Improving the Hemodynamic Profile Of Chronic Renal Patients by Use of Bioimpedance
Conditions: Chronic Kidney Failure
Sponsor: Ziekenhuis Oost-Limburg

Research Protocol  
 
HORUZ study 
 
Investigating the Hemodynamic profile 
Of chronic Renal patients by Use of 
bioimpedance 
 
Melanie K. Schoutteten 
 
Willemijn Groenendaal  
Chris van Hoof  
Jeroen P. Kooman 
Jacques Peeters 
Christophe JP. Smeets 
Pieter M. Vandervoort  
 
NCT number: not yet available 
3th December 2019 
 
 
Confidentiality statement 
The information contained in this document is the property of the Limburg Clinical Research Center 
(UHasselt-Future Health ZOL), or under its control, and therefore provided to you in confidence as a 
(potential) participant of this interventional study, potential investigator or consultant, for review by 
you, your staff and an applicable Independent Ethics Committee. 

Investigating the Hemodynamic profile Of chronic Renal patients by Use of Bioimpedance 
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Coordinating investigator: 
 
M.K. Schoutteten MD 
Principal investigator:  
 
P.M. Vandervoort MD PhD 
Principal local investigator per site: 
 
 
Name Site 1: Ziekenhuis Oost-Limburg, Schiepse Bos 6, 3600 Genk, België 
- 
Name local researcher: Melanie Schoutteten 
- 
E-mail local researcher: melanie.schoutteten@uhasselt.be 
Coordinates contact person: 
- 
Name site: Ziekenhuis Oost-Limburg 
- 
Name contact person: Dr. Melanie Schoutteten 
- 
E-mail contact person: melanie.schoutteten@uhasselt.be 
- 
Telephone contact person: 0032 (0) 89 21 20 59 
 
 
Sponsors (in Dutch: verrichter/opdrachtgever):  
Ziekenhuis Oost-Limburg, Schiepse Bos 6, 3600 Genk, België 
 
 
Laboratory sites: 
Ziekenhuis Oost-Limburg, Schiepse Bos 6, 3600 Genk, België 
 
 
 

Investigating the Hemodynamic profile Of chronic Renal patients by Use of Bioimpedance 
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PROTOCOL SIGNATURE SHEET 
 
Name
 
Signature
Date
Coordinating Investigator
M.K. Schoutteten MD 
 
Removed on request of Clinicaltrails.gov
25.10.2019
Principal Investigator
P.M. Vandervoort MD PhD 
 
Removed on request of Clinicaltrails.gov
 
25.10.2019
 
 
 

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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ---------------------------------------------------------------------------------------------  
SUMMARY ---------------------------------------------------------------------------------------------------------------  
INTRODUCTION AND RATIONALE ----------------------------------------------------------------------------------  
OBJECTIVES --------------------------------------------------------------------------------------------------------------  
STUDY DESIGN ----------------------------------------------------------------------------------------------------------  
STUDY POPULATION --------------------------------------------------------------------------------------------------  
1. Population 
2. Inclusion criteria 
3. Exclusion criteria 
4. Sample size calculation 
METHODS ----------------------------------------------------------------------------------------------------------------  
1. Study parameters/endpoints 
2. Randomization 
3. Study procedures 
4. Withdrawal of individual subjects 
5. Replacement of subjects withdrawn from treatment 
6. Premature termination of the study 
SAFETY REPORTING ---------------------------------------------------------------------------------------------------  
1. Temporary halt for reasons of subject safety 
2. Adverse and serious adverse events 
2.1 Adverse event (AE) 
2.2 Serious adverse event (SAE) 
2.3 Suspected unexpected serious adverse reactions (SUSAR) 
3. Follow-up of adverse events 
4. Data Safety Monitoring Board (DSMB) 
STATISTICAL ANALYSIS ------------------------------------------------------------------------------------------------  
ETHICAL CONSIDERATIONS ------------------------------------------------------------------------------------------  
1. Regulation statement 
2. Recruitment and consent 
3. Objection by minors or incapacitated subjects 
4. Benefits and risks assessment, group relatedness 
5. Compensation for injury 
6. Incentives 

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ADMINISTRATIVE ASPECTS AND PUBLICATION ----------------------------------------------------------------  
1. Handling and storage of data and documents 
2. Amendments 
3. Annual progress report 
4. End of study report 
5. Public disclosure and publication policy 
REFERENCES -------------------------------------------------------------------------------------------------------------  
APPENDIX  ---------------------------------------------------------------------------------------------------------------  
 
 

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LIST OF ABBRIVIATIONS AND RELEVANT DEFINITIONS 
 
BCM 
 
body composition monitor 
BIS 
 
bioimpedance spectroscopy 
BP 
 
blood pressure 
CKD 
 
chronic kidney disease 
CRP 
 
C-reactive protein 
CrCl 
 
creatinine clearance 
CrUrCl   
mixed creatinine and urea clearance 
CV  
 
cardiovascular 
DSMB  
data safety monitoring board 
ECG 
 
electrocardiography 
ECV 
 
extracellular volume 
ECW 
 
extracellular water 
EDD 
 
end diastolic diameter 
eGFR   
estimated glomerular filtration rate 
ESRD 
 
end stage renal disease 
FO 
 
fluid overload 
FS 
 
fluid status 
ICD 
 
implantable cardiac defibrillator 
ICV 
 
intracellular volume 
ICW 
 
intracellular water 
IVS 
 
interventricular septum 
LTI 
 
lean tissue index  
LVEF 
 
left ventricle ejection fraction 
LVH 
 
left ventricular hypertrophy 
LVMI 
 
left ventricle mass index 

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METC  
medical research ethics committee, in Dutch: medisch ethische toetsing commissie 
MRI 
 
