The role of skin sodium accumulation in chronic kidney disease

Recent studies demonstrated that sodium can be stored in high concentrations in
the skin without water retention. This was mainly observed in medical
conditions associated with systemic sodium overload and water excess such as in
patients with chronic kidney disease (CKD). In this group of patients,
increased skin sodium content is associated with left ventricular hyperthrophy
and increased mortality in dialysis patients.
However, the exact pathophysiology and consequences of elevated tissue sodium
in CKD remains unclear. The exact link between skin sodium and hypertension is
also not understood. Skin sodium accumulation may results in hypertension due
to endothelial dysfunction and microvascular rarefraction. But one may also
argue that skin sodium is merely the result of hypertension.
In other words, sodium accumulation under the skin in CKD patients is related
to cardiovascular disease and complications. However, only a few studies have
addressed the relationship between sodium storage under the skin and long-term
disease outcomes in renal patients.

A relatively new hypothesis regarding skin sodium storage in CKD is that it is
a compensation mechanism for increased renal water loss. At an eGFR of 15-29
ml/min/1.73m2 the median fasting urine osmolality declines to 400 mOsm/kg,
whereas the maximum concentrating capacity of a healthy kidney is 1200 mOsm/kg.
In rat studies, researchers have demostrated that fluid intake did not
compensate fully for the increased renal water loss, indicating that other
compensatory mechanisms are involved. These mechanisms included cutaneous
vasoconstriction and skin electrolyte accumulation, which together reduced
transepidermal water loss.

Previous intervention studies have demonstrated that sodium stored in the skin
can be mobilized by loop diuretics, sodium-glucose co-transporter-2 (SGLT-2)
inhibitor and dialysis. Furthermore, high sodium intake was associated with an
increased skin and muscle sodium content in healthy volunteers. To present
date, it is unknown whether tissue sodium content in CKD patients can be
lowered by increasing renal sodium excretion or water intake or limiting sodium
intake. We hypothesize that skin sodium content in CKD patients can be lowered
by increasing renal sodium excretion, increasing water intake or limiting
sodium intake, and that lower skin sodium content is associated with better
micro- and macrovascular function in CKD.

Main objectives
Cohort study:
To investigate the prognostic implications of skin sodium accumulation for CKD 
patients.

Sodium excretion intervention study:
To study the effect of increased renal sodium excretion, with and without 
aldosterone blockade, on tissue sodium content in CKD.

Sodium intake intervention study:
To define the effect of high and low sodium intake on tissue sodium content in 
CKD.

Water intake intervention study:
To assess safety of increasing water intake in CKD stage 4. 
To study the effect of increased water intake on skin sodium content and 
transepidermal water loss (TEWL).

Secondary objectives
Cohort study:
- To study the micro- and macrovascular consequences of tissue sodium 
accumulation and changes in tissue sodium content in CKD patients. 
- To test whether skin sodium accumulation is correlated with the quality of 
life in CKD patients.

Water intake intervention study:
- The effect of water intake on blood pressure, copeptin, systemic vascular 
resistance and microcirculation.

This project is divided in four studies:
- 1 cohort study
- 1 open label randomized crossover sodium intake intervention
- 1 open label randomized crossover sodium excretion intervention 
- 1 open label randomized crossover water intake intervention.

Sodium intake intervention
The participants in this group will receive 2 weeks high sodium diet 
(>200mmol) and 2 weeks low sodium diet (<50mmol). Between both diets, 
participants will have to 2 weeks washout period. 

Sodium excretion intervention
In a randomized crossover method, we will compare the effect of two sodium 
depleting antihypertensive drugs (hydrochlorothiazide, spironolactone) and a 
non-sodium depleting antihypertensive agent (lercarnidipine).This in order to 
determine whether tissue sodium content is dependent on systemic sodium 
overload, hypertension or both and to study the role of aldosteron in this 
proces. 

Water intake intervention
The participants in this group will receive a water intervention in which they 
drink their habitual water intake for 4 weeks and a high water intake (1L more 
than their mean 24-hour urine volume at screening and baseline) for 4 weeks. 
Between both water intakes, participants will have a 2-week washout period.

Cohort
Subjects will visit the clinic once for an extensive baseline measurements (3 
hours). The measurements are not harmful or painful and no adverse events are 
expected. Patients will be asked consent for follow-up until the start of renal 
replacement therapy or a maximum of 15 years. At baseline and every 12 months 
during follow up, we will take the Kidney Disease Quality of Life (KDQOL-36) 
questionnaire. The questionnaire mentioned above possess no risk for the 
subject and has no consequences for the regular outpatient care that they will 
receive. 

Sodium intake intervention
The patients will receive a 2-week low and a high sodium diet with a wash out 
period in between of at least 2 weeks. Subjects will visit the clinic 7 times 
(+/- 12 hours) for the measurements including 23Na-MRI. 24-hour urine will be 
checked 7 times to check dietary adherence. 24-hour blood pressure will be 
measured 3 times. We do not expect any adverse events related to the dietary 
interventions due to the short study duration.

Sodium excretion intervention
All participant will receive 3 different antihypertensive drugs for a 6-week 
period to alter renal sodium excretion. All drugs are extensively used in daily 
clinical practice of hypertension treatment and the safety has been proven. We 
will include hypertensive subjects with an eGFR >30 ml/min/1.73m2 and a plasma 
potassium <5.0 mmol/L to limit the risk of adverse events such as hypotension 
and hyperkalemia. The participants will visit the clinic in total 8 times (+/- 
15 hours) to perform various measurements, including 23Na-MRI, blood sampling 
and evaluation of adverse effects. 24-hour urine and 24-hour blood pressure 
measurements will be collected in total 4 times.

Water intake intervention
The patient will receive a 4-week habitual and increased water intake with a 
wash out period in between of at least 2 weeks. Subjects will visit the clinic 
9 times (+/- 12 hours in total) to perform various measurements, including 
three 23Na-MRIs (during the 3 long visits), blood sampling and evaluation of 
adverse effects. 24-hour urine will be checked 11 times. 24-hour blood pressure 
will be measured 3 times. As the ability to excrete free water is not 
substantially impaired when eGFR is >15 ml/min/1.73m2, the risk for 
hypervolemia or hyponatremia is low. Nevertheless, we will exclude patients 
with a history of heart failure, dysnatraemia or medications known to influence 
the concentrating capacity of the kidney to further limit the risk of these 
adverse events.