Renal Failure, 2013; 35(3): 344–351

Copyright © Informa Healthcare USA, Inc.

ISSN 0886-022X print/1525-6049 online
DOI: 10.3109/0886022X.2012.760407

CLINICAL STUDY

Does Arterio-Venous Fistula Creation Affects Development of Pulmonary

Hypertension in Hemodialysis Patients?

Aydin Unal1, Mustafa Duran2, Kutay Tasdemir3, Sema Oymak4, Murat Hayri Sipahioglu1,
Bulent Tokgoz1, Cengiz Utas1 and Oktay Oymak1
1
Department of Nephrology, Erciyes University Medical School, Kayseri, Turkey; 2Department of Cardiology, Erciyes University
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Medical School, Kayseri, Turkey; 3Department of Cardiovascular Surgery, Erciyes University Medical School, Kayseri, Turkey;
4
Department of Pulmonology, Erciyes University Medical School, Kayseri, Turkey

Abstract
Background: Pulmonary arterial hypertension (PAH) is a common complication in hemodialysis (HD) patients and its
pathogenesis is not explained clearly. Arterio-venous fistulas (AVFs) creation may contribute to the development of
PAH because of increased pulmonary artery blood flow. However, it was not prospectively evaluated that effect of AVF
on the development of PAH. Aim: We aimed to evaluate the effects of AVF on PAH and the relationship between blood
flow rate of AVF and pulmonary artery pressure (PAP) in HD patients. Patients and Method: The prospective study
For personal use only.

included 50 patients with end-stage renal disease. Before an AVF was surgically created for hemodialysis, the patients
were evaluated by echocardiography. Then, an AVF was surgically created in the patients. After mean 76.14
11.37
days, the second evaluation was performed by echocardiography. Results: Before AVF creation, 17 (34%) out of 50
patients had PAH. The systolic PAP was significantly higher in the patients with PAH compared with patients without
PAH (47.82
9.82 mmHg vs. 30.15
5.70 mmHg, respectively, p ¼ 0.001). In the second evaluation, 19 (38%) out of 50
patients had PAH. The systolic PAP values were significantly higher in the patients with PAH compared with patients
without PAH (47.63
8.92 mmHg vs. 25.03
7.69 mmHg, P ¼ 0.001, respectively). There was no relationship between
the blood flow rate of AVF and PAP. Conclusion: PAH is a common problem in HD patients. AVF has no significant effect
on the development of PAH within a short period. Similarly, blood flow rate of AVF also did not affect remarkably the
systolic PAP.

Keywords: arterio-venous fistula, blood flow rate, end-stage renal disease, hemodialysis, pulmonary arterial hypertension

INTRODUCTION Arterio-venous fistulas (AVFs) induce problems such

Pulmonary arterial hypertension (PAH) is characterized by
elevated systolic pulmonary artery pressure (PAP) due to
heart, lung, or systemic diseases.1 Regardless of the cause, it
is associated with increased mortality and morbidity.2
Although specific mechanisms of PAH development are
not fully known, several mechanisms have been suggested.
The main vascular findings in PAH are vasoconstriction,
proliferation of smooth muscle cells and endothelial cells,
and thrombosis.3 In literature there were a few studies, in
which the prevalence and pathogenesis of the disease were
investigated in hemodialysis (HD) patients. In these studies,
the prevalence of PAH was detected to be approximately
25– 45% in HD patients.4–7
as high-output cardiac failure and coronary ischemia in
HD patients.8,9 In addition, increase in cardiac output
due to AVF creation contributes to the development of
PAH because of increased pulmonary artery blood flow.5
The aim of this study was to evaluate the effect of AVF,
which was created surgically for vascular access, on the
development of PAH and relationship between blood
flow rate of AVF and PAP in the patients with end-stage
renal disease (ESRD).
PATIENTS AND METHOD
The study was performed between March 2007 and
January 2008 at the Department of Nephrology, Erciyes

The manuscript has been presented at The World Congress of Nephrology, Milan, Italy, May 23, 2009 (Sa509).
Address correspondence to Dr. Aydin Unal, Department of Nephrology, Erciyes University Medical School, Kayseri, Turkey. E-mail:
aydinunal2003@gmail.com; a.unal@erciyes.edu.tr
Received 15 October 2012; Accepted 17 December 2012

