Mechanisms and Phenotypes of Hypertension in Patients in Chronic Hemodialysis
Conditions: Arterial Hypertension, Hemodialysis
Sponsor: Bernardo Rodríguez Iturbe

 
 
 
 
 
MECHANISMS AND PHENOTYPES OF 
HYPERTENSION IN PATIENTS IN 
CHRONIC HEMODIALYSIS 
 
 
 
NCT06764277 
 
 
DATE: 09/11/2025 
 
 
STUDY PROTOCOL 
 
 

 
 
 
Instituto Nacional  de Ciencias Médicas y Nutrición 
Salvador Zubirán 
 
 
 
 
 
 
 
 
 
 
 
 
 
Title  
Mechanisms and Phenotypes of Hypertension in Patients in Chronic Hemodialysis 
 
Number  
Clinical Trials.gov protocol NCT06764277.     
Investigation type  
Observational transversal studies of mechanisms, markers (diagnostic/predictive) and prevalence of 
phenotypes in patients in chronic hemodialysis 
Population (one)  1 (categorized by severity of hypertension in 3 groups: normotensive, prehypertensive, 
hypertensive)  
Study: Prospective, observational, unicentric, Open  
 
Investigators 
INVESTIGATOR 
Institutional 
position  
Role in the 
project 
Telephone 
(ext.) 
Correo-E 
Dr. Bernardo 
Rodríguez Iturbe 
Staff member, Dept 
of Nephrology and 
Mineral Metabolism  
Principal 
Investigator  
 
brodrigueziturbe@gmail.c
om 
 
Dr. Ricardo Correa 
Rotter 
Staff member, Dept 
of Nephrology and 
Mineral Metabolism 
Investigator 
555487090
0 (2206) 
correarotter@gmail.com 
 
Dra. Olynka Vega  
Staff member, Dept 
of Nephrology and 
Mineral Metabolism 
Investigator 
555487090
0 (5606) 
olynkavega@hotmail.com 
 
Dr. Eduardo Ríos 
Argaiz 
Staff member, Dept 
of Nephrology and 
Mineral Metabolism  
Investigator 
551655829
5(4142) 
lalo.argaiz@gmail.com 
 
Dra. Angeles Espinosa 
Cuevas 
Bioimpedance Dpt.  
Investigator 
555487090
0 (7876) 
angespinosac@gmail.com 
 
Note. 2 new co-investigators added: Adolfo Díaz (Nephrology resident) and Brenda Delgado-Avila (nephrology 
resident 
 
Investigators experience and role in the investigation 
Investigator 
Previous research experience  
 
Dr. Bernardo Rodríguez Iturbe 
Research experience in nephrology and hypertension  
 
Dr. Ricardo Correa Rotter 
Research Experience in nephrology and renal replacement therapy  
 
Dra. Olynka Vega Vega 
Research Experience in nephrology and renal replacement therapy  
 