magnetic resonance imaging 
OH 
 
overhydration 
PCR 
 
urine protein-to-creatinine ratio 
PM  
 
pacemaker 
PWT 
 
posterior wall tickness 
RCT 
 
randomized controlled trial 
RRF 
 
residual renal function 
RWT 
 
relative wall thickness 
(S)AE 
 
(serious) adverse event 
Sponsor 
The sponsor is the party that commissions the organization or performance of the 
research, for example a pharmaceutical company, academic hospital, scientific 
organization or investigator. A party that provides funding for a study, but does not 
commission it, is not regarded as the sponsor, but referred to as a subsidizing party. 
SF36 
 
short form 36 questionnaire 
SUSAR  
suspected unexpected serious adverse reaction 
TBW  
 
total body water 
Tx 
 
transplantation 
 

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SUMMARY 
Rationale: Preservation of residual renal function is independently associated with reduced mortality 
and improved outcomes in patients with end stage renal disease. Fluid status and blood pressure 
influence the rate of kidney function decline early in the course of chronic kidney disease (CKD). The 
technique of bioimpedance spectroscopy (BIS) can offer valuable information on fluid dynamics and 
body composition, in addition to standard care. 
Objectives: This study aims to investigate the role of thoracic and whole body BIS in the hemodynamic 
profile of patients with CKD. The primary objective is to associate the BIS-determined fluid status [fluid 
overload (FO) versus non-FO] with kidney function decline in patients with CKD stage 3 (CKD-EPI 59-
30ml/min), 4 (CKD-EPI 29-15ml/min) and 5 (CKD-EPI < 15 ml/min). The secondary objective is to 
identify the clinical factors associated with FO during a longitudinal follow up. Secondary outcomes of 
interest are the central volume status (measured by echocardiography and thoracic BIS in combination 
with photoplethysmography), the cardiac systolic and diastolic function, CV events, hospitalizations, 
inflammatory- and nutrition status, and quality of life, between CKD stages 3, 4 and 5 and compare 
them to an age- and sex- matched healthy control group. 
Study design: An non-randomized intervention study with a longitudinal follow up of the cohort and 
some cross-sectional analysis. 
Study population: Prevalent CKD patients stage 3 - 5 not on dialysis and an age- and sex- matched 
healthy control group, will be included during a period of 18 months and prospectively followed up 
over a period of 12 months. 
Intervention: During each study visit BIS- and blood pressure measurements will be performed, and 
blood- and urine samples will be taken in each subject.  
Main study parameters/endpoints:  
 

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- 
Whole body fluid status, measured by whole body BIS 
- 
Central volume status, measured by thoracic BIS, photoplethysmography and 
echocardiography 
- 
Blood pressure, measured by automatic oscillometric device 
- 
Determinants of BIS signal in CKD population: gender, comorbidities 
- 
Rate of kidney function decline, determined by eGFR CKD-EPI, mixed urea and creatinine 
clearance, and urine volume measured by 24h urine collection 
 
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness:  
- 
BIS and blood pressure measurements will be achieved by non-invasive techniques which 
pose a minimal burden to the patient.  
- 
Blood sampling will as much as possible coincide with regular blood samplings for clinical 
purposes. The risk of venipuncture-related complications is considered moderate when 
performed in the non-dominant arm, as this can influence negatively on a future vascular 
access. 
- 
All subjects undergo echocardiography. Analysis of the echocardiography will be done during 
follow-up period. Aberrant results will be discussed with an expert. 
- 
All study-related costs will not be charged to the patient. 
 

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INTRODUCTION AND RATIONALE 
Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function, present for 
more than 3 months, with implications for health.1 Classification of CKD is structured according to the 
estimated glomerular filtration rate of creatinine (eGFR) and albuminuria (Figure 1). CKD is a major 
health problem and continues to rise globally. Prevalence of CKD is estimated at 11-13% of the adult 
population, of which 0.1% results in end stage renal disease (ESRD, defined as eGFR < 15ml/min or the 
need for renal replacement therapy).2,3 As well in developed as in developing countries, aging and the 
higher rate of cardiovascular (CV) events in the general population explains the increase of CKD.2 Not 
only prevalence, but also mortality in CKD population is mainly determined by CV comorbidities.4,5 
Besides the Framingham classics, novel CV risk factors such as fluid status (FS), malnutrition, 
inflammation and impaired kidney function itself have gained importance.4,6,7 
 
Figure 1 Classification of chronic kidney disease according to glomerular filtration rate and albuminura. Colors represent the 
cardiovascular prognosis. Green: low risk; yellow: moderately increased risk; orange: high risk; red: very high risk. 
 

