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Original Report: Patient-Oriented, Translational Research

American

Journal of

Nephrology

Am J Nephrol 2014;39:171182
DOI: 10.1159/000358603

Received: January 13, 2014


Accepted: January 13, 2014
Published online: February 11, 2014

Chlorthalidone for Poorly Controlled


Hypertension in Chronic Kidney Disease:
An Interventional Pilot Study
Rajiv Agarwal Arjun D. Sinha Maria K. Pappas Farah Ammous
Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center,
Indianapolis, Ind., USA

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-

2014 S. Karger AG, Basel


02508095/14/03920171$39.50/0
E-Mail karger@karger.com
www.karger.com/ajn

minuria was significantly reduced by 4045%. Adverse


events were seen following chlorthalidone therapy in 7 subjects who experienced 18 events as follows: hypokalemia
(n = 4), hyperuricemia (4), hyponatremia (3), transient creatinine changes (3), dizziness (2), hyperglycemia (1), and
constipation (1). One subject had ischemic stroke during the
study. In conclusion, among people with moderate to advanced CKD with poorly controlled hypertension, chlorthalidone may significantly reduce BP via volume contraction; a
randomized trial is needed to define the risks and benefits.
Adverse effects may occur within a few weeks and should be
carefully monitored.
2014 S. Karger AG, Basel

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

Poorly controlled BP was defined as 135 systolic or 85 mm Hg


by 24-hour ambulatory BP monitoring. Initially, the study was designed to study those with resistant hypertension, but due to difficulties with recruitment, we amended the protocol to study those
with poorly controlled but treated hypertension. Prescription of a
loop diuretic at baseline was preferred but not required. However,
we required that one of the nondiuretic drugs be either an ACE
inhibitor or angiotensin receptor blocker. If these were contraindicated, then use of a beta-blocker was required. We excluded subjects who used thiazide or thiazide-like drugs in the previous 3
months, were prescribed furosemide in a dose >80 mg/day, or had
ambulatory BP that was deemed unsafe to participate (160 systolic or 100 mm Hg diastolic by 24-hour ambulatory BP monitoring). Other exclusions are listed in the online supplementary
appendix.
Study Intervention
Subjects with CKD and poorly controlled hypertension confirmed by ambulatory BP monitoring after the 2-week run-in who
met the inclusion and exclusion criteria were administered
chlorthalidone in increasing doses. There are 8 study-related visits
at weeks 3, 2, 0, 4, 8, and 12. At weeks 0 and 12, visits were needed on consecutive days to evaluate 24-hour ambulatory BP and
urine collection.
Subjects were identified in the renal clinic on the basis of estimated GFR. If they were on BP medications including a diuretic
and thought to have poorly controlled hypertension, they were dispensed a home BP monitor. If home BP monitoring was >130/80
mm Hg, they were studied further.
At the beginning of the run-in, all subjects received a standard
regimen of lisinopril 2040 mg/day, amlodipine 10 mg/day, and
torsemide 1020 mg/day. These doses were selected based on the
existing regimen of the subject. For those on clonidine or minoxidil as fourth and fifth drugs, the doses of these drugs were left unchanged. Some subjects received alpha-blockers for prostatic
symptoms. The dose of alpha-blockers was also not changed.
Chlorthalidone was selected over hydrochlorothiazide since it
has a longer half-life (4060 vs. 2.5 h in those with normal renal
function) and potentially greater BP-lowering effects. It is generic
and can be administered once daily.
Instead of a fixed dose study, we designed a forced-titration
study because of uncertainty in the dose at which chlorthalidone
may lower BP. Since BP-lowering effects may vary according to the
GFR, the dose at which chlorthalidone improves BP was individualized according to response. Other antihypertensive agents were
held constant during the intervention phase.
Goal BP was defined by home BP monitoring. At least 6 readings were needed to make a decision with home BP. We asked subjects to provide 14 BP readings in 1 week. The average of these was
used for decision to titrate the drug. However, if <6 home BP readings were available, we made decisions based on clinic BP.
Chlorthalidone dose was not increased if the subject had any
of the following: home systolic BP of <125 mm Hg, symptomatic hypotension, or other drug-attributable adverse event. In
these instances, the dose of the drug was maintained or downtitrated.
Procedures
Ambulatory BP monitoring over 24 h was performed in all subjects at baseline and at the end of the 12 weeks of treatment using

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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.

