Acute effect of hemodialysis on serum levels of the proinflammatory cytokines

Article (PDF Available)inMediators of Inflammation 12(1):15-9 · February 2003with52 Reads
DOI: 10.1080/0962935031000096935 · Source: PubMed
Abstract
Chronic inflammation is a common feature of end-stage renal disease, which carries a heightened risk of atherosclerosis and other co-morbid conditions. Dialysis treatment per se can bring additional risk factors for inflammation, such as increased risk of local graft and fistula infections, impure dialysate or bio-incompatible membranes. Our study was designed to determine whether a hemodialysis session leads to an acute substantial alteration in the plasma levels of the proinflammatory cytokines interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α, the T-lymphocyte activation factor soluble IL-2 receptor (sIL-2R), and an inflammation mediator and chemotactic granulocyte factor, IL-8, in end-stage renal disease patients receiving chronic intermittent HD. In this study, 21 (12 male/nine female) patients undergoing chronic hemodialysis were enrolled. The acute effect of a hemodialysis session on serum cytokine concentrations was assessed by comparison of pre-hemodialysis and post-hemodialysis determinations. Serum IL-1β, sIL-2R, IL-6, IL-8 and TNF-α levels were determined with chemiluminescence enzyme immunometric assays.
C
HRONIC
inflammation is a common feature of end-
stage renal disease, which carries a heightened risk of
atherosclerosis and other co-morbid conditions. Dia-
lysis treatment per se can bring additional risk
factors for inflammation, such as increased risk of
local graft and fistula infections, impure dialysate or
bio-incompatible membranes. Our study was de-
signed to determine whether a hemodialysis session
leads to an acute substantial alteration in the plasma
levels of the proinflammatory cytokines interleukin
(IL)-6, IL-1b and tumor necrosis factor (TNF)-a, the T-
lymphocyte activation factor soluble IL-2 receptor
(sIL-2R), and an inflammation mediator and chemo-
tactic granulocyte factor, IL-8, in end-stage renal
disease patients receiving chronic intermittent HD.
In this study, 21 (12 male/nine female) patients
undergoing chronic hemodialysis were enrolled.
The acute effect of a hemodialysis session on serum
cytokine concentrations was assessed by comparison
of pre-hemodialysis and post-hemodialysis determi-
nations. Serum IL-1b, sIL-2R, IL-6, IL-8 and TNF-a
levels were determined with chemiluminescence
enzyme immunometric assays.
A significant difference was not observed for IL-1b, IL-
6, TNF-a, and sIL-2R concentrations in pre-hemodia-
lysis and post-hemodialysis specimens (p
/0.05).
Serum median (25th
/75th percentiles) IL-8 concen-
tration was 69.4 (34.9
/110.3) pg/ml before hemodia-
lysis, and decreased to 31.5 (18.0
/78.8) pg/ml
following hemodialysis (p : 0.006). Clearance of IL-8
increased by 0.479
/0.08 pg/ml for each unit increase
in pre-dialysis IL-8 (p B
/0.001) and decreased by
5.639
/2.59 pg/ml for each unit increase in pre-
dialysis urea mmol/l (p B
/0.05).
In conclusion, the results of our study demonstrate
that a hemodialysis session markedly decreases IL-8
concentration, which is significantly affected by pre-
dialysis concentrations, indicating that removal of IL-
8 is a concentration gradient-dependent action, but
does not change the serum levels of IL-1b, sIL
/2R, IL-
6, and TNF-a, underlining importance of the structur-
al characteristics of the molecules.
Key words: Hemodialysis, Proinflammatory cytokines,
Soluble interleukin-2 receptor, Interleukin-8, Clearance
Mediators of Inflammation, 12,15
/19 (2003)
Acute effect of hemodialysis on
serum levels of the
proinflammatory cytokines
Mehmet Tarakc
¸ı
og˘lu
1,CA
,Ays
¸
e Binnur Erbag˘ci
1
,
Celalettin Usalan
2
, Rukiye Deveci
1
and
Ramazan Kocabas
¸
1
1
Department of Biochemistry and Clinical
Biochemistry and
2
Department of Nephrology,
Gaziantep University, Medicine Faculty, 27310
S
¸
ehitkamil Gaziantep, Turkey
CA
Corresponding Author
Tel:
/90 342 3606060/7135
Fax:
/90 342 3601617
E-mail: tarakcioglu@gantep.edu.tr
Introduction
Recent evidence points to chronic inflammation as a
major contributor to morbidity and mortality in end-
stage renal disease (ESRD).
