The Microcirculation, Dialysis Modality and Sequestered Salt (MIMOSA)

The aim of this clinical trial is to investigate the effect of 5 different dialysis treatments (combinations of dialysis mode and dialysis fluid sodium content) on the microcirculation (MC) and sequestered sodium content (SSC) in adult prevalent end-stage kidney disease (ESKD) patients treated with hemodialysis (HD) or hemodiafiltration (HDF). The main questions it aims to answer are:

1. What are the effects on the sequestered sodium content and microcirculation after 4 weeks of treatment with the following dialysis modes?

   • HDF with an expected zero diffusive sodium balance (Dialysate sodium concentration (DNa)= Plasma sodium concentration (PNa)) compared to
   • HDF with an expected diffusive sodium efflux (DNa < PNa, difference 3 mmol/L) compared to
   • HD with an expected zero diffusive sodium balance (DNa = PNa) compared to
   • HD with an expected diffusive sodium efflux (DNa < PNa, difference 3 mmol/L) compared to
   • Isolated ultrafiltration for 30 minutes followed by HD with an expected zero diffusive sodium balance (DNa = PNa)
2. Are the SSC and MC interrelated in this patient group?

This study is a randomized cross-over trial. Participants will be subjected to the abovementioned dialysis treatment modes in random order.

Study Overview

• Status: Not yet recruiting
• Conditions: End-stage Renal Disease
• Intervention / Treatment: Device: Hemodialysis (DNa; Device: Hemodialysis after isolated ultrafiltration (DNa=PNa); Device: High volume hemodiafiltration (DNa=PNa); Device: High volume hemodiafiltration (DNa; Device: Hemodialysis (DNa = PNa)

Detailed Description

The life expectancy of patients with end-stage kidney disease (ESKD) is poor. Post-dilution online hemodiafiltration (HDF) is associated with a lower mortality than standard hemodialysis (HD), especially when a high convection volume is achieved (high-volume HDF; hvHDF). It is unclear, however, why (hv)HDF improves survival. Neither an increased clearance of middle molecular weight uremic toxins, nor an improved bio-incompatibility can explain the difference. As the effects are already observed within 2.5 years, recovery of a functional disorder is more likely than restoration of structural alterations. The recuperation of vascular dysfunction may be the missing piece of the puzzle. Previous literature showed (1) that the microcirculation (MC) is severely disturbed in dialysis patients, (2) excess sodium can bind to glycosaminoglycans in the interstitium and in the glycocalyx of blood vessels without commensurate water retention (sequestered sodium content [SSC]) and (3) that in patients with non-dialysis dependent chronic kidney disease, a disturbed SSC is related to capillary rarefaction and dysfunction. Therefore, the present study aims to assess the influences of both the modality (HD and HDF) and the dialysate sodium concentration (DNa) on the SSC and the MC.

Therefore the following hypotheses will be evaluated: (1, 2) treatment with hvHDF improves the SSC and MC, if compared to HD; (3, 4) disorders of the SSC and the MC are influenced by differences between the dialysate sodium [DNa] and plasma sodium [PNa] concentrations; (5) SSC and MC are interrelated in this patient group.

• Study Type: Interventional
• Enrollment (Estimated): 22
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Muriel PC Grooteman, MD PhD; Phone Number: +3120 566 5990; Email: mpc.grooteman@amsterdamumc.nl
• Study Contact Backup: Name: Sabrine Chaara, MD; Phone Number: +316463173499; Email: s.chaara@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥18 years
• Treatment with HD or HDF 3 x per week during at least 4 hours for at least 3 months
• Blood flow rate feasiblity of ≥350 ml/min
• Residual diuresis <200 ml/day
• Plasma Na before dialysis 137-145 mmol/L at baseline
• spKt/Vurea ≥ 1.2
• Ability to understand study procedures and willingness to provide informed consent

Exclusion Criteria:

• Severe incompliance to dialysis procedure and accompanying prescriptions, especially frequency and duration of dialysis treatment
• Life expectancy < 3 months due to non-renal disease
• Expected transplantation within 6 months
• Access recirculation > 10%
• Participation in another clinical intervention trial
• Metal implants (e.g. implantable cardioverter defibrillators)
• Severe obesity (MRI Ø 60 cm ≈ abdominal circumference ≤ 188 cm)
• Claustrophobia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Hemodialysis (DNa=PNa); High-flux hemodialysis with expected diffusive zero sodium balance (DNa=PNa)	Device: Hemodialysis (DNa; High-flux hemodialysis with expected diffusive sodium efflux (DNa; Device: Hemodialysis after isolated ultrafiltration (DNa=PNa); High-flux hemodialysis after isolated ultrafiltration with an expected zero diffusive sodium balance (DNa=PNa); Device: High volume hemodiafiltration (DNa=PNa); High volume hemodiafiltration with an expected zero diffusive sodium balance (DNa=PNa) Convection volume: ≥23L/session; Device: High volume hemodiafiltration (DNa; High volume hemodiafiltration with expected diffusive sodium efflux (DNa
Active Comparator: Hemodialysis (DNa<PNa); High-flux hemodialysis with expected diffusive sodium efflux (DNa<PNa, difference: 3 mmol/L)	Device: Hemodialysis after isolated ultrafiltration (DNa=PNa); High-flux hemodialysis after isolated ultrafiltration with an expected zero diffusive sodium balance (DNa=PNa); Device: High volume hemodiafiltration (DNa=PNa); High volume hemodiafiltration with an expected zero diffusive sodium balance (DNa=PNa) Convection volume: ≥23L/session; Device: High volume hemodiafiltration (DNa; High volume hemodiafiltration with expected diffusive sodium efflux (DNa; Device: Hemodialysis (DNa = PNa); High-flux hemodialysis with an expected zero diffusive sodium balance (DNa = PNa)
Active Comparator: Hemodialysis after isolated ultrafiltration (DNa=PNa); High-flux hemodialysis after isolated ultrafiltration with expected zero sodium balance (DNa=PNa)	Device: Hemodialysis (DNa; High-flux hemodialysis with expected diffusive sodium efflux (DNa; Device: High volume hemodiafiltration (DNa=PNa); High volume hemodiafiltration with an expected zero diffusive sodium balance (DNa=PNa) Convection volume: ≥23L/session; Device: High volume hemodiafiltration (DNa; High volume hemodiafiltration with expected diffusive sodium efflux (DNa; Device: Hemodialysis (DNa = PNa); High-flux hemodialysis with an expected zero diffusive sodium balance (DNa = PNa)
Active Comparator: High volume hemodiafiltration (DNa=PNa); High volume hemodiafiltration with expected diffusive zero sodium balance (DNa=PNa)	Device: Hemodialysis (DNa; High-flux hemodialysis with expected diffusive sodium efflux (DNa; Device: Hemodialysis after isolated ultrafiltration (DNa=PNa); High-flux hemodialysis after isolated ultrafiltration with an expected zero diffusive sodium balance (DNa=PNa); Device: High volume hemodiafiltration (DNa; High volume hemodiafiltration with expected diffusive sodium efflux (DNa; Device: Hemodialysis (DNa = PNa); High-flux hemodialysis with an expected zero diffusive sodium balance (DNa = PNa)
Active Comparator: High volume hemodiafiltration (DNa<PNa); High volume hemodiafiltration with expected diffusive sodium efflux (DNa<PNa, difference: 3 mmol/L)	Device: Hemodialysis (DNa; High-flux hemodialysis with expected diffusive sodium efflux (DNa; Device: Hemodialysis after isolated ultrafiltration (DNa=PNa); High-flux hemodialysis after isolated ultrafiltration with an expected zero diffusive sodium balance (DNa=PNa); Device: High volume hemodiafiltration (DNa=PNa); High volume hemodiafiltration with an expected zero diffusive sodium balance (DNa=PNa) Convection volume: ≥23L/session; Device: Hemodialysis (DNa = PNa); High-flux hemodialysis with an expected zero diffusive sodium balance (DNa = PNa)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Skin microcirculation	Skin microcirculatory perfusion/vasoreactivity (arbitrary units) measured with a laser speckle contrast analysis (LASCA) perfusion imager	up to 20 weeks; assessed every 4 weeks before the last dialysis session of each treatment period (i.e. 5 times in total)
Sequestered salt content (SSC)	SSC measured with a 7 Tesla 23-Sodium MRI	up to 20 weeks; assessed every 4 weeks before the last dialysis session of each treatment period (i.e. 5 times in total)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intradialytic hypotension	A systolic blood pressure (SBP) ≤ 90 mmHg in patients with a pre-dialysis SBP < 160 mmHg and a SBP < 100 mmHg in patients with a pre-dialysis SBP ≥ 160 mmHg.	up to 4 hours (=one dialysis treatment); assessed during all dialysis sessions (12 treatments per intervention, measured 4x/hour)
Change in intradialytic blood pressure	Change in systolic and diastolic blood pressure (mmHg) during one dialysis session	up to 4 hours (=one dialysis treatment); assessed during all dialysis sessions (12 treatments per intervention, measured 4x/hour)
Peridialytic blood pressure	Change in systolic and diastolic blood pressure (mmHg) between dialysis sessions	up to 24 hours (=one interdialytic day): measured 3x/day every 4 weeks during the last interdialytic day of each treatment period (i.e. 5 times in total)