Dr. Eduardo Ríos Argaiz 
Nephrology resident 
 

Dra. Angeles Espinosa Cuevas 
Research experience in bioimpedance  
 
 
Institution   
 
Approved the project 
Instituto Nacional de Ciencias Médicas y Nutrición Salvador 
Zubirán. 
Yes (protocol NMM 4512-23-24-1 
Sponsorships  of other institutions          
             No _______________________________ 
Payment to investigators (other than employment in the institution) 
                        No . 
Abstract/Summary   
Title: Mechanisms and Phenotypes of Hypertension in Patients in Chronic Hemodialysis 
Justification. Cardiovascular complications associated to arterial hypertension are critical determinants of 
the mortality of patients in chronic hemodialysis. Identification of the activity of the renin-angiotensin system 
and immune reactivity in association with water overload is of clinical importance because they are 
potentially treatable. 
Aims. To examine systemic arterial blood pressure ambulatory blood pressure monitoring (ABPM) in the 
interdialytic period and its relation to the activity of the renin angiotensin system, immune reactivity and 
interdialytic weight gain in patients in chronic hemodialysis. 
General design.  Prospective study of a cohort of patients in the chronic hemodialysis program in the Instituto 
Nacional de Ciencias Médicas y Nutrición Salvador Zubirán.  Patients with the inclusion criteria will be 
evaluated with ABPM during the 24 hours in the interdialytic period.  Weight, blood pressure, dialysis 
characteristics will be recorded. Blood samples will be obtained for hormonal determinations and immune 
reactivity at the end of the interdialytic period.  Ultrasound will be used for determination of cardiac output 
and central venous pressure. Systemic vascular resistance will be calculated. Electric bioimpedance will be 
obtained would be obtained the first post dialysis day of the long interdialytic interval. * 
 Note: bioimpedance was not obtained and was not part  of the study 
Background.  
Chronic kidney disease (CKD) is associated with arterial hypertension (AHT). AHT is more frequent in renal 
vascular disease, diabetic nephropathy and polycystic kidney disease 1, the incidence of AHT in end stage 
CKD (eGFR<10ml/min/1.73m2) of any etiology is over 90% 2. In CKD patients the etiology of AHT is 
multifactorial and sodium retention and volume expansion 3,4 , overactivity of the renin angiotensin system 
5, proinflammatory immune reactivity 6-9, endothelin system 10,11, the sympathetic nervous system12, 
secondary hyperparathyroidism13, reduced kallikrein/kinin 14 and endothelial cell dysfunction and nitric oxide 
reduction15, are known to play a role. 
In the patient with end stage CKD, the most important prohypertensive factor is sodium and water retention 
with extracellular volume expansion that results in increase in cardiac output and peripheral vascular 
resistance16.   For this reason, the universally accepted therapeutic measure is to attempt to keep in the so-
called dry weight 17.  The determination of “dry weight” is controversial and in addition to absence of clinical 
signs of  vascular congestion,  
bioimpedance determinations have been used to estimate subclinical overhydration but its use has been 
associated with higher risk of dialysis hypotension and clinical determination of the lowest weight that is not 
associated with postural and dialysis hypotension or cramps and malnutrition 18,19,20. 
 
With the emphasis placed in overhydration as a cause of AHT in end stage CKD, not enough attention has 
been placed to other factors which may play an important role especially because there is no predictable 
correlation between the severity of overhydration and the severity of hypertension, patients with normal 
blood pressure have significant overhydration and patients with bioimpedance-determined dry weight may 

