Acute effect of hemodialysis on serum levels of the proinflammatory cytokines.
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-1beta and tumor necrosis factor (TNF)-alpha, 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-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha levels were determined with chemiluminescence enzyme immunometric assays. A significant difference was not observed for IL-1beta, IL-6, TNF-alpha, and sIL-2R concentrations in pre-hemodialysis and post-hemodialysis specimens (p>0.05). Serum median (25th-75th percentiles) IL-8 concentration was 69.4 (34.9-110.3) pg/ml before hemodialysis, and decreased to 31.5 (18.0-78.8) pg/ml following hemodialysis (p: 0.006). Clearance of IL-8 increased by 0.47+/-0.08 pg/ml for each unit increase in pre-dialysis IL-8 (p<0.001) and decreased by 5.63+/-2.59 pg/ml for each unit increase in pre-dialysis urea mmol/l (p<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-1beta, sIL-2R, IL-6, and TNF-alpha, underlining importance of the structural characteristics of the molecules.
- SourceAvailable from: Peter Stenvinkel[show abstract] [hide abstract]
ABSTRACT: Chronic inflammation is a common feature of end-stage renal disease (ESRD) that is gaining increasing attention as a major cause of morbidity and mortality. It is well established that ESRD per se carries a heightened risk of inflammatory disorders and other co-morbid conditions, but it should also be pointed out that dialysis treatment per se can bring additional risk factors for inflammation, such as impure dialysate or bio-incompatible membranes. Inflammation has recently been associated with atherosclerosis and malnutrition in ESRD, and this link has led to the development of the malnutrition, inflammation, atherosclerosis (MIA) hypothesis. This describes a syndrome whereby raised levels of pro-inflammatory cytokines (such as IL-1, IL-6 and TNF-alpha) are a common link between malnutrition, inflammation and atherosclerosis. Also, anaemia appears to be an important element linking elevated cytokine levels with poor patient outcomes. Several mechanisms for cytokine-induced anaemia have been proposed, including intestinal bleeding, impaired iron metabolism and suppression of bone marrow erythropoiesis and erythropoietin production. These effects suggest that pro-inflammatory cytokines may also be an important cause of lack of response to recombinant human erythropoietin (rh-Epo) therapy. In the light of this putative role of pro-inflammatory cytokines, anti-cytokine agents may prove useful to optimize efficacy of rh-Epo in anaemic chronic renal failure patients. Other potential therapeutic strategies include minimizing exposure to causes of inflammation from various co-morbid conditions, such as persistent infections and chronic heart failure.Nephrology Dialysis Transplantation 02/2001; 16 Suppl 7:36-40. · 3.37 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Chronic renal failure (CRF) is associated with an increased risk of ischaemic heart disease (IHD), but the mechanisms responsible are controversial. We investigated the relationship of two sets of candidate mechanisms-indices of LDL oxidation and markers of inflammatory activity-with vascular endothelial dysfunction (VED). We carried out cross-sectional analysis of 23 dialysed and 16 non-dialysed CRF patients, 28 healthy controls, and 20 patients with stable angina and normal renal function. The following were determined: (i) LDL oxidation by Cu(2+) and ultraviolet light, serum autoantibodies to oxidized LDL (oxLDL); (ii) forearm flow-mediated vasodilatation, plasma concentrations of adhesion molecules, and von Willebrand factor (vWF); and (iii) circulating levels of TNF-alpha and IL-6, C-reactive protein (CRP), and fibrinogen. Endothelium-dependent vasodilatation (EDV) was lower in angina, pre-dialysis, and dialysis CRF patients than in controls (all P<0.005). Compared with controls, vWf (P<0.005) and adhesion molecules (vCAM-1, P<0.005; iCAM-1, P=0.01; E-selectin, P=0.05) were raised in dialysis, and vCAM-1 (P=0.01) in pre-dialysis CRF patients. Dialysed patients had lower HDL cholesterol (P=0.01) and higher triglyceride (P=0.05) than controls, but LDL-oxidation was similar in all groups. Autoantibodies to oxLDL were raised in angina (P<0.005) and pre-dialysis (P=0.006), but were absent in most dialysed patients. Concentrations of IL-6, TNF-alpha, CRP and fibrinogen were elevated in CRF compared with control and angina patients (P<0.005). In the whole population, IL-6 and TNF-alpha correlated negatively with EDV, HDL cholesterol, and positively with triglyceride, blood pressure, vWf, iCAM-1, vCAM-1 and E-selectin (r=-0.43 to +0.70, all P<0.05). Endothelial dysfunction is unrelated to LDL oxidation, suggesting that LDL oxidation might not be a major cause of VED in CRF. In contrast VED was more severe in CRF than in angina patients and is associated with increased acute-phase proteins and plasma cytokines, demonstrating a chronic inflammatory state. These observations may explain the VED and increased IHD risk of patients with CRF.Nephrology Dialysis Transplantation 06/2001; 16(6):1189-97. · 3.37 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Patients on chronic intermittent haemodialysis (HD) show an impaired cellular and humoral immune response that clinically appears with frequent infectious complications and low vaccination responses. This immune defect strongly correlates with reduced in vitro proliferative responses of T cells. The defect is localized in antigen presenting cells, which show a decreased co-stimulatory activity. Furthermore, the