The Role of Skin Sodium Accumulation in Chronic Kidney Disease

Not Applicable

Recruiting

• Conditions: Chronic Kidney Diseases
• Interventions: Drug: Hydrochlorothiazide; Dietary Supplement: High sodium dietary intake (>200mmol/l); Dietary Supplement: High water intake; Drug: Spironolactone; Dietary Supplement: Low sodium dietary intake (<50mmol/l); Dietary Supplement: Habitual water intake; Drug: Lercanidipine

• Registration Number: NCT07020104
• Lead Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Brief Summary

This project consists of four substudies: a cohort study (A) and a sodium intake intervention (B) and a sodium excretion intervention (C) and a water intervention study (D).

The main objective of the cohort study (A) is to investigate the prognostic implications of tissue sodium accumulation in CKD patients. The primary objective of the sodium intervention studies is to study the effect of high and low sodium intake (B) and increased renal sodium excretion (C) on tissue sodium content. The main objective of the water intervention study (D) is to investigate the effect of increased and habitual water intake on tissue sodium content and transepidermal water loss.

Detailed Description

Cohort study (A):

60 CKD patients (eGFR 15 - 60 ml/min/1.73m2) are included in this cohort study. At the start of the study the association between tissue sodium content and micro-and macrovascular function will be evaluated. These patients will be followed up to investigate the association between tissue sodium content, quality of life and renal and cardiovascular events.

Sodium intake intervention (B):

A subgroup of 14 CKD patients (eGFR 15 - 60 ml/min/1.73m2) will be randomized to a 2-week low sodium diet and a 2-week high sodium diet in a cross-over study.

Sodium excretion intervention (C):

A subgroup of 12 CKD patients (eGFR 30 - 60 ml/min/1.73m2) with hypertension will be randomized to receive 6 weeks of treatment with hydrochlorothiazide, spironolactone and lercanidipine in a randomized open-label cross-over trial.

Water intake intervention (D) A subgroup of 12 CKD patients (with eGFR 15-30 ml/min/1.73m2, hypertension and fasting morning urine osmolality \< 425 mOsm/kg for men and \< 400 mOsm/kg for women) will be randomized to a 4-week habitual water intake and 4-week increased water intake in a cross-over study.

Study Timeline

• Study Start: 2025-01-07
• Study First Submitted: 2025-04-15
• Status Verified: 2025-06
• Study First Submitted QC: 2025-06-05
• Last Update Submitted: 2025-06-05
• Study First Posted: 2025-06-13
• Last Update Posted: 2025-06-13
• Primary Completion: 2039-12-01
• Study Completion: 2039-12-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

1. Chronic kidney disease with an eGFR between 15 and 60 ml/min/1.73m2.
2. Stable diuretic and antihypertensive treatment for the previous 6 weeks.

Additional inclusion criteria for the sodium excretion intervention 1. Office systolic blood pressure (SBP) >135 mmHg

Additional inclusion criteria for the water intervention

1. Chronic kidney disease with an eGFR between 15 and 29 ml/min/1.73m2
2. Office blood pressure ≥140/90 mmHg or use of antihypertensive medication
3. Fasting morning urine osmolality <425 mOsm/kg for men and < 400 mOsm/kg for women

Exclusion Criteria

1. Age <18 years.
2. The patient is expected to start renal replacement therapy or is planned to receive a kidney transplantation within 3 months.
3. An active diagnosis of nephrotic syndrome at inclusion.
4. (Recurrent) acute glomerulonephritis within 1 year prior to the study.
5. Salt losing nephropathy.
6. Use of oral or intravenous glucocorticoids with an equivalent of prednisolone >5mg/day.
7. Contra-indication for MRI.
8. Cardiovascular event/ surgery in the previous 3 months.
9. Pregnant women, women of child bearing age planning to conceive for the study duration, women of child bearing age without contraception.
10. Participation in other (pharmacological) intervention studies.
11. Presence of significant comorbidities with a life expectancy of less than 1 year.
12. Disorder that compromises the participants' ability to give truly informed consent for participation in this study.
13. Patients with an active infection and/or auto-immune diseases with involvement of the lower extremities.
14. Any other issues that in opinion of the investigator could be harmful to the subject or compromise interpretation of the data.

Additional exclusion criteria for the sodium intake intervention

1. Chronic use of NSAID

Additional exclusion criteria for the sodium excretion intervention

1. Serum potassium concentration >5.0 mmol/l.
2. eGFR <30 ml/min/1.73m2
3. Uncontrolled hypertension (>180/100 mmHg)
4. Severe heart failure with left ventricular ejection fraction <30%.
5. Contra-indication for investigational drugs.
6. Severe symptoms of (orthostatic) hypotension.
7. Patients with obstruction of the outflow tract of the left ventricle such as aortic valve stenosis.
8. Refractory hypokalemia, hyponatremia or hypercalcemia.
9. Severe liver insufficiency Child Pugh B/C
10. Chronic use of NSAID.