Outcome and Safety


The primary outcome variable in this trial was the change from
baseline to 12 weeks in systolic ambulatory BP in the chlorthalidone group. Safety of continued participation was assessed at each
study visit. Prespecified stop points were treatment-emergent severe adverse event that precluded further exposure to the drug
such as an allergic drug reaction, initiation of renal replacement
therapy or home BP >160/100 mm Hg confirmed at repeat visit
within 2 weeks.
Statistical Methods
Data were plotted to examine individual level information. After thorough evaluation of data integrity, 24-hour ambulatory BP
data were analyzed. Hourly averages were first calculated. Subsequently, each hourly BP was averaged to obtain the 24-hour BP.
The primary method of data analysis was by mixed models [9].
Outcome variable was the 24-hour ambulatory systolic BP. Subject
was used as a random variable, and visit was the fixed categorical
variable. The statistical significance of change from baseline after
fitting the model was calculated using Wald tests. Similar models
were used to assess volume and weight. Plasma renin activity, aldosterone, B-type natriuretic peptide, and albumin/creatinine ra-

Chlorthalidone in CKD

tio were log-transformed to approximate a normal distribution.


Statistical analysis was performed on these transformed variables.
With respect to the transformed variables, the modeled means and
their 95% confidence intervals were reported in the original units.
The change from baseline of these transformed variables is therefore interpreted as fold change from baseline.

Results

Subjects were recruited from the renal clinic at Richard


L. Roudebush VA Medical Center, Indianapolis, Ind.,
USA, between September 18, 2012, and May 15, 2013.
The last subject completed the last visit on August 8, 2013.
Six hundred and two patients were screened, out of
which 548 did not meet the initial eligibility criteria. Of
the 52 eligible subjects, 39 consented and 34 underwent
baseline home BP monitoring (at week 2); 5 did not
show up for the initial visit. One subject was excluded because of too low a BP at home and 3 others were not adherent with baseline procedures and therefore could not
be further studied. Of the 30 remaining subjects, BP medication changes were made, and subsequently ambulatory
BP was found to be normal in 13 and too high in 3; thus,
14 remained eligible for further participation.
Of the 14 subjects who took at least one dose of the
study drug, 2 did not complete the study. One withdrew
consent because he no longer wanted to take the study
medication after 2 days of treatment. One subject had to
be excluded per protocol 2 weeks after treatment when
home BP was noted to be persistently elevated (>160/100
mm Hg) despite chlorthalidone. The remaining 12 completed 12 weeks of chlorthalidone therapy.
Baseline characteristics of the 14 subjects who took at
least one dose of chlorthalidone was as follows: age 67.5
10.2 years (range 4386); men (14); race: white (6),
black (8); diabetes mellitus (12); insulin use (7); oral hypoglycemic drug use (6); current tobacco use (2); current
alcohol use (4), and sleep apnea (6) which was treated
with continuous positive airway pressure device in 3.
Vascular disease was extensive: past myocardial infarction (4); coronary revascularization (5); stroke (3); peripheral revascularization (1), and hospitalization for
heart failure (2). All subjects had treated but poorly controlled hypertension and at the end of the run-in period
were on a mean of 3.8 1.3 drugs (median 4, range 16),
which included the following medications: ACE inhibitor
or angiotensin receptor blocker (11); beta-blocker (11);
calcium channel blocker (12); loop diuretic (9); alphablocker (2); spironolactone (3); central agents (3), and
vasodilator (1). Baseline estimated GFR after run-in was
Am J Nephrol 2014;39:171182
DOI: 10.1159/000358603

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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-