impaired immune response correlates with an increased production of pro-inflammatory cytokines. In response to primary activation, CD4 positive T helper (Th) cells mainly differentiate into either Th1 or Th2 cells. Th1 cells support cell mediated immunity whereas Th2 cells enhance humoral immune responses. Since both types of responses mutually inhibit each other, the impaired humoral immune response seen in HD patients could either be due to a reduced number of Th2 cells or to a predominant Th1 response. We analysed the Th cell profile in HD patients using flow cytometry. Monocytic cytokine expression was analysed using both flow cytometry and enzyme linked immunoadsorbant assays. Our data demonstrate that the cytokine differentiation profile in circulating T cells from HD patients is dysregulated and characterized by an increase in Th1 cells, but a normal amount of Th2 cells. Moreover, the skewed helper cell responses correlate with a higher percentage of monocytes capable of secreting the Th1 promoting cytokine interleukin 12 (IL-12). Our findings contribute to a better understanding of the pathogenesis of impaired cellular immune functions in dialysis patients and, in particular, the decreased antibody production after vaccination. They provide a link between overproduction of pro-inflammatory cytokines (IL-12) and imbalanced T-cell activation.Nephrology Dialysis Transplantation 09/2000; 15(8):1217-23. · 3.37 Impact Factor
CHRONIC 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-
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.
tration was 69.4 (34.9?/110.3) pg/ml before hemodia-
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
Mehmet Tarakc ¸ıog ˘lu1,CA, Ays ¸e Binnur Erbag ˘ci1,
Celalettin Usalan2, Rukiye Deveci1and
Ramazan Kocabas ¸1
1Department of Biochemistry and Clinical
Biochemistry and2Department of Nephrology,
Gaziantep University, Medicine Faculty, 27310
S ¸ehitkamil Gaziantep, Turkey
Tel:? /90 342 3606060/7135
Fax:? /90 342 3601617
Recent evidence points to chronic inflammation as a
major contributor to morbidity and mortality in end-
stage renal disease (ESRD).1It has been proposed
that a chronic inflammatory state could account for
the high risk of ischemic heart disease in patients
with ESRD.2Malnutrition and chronic systemic in-
flammatory response syndrome not only co-exist in
uremia, but may also have a bi-directional cause and
effect relationship.3Also, 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.4About 35?/65% of ESRD
patients receiving hemodialysis (HD) show signs of
inflammation, whereas the prevalence in pre-dialysis
patients may be somewhat lower.1Dialysis 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?6Actually, 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
ISSN 0962-9351 print/ISSN 1466-1861 online/03/010015-05 – 2003 Taylor & Francis Ltd
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?10On 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?16were
determined in sera specimens before and after HD.
Materials and methods
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/m2. 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 m2surface 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
Mediators of Inflammation? Vol 12? 2003
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-
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.
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.17By 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.
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 (pB/0.001) and decreased by 5.639 /
2.59 pg/ml for each 1.0 mmol/l increase in pre-
dialysis urea (pB/0.05). This model explains 58.7% of
the variation in PD IL-8 (pB/0.005).
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-6,9,11,18IL-1,9,19and
TNF-a18during 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.18It 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.20,21It
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,18and HD membranes may increase cyto-
cells.9,10,12Magnitude 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
Mediators of Inflammation? Vol 12? 2003
Table 1. Circulating cytokine levels in pre-hemodialysis and post-hemodialysis specimens
Before hemodialysis After hemodialysis
Total protein (g/l)
TNF-a (pg/ml)/total protein (g/l)
sIL-2R (U/ml)/total protein (g/l)
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-
Cytokines and hemodialysis
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.22CVi for IL-6
was 30.5% in a short-term variability study.23These
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
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
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.14,20Xie 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
Mediators of Inflammation? Vol 12? 2003
differential IL-8 expression.14Therefore, decreased
NO may be a contributing factor to decreased serum
IL-8.24The 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
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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Table 2. Univariate linear regression analysis, paired difference (PD) (pre-hemodialysis minus post-hemodialysis values) of IL-
8 levels as the dependent variable
CovariateB 95% confidence intervalSignificance
Lower bound Upper bound
Pre-dialysis IL-8 (pg/ml)
Pre-dialysis total protein (g/l)
PD total protein (g/l)
Pre-dialysis urea (mmol/l)
PD urea (mmol/l)
? /309.0 225.4
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Received 2 October 2002
Accepted 2 December 2002
Cytokines and hemodialysis
Mediators of Inflammation? Vol 12? 200319