The Role of Skin Sodium Accumulation in Chronic Kidney Disease

N/ARecruitingNCT07020104

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)60 enrolled

Overview

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.

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

OTHER

Masking

NONE

Enrollment

Interventions

HydrochlorothiazideDRUG

Each patient will receive 1 tablet of hydrochlorothiazide 12.5mg once a day for the first 3 weeks of the drug cycle. If clinical and biochemical parameters allow, the dosage is doubled to 2 tablets of hydrochlorothiazide 12.5mg once daily for the following 3 weeks. If the laboratory results and clinical parameters do not allow dose intensification, the initial dosage will be continued during the second half of the drug cycle.

SpironolactoneDRUG

Each patient will receive 1 tablet of spironolacton 12.5mg once a day for the first 3 weeks of the drug cycle. If clinical and biochemical parameters allow, the dose is doubled to 2 tablets of spironolacton 12.5mg once daily for the following 3 weeks. If the laboratory results and clinical parameters do not allow dose intensification, the initial dosage will be continued during the second half of the drug cycle.

LercanidipineDRUG

Each patients will receive 1 tablet of lercanidipine 10mg once a day for the first 3 weeks of the drug cycle. If clinical and biochemical parameters allow, the dose is doubled to 2 tablets of lercanidipine 10mg once daily for the following 3 weeks. If the laboratory results and clinical parameters do not allow dose intensification, the initial dosage will be continued during the second half of the drug cycle.

High sodium dietary intake (>200mmol/l)DIETARY_SUPPLEMENT

The patients will receive a 2-week high sodium diet. The patients will receive dietary advice to achieve this goal of \>200mmol/l sodium (\>12g salt) intake per day.

Low sodium dietary intake (<50mmol/l)DIETARY_SUPPLEMENT

The patients will receive a 2-week low sodium diet. The patients will receive dietary advice to achieve this goal of \<50mmol/l sodium (\<3g salt) intake per day.

High water intakeDIETARY_SUPPLEMENT

During the increased water intake period, the patients will be instructed to drink 1 L more than their mean 24-hour urine volume at screening and baseline.

Habitual water intakeDIETARY_SUPPLEMENT

During this part of the intervention, the patients will be instructed to maintain their habitual water intake.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Skin sodium content at baseline (A)

Skin sodium content will be measured using the 7T sodium MRI

Time frame: 0 week

Muscle sodium content at baseline (A)

Muscle sodium content will be measured using the 7T sodium MRI

Time frame: 0 week

Change from baseline in tissue sodium content after low and high sodium diet (B)

Time frame: 2 weeks

Change in tissue sodium content after treatment with hydrochloorthiazide, spironolacton and lercanidipine (C)

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.

Time frame: 6 weeks

Change from baseline in tissue sodium content after habitual and high water intake (D)

To evaluate the effect of high and habitual water intake on tissue sodium content.

Time frame: 4 weeks

Change from baseline in transepidermal water loss after habitual and high water intake (D)

To evaluate the effect of high and habitual water intake on transepidermal water loss.

Time frame: 4 weeks

Incidence of hyponatremia and hypervolemia (D)

Safety of high water intake in CKD patients with eGFR between 15 and 30ml/min/1.73m2

Time frame: 4 weeks

Secondary Outcomes

Correlation between tissue sodium content and total vessel density (A)

Correlation between tissue sodium content measured with 7T Na-MRI and total vessel density using Sidestream Dark Field imaging.

Time frame: 0 week

Correlation between tissue sodium content and perfused vessel density (A)

Correlation between tissue sodium content measured with 7T Na-MRI and perfused vessel density using Sidestream Dark Field imaging.

Time frame: 0 week

Correlation between tissue sodium content and proportion of perfused vessels (A)

Correlation between tissue sodium content measured with 7T Na-MRI and proportion of perfused vessels using Sidestream Dark Field imaging.