1
It has been proposed
that a chronic inflammatory state could account for
the high risk of ischemic heart disease in patients
with ESRD.
2
Malnutrition and chronic systemic in-
flammatory response syndrome not only co-exist in
uremia, but may also have a bi-directional cause and
effect relationship.
3
Also, anemia appears to be an
important element linking elevated proinflammatory
cytokine levels with poor patient outcomes.
1
Although the uremic state itself may impair lym-
phocyte, granulocyte and monocyte/macrophage
function, defects in immunity can occur as a direct
consequence of therapy.
4
About 35/65% of ESRD
patients receiving hemodialysis (HD) show signs of
inflammation, whereas the prevalence in pre-dialysis
patients may be somewhat lower.
1
Dialysis has been
associated with acute changes in the complement
activation, granulocyte markers, macrophage func-
tion, T-cell activation and the release of various
proinflammatory cytokines.
4 6
Actually, recent data
suggest that levels of the proinflammatory cytokines
in HD patients are eight-fold to 10-fold higher than in
healthy controls. Several studies have linked high
Research Communication
ISSN 0962-9351 print/ISSN 1466-1861 online/03/010015-05 2003 Taylor & Francis Ltd
DOI: 10.1080/0962935031000096935
15
levels of proinflammatory cytokines with poor out-
comes in renal patients. In contrast, high levels of
cytokines associated with better T cell function, such
as interleukin (IL)-2 and IL-12, were associated with a
survival advantage for these patients.
1,7
Activation of the proinflammatory system in HD
patients may be due to three mechanisms. Suscept-
ibility to local graft and fistula infections, inflamma-
tory response induced by bioincompatible dialysis
membranes and exposure to contaminated dialysate
containing cytokine-inducing substances such as
endotoxins.
1,3,8 10
On the other hand, clearance or
membrane adsorption of cytokines during hemodia-
lysis may alter circulating cytokine levels.
11,12
Our study was designed to determine whether a
HD session leads to an acute substantial alteration in
the plasma levels of cytokines in ESRD patients
receiving chronic intermittent HD. The proinflamma-
tory cytokines IL-6, IL-1b and tumor necrosis factor
(TNF)-a, the T-lymphocyte activation factor soluble
IL-2 receptor (sIL-2R), and an inflammation mediator
and chemotactic granulocyte factor, IL-8,
13 16
were
determined in sera specimens before and after HD.
Materials and methods
Patients
This study was conducted in 2001. Informed consent
was obtained from all subjects according to the
Helsinki declaration as revised in 1996. Twenty-one
patients (12 male/nine female) with chronic renal
impairment undergoing hemodialysis were recruited.
Mean age (9
/SD) was 47.39/14.2 years. Body mass
index of the subjects was 20.09
/2.4 kg/m
2
. Patients
received an average of 12 h hemodialysis three times
a week on a non-reprocessed synthetic dialyzer using
polysulfone membranes: Fresenius F-6, 40 mm thick
of 1.3 m
2
surface area (F6 polysulfone UF 5.5;
Fresenius St, Wendel GmbH, Frankfurt, Germany).
Mean dialysis time was 3.79
/4.8 years. Patients
received no other medication except phosphate
binders, ferrous sulfate, essential amino acids and
angiotensin-converting enzyme inhibitors. The etiol-
ogy of the ESRDs was diabetes mellitus (n
/6),
hypertensive malign nephrosclerosis (n
/4), uro-
lithiasis (n
/4), polycystic kidney disease (n/2),
chronic glomerulonephritis (n
/5).
