14
0
0
14
-10.0 2.8
<0.001
0
11
-20.2 3.1
<0.0001
-10.2 3.1
<0.001
10
-23.3 3.2
<0.0001
-13.4 3.2
<0.0001
11
-19.3 3.1
<0.0001
-9.4 3.1
<0.01
90.0
87.5
87.4
85.0
82.5
82.6
80.0
78.9
n
CFB ( SE)
CFB (p)
CAD (SE)
CAD (p)
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14
0
0
14
-4.8 1.4
<0.001
0
11
-9.6 1.6
<0.0001
-4.8 1.6
<0.01
10
-10.8 1.6
<0.0001
-6.0 1.6
<0.001
11
-8.5 1.6
<0.0001
-3.7 1.6
0.02
-2
4
Week of study
12
76.6
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75.0
77.8
CTD start
77.5
Baseline
study. Upper graph shows the mean systolic BP and lower graph the mean diastolic BP over time. Circles show the mean and
whiskers the standard error of the mean.
Week 2 represents the baseline BP after
which the usual medications were adjusted
to a standard antihypertensive regimen.
Two weeks after adjustment, at week 0,
chlorthalidone was initiated in a dose of
25 mg once daily. Home BP was monitored
at least every 4 weeks during the course of
the study. The table below the graph shows
the number of participants at each time
point, the CFB standard error (SE) of the
mean, the statistical significance of the
change from baseline [CFB (p)], the change
after drug initiation (CAD) and its statistical significance [CAD (p)]. All changes
measured either as change from baseline or
change after drug initiation were statistically significant.
170
77.5
160
159.4
155
150
145
140
142.5
137.7
135
130
130.2
129.0
125
124.4
120
14
14
12
12
12
n
CFB (SE)-16.94.7-21.74.7 -30.4 5.0 -35.0 5.0 -29.2 5.0
CFB (p) <0.001 <0.0001
<0.0001
<0.0001
<0.0001
CAD (SE) 0
0
-8.7 5.0 -13.3 5.0 -7.5 5.0
0.08
<0.01
0.13
CAD (p)
-3-2 0
4
8
Week of study
165
75.0
72.5
73.6
70.0
67.5
68.3
65.0
66.0
65.4
62.2
61.9
n
14
14
12
12
12
CFB ( SE)-5.32.4 -8.22.4 -11.3 2.5 -11.7 2.5 -7.6 2.5
CFB (p) 0.03 <0.001
<0.0001
<0.0001
<0.01
CAD (SE)
0
0
-3.1 2.5 -3.4 2.5 0.6 2.5
CAD (p)
0.22
0.17
0.80
-3-2 0
4
8
Week of study
12
170
12
77.5
165
75.0
155
155.5
150
145
140
141.7
135
130
131.0
125
127.9
126.2
120
116.8
160
72.5
74.0
70.0
69.7
67.5
65.0
65.3
63.5
64.6
63.3
14
12
12
12
n
14
CFB (SE) -13.86.4-24.56.4 -27.6 6.8 -38.7 6.9 -29.3 6.9
<0.0001
<0.0001
<0.0001
CFB (p) 0.03 <0.001
0
0
-3.1 6.6 -14.2 6.8 -4.8 6.8
CAD (SE)
0.64
0.04
0.48
CAD (p)
n
14
14
12
12
12
CFB ( SE)4.33.5 -6.2 3.5 -4.4 3.7 -6.4 3.8 -5.0 3.8
CFB (p) 0.21
0.08
0.23
0.09
0.18
CAD (SE) 0
0
1.8 3.6 -0.2 3.7 1.1 3.7
CAD (p)
0.62
0.95
0.76
-3-2 0
4
8
Week of study
-3-2 0
4
8
Week of study
12
12
00
-0.8
-2
-4
-1.0
-3.2
-5
-4.2
-6
-6.7
-8
-7.5
-10
n
14
14
CFB ( SE) 2.3 4.8 -3.54.8
CFB (p)
0.63
0.47
CAD (SE)
0
0
CAD (p)
12
2.1 5.1
0.67
5.6 5.0
0.26
12
-4.3 5.2
0.40
-0.8 5.1
0.87
-3-2 0
4
Week of study
12
-1.0 5.2
0.85
2.5 5.1
0.62
12
7.00
6.00
6.2
5.7
5.00
5.2
4.7
4.00
3.00
4.6
4.1
n
14
14
12
12
CFB ( SE)1.5 1.3 0.41.3 -0.1 1.4 -0.7 1.4
CFB (p)
0.26
0.74
0.94
0.65
CAD (SE)
0
0
-0.5 1.4 -1.1 1.4
CAD (p)
0.69
0.44
-3-2 0
4
8
Week of study
12
1.0 1.4
0.50
0.5 1.4
0.70
12
Chlorthalidone in CKD
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95
95
93
93
91
91.5
90
91.0
90
89.8
89
90.3
87
volume (L)
Weight (kg)
91
89.6
89
88.8
88.1
87.8
87
85
85
14
12
12
12
Mean ( SE)
91.5 3.5
91.0 3.5
89.8 3.5
90.3 3.5
CFB ( SE)
-0.5 0.8
-1.7 0.8
0.57
0.05
CFB (p)
-2
4
8
Week of study
14
12
12
12
Mean ( SE)
89.6 3.5
88.8 3.5
87.8 3.5
88.1 3.5
-1.2 0.9
CFB ( SE)
-0.8 0.7
-1.9 0.7
-1.5 0.7
0.18
CFB (p)
0.24
<0.01
0.03
12
-2
4
8
Week of study
12
12
11.0
4.5
4
3.5
3
2.5
2.7
2.1
1.5
1.9
1
0.5
0.8
0
n
14
12
10
12
6
5.5
10
9.0
8
7.0
<0.0001
-2
<0.0001
4
8
Week of study
4.5
3.7
3.0
CFB (p)
6.3
5.0
Mean (CI) 0.8 (0.4,1.7 ) 2.1 (1.0,4.6 ) 2.7 (1.3,6.0 ) 1.9 (0.9,4.0 )
CFB fold change (CI)
6.9
<0.0001
n
14
12
10
12