Fig. 1. Individual and mean 24-hour ambulatory BP. Upper panel

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-

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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

ing (Hrs), the change from baseline (CFB) in all 14 subjects


(CFB14) or in the 12 completers (CFB12) and their p values
[CFB14 (p), CFB12 (p) derived from mixed models]. The symbol
reflects the standard error of the mean. The CFB in mean 24-hour
SBP was significant [CFB14 (p) = 0.01] at 10.5 mm Hg using the
mixed model in 14 subjects (CFB14); in 12 subjects who had paired
measurements, the decline was also significant [CFB12 (p) = 0.05]
at 8.5 mm Hg (CFB12). Declines were seen in awake and sleep systolic BP. Diastolic BP did not decline significantly.
(For fig. 1 see next page.)
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26.8 8.8 ml/min/1.73 m2, and stage 3B CKD was present


in 4, stage 4 in 8, and stage 5 in 2 subjects. The latter 2 had
stage 4 CKD before medications were adjusted. The 2
subjects who dropped out had stage 4 CKD. Urine was
collected during wake and sleep hours. Median baseline
urine albumin excretion rate during waking hours was
923 mg/g creatinine (IQR 5632,556) and during sleep it
was 873 mg/g creatinine (IQR 4773,037).

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

Diastolic awake ambulatory BP (mmHg)

Systolic 24h ambulatory BP (mmHg)

165

Diastolic 24h ambulatory BP (mmHg)

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

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165

Diastolic sleep ambulatory BP (mmHg)

Systolic sleep ambulatory BP (mmHg)

110
170

170

Systolic home BP (mmHg)

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

Fig. 2. Home BP at baseline and during the

87.5

87.4

85.0
82.5

82.6

80.0
78.9

n
CFB ( SE)
CFB (p)
CAD (SE)
CAD (p)

Fig. 3. Clinic oscillometric BP at baseline and during the study.


Top row shows seated clinic systolic BP and diastolic BP over time,
middle row the standing systolic BP and standing pulse rate, and
the bottom row the orthostatic change in systolic BP and pulse rate.
Circles show the mean and whiskers the standard error of the
mean. Week 3 represents the first clinic visit at which home BP
monitor was dispensed. Week 2 represents the baseline BP after
which the usual medications were adjusted to a standard antihy-

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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

pertensive regimen. Two weeks after adjustment, at week 0,


chlorthalidone was initiated in a dose of 25 mg once daily. Clinic
BP both seated and upon standing for 1 min was monitored at
baseline and 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
CFB (p), the CAD and CAD (p).
(For fig. 3 see next page.)

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75.0

77.8

CTD start

77.5

Baseline

Diastolic home BP (mmHg)

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

Seated clinic diastolic BP (mmHg)

Seated clinic systolic BP (mmHg)

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

Standing pulse rate (/min)

Standing systolic BP (mmHg)

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

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Orthostatic change in pulse rate (/min)

Orthostatic change in systolic BP (mmHg)

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

Plasma aldosterone (ng/dL)

Plasma renin activity (ng/mL/h)

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

2.7 (1.9,3.9 ) 3.5 (2.4,5.2 ) 2.4 (1.7,3.5 )

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

(For legend see next page.)


178

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Plasma BNP (pg/dL)

100

Plasma creatinine (mg/dL)

110

of hypokalemia, onset was as early as 2 weeks and as late


as 4 weeks. In 1 subject, hypokalemia persisted until week
8. Similarly, hyperuricemia was seen by 6 weeks, and in 1
subject with a prior history of gout, it precipitated ankle
pain thought to be gout. Hyperglycemia was seen within
2 weeks and transient elevations in serum creatinine between 2 and 6 weeks. Onset of dizziness in 2 subjects was
at 2 and 4 weeks after chlorthalidone. Hyponatremia on

the other hand occurred at 48 weeks. Counting all, 22


adverse events were recorded in 7 subjects after initiating
chlorthalidone.
Two serious advents were noted. One subject following an elective kidney biopsy experienced a drop in hemoglobin from 12.1 to 10.3 g/dl and was admitted for
concern of internal bleeding. A computed tomographic
scan showed no evidence for abdominal or renal bleed.

