Modulation of Tissue Sodium in Hemodialysis Patients

Study Overview
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Brief Summary
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Salt (NaCl) intake is implicated in causing hypertension and cardiovascular disease, the commonest cause of death worldwide. The investigators recently established that Na+ is stored in tissues, bound to glycosaminoglycans (GAGs) in skin and muscle. The resulting local hypertonicity leads to immune cell-driven induction of local tissue electrolyte clearance via modulation of cutaneous lymph capillary density. To visualize these complex processes in man directly, the investigators established Na+ magnetic resonance imaging (23Na-MRI) and investigated Na+ stores in hemodialysis (HD) patients. Hemodialysis patients were sodium-overloaded and HD treatment lowered tissue Na+ stores in this study. The observed effects were highly variable and independent of Na+ or water removal from the body during a dialysis session. Tissue Na+ mobilization correlated with circulating vascular endothelial growth factor-C (VEGF-C). The investigators believe that excessive Na+ storage is a reversible condition and therefore susceptible for therapeutic interventions. The investigators hypothesize that lowering dialysate Na+ concentration may favorably affect accelerated tissue Na+ accumulation in hemodialysis patients. Besides, improved tissue Na+ storage, osmostress-induced as well as pro-inflammatory immune cell response should be affected by such a revised dialysis management.

Detailed Description
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To evaluate effects of moderate reduction of dialysate Na+ concentration on tissue Na+ content the investigators intend to recruit 40 hemodialysis patients, who will be offered a therapeutic change of their dialysate Na+ concentration. After detection of tissue Na+ content using 23Na-MRI technique, the applied dialysate [Na+] will be initially increased stepwise by 2 mmol/l per week from 138 to 142 mmol/l and maintained for a period of 5 weeks. After another 23Na-MRI measurement, dialysate [Na+] will then be lowered stepwise by 1-2 mmol/l per week to a minimum of 135 mmol/l, which will be also maintained for a period of 5 weeks followed by a final 23Na-MRI assessment. Hypothesis: Reduction of dialysate Na+ concentration will decrease tissue sodium storage. Additionally, the investigators will assess changes in body fluid distribution by bioimpedance spectroscopy. Furthermore, vascular compliance in response to the modulation of dialysate [Na+] and its correlation with tissue Na+ will be assessed. To investigate the immune response to tissue Na+ accumulation, the osmostress-induced as well as pro-inflammatory immune cell response of isolated monocytes will be quantified.

Official Title
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Impact of Changes in Dialysis Sodium Concentration on Tissue Sodium Storage in Hemodialysis Patients

Conditions
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Chronic Kidney Disease Requiring Chronic Dialysis

Intervention / Treatment
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* Procedure: Change of dialysate [Na+]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic Kidney Disease Stage 5D, hemodialysis performed for at least 6 months, three times hemodialysis per week, signed informed consent Exclusion Criteria: Pregnancy, severe heart failure (NYHA III - IV), severe liver disease (CHILD C), acute infection, pacemaker or other non-MRI suitable conditions, hyponatremia < 132 mmol/l

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: dialysate [Na+] 138 mmol/l<br>Intervention: Change of dialysate [Na+] from 138 mmol/l to 142 mmol/l The dialysate [Na+] will be increased by 2 mmol/l per week and kept constant for 5 weeks (altogether 6 weeks). Before and after intervention tissue [Na+] will be determined by sodium MRI. Additionally body fluid distribution (by bioimpedance spectroscopy) and central arterial pressure wave form, pulse wave velocity as well as flow-mediated vasodilatation will be assessed. | Procedure: Change of dialysate [Na+]<br>* Stepwise modulation of dialysate sodium concentration by 1-2 mmo/l per week<br>|
| Active Comparator: dialysate [Na+] 142 mmol/l<br>Intervention: Change of dialysate [Na+] from 142 mmol/l to 135 mmol/l The dialysate [Na+] will be decreased by 2 mmol/l per week for 3 weeks and by 1mmol/l for 1 further week. Afterwards the dialysate [Na+] will be kept constant for 5 weeks (altogether 8 weeks). Before and after intervention tissue [Na+] will be determined by sodium MRI. Additionally body fluid distribution (by bioimpedance spectroscopy) and central arterial pressure wave form, pulse wave velocity as well as flow-mediated vasodilatation will be assessed. | Procedure: Change of dialysate [Na+]<br>* Stepwise modulation of dialysate sodium concentration by 1-2 mmo/l per week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tissue sodium content | Tissue sodium content measured by 23Na MRI | 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lymphangiogenic profile | Serum VEGF-C and sFLT4 levels will be determined | 14 weeks | 
| Body fluid distribution (extracellular and intracellular water) | Change in body fluid distribution will be assessed by body composition monitor (bioimpedance spectroscopy) | 14 weeks | 
| Pulse wave analysis and pulse wave velocity | Change in central arterial pressure wave form and pulse wave velocity will be analyzed by SphygmoCor | 14 weeks | 
| Flow-mediated vasodilatation (FMD) | Measurement of vasodilatation and thereby arterial stiffness by a semi-automated ultrasound System (UNEXEF) | 14 weeks | 
| Immune response to tissue Na+ accumulation | Blood monocytes will be isolated and their osmotic and inflammatory response will be determined | 14 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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23Na MRI