344

University Hospital, Kayseri, Turkey. The study protocol
was approved by the local ethics committee. The study
procedures were approved by all patients and healthy
volunteers.
Patients
Sixty-one patients with ESRD, who were planned for an
AVF creation for vascular access to HD, were enrolled to
the study. Two patients died before the second echocar-
diographic evaluation. Primary failure developed after an
AVF creation in five patients. Although two patients were
included in this study, they underwent peritoneal dialysis
(PD) without an AVF creation. One patient refused renal
replacement treatment (RRT). Indication of RRT dis-
appeared in one patient because renal function improved
partially. Finally, 50 patients (26 males and 24 females)
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with ESRD, who underwent HD via an AVF which was
surgically created, were enrolled to the study. Twenty
PD patients (10 males and 10 females) and 15 healthy
volunteers (8 males and 7 females) were included to the
study as control groups.
The patients who were under the age of 18 and who
had chronic obstructive pulmonary disease (COPD),
connective tissue disease, left ventricular ejection frac-
tion <50%, severe mitral or aortic valve disease, chest
For personal use only.
wall or parenchymal lung disease, and a history of pul-
monary thromboembolism were excluded.
The patient’s demographic data such as age and gen-
der, comorbid diseases such as diabetes mellitus, clinical
data including use of antihypertensive drug and erythro-
poietin (EPO), smoking, height, weight, and cause of
ESRD were recorded.
The Echocardiographic Evaluation
It has been reported that there was excellent correlation
between the measurements of PAP by invasive method and
by Doppler echocardiography.10 Therefore, we used an
echocardiographic method for evaluation of PAP. All
echocardiographic evaluations were performed by the
same cardiologist (MD) using the Vivid 7 Dimension
(GE Medical Systems, Horten, Norway) echocardiogra-
phy machine. Two-dimensional and M-mode Doppler
echocardiographic images were obtained from apical or
parasternal windows in the left lateral recumbent position
in each patient and control. In the presence of tricuspid
valve regurgitation, systolic right ventricular (or systolic
pulmonary artery) pressure was calculated by using the
modified Bernoulli equation: PAP ¼ 4  (tricuspid systolic
jet)2 þ 10 mmHg.11 PAH is defined as an elevation of the
mean PAP above 25 mmHg at rest in the setting of normal
or reduced cardiac output and normal pulmonary capillary
pressure. If echocardiographic criteria are used, it is
defined as systolic PAP > 35 mmHg at rest.12 Therefore,
PAH was defined as systolic PAP > 35 mmHg at rest in the
present study. End-diastolic left ventricular septal and pos-
terior wall thickness and internal dimensions were used to
© 2013 Informa Healthcare USA, Inc.
Arterio-Venous Fistula and Pulmonary Hypertension 345
calculate left ventricular mass by using the following equa-
tion: left ventricular mass ¼ 1.04  0.8 [(left ventricular
wall thickness þ internal dimension) – (internal
dimension)]þ 0.6 g. Left ventricular hypertrophy (LVH)
was defined as left ventricular mass index (LVMI), which
was calculated with left ventricular mass in grams divided
by body surface area in square meters, higher than
116.0 g/m2 for men and 104.0 g/m2 for women.13 Body
surface area was calculated by using Mosteller’s formula.14
Blood flow of AVF was automatically obtained by
using Doppler echocardiography. The echocardio-
graphic evaluation was performed once in PD patients
and control subjects and twice in HD patients. In HD
patients, it was performed before an AVF creation. Then
an AVF was created surgically. After HD was started via
an AVF after AVF maturation, the second echocardio-
graphic evaluation, which was performed within 24 h
after HD session to avoid volume loading, was per-
formed. At the second evaluation, the blood flow rate of
AVF was also measured.
Blood Samples
Blood samples were obtained from all patients and
healthy volunteers for biochemical examinations,
including whole blood count, blood urea nitrogen
(BUN), serum creatinine, serum albumin, serum cal-
cium, serum phosphorus, serum alkaline phosphatase,
intact parathyroid hormone (iPTH), high-sensitive
C-reactive protein (hsCRP), and total lipid profile at
the same day in which were performed echocardio-
graphic evaluation. The iPTH was measured by radio-
immunoassay (Immunotect, Marseille, France). Serum
hsCRP was measured by CardioPhase hsCRP (Dade
Behring) on a Dade Behring.
Statistical Analysis
SPSS 11.0 statistic software was used for the statistical
analysis. The Kolmogorov–Smirnov test was used to
determine the normality of distributions of variables.
Continuous variables with normal distribution were
presented as mean
standard deviation. Median
value was used in variables without normal distribu-
tion. Statistical analysis for the parametric variables
was performed by one-way ANOVA with Scheffe’s
post-hoc test between three groups. The Kruskal–
Wallis test was used to compare the nonparametric
variables. Then, the Mann–Whitney U-test with
Bonferroni correction was used to assess differences
among the groups. The qualitative variables were
given as percent and the correlation between categori-
cal variables was investigated by the χ2 test. To com-
pare variables before an AVF creation and after an AVF
creation in HD group, paired t-test (for the parametric
variables), Wilcoxon test (for the nonparametric
variables), and McNemar test (for categorized vari-
ables) were performed. The correlation analysis was
 346 A. Unal et al.