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As glomerular function, and salt- and water excretion decline, extracellular fluid expansion develops, 
causing hypervolemia.8 Fluid overload (FO) in Asian populations with CKD stages 3-5 is cause and 
consequence of renocardiac complications,6 leads to progression of CKD,9 and is associated with 
increased risk for all-cause mortality or CV morbidity.10 
Hypervolemia and hypertension in CKD population represent the hemodynamic triggers to formation 
of left ventricular hypertrophy (LVH), respectively as increased preload and increased afterload.11 
Prevalence of LVH is estimated at 45-79% in the predialysis group,12-15 and rises to 75-85% after start 
of HD.13,16 LVH leads to left ventricle stiffness and this results in diastolic heart failure.17 LVH is 
independently associated with increased mortality and CV events.18-20  
FO is one of the multifactorial pathophysiological causes of chronic systemic inflammation in the CKD 
population. Inflammation, assessed by C-reactive protein, serum-albumin or ferritin levels, and 
malnutrition accelerate the generalized atherosclerosis in advanced CKD, leading to CV complications 
and progression of kidney function decline.21-23 
Kidney function decline is associated with an exponential increase in risk of death, left ventricle mass 
index, blood pressure (BP), CV events and hospitalization, and reduced removal of uremic toxins, 
independent from classical risk factors.4,7,24 
Based on the above mentioned associations between risk factors and outcome in the CKD population, 
the question rises what specific hemodynamic profile (including FS and BP) is associated with a severe 
CV comorbidity cascade leading towards more CV events, hospitalizations, rapid decline of kidney 
function and acceleration of the initiation of renal replacement therapy. 
 
 
 

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Assessment of the hemodynamic profile, cardiac- and kidney function in predialysis patients 
During progression to ESRD, accumulation of fluid occurs silently. Clinical assessment of FS is not 
straightforward in CKD patients. While prevalence of overhydration in CKD stages 3 - 5 is estimated at 
50%,6,25,26 20% of these patients is non-edematous at clinical examination.6 The gold standard to 
measure fluid distribution in the human body is dilution of deuterium and sodium bromide solution 
for extracellular water (ECW) and total body potassium for intracellular water (ICW). However, these 
techniques are invasive and not applicable in routine clinical practice. Bioimpedance spectroscopy 
(BIS) is a noninvasive and easy-to-use technology in fluid assessment. Some BIS instruments have been 
validated in hemodialysis patients against dilution methods.27-30 BIS provides the possibility to estimate 
total body water (TBW), extracellular volume (ECV), intracellular volume (ICV), fat-free mass, fat mass 
and muscle mass.31,32 Also, blood volumes can be accurately estimated by BIS and can optimize BP 
treatment.33 
In contrast to the hemodialysis population, the clinical use of BIS in fluid management of non-dialysis 
CKD stages 3 - 5 is less frequently implemented. Observational research has shown that BIS identifies 
FO in 20% of non-edematous patients with CKD stages 3 - 5, and showed impairment of body 
composition in absence of overt signs of malnutrition.6,25 BIS-derived parameters as FO or lean tissue 
mass are associated with more rapid decline in residual renal function (RRF), higher CV morbidity and 
mortality compared to euvolemic CKD-patients.9,10,26 
The combination of electrocardiography (ECG) and echocardiography is the easiest and cheapest 
reliable method to evaluate LVH. However, the gold standard is magnetic resonance imaging (MRI), 
this is not widely used because of individual MRI tolerance and costs. 
Clinical evaluation of kidney function decline is currently performed by longitudinal follow up of serum 
creatinine concentration and eGFR of creatinine (expressed by the eGFR CKD-EPI equitation), and 
albuminuria.1,34 However, due to the variability of creatinine production and tubular secretion, eGFR 

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or creatinine is often precluded from clinical trials. Creatinine clearance [creatinine clearance (CrCl) = 
(urine creatinine concentration x urine volume) / serum creatinine concentration] or mixed creatinine 
and urea clearance (CrUrCl) improves accuracy.35 
 
Hemodynamic management of CKD progression and CV morbidities in predialysis patients 
Prevention of progression to ESRD and CV complications in predialysis patients is currently addressed 
by targeting the classical risk factors (BP and glycemic control, salt intake and dietary advice, smoking 
cessation, albuminuria, physical activity). Management of novel CV risk factors like FS is not 
incorporated in the KDIGO CKD guidelines.1 Furthermore, the recommendation to keep BP in CKD 
patients ≤ 140 mmHg systolic and ≤ 90 mmHg diastolic because of reduced risk of CV mortality and CV 
events, is based on office measurements.1,36 Home-measured BP is more strongly associated with LVH 
and is a stronger predictor of CV risk than office BP.37-40 Also, there is a lack of evidence for the optimal 
medical management of heart failure in ESRD population.1 The effect of BP control on LVH in CKD 
patients has not been clearly evaluated yet.36,41  
Preservation of RRF in hemodialysis patients is associated with prolonged survival and reduction in CV 
morbidities. Hence, we should move forward in our attempts to preserve renal function and start with 
innovative interventions in the predialysis period. 
 
Hypothesis 
We hypothesize that FO assessed by BIS is associated with a more rapid decline in RRF and that the 
follow up of the thoracic BIS signal is an equivalent predictor for cardiac function compared to 
echocardiography. Eventually we hope that our intervention might lead to a better hemodynamic 

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management, deceleration of kidney function decline and reduction of CV morbidity and mortality in 
CKD population, although this is beyond the scope of this research study. 
In order to investigate this hypothesis, we want to perform the HORUZ study. We are interested in the 
fluid status, BP and thoracic BIS signal of patients with CKD 3 – 5, not on dialysis. We aim to provide 
more evidence to further support the frequent use of BIS in diagnostic guidelines of patients with CKD.

