Microcirculatory dysfunction plays a key role in uremic vasculopathy

In the early stages of CRF (stage I) the risk on cardiovascular disease (CVD)
is mainly determined by traditional risk factors, including hypertension,
hypercholesterolemia and obesity. Both modifications in lifestyle and
pharmacological treatment lower the risk on CVD analogous to non-renal
patients. As renal function deteriorates (stages II and III), mild uremic
vasculopathy develops, not only in large and medium size conduit vessels, but
also in the microcirculation. As severe CRF (stage IV) progresses to end stage
renal disease (ESRD, stage V), advanced uremic vasculopathy develops, which
appears almost completely resistant to current treatment strategies. Reverse
epidemiology emerges when traditional risk factors for CVD are overridden by
other factors, such as a derangement of mineral metabolism, which is a
characteristic feature of CRF. As a consequence, classical atherosclerosis is
converted gradually in the syndrome of uremic vasculopathy, which is a distinct
pathological entity consisting of both classical atherosclerosis and osteogenic
calcifications in the intimal and medial layers of large and medium size
conduit arteries, as well as in small resistance vessels. These alterations
result in malnutrition, insulin resistance and catabolism of varies tissues. As
uremic vasculopathy is different from classical atherosclerosis, conventional
anti-atherosclerotic therapy is less effective or not effective at all. Hence,
it is of paramount importance to determine and characterize the underlying
factors, in order to prevent or postpone the occurrence of uremic vasculopathy
in patients with ESRD.

In this trial we will investigate the following hypothesis:
- Uremic vasculopathy develops, not only in large and medium sized conduit
vessels, but also in the microcirculation.
- There is a relationship between the rate of microcirculatory dysfunction
[measured by capillary microscopy of the nailfold, laser Doppler flux metry,
the sublingual Side-stream Darkfield (SDF) microscopy] and the vascular
stiffness of the large vessels, as reflected in the increased pulse wave
velocity.
- As medial calcification affects arterioles, we suppose that both the
endothelium-dependent and endothelium-independent vasodilatation of the
microcirculation will be disturbed.
- The rate of microcirculatory dysfunction correlates with the progression in
renal failure. The microcirculatory dysfunction depends on renal function.
- Microcirculatory dysfunction sublingually (the tongue is the proximal part of
the gastrointestinal tract) represents the disturbed microcirculation in other
vital organs.
- So during a dialysis treatment the microcirculation could be visualised with
the small and handy-sized SDF microscopy.

Uremic vasculopathy will be studied cross-sectional in 120 patients with
various stages of CRF (grades I-V). CRF stage V will consist of 20 chronic
hemodialysis and 20 chronic ambulant peritoneal patients. Both macro- and
microcirculatory changes will be assessed and correlated with various
laboratory parameters of endothelial activation. In addition, circulating
endothelial cells as well as circulating endothelial progenitor cells will be
assessed. With respect to mineral and lipid metabolism, at regular intervals
various parameters will be measured, including calcium, phosphate, 1,25(OH)2
vit D, PTH and total chol/HDL/LDL/triglyceride. All medication prescribed will
be recorded.
The insulin resistance index by homeostasis model assessment (HOMA-IR) will be
used as an alternative method to assess insulin resistance in patients by
measuring fasting glucose and fasting insulin.
In the prospective observational part of the study these parameters will be
assessed annually within a follow-up period of 2 years in patients with CRF
stage III with MDRD clearance < 35 ml/min and CRF stage IV. When dialysis will
be started within these 2 years an extra vascular and blood measurement will be
done at the start of renal replacement therapy.

In the cross sectional part of the study patients will participate in the study
for a total of 4 hours. For the prospective observational part of the study,
this will consist of patients with CRF stage III with MDRD clearance < 35
ml/min and CRF stage IV. This part of the study will consist 3 x 4 hours
individually.
The sublingual microcirculation will be assessed by Sidestream Darkfield
Imaging in combination with nitroglycerin. The nitroglycerin given sublingually
can shortly cause headache and hypotension.
With the Laser Doppler Flowmetry in combination with iontophoresis some people
will experience a feeling of numbness of the local skin. This is not painful or
dangerous and is usually well tolerated.