Protocol and experimental study
Pre-HD and post-HD venous blood samples were
collected using standard venipuncture technique 20
min before and after HD, respectively, into plain
tubes. Sera were separated immediately after centri-
fugation at
/48C, 2000 g for 10 min and stored at
/208C for 1 month. Serum IL-1b, sIL-2R, IL-6, IL-8
and TNF-a levels were determined with chemilumi-
nescence enzyme immunometric assays on an Im-
mulite Immunoassay Analyzer (Immulite DPC, Los
Angeles, CA, USA). Analytical sensitivities of IL-1b,
sIL
/2R, IL-6, IL-8, and TNF-a assays were 1.5 pg/ml,
10 U/ml, 1.0 pg/ml, 2.0 pg/ml and 1.7 pg/ml, and the
lower reportable ranges were 5.0 pg/ml, 50 U/ml, 5.0
pg/ml, 5.0 pg/ml and 4.0 pg/ml, respectively. Im-
mulite cytokine controls were included in each
analytical run. Intra-assay and inter-assay precision
performances of the assays were determined on 10
replicates in a single run and in 20 different runs,
respectively and yielded coefficients of variation
within the 4.2
/8.9% range.
Total protein, albumin and urea concentrations
were determined on a Roche/Hitachi modular analy-
tics system (Roche Diagnostics, Indianapolis, IN,
USA) with Roche reagents according to the manu-
facturer’s instructions.
Statistical analyses
Demographic data were expressed in terms of
mean9
/SD. The selected laboratory parameters are
presented as median (25th
/75th percentiles). IL-1b
was expressed as proportion of detectable (]
/5.0 pg/
ml) cases. Paired differences were evaluated with the
paired samples t-test and the Wilcoxon signed-rank
test when necessary. Significant predictors of the
paired difference (pre-HD minus post-HD values) of
IL-8 levels were evaluated with univariate linear
regression analysis. Statistical significance of the
variables was established at the level pB
/ 0.05. The
SPSS 9.0 (SPSS Inc., Chicago, IL, USA) program was
used for statistical analyses and illustrations.
Results
Serum levels of the cytokines in samples taken before
and after HD were compared. IL-1b values in most
cases were below the detection limit. Three cases
with detectable IL-1b in pre-dialysis and four cases in
post-dialysis revealed p
/0.407 by Wilcoxon signed-
rank test. Significant differences were not observed
for IL-6, and sIL-2R concentrations in pre-HD and
post-HD specimens (p
/ 0.05). Serum median (25th/
75th percentiles) IL-8 concentration was 69.4 (34.9/
110.3) pg/ml before HD, and decreased to 31.5
(18.0
/78.8) pg/ml following HD (p /0.006). A sig-
nificant increase for TNF-a (p
/0. 011) was noticed
during hemodialysis (Table 1).
Serum total protein and albumin concentrations
were significantly elevated after HD, a well-known
criteria for hemoconcentration.
17
By determining the
values of relatively big molecules, sIL-2R and TNF-a
per gram of total protein, we aimed to exclude
M. Tarakc
¸
iog
˘
lu et al.
16 Mediators of Inflammation
×
Vol 12
×
2003
possible effects of the hemoconcentration effect
(Table 1). After correction for hemoconcentration,
the increase in TNF-a concentration disappeared,
possibly indicating a hemoconcentration rather than
an absolute change in total serum. The paired
difference for sIL-2R remained insignificant after
correction for hemoconcentration. Pre-HD and post-
HD IL-8 concentrations of the patients are illustrated
in Fig. 1.
Results of univariate regression analysis paired
difference (PD) (pre-HD minus post-HD values) of
IL-8 levels as the dependent variable are presented in
Table 2. The model included pre-dialysis IL-8 values
representative of the concentration gradient (as the
dialysis solution does not contain any IL-8 at the
beginning of the session), pre-dialysis and PD urea
representative of accumulation and clearance of
freely diffusible molecules, and pre-dialysis and PD
of total protein concentrations representative of
hemoconcentration. Only pre-dialysis IL-8 and pre-
dialysis urea concentrations were significant predic-
tors of the PD IL-8. The relation with the PD of urea
did not reach the significance level (p
/0.091). The
PD, or in other words removal of IL-8, increased by
0.479
/0.08 pg/ml for each unit increase in pre-
dialysis IL-8 (p B
/0.001) and decreased by 5.639/
2.59 pg/ml for each 1.0 mmol/l increase in pre-
dialysis urea (p B
/0.05). This model explains 58.7% of
the variation in PD IL-8 (p B/0.005).
