People with end stage kidney disease cannot regulate salt and water normally, which often leads to high blood pressure, fluid overload, and a higher risk of heart disease.

Hemodialysis is a life sustaining treatment that removes waste products, excess fluid, and electrolytes from the blood. However, the treatment itself can influence blood pressure and how the blood vessels function. Many patients experience symptoms such as thirst, headaches, fatigue, and swelling, which affect both daily well being and long term health. One possible way to reduce these problems may be as simple as adjusting the amount of sodium in the dialysis fluid.

During dialysis, substances move between the patient's blood and the dialysate, the special fluid used in the machine. Sodium is one of the most important components because it helps regulate fluid balance and blood pressure. A higher sodium concentration in the dialysate can make patients feel more thirsty, cause them to drink more, and lead to fluid retention and higher blood pressure. On the other hand, lowering sodium too much can cause dizziness, low blood pressure, cramps, and discomfort during treatment. Because of this, there is ongoing debate about what the "right" sodium level should be.

Too much sodium over time may also harm the blood vessels. The inner lining of the vessels, called the endothelium, is protected by a thin layer known as the glycocalyx. This layer helps prevent sodium from entering the vessel wall and supports the production of nitric oxide, a molecule that relaxes blood vessels and reduces inflammation. High salt exposure can damage the glycocalyx and reduce nitric oxide production, making the vessels stiffer and raising blood pressure. In dialysis patients, low nitric oxide levels are linked to worse outcomes and episodes of rising blood pressure during treatment. Some small studies suggest that lowering dialysate sodium can improve blood pressure and endothelial function, but larger studies have not shown clear effects on survival. This indicates that we still do not fully understand which patients benefit most or how sodium changes affect both physical and subjective symptoms.

This study aims to fill these knowledge gaps by examining how a lower sodium concentration in the dialysate affects blood pressure, blood vessel function, fluid overload, inflammation, and patient reported symptoms. The goal is to provide new insights that could help tailor dialysis treatment to individual patients in a simple and cost effective way.

The study will compare two sodium concentrations: a lower level (133 mmol/L) and the standard level used in many clinics (139 mmol/L). Twenty five patients receiving chronic in center hemodialysis will participate. Each patient will undergo both treatments for three weeks each, in random order, with a two week washout period in between. This crossover design allows each patient to serve as their own control, making it easier to detect meaningful differences.

The main outcome is the difference in 24 hour systolic blood pressure between the two sodium levels. Secondary outcomes include changes in nitric oxide levels in the blood, measures of fluid overload using two different techniques, markers of inflammation, arterial stiffness, and patient reported symptoms such as thirst, fatigue, and overall well being. The study will also compare two methods for assessing fluid overload: bioimpedance spectroscopy and a newer carbon monoxide rebreathing technique.

Blood pressure and arterial stiffness will be measured over 44 hours using a portable device. Blood samples will be collected to analyze nitric oxide, inflammatory markers, and sodium handling in red blood cells. Fluid status will be measured using both bioimpedance and the CO rebreathing method. Patients will complete a weekly questionnaire developed together with dialysis patients to capture their experiences and symptoms.

1. Background Patients with end stage renal disease lose the ability to effectively regulate the body's sodium and fluid balance. This leads to chronic sodium and fluid accumulation, contributing to elevated blood pressure, increased risk of cardiovascular complications, and fluid retention in tissues. Hemodialysis is therefore a life sustaining treatment in which waste products, electrolytes, and excess fluid are removed from the blood through a filter into dialysate, with the aim of partially restoring this balance. The dialysate is composed by the dialysis machine, where sterile water is mixed with, among other components, salt (sodium), which plays a central therapeutic role.

