Chlortalidone and Bumetanide in Advanced Chronic Kidney Disease: HEBE-CKD Trial
Phase: PHASE2
Conditions: Renal Insufficiency, Chronic
Sponsor: Hospital General de México Dr. Eduardo Liceaga

 
CHLORTALIDONE 
AND 
BUMETANIDE 
IN 
ADVANCED CHRONIC KIDNEY DISEASE:  
HEBE-CKD TRIAL 
 
NCT03923933 
 
RESEARCH PROTOCOL 
20/03/19 
 
FABIO SOLIS JIMENEZ M.D.  
PRINCIPAL INVESTIGATOR 
LUCIA MONSERRAT PÉREZ NAVARRO 
RESEARCH ASSOCIATE 
RAFAEL VALDEZ ORTIZ M.D. PhD 
RESPONSIBLE INVESTIGATOR  
 
 
 
 
 
 
HOSPITAL GENERAL DE MEXICO "DR. EDUARDO LICEAGA” 
NEFROLOGY DEPARTMENT 
 

CHLORTALIDONE AND BUMETANIDE IN ADVANCED CHRONIC 
KIDNEY DISEASE: HEBE-CKD TRIAL 
 
1. BACKGROUND 
 
1.1 INTRODUCTION 
Nowadays, chronic kidney disease (CKD) is considered a public health problem 
due to its marked increase in prevalence and incidence that currently far exceeds 
estimates made in previous years. (1) One of the main features of CKD is volume 
overload, which is accentuated as the disease progresses and confers multiple 
complications that directly impact the morbidity and mortality of patients suffering 
from it. (2) 
The treatment of choice for volume overload, decrease extracellular fluid (ECF) 
and control of hypertension in CKD, is the use of diuretics, manly loop diuretics. (3) 
However, adaptive changes in the distal nephron secondary to prolonged use of 
loop diuretics, may decrease its effectiveness, so it is necessary to change the 
treatment for a more potent diuretic such as Bumetanide, or add another diuretic 
that acts at a different site from the nephron, as thiazide diuretics. (4) 
Although the effect of thiazides on advanced CKD has been studied, most studies 
are observational and there are no randomized clinical trials with adequate 
statistical power that strongly recommend the use of thiazides in these patients. (5) 
 
 
CONSERVATIVE TREATMENT IN CHRONIC RENAL DISEASE 

 
Although renal function replacement therapy is the treatment of choice in patients 
with stage 5 chronic kidney disease of the KDIGO classification (ERC-5), 
approximately 15% of them prefer not to undergo dialysis and remain in 
conservative treatment in order to reduce symptoms and improve the quality of life. 
(6) (7) Recently, the tendency to recommend replacement therapy to all patients 
with CKD-5 has been questioned because all the evidence focuses exclusively on 
improving survival, leaving aside the quality of life and decisions based on patient 
preferences. (8) (9) While it is true that patients who choose to be treated with 
hemodialysis live longer, there are studies that show that patients who prefer 
conservative treatment have a lower rate of hospital visits, admission and days of 
hospital stay, which means improvement in quality of life and reduction of 
treatment costs (10) However, up to a third of patients have symptoms despite 
conservative treatment, of which the majority described as disabling, are 
secondary to volume overload. This indicates that the current treatment may be 
insufficient. (11) 
 
IMPACT OF VOLUME OVERLOAD ON ERC 
 
Patients with CKD who suffer from volume overload have an increased risk of 
mortality from all causes compared to those patients with CKD who do not suffer 
from it. (12) This is explained by the high cardiovascular risk that these patients 
have, since volume overload has been associated with the development of 
ventricular hypertrophy (13), hypertension and endothelial damage, (14) which 

results in up to 38% of the deaths are attributed to atherothrombotic cardiovascular 
events and 24.3% to arrhythmias. (15) 
It has also been shown that the treatment focused on reducing volume overload 
directly impacts, in addition to reducing all the aforementioned complications, to 
improve the quality of life of the patient with CKD. (16) 
 