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OBJECTIVES 
The primary objective of the HORUZ study is to associate fluid status with kidney function decline in 
patients with CKD stage 3 (CKD-EPI eGFR 60-30ml/min), 4 (30-15ml/min) and 5 (< 15 ml/min) and 
compare them to an age- and sex- matched healthy control group. Primary outcome is the mean eGFR 
decline which will be compared between the FO-group and the non-FO-group.   
The secondary objective is to identify the clinical factors associated with FO during a longitudinal follow 
up. Secondary outcomes of interest are the central volume status (measured by echocardiography and 
thoracic BIS in combination with photoplethysmography), the cardiac systolic and diastolic function, 
CV events, hospitalizations, inflammatory- and nutrition status, and quality of life, between CKD stages 
3, 4 and 5 and compare them to an age- and sex- matched healthy control group. 
 
STUDY DESIGN 
The HORUZ study is a non-randomized trial with intervention of regular BIS- and BP measurements, 
blood- and urine sampling. Prevalent patients with CKD stages 3, 4 and 5 and an age- and sex- matched 
healthy control group will be included. Inclusion period will last 18 months and CKD-patients will be 
followed up for 12 months. 
 
 

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STUDY POPULATION 
1. Population 
206 patients with CKD stages 3-5 will be included from the outpatient clinic of Ziekenhuis Zuid-Oost 
Limburg in Genk (Belgium). 
A healthy control group for the cross-sectional part will be recruited through visitors and/or personnel 
of Ziekenhuis Oost-Limburg in Genk (Belgium). 
 
2. Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet the following criteria: 
- 
Prevalent non-dialysis patients with eGFR < 60 ml/min (for CKD subjects) 
- 
Age > 18 years 
- 
Signed informed consent 
 
3. Exclusion criteria 
A subject who meets any of the following criteria will be excluded from participation in this study: 
- 
Acute kidney injury 
- 
eGFR < 20ml/min directly post-nephrectomy 
- 
Clinical conditions affecting BIS measurements: limb amputation, impaired skin integrity, 
brain stimulator, pacemaker with low threshold or unipolar pacemaker. 
- 
Clinical conditions affecting body composition: liver cirrhosis, active infectious disease or any 
acute CV event (defined as cerebrovascular event, myocard infarction, decompensatio cordis) 
during the 3 months before screening for inclusion 
- 
Pregnancy 

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- 
Not able to sign informed consent 
 
4. Sample size calculation 
The primary outcome parameter is the mean eGFR decline which will be compared between the FO-
group and the non-FO-group. We hypothesize that the mean difference between eGFR between these 
two groups will be 2 µmol/ml/year. Because the study of Levin et al. does not report a SD, we take the 
SD of the MDRD study1: 4.7 µmol/ml/year1,42,43. In order to show an alpha of 0.05 and a power of 0.8, 
at least 86 patients would be needed per group. In order to correct for drop-outs, at least 103 patients 
per group have to be included. 

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METHODS 
1. Study parameters/endpoints 
1.1 Demographic and clinical data 
The prevalent CKD stage 3 – 5 population will be screened by the researcher. After verification of the 
in- and exclusion criteria, eligible patients will be invited to participate the HORUZ study, with approval 
of their treating nephrologist. After signing the informed consent, data at baseline and during follow-
up visits will be collected on paper clinical report forms (Table 1). Hypertension is defined as an office 
BP ≥ 140/90 mmHg or home BP ≥ 130/80 mmHg, or current medication for hypertension.1 Diabetes 
mellitus will be assumed to be present in patients who report use of insulin and/or oral hypoglycemic 
agents. CV diseases include coronary artery disease, as documented by coronary angiography or a 
history of myocardial infarction, congestive heart failure, cerebrovascular accident, or known 
peripheral vascular disease. Fluid assessments, including BIS measurements, will be recorded on the 
HORUZ registration form (Appendix). 
The healthy controls included for the cross-sectional analysis will only be followed according to visit 0 
and 1. 
Table 1 Schedule of the main data to collect in CKD subjects. 
 
Baseline 
Visit 0 
Month 1
Visit 1 
Month 3
Visit 2 
Month 6
Visit 3 
Month 9
Visit 4 
Month 12/ end of study
Visit 5 
 
Consent
X
 
Demographics:
Age (y) 
Gender 
Height (cm) 
Smoking status 
Etiology CKD 
Hypertension 
Diabetes 
CV disease 
Tx list 
X
eGFRcreat
x
x
x
x
x
x
CrUrCl
x
x
x
x
x
24h urine
x
x
x
x
x

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BP 
 
x
x
x
x
x
ECG
 
x
x
x
x
x
Echo cor
 
x
x
CV events
 
x
x
x
x
x
Hospitalization
 
x
x
x
x
x
Medication
x
x
x
x
x
Whole body BIS
 
x
x
x
x
x
Thoracic BIS
 
x
x
x
x
x
SF36
 
x
x
Adverse event
 
x
x
x
x
x
Abbreviations: BIS, bioimpedance spectroscopy; BP, blood pressure; CKD, chronic kidney failure; Creat, creatinine; CrUrCl, mixed creatinine 
and urea clearance; CV, cardiovascular; ECG, electrocardiography; M, month; SF36, short form 36 questionnaire; Tx, transplantation. 
 