Table 1. Baseline and the time course of changes in blood chemistries

Chemical component or p value

Baseline

Change at 4 weeks

Change at 8 weeks

Change at 12 weeks

Sodium, mEq/l
p

137.9 (136.3, 139.6)

2.7 (4.4, 1.0)


<0.01

2.1 (3.8, 0.4)


0.01

1.4 (3.1, 0.3)


0.11

Potassium, mEq/l
p

4.31 (4.04, 4.57)

0.26 (0.53, 0.01)


0.06

0.05 (0.32, 0.21)


0.69

0.00 (0.28, 0.27)


0.98

Bicarbonate, mEq/l
p

25.9 (24.1, 27.6)

0.38 (1.17, 1.93)


0.63

0.12 (1.67, 1.43)


0.88

0.55 (1.00, 2.10)


0.49

Uric acid, mg/dl


p

7.27 (6.07, 8.47)

1.64 (0.77, 2.51)


<0.001

Fasting glucose, mg/dl


p

146 (97, 196)

3 (51, 45)
0.91

30 (18, 77)
0.22

10 (37, 58)
0.67

Calcium, mg/dl
p

8.89 (8.60, 9.17)

0.10 (0.34, 0.13)


0.39

0.13 (0.11, 0.37)


0.29

0.04 (0.20, 0.27)


0.76

Phosphorus, mg/dl
p

3.99 (3.65, 4.32)

0.23 (0.18, 0.63)


0.27

0.11 (0.51, 0.29)


0.6

0.03 (0.38, 0.44)


0.89

Magnesium, mg/dl
p

2.00 (1.78, 2.22)

0.30 (0.06, 0.55)


0.02

0.18 (0.06, 0.43)


0.14

0.12 (0.13, 0.36)


0.34

Parathryoid hormone-intact, pg/ml


p

114.2 (71.9, 181.4)

0.10 (0.32, 0.13)


0.4

Cholesterol, mg/dl
p

151.7 (130.4, 173.1)

3.4 (32.6, 25.8)


0.82

Hemoglobin A1C, %
p

7.56 (6.47, 8.66)

1.64 (0.77, 2.51)


<0.001

1.53 (0.65, 2.40)


<0.001

0.41 (0.45, 1.27)


0.35

Fig. 4. Markers of volume at baseline and during the study. Top


panel shows measurements by BodPod of weight and total body
volume. Maximal changes in both of these measures were seen at
8 weeks. Middle panel shows seated plasma renin activity and plasma aldosterone. Renin was 2.7-fold higher within 4 weeks of starting chlorthalidone and was maximally stimulated at 8 weeks. Aldosterone on the other hand was maximally stimulated at 4 weeks
and remained stimulated at 8 weeks. However, at 12 weeks, aldosterone was not different compared to baseline. Bottom panel:

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)

CFB fold change (CI)

333 (121,918)

Urine alb/creat ratio nighttime (mg/g cr)

12

Urine alb/creat ratio daytime (mg/g cr)

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)

CFB fold change (CI)

<0.01

CFB (p)

12
Week of study

Urine sodium excretion rate (mEq/d)

14

Central systolic BP (mmHg)

Pulse wave velociy (m/sec)

140

Augmentation index at 75/min heart rate (mmHg)

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
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Discussion

Among subjects with moderate to advanced CKD and


uncontrolled treated hypertension, the major findings of
the study are as follows. (1) Chlorthalidone therapy may
lower BP predominantly systolic over a few weeks. (2) In
contrast to clinic BP measurements, the BP-lowering effects of therapy were better detected by out-of-office BP
monitoring; home BP monitoring showed significant improvement in both systolic and diastolic BP, whereas clinic BP monitoring could not detect improvement in diastolic BP. (3) Lowering of BP is likely evoked by lowering
of extracellular fluid volume (as shown by lowering of
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The other subject, a 59-year-old black man with multiple


strokes in the past, diabetes mellitus, and history of seizures, had a new-onset ischemic stroke. He at a later date
contributed to 4 more serious adverse events: hypotension on 2 occasions and syncope on another 2 occasions.
This subject volitionally stopped all antihypertensive
medications, did not measure BP at home beyond 4
weeks and was the only one to experience a rise from
baseline in systolic and diastolic ambulatory BP at 12
weeks.
Given the pilot nature of the study and the high likelihood of false discovery, subgroup analyses were not performed.