Discussion
The results of our study demonstrate that the serum
concentrations of IL-8 are decreased during HD but
IL-1b, sIL
/2R, IL-6, and TNF-a remained unchanged
over the course of measurement. Several studies
reported unchanged serum IL-6,
9,11,18
IL-1,
9,19
and
TNF-a
18
during HD concurrent with increased clear-
ance or membrane adsorption of these cytokines.
7,11
The reasons for this phenomenon probably depend
on cytokine kinetics. The half-lives of IL-6 (3
/7 min),
and TNF-a (5
/10 min) are known to be rather short.
Since plasma cytokines are rapidly bound to cell
surface receptors, this implies that stable plasma
concentrations are achieved by a continuously high
production rate. As a consequence, the entire amount
of cytokines potentially eliminated via hemodialysis
is probably considerably lower when compared with
the endogenous production.
18
It is not unlikely that
the serum concentrations of cytokines serve as target
of feedback mechanisms, since their endocrine action
has been shown, apart from paracrine actions.
20,21
It
must also be taken into account that adsorption of
cytokines occurs mainly in the first minutes of HD
and may not reflect a substantial amount of cytokine
removal,
18
and HD membranes may increase cyto-
kine production by activating mononuclear
cells.
9,10,12
Magnitude and impact of biological varia-
tion of cytokines merit consideration for interpreta-
tion of the results of this study. Gonzales et al .
assessed within-subject coefficients of variation (CVi)
for cytokines by measurements at monthly intervals
over a period of six consecutive months in healthy
Table 1. Circulating cytokine levels in pre-hemodialysis and post-hemodialysis specimens
Before hemodialysis After hemodialysis
p
Total protein (g/l) 69.9 (65.7 /73.5) 76.1 (70.6 /84.9) 0.001
Albumin (g/l) 38.7 (36.0
/41.8) 42.6 (38.3/48.9) 0.001
Urea (mmol/l) 26.1 (20.1
/28.7) 10.8 (9.13/12.5) 0.000
IL-1b (detectable%)
n
/3, 14%
n
/4, 19% 0.407
IL-6 (pg/ml) 15.3 (7.0
/24.9) 21.4 (7.0 /26.5) 0.913
IL-8 (pg/ml) 69.4 (34.9
/110.3) 31.5 (18.0 /78.8) 0.006
TNF-a (pg/ml) 23.1 (20.1
/30.3) 26.2 (24.4/32.2) 0.011
sIL-2R (U/ml) 4292 (2431
/6975) 4473 (2191/8474) 0.968
TNF-a (pg/ml)/total protein (g/l) 0.35 (0.29
/0.43) 0.36 (0.29/0.45) 0.679*
sIL-2R (U/ml)/total protein (g/l) 64.2 (35.4
/95.8) 58.6 (27.1/19.1) 0.601*
Data presented as presented as median (25th /75th percentiles).
*Significance after correction for hemoconcentration.
FIG. 1. Pre-hemodialysis and post-hemodialysis IL-8 concen-
trations of the patients arranged according to the pre-
hemodialysis IL-8 values in ascending order on a semi-
logarithmic scale.
Cytokines and hemodialysis
Mediators of Inflammation
×
Vol 12
×
2003 17
individuals. The within-subject variation is the aver-
age variation of results around the homeostatic mean
of the individual. The CVi for IL-1b, IL-8, and TNF-a
were 30%, 24%, and 43%, respectively.
22
CVi for IL-6
was 30.5% in a short-term variability study.