   Chronic sodium and fluid overload in hemodialysis patients is associated with increased mortality, particularly related to cardiovascular disease. Previous studies have shown that cardiovascular mortality increases with the degree of fluid overload and the need for high ultrafiltration volumes during dialysis. The sodium concentration of the dialysate directly affects blood pressure control and interdialytic fluid accumulation. Several studies have demonstrated that a lower sodium concentration in the dialysate can reduce blood pressure and interdialytic weight gain. However, this strategy is associated with risks such as hypotension, muscle cramps, and dehydration. Conversely, a higher sodium concentration may increase thirst, blood pressure, and make it more difficult for patients to adhere to fluid restrictions. A study comparing low versus standard dialysate sodium found reductions in blood pressure and fluid overload after only four dialysis sessions.

   The hemodynamic effects of sodium cannot, however, be explained solely by changes in intravascular volume. The endothelium-the innermost cell layer of blood vessels-plays a central role in regulating vascular tone and is covered by a protective glycocalyx layer. Sodium accumulation in tissues can damage this layer and reduce the production of nitric oxide (NO), which is essential for endothelium dependent vasodilation. Reduced NO bioavailability is associated with increases in blood pressure during dialysis and is a negative prognostic marker in hemodialysis patients. Endothelial function can be assessed by measuring plasma NOx and by the Salt Blood Test, which reflects erythrocytes' ability to bind sodium and thereby the systemic capacity for sodium buffering.

   Although some interventional studies have shown improvements in endothelial function and blood pressure with lower dialysate sodium, larger meta analyses have not demonstrated a clear reduction in mortality. This suggests that the effect of sodium reduction is likely heterogeneous, and that we still lack knowledge about which patients benefit most from increased sodium removal and through which mechanisms these effects manifest-both clinically and subjectively.

   The aim of this study is therefore to investigate whether removing more sodium during dialysis-achieved by reducing the sodium concentration in the dialysate-can improve blood pressure outside dialysis and enhance endothelial function in the short term, while systematically documenting patient experiences and side effects. By combining clinical measurements with patient involvement and a novel method for assessing fluid overload based on carbon monoxide (CO) rebreathing, the study seeks to provide a more precise and holistic understanding of the role of sodium balance in hemodialysis patients.

2. Objective The objective of the study is to investigate whether a low sodium concentration in the dialysate (133 mmol/L) over a 3 week period, compared with the standard concentration (139 mmol/L), affects blood pressure, endothelial function, fluid status, and patient reported experiences of dialysis treatment in patients undergoing chronic in center hemodialysis.

3. Hypothesis

   We hypothesize that a lower sodium concentration in the dialysate-compared with the standard concentration-will remove additional sodium during dialysis and thereby:

   • Reduce 24 hour blood pressure as an indicator of improved blood pressure control.
   • Increase plasma NOx levels as a marker of improved endothelial function.
   • Reduce fluid overload, measured by bioimpedance and the CO rebreathing technique.
   • Lower the Salt Blood Test value, indicating improved erythrocyte sodium buffering capacity.
   • Reduce plasma levels of inflammatory cytokines, including IL 17, IFN γ, IL 10, IL 6, IL 1β, IL 17A, and TNF α, indicating a lower inflammatory burden.
   • Reduce the need for ultrafiltration during dialysis and decrease patient reported thirst.

4. Perspective Dialysis patients have a markedly increased risk of cardiovascular disease and premature death compared with the general population, primarily due to disturbances in the regulation of sodium and fluid, which affect both blood pressure and vascular function. Despite this, limited knowledge exists regarding how variations in dialysate sodium concentration influence both physiological and subjective parameters in chronic hemodialysis patients.

   This study addresses a key knowledge gap by combining objective measures (blood pressure, NOx, fluid overload, inflammation) with patient reported symptoms (thirst, dizziness, headache), thereby providing a more comprehensive understanding of sodium balance in this population.

   If a lower sodium concentration proves effective, it represents a simple and cost effective improvement to dialysis treatment. Adjusting dialysate sodium is already part of routine clinical practice, but optimal individualization remains unclear. Changing dialysate sodium requires no new equipment and can be widely implemented. Improved blood pressure control and reduced inflammatory burden may reduce medication needs, hospitalizations, and complications, potentially lowering healthcare costs. The study will form the basis for future long term studies examining effects on vascular function and prognosis.