DIURETIC RESISTANSE  
 
One of the biggest limitations with the use of diuretics to treat volume overload in 
CKD is diuretic resistance. This is defined as the inability to achieve the desired 
therapeutic reduction of edema when effective doses of the drugs are used. (17) 
There are multiple mechanisms that explain the development of diuretic resistance, 
most include alterations that modify the pharmacokinetics of diuretics and that can 
be resolved by increasing the dose above those recommended in patients who do 
not have CKD. (18)  
Another mechanism described is the development of adaptive changes in the distal 
nephron, triggered by the chronic use of loop diuretics. (19) Under normal 
conditions up to 25% of filtered sodium is reabsorbed in the thick ascending portion 
of the loop of Henle (site of action of loop diuretics) and 5-10% in the distal 
contoured tubule (site of action of thiazide diuretics). (20) However, in patients who 
use loop diuretics chronically, unusual amounts of sodium reach the distal 
contoured tubule, causing epithelial cell hyperplasia and consequently a greater 
sodium reabsorption at this level, which decreases the therapeutic effect of loop 
diuretics. (21) 

 
STUDIES ON THIAZIDES AND CKD 
 
In the decade of the 90’s the first controlled clinical trials were conducted on the 
use of thiazide diuretics, loop and its combination. The first of them in the year 
1994 analyzed 10 patients with glomerular filtration rate (GFR) <15 mL / min / 
1.73m2 and showed that the combined use of a loop diuretic and a thiazide 
increases its natriuretic effect compared to the individual administration (22) The 
following year a similar study was carried out in patients with a mean GFR of 39 in 
which the same result was shown. (23) 
It was until 2005 when the first clinical trial was conducted following a double-blind 
model. In this study, 7 patients were randomized to receive 60 mg of furosemia a 
day or hydrochlorothiazide 25 mg per day for 30 days and it was found that 
individual use of hydrochlorothiazide significantly increased natriuresis and 
decreased an average of 15 mmHg of blood pressure in a month of follow-up, 
without finding benefit of combined use. (24) In 2012, the same work team led by 
Dussol and collaborators, carried out a similar study but with a sample of 23 
patients and a 3-month follow-up, reporting contrasting results with the previous 
trial, since in the latter they did find benefit from combined use of both diuretics. 
(25) In 2014, studies began with chlorthalidone, a molecule that is called thiazide-
like because, although it does not have the chemical characteristics of this 
pharmacological family, it has the same mechanism of action. (26) The first was a 
pilot study, in which 14 patients with uncontrolled hypertension and GFR between 
20 - 45 mL / min / 1.73m2 were recruited, 50 mg of chlorthalidone was given and 

followed up for 12 weeks. It was found that these patients decreased 10.5 mmHg 
of blood pressure, lost 1.5 liters of water and 1.2 kg of weight. (27) Subsequently, a 
study was conducted where 60 patients with uncontrolled hypertension and GFR 
<60 mL / min / 1.73 m2 were recruited and a dose of 25 milligrams of 
chlorthalidone was administered for 8 weeks. At the end of the follow-up, a 
decrease in systolic blood pressure of 19 mm and a weight reduction of 0.88 kg 
was found. (28) 
 
PROBLEM STATEMENT  
 
Chronic kidney disease is a growing health problem. In the disease, as the 
deterioration of renal function progresses, the volume overload becomes more 
evident and in advanced stages it implies high morbidity and mortality, because it 
causes respiratory distress, uncontrolled arterial hypertension, heart failure and 
peripheral edema. Nowadays, the treatment of volume overload in patients with 
advanced CKD is limited to the prescription of loop diuretics, which although they 
are useful drugs in the early stages, as the disease progresses and with its 
constant use, they decrease its effectiveness due to diuretic resistance. This 
means that the current treatment is insufficient. 
 