1.2 Primary endpoint 
The association between fluid status and kidney function decline in patients with CKD stage 3 (CKD-EPI 
60-30ml/min), 4 (CKD-EPI 30-15ml/min) and 5 (CKD-EPI < 15 ml/min) is the primary objective of the 
HORUZ study.  
The primary endpoint is the mean eGFR decline which will be compared between the FO-group and 
the non-FO-group. BIS-measured FO will be expressed as overhydration (OH) normalized to ECW and 
noted as a percentage of ECW (OH/ECW).6,44 FO is defined as an OH/ECW ≥ 7% (or an absolute OH ≥ 
1.1 L).45  
Rate of kidney function decline will be assessed by the slope in eGFRcreat CKD-EPI (see formula below), 
defined as the regression coefficient between eGFRcreat and time, in units of mL/min/1.73m2 per year. 
At least 3 eGFRcreat values are required to evaluate eGFRcreat slope. All eGFRcreat CKD-EPI will be 
uniformly calculated in the laboratory. eGFRcreat decline is assessed by changes in eGFR over time. Rapid 
eGFRcreat decline is defined as the quartile with the steepest eGFR slope (eGFRcreat decline > 
3mL/min/1.73m2 per year).9 

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eGFRcreat = 141 × min(Screat/κ, 1)α × max(Screat /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black] 
Screat (standardized serum creatinine) = mg/dL 
κ = 0.7 (females) or 0.9 (males) 
α = -0.329 (females) or -0.411 (males) 
min = indicates the minimum of Screat/κ or 1 
max = indicates the maximum of Screat/κ or 1 
age = years 
Average CrUrCl will be determined by creatinine and urea measurements in blood- and urine samples 
(Table 2). 
Residual urine output (mL per 24h) will be collected every study visit and analyzed on volume, urea, 
creatinine, sodium, osmolarity and albumin/creatinine ratio (ACR) (Table 2).  
Time to renal replacement therapy will be recorded. 
 
1.3 Secondary endpoints 
The secondary objective is to identify the clinical factors associated with FO during a longitudinal follow 
up. Secondary outcomes of interest are the central volume status (measured by echocardiography and 
thoracic BIS in combination with photoplethysmography), BP, the cardiac systolic and diastolic 
function, CV events, hospitalizations, inflammatory- and nutrition status, and quality of life, between 
CKD stages 3, 4 and 5. 
1. Cardiac function: Electrocardiography and echocardiography (see point 3.3) will be scheduled 
at baseline, and at 12 months or at end of study visit.  
2. Thoracic BIS values: a wearable device from Imec Eindhoven will be used to measure thoracic 
BIS values in combination with photoplethysmography and cardiopulmonary index. 
3. Blood pressure: patients will be asked to take BP measurements at home three times a week 
twice daily with an automatic BP monitor. Mean arterial pressure corrected for heart 

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frequency will be calculated. BP measurements can be transmitted to the researcher by use of 
the local Dharma platform.  
4. CV events: CV events defined as hospitalization for coronary disease, heart failure, stroke or 
peripheral artery disease will be recorded during follow-up. 
5. Hospitalization rate – and indication: hospitalization rate and – indication will be listed. 
6. Inflammatory- and nutrition status: CRP, ferritin and albumin will be determined every visit 
(Table 2). Fat tissue mass and lean tissue mass will be analyzed by BIS measurements. 
7. Quality of Life assessment: SF36 questionnaire will be filled in at baseline and end of study 
visit. 
Table 2 Overview of parameters evaluating kidney function, renal metabolism and inflammation in HORUZ study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assay
Material
Standard care
Frequency
Residual renal function
Urea
Plasma/serum
yes
Every study visit
 
Creatinine
Metabolism and electrolytes
Hemoglobin
Plasma/serum
yes 
Every study visit
Sodium
Potassium
Bicarbonate
Phosphate
Calcium
NT-proBNP
No
Every study visit
Inflammation
C-reactive protein
Plasma/serum
yes
Every study visit
 
Leucocytes
Albumin
Ferritin
24 urine collection
Quantity
Urine
No
Every study visit
 
Creatinine
Urea
Sodium
Albumin
Protein

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2. Randomization 
Not applicable. 
 
3. Study procedures and interventions 
After inclusion during the baseline visit, a research visit will be scheduled every 3 months until end of 
study or withdrawal. Study visits will be scheduled as much as possible before the regular visit to the 
treating nephrologist. During this period of follow up, all participants will undergo the following 
procedures to determine the predefined research parameters (Table 1): 
At the first visit, patient’s medical file will be checked for baseline demographic information, 
comorbidities, risk factors and medication use. Patients will be asked about complains or symptoms 
related to fluid homeostasis (weight gain, shortness of breath, thoracic pressure, palpitations, muscle 
cramps, dizziness, fatigue, thirst, obstipation). Physical signs of fluid imbalance (subcutaneous edema) 
will be evaluated by physical examination. Subjects will be requested to collect 24h urine sample and 
take a blood sample to determine the mixed urea and creatinine clearance. BP, ECG and 
echocardiography will be performed in all subjects. BIS will be performed by the reference and 
wearable device. Patients will be asked to fulfill the SF36 questionnaire. 
During subsequent visits, anamnesis, physical examination, blood- and urine samples, BP and BIS 
measurements will be taken from all subjects. 
At 3 and 12 months of follow up, additional evaluation of cardiac function and quality of life will be 
performed. 
 
 

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3.1 BP measurements 
All subjects will be asked to measure BP three times a week, twice a day (morning and evening before 
sleeping). BP will be measured by an automatically oscillometer. The researcher will evaluate the BP 
each study visit. A mean value of morning and evening measurements will be calculated. 
 
3.2 BIS measurements 
Multifrequency BIS measurements will be performed using a commercially available reference device 
[i.e. Fresenius Medical Care, Body Composition Monitor® (BCM)] (Figure 2), and a research device from 
Imec Eindhoven® (Figure 3). 
 
