Kidney International, Vol. 58, Suppl. 76 (2000), pp.
S-104–S-111
Clinical relevance of cytokine production in hemodialysis
GIOVANNI PERTOSA, GIUSEPPE GRANDALIANO, LORETO GESUALDO,
and FRANCESCO PAOLO SCHENA
Division of Nephrology, Department of Emergency and Transplantation, University of Bari, Policlinico, Bari, Italy
Clinical relevance of cytokine production in hemodialysis.
Blood–dialyzer interaction in hemodialysis has the potential
to activate mononuclear cells leading to the production of
inflammatory cytokines. The extent of activation is dependent
on the dialyzer material used and is considered an index of
biocompatibility. Cytokines, such as interleukin-1␤ (IL-1␤),
tumor necrosis factor-␣ (TNF-␣), and IL-6, may induce an
inflammatory state and are believed to play a significant role in
dialysis-related morbidity. The interleukin hypothesis suggests
that the release of proinflammatory cytokines acts as an under-
lying pathophysiologic event in hemodialysis-related acute
manifestations, such as fever and hypotension. Nevertheless,
a cytokine overproduction may alter sleep pattern in chronic
hemodialyzed patients, thus explaining the presence of sleep
disorders in these patients. A potential role of cytokines in
chronic-related morbidity has also been suggested. High levels
of some inflammatory cytokines are often associated with ane-
mia caused by hyporesponsiveness to erythropoietin. Cytokine
production may also play a relevant role in bone remodeling by
regulating osteoblast/osteoclast cell functions and parathyroid
hormone (PTH). Finally, cytokine release may have a long-
term deleterious effect on mortality of uremic patients by alter-
ing immune response and increasing susceptibility to infections.
Bioincompatibility of dialytic membranes may also contribute
to malnutrition in dialysis patients by increasing the monocyte
release of catabolic cytokines such as TNF-␣ and IL-6. Bioin-
compatible dialytic treatment may induce an inappropriate
monocyte activation and cytokine production, which, in turn,
may mediate some of the immune and metabolic dysfunction
associated with hemodialysis. The use of biocompatible dialytic
membranes appears to reduce the monocyte activation and to
improve the survival of hemodialysis patients.
During hemodialysis, blood contact with a foreign sur-
face, such as a complement-activating dialytic mem-
brane, promotes a variety of complex and interrelated
events, leading to an acute inflammatory response. In
particular, activation of mononuclear cells and concomi-
tant complement activation induce the release of an
array of inflammatory mediators into the extracellular
environment, including cytokines, reactive oxygen spe-
cies (ROS), and nitric oxide (NO) [1–3]. Thus, hemodial-
ysis imbalances several homeostasis systems and gener-
Key words: biocompatibility, cytokines, hemodialysis complications.
 2000 by the International Society of Nephrology
S-104
ates a complex of acute and chronic side effects also
known as “bioincompatibility phenomena” [4, 5].
Many aspects regarding morbidity and mortality of
dialysis patients may be related to these cellular events
and, in particular, to the production of cytokines by pe-
ripheral blood mononuclear cells (PBMCs) [6, 7]. Cyto-
kines are a family of pleiotropic polypeptides with a
molecular weight ranging from 10 to 45 kD that, pro-
duced by different cells in response to inflammatory stim-
uli, may modulate a variety of functions not only in
circulating immune cells, but also in mesenchymal, endo-
thelial, and epithelial cells [8]. There is an increasing
body of evidence that the interaction between blood
and dialytic membranes induces the release of several
cytokines from circulating mononuclear cells, such as
interleukin-1 (IL-1), IL-6, IL-8, tumor necrosis factor-␣
(TNF-␣), and monocyte chemotactic factor-1 (MCP-1).
The specific action of any of these monocyte-derived
cytokines may be relevant in the pathogenesis of clinical
manifestations often observed in end-stage renal disease
(ESRD) patients undergoing chronic hemodialysis [9, 10].