Time frame: 0 week

Correlation between tissue sodium content and microvascular flow index (A)

Correlation between tissue sodium content measured with 7T Na-MRI and microvascular flow index using Sidestream Dark Field imaging.

Time frame: 0 week

Correlation between tissue sodium content and microvascular health score (A)

Correlation between tissue sodium content measured with 7T Na-MRI and microvascular health score using Sidestream Dark Field imaging.

Time frame: 0 week

Correlation between tissue sodium content and total pheripheral resistance (A)

Total pheripheral resistance will be measured using the Nexfin device and tissue sodium content will be measured using the 7T Na-MRI

Time frame: 0 week

Correlation between tissue sodium content and cardiac output (A)

Cardiac output will be measured using the Nexfin device and tissue sodium content will be measured using the 7T Na MRI

Time frame: 0 week

Correlation between tissue sodium content and transepidermal water loss (A)

Transepidermal water loss will be measured with the Tewameter® TM Hex probe and tissue sodium content will be measured using the 7T Na MRI

Time frame: 0 week

Correlation between tissue sodium content and office systolic and diastolic blood pressure (A)

Tissue sodium content will be measured using the 7T sodium MRI

Time frame: 0 week

Correlation between tissue sodium content and 24-hour systolic and diastolic blood pressure (A)

Tissue sodium content will be measured using the 7T Na MRI

Time frame: 0 week

Correlation between tissue sodium content and nightime blood pressure dipping pattern (A)

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.

Time frame: 0 week

Correlation between tissue sodium content and total body water (A)

Total body water (liter) will be measured using the bioelectrical impendance analysis and tissue sodium content will be measured using the 7T Na MRI

Time frame: 0 week

Correlation between tissue sodium content and quality of life (A)

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

Time frame: At baseline and yearly during follow-up

The correlation between tissue sodium content and traditional cardiovascular risk factors (A)

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.

Time frame: 15 years

Change from baseline in plasma co-peptine concentrations (D)

For waterintake intervention study

Time frame: 4 weeks

Change from baseline in seated systolic and diastolic office blood pressure (B/C/D)

Seated office systolic and diastolic blood pressure after interventions compared to baseline

Time frame: 2 weeks

Change from baseline in 24-hour systolic and diastolic blood pressure (B/C/D)

24-hour systolic and diastolic blood pressure after interventions compared to baseline

Time frame: 2 weeks

Change from baseline in percentage of patients with a night-time blood pressure dipping pattern (B/C/D)

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.

Time frame: 2 weeks

Change from baseline in transepidermal water loss (B/C/D)

Transepidermal water loss will be measured with the Tewameter® TM Hex probe

Time frame: 2 weeks

Change from baseline in total body water (B/C/D)

Total body water will be measured using the bioelectrical impendance analysis

Time frame: 2 weeks

Change from baseline in total vessel density (B/C/D)

The total vessel density will be measured using Sidestream Dark Field imaging.

Time frame: 2 weeks

Change from baseline in perfused vessel density (B/C/D)

The perfused vessel density will be measured using Sidestream Dark Field imaging.

Time frame: 2 weeks

Change from baseline in proportion of perfused vessel (B/C/D)

The proportion of perfused vessels will be measured using Sidestream Dark Field imaging.

Time frame: 2 weeks

Change from baseline in microvascular flow index (B/C/D)

The microvascular flow index will be measured using Sidestream Dark Field imaging.

Time frame: 2 weeks

Change from baseline in microvascular health score (B/C/D)

The microvascular health score will be measured using Sidestream Dark Field imaging.

Time frame: 2 weeks

Change from baseline in total peripheral resistance (B/C/D)

The total pheripheral resistance will be measured using the Nexfin device

Time frame: 2 weeks

Change from baseline in cardiac output (B/C/D)

The cardiac output will be measured using the Nexfin device

Time frame: 2 weeks

The Role of Skin Sodium Accumulation in Chronic Kidney Disease

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts