In this study we will identify the role of the endothelial GAGs in Na+ and volume homeostasis. Is there a link between the ESL and individual susceptibility to Na+-excess?
ID
Source
Brief title
Condition
- Other condition
- Vascular hypertensive disorders
Synonym
Health condition
fysiologie van natrium- en volumebalans
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
We will primarily study the effects of a salt load on the haemodynamics, ECV
and ESL in patients with acquired and congenital loss of the ESL. Primary
endpoint will be the ECV as represented by body weight, BP and iohexol
measurements.
Secondary outcome
Other study paramaters consist of indirect measurements of the ESL dynamics and
function assessed by imaging of the sublingual microvasculature, measurement of
ESL shedding products and determination of the transcapillary escape rate (TER)
of I125-albumine. The kidney function will be studied by estimating the
glomerular filtration rate (eGFR) and measurement of the fractional Na+
excretion and albuminuria. Finally, skin biopsies will allow studying the role
of interstitial GAGs and macrophage influx in response to a salt load.
Background summary
Sodium (Na+) plays a key role in maintaining volume homeostasis and blood
pressure (BP). The difference between Na+ intake and excretion, the Na+
balance, is regulated by the kidney. Regulation of the Na+ balance by the
kidney is believed to be the main determinant of extracellular fluid volume
(ECV). Recent studies have revealed that the Na+ balance is not only regulated
by the kidney, but also in the interstitium of the skin. Here, binding of Na+
to glycosaminoglycans (GAGs) allows non-osmotic handling of Na+, thereby acting
as a Na+ buffer. Based on these findings, we hypothesize that the endothelial
surface layer (ESL), representing a complex sugar layer principally composed of
negative-charged GAGs lining the endothelium, is an important determinant of
volume homeostasis and BP by its ability to act as an immediate non-osmotic Na+
buffer. A perturbed ESL might therefore lead to an increase in ECV and BP after
a salt load. The volume of the ESL varies highly between individuals (0.5-2.3
L) and is known to be smaller in specific patient groups such as diabetic
patients and patients with chronic kidney disease.
The putative non-osmotic buffer capacity of the endothelial GAGs without
commensurate water retention has only been limitedly studied yet, but seems
particularly relevant in clinical conditions characterized by volume overload
(e.g., heart failure, hypertension, chronic kidney disease). If the endothelial
GAGs are involved in non-osmotic Na+ storage, treatment strategies directed to
restoration of the ESL would lead to improved BP and ECV control and,
conceivably, to better cardiovascular outcome. This study focuses on a novel
function of the ESL, namely the capacity to store Na+ non-osmotically.
Study objective
In this study we will identify the role of the endothelial GAGs in Na+ and
volume homeostasis. Is there a link between the ESL and individual
susceptibility to Na+-excess?
Study design
In this project, we plan to conduct an experimental interventional cross-over
study to investigate the Na+ storing capacity of the endothelial GAGs. For
this, the effect of different Na+ conditions on ESL, ECV and BP, will be
studied in diabetic and hereditary multiple exostosis (HME) patients.
Intervention
High salt diet (>200 mmol Na+ daily) for 1 week, and low salt diet (<50 mmol
Na+ daily) for 1 week, each in random order. Furthermore, all subjects will
receive a hypertonic salt infusion at day 15 of the low salt diet to study the
effects of an acute salt load.
Study burden and risks
The burden of this study consists of a total of 3 visits in which they will
spend about 17 hours in the hospital. All subjects will be asked to adhere to a
low and a high Na+ diet and collect 24-hour urine samples during the diet. The
study comprises extra venous blood drawing and various extra diagnostic tests.
Invasive measurements with different tracers for ECV and GFR (iohexol), plasma
volume (PV) and TER (125I-albumin) will take place. The radiation exposure is
*minor* (maximum 0,1 mSV). At present, the function of the ESL in relation to
salt intake and CVD is not well understood. Novel strategies for targets for
treatment of complex diseases with concepts of volume overload are prevalent.
For the patients there is no direct benefit when participating in this study,
but the outcome of the study is essential for further investigations on this
topic. The findings of this study might influence future treatment for diseases
characterized by an expanded ECV.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
1. Diabetic patients (n<=12)
- Male between 18 and 40 years old
- Known with Diabetes Mellitus - type 1
- With or without microalbuminuria defined as:
o either albuminuria 20-200 mg/L in a morning urine sample
o or albuminuria 30-300 mg/24 hrs collected in a 24-hours urine collection
o or albumin-to-creatinin ratio 2,5-25 mg/mmol in a morning urine sample.
- Stable renal function (creatine clearance > 60 ml/min and < 6 ml/min per year decline) with or without stable therapy with RAAS inhibiting agents
- HbA1c levels between 6.0 and 10.0% (42-86 mmol/mol) during the 6 months preceding the study
- Multiple injections of insulin a day
- Able to provide written informed consent and to comply with the requirements and restrictions listed in the informed consent form;2. HME patients (n<=12)
- Male between 18 and 40 years old
- Documented Hereditary Multiple Exostoses
- Stable renal function (creatinin clearance > 60 ml/min and < 6 ml/min per year decline, no proteinuria)
- Able to provide written informed consent and to comply with the requirements and restrictions listed in the informed consent form
Exclusion criteria
- An office blood pressure >140/90 mmHg
- A body mass index > 30 kg/m2
- A major illness in the past 3 months or any significant chronic medical illness that the Investigator would deem unfavourable for enrolment, including chronic inflammatory diseases
- A history of any type of malignancy within the past 5 years with the exception of successfully treated basal cell cancer of the skin
- A history of any renal disease
- A history of cardiovascular disease (in the past 6 months) defined as documented coronary artery disease including myocardial infarction, (un-)stable angina pectoris or acute coronary syndrome, precutenaous transluminal coronary angioplasty, coronary artery bypass grafting, cerebrovascular disease including ischemic and hemorrhagic stroke or a subarachnodial bleeding, or peripheral artery disease including aortic aneurysmata
- A history of coagulation disorders
- A history of primary hyperlipoproteinemias
- A history of hypersensitivity or allergy to iodium or to shell fish
- A history, within 3 years, of drug abuse (including benzodiazepines, opioids, amphetamine, cocaine, THC, methamphetamine)
- A history of alcoholism and/or is drinking more than 3 units of alcohol per day. Alcoholism is defined as an average weekly intake of >21 units for males. One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits
- Difficulty in donating blood or limited accessibility of a vein in left and right arm
- Subject has donated blood in last 3 months
- Use of tobacco products
- Any other issue that, in the opinion of the Investigator, could be harmful to the subject or compromise interpretation of the data
- Any clinically relevant abnormality noted on the 12-lead ECG as judged by the Investigator or an average QTcB or QTcF > 450 millisec
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| CCMO | NL48278.018.14 |
| OMON | NL-OMON28711 |