total body volume, lowering of B-type natriuretic peptide


(BNP), and an increase in renin and aldosterone concentration); mitigation of these effects over time suggests
nonvolume mechanisms such as lowering of vascular resistance maintaining the BP-lowering effect. (4) Side effects such as hypokalemia, hyponatremia, hyperuricemia,
transient expected changes in serum creatinine concentration, and orthostatic hypotension are common; such
adverse effects are likely to be seen within a few weeks of
starting drug therapy and therefore close monitoring is
essential. The occurrence of these side effects further confirms the biological activity of chlorthalidone in advanced
CKD. Our data support evidence from earlier studies, albeit of small size and short durations, that thiazide and
thiazide-like diuretics can indeed be effective in people
with moderate to advanced CKD (see online suppl. appendix for details) [1014].
Our study adds to the existing knowledge of the use of
thiazides in advanced CKD in several ways. First, although the duration of intervention was 12 weeks, the
study was the longest reported. Second, it is the only study
to our knowledge that evaluated the effect of thiazides on
BP with the use of the reference standard of 24-hour ambulatory BP monitoring. Third, the study evaluated the
mechanisms of BP reduction. To our knowledge, this is
the first time that the measurement of total body volume
has been evaluated in a clinical trial with diuretics. It offers an objective way of evaluating total body volume, and
we demonstrated highly significant reduction in total
body volume within weeks of starting chlorthalidone.
Coupled with reduction in BNP early and renin/aldosterone a few weeks later, it provides a strong argument that
these drugs probably act by reducing plasma volume.
Fourth, the reduction in albumin excretion rate during
awake and asleep hours suggests that this drug has the
potential to abrogate target organ damage and potentially protect the kidney and the cardiovascular system in the
long term [15]. Fifth, the intense monitoring of subjects
every 4 weeks revealed that the drug is not without adverse effects. It is clear that using this drug will require

close monitoring of BP, renal function, electrolytes, glycemia, and gout.


There are several limitations to this study. First, it was
limited to a small number of subjects and there was no
placebo group. This design was deliberate given that the
intent of the study was to generate preliminary data to
design a future randomized trial. Second, the study included 4 subjects with stage 3B CKD. In such subjects,
thiazides or thiazide-like diuretics are generally recommended. However, 8 of the 12 subjects completing the
study had estimated GFR <30 ml/min/1.73 m2, a stage of
kidney disease where thiazide diuretics are generally considered futile.
In summary, this pilot study addresses an important
question of how to treat poorly controlled hypertension
in CKD with an established but a poorly utilized drug
better. At present, guidelines do not recommend the use
of thiazides in patients with advanced CKD. This pilot
study suggests that chlorthalidone may improve BP control in patients with moderately advanced CKD, but it
might also cause adverse effects. These data may help
design a double-blind, placebo-controlled, randomized
trial in patients with CKD and poorly controlled hypertension. Only then can we evaluate the true risks and
benefits of chlorthalidone such that its place in the management of hypertension in subjects with CKD can be
established.

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.

1 Coresh J, Wei GL, McQuillan G, Brancati FL,


Levey AS, Jones C, Klag MJ: Prevalence of
high blood pressure and elevated serum creatinine level in the United States: findings
from the third National Health and Nutrition
Examination Survey (19881994). Arch Intern Med 2001;161:12071216.

Chlorthalidone in CKD

2 Vasavada N, Agarwal R: Role of excess volume in the pathophysiology of hypertension


in chronic kidney disease. Kidney Int 2003;64:
17721779.
3 http://www.kidney.org/professionals/kdoqi/
guidelines_bp/guide_12.htm.

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.

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