 
 
 
 

JUSTIFICATION 
 
 
Since the volume overload treatment options in patients with advanced chronic 
kidney disease are limited, it is necessary to seek treatment options different from 
those currently recommended. 
In this sense, thiazide diuretics promise to be a viable option for the treatment of 
volume overload in these patients because they inhibit the loop diuretic resistance 
mechanism created with prolonged use of diuretics. 
Unfortunately, the current evidence regarding the use of thiazide diuretics in 
advanced chronic kidney disease is not conclusive, so it is necessary to perform 
more studies with the appropriate methodology, in order to improve morbidity, 
mortality and quality of life in these patients. 
 
HYPOTHESIS 
 
If, the combination of chlorthalidone and bumetanide is more effective as a 
treatment for volume overload in patients with advanced CKD than the use of 
isolated bumetanide, then, patients with CKD and volume overload who receive 
treatment for four weeks with chlorthalidone and bumetanide , will have a decrease 
in the percentage of total body water greater than 10% compared to those who 
only receive bumetanide and placebo. 
 
 
 

OBJETIVES 
 
To evaluate the effect of bumetanide versus bumetanide plus chlorthalidone as a 
treatment to reduce volume overload in patients with advanced CKD. 
SPECIFIC 
- 
To assess the effect of pharmacological intervention as an antihypertensive 
treatment 
- 
Describe the clinical and biochemical characteristics of the population in 
zero time, at the week and at the end of the treatment. 
- 
Compare the baseline clinical and biochemical variables, during the follow-
up and at the end of the study, according to the type of treatment assigned. 
- 
Evaluate the change in volume overload with the intervention using 
bioimpedancemetry vectors 
- 
To assess the effect of treatment on cerebral natriuretic peptide (BNP). 
- 
Evaluate the occurrence of adverse effects with the treatment implemented. 
 
METHODOLOGY 
 
STUDY DESING 
Randomized, double-blind, placebo-controlled clinical trial. 
 
 
 
 

POPULATION AND SAMPLE SIZE 
 
A statistical power analysis was performed to estimate the sample size, based on 
data from the study entitled "Parallel-group 8-week study on chlorthalidone effects 
in hypertensives with low kidney function" published in the journal Hypertension in 
2014 (n = 60). The effect size of the study was 0.5 considered as medium using 
the Cohen criteria (1988). With an alpha = 0.05 and power = 0.80, the projected 
sample size needed with this effect size was calculated in GPower 3.1.9.2 
considering an ANOVA test of repeated samples between factors, resulting in n = 
32 for this simple comparison between the groups. 
Therefore, our proposed 32 + 8 sample size will be more than sufficient for the 
main objective of this study and should also allow for expected attrition and meet 
our additional objectives of controlling possible mediating factors / moderators / 
subgroup analysis, etc. 
 
SELECTION CRITERIA 
 
- Patients over 18 years of age. 
- Glomerular filtration rate <30 ml / min determined by the CKD-EPI formula. 
- Residual uresis of at least 100ml per day. 
- Without replacement treatment of renal function (peritoneal dialysis or 
hemodialysis). 
- Patients who after explaining in detail the benefits of renal replacement therapy, 
do not wish to undergo it. 

- Current treatment with a loop diuretic for at least one month prior to contact. 
- That they sign informed consent and agree to participate in the study. 
 