 
Figure 2 Body composition monitor 
 
 
Figure 3 Wearable Imec BIS device 

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Measurements are non-invasive. For every BIS measurement, the patient is asked to lie down in the 
most comfortable position at around 20/30° supine position with at least 5 minutes of equilibration 
time before measurements starts. For the reference device, a standardized electrode configuration 
will be used: two electrodes attached on the foot and two on the hand, ipsilateral. If for one or another 
reason, it is not possible to attach it on the right side of the body, the left side will be used. No other  
measurements will be taken simultaneously (i.e. ECG). The applied micro current is alternating 
between 5 and 1000 kHz. 
Next, the wearable research device is attached to the thorax using a total of 9 electrodes, 4 electrodes 
serve for BIS measurement, 1 bias, 2 for ECG, and 2 other electrodes are necessary to attach the 
research device to the patient and keep it in a stable position. The five leads are placed in a 
standardized manner as shown in Figure 4. Each measurement takes 20 minutes. 
 
Figure 4 Thoracic electrode configuration of the research device, BIS measurement. 
I, current; V, voltage 
 
3.3 Cardiac function 
At baseline (Visit 0), Visit 2 and Visit 5 of the study, ECG will be performed. At baseline and end of the 
study, an echocardiography will be planned to evaluate cardiac function. Echocardiography will be 
performed by professional echocardiographists according to a standardized protocol (in Dutch):

Investigating the Hemodynamic profile Of chronic Renal patients by Use of Bioimpedance 
HORUZ study 
 
27 
 
1. Parasternale lange as (PLAX) 
2. Parasternale korte as (PSAX) 
3. Apicale 4 kamer (A4C) window + idem met nauwe sector width voor offline strain (+ color) 
4. Apicale 2 kamer (A2C) window + idem met nauwe sector width voor offline strain (+ color) 
5. Apicale 3 kamer (A3C) window + idem met nauwe sector width voor offline strain (+ color) 
6. Graag ook in A4C licht uitgedraaid LA beeld met nauwe sector width (voor offline LA strain) 
7. Graag RV modified view nauwe sector width 
8. Graag 3D TTE-beeld  (bij voorkeur 4 loop beat, zo belangrijke stitching high volume rate) 
9. Graag 3D-beeld RV  (bij voorkeur 4 loop beat, zo belangrijke stitching high volume rate) 
10. Subcostaal (met VCI view) 
11. Pulsed wave at opening MV leaflets 
12. Pulsed wave pulmonaal vene 
13. TDI septale mitraal annnulus  
14. TDI laterale mitraal annulus 
15. Pulsed wave LVOT 
16. Continuous wave AV 
17. TAPSE RV 
18. TDI met PW op Tricuspiedannulus (voor RV S’) 
19. So moderate to servere MI : downshift baseline voor offline PISA 
20. RVSP 
Er moeten geen online metingen uitgevoerd worden. 
Measurements will be performed by a specialized nurse or the researcher. The parameters will be 
analyzed by the researcher to minimize inter-observer variability. The following echocardiographic 
parameters will be ascertained: left ventricle mass index (LVMI = LVM/m2), left ventricular hypertrophy 
(LVH), relative wall thickness (RWT), left ventricle ejection fraction (LVEF), left ventricle geometry, and 
diastolic dysfunction.12,17  
LVM will be calculated via the area-length method [specific gravity and LV muscle volume (epicardial 
volume minus chamber volume, or endocardial volume)]: 
LVM  (g) = 𝜌 [
ହ
଺𝐴ଵ(𝐿+ 𝑡) −(
ହ
଺𝐴ଶ 𝐿)] 
𝜌= 𝑠𝑝𝑒𝑐𝑖𝑓𝑖𝑐 𝑔𝑟𝑎𝑣𝑖𝑡𝑦 𝑜𝑓 𝑚𝑢𝑠𝑐𝑙𝑒=  1.05𝑔/𝑚𝐿 
𝐴ଵ=  𝑒𝑝𝑖𝑐𝑎𝑟𝑑𝑖𝑎𝑙 𝑎𝑟𝑒𝑎 𝑎𝑡 𝑒𝑛𝑑 𝑑𝑖𝑎𝑠𝑡𝑜𝑙𝑒 (cm2) 
𝐴ଶ= 𝑒𝑛𝑑𝑜𝑐𝑎𝑟𝑑𝑖𝑎𝑙 𝑎𝑟𝑒𝑎 𝑎𝑡 𝑒𝑛𝑑 𝑑𝑖𝑎𝑠𝑡𝑜𝑙𝑒 (cm2) 
𝐿= 𝑣𝑒𝑛𝑡𝑟𝑖𝑐𝑙𝑒 𝑙𝑒𝑛𝑔𝑡ℎ 𝑎𝑡 𝑒𝑛𝑑 𝑑𝑖𝑎𝑠𝑡𝑜𝑙𝑒 (𝑐𝑚) 
𝑡= 𝑎𝑣𝑒𝑟𝑎𝑔𝑒 𝑤𝑎𝑙𝑙 𝑡ℎ𝑖𝑐𝑘𝑛𝑒𝑠𝑠 (𝑐𝑚) 
 

Investigating the Hemodynamic profile Of chronic Renal patients by Use of Bioimpedance 
HORUZ study 
 
28 
 
LVH will be defined according to the Cornell Criteria: normal (0.50g/m2 for man, 0.47 g/m2 for women).  
RWT is calculated as: 
ூ௏ௌା௉ௐ்
ூ௏ௌା௉ௐ்ାா஽஽;  0.45 is the cutoff point.  
IVS = interventricular septum thickness 
PWT = posterior wall thickness 
EDD = end diastolic diameter of the left ventricle 
 