Additional exclusion criteria for the water intake intervention

1. Recent history of severe hyponatremia (outpatient plasma sodium < 130 mmol/L in the last 6 months)
2. Plasma sodium <135 mmol/L at screening
3. History of heart failure
4. Use of lithium, vasopressin analoga, vasopressin antagonists, oral or intravenous glucocorticoids, thiazide diuretics.
5. 24-hour urine volume > 2L
6. Chronic use of NSAID

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Sodium excretion intervention (C)	Hydrochlorothiazide	In this intervention group, the patients will receive three antihypertensive drugs in a randomized order. Thus the following orders are possible: 1. Lercanidipine - Spironolactone - Hydrochlorothiazide 2. Lercanidipine - Hydrochlorothiazide - Spironolactone 3. Hydrochlorothiazide - Lercanidipine - Spironolactone 4. Hydrochlorothiazide - Spironolactone - Lercanidipine 5. Spironolactone - Lercanidipine - Hydrochlorothiazide 6. Spironolactone - Hydrochlorothiazide- Lercanidipine
Sodium excretion intervention (C)	Spironolactone	In this intervention group, the patients will receive three antihypertensive drugs in a randomized order. Thus the following orders are possible: 1. Lercanidipine - Spironolactone - Hydrochlorothiazide 2. Lercanidipine - Hydrochlorothiazide - Spironolactone 3. Hydrochlorothiazide - Lercanidipine - Spironolactone 4. Hydrochlorothiazide - Spironolactone - Lercanidipine 5. Spironolactone - Lercanidipine - Hydrochlorothiazide 6. Spironolactone - Hydrochlorothiazide- Lercanidipine
Sodium excretion intervention (C)	Lercanidipine	In this intervention group, the patients will receive three antihypertensive drugs in a randomized order. Thus the following orders are possible: 1. Lercanidipine - Spironolactone - Hydrochlorothiazide 2. Lercanidipine - Hydrochlorothiazide - Spironolactone 3. Hydrochlorothiazide - Lercanidipine - Spironolactone 4. Hydrochlorothiazide - Spironolactone - Lercanidipine 5. Spironolactone - Lercanidipine - Hydrochlorothiazide 6. Spironolactone - Hydrochlorothiazide- Lercanidipine
Sodium intake intervention (B)	High sodium dietary intake (>200mmol/l)	In this intervention group, the patients will receive two sodium diets in a randomized order. The following orders are possible: 1. High sodium intake- Low sodium intake 2. Low sodium intake- High sodium intake
Sodium intake intervention (B)	Low sodium dietary intake (<50mmol/l)	In this intervention group, the patients will receive two sodium diets in a randomized order. The following orders are possible: 1. High sodium intake- Low sodium intake 2. Low sodium intake- High sodium intake
Water intake intervention (D)	High water intake	In this intervention group, the patients will be prescribed two water interventions in a randomized order. The following orders are possible: 1. High water intake- Habitual water intake 2. Habitual water intake- High water intake
Water intake intervention (D)	Habitual water intake	In this intervention group, the patients will be prescribed two water interventions in a randomized order. The following orders are possible: 1. High water intake- Habitual water intake 2. Habitual water intake- High water intake

Primary Outcome Measures

Name	Time	Method
Skin sodium content at baseline (A)	0 week	Skin sodium content will be measured using the 7T sodium MRI
Muscle sodium content at baseline (A)	0 week	Muscle sodium content will be measured using the 7T sodium MRI
Change from baseline in tissue sodium content after low and high sodium diet (B)	2 weeks
Change in tissue sodium content after treatment with hydrochloorthiazide, spironolacton and lercanidipine (C)	6 weeks	To study the effect of hydrochloorthiazide, spironolacton and lercanidipine on tissue sodium content, to compare the effect among the various antihypertensive agents and to assess the effect of blood pressure regulation, increased renal sodium excretion and aldosteron blockade on tissue sodium content.
Change from baseline in tissue sodium content after habitual and high water intake (D)	4 weeks	To evaluate the effect of high and habitual water intake on tissue sodium content.
Change from baseline in transepidermal water loss after habitual and high water intake (D)	4 weeks	To evaluate the effect of high and habitual water intake on transepidermal water loss.
Incidence of hyponatremia and hypervolemia (D)	4 weeks	Safety of high water intake in CKD patients with eGFR between 15 and 30ml/min/1.73m2