EXCLUSION CRITERIA 
 
- Patients with suspected or documented infection 
- Sulfate allergy 
- Established diagnosis of heart failure with reduced ejection fraction (less than 
40%). 
- Cognitive disorders 
- Other comorbidities that compromise renal flow (malignant neoplasia, liver failure 
and respiratory failure.) 
- Pregnant patients 
 
ELIMINATION CRITERIA 
 
- Patients who do not attend a follow-up consultation 
- Patients who during the follow-up request to start renal replacement therapy 
- Patients who, during follow-up, begin dialysis or hemodialysis due to dialysis 
emergency 

DEFINITION OF VARIABLES 
VARIABLE CONCEPTUAL 
DEFINITION 
OPERATIONAL DEFINITION 
VARIABLE 
TYPE 
MEASUREMENT 
SCALE 
INDICATOR 
Age. 
Time that has lived 
a person or another 
living being counting 
from birth. 
Its 
measurement 
will 
be 
established in years based on the 
years completed at the time of 
patient selection. 
Quantitative 
discrete. 
Years. 
It 
will 
be 
considered 
number 
of 
years. 
Mean ± SD 
Gender 
Set of people or 
things 
that 
have 
common 
general 
characteristics. 
It will be established based on 
physical examination. 
Qualitative 
dichotomous. 
Man, woman. 
Absolute 
and relative 
frequency of 
the 
population in 
2 
gender 
categories 
(male 
and 
female). 
Systemic 
blood 
It is the pressure 
exerted by the blood 
It will be established based on the 
sphygmomanometer socket. It will 
Continuous 
quantitative 
mmHg 
Absolute 
and relative 

pressure 
against the walls of 
the arteries as the 
heart pumps blood 
to your body 
be considered hypertensive one 
whose values are greater than 
140/90 mmHg 
frequency of 
patients with 
HTAS 
Mean ± SD 
Edema 
of 
pelvic 
limbs 
Accumulation 
of 
fluids 
at 
the 
subcutaneous 
interstitial level 
It will be established according to 
patient clinic 
Grade I: minimum 
Grade II: 15 seconds 
Grade III: 1 minute 
Grade IV: 2 to 5 minutes 
Qualitative 
ordinal 
Clinic based on 
Godette 
Grade 
I: 
minimum 
Grade II: 15 
seconds 
Grade III: 1 
minute 
Grade IV: 2 
to 5 minutes 
Serum 
creatinine 
Creatinine 
is 
an 
organic 
compound 
generated from the 
degradation 
of 
creatine, which is a 
useful nutrient for 
muscles. 
Creatinine measurement is the 
simplest way to monitor kidney 
function. 
Quantitative 
continues.  
mg/dl. 
Mean ± SD 

Serum 
urea 
It is the end result of 
protein metabolism. 
It is formed in the 
liver 
from 
the 
destruction 
of 
proteins. 
It will be taken at your first 
consultation, then a week and at 
the end of the study. 
Quantitative 
continue 
mg/dl. 
Mean ± SD 
Serum 
sodium 
It is the positive ion 
that is found mainly, 
outside the cells, in 
the extracellular 
fluids of the human 
body. 
It will be taken at your first 
consultation, then a week and at 
the end of the study. 
Quantitative 
continue 
meq/l 
Mean ± SD 
Serum 
chlorine 
It has the ability to 
enter and leave the 
cells 
along 
with 
sodium 
and 
potassium 
or 
combined with other 
major cations such 
as calcium.  
It will be taken at your first 
consultation, then a week and at 
the end of the study. 
Quantitative 
continue 
mg/dl 
Mean ± SD 

Serum 
potassium 
It is the positive ion 
that 
is 
found 
primarily within the 
cells of the human 
body. 
The 
concentration in the 
cells is 30 times 
higher 
than 
the 
extracellular space 
and 
serves 
to 
maintain 
the 
electrical charge of 
the cell membrane. 
It will be taken at your first 
consultation, then a week and at 
the end of the study. 
Quantitative 
continue 
mg/dl 
Mean ± SD  
Uric acid 
It is a chemical that 
is created when the 
body breaks down 
purines. Most of it 
dissolves 
in 
the 
blood and travels to 
the kidneys. 
It will be taken at your first 
consultation, then a week and at 
the end of the study. 
Quantitative 
continue 
mg/dl 
Mean ± SD 