Mean (CI) 3.7 (2.1,6.7 ) 6.9 (3.8,12.6 ) 6.3 (3.4,11.7 ) 4.5 (2.4,8.1 )
1.8 (1.2,2.9 ) 1.7 (1.0,2.7 ) 1.2 (0.8,1.9 )
CFB fold change (CI)
CFB (p)
<0.01
0.03
0.44
-2
12
4
8
Week of study
12
3.4
120
90
80
70
72.5
60
61.4
50
51.4
40
35.1
30
20
12
12
14
12
n
Mean (CI) 73 (42,125 ) 35 (20,62 ) 51 (29,91 ) 61 (35,108 )
CFB fold change (CI)
0.5 (0.3,0.8 ) 0.7 (0.4,1.1 ) 0.8 (0.5,1.3 )
0.48
0.14
<0.01
CFB (p)
-2
4
8
Week of study
12
3.20
3.12
3.0
3.04
2.92
2.87
2.80
2.6
14
12
12
12
Mean ( SE) 2.87 0.24 3.04 0.25 3.12 0.25 2.92 0.25
CFB ( SE)
0.17 0.14 0.24 0.14 0.04 0.14
CFB (p)
0.21
0.07
0.74
-2
4
8
Week of study
12
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100
110
Baseline
Change at 4 weeks
Change at 8 weeks
Change at 12 weeks
Sodium, mEq/l
p
Potassium, mEq/l
p
Bicarbonate, mEq/l
p
3 (51, 45)
0.91
30 (18, 77)
0.22
10 (37, 58)
0.67
Calcium, mg/dl
p
Phosphorus, mg/dl
p
Magnesium, mg/dl
p
Cholesterol, mg/dl
p
Hemoglobin A1C, %
p
BNP was half that of the baseline at 4 weeks, but gradually returned
to baseline. Plasma creatinine was changed maximally by 0.24 mg/
dl at 8 weeks but also returned toward baseline at 12 weeks. The
table below the graph shows the number of participants at each
time point, the CFB standard error (SE) of the mean or the 95%
confidence interval of the fold change in case of renin, aldosterone,
and BNP. The statistical significance of the change from baseline
is in row labeled CFB (p).
Chlorthalidone in CKD
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p values reflect the change from baseline. Values in parentheses represent minimum and maximum.
13.5
12.6
12
12.2
12.2
137.4
136.6
135
134.9
130
10
12
11
11
12
11
CAD (SE) 0
-1.3 1.5
-0.9 1.5
-1.3 1.5
CAD (SE)0
-2.4 4.5
0.3 4.4
-0.7 4.5
CAD (p)
0.36
0.53
0.39
CAD (p)
0.59
0.94
12
-2
-2
12
4
8
Week of study
2000
1750
1500
1250
1000
750
500
604
250
333
n
Mean (CI)
13
11
604 (221,1646)
333 (121,918)
12
137.7
4
8
Week of study
18.1
17.5
16
14
14.2
12
10
12
11
-7.1 2.1
-3.1 2.2
0.87
CAD (p)
0.08
<0.001
0.16
12
-2
14
4
8
Week of study
12
175
1250
1000
750
500
535
250
Week of study
18
11
1500
12
21.2
20
-3.7 2.2
1750
<0.01
22
CAD (SE) 0
2000
0.55 (0.37,0.83)
CFB (p)
14
322
n
Mean (CI)
13
11
535 (196,1462)
322 (117,887)
0.60 (0.42,0.86)
<0.01
CFB (p)
12
Week of study
14
140
16
150
125
130
120
100
13
n
Mean (CI) 130 (101,158)
CFB (CI)
CFB (p)
11
120 (90,150)
-9.4 (-39.6,20.7)
0.54
12
Week of study
Fig. 5. Markers of target organ damage at baseline and during the study. The top panel shows carotid-to-femoral
pulse wave velocity, central systolic BP, and augmentation index corrected to heart rate at 75 beats/min. The bottom panel shows the results of urinary excretion of albumin during the day and night as well as 24-hour urinary
sodium excretion rate at baseline and at 12 weeks of study. creat and cr = Creatinine.
180
Am J Nephrol 2014;39:171182
DOI: 10.1159/000358603
Discussion
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Acknowledgments
We thank Megan Roadley, Opeyemi Olorungbounmi and
America Newnum for technical assistance in the study.
This work was supported by the Indiana Institute for Medical
Research.
Disclosure Statement
None.
Chlorthalidone in CKD
4 Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW,
Materson BJ, Oparil S, Wright JT Jr, Roccella
EJ: Seventh report of the Joint National Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure. Hypertension 2003;42:12061252.
Am J Nephrol 2014;39:171182
DOI: 10.1159/000358603
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References
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Am J Nephrol 2014;39:171182
DOI: 10.1159/000358603
Agarwal/Sinha/Pappas/Ammous
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