Change in CK-MB	Marker of cardiac damage, assessment in blood from arterial line of extracorporeal circuit	up to 4 hours (=one dialysis treatment); measured before and immediately after the last dialysis session of each treatment period (i.e. 10 times in total)
Change in high sensitivity C-reactive protein (hs-CRP)	Marker of inflammation, assessment in blood from arterial line of extracorporeal circuit	up to 4 hours (=one dialysis treatment); measured before and immediately after the last dialysis session of each treatment period (i.e. 10 times in total)
Change in interleukin-6 receptor (IL-6R)	Marker of inflammation, assessment in blood from arterial line of extracorporeal circuit	up to 4 hours (=one dialysis treatment); measured before and immediately after the last dialysis session of each treatment period (i.e. 10 times in total)
Change in soluble CD163 (sCD163)	Marker of inflammation, assessment in blood from arterial line of extracorporeal circuit	up to 4 hours (=one dialysis treatment); measured before and immediately after the last dialysis session of each treatment period (i.e. 10 times in total)
Change in soluble intercellular adhesion molecule-1 (s-ICAM-1)	Marker of inflammation, assessment in blood from arterial line of extracorporeal circuit	up to 4 hours (=one dialysis treatment); measured before and immediately after the last dialysis session of each treatment period (i.e. 10 times in total)
Change in serum glycosaminoglycans	Marker related to sequestered sodium content, assessment in blood from arterial line of extracorporeal circuit	up to 4 hours (=one dialysis treatment); measured before and immediately after the last dialysis session of each treatment period (i.e. 10 times in total)
Change in syndecan-1	Marker related to sequestered sodium content, assessment in blood from arterial line of extracorporeal circuit	up to 4 hours (=one dialysis treatment); measured before and immediately after the last dialysis session of each treatment period (i.e. 10 times in total)
Change in vascular endothelial growth factor C (VEGF-C)	Marker related to sequestered sodium content, assessment in blood from arterial line of extracorporeal circuit	up to 4 hours (=one dialysis treatment); measured before and immediately after the last dialysis session of each treatment period (i.e. 10 times in total)
Change in extracellular vesicles (EVs)	Marker for tissue-injury and inflammation, assessment in blood from arterial line of extracorporeal circuit	up to 4 hours (=one dialysis treatment); measured before and immediately after the last dialysis session of each treatment period (i.e. 10 times in total)
Change in skin microcirculation	Change in skin microcirculatory perfusion/vasoreactivity (arbitrary units) measured with a laser speckle contrast analysis (LASCA) perfusion imager during one dialysis session. This will be assessed in 5 patients only.	up to 4 hours (=one dialysis treatment); measured before and immediately after the last dialysis session of each treatment period (i.e. 10 times in total)
Change in sequestered salt content (SSC)	Change in SSC measured with a 7 Tesla 23-Sodium MRI during one dialysis session. This will be assessed in 5 patients only.	up to 4 hours (=one dialysis treatment); measured before and immediately after the last dialysis session of each treatment period (i.e. 10 times in total)
modified Dialysis symptom index (mDSI)	Standardized questionnaire for the evaluation of physical symptoms and recovery time in dialysis patients, consisting of 13 items. Participants rate the severity of each item on a 5-point likert scale, ranging from 0 ('not at all') to 4 ('very much'). Higher scores indicate a greater perceived severity of symptoms.	up to 20 weeks; evaluated every 4 weeks, during/after the last dialysis session of each treatment period
Thirst distress scale (TDS)	The thirst distress scale is a 6-item questionnaire that measures thirst distress on a scale from 1 to 5, where 1 corresponds to 'Strongly disagree' and 5 to 'Strongly agree'. Higher scores indicate greater perceived thirst distress.	up to 20 weeks; evaluated every 4 weeks, during/after the last dialysis session of each treatment period
EQ Visual analogue scale (EQ VAS)	The EQ VAS records the patients's self-rated health-related quality of life on a vertical visual analogue scale where 0 means 'the worst health you can imagine' and 100 means 'the best health you can imagine'. Higher scores indicate a better perceived health-related quality of life.	up to 20 weeks; evaluated every 4 weeks, during/after the last dialysis session of each treatment period

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Collaborators: Dutch Kidney Foundation; B.Braun Avitum AG; Niercentrum aan de Amstel
• Investigators: Principal Investigator: Muriel PC Grooteman, MD PhD, Amsterdam UMC

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: February 21, 2024
• First Submitted That Met QC Criteria: March 22, 2024
• First Posted (Actual): March 25, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Hemodialysis; Microcirculation; Hemodiafiltration; Sequestered salt content
• Additional Relevant MeSH Terms: Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease Attributes; Renal Insufficiency; Renal Insufficiency, Chronic; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Failure, Chronic
• Other Study ID Numbers: NL83566.018.24

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No