5. Outcome Measures Effects will be measured as the difference between parameters during dialysate sodium concentrations of 133 mmol/L and 139 mmol/L (standard).

   Primary outcome:

   - Difference in systolic 24 hour blood pressure.

   Secondary outcomes:

   • Plasma NOx levels
   • Fluid overload (BCM and CO method)
   • Volume assessed by the CO method
   • Dialysis data, including clinically assessed ultrafiltration needs (dry weight)
   • Pulse wave velocity (arterial stiffness)
   • Plasma levels of inflammatory cytokines
   • Side effects (questionnaire based)

6. Study Design The study is a randomized, crossover, single blinded interventional trial in which each participant receives both interventions-dialysis with low and standard sodium concentration-in two consecutive 3 week periods. Participants are blinded, while dialysis nurses and investigators are unblinded.

   Interventions:

   • Low sodium concentration: 133 mmol/L
   • Standard sodium concentration: 139 mmol/L The sequence is determined by randomization. After the first 3 week period, participants cross over to the opposite intervention following a 2 to 3 week washout period.

7. Participants 7.1 Inclusion Criteria

   • ≥18 years
   • Chronic in center hemodialysis ≥3 months
   • Hemodialysis 3 times weekly
   • Plasma sodium >132 mmol/L at the two most recent tests within 3 months
   • Expected continuation of dialysis >3 months 7.2 Exclusion Criteria
   • AMI or diagnosed heart failure with EF <50% within the past 6 months
   • Stroke or TIA within the past 6 months
   • Bilateral lower limb amputation
   • DDD pacemaker 7.3 Withdrawal Criteria
   • Discontinuation of dialysis
   • Unacceptable side effects
   • Development of an exclusion criterion
   • Participant request
   • Non compliance 7.4 Recruitment Participants will be recruited from the Dialysis Clinic, Regional Hospital Gødstrup.

   7.5 Sample Size and Statistical Power With an expected SD of 10 mmHg, 80% power, and a significance level of 5% (p < 0.05), 24 completed participants are required to detect a mean difference of 6 mmHg in systolic 24 hour blood pressure. Allowing for ≥30% dropout, up to 35 participants may be included.

8. Procedure for Recruitment and Inclusion 8.1 Screening of Potential Participants Before contacting a potential participant, the principal investigator reviews the electronic patient journal (EPJ) to assess whether the patient meets the inclusion criteria (≥18 years, ≥3 months of hemodialysis, dialysis three times weekly, plasma sodium >132 mmol/L on recent blood tests). Plasma sodium must be above 132 mmol/L on the two most recent measurements taken in the Dialysis Clinic within the past 3 months to be eligible. This can be reassessed after a minimum of 3 months if needed.

   8.2 Recruitment and Information Meeting Patients deemed eligible are approached in person by the principal investigator, the consulting physician, or the project nurse during their routine dialysis sessions. They receive a brief introduction to the project, and if they express interest, a time and place for a full information meeting is arranged. Patients may bring a companion to the meeting. During the information meeting, oral information is provided by the project investigator based on the written participant information (Appendix 2), which is handed out and includes details on the study's purpose, procedures, methods, potential risks, and participant rights. Patients are also informed that health related and other confidential information may be shared with individuals responsible for mandatory quality control of the study.

   8.3 Reflection Period and Opportunity for Private Discussion All patients are offered a minimum reflection period of one week before deciding on participation. They are given the opportunity to ask questions and to speak with the investigator in private if desired. It is emphasized that participation is voluntary and will not affect their usual treatment.

   8.4 Informed Consent If the patient wishes to participate, a written informed consent form (Appendix 3) is signed. The consent covers participation in the intervention, blood sampling, questionnaires, and the transfer of relevant data from EPJ and Therapy Manager to the research database (REDCap). It also includes consent for collection of biological material (blood) for storage in a research biobank for later analyses. Participants may opt out of receiving information about significant health findings discovered during the project. Consent is stored in accordance with applicable legislation.