Albumin 
Albumin is a protein 
that is found in a 
large proportion in 
the blood plasma, 
being 
the 
main 
protein in the blood, 
one of the most 
abundant in being. 
It will be taken at your first 
consultation, then a week and at 
the end of the study. 
Quantitative 
continue 
g/l. 
Mean ± SD 
Glomerular 
Filtration 
Rate. 
It is the volume of 
fluid filtered per unit 
of time from the 
renal 
glomerular 
capillaries into the 
Bowman's capsule. 
It will be taken at your first 
consultation, then a week and at 
the end of the study. 
Quantitative 
continue 
ml/min/1.73 
Mean ± SD 
Sodium 
excretion 
fraction 
Represents 
the 
relationship 
between 
sodium 
fractions 
excreted 
and filtered by the 
kidneys 
It will be taken at your first 
consultation, then a week and at 
the end of the study. 
Quantitative 
continue 
 
mmoL/day 
 
Mean ± SD 

Weight 
The 
mass 
or 
amount of weight of 
an individual. It is 
expressed in units 
of 
pounds 
or 
kilograms 
Weight in kilograms of the patient. 
The measurement will be done 
without shoes or heavy clothing, 
and preferably at least two hours 
after eating food. 
Quantitative 
continue 
Kilograms  
Mean ± SD 
Height 
The 
perpendicular 
distance 
between 
the 
transverse 
planes of the Vertex 
point 
and 
the 
bottom of the feet. 
It will be measured with the 
subject standing, with the heels, 
buttocks and the upper back in 
contact with the scale, with the 
head in Frankfurt plane. 
Quantitative 
continue 
Centimeters 
Mean ± SD  
 
 
 
Body mass 
index (BMI 
kg / m2) 
It 
describes 
the 
relative weight for 
height 
and 
is 
significantly 
correlated with the 
total fat content of 
the individual. 
It will be obtained through the 
measurement of weight and height 
with the following formula: 
BMI (kg / m2): weight in kilograms 
/ height in m2 
Quantitative 
continue 
kg/m2 
Mean ± SD  
 

Uresis 
It is defined as the 
amount 
of 
urine 
produced in a given 
time 
It will be obtained from the daily 
collection of urine by the patient 
on an outpatient basis. 
Quantitative 
continue 
Milliliters 
Mean ± SD  
 
Ballast 
Force that opposes 
the passage of a 
current because of 
a conductor, also 
given in this vessel 
by the polarity of 
cell membranes. Mi 
of the conductivity 
of cell membranes 
The electrical properties of the 
body will be analyzed at mono 
frequency 
(50 
kHz) 
and 
the 
reactance 
value 
of 
the 
RJL 
equipment will be taken. 
Quantitative 
continue 
 
Mean ± SD  
 
Phase 
angle 
Tangent 
arc 
between resistance 
and reactance in a 
series 
or 
parallel 
circuit 
The electrical properties of the 
body will be analyzed at mono 
frequency (50 kHz) and the phase 
angle value of the RJL equipment 
will be taken. 
Quantitative 
continue 
 
Mean ± SD  
 

PROCEDURE 
 
During the period between June and August of the year 2019, patients from the 
external nephrology clinic of the General Hospital of Mexico will be selected 
who have GFR less than 30 mL / min / 1.73 m2 estimated by CKD-EPI and will 
be offered to perform a bioimpedancemetry, where those patients who meet 
volume overload criteria will be offered to participate in the study. 
Once they agree to participate in the study, the consent is signed and through a 
randomization 
process 
carried 
out 
through 
an 
online 
program 
(https://www.graphpad.com/quickcalcs/randomize1.cfm) 
a 
group 
will 
be 
assigned. This group will be known as A or B, without the investigator or the 
patient knowing which will be the intervention and which the control group. 
Subsequently they will be granted an appointment in order to obtain the initial 
measurements. 
Appointment 1 (day 1): Patients will be scheduled at 8:00 a.m. with 8-hour fast 
and 24-hour urine collection, to the nephrology service where a brief 
questionnaire will be made in order to obtain demographic data and personal 
background of importance for the trial. Anthropometric measurements will be 
made (weight, BMI size) and blood pressure measurement will be performed 
after asking the patient to remain in a sitting room and in a quiet environment for 
15 minutes, and without having consumed any substance that modifies the 
pressure taking. Measurements of both arms were taken and the average of 
both will be recorded. 
Subsequently, a bioimpedancemetry study will be carried out again, for which 
patients were asked to shed any metal object. Finally, they will be given the 