have significant hypertension.  It is our rough estimate that in 85-90% of patients in chronic hemodialysis 
hypertension is associated to volume overload without predictable correlation and 10-15% of the patients 
have normal blood pressure despite various degrees of water overload.  
The purpose of the study is to evaluate factors that may importantly contribute to hypertension in chronic 
dialysis patients; in particular, the renin-angiotensin system (RAAS)., the sympathetic nervous system  and 
inflammatory immune reactivity.  In relation to the RAAS, Neuman at al.21, found that basal levels of 
angiotensin II are higher in patients with CKD than in normal controls, but  the reduction resulting from  with 
volume expansion is normal, indicating that physiologic responses are  normal. We also know from the 
studies of Shalekamp et al.22 that the activation of the renin-angiotensin system in CKD is not uniform and 
there are patients with normal and patients with high renin activity. In relation to inflammatory reactivity 
generated by autoimmune mechanisms, studies of several groups including ourselves 6.7,23,24 have 
established the inflammation in the arterial wall,  in the central nervous system and in the kidney play an 
important pathogenic role by reducing vasodilatory responses that may be corrected with T regulatory 
cells25, increasing the activity of the sympathetic nervous system 26-28, inhibiting pressure natriuresis29 and 
stimulating sodium reabsorption30, 31.  If these findings are shown in dialysis patients it is possible that anti-
inflammatory treatment could have anti-hypertensive effects as it has been shown in experimental models 
and in patients32. 
An important aspect is the relationship between interdialytic weight gain  and the phenotypes of arterial 
hypertension (sustained hypertension, diurnal and nocturnal hypertension, normal nocturnal dipping, non-
dipping, exaggerated dipping and reverse dipping) that may be evaluated with ambulatory blood pressure 
monitoring (ABPM) 33 that are associated with worse prognosis 34,35.  Of interest, there are significant 
differences between ABPM and pre and post-dialysis blood pressure that are worthy to examine. and there 
is a high incidence of non-dippers in patients with CKD36 and in patients with inflammation 37-39.   
Hypothesis and research questions.   
What is the relative importance of the renin-angiotensin system, the inflammatory immune reactivity and 
water  overload in the interdialytic blood pressure in dialysis patients?   
Working hypothesis: In patients in chronic dialysis the activity of the renin-angiotensin system and the 
inflammatory reactivity play a critical role in the severity of hypertension and in the absence of nocturnal 
dipping of blood pressure 
Outcomes.  
Primary Outcome :  
Determine the relationship of blood pressure determined by ambulatory monitoring (ABPM) in the 
interdialytic period and the interdialytic weight gain and the levels of angiotensin II and inflammatory 
markers in patients in chronic dialysis.   
Secondary Outcomes: 
1) Determine the relationship of other parameters relevant to blood pressure pathophysiology with 
interdialytic weight gain and blood pressure 
2) Evaluate the relationship between interdialytic weight gain, and other variables under study with 
hemodynamic parameters (systemic vascular resistance and cardiac output). 
3) Evaluate differences between ABPM and dialysis blood pressure.  
Methods.  . 
General 
 Design of the study: One cohort.  Observational prospective study.   
 Patients: Patients in the chronic hemodialysis program in the Instituto Nacional de Ciencias 
Médicas y Nutrición “Salvador Zubirán” that meet the inclusion criteria and sign informed consent 
 Date.   abril 2023– junio 2024 

 Days and hemodialysis and hemodialysis prescription will not be modified in the study.  .  
 
Ambulatory blood pressure monitoring will be started after dialysis when the patient will be fitted with 
the equipment for ambulatory blood pressure monitoring  and receive the instructions for its use.  
 
Blood simples (10 ml) will be taken at the end of the interdialytic period, (prior to the next dialysis) for the 
biomarkers under study.  
 
1-2 hours after the end of dialysis the determination of cardiac output and central venous pressure 
determinations for calculation of the peripheral vascular resistance will be done by experts with 
experience in ultrasound methodology. 
Methods   
Hemodynamic determinations. Cardiac output will be measured by experts with experience by transthoracic 
echocardiography using ultrasound equipment Siemens Acuson P500 with convex transducer of 2-5Mhz and 
lineal transducer of 7.5Mhz. Measurements will be done in the 4th intercostal space at the mid clavicular 
line.  Cardiac output (systolic volume x heart frequency) will be determined by ultrasound doppler of the 
flow of the outlet of left ventricle and the aortic area.  
Ambulatory blood pressure monitoring will be done with Space Lab ambulatory monitor (SpaceLabs Co)  
with cuffs appropriate for the patient’s size starting after dialysis.  Measurement will be programed to be 
taken every 30 minutes during the day and every hour when the patient goes to bed.  The patient will bring 
the equipment to the hospital when he comes for the next dialysis. 
Biometric Bioimpedance. It was impossible to coordinate bioimpedance determinations within one week of 
the studies and this part of the study was omitted. 
Blood samples and laboratory determinations.  Blood samples (10 ml) will be taken from the venous side of 
the vascular access before the beginning of dialysis (end of the interdialytic period) and allowed to coagulate 
at 2-4°C.  Serum samples will be stored at -80°C until the time of assay.   All determinations will be done in 
the research laboratory of the Dept. of Nephrology and Mineral Metabolism of the Instituto de Ciencias 
Medicas y Nutrición “Salvador Zubirán”. Angiotensin II will be determined by ELISA (my BioSource Cat.# 
MBS703599); Norepinephrine by ELISA (ABCAM, Cat. # AB287789); Copeptin by ELISA (Bio-
techne/NovusBiological, Cat, # NBP2-69822), TNFα by ELISA (Human TNF-alpha Quantikine HS ELISA, R&D 
systems, Cat.# HSTA00E).  All laboratory determinations will be done following the instructions of the 
commercial supplier.  Peripheral white cell counts were used to calculate the NMLR (neutrophils + monocytes 
/lymphocytes ratio) inflammation index.   
Informed Consent.   
Presented separately 
Medical Intervention 
None.  Is an observational study.  
Sample size 
All the patients in the chronic hemodialysis program of the INCMNSZ  that meet the inclusion criteria will be 
invited to participate.   
Inclusion criteria 
 