   8.5 Inclusion in the Study After signing consent, inclusion and exclusion criteria are reviewed. If the patient meets all criteria, an intervention sequence is assigned by randomization, and study participation is scheduled. The participant is informed about practical aspects, including measurement time points, questionnaires, and contact persons.

9. Procedure for Study Participation The intervention sequence is assigned by randomization in REDCap. Participants are not informed of the sequence.

   Study Periods Each intervention period lasts 3 weeks, and all participants complete both periods in a crossover design, separated by a 2 week washout period (extendable to 3 weeks). Study participation is aligned with each patient's fixed dialysis schedule whenever possible. Patients on evening dialysis may remain on their usual schedule but will be asked to arrive earlier on examination days so that blood sampling and nuclear medicine assessments can be completed before 15:00.

   Each study period includes 9 dialysis sessions. Examinations are performed during the 9th dialysis session of each period.

   To ensure consistency, all study assessments are conducted during the second dialysis session of the calendar week (typically Wednesday or Thursday). Therefore, each study period begins with the third dialysis session of the week (typically Friday or Saturday).

   Examinations

   On the examination day (calendar week's second dialysis session in study week 3), the following procedures are performed:

   • Volume status (CO rebreathing technique): before dialysis at the Department of Nuclear Medicine
   • Bioimpedance (BCM): at Nuclear Medicine after CO measurement, or in the Dialysis Clinic immediately before dialysis
   • Blood samples: in the Dialysis Clinic immediately before dialysis
   • Questionnaire (Appendix 4): completed during the dialysis session
   • 24 hour blood pressure monitoring: applied after dialysis and removed at the next dialysis session Transition Between Periods / Washout After the first study period, a 2 week washout period begins (extendable by up to 1 week). During washout, dialysate sodium is set to the pre study level. After washout, the second period begins, and the dialysate sodium concentration is changed at the third dialysis session of the calendar week.

   Purpose of the Structure This structure ensures that measurements are taken at a stable interval between dialysis sessions, minimizing variation in fluid status and blood pressure that could otherwise influence results. It also avoids affecting patients' weekends and is feasible for staff.

   Dialysis treatments continue as usual, with no changes to dialysis duration, frequency, ultrafiltration targets, or other technical parameters. The only modification is the sodium concentration in the dialysate, adjusted to either 133 mmol/L or 139 mmol/L depending on the assigned period.

   Diet and medication remain unchanged throughout the study unless clinical needs require adjustments. Participants are encouraged to follow their usual dietary guidance and medication regimen, and any changes are documented.

10. Methods 10.1 Intervention The intervention consists of hemodialysis with two different sodium concentrations in the dialysate. Dialysate for in center hemodialysis is produced automatically in the dialysis machine, where sterile water from the water purification system in the Dialysis Clinic is mixed with concentrated electrolyte solutions. The machine doses the salts according to the selected settings to achieve the desired dialysate composition. The standard sodium concentration in the dialysate at Gødstrup is 139 mmol/L, but it is normally adjusted individually based on plasma sodium, blood pressure, and fluid overload. In this study, 139 mmol/L is used as the control condition. The lower concentration of 133 mmol/L is chosen based on previous studies and is considered safe and clinically relevant. Participants are randomized to start with either the high or low sodium concentration for three weeks and then cross over after a 2 week (up to 3 week) washout period. The assigned concentration is used for all dialysis sessions during the period.

    10.2 Measurements Ambulatory blood pressure and arterial stiffness Measured using the Mobil O Graph PWA device over 44 hours at baseline and at the end of each intervention period. The device is applied after dialysis on the non fistula arm if the patient has a fistula; otherwise, on the non dominant arm. It performs one measurement per hour and records both blood pressure and pulse wave velocity as an indicator of arterial stiffness. The extended measurement period covers the entire interval between two dialysis sessions, providing a more accurate representation of blood pressure variation.