LVEF will be calculated using diastolic and systolic LV volumes measured by the single-plane Simpson’s 
rule method: ((Dvol - Svol)/Dvol) x 100; 0.50 is the cutoff point. 
LV geometry is divided into four categories, based on LVMI and RWT:  
 
Figure 5 Left ventricle classification system of Koren et al., adapted from Middleton et al.17 
 
Diastolic dysfunction is defined as an abnormality of diastolic distensibility, filling, or relaxation of the 
left ventricle, regardless of whether the ejection fraction is normal or abnormal and whether the 
patient is symptomatic or asymptomatic.46 
 
 
 

Investigating the Hemodynamic profile Of chronic Renal patients by Use of Bioimpedance 
HORUZ study 
 
29 
 
4. Withdrawal of individual subjects 
Participants can exit the study at any time for any reason if they wish to do so. The investigator can 
decide to withdraw a subject from the study for urgent medical reasons. In case of withdrawal, an end 
of study visit will be scheduled to perform last measurements according to visit 5. As there is no 
medication intervention in this study, there is no need for a safety procedure during withdrawal. 
Withdrawals will not be further followed. 
 
5. Replacement of subjects withdrawn from treatment 
Patients who withdraw from the study will not be replaced, as this has already been taken into account 
in the sample size calculation. 
 
6. Premature termination of the study 
As the interventions in this study are non-invasive and no medication is used, no specific termination 
criteria are formulated. 

Investigating the Hemodynamic profile Of chronic Renal patients by Use of Bioimpedance 
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30 
 
SAFETY REPORTING 
1. Temporary halt for reasons of subject safety 
The sponsor will suspend the study if there is sufficient ground that continuation of the study will 
jeopardize subject health or safety. The sponsor will notify the accredited Ethical Committee without 
undue delay of a temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited Ethical Committee. The investigator will take care 
that all subjects are kept informed. 
 
2. Adverse and serious adverse events, SUSARs 
2.1 Adverse event (AE) 
Adverse events are defined as any undesirable experience occurring to a subject during a clinical trial, 
whether or not considered related to the investigational treatment. All adverse events reported 
spontaneously by the subject observed by the investigator or her staff will be recorded.  
 
2.2 Serious adverse event (SAE) 
A serious adverse event is any untoward medical occurrence or effect that:  
- 
results in death; or 
- 
requires hospitalization or prolongation of existing inpatients’ hospitalization; or 
- 
results in persistent or significant disability or incapacity; or 
- 
is a new event of the trial likely to affect the safety of the subject, such as an unexpected 
outcome of an adverse reaction. 
All SAE’s will be reported to the accredited Ethical Committee that approved the protocol. 

Investigating the Hemodynamic profile Of chronic Renal patients by Use of Bioimpedance 
HORUZ study 
 
31 
 
 
2.3 Suspected unexpected serious adverse reactions (SUSAR) 
Not applicable. 
 
3. Follow-up of adverse events 
AE according to the study are considered very unlikely, due to the fact that only non-invasive methods 
are used. All AEs will be followed until a stable situation has been reached and treated to standard 
procedures. 
 
4. Data Safety Monitoring Board (DSMB) 
Not applicable. 
 
 

Investigating the Hemodynamic profile Of chronic Renal patients by Use of Bioimpedance 
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32 
 
STATISTICAL ANALYSIS 
A table with baseline characteristics of all subjects will be provided. Baseline characteristics of the 
population will be expressed as the mean ± standard deviation if normally distributed, or as the median 
[25th – 75th percentile] as not normally distributed, for continuous and dichotomous data, and as the 
frequency (%) for categorical data. Measurements of drop-outs will be included until the moment of 
withdrawal from the study. Normality in distribution will be tested by the Shapiro-Wilk statistic. 
Repeated measurements ANOVA techniques will be used for analysis. Pearson’s Chi-squared test will 
be used to assess whether there is any distinction between subgroups in rate of kidney function 
decline. In case the analysis of the baseline characteristics showed any clinically relevant imbalance, 
we will also perform a multivariable logistic regression analysis in order to correct for this imbalance. 
Differences in LVH will be corrected for systolic BP and haemoglobin, as these are predictors of LVH in 
predialysis population.15 Depending on the level of measurement a Chi-squared test or a T-test will be 
used to assess differences in secondary study parameters, and logistic and linear regression for 
baseline-corrected estimates. Tests will be considered significant if p-values are ≤ 0.05. 
 
 

Investigating the Hemodynamic profile Of chronic Renal patients by Use of Bioimpedance 
HORUZ study 
 
33 
 
ETHICAL CONSIDERATIONS 
1. Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki (Fortaleza, Brasil, 
2013). 
 
2. Recruitment and consent 
All eligible patients and/or their legal representatives will receive an information leaflet by the 
researcher. The leaflet informs about the aims and conduct of the study, the burden and risks 
associated with participation. If the patient is interested in participation, he or she will mention his or 
her interest to the researcher, who will explain the procedure verbally in detail. Each participant will 
have at least one week time to decide whether he or she wishes to participate in the study. The consent 
and insurance procedures will be explained by the researcher. After signing the informed consent 
form, the study will be initiated. 
 
3. Objection by minors or incapacitated subjects 
Not applicable. 
 
4. Benefits and risks assessment, group relatedness 
Only non-invasive techniques which pose a minimal burden to the patient will be used. Blood sampling 
will coincide as much as possible with regular blood takings for clinical purposes. The risk of 
venipuncture-related complications is considered low. The burden associated with BIS and BP 
measurements is considered low. All subjects undergo echocardiography. Costs of this examination 

Investigating the Hemodynamic profile Of chronic Renal patients by Use of Bioimpedance 
HORUZ study 
 
34 
 
will not be charged to the patient. Analysis of the echocardiography will be done during follow-up 
period. Aberrant results will be discussed with an expert. 
 
5. Compensation for injury 
In case of injury due participation to HORUZ study, the sponsor has a liability insurance which is in 
accordance with the legal requirements in Belgium: ‘de wet inzake experimenten op de menselijke 
person van 7 mei 2004’. This insurance provides cover for damage to research subjects through injury 
or death caused by the study. 
 
6. Incentives 
No direct incentives will be given to the participants. None of the research examinations will be 
charged to the patients. For each study visit, parking ticket will be provided. 
 
 

Investigating the Hemodynamic profile Of chronic Renal patients by Use of Bioimpedance 
HORUZ study 
 
35 
 
ADMINISTRATIVE ASPECTS AND PUBLICATION 
1. Handling and storage of data and documents 
All documents will be handled confidentially according to the General Data Protection Regulation. 
Storage of all data occurs on the ‘T-schijf’ of Ziekenhuis Oost-Limburg Genk.  
 
2. Amendments 
All amendments will be notified to the Ethical Committee that gave a favorable opinion. 
 
3. Annual progress report 
The investigator will submit a summary of the progress of the trial to the accredited Ethical 
Committee once a year. Information will be provided of the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, serious adverse 
events, other problems, and amendments. 
 
4. End of study report 
The investigator will notify the accredited Ethical Committee of the end of the study within a period of 
8 weeks. The end of the study is defined as the last patient’s visit.  
In case the study is ended prematurely, the investigator will notify the accredited Ethical Committee, 
including the reason for the premature termination.  
Within one year after the end of the study, the investigator will submit a final study report with the 
results of the study, including any publications/abstracts of the study, to the accredited Ethical 
Committee. 

Investigating the Hemodynamic profile Of chronic Renal patients by Use of Bioimpedance 
HORUZ study 
 
36 
 
 
5. Public disclosure and publication policy 
All data that result from the HORUZ study will be made known, and will be offered for publication in 
peer-reviewed journals.  
 
 

Investigating the Hemodynamic profile Of chronic Renal patients by Use of Bioimpedance 
HORUZ study 
 
37 
 
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APPENDIX: HORUZ REGISTRATION FORM 
Studynumber:  HZOL … 
 
Age                           …. y 
Gender                    M / F 
Height                      …. cm 
Smoking status       no / yes / smoking cessation date: … 
Etiology CKD           …. 
Hypertension          no / yes 
Diabetes                  no / yes 
CV disease               no / yes: …. 
Tx list                        no / yes 
Visit 
 
 
number 
date 
 
 
 
 
complains*    weight            office BP§      oedeem** 
BIS thoracaal ….  
 
BIS whole body        
TBW / ECW / ICW  
OH / LTM / FTM          
Cardiac 
function 
 
ECG 
Echo cor 
Medication 
SF36 
 
homeBP¥  
 
 
morning 
evening  
Kidney 
function 
eGFRcreat 
CrUrCl 
24h urine 
CV event 
Hospitalisation 
AE/ SAE 
0 
….......... 
… 
 
… 
… 
… 
……. / ……… / ……… 
……. / ……… / ……… 
 
... 
 
… 
… 
 
… 
… 
… 
 
1 
 
 
 
 
 
Date 
echo cor: 
 
 
 
… 
… 
… 
… 
… 
2 
….......... 
… 
 
… 
… 
… 
……. / ……… / ……… 
……. / ……… / ……… 
… 
 
… 
 
 
… 
… 
… 
… 
… 
… 
… 
… 
3 
….......... 
… 
 
… 
… 
… 
……. / ……… / ……… 
……. / ……… / ……… 
 
… 
 
… 
 
 
… 
… 
… 
… 
… 
… 
… 
… 

 
 
4 
….......... 
… 
 
… 
… 
… 
……. / ……… / ……… 
……. / ……… / ……… 
 
… 
 
… 
 
 
… 
… 
… 
… 
… 
… 
… 
… 
5/End 
……….. 
 
 
… 
 
 
 
… 
… 
… 
……. / ……… / ……… 
……. / ……… / ……… 
 
… 
Date 
echo cor: 
… 
 
… 
 
… 
… 
 
… 
… 
… 
… 
… 
… 
 
Abbreviations: AE adverse event, BIS bioimpedance spectroscopy, BP blood pressure, ECW extracellular water, ICW intracellular water, FTM fat tissue mass, LTM lean tissue mass, OH 
overhydratie, TBW total body water, SAE severe adverse event 
§ office BP: BP measured during visit 
¥ home BP: mean of home measurements 
*complains: dyspnoe 1, orthopnoe 2, druk op de borst 3, palpitaties 4, pijnlijke gezwollen voeten 5, spierkrampen 6, duizelig 7, dorst 8, obstipatie 9, anders 10 
**perifeer oedeem: geen 1, matig 2, veel 3 
AE: any undesirable experience occurring to a subject during the clinical trial, whether or not considered related to the investigational treatment.  
SAE: results in death; or requires hospitalization or prolongation of existing inpatients’ hospitalization; or results in persistent or significant disability or incapacity; or is a new event of the trial 
likely to affect the safety of the subject, such as an unexpected outcome of an adverse reaction