18 years of age or older  
 
More than 3 months in chronic dialysis  
 Stable clinical conditions with no evidence of infection or treatment changes in the previous month 

 Signed informed consent to participate in the study.   
Exclusion Criteria 
 
 Previous nephrectomy 
 Participation of the patient in another clinical trial requiring interventional treatment  
 Patients with prosthesis and pacemakers  
 Incapacity of placement of ABPM or insufficient valid recordings 
 Incomplete collection of data 
 Voluntary withdrawing of informed consent  
 
Statistical  Analysis.  .  
 Gaussian (normal) distribution will be evaluated with Kolmogorov-Smirnoff tests. Data will be expressed 
with mean and standard deviation or standard error of the mean and 95% confidence interval.  Variables 
with not normal distribution will be expressed with median and interquartile range.  Categorical variables 
will be expressed as frequencies and percentages.  Comparisons between two groups with normal 
distribution will be done with t tests and between several groups with one way ANOVA with Tukey post-
tests. Comparisons in groups that do not have a normal distribution will be done with Kruskal-Wallis tests.  
Correlations will be explored with Pearson (data with normal distribution) or Spearman (data with not normal 
distribution).  Normality of log2 data distribution will be explored when obtained data do not fit with a normal 
distribution.  Statistical calculations will be done with software STATA (Statistic Data Analysis version 14.1 or 
with Graphpad 10 program.  Two-tail p values <0.05 will be considered significant. 
  
Groups.  
There is one population of patients and for the purpose of some analyses, patients will be categorized in 3 
groups by their mean ambulatory systolic blood pressure (ABP-SBP) : 1. ABP-SBP <130 mmHg 
(normotensives); 2) ABP-SBP 130-139 mmHg (prehypertensives) and 3) ≥140 mmHg (hypertensives) 
Mechanisms for assignation of treatments.  
There will be no treatment assigned as part of the study 
Recruitment potential  
We aim to recruit all patients that meet the inclusion criteria.  Our estimate is 40-45  patients from a total 
of 50-55 in the chronic hemodialysis program of  the INCMNSZ. 
Recruitment incentives. 
There will be no incentives. 
Therapy  
There will be no therapy as part of the study.  Treatment received by the patient will not be modified. 
Retirement of participants 
Premature retirement of a participant could occur at the patient’s request or by the unexpected 
development of fever or adverse event during the study.  Cause of retirement will be duly recorded  
Samples, administration and monitoring of the study.   
Samples will be used only for the purposes of the study.  The study will be conducted or supervised by one 
of the investigators.  Any adverse event will be immediately notified to the treatment physician.  
Investigates will meet every month to discuss the progress of the study.   
Methods of contacting the participants 
Patients will be contacted when they come to their regular hemodialysis treatment. As specified in the 
informed consent, the patients will have telephone access to the following investigators +52.19991490061 

(Dr. Rodríguez-Iturbe), +52.15579597066 (Ricardo Correa-Rotter), +52.5518437638, (Dr. Eduardo Ríos 
Argaiz) 
Risks.  
This is an observational study that does not include invasive studies.  The patient will receive explanation 
on the procedure of ABPM.  Ultrasound studies are routinely used in patients in chronic dialysis 
  
Expected benefits. 
There will be no direct benefits for the patient.  Knowledge of heart function and hypertension phenotype 
may have indirect benefits for the indication of treatment by his/her treatment physician to whom the results 
of the study will be available.  The patient will not be charged by any of the studies 
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