MECHANISMS INVOLVED IN CYTOKINE
PRODUCTION DURING HEMODIALYSIS
In vitro and in vivo data support the hypothesis that
cytokine transcription and/or production during hemodi-
alysis are mainly caused by (1) direct contact of PBMCs
with dialysis membrane, (2) active complement frag-
ments (C3a, C5a, C5b-9) generated during hemodialysis,
and (3) backtransport of bacterial-derived material [for
example, lipopolysaccharide (LPS)] from the dialysate
to the blood compartment.
The dialyzer used seems to play an important role,
both directly and directly, in cytokine induction during
hemodialysis through complement activation. It is well
known that in the absence of any other stimulus, adher-
ence to dialysis membrane induces selective mRNA ex-
pression of monocyte mediators and proto-oncogenes.
Indeed, Betz et al have demonstrated that cuprophan
membranes stimulate IL-1 expression in monocytes in
the absence of complement [11]. On the other hand,
 Pertosa et al: Hemodialysis and cytokine production
cellulosic membranes can activate, through the alterna-
tive pathway, the complement cascade and can generate
active fragments able to stimulate cytokine gene expres-
sion and secretion by monocytes [12, 13]. Furthermore,
several studies support the hypothesis that terminal com-
plement complex (TCC) generation may have a potential
role in activating mononuclear cells [14]. Sublethal TCC
doses can affect cell metabolism and constitute a potent
signal for activation of monocytes to produce inflamma-
tory mediators such as TNF-␣ and IL-6 [13]. The third
possible pathogenic factor to consider in the increased
cytokine production during hemodialysis is the LPS frag-
ments contaminating the dialysate and able to cross the
membrane [15]. We have demonstrated that the basal
release of TNF-␣ and IL-6 during hemodialysis is inde-
pendent of the biocompatibility features of the mem-
brane used, while it is considerably influenced by the
endotoxin content of the dialysate [16]. Indeed, mono-
cytes, isolated from uremic patients treated with a dialy-
sate characterized by high endotoxin levels, spontane-
ously released a significantly greater amount of TNF-␣
and IL-6 compared with healthy controls and nondia-
lyzed uremic patients. In contrast, the use of a dialysate
with low endotoxin concentration significantly reduced
the cytokine production.
The contact with the dialysis membrane as well as the
interactions with complement fractions, although able
to induce a selective cytokine gene transcription in
monocytes, does not always automatically stimulate the
translation of the specific proteins. We have previously
shown that IL-6 gene expression is strikingly increased
during hemodialysis with cuprophan membrane, but its
protein secretion is clearly down-regulated [17]. Interest-
ingly, Schindler et al have demonstrated that recombi-
nant C5a in vitro stimulates transcription rather than
translation of IL-1 and that LPS or IL-1 itself is required
as a translational signal [12]. In support of this hypothe-
sis, we and others have demonstrated that patients
treated with cuprophan have higher mRNA levels for
different cytokines, but in order to obtain a higher trans-
lation, a second stimulus, such as LPS, is required [12, 16].
In contrast, some authors have reported an impaired
endotoxin-induced IL-1 and IL-6 release from PBMCs
of hemodialysis patients, suggesting a reduced ability of
the immune cells of these patients to respond to patho-
logic stimuli [18, 19]. Finally, other authors did not see
evidence of any production or release of different cyto-
kines (TNF-␣, IL-6, and mRNA coding for IL-1␤) by
monocytes during high-flux bicarbonate hemodialysis,
neither with complement-activating membranes nor with
contaminated dialysate [20]. Because of the great vari-
ability of the experimental design and techniques used,
these conflicting results can easily generate confusion.
Moreover, in the last few years, the discovery of cyto-
kine-specific inhibitory proteins, such as IL-1RA and
S-105
soluble TNF receptors, has further complicated this
cloudy issue [21]. The quality of the antibodies and the
enzyme-linked immunosorbent assay (ELISA) or radio-
immunoassay kits (RIA) used were not always highly
reliable. Studies using bioassays (considered useful in
the past), in light of the discovery of cytokine-specific
inhibitors, are now questionable. The introduction of
molecular biological techniques to the study of cytokines
production has partly overcome some of these difficulties
[22]. Unlike bioassays, these techniques are highly spe-
cific and are not influenced by cytokine-binding proteins
and inhibitors. Using appropriate probes, these tech-
niques allow the researcher to detect specific cytokine
mRNAs and their cellular source. By using these tech-
niques, we recently evaluated the role of different hemo-
dialysis membranes in regulating spontaneous IL-6, IL-8,
and MCP-1 gene expression and protein synthesis by
PBMCs isolated from chronic hemodialyzed patients.
