Effect of Isovolemic, Isothermic Hemodialysis on Cerebral
Perfusion and Vascular Stiffness Using Contrast
Computed Tomography and Pulse Wave Velocity
Ansgar Reising1., Saskia Sambale1., Frank Donnerstag2, Julius J. Schmidt1, Carsten Hafer1,
Bernhard M.W. Schmidt1, Jan T. Kielstein1*
1Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany, 2Institute of Diagnostic and Interventional Neuroradiology, Medical
School Hannover, Hannover, Germany
Background: Patients undergoing hemodialysis treatment have a six-fold increased risk for stroke relative to the general
population. However, the effect of hemodialysis on cerebral blood flow is poorly studied and confounding factors like blood
pressure and ultrafiltration as well as temperature changes have rarely been accounted for. The aim of our study was to use
state-of-the-art technology to evaluate the effect of a single dialysis session on cerebral perfusion as well as on vascular
Methods: Chronic hemodialysis patients (7 male/3 female, mean age 58 years) were recruited. Cerebral blood flow and
arterial pulse wave velocity were measured before and immediately after a hemodialysis session. To exclude effects of
volume changes we kept ultrafiltration to a minimum, allowing no change in body weight. Isothermic conditions were
maintained by using the GENIUS single-pass batch-dialysis system with a high-flux polysulfone dialyser. Cerebral blood flow
was measured by contrast-enhanced computed tomography. Pulse wave velocity was measured using the SphygmoCor
(AtCor Medical, USA) device by a single operator.
Results: This study shows for the first time that isovolemic, isothermic hemodialysis neither affected blood pressure or heart
rate, nor total or regional cerebral perfusion. There was also no change in pulse wave velocity.
Conclusions: Mechanisms other than the dialysis procedure itself might be causative for the high incidence of ischemic
strokes in this patient population. Moreover, the sole removal of uremic toxins does not lead to short-term effects on
vascular stiffness, underlying the importance of volume control in this patient population.
Citation: Reising A, Sambale S, Donnerstag F, Schmidt JJ, Hafer C, et al. (2013) Effect of Isovolemic, Isothermic Hemodialysis on Cerebral Perfusion and Vascular
Stiffness Using Contrast Computed Tomography and Pulse Wave Velocity. PLoS ONE 8(2): e56396. doi:10.1371/journal.pone.0056396
Editor: Theodore I. Steinman, Harvard Medical School, United States of America
Received December 3, 2012; Accepted January 2, 2013; Published February 22, 2013
Copyright: ? 2013 Reising et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported by an unrestricted grant of the Else-Kro ¨ner-Fresenius Foundation (P63/06//EKMS 06/03). The funders had no role in study
design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: JTK recieved unrestricted research support from Fresenius Medical Care Germany. JTK received speaker fees from Fresenius Medical Care
Germany. All other authors have declared that no competing interests exist. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing
data and materials.
* E-mail: Kielstein@yahoo.com
. These authors contributed equally to this work.
The high prevalence of cardiovascular disease in chronic kidney
disease (CKD) stage 5 D, i.e. dialysis patients has been known for
decades . Traditional cardiovascular risk markers do not solely
explain these events. Functional test like the measurement of pulse
wave velocity have been shown to be independent predictor of
cardiovascular morbidity and mortality in this patient population
[2,3]. Despite an extensive pharmacological treatment the success
in preventing or delaying cardiovascular events in CKD 5 D
patients is limited . Hence the dialysis procedure itself is thought
to play an essential role in the pathophysiology of cardiovascular
events, yet their short term impact on vascular function has not
been extensively studied. For instance the effect of a single
hemodialysis session on the cerebral blood flow is controversially
discussed. While one group found an improvement of cerebral
blood flow due to dialysis  other groups do see either no effect at
all [6,7] or even a decrease in cerebral blood flow . Also the
effect of a single hemodialysis on arterial stiffness, the result of a
complex interaction between structural and functional changes in
the vessel wall, has not been the focus of clinical research, making
it difficult to dissect the importance of abnormal arterial
calcification from volume overload uremic toxins and various
endocrine abnormalities [9,10]. Clinical studies on pulse wave
velocity measurements are contradicting. Ranging from absent
effects  to a decrease  or even increase [13–14] in pulse
wave velocity (PWV) caused by dialysis, a discrepancy that might
be due to either temperature effects of dialysis or the hydration
status which has been shown to influence PWV . Due to the
PLOS ONE | www.plosone.org1February 2013 | Volume 8 | Issue 2 | e56396
scarce data about this topic, the unreliable Doppler ultrasound
studies of cerebral blood flow, the aim of our study was to analyze
the cerebral blood flow and the pulse wave velocity of patients with
CKD 5 D before and after a single hemodialysis using the gold
standard for the cerebral blood flow measurement, i.e. computer
tomography based cerebral perfusion.