evaluated by the Pearson’s correlation test. p-Value
<0.05 was considered to be significant.
RESULTS
ESRD is mostly caused by diabetes mellitus and hyper-
tension (16 and 10 of 50 HD patients vs. 6 and 10 of 20
PD patients, respectively). There was significantly no
difference between the HD and PD groups with regard
to the presence of diabetes mellitus and hypertension.
The comparison of clinical, biochemical, and echo-
cardiographic parameters among the three groups are
shown in Table 1. LVH and PAH were the most fre-
quently observed in PD group and HD group, respec-
tively. There was significantly no difference among the
three groups in terms of gender, smoking, white blood
cell (WBC), concentrations of serum glucose, trigly-
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blood pressures, use of angiotensin-converting enzyme
inhibitor, angiotensin 2 receptor blocker, and beta-blocker,
WBC, level of serum glucose, total cholesterol and HDL,
serum creatinine concentration, level of iPTH and hsCRP,
systolic PAP value, and presence of PAH (p > 0.05). The
levels of hemoglobin, triglyceride, alkaline phosphatase,
and serum albumin, LVMI value and the presence of
LVH were significantly higher in period after an AVF
creation than in period before an AVF creation. On the
other hand, the levels of low-density lipoprotein (LDL)
and BUN, calcium-phosphorus product (Ca  P product),
uric acid, use of antihypertensive drug and calcium canal
blocker, and ejection fraction were significantly lower in
period after an AVF creation than in period before an AVF
creation (see Table 2).
Systolic PAP value did not correlate with blood flow of
AVF. Although there was no significant correlation between

ceride, and high-density lipoprotein (HDL).
In HD patients, when the parameters which were
evaluated before an AVF was surgically created, were com-
pared to those which were evaluated after an AVF was
surgically created, there was meaningfully no difference
in terms of body mass index (BMI), systolic and diastolic
systolic PAP value and the duration after an AVF creation,
the p-value was 0.052.
Table 3 shows the comparison of clinical and
echocardiographic parameters between HD patients
with PAH and those without PAH at period before an
AVF creation. Systolic blood pressure, systolic PAP, and

Table 1. Comparison of clinical, biochemical, and echocardiographic parameters among the three groups.
For personal use only.