corresponding medicine for the first week of follow-up, in closed and labeled 
packages for the assigned group. That same day, they will be granted a 
nutrition consultation where they were given nutritional recommendations on the 
consumption of sodium and water. Finally they were explained by probable side 
effects and alarm data with which they will be able to go to the emergency 
department, a new appointment will be scheduled within a period of 7 days and 
they will be asked to go to the central laboratory where trained personnel will be 
responsible for carrying out the Sample collection and processing. 
Appointment 2 (day 7): The same procedure and measurements were 
performed, the corresponding medication was granted for the rest of the follow-
up. A new appointment was granted within a period of 3 weeks. 
Appointment 3 (day 28): The same procedure was performed and the final 
measurements were taken. 
 
WORKPLACE 
 
Patient recruitment will be carried out in the outpatient department of the 
nephrology service. The citations of the essay will be carried out in the research 
section in nephrology and nutrition, located inside the nephrology service. 
Sampling and processing were performed in the central laboratory. All within the 
facilities of the General Hospital of Mexico "Eduardo Liceaga". 
 
 
 
 

INTERVENTIONS 
 
Patients will be randomized to two groups (control and intervention), which will 
be blinded to the patient and the researcher throughout the study and will 
consist of the following: 
1. Control: Bumetanide plus placebo 
2. Intervention: Bumetanide plus Chlorthalidone 
The initial dose of bumetanide will be 3 milligrams, which will be administered 
as follows: 2 milligrams at 10:00 a.m. and 1 milligram at 4 p.m. 
The initial dose of Chlorthalidone will be 50 milligrams, which will be 
administered as follows: 50 milligrams at 12 p.m. 
After a week of follow-up, if the patients have no adverse effect, the dose of the 
medication will be increased, as follows: 
Bumetanide 4 milligrams, which will be administered as follows: 2 milligrams at 
10:00 a.m. and 2 milligrams at 4 p.m. 
Chlorthalidone 100 milligrams, which will be administered as follows: 50 
milligrams at 12 p.m. and 50 milligrams at 6 p.m. 
Unmanaged doses of chlorthalidone to the control group will be replaced by 
placebo capsules, identical (sight and touch) to chlorthalidone capsules. The 
placebo will consist of cornstarch (powder). 
 
 
 
 
 

STATISTICAL ANALYSIS 
 
Data capture will be done in Excel, which will be reviewed and validated by a 
third party to rule out errors in the capture. Subsequently, the information will be 
exported to the SPSS statistical program. 
Parametric and non-parametric statistics will be performed depending on the 
distribution of variables. Average and standard deviation will be applied for 
continuous variables, with Student's t-test, and X2 test for nominal variables, 
considering a value of p <0.05, with 95% CI as statistical significance. 
 
ETHICAL AND BIOSECURITY  
 
The study is considered to be greater than the minimum risk for the patient, 
since it was subjected to blood sampling; Each patient will be fully explained 
that the adverse effects that could occur if they were included in the study were: 
hypokalemia, hyperuricemia, increased azoa, impaired renal function, 
hypotension, dizziness, vomiting, even urgent dialysis requirement. 
All admitted patients must sign an informed consent where the objective of the 
study will be described and their participation. 
The protocol was approved by the research committee and the research ethics 
committee in March 2019 and granted the approval number: DI / 19/105-B / 
03/018. 
 
 
 

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