23
These
data apparently indicate that the impact of biological
variation of the cytokines is large on numerical
results. So, it is possible to assume that any effect of
hemodialysis on IL-1b, sIL
/2R, IL-6, and TNF-a may
be masked by a biological variation of higher
magnitude. However, the expected intra-individual
variation of IL-8 (Cvi
/24%) is much smaller than the
CVi in our study (54.1%; data not shown). Therefore,
biological variation does not explain the observed
difference between pre-dialysis and post-dialysis IL-8
concentrations.
Diverse elimination kinetics of the studied cyto-
kines may be related to the differences in molecular
structure. IL-6 (26.5 kDa), TNF-a (biologically active
heterotrimeric form, 53 kDa), IL-1b (17.5 kDa), sIL
/
2R (varies, 55 /75 kDa) are relatively large molecules.
IL-8 is a low molecular weight protein (10 kDa) with
a globular three-dimensional conformation,
20,21
which possibly enables its diffusion through the
dialysis membrane. In our study, the significant effect
of pre-dialysis IL-8 levels on elimination of IL-8
observed may represent a concentration gradient,
confirming this diffusion effect. Alternative or addi-
tional possible mechanisms of the observed decrease
may be altered IL-8 production or stability, mem-
brane adsorption of IL-8, or IL-8 producing cells
during hemodialysis. It is now known that IL-8
production by various normal and pathological hu-
man cells can be either constitutive or can be induced
by various stimuli, such as lipopolysaccharide, leu-
kotrienes, IL-1, TNF-a. Several stress factors such as
hypoxia, acidosis, and nitric oxide (NO) significantly
influence expression of IL-8 in tumorogenic human
cells.
14,20
Xie suggested that NO serves as an intra-
cellular second messenger to regulate IL-8 gene
expression, increasing IL-8 protein secretion and
promoter activity. The rate of IL-8 gene transcription
was correlated with the level of IL-8 expression,
suggesting that a constitutive level of IL-8 gene
transcription was a major contributing factor in
differential IL-8 expression.
14
Therefore, decreased
NO may be a contributing factor to decreased serum
IL-8.
24
The negative correlation of pre-dialysis urea
levels with the PD of IL-8, however, is an unexpected
finding and may simply result from a competition
between freely diffusible molecules or somewhat
lower pre-dialysis IL-8 levels in patients with higher
pre-dialysis urea concentrations.
Heering et al. have demonstrated removal of IL-8
from the circulation by continuous hemofiltration but
a reduction of plasma IL-8 levels is contradictory.
25,26
Differences in the flow rates, amount of fluids and
nature of membranes as well as the differences in the
pathophysiology of the diseases (as they investigated
critically ill patients) in our study and the aforemen-
tioned studies may have implications on the observed
differences.
This study has some methodological limitations
that might contribute to the fact that we did not find a
significant difference for IL-1b. The majority of the
pre-HD and post-HD specimens had lower serum
levels than the detection limit of the assay, which
raises the possibility that phase differences might be
present below the detection limit. Another potential
limitation was the small number of the study group. A
larger study population and a longitudinal study
design, including more sessions, are needed to
elucidate whether these alterations are consistent.
In conclusion, the results of our study demonstrate
that a HD session markedly decreases IL-8 concen-
tration, which is significantly affected by pre-dialysis
concentrations, indicating that removal of IL-8 is a
concentration gradient-dependent action. But a HD
session does not change serum levels of IL-1b, sIL
/
2R, IL-6, and TNF-a, underlining importance of the
structural characteristics of the molecules.