HD group, n ¼ 50 PD group, n ¼ 20 Controls, n ¼ 15 p-value

Age (year)a
57.50
13.64 a
50.80
11.25 47.27
7.50 a
0.009
Body mass index (kg/m2)b 26.80
4.99 29.68
6.18 30.72
5.03 0.018
Diastolic BP (mmHg)c 80 (60–90) 88 (62–131) 75 (60–75) 0.001
Systolic BP (mmHg)d 130 (90–160) 144.5 (98–209) 120 (90–130) 0.001
Hemoglobin (g/dL)e 9.71
1.46e 11.31
1.50e 14.67
1.43e 0.001
Total cholesterol (mg/dL)f 173.80
42.00 215.35
50.63 202.53
30.75 0.001
Low density lipoprotein (mg/dL)f 113.01
30.98 142.38
43.71 137.67
28.21 0.002
Blood urea nitrogen (mg/dL)g 71.92
31.08 48.10
14.00 12.67
3.41 0.001
Serum creatinine (mg/dL)h 6.73
3.83 8.66
3.77 0.78
0.15 0.001
Ca  P product (mg2/dL2)a 50.14
15.23 41.49
13.34 35.80
6.09 0.001
Alkaline phosphatase (U/L)c 83 (40–308) 132 (64–339) 65 (45–139) 0.001
Intact parathormone (pg/mL)a 200.9 (6.7–1599.0) 81.4 (11.7–852.0) 46.0 (14.8–124.4) 0.001
Uric acid (mg/dL)a 7.34
1.91a 6.42
1.48 5.07
1.06a 0.001
Serum albumin (g/dL)i 2.91
0.76 3.19
0.50 3.85
0.26 0.001
hsCRP (mg/dL)h 10.0 (3.1–148.0) 6.4 (3.1–44.0) 3.1 (3.1–6.4) 0.001
Ejection fraction (%)f 59.60
5.67 68.60
8.19 63.80
4.47 0.001
Systolic PAP (mmHg)g 36.16
11.14 23.90
6.76 14.27
4.60 0.001
Presence of PAH 17 (34%) 2 (10%) 0 (–) 0.007
LVMI (g/m2)h 113.18
29.39 121.80
31.31 83.06
28.26 0.001
Presence of LVH 21 (42%) 12 (60%) 2 (13.4%) 0.021

Notes: Data, which did not statistically significant, were not expressed. HD, hemodialysis; PD, peritoneal dialysis; BP, blood pressure; Ca,
calcium; P, phosphorus; hsCRP, high-sensitive C-reactive protein; PAP, pulmonary artery pressure; PAH, pulmonary arterial hypertension;
LVMI, left ventricular mass index; LVH, left ventricular hypertrophy.
a
Age, Ca  P product, iPTH, uric acid were significantly higher in HD group compared to control group.
b
Body mass index was significantly higher in control group compared with HD group.
c
Diastolic BP and alkaline phosphatase were significantly higher in PD groups compared with HD and control groups.
d
Systolic BP was significantly lower in control group compared with HD and PD groups. It was meaningfully higher in PD group
compared with HD group.
e
Hemoglobin level was significantly higher in control group compared with HD and PD groups. It was meaningfully higher in PD group
compared with HD group.
f
Levels of total cholesterol and LDL and ejection fraction value were significantly higher in PD group compared with HD group.
g
BUN concentration and systolic PAP value were significantly higher in HD group compared with PD and control groups. It was mean-
ingfully higher in PD group compared with control group.
h
Levels of serum creatinine and hsCRP, and LVMI value were significantly lower in control group compared with HD and PD groups.
i
Serum albumin level was significantly higher in control group compared with HD and PD groups.

Renal Failure
 Arterio-Venous Fistula and Pulmonary Hypertension 347

Table 2. Comparison of biochemical, clinical, and echocardio- Table 4. Comparison of clinical, biochemical, and echocardio-
graphic parameters in HD patients. graphic parameters between hemodialysis patients with PAH and
those without PAH at period before an AVF creation.
Before an AVF After an AVF
creation creation p-value Patients with Patients without
PAH, n ¼ 19 PAH, n ¼ 31 p-value
Hemoglobin (g/dL) 9.71
1.46 11.29
1.46 0.001
Triglyceride (mg/dL) 114 (51–402) 174 (46–398) 0.007 Duration of 80.63
14.22 73.39
8.32 0.027
Low-density 113.01
30.98 100.05
31.57 0.008 fistula (day)
lipoprotein (mg/dL) Hemoglobin 10.59
1.52 11.73
1.26 0.006
Blood urea nitrogen 71.92
31.08 50.61
23.31 0.001 (g/dL)
(mg/dL) High-density 28.27
10.91 35.19
11.20 0.038
Ca  P product 50.14
15.23 42.55
13.15 0.001 lipoprotein
(mg2/dL2) (mg/dL)
Alkaline phosphatase 83 (40–308) 94 (44–585) 0.003 Serum albumin 3.03
0.65 3.44
0.63 0.030
(IU/L) (g/dL)
Uric acid (mg/dL) 7.34
1.91 6.13
1.77 0.001 hsCRP (mg/dL) 25.9 (3.1–138.0) 4.3 (3.1–114.0) 0.011
Serum albumin (g/dL) 2.91
0.76 3.29
0.66 0.001 Systolic PAP 47.63
8.92 25.03
7.69 0.001
Use of antihyperten- 32 (64%) 22 (44%) 0.013 (mmHg)
sive drug Blood flow of 687.25
382.09 728.04
407.76 0.723
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Use of CCB 25 (50%) 15 (30%) 0.013 AVF (mL/min)

Ejection fraction (%) 59.60
5.67 56.98
5.86 0.023
LVMI (g/m2) 113.18
29.39 125.83
27.68 0.003 Note: PAH, pulmonary arterial hypertension; AVF, arterio-venous
Presence of LVH 21 (42%) 35 (70%) 0.003 fistula; hsCRP, high-sensitive C-reactive protein; PAP, pulmonary
Systolic PAP (mmHg) 36.16
11.14 33.62
13.81 0.175 artery pressure.
Presence of PAH 17 (34%) 19 (38%) 0.774

Note: HD, hemodialysis; AVF, arterio-venous fistula; Ca, calcium; Table 4 shows the comparison of clinical, biochemical,
P, phosphorus; CCB, calcium canal blocker; LVMI, left ventricular
mass index; LVH, left ventricular hypertrophy; PAP, pulmonary
and echocardiographic parameters between HD patients
artery pressure; PAH, pulmonary arterial hypertension. with PAH and those without PAH at a period after an
AVF creation. The duration of fistula, hsCRP level, and
For personal use only.

Table 3. Comparison of clinical and echocardiographic para- systolic PAP value were significantly higher in patients
meters between hemodialysis patients with PAH and those without with PAH compared with patients without PAH. On the
PAH at period before an AVF creation.
other hand, the levels of hemoglobin, HDL, and serum
Patients with Patients without albumin were significantly lower in patients with PAH
PAH, n ¼ 17 PAH, n ¼ 33 p-value compared with those without PAH. However, there were
no significant differences between patients with and
Presence of 15 (88.2%) 18 (54.5%) 0.026
hypertension
without PAH in terms of age, gender, smoking, presence
Systolic blood 130 (120–150) 120 (90–160) 0.023 of diabetes mellitus and hypertension, EPO use, BMI,
pressure diastolic and systolic blood pressures, WBC, serum glu-
(mmHg) cose, total cholesterol, triglyceride, LDL, BUN, serum
Systolic PAP 47.82
9.82 30.15
5.70 0.001 creatinine, Ca  P product, alkaline phosphatase, uric
(mmHg)
Ejection 56.82
5.03 61.03
5.53 0.011
acid, iPTH, ejection fraction, LVMI, presence of LVH,
fraction (%) and blood flow of AVF (p > 0.05).
LVMI (g/m2) 121.38
25.63 108.96
30.67 0.159
Presence of LVH 11 (64.7%) 10 (30.3%) 0.033
DISCUSSION
Note: PAH, pulmonary arterial hypertension; AVF, arterio-venous
fistula; PAP, pulmonary artery pressure; LVMI, left ventricular PAH is a disorder that is characterized by an increase of
mass index; LVH, left ventricular hypertrophy. artery pressure and vessel resistance in the pulmonary
vessels.15 There are two mechanisms, namely high vessel
the presence of hypertension and LVH were significantly resistance and increased pulmonary blood flow for the
higher in patients with PAH compared with those with- development of PAH.5 Increment in pulmonary artery
out PAH. On the other hand, ejection fraction value was resistance is associated with three factors. The first and
significantly lower in patients with PAH compared with the most important factor is the pulmonary vascular
patients without PAH. However, there were no signifi- remodeling, which is characterized by the presence of
cant differences between patients with and without PAH smooth muscle cells within small arterioles of respiratory
in terms of age, gender, smoking, WBC, hemoglobin, acinus. The other factors are vasoconstriction and
serum glucose, total cholesterol, triglyceride, HDL, thrombosis.16
LDL, BUN, serum creatinine, Ca  P product, alkaline The possible cause of vasoconstriction in pathogenesis
phosphatase, uric acid, serum albumin, iPTH, hsCRP, of PAH in HD patients is increased endothelin 1 (ET-1)
presence of diabetes mellitus, BMI, diastolic blood and decreased nitric oxide (NO). Nahhoul et al. reported
pressure, and LVMI (p > 0.05). that ET-1 levels were significantly higher in both HD

© 2013 Informa Healthcare USA, Inc.