Subjects and Methods
The study protocol was approved by the Hannover Medical
School Ethics Committee (protocol # 3952). Stable adults
undergoing chronic hemodialysis treatment were studied after
written informed consent was obtained from the patients.
Participants of the Study
Participants included were undergoing chronic hemodialysis for
at least one year with a regimen of at three times per week. None
of the patients suffered from instable coronary artery disease or
had signs of severe heart failure (.NYHA II). The patients had no
signs of infections based on c-reactive protein (CRP) and clinical
examination. Exclusion criteria were participation in other studies
during the previous three month, allergy against contrast agents or
iodine, hyperthyroidism or unclear dysfunction of thyroid gland,
premenopausal women, history of radiation of the cranium,
residual diuresis ($500 ml/day), history of stroke within six weeks
prior to study participation, taking nutrition supplements contain-
ing L-arginine, and any further conditions at the discretion of the
The study participation took place on the patient’s midweek
dialysis day. After measurement of the predialysis body weight,
heart rate, blood pressure and body temperature the dialysis
needles (17 Gauge, Bionic Medizintechnik, Friedrichsdorf, Ger-
many) were placed as usual in the dialysis fistula and a blood gas
analysis (BGA) including determining sodium and potassium was
Afterwards the patient was taken to the computed tomography
(CT) scan in supine and resting position, to rule out influences by
altered hemodynamics. The initial CT-scan was performed as
described below and the patient was taken back to the dialyis unit.
The four hour lasting dialysis session was performed using the
GeniusH (Fresenius Medical Care, Bad Homburg Germany)
single-pass batch-dialysis system with a high-flux polysulfone
dialyser FX 60 (Fresenius Medical Care, Bad Homburg Ger-
many). The dialysis solution was composed according to the
patient’s requirements. The blood flow and the countercurrent
dialysate flow ranged between 200 and 250 ml/min, there was no
net ultrafiltration. After 4 hours the patients underwent a second
pulse wave analysis and subsequently a second CT.
Perfusion CT Imaging Protocol
The method used was described previously and adapted due to
modified CT hardware . In brief, all perfusion CT imaging
examinations were performed at a Lightspeed 16 row helical CT
scanner (GE Medical Systems, Milwaukee, Wis.). The position of
the scan region was determined from a previously acquired
unenhanced baseline CT. Two adjacent slices at the level of the
basal ganglia included the vascular territory of the anterior, middle
and posterior cerebral artery. During a scan time of 45s the total
number of 90 slices for each position with a thickness of 10-mm
sections of continuous (cine) scanning (80 kV, 200 mA) were
obtained. CT was initiated 4s after injection (injection rate
2.5 mL/s) of iodinated contrast material with an iodine concen-
tration of 400 mg/dl (Imeron 400, Altana, Konstanz, Germany)
with a total volume of 40 mL. The contrast agent was injected via
one of the placed dialysis needles followed by a saline flush with
the same injection rate with a power injector (Stellant Medrad,
Indianola, USA). Parametric maps of brain perfusion parameter
were created from the resulting tracer kinetic images using
commercially available software (Perfusion 3, AW 4.0, GE
Healthcare, Milwaukee, USA). This software algorithm computed
the regional cerebral blood flow (CBF) in mL/min/100 g brain
tissue with the deconvolution of the parenchymal time-concen-
tration curves by a reference arterial input function (AIF). The
region of interest (ROI) that provided the AIF was placed in each
anterior cerebral artery (to cover bilateral vessels); the venous
outflow function ROI placed in the transverse sinus. Total
cerebral perfusion was obtained by averaging blood flow from 4
standardized ROIs in each hemisphere as previously described
Measurement of Pulse Wave Velocity
Carotid-aortic PWV was determined using a validated system
(SphygmocorTM; AtCor Medical, Sydney, Australia), which
employs high-fidelity applanation tonometry by a pencil-type
probe for non-invasive registration of peripheral arterial pressure
waves. Pulse waveforms of the common carotid artery and the
femoral artery were obtained sequentially and PWV was
calculated as the distance between the suprasternal notch and
the femoral artery recording site minus the distance between the
suprasternal notch and the carotid artery recording site, divided by
the time interval between the feet of the flow waves. The device
uses the foot-to-foot methods as described previously .
Measurement of Body Temperature
Body temperature was measured with an infrared tympanic
thermometer (GeniusTM2, Covidien, Mansfield, MA, USA) with
an accuracy of +/20.1uC.
Patient demographics and laboratory data are reported in
Table 1. Isovolemic conditions could be confirmed by comparing
the median [interquartile range] pre dialysis weight (71.15 [65.40–
79.88] kg ) with the post dialysis weight (71.09 [65.33–79.75] kg),
which revealed no difference (p=0.9884). Isothermic hemodialysis
could be confirmed by the lack of significant differences comparing
pre and post dialysis body temperature (Figure 1). Moreover,
neither systolic or diastolic blood pressure and heart rate nor
pCO2or pH changed significantly (Figure 1). There was also
neither a change in total cerebral blood flow (Figure 2), nor in the
different territories of the anterior, middle and posterior cerebral
artery. Also pulse wave velocity remained unaffected by the
dialysis procedure (Figure 3). The none-invasively measured
blood pressure and heart rate, determined at 30 min intervals, did
not show any significant changes over the course of the
hemodialysis session (data not shown). The absolute median
(range) amount of the removed uremic toxins markers in the
collected spent dialysate were 428 (112–630) mmol urea and 15.4
(6.3–22.1) mmol creatinine.
The main finding of our study is, that isovolemic, isothermic
hemodialysis has neither an effect on cerebral perfusion nor in
vascular elasticity in chronic hemodialysis patients.
Effect of Hemodialysis on Cerebral Blood Flow
PLOS ONE | www.plosone.org2February 2013 | Volume 8 | Issue 2 | e56396
Pulse Wave Velocity
Pulse wave velocity is well known as an independent and highly
predictive risk marker for cardiovascular events in general
population  as well as in CKD 5D patients on hemodialysis
[2,3]. Thus far the reports on the effect of a single hemodialysis
session on PWV are conflicting. Some authors found no effect of
hemodialysis on PWV [11,20] while other authors described a
significant increase of PWV . The latter group discussed a
post-dialytic increase in heart rate and sympathetic nervous
activity as causative for these findings . Di Iorio et al found the
marked inter- and intradialytic changes of hydration status as the
major determinant for a decreasing PWV during dialysis sessions
. This finding is supported by our results as we did not perform
a net ultrafiltration in our study, specifically to address the
potential effect of volume on PWV. Indeed, in all studies
investigating the effect of hemodialysis on PWV so far ultrafiltra-
tion/weight reduction ranging between ,1500 ml  to
,3.2 kg . Nevertheless several of these and other authors
discussed effects of the hemodialysis procedure itself, - independent
of the hydration or hemodynamic effects due to ultrafiltration - like
leukocyte, platelet complement activation and disordered leuko-
cyteendothelial interactions, and increased release of oxidative
radicals [11,13,21]. Thermal changes during dialysis strongly
influence intradialytic hemodynamics  a truth that arose from
the pioneering clinical observation of Jonas Bergstroem .
Indeed, beside from maintaining peripheral vascular resistance,
keeping the body temperature stable also ameliorates the left
ventricular dysfunction, which is often associated with hemodial-
ysis . As the sole elimination of uremic toxins in our study did
not have any effect on PWV we consider volume changes and
body temperature to be of major importance for short term
changes in PWV.
