Evaluation of microvascular reactivity with laser Doppler flowmetry in chronic kidney disease.

Abstract

Cardiovascular diseases are the major causes of mortality in patients with chronic kidney disease (CKD). The complex process of accelerated athero- and arteriosclerosis in CKD is associated with this phenomenon, where endothelial dysfunction (ED) is one of the initial steps. Hence, the early diagnosis of ED can potentially lead to early interventions which could result in a better outcome for these patients. Several methodologies have been developed for the diagnosis of ED. Laser Doppler flowmetry (LDF) enables us to study the microcirculation continuously in a non-invasive manner. In our review we would like to focus on different tests developed for LDF, like postocclusive reactive hyperaemia, local heating, iontophoresis, microdialysis or analysis of flowmotion. We would also like to summarize the available data in CKD with these methodologies to enlighten their perspectives in the clinical use on this patient population.

Full text

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doi:10.5527/wjn.v2.i3.77
World J Nephrol 2013 August 6; 2(3): 77-83
ISSN 2220-6124 (online)
© 2013 Baishideng. All rights reserved.
World Journal of
Nephrology
W J N
Evaluation of microvascular reactivity with laser Doppler
owmetry in chronic kidney disease
Levente Babos, Zoltán Járai, János Nemcsik
Levente Babos, János Nemcsik,
Department of Family Medi-
cine, Semmelweis University, 1125 Budapest, Hungary
Zoltán Járai,
Department of Cardiology, St. Imre Teaching Hos-
pital, 1115 Budapest, Hungary
Author contributions:
Babos L solely contributed to this paper;
Járai Z and Nemcsik J revised it critically for important intellec-
tual content.
Correspondence to: János Nemcsik MD, PhD,
Department of
Family Medicine, Semmelweis University, Kútvölgyi str. 4, 1125
Budapest, Hungary. janos.nemcsik@gmail.com
Telephone:
+36-14-694667
Fax:
+36-13-358530
Received:
June 13, 2013
Revised:
July 31, 2013
Accepted:
August 2, 2013
Published online:
August 6, 2013
Abstract
Cardiovascular diseases are the major causes of mor-
tality in patients with chronic kidney disease (CKD).
The complex process of accelerated athero- and arte-
riosclerosis in CKD is associated with this phenomenon,
where endothelial dysfunction (ED) is one of the initial
steps. Hence, the early diagnosis of ED can potentially
lead to early interventions which could result in a bet-
ter outcome for these patients. Several methodologies
have been developed for the diagnosis of ED. Laser
Doppler flowmetry (LDF) enables us to study the mi-
crocirculation continuously in a non-invasive manner. In
our review we would like to focus on different tests de-
veloped for LDF, like postocclusive reactive hyperaemia,
local heating, iontophoresis, microdialysis or analysis of
owmotion. We would also like to summarize the avail-
able data in CKD with these methodologies to enlighten
their perspectives in the clinical use on this patient
population.
© 2013 Baishideng. All rights reserved.
Key words:
Chronic kidney disease; Laser Doppler ow-
metry; Endothelial dysfunction; Iontophoresis; Postoc-
clusive reactive hyperaemia; Local heating; Microdialy-
sis; Flowmotion
Core tip:
Atherosclerotic diseases are the leading
causes of death in chronic kidney disease (CKD) pa-
tients. Endothelial dysfunction is an important initial
step of atherosclerotic processes, so with the early di-
agnosis and treatment of endothelial dysfunction many
cardiovascular events can potentially be prevented.
Laser Doppler flowmetry (LDF) gives the opportunity
of the non-invasive study of microcirculation and en-
dothelial function. This review summarizes the results
of different LDF techniques and their usefulness in the
diagnosis of endothelial dysfunction in CKD patients.
