Main objective:To investigate the association between systemic vascular- and urinary albumin leakage in patients with diabetes.Secondary objectives:-To investigate whether systemic vascular- and/or urinary albumin leakage is associated with systemic…
ID
Source
Brief title
Condition
- Renal disorders (excl nephropathies)
- Vascular disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. The 99mTC-HSA clearance and urine albumin-creatinine ratio (uACR) as proxy
for systemic vascular albumin leakage and albuminuria:
This will be calculated via the transcapillary escape rate of 99mTC-HSA
(TERalb). TERalb will be measured by the fractional disappearance rate of
99mTC-HSA from the total intravascular compartment in 1 hour after intravenous
injection. Albuminuria will be defined as the amount of albumin found in the
urine and will be calculated via the uACR.
Secondary outcome
2. Arterial [18F]-FDG uptake as proxy for arterial inflammation.
Arterial inflammation will be quantified as the FDG uptake maximal standardized
uptake value (SUVmax). SUVmax will be corrected for the prescan glucose level.
A target-to-background ratio (TBR) will be calculated by dividing the SUVmax of
the arteries by the SUVmean of the caval veins (bloodpool). TBRs will be
calculated for four individual segments (carotid arteries, ascending aorta and
aortic arch, descending and abdominal aorta, and iliac and femoral arteries)
and averaged for the total aortic tree (meanTBR).
3. Measuring the endothelial glycocalyx as proxy for systemic vascular damage.
The perfused boundary region (PBR), a marker of the glycocalyx barrier
function, will be measured non-invasively in sublingual microvessels with a
diameter of 5-25*µm using a Sidestream Dark Field camera (GlycoCheck BV,
Maastricht, The Netherlands). Increased PBR indicates reduced glycocalyx
thickness.
4. The amount of heparanase, heperan sulfate (HS) and metalloproteinase (MMP) 2
and 9 as proxy for endothelial glycocalyx damage:
The amount of heparanase will be measured via the human heparanase ELISA kit.
Plasma will be used and the amount will be noted as pg/ml. HS will be measured
via the human HS ELISA kit and the amount of HS will be noted as pg/ml. The
amount of MMP 2 and 9 will be tested via a urinary activity assay and will be
noted as mg/mmol creatinine. HS, MMP 2 and 9 will be measured by a single
urinary morning void.
5. Brachial arterial blood pressure, central arterial blood pressure and
carotid to femoral pulse wave velocity (PWV) will be measured as proxy for
arterial stiffness. The PWV will be calculated by dividing travelled distance
by transit time (PWV = distance [meters]/transit time [seconds]).
6. Nailfold capillaroscopy will be performed as a method to examine a patient*s
microcirculation and assess pathological changes. Nailfold capillary images
will be collected with the Dino-lite CapillaryScope 200 PRO (MEDL4N Pro),
maximum magnification 200x, measurement software Dinocapture 2.0. Stills of
the capillariscopic appearance of the index fingers of both hands will be
studied. Additionally, during a capillaroscopic assessment, the practitioner
assesses a number of different morphological and functional changes in the
capillaries. These include capillary visibility, morphology, diameter, length,
distribution, density, microhaemorrhages and blood flow.
Background summary
Type 2 diabetes mellitus (T2DM) is associated with a strong increase in
cardiovascular risk, which is a consequence of accelerated vascular ageing.
This process is hallmarked by systemic low-grade vascular- inflammation,
remodeling, calcification, and increased vascular stiffness.
However, although the association between T2DM and systemic vascular
inflammation has been well established, the underlying pathophysiological
mechanism is not completely understood.
Albuminuria is the first clinical indication of diabetic nephropathy and is
associated with an increased risk of kidney failure and CVD, as well as
low-grade inflammation. The endothelial glycocalyx, a gell-like structure
covering the endothelium in all vascular beds, is the first barrier against
albumin leakage. Impairment of the glycocalyx in the kidney has been shown to
be associated with increased albuminuria. As a systemic factor in all vascular
beds, this might be a proxy for systemic vascular albumin leakage. Furthermore,
increased glomerular leakage of albumin has been demonstrated to lead to
enhanced tubular exposure of albumin which elicits a pro-inflammatory milieu,
causes tubulo-interstitial damage, and impairs kidney function. Measuring
systemic vascular albumin leakage could therefore be a potential marker of
early disease and could be causally associated with systemic vascular
inflammation in chronic diseases linked to widespread vascular involvement.