 348 A. Unal et al.
patients with PAH and those without PAH compared
with control subjects, and NO levels were significantly
lower in HD patients with PAH compared with HD
patients without PAH and controls.17 Similarly,
increased ET-1 expression and decreased NO synthesis
within the pulmonary arteries of patients with PAH who
had normal renal function has been demonstrated.18,19
PAH is a frequent complication in HD patients. Its
prevalence was found to be approximately 25–57% in
different studies.4–7,20 Similarly, in the present study we
found that the prevalence of PAH was 34% and 38% at
the period before an AVF creation and after an AVF
creation, respectively.
AVF induces high-output cardiac failure.8,9 The pos-
sibility of heart failure is higher in HD patients who had
AVF with high blood flow. In the most such patients, the
blood flow rate of AVF is higher than 1.5 L/min.21
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Therefore, the risk of development of high-output car-
diac failure is higher in upper arm fistulas, which have
high blood flow rate.22
As mentioned above, an increase in pulmonary blood
flow rate is one of the two main mechanisms in the
development of PAH. An AVF creation increases further
pulmonary blood flow rate. Although it has been
reported that 1500 mL/min of a fistula blood flow rate
is a threshold for the development of high-output cardiac
For personal use only.
failure, there is no information about AVF blood rate
required for the development of PAH in the literature.
It is logical that the higher fistula blood flow, the higher
pulmonary artery blood flow.
There were two studies which investigated the rela-
tionship between blood flow rate of AVF and
PAP. Havlucu et al. detected the relationship between
blood flow rate of AVF and systolic PAP value.20 On the
other hand, Acarturk et al. did not observe significant
association between systolic PAP and fistula blood flow
rate.5 In these studies, HD patients had already an AVF
for vascular access. To the best of our knowledge, in
literature, there was no study which investigated the
relationship between PAP and fistula blood flow in HD
patients in whom evaluations before and after an AVF
creation were performed. This study is the first such
study. In the present study, we did not detect the rela-
tionship between and systolic PAP value and fistula
blood flow rate.
In the literature also there was no information about
the duration after an AVF creation for the development
of PAH. It is logical that the longer the duration of AVF,
the higher the risk of the PAH development. Acarturk
et al.5 in his study reported that the mean duration of
AVF creation was 32.7
34.1 months. This duration
was 45.2
40.0 months and 24.6
28.0 months in PAH
group and non-PAH group, respectively, and there was
no significant difference between the two groups with
regard to this duration. On the other hand, Havlucu
et al.20 reported that the duration of AVF creation was
16.2
12.4 months and 6.7
5.3 months in PAH group
and non-PAH group, respectively, and there was
significant difference between the two groups with regard
to this duration. Also, the duration positively correlated
with systolic PAP value. In a study performed Nakhoul
et al.,17 although this duration was higher in PAH group
compared with non-PAH group (34.9
25.2 months vs.
50
30.1 months, respectively), there was no significant
difference between the two groups. In our study, the
duration of fistula was significantly higher in patients
with PAH compared with patients without PAH. In addi-
tion, although the systolic PAP value did not correlate
with the duration of AVF, the p-value was 0.052.
The interpretation of the above information is that it is
logical that the duration of fistula and the blood flow rate
of fistula may be a risk factor of the development of PAH
in HD patients. However, data in literature and our study
did not support precisely the opinion. The important
point is that there are multiple mechanisms, including
uremia, endothelial dysfunction, anemia, and hyperpar-
athyroidism as well as increase in pulmonary blood flow
for the development PAH in HD patients.
The most important cause of mortality in patients with
ESRD is cardiovascular diseases, which resulted mainly
from atherosclerosis. Inflammation plays a central role in
the pathogenesis of atherosclerosis.23 C-reactive protein
(CRP), an acute-phase reactant, is the most important
inflammatory marker for the risk of the development of
cardiovascular disease.24 There are a few studies that
investigated the effects of inflammation in pathogenesis
of PAH, which is a vascular disease.25–27 Joppa et al.25
reported that in patients with COPD, the levels of serum
CRP and tumor necrosis factor alpha (TNF-α) were sig-
nificantly higher in patients with PAH compared to those
without PAH. They also detected that PAP value signifi-
cantly correlated with CRP. Elstein et al.26 found that high
CRP levels were important risk factor for the development
of PAH in patients with Gaucher disease. High levels of
inflammatory cytokines and acute-phase reactants are a
frequent condition in patients with ESRD.28 Several
causes of this condition include underlying progressive
kidney disease, infections, and interactions between
blood and dialysis membrane.28,29 There was only one
study in which the relationship between inflammation
and PAH was evaluated in patients with ESRD.27 In this
study, we reported that there was no correlation between
inflammation markers such as hsCRP and WBC and PAP
value and there was no significant difference between
patients with PAH and those without PAH in terms of
hsCRP and WBC.27 In the present study, we found that
hsCRP levels were significantly higher in HD and PD
patients compared with controls. However, at period
before an AVF creation, there was no significant differ-
ence between patients with PAH and those without PAH
with regard to hsCRP. On the other hand, at period after
an AVF creation, the hsCRP levels were significantly
higher in patients with PAH compared to those without
PAH. With findings of our study, it is difficult to say that
inflammation is an important factor for the development
of PAH in HD patients.
Renal Failure

Vascular calcifications, a common finding, are the risk
factors for cardiovascular mortality in patients with
ESRD. Impairment in calcium–phosphorus balance
and secondary hyperparathyroidism play an important
role in the pathogenesis of the calcifications.30 They
develop in the interstitial space of the alveolar septum
and in the walls of pulmonary vessels in lungs and nega-
tively affect the functions of both the lung and right
ventriculi.31,32 It was reported that high PTH levels
induce pulmonary calcification and pulmonary hyper-
tension in animals with chronic renal failure.32 Kumbar
et al.33 found that there was a significant relation between
PAP values and PTH levels in PD patients. Similarly,
Havlucu et al.20 detected that PTH levels were mean-
ingfully higher in HD patients with PAH compared with
patients without PAH. On the other hand, in a study
performed in 39 HD patients, Yigla et al.34 investigated
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the role of extra-osseous pulmonary calcifications, which
were detected by 99mTc-MDP scintigraphy, in the devel-
opment of PAH. They find that there is no significant
difference between patients with pulmonary calcifica-
tions and those without the calcifications in terms of
systolic PAP value, PTH level, and Ca  P product.
Similarly, Amin et al.6 find that there is no relationship
between PAH and frequency and severity of pulmonary
artery calcifications in 51 HD patients. In the present
For personal use only.
study, we observed no significant difference between
patients with PAH and those without PAH with regard
to PTH levels and Ca  P product at periods before and
after an AVF creation.
Anemia, a common complication of chronic kidney
disease, can contribute to the development of PAH
through increase in cardiac output.35 However, in most
studies that investigated PAH in HD patients, it was
found that there was no significant difference between
patients with PAH and those without PAH in terms of
hemoglobin levels.5,7,17,20 In the present study, it was it
was found that there was significant difference between
period before AVF creation and period after AVF crea-
tion with regard to hemoglobin levels, which were mean-
ingfully higher at period after AVF creation. The cause of
this condition was possibly the use of EPO for the treat-
ment of anemia at period after an AVF creation, in which
the hemoglobin level was significantly lower in patients
with PAH compared with those without PAH. On the
other hand, at period before an AVF creation there was
no difference between the two groups in terms of hemo-
globin levels. However, the patients did not receive EPO
for the treatment of anemia and had severe anemia. This
condition appears to cause no difference between
patients with PAH and those without PAH with regard
to hemoglobin levels at period before an AVF creation.
All findings about hemoglobin levels in this study sup-
port the opinion that anemia is an important factor in the
development of PAH in HD patients.
LVH is a predictor for cardiovascular mortality and
morbidity. In literature, there are a few prospective stu-
dies, in which short-duration effects of a newly created
© 2013 Informa Healthcare USA, Inc.
Arterio-Venous Fistula and Pulmonary Hypertension 349
AVF on left ventriculi has been investigated.36,37
Iwashima et al.36 reported that in 16 HD patients with a
newly created AVF, 15% increase in cardiac output and a
significant increase in left ventricular end-diastolic dia-
meter had occurred at the second week after an AVF
creation. Similarly, Ori et al.37 reported that a significant
increase in stroke volume, ejection fraction, cardiac out-
put, cardiac index, and left ventricular end-diastolic dia-
meter had occurred at 10th day after an AVF creation in
10 patients on HD. However, in these studies, LVMI and
LVH were not evaluated. On the other hand, unfortu-
nately, there was no prospective study, in which long-
term effects of a newly created AVF on left ventriculi had
been investigated. In a few studies that was performed in
patients with renal transplantation, it was shown regres-
sion of LVF after AVF closure.38,39 The finding indir-
ectly indicates that AVF creation is a contributing factor
for the development of LVH.
Several studies reported that there was no significant
difference in LVH between ESRD patients with and
without PAH. However, in study that was performed in
PD patients, we found that PAP significantly correlated
with LVMI and LVMI was the most important para-
meter, which affects PAP value in multivariate analysis.27
In the present study, we observed that LVMI value and