Babos L, Járai Z, Nemcsik J. Evaluation of microvascular reactiv-
ity with laser Doppler owmetry in chronic kidney disease.World
J Nephrol
2013; 2(3): 77-83 Available from: URL: http://www.
wjgnet.com/2220-6124/full/v2/i3/77.htm DOI: http://dx.doi.
org/10.5527/wjn.v2.i3.77
ENDOTHELIAL DYSFUNCTION AS AN
INITIAL STEP OF ATHEROSCLEROSIS
Endothelial dysfunction (ED) has been implicated as one
of the major pathophysiological mechanisms contribut-
ing to the development of atherosclerosis. ED refers to
the impairment in the homeostatic properties of the en-
dothelial layer, like endothelium-dependent regulation of
vascular tone, hemostasis, permeability, cell adhesion and
inammation. Endothelial dysfunction or more correctly
“endothelial activation” is considered as a key initiating
step in atherogenesis and also contributes to arterial stiff-
ening. Besides, endothelial dysfunction is predictive of
cardiovascular events in patients with established cardio-
vascular disease
[1]
.
MINIREVIEWS
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EVIDENCE OF ENDOTHELIAL
DYSFUNCTION IN CHRONIC KIDNEY
DISEASE
Patients with chronic kidney disease (CKD) are at high
risk of cardiovascular disease, and often suffer from ac-
celerated atherosclerosis
[2,3]
. CKD can progress to end
stage renal failure however patients are more likely to die
of a cardiovascular disease before reaching the terminal
renal stage
[4,5]
. Although classic cardiovascular risk factors
like hypertension, diabetes and obesity are present and
frequent in this population, excessive and accelerated car-
diovascular diseases cannot be explained by these alone.
There is plenty of evidence indicating that ED has
high importance in patients with CKD
[5-8]
. ED begins
early in the progression of CKD, independently of tra-
ditional cardiovascular risk factors, and is also observed
in children with CKD
[9-11]
. Amongst the pathophysiologi-
cal reasons chronic inflammation and excessive oxida-
tive stress seem to be the most important
[5]
. The causes
of inammation are multiple, including decreased renal
function, chronic volume overload, comorbidities, factors
associated with the dialysis procedure, and genetic fac-
tors. C-reactive protein (CRP) was initially suggested to
be merely a biomarker of inammation, but recent data
show that circulating CRP is also a mediator of athero-
genesis and inflammation
[12-14]
. An inverse relationship
between CRP and endothelium-dependent vasoreactivity
has been described, which suggests that CRP can be a
link between inammation and ED
[15]
.
Nitrogen monoxide (NO) is one of the most impor-
tant vasodilating substances released by the endothelium.
In CKD decreased NO level has often been reported and
is associated with impaired endothelial function. The de-
creased NO may be connected to the reduced endothe-
lial nitric oxide synthase activity which is a consequence
of endogenous or exogenous inhibitors. There is some
evidence for the accumulation of an endogenous inhibi-
tor of nitric oxide synthase in haemodialysed patients
[16]
.
Asymmetrical dimethyl arginine inhibits NO synthesis, in-
crease vascular resistance and blood pressure
[16-18]
. There
is much evidence which suggest that oxidative stress
also plays an important role in decreased bioavailability
of NO in CKD. Oxidative stress markers are elevated
in CKD and it has been reported that the antioxidant
vitamin-C microdialysed into the forearm skin improved
the endothelial function
[19,20]
. These ndings suggest that
decreased NO availability as a consequence of increased
oxidative stress can be another reason of early ED in
CKD.
METHODS FOR THE ASSESSMENT OF
THE MICROVASCULAR FUNCTION
The cutaneous circulation is an easily accessible vascular
bed for the assessment of
in vivo
human microcirculatory
function, and may be representative of systemic vascular
function
[21,22]
. Furthermore alterations in microvascular
function may occur early in the progression of cardiovas-
cular disease
[22,23]
. This phenomenon gives the opportuni-
ty that with the study of cutaneous microcirculation and
early diagnosis of ED quick therapeutical interventions
could be performed to avoid the development of severe
cardiovascular events.
There are several methods for investigating endothe-
lial dysfunction non-invasively. Evaluation of ow medi-
ated vasodilatation (FMD) by ultrasound is widely used
to study ED in coronary artery disease, hyperlipidaemia,
hypertension and diabetes
[4]
. However, it has become
more prominent in recent years, that the process is not
completely dependent on the release of NO in response
to increased shear stress, especially the rst phase of the
hyperaemia
[24]
. Another approach is to study forearm
blood ow using venous strain-gauge plethysmography.
Although this well reproducible method was the gold
standard in the assessment of ED for a long time, today
its daily use is limited because it requires specially trained
investigators and brachial artery catheterization for the
administration of the vasoactive drugs
[25]
. Recently for the
assessment of microvascular function the most widely
used noninvasive method has been laser Doppler owm-
etry (LDF) of the skin.
LASER DOPPLER FLOWMETRY IN THE
STUDY OF ENDOTHELIAL DYSFUNCTION
LDF is based on the reection of laser beam light. Light
undergoes changes in wavelength (Doppler shift) when
it is reflected by the moving red blood cells in the mi-
crovasculature and a photodiode measures the emerged
beam. The magnitude and frequency distribution of
these changes in wavelength are related to the number
and velocity of moving red blood cells
[14,26,27]
. Several dif-
ferent signals can be recorded but the red blood cell ux
is used the most. LDF enables the evaluation of cutane-
ous microvascular blood ow over time and its changes.
The LD output is semi-quantitative and expressed in
perfusion unit (PU) of output voltage (1 PU = 10 mV)
in accordance with general consensus (European Laser
Doppler Users Groups, London 1992). Many techniques
can be associated to LDF such as local heating, post-
occlusive reactive hyperaemia, iontophoresis, or microdi-
alysis.
DIFFERENT LDF TECHNIQUES IN THE
ASSESSMENT OF ENDOTHELIAL
DYSFUNCTION
Postocclusive reactive hyperaemia
Postocclusive reactive hyperaemia (PORH) refers to
the increase in skin blood ow following a brief arterial
occlusion. The procedure starts with the occlusion of
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. Laser Doppler owmetry in CKD

the brachial artery using a pressure cuff placed around
the upper arm and inflated up to 20 mmHg above the
systolic blood pressure. The commonly used ischaemic
period varies between 3-10 min (unfortunately there is
no standardized protocol), and a quick deation nishes
the procedure. A linear correlation between the period
of ischaemia and the amplitude of the response has been
reported
[27,28]
; however the length of the ischaemic period
is coupled with the increasing pain of the subject. Lots
of parameters can be calculated from the response curve.
The most widely used as the primary endpoint is the
peak hyperaemia after the cuff release. Other parameters
used are the area under the hyperaemic curve, the raw
value of the peak minus biological zero, the increase in
postischaemic ow using area under the curve at baseline
and postischaemia
[27,29,30]
, (Figure 1). Four major factors
have been thought to play a role in the hyperaemic re-
sponse: metabolic vasodilators, endothelial vasodilators,
myogenic response to shear stress and sensory nerves.
Interestingly NO does not play a crucial role in this test,
because the response to ischaemia is mostly mediated by
prostanoids
[31]
. In summary, PORH represents a complex
microvascular response to an acute period of ischaemia,
in which endothelium has a less pronounced role
[27]
.
Some clinical data are available with PORH. Yamamoto
et al
[32]
found decreased microvascular response during
PORH test in patients with type 2 diabetes mellitus and
similar results have been reported in patients with type 1
diabetes
[33]
. There are only a few articles in the literature
that have used PORH in order to study endothelial func-
tion in patients with CKD, and the results are controver-
sial. Stewart
et al
[29]
studied patients with end-stage renal
disease (ESRD) with and without diabetes and cardiovas-
cular disease. They found decreased hyperaemic response
in patients with renal disease and also with cardiovascular
disease and diabetes, but they could not demonstrate dif-
ference between patients with ESRD only and healthy
controls. Previously we demonstrated decreased peak
ow values compared to healthy controls both in patients
with hypertension only and in hypertensive patients with
ESRD. Among the hypertensive ESRD patients no fur-
ther decrease of the peak ow was found compared with
the hypertensive group
[34]
. In a follow-up study which is
the only one available so far with LDF in CKD, Kruger
et al
[35]
found that although PORH parameters did not
correlate with Framingham and Cardiorisk cardiovascular
risk scores, but the magnitude of peak ow was associ-
ated with the development of cardiovascular disease. Ac-
cording to these results the magnitude of the peak ow
can be a useful PORH parameter in the future, but more
data are necessary to conrm its value.