This study will deliver new insights into the role of albumin leakage as a
pathophysiological link between T2DM and systemic vascular inflammation.
Ultimately, we hope to introduce urinary- and systemic albumin leakage as novel
potential targets for early diagnosis, monitoring, and possibly more
personalized treatment of CVD.
Study objective
Main objective:
To investigate the association between systemic vascular- and urinary albumin
leakage in patients with diabetes.
Secondary objectives:
-To investigate whether systemic vascular- and/or urinary albumin leakage is
associated with systemic vascular inflammation.
-To investigate whether systemic vascular- and/or urinary albumin leakage is
associated with damage to the endothelial glycocalyx.
Study design
Single center, cross-sectional and observational study.
Study burden and risks
Attempts will be made to have patients visit our center for assessment of all
study parameters in two days. Participation in the proposed study is
accompanied with only minor risks. The blood samples will be drawn by means of
venepuncture. Very rarely some bleeding from the skin biopsy occurs and has to
be stitched or a small hematoma occurs after injection with the [18F]-FDG PET
tracer or the 99mTC-HSA.
The usage of positron emitting isotopes in the [18F]-FDG- PET/CT scan to
measure the systemic inflammation translates to an exposure to ionizing
radiation. Because of the potential hazards of radiation exposure, guidelines
for the exposure of volunteers are laid down in *Besluit stralingsbescherming,
artikel 60, staatblad 2001, 397* in accordance with the guidelines of the
International Commission on Radiological Protection (ICRP). The effective dose
of [18F]FDG is 0.019 mSv/MBq1 for the standard adult male. With an activity of
2 MBq/kg and a standard weight of 73.7 kg this gives a dose of a single FDG-PET
scan of 2.8 mSv. In addition, a low-dose CT-scan is made for attenuation
correction, giving an additional dose of 1 mSv. Therefor the total radiation
dose for the FDG scans becomes: EFDG+LDCT = 2.8 + 1 = 3.8 mSv.
The injection with 350 MBq of [99mTc]HSA is associated with a radiation dose of
0.0062 mSv/MBq giving a total effective dose of: EHSA = 2.7 mSv.
The total radiation dose for this study thus becomes: Esalvate = 3.8 + 2.7 =
6.5 mSv. According to ICRP62 the total dose to the volunteers is in category
2b. Potential abnormalities found with these investigations will be
communicated with the patient and their treating physician. The radiation dose
is calculated by our local clinical physicist dr. A. Willemsen.
Benefits: Although participants have no direct benefit, this research may lead
to the reveal of cardiovascular diseases at an early stage as well as an
extensive evaluation of their disease state, potentially allowing earlier
treatment and a better outcome. Also, coincidental findings will be reported,
and may be beneficial to the patients to allow a quick treatment. However, we
are aware of lead time bias. Early identification of (cardiovascular) diseases
may not always be a benefit when treatment options are not available (anymore).
Hanzeplein 1
Groningen 9713GZ
NL
Hanzeplein 1
Groningen 9713GZ
NL
Listed location countries
Age
Inclusion criteria
• Men and women, age >= 18 years.
• Written informed consent.
• eGFR above 60 ml/min/1,73m2.
• Using renin-angiotensin system (RAS) inhibitors.
• Fulfils ADA criteria for diabetes.
o Fasting plasma glucose >= 7.0 mmol/l.
o Random plasma glucose >= 11.1 mmol/l.
o HbA1C >= 6,5%.
Exclusion criteria
• Patients who are mentally incompetent and cannot sign a Patient Informed
Consent or are unwilling to sign a Patient Informed Consent.
• Women who are currently pregnant, planning to become pregnant, breastfeeding
women, or women with childbearing potential not using appropriate contraceptive
measures. This will be discussed during the intake conversation and women who
answer yes on any of the previous questions will be excluded.
• Other causes for macroalbuminuria than nephropathy.
• Systemic auto-immune disease or vasculitis.
• Inflammation of unknown origin or sepsis.
• Patients who use immunosuppressives or anti-inflammatory drugs that could
interfere with the study results.
• Recent (< 3 months) acute disease such as cardiovascular event or infection
for which admission to hospital was necessary.
• Recent (< 3 months) surgical procedure, excluding procures under local
anaesthetics.
• Active malignancy, excluding skin malignancies: basal cell carcinoma and
squamous cell carcinoma,
• Patients who have claustrophobia.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL83989.042.24 |