Our data demonstrated the independent modulation of
cytokines, gene expression, and protein secretion in un-
stimulated PBMCs by different hemodialysis mem-
branes. Indeed, the transcriptional activation of these
cytokines occurred in unstimulated PBMCs following
the use of cellulosic membranes, whereas their protein
synthesis was seemingly impaired [23]. By contrast, we
observed that long-term hemodialysis with synthetic
high-flux membranes, such as polymethylmethacrylate
(PMMA) and polyamide, down-regulated cytokine gene
expression and improved the ability of PBMCs to secrete
cytokines in culture. Thus, molecular biology techniques
can help to identify the mechanisms leading to cytokine
transcription during hemodialysis. Overall, the applica-
tion of these techniques may shed light on the study
of bioincompatibility of different dialyzers and dialysis
procedures.
CLINICAL RELEVANCE OF CYTOKINE
PRODUCTION IN HEMODIALYSIS:
ACUTE AND CHRONIC EFFECTS
More than 15 years ago, Henderson et al first proposed
the “interleukin hypothesis,” incriminating IL-1 produced
during dialysis as the cause of different acute responses
observed in patients on hemodialysis [24]. The better
understanding of the biological effects of proinflamma-
tory cytokines gained over the last decade strongly sup-
ports the hypothesis that these soluble mediators may
be involved in the pathogenesis of both acute and chronic
complications of dialysis treatment, including fever, hy-
potension, sleep disorders, dialysis-related amyloidosis,
impaired immunity, bone disease, malnutrition, and ane-
mia (Table 1).
Herein, we describe the main pathophysiologic mecha-
nisms underlying dialysis-adverse clinical events poten-
tially related to an altered cytokine production.
S-106 Pertosa et al: Hemodialysis and cytokine production
Table 1. Clinical relevance of cytokine production
in hemodialysis patients
Acute Chronic
Fever Anemia
Sleep disorders Bone disease
Hypotension Malnutrition
Immunological dysfunction
FEVER
Fever and chills commonly occur during or after dial-
ysis in the presence of endotoxin-contaminated dialysate.
This specific endotoxin-induced effect may be potenti-
ated by the use of a bioincompatible complement-acti-
vating membrane. However, a slight increase in body
temperature can also be observed in patients undergoing
hemodialysis with an uncontaminated dialysate.
Fever is a coordinate endocrine, autonomic, and be-
havioral response organized by the brain as a reaction
to an inflammatory stimulus. The classic model of fever
pathogenesis suggests that IL-1, IL-6, or TNF-␣ pro-
duced by PBMCs in the bloodstream may be recognized
as pyrogenic signal by specific centers within the central
nervous system [25]. At this level, they can induce the
synthesis of prostaglandins that represent the central
mediators of the coordinated response leading to fever.
Luheshi demonstrated that local administration of LPS
into a subcutaneous rat air pouch elicits marked fever,
accompanied by an increase in TNF-␣, IL-1, and IL-6
levels in the pouch, but only IL-6 in the plasma [26].
The author suggests that TNF-␣ and IL-1 probably act
locally to stimulate the release of one or more secondary
circulating mediator(s) (for example, IL-6) that can in-
teract with the brain. By contrast, Kozak et al demon-
strated that the injection of high dose of LPS can induce
fever in mice with a null mutation of IL-6 gene, but
not in mice with the disruption of IL-1␤ gene [27]. The
authors concluded that IL-1␤ may have a critical role
in inducing fever during systemic inflammation. Indeed,
several lines of evidence suggest that IL-1 may act di-
rectly on specific regulatory sites within the hypothala-
mus, turning up the set point of the physiologic thermo-
stat and causing an increase in body temperature via the
normal thermoregulatory pathways. This hypothesis is
strongly supported by Hammond et