Local thermal hyperaemia
Local thermal hyperaemia leads to a temperature depen-
dent increase in skin blood flow and achieves maximal
vasodilatation between 42-44ºC. This maximal thermal
vasodilatation corresponds to the maximal vasodila-
tor capacity of the vessels
[27,36]
. Local heating-provoked
vasodilatation is mediated by at least two independent
mechanisms: the initial peak during the rst 10 min re-
lies on local sensory nerves, and is mediated by an axon
reflex, which is thought to be dependent on calcitonin
gene related peptide and substance P. The plateau phase
which occurs after 20-30 min of warming is mediated
by NO
[37,38]
. Previously it was found, that thermal hy-
peraemia is impaired in type 1 and 2 diabetes and in sys-
temic sclerosis
[29,39-41]
. In ESRD both DuPont
et al
[20]
and
Stewart
et al
[29]
have found decreased thermal peaks and
plateau compared to controls. In the follow-up study of
Kruger
et al
[35]
it was demonstrated that thermal hyper-
aemia parameters (first and second peak flow and area
under the curve) were associated significantly with the
calculated cardiovascular risk using Framingham and Car-
diorisk risk scores. They found that both cardiovascular
mortality and the development of congestive heart failure
were signicantly associated with the rst thermal peak
and the plateau. As this study was performed only on
70 ESRD patients the authors concluded that although
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. Laser Doppler owmetry in CKD
c
d
b
a
AUC
Figure 1 Laser Doppler parameters during postocclusive reactive hyperaemia test. a: Resting ow; b: Biological zero during arterial occlusion; c: Peak ow after
cuff release; d: Time to peak; AUC: Area under the curve after cuff release.

abnormal LDF parameters were sensitive indicators of
increased cardiovascular risk, but a longitudinal study for
further diagnostic and prognostic validation of the meth-
od would have been required
[35]
. Unfortunately no such
kind of study was published so far. In summary, the mag-
nitude of the thermal peaks and the plateau are promis-
ing parameters of the local thermal hyperaemia test, but a
study with higher number of patients would be required
to assess further clinical data about its usefulness.
Iontophoresis
Iontophoresis is based on the principle that a charged
drug in solution will migrate across the skin under the in-
uence of a low intensity electric current
[42]
. The quantity
of the penetrating drug depends on the magnitude and
duration of the current applied and on the diffusional
and electrical characteristics of the skin. When combined
with laser Doppler flowmetry this method enables the
detection of alterations in cutaneous blood flow in re-
sponse to the delivery of the vasoactive drug. Usually two
types of vasoactive drugs are used; acetylcholine (Ach)
and sodium nitroprusside (SNP). Ach and SNP are used
to generate endothelium-dependent and independent
vasodilatation, respectively
[14,27]
. A reduction on vascular
response to Ach with no concurrent reduction in SNP
response indicates endothelial dysfunction. Vascular re-
sponse during Ach iontophoresis has been found to be
impaired in obstructive sleep apnea syndrome, obesity,
diabetes, hypercholesterolemia and hypertension
[41,43-45]
.
Data in patients with CKD are controversial. Thang
et
al
[46]
found that Ach and SNP iontophoresis provoked
vasodilatation was altered in patients with advanced CKD
compared to healthy controls. In contrast, Cupisti
et al
[47]
found no alternations in the hyperaemic response after
Ach and SNP iontophoresis in patients with CKD com-
pared to healthy controls. Previously we demonstrated
decreased SNP and Ach response in hypertensive ESRD
patients compared to healthy controls and patients with
hypertension without CKD
[34]
. These data suggest that
in conservatively treated CKD patients ED cannot be
demonstrated with iontophoresis of Ach and SNP, but in
ESRD, where marked microvascular alterations are pres-
ent this methodology can have clinical implications.
Laser Doppler owmetry coupled with microdialysis
Microdialysis is a technique which enables us to take ions
or molecules into the interstitial space of the skin. It can
be used to deliver pharmacological agents to a small area
of tissue so that no confounding systemic effects occur.