    Blood samples

    Blood samples are collected at the start of dialysis via the dialysis access. Samples are taken for:

    Plasma sodium (standard analysis at the Department of Clinical Biochemistry, RHG), sent immediately for analysis (4 mL).

    Salt Blood Test (3 mL), analyzed immediately at the University Clinic, Gødstrup. Method: Care Diagnostica, Laborragenzien GmbH, Voerde, DE.

    Plasma nitric oxide (NOx) (4 × 4 mL). Samples are frozen in the biobank and later analyzed using a Sievers NO analyzer based on ozone chemiluminescence detection at the University Clinic, Gødstrup.

    Inflammatory cytokines: IL 17, IFN γ, IL 10, IL 6, IL 1β, IL 17A, TNF α. Samples are frozen in the research biobank and later analyzed at the Department of Molecular Medicine, SDU (3 mL).

    Biobank samples: An additional 14.5 mL of blood is collected and stored (1×4 mL Li Heparin, 1×3 mL K EDTA, 1×3.5 mL citrate, 1×4 mL serum) for later analyses specified in the protocol.

    CO rebreathing

    Total blood volume (erythrocyte and plasma volume) is measured using the CO rebreathing technique (Detalo Clinical™, Detalo Health, Hørsholm). The measurement is performed at the Department of Nuclear Medicine, Gødstrup. The method does not involve radioactivity. Procedure:

    The patient inhales a small, controlled amount of carbon monoxide (CO) through a special device.

    CO binds to hemoglobin, and the device calculates blood volume based on this. A standard blood sample is taken to analyze hemoglobin and gases. The procedure takes approximately 10-15 minutes and does not require advanced equipment or specially trained personnel.

    Body composition analysis Used to assess fluid overload and body composition. This non invasive test measures total body water using electrical impedance. Measurements are performed at baseline and at the end of each intervention period. The test is conducted either with the seca mBCA 515/514 at Nuclear Medicine after blood volume measurement, or with the BCM - Body Composition Monitor (Fresenius Medical Care) in the Dialysis Clinic, with the participant lying supine after at least 2 minutes of rest.

    Questionnaire Completed in week 3 of each study period (Appendix 4) and documents symptoms such as thirst, dizziness, cramps, quality of life, and side effects.

    Dialysis data Nurses record blood pressure drops, ultrafiltration volume, and dry weight as part of routine documentation. From Therapy Manager, start and end blood pressure and the lowest intradialytic blood pressure are extracted.

    Medication registration Information on antihypertensive and anti inflammatory medication is obtained from the national medication database (FMK) at inclusion and any changes are recorded on examination days.

    10.3 Data Management All data are entered into REDCap, a secure research database with restricted access. Questionnaires may be completed electronically or on paper. Paper forms are scanned into REDCap, and originals are stored under the participant's study ID. Biological material is stored in the research biobank under the study ID and will be destroyed no later than at project completion.

    10.4 Statistics All analyses are performed in SPSS or R. The significance level is set at p < 0.05. All data are analyzed to evaluate the effect of dialysate sodium concentration on blood pressure, endothelial function, fluid overload, and inflammatory markers. The study is a randomized crossover design in which each participant serves as their own control.

    Primary comparisons between the two interventions are performed using paired t tests if data are normally distributed. If normality cannot be assumed, the non parametric Wilcoxon signed rank test is used. Normality is assessed by visual inspection (histogram, Q Q plot) and statistical testing (Shapiro Wilk).

    If adjustment for confounders or analysis of repeated measures is required, linear mixed models or repeated measures ANOVA will be used depending on data type and structure.

    Descriptive statistics are used to summarize baseline characteristics and side effect profiles. Correlation analyses (Pearson or Spearman) are used to explore associations between physiological measurements and patient reported outcomes.

    Missing data are handled according to extent and pattern. For sporadic missingness, pairwise deletion is used; for systematic missingness, multiple imputation may be considered if methodologically appropriate.

11. Location The study is conducted at the Dialysis Clinic, Regional Hospital Gødstrup, and at the University Clinic for Kidney Disease and Hypertension, Regional Hospital Gødstrup. The biobank is located at NIDO, Regional Hospital Gødstrup.