the presence of LVH were significantly higher at period
after an AVF creation compared to at period before an
AVF creation, and so severe negative effects of AVF
creation on the development of LVH.
Hypoalbuminemia is one of the most important risk
factors for mortality in patients with ESRD.40 In only
two studies evaluated PAH in patients with ESRD, there
was information about serum albumin concentration.
Kumbar et al.33 found that serum albumin level was
higher in PD patients with PAH compared with patients
without PAH, although the difference between the two
groups was not statistically significant. We found that
there was negatively significant correlation between PAP
and serum albumin level, and albumin level was an inde-
pendent risk factor for PAP value in multivariate analysis
in PD patients.27 Similarly, in the present study, serum
albumin level was significantly lower in patients with PAH
compared with those without PAH at period after an AVF
creation. The findings can indicate that one of causes of
the condition, that hypoalbuminemia is a risk factor for
mortality in patients with ESRD, is that hypoalbuminemia
is more frequent in patients with PAH.
There is controversial information about the effects of
EPO on pulmonary vessels. In some studies, it was found
that EPO decreased the PAP values.41,42 On the other
hand, in the other studies, it was detected that EPO
induces the development of PAH.43,44 However, in the
present study, we observed that there was no significant
relationship between EPO use and PAH. Similar finding
was observed in our study performed in PD patients.27
Perhaps, increase in pulmonary blood flow induced
by AVF and detrimental effects of inflammation on
pulmonary circulation might be balanced by several
 350 A. Unal et al.
factors, was induced by HD, including better clearance
of uremic toxins with HD, correction of anemia with
EPO treatment, a better calcium–phosphorus balance
with HD and use of phosphorus binding agents, correc-
tion nutrition and hence increase of serum albumin
level with correction of appetite. Also, there may be
effects of the other factors, which were not evaluated
in the present study, on the development of PAH in
patients with HD.
In conclusion, PAH was a common complication in
HD patients. There was no significant short-term effect
of an AVF created surgically on the development of
PAH. Similarly, there was considerable no relationship
between fistula blood flow rate and systolic PAP
measurement.
Ren Fail Downloaded from informahealthcare.com by University of Connecticut on 10/29/14
STUDY LIMITATIONS
1. The invasive procedure (right heart catheterization)
is the best method to estimate PAP. However, in
literature, to the best of our knowledge, in all studies,
in which pulmonary hypertension was investigated in
patients with ESRD, PAP was estimated by echocar-
diographic method. Also, Marangoni et al.10 reported
that there was excellent correlation between the mea-
For personal use only.
surements of PAP by Doppler echocardiography and
by invasive method. In addition, invasive method in
estimating PAP is difficult and traumatic procedure
for the patients. Also, it was so difficult that approval
of the patients, which were included to the study, for
invasive procedure because of the above–mentioned
reasons. Therefore, we chose echocardiographic
method to estimate systolic PAP because of the
above–mentioned reasons.
2. The patients with double–lumen tunneled cuffed
catheters could be included in the study as control
group. However, we never prefer the catheters as the
first choice for vascular access. The patients, who
were enrolled to the study, had newly diagnosed
ESRD and started HD for renal replacement therapy.
During the study, only one patient, who had cervix
cancer, was dialyzed using double–lumen tunneled
cuffed catheters as the first choice for vascular access.
Therefore, patients with tunneled cuffed catheters
were not include in the present study because of
above–mentioned reasons.
3. The number of patients in this study was relatively
low. In literature, however, the number of patients
was low, in which PAH was investigated in patients
with ESRD. In the future, the matter will be evalu-
ated in multicenter studies.
4. In the present study, our observation that the AVF
creation had no significant effect on PAP may be due
to the evaluation of PAP too shortly after the AVF
creation. A longer follow–up could have provided
different results.
Declaration of interest: The authors report no conflicts
of interest.
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