Secondary Outcome Measures

Name	Time	Method
Correlation between tissue sodium content and total vessel density (A)	0 week	Correlation between tissue sodium content measured with 7T Na-MRI and total vessel density using Sidestream Dark Field imaging.
Correlation between tissue sodium content and perfused vessel density (A)	0 week	Correlation between tissue sodium content measured with 7T Na-MRI and perfused vessel density using Sidestream Dark Field imaging.
Correlation between tissue sodium content and proportion of perfused vessels (A)	0 week	Correlation between tissue sodium content measured with 7T Na-MRI and proportion of perfused vessels using Sidestream Dark Field imaging.
Correlation between tissue sodium content and microvascular flow index (A)	0 week	Correlation between tissue sodium content measured with 7T Na-MRI and microvascular flow index using Sidestream Dark Field imaging.
Correlation between tissue sodium content and microvascular health score (A)	0 week	Correlation between tissue sodium content measured with 7T Na-MRI and microvascular health score using Sidestream Dark Field imaging.
Correlation between tissue sodium content and total pheripheral resistance (A)	0 week	Total pheripheral resistance will be measured using the Nexfin device and tissue sodium content will be measured using the 7T Na-MRI
Correlation between tissue sodium content and cardiac output (A)	0 week	Cardiac output will be measured using the Nexfin device and tissue sodium content will be measured using the 7T Na MRI
Change from baseline in percentage of patients with a night-time blood pressure dipping pattern (B/C/D)	2 weeks	Nighttime blood pressure dipping status will be measured with a 24-hour blood pressure measurements. Patients will be classified as a 'dippers' when the nighttime systolic blood pressure and/or diastolic blood pressure falls \>10% and \<20% compared to daytime readings. Exteme dippers are described as those with blood pressure fall of at least 20%. Patients with blood pressure fall between 0 and 10% are classified as non-dippers.
Change from baseline in transepidermal water loss (B/C/D)	2 weeks	Transepidermal water loss will be measured with the Tewameter® TM Hex probe
Change from baseline in total body water (B/C/D)	2 weeks	Total body water will be measured using the bioelectrical impendance analysis
Change from baseline in total vessel density (B/C/D)	2 weeks	The total vessel density will be measured using Sidestream Dark Field imaging.
Change from baseline in perfused vessel density (B/C/D)	2 weeks	The perfused vessel density will be measured using Sidestream Dark Field imaging.
Change from baseline in proportion of perfused vessel (B/C/D)	2 weeks	The proportion of perfused vessels will be measured using Sidestream Dark Field imaging.
Change from baseline in microvascular flow index (B/C/D)	2 weeks	The microvascular flow index will be measured using Sidestream Dark Field imaging.
Change from baseline in microvascular health score (B/C/D)	2 weeks	The microvascular health score will be measured using Sidestream Dark Field imaging.
Change from baseline in total peripheral resistance (B/C/D)	2 weeks	The total pheripheral resistance will be measured using the Nexfin device
Change from baseline in cardiac output (B/C/D)	2 weeks	The cardiac output will be measured using the Nexfin device
Change from baseline in seated systolic and diastolic office blood pressure (B/C/D)	2 weeks	Seated office systolic and diastolic blood pressure after interventions compared to baseline
Correlation between tissue sodium content and total body water (A)	0 week	Total body water (liter) will be measured using the bioelectrical impendance analysis and tissue sodium content will be measured using the 7T Na MRI
Change from baseline in 24-hour systolic and diastolic blood pressure (B/C/D)	2 weeks	24-hour systolic and diastolic blood pressure after interventions compared to baseline
The correlation between tissue sodium content and traditional cardiovascular risk factors (A)	15 years	In the cohort study, the correlation between tissue sodium content measured with 7T Na MRI and the known traditional cardiovascular risk factors will be studied.
Correlation between tissue sodium content and transepidermal water loss (A)	0 week	Transepidermal water loss will be measured with the Tewameter® TM Hex probe and tissue sodium content will be measured using the 7T Na MRI
Correlation between tissue sodium content and office systolic and diastolic blood pressure (A)	0 week	Tissue sodium content will be measured using the 7T sodium MRI
Correlation between tissue sodium content and quality of life (A)	At baseline and yearly during follow-up	Quality of life(QoL) will be measured with the Kidney Disease Quality of Life questionnaire at baseline and yearly during follow-up and tissue sodium comntent will be measured using the 7T Na MRI at baseline
Correlation between tissue sodium content and 24-hour systolic and diastolic blood pressure (A)	0 week	Tissue sodium content will be measured using the 7T Na MRI
Correlation between tissue sodium content and nightime blood pressure dipping pattern (A)	0 week	The nighttime blood pressure dipping pattern will be measured with a 24-hour blood pressure measurements. Patients will be classified as a 'dippers' when the nighttime systolic blood pressure and/or diastolic blood pressure falls \>10% and \<20% compared to daytime readings. Exteme dippers are described as those with blood pressure fall of at least 20%. Patients with blood pressure fall between 0 and 10% are classified as non-dippers.
Change from baseline in plasma co-peptine concentrations (D)	4 weeks	For waterintake intervention study

Trial Locations

Locations (1)

Amsterdam UMC; 🇳🇱 Amsterdam-Zuidoost, North Holland, Netherlands