Cerebral Blood Flow
In our study we could not detect any effect of isovolemic,
isothermic hemodialysis on cerebral blood flow, even by employ-
ing an FDA approved method, i.e. computed tomography
perfusion technique . Previous published studies on the effect
of hemodialysis on cerebral blood flow used transcranial Doppler
sonography, which is a poorly reproducible technique. The
technique does not directly measure cerebral blood flow but
Figure 1. Vital signs and blood gas analysis. Predialysis and postdialysis systolic blood pressure, diastolic blood pressure, heart rate, venous
pCO2and pH depicted as box and whisker plots. Horizontal bars indicate median values.
Figure 2. Cerebral blood flow. Predialysis and postdialysis cerebral
blood flow depicted as box and whisker plots. Horizontal bars indicate
median values. p=0.16 comparing pre- and post-dialysis measure-
Figure 3. Pulse wave velocity. Predialysis and postdialysis pulse
wave velocity depicted as box and whisker plots. Horizontal bars
indicate median values. p=0.39 comparing pre- and post-dialysis
Effect of Hemodialysis on Cerebral Blood Flow
PLOS ONE | www.plosone.org3 February 2013 | Volume 8 | Issue 2 | e56396
blood flow velocity. Under conditions of constant vascular
resistance cerebral blood flow can be estimated. However we
know that the dialysis procedure itself may affect vascular
elasticity, either decreasing  or increasing it . In contrast
to all those studies we could not see a significant change of the
cerebral blood flow while eliminating uremic toxins. As we kept
blood pressure and the heart rate constant, we could exclude that
volume alterations interfered the cerebral blood flow measure-
ments. This could explain the difference to other studies [5,8] in
which a marked rate of ultrafiltration of about 2200 ml was
performed. Beside ultrafiltration and the loss of body weight the
hemoconcentration was associated with change of cerebral flow in
this studies. In our study with no net ultrafiltration those
parameters were kept stable. Therefore we postulate that the
ultrafiltration during dialysis plays a crucial role for the decreased
blood flow seen by other authors. Furthermore we conclude that
the solute removal itself has no influence on cerebral blood flow.
This assumption is supported by data showing that high
interdialytic weight gain is associated with a high mortality .
Higher rates of ultrafiltration are associated with significant
increase in all-cause and cardiovascular mortality, probably
induced by repetitive transient cardiac ischemia due to the
intravascular hypovolemia . The same effect might happen to
the brain that suffers from cyclic states of reduced perfusion
following ultrafiltration during hemodialysis. Accelerated aging of
the brain due to reduced cerebral blood flow has also been
proposed as an important mechanism in the Framingham
Limitations of the Study
We wish to point out important limitations of our study. Firstly
the number of subjects studied is rather small, yet the use of state
of the art methodology subjecting patients to an x-ray based
procedure. Secondly, we did not perform a net ultrafiltration, as
we felt that had been done in several studies performed previously.
Thirdly due to methodology it was not possible to measure
cerebral blood flow during the dialysis session, therefore we cannot
rule out intermediate fluctuations. Fourthly, patients were treated
with the GENIUS dialysis system which has some peculiar
properties, such as the absence of an in-built heating. Nevertheless,
a drop in body temperature had so far not been reported over the
course of a four hour treatment [28,29]. Last but not least we
specifically excluded patients with diabetic nephropathy.
In summary, during a single hemodialysis session, the removal
of uremic toxins alone had neither an effect on vascular stiffness
nor on cerebral blood flow. Hence most like the combination of
long term changes in the vessel wall anatomy in combination with
short term volume shifts might be responsible for the high
prevalence of asymptomatic silent cerebral infarction in CKD 5 D
Conceived and designed the experiments: AR SS JTK. Performed the
experiments: AR SS FD CH JS BMWS. Analyzed the data: AR SS JTK.
Contributed reagents/materials/analysis tools: FD. Wrote the paper: AR
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fistulaUnderlying renal disease
M 7123.910.1 11.835 yes nephrosclerosis
M 39 22.84.2 12.242yesunknown
F 5528.84.512.0 29yesFSGS
M 49 22.14.0 11.030 yes unknown
F 88 29.8 5.5 9.625yes chronic GN
M 40 220.127.116.111 yesreflux nephropathy
M 57 22.1 3.58.928yesADPKD
M7426.19.5 12.846 yesnephrosclerosis
Abbreviations: BMI=body mass index; AV-fistula=arteriovenous fistula; FSGS=focal segmental glomerulosclerosis; ADPKD=autosomal dominant polycystic kidney
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