12. Duration The project is expected to be approved and ready to start in spring 2026. From that point, the study is planned to run for approximately 3 years, during which inclusion and intervention will take place. All measurements and data collection are integrated into routine clinical workflows and will be completed as participants finish both study periods.

    After completion of the clinical phase, the following steps will take place:

    Processing and analysis of blood samples (NOx, cytokines, Salt Blood Test) Data review and statistical analysis Interpretation of results and preparation of publications The project is expected to be fully completed by 31 December 2030

13. Funding The University Clinic for Kidney Disease and Hypertension, Regional Hospital Gødstrup, is the initiator and responsible institution for the project. The total project budget is approximately DKK 1.000.000 , covering salary for the project investigator, biochemical analyses (both in Gødstrup and at SDU), and nuclear medicine analyses (Department of Nuclear Medicine, Regional Hospital Gødstrup).

    No honorarium is provided to study participants. The project is supported by internal funds and external grants, and applications are submitted continuously to secure full funding.

14. Practical Feasibility The project is conducted in the Dialysis Clinic at Regional Hospital Gødstrup, which treats approximately 120 chronic hemodialysis patients and has extensive experience participating in clinical research projects. The clinic has the necessary technical setup and professional capacity to integrate the project into routine operations.

    Dialysis staff are accustomed to protocol driven workflows and have experience with data documentation, patient management, and research support. Project nurses will assist with implementation and ensure that measurements and data collection are performed systematically and without disrupting routine care.

    All measurements (blood pressure, body composition analysis, CO rebreathing, blood samples) are performed in connection with routine dialysis sessions, minimizing additional burden for patients and supporting high participation rates. Questionnaires are completed electronically or on paper.

    Dialysate sodium concentration is adjusted using existing software and requires no new equipment or changes to the treatment system. The intervention is therefore easy to implement.

    The project is designed with flexibility to allow expansion to additional centers if needed. Approval will be sought if such expansion is pursued. Organizational changes will be addressed through early staff involvement, training, and ongoing support. Experience from previous studies in the clinic shows that this approach ensures high data quality and strong participant retention.

    Established collaborations exist with the Department of Nuclear Medicine, Regional Hospital Gødstrup, for CO rebreathing measurements, and with the research group at SDU, Odense, for analysis of inflammatory markers.

15. Ethical Considerations and Data Disclosure The project will be approved by the Regional Committee on Health Research Ethics before initiation and conducted in accordance with applicable legislation, including the General Data Protection Regulation (GDPR), the Danish Health Act, and the Committee Act. The project is registered in the regional research registry, and procedures are in place for secure handling of personal data and biological material.

    Participation is voluntary, and all patients receive thorough oral and written information. Adequate reflection time is provided, and participation does not affect routine treatment. Patients may withdraw at any time without consequences.

    Before contacting potential participants, the principal investigator reviews the electronic patient record (EPJ) to assess eligibility, including age, dialysis duration, frequency, and plasma sodium. This review is solely for identifying potential candidates, and the data are disclosed only to the investigator. Approximately 75 patient records are expected to be screened to identify eligible participants, as some will meet exclusion criteria and others may decline participation.

    Once informed consent is obtained, relevant data are transferred to the research database (REDCap). The following data are disclosed to the research team:

    From EPJ / FMK:

    • Name, age, sex
    • Medication doses (antihypertensives, diuretics)
    • Cardiac conditions (e.g., heart failure or AMI, including date of diagnosis) or pacemaker (type)
    • Previous stroke or TIA (date of diagnosis)
    • Limb amputation status
    • Type of kidney disease
    • Diabetes status, including medication and most recent HbA1c
    • During the project, additional data from Therapy Manager:
    • Blood pressure before, during, and after dialysis
    • Ultrafiltration volume and dry weight
    • Dialysis parameters (duration, volume, sodium concentration) Participant consent grants the investigator, sponsor, sponsor representatives, and regulatory authorities direct access to the patient's medical records, including electronic records, for information necessary to conduct the study and for monitoring, quality control, and regulatory oversight. Data disclosure follows applicable data protection legislation and is approved by the Ethics Committee. Data are stored securely and used only for purposes described in the protocol.