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Corrected model
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/0.81 9.80 0.091
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Received 2 October 2002
Accepted 2 December 2002
Cytokines and hemodialysis
Mediators of Inflammation
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    • "This agreed with Massey and McPherson [35] finding that suggested a diverse elimination kinetic behavior of IL-6 cytokines despite its relative low molecular weight (26.5 kDa). Tarakc et al. [36] stated that HD session does not change serum levels of IL-1, IL-6, and TNF-a, underlining importance of the structural characteristics of the molecules. Girndt et al. [37] also reported unchanged serum IL-6, during HD concurrent with increased clearance or membrane adsorption of these cytokines. "
    [Show abstract] [Hide abstract] ABSTRACT: Inflammation and oxidative stress are two faces of one coin in end stage renal disease patients (ESRD) on maintenance hemodialysis. Their interconnection induces anemia complicated with erythropoietin hyporesponsiveness. The biochemical bases behind the resistance to erythropoietin therapy with frequent hemoglobinemia, oxidative stress and iron status have not been fully understood. Here two equal groups (40 patients each) of responders and non-responders to recombinant human erythropoietin therapy (higher than 300 IU /kg/wk of epoetin) were investigated. Hematological and biochemical analysis of collected blood and serum samples were performed along with serum electrophoretic protein footprinting. The leucocytic DNA fragmentation was used to evaluate the degree of oxidative insult. The good responders showed lower erythrocyte malondialdehyde (E-MDA) level; less DNA fragmentation of circulating leukocytes than poor responders with elevated hemoglobin, albumin, A/G ratio, total iron, and ferritin levels. Contrariwise, lower erythrocyte superoxide dismutase (E-SOD) and catalase activities in EPO poor responder group were noticed. Neither other serum constituents nor electrophoretic protein pattern showed any difference between the two groups. There were higher levels of inflammatory markers, interleukin-6 (IL6) and C- reactive protein (CRP) in EPO poor responder than good responder. The negative correlations between Hb and both IL6 and CRP levels in the present data remotely indicates a positive correlation between inflammatory markers and severity of anemia. A direct correlation between Hb and antioxidant enzymes (E-SOD and catalase) was noticed, while inverse correlation with E-MDA was recorded. The study proved that oral supplementation of vitamin C to ESRD patients might mitigate the previously elevated serum MDA level in these patients.
    Full-text · Article · Feb 2016
    • "systemic atherosclerosis, heart failure or (occult) infections [69,717273. Dialysis-related factors, such as bioincompatible membranes may play a role in its pathogenesis [74] although, also with the use of synthetic membranes was an inflammatory response observed during dialysis [75, 76]. Also dialysate impurity may play a role, given the fact that markers of inflammation and oxidative stress were significantly lower in patients treated with ultrapure versus standard dialysate [77]. "
    [Show abstract] [Hide abstract] ABSTRACT: The first year following the start of haemodialysis (HD) is associated with increased mortality, especially during the first 90–120 days after the start of dialysis. Whereas the start of dialysis has important effects on the internal environment of the patient, there are relatively few studies assessing changes in phenotype and underlying mechanisms during the transition period following pre-dialysis to dialysis care, although more insight into these parameters is of importance in unravelling the causes of this increased early mortality. In this review, changes in cardiovascular, nutritional and inflammatory parameters during the first year of HD, as well as changes in physical and functional performance are discussed. Treatment-related factors that might contribute to these changes include vascular access and pre-dialysis care, dialysate prescription and the insufficient correction of the internal environment by current dialysis techniques. Patient-related factors include the ongoing loss of residual renal function and the progression of comorbid disease. Identifying phenotypic changes and targeting risk patterns might improve outcome during the transition period. Given the scarcity of data on this subject, more research is needed.
    Full-text · Article · Jun 2015
    • "The concept that hemodialysis evokes an inflammatory response is based on the observation that dialysis causes the release in blood of inflammatory cytokines, such as TNF-α, IL-1 and IL-65657585965,66]. IL-6 was firstly described by Ritchie et al. in 1983 [67], who characterized a polypeptide produced by monocytes involved in the regulation of acute phase response and defined hepatocytes stimulating factor, and afterwards IL-6. "
    [Show abstract] [Hide abstract] ABSTRACT: Oxidative response and inflammation constitute a major defense against infections, but if not properly regulated they could also lead to a number of deleterious effects. Patients affected by different stages of acute and chronic kidney disease, particularly patients on hemodialysis, present a marked activation of oxidative and inflammatory processes. This condition exposes these patients to an elevated risk of morbidity and mortality. This Review is up to date and it analyses the newest notions about pathophysiological mechanisms of oxidative stress and inflammation in patients with renal diseases, also considering the different strategies studied to counterbalance this high risk state.
    Full-text · Article · Jul 2011
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