In addition, the concentration of substances released in
response to the pharmacological action can be measured
in the dialysate efuent uid
[27]
. This approach has been
used to assess the role of NO in postocclusive and ther-
mal hyperaemia and opens a new era in the assessment
of human skin microcirculation
[37,48]
. The major limitation
of this technique is its microinvasive approach. There are
a very limited number of studies in the literature which
used microdialysis in CKD patients in order to evalu-
ate endothelial function. Dupont
et al
[20]
combined local
heating with dialysation of Ringer solution, ascorbic acid,
L
-arginine and nitro-
L
-arginine methyl ester (
L
-NAME)
in patients with stage 3-4 CKD and age, sex matched
controls. They found in the CKD patients impaired cuta-
neous vasodilation response to local heating, which could
have been reversed with the local infusion of ascorbic
acid or
L
-arginine. These ndings conrm the results of
other workers which suggested that oxidative stress plays
important role in the vascular dysfunction in stage 3-4
CKD. According to its microinvasive feature, microdi-
alysis will probably be used in the future only for experi-
mental studies on limited number of patients.
Analysis of owmotion
Periodic oscillations of cutaneous blood ow, also called
owmotion, can be quantied by spectral analysis. These
periodic oscillations correlate well with endothelial func-
tion and spontaneous smooth muscle wall activity. Spec-
tral analysis of laser Doppler signal allows ve different
frequency intervals to be detected. These oscillations
represent the inuence of the heartbeat (1 Hz), respira-
tion (0.3 Hz), myogenic activity (0.1 Hz), neurogenic
activity (0.04 Hz), and the frequency sub-interval of 0.01
Hz is mostly endothelium dependent
[49-51]
. The only study
which investigated the skin blood ow oscillations dur-
ing laser Doppler owmetry in CKD found blunted post
ischemic increase of the endothelium dependent skin
blood owmotion sub-interval, which can be considered
as an early sign of microvascular endothelial dysfunction
in this patient population
[52]
. So more data are needed
with this operator-independent LDF method to discover
its usefulness in CKD patients.
CRITICAL ASPECTS OF LDF
One major limitation of LDF is, that it is not possible
to measure absolute perfusion values. Measurements in
most studies are expressed in arbitrary units called PU
and are referred to as flux rather than flow. Moreover,
laser Doppler has often considered poorly reproducible,
but when the recording site is standardized, and tempera-
ture controlled room and heated probes were used, the
day to day reproducibility of PORH, thermal hyperaemia
and iontophoresis compares well with that of ow medi-
ated dilatation of the brachial artery
[27,53]
. Besides there
are some difculties in interpreting observational studies
of patients with CKD because many diseases that cause
CKD (
e.g.,
diabetes mellitus, hypertension) themselves are
already associated with endothelial dysfunction. In addi-
tion there are no standardized protocols available with
the different methods of LDF, which makes it highly dif-
cult to compare data from different studies.
CONCLUSION
Epidemiological evidence has already established the
connection between CKD and cardiovascular disease
[35,54]
.
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ED plays a major role in this linkage. Therefore early
detection of ED in CKD would be very important.
Among other possibilities the measurement of surrogate
markers like C-reactive protein, homocysteine, circulating
selectins, plasminogen activator inhibitor-1, and asym-
metric dimethylarginine
[55,56]
, or semi-invasive techniques
such as strain-gauge plethysmography and FMD can be
mentioned. An advantage of LDF over these methods is
that it gives a good opportunity for the direct, real time
assessment of microvascular function in a non invasive
manner. Furthermore LDF is an easy and relatively cost
effective technique which offers the opportunity of fu-
ture clinical implications.
But unfortunately we are far from this in CKD.
Among the above described LDF methodologies PORH
and local thermal hyperaemia have the only evidence in
CKD in respect of prediction of cardiovascular events.
However, these data originate from only one follow-up
study which was performed on a low number of patients.
In summary, much more studies are required to assess the
predictive value of different parameters evaluated with
different tests in CKD, before LDF would gain clinical
application.
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P- Reviewers
Lopez-Hernandez FJ, Olowu WA
S- Editor
Gou SX
L- Editor
A
E- Editor
Lu YJ
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