    Dialysate sodium concentrations used in the study are safe and part of routine clinical practice; therefore, no increased risk is expected. The 44 hour blood pressure monitoring uses low frequency measurements (once per hour) and poses no risk. Blood samples are drawn through the dialysis access and do not require additional needle sticks. The total blood volume collected is 81 mL (40.5 mL per study day), which does not pose a risk to participants.

    Research biobank: Biological material (blood) is stored in a locked research biobank under study ID in accordance with regulations and used for the specified analyses. Some material is stored for later analysis, which will only be performed after Ethics Committee approval. Material is stored for 10 years and then destroyed.

    The project is designed with respect for patient integrity and with focus on minimizing burden and risk. Patient experiences are documented systematically, and clear procedures are in place for handling side effects and withdrawal. Participants are covered by the national patient compensation scheme.

16. Guidelines for Information and Consent During the initial information meeting in the Dialysis Clinic, participants may bring a companion and request a private conversation. Potential participants receive oral and written information ("Participant Information," Appendix 2). They are informed about the study purpose, procedures, and potential side effects, as described in the written material, and about their right to a minimum one week reflection period.

    After the reflection period, written consent (Appendix 3) is obtained if the patient wishes to participate. The investigator signs the consent form to confirm that both oral and written information have been provided as described. Original consent forms are stored in the study file, and a copy is given to the participant.

    If new information arises regarding risks, complications, or disadvantages, or if significant changes are made to the study design, participants will be informed and new consent obtained.

17. Publication and Dissemination The project will be registered on clinicaltrials.org. After study completion, data will be analyzed for publication in an international peer reviewed journal. Regardless of whether results are positive or negative, they will be presented at relevant national and international conferences and specialty forums to contribute to scientific discussion and support evidence based practice.

The project investigator participates actively in a national professional group for physicians involved in dialysis care, and results will also be presented there. This ensures rapid dissemination of findings to clinicians and supports translation into improved patient care.

Inclusion Criteria:

• Adults receiving chronic in-center hemodialysis at Regional Hospital Gødstrup
• Age ≥ 18 years
• On thrice-weekly hemodialysis for a stable period (as assessed in EPJ)
• Plasma sodium within the range required for safe participation (as per screening)
• Able to understand study information and provide written informed consent
• Eligible based on review of electronic patient record (dialysis duration, frequency, age, p-sodium)

Exclusion Criteria:

• Significant cardiac disease that may interfere with participation, including:
• Heart failure (with clinically relevant instability)
• Recent acute myocardial infarction (date verified in EPJ)
• Pacemaker (specific types that interfere with measurements)
• History of stroke or TCI (date verified in EPJ)
• Amputation of an extremity (affects body composition measurements)
• Diabetes with unstable glycemic control or recent major treatment changes
• Any condition that prevents accurate blood pressure measurement or CO-rebreathing
• Inability to complete study procedures (questionnaires, monitoring, blood sampling)
• Expected inability to complete both intervention periods (e.g., planned transfer, transplantation)
• Declines participation after receiving oral and written information

IPD that underlie results in a publication will be available upon reasonable request to the corresponding author after publication. Data will be shared with researchers who provide a methodologically sound proposal and for the purpose of achieving the aims of the approved proposal. Access may require a data sharing agreement in accordance with institutional and ethical regulations.

From publication (date unknown) untill 5 years after publication.

De-identified individual participant data underlying the results reported in this study will be available to researchers upon reasonable request to the corresponding author after publication. Data will be shared with researchers who provide a methodologically sound proposal and whose proposed use aligns with the aims of the approved project. Access may require a data sharing agreement in accordance with institutional and ethical regulations. Details regarding which data will be shared and the method of access will be arranged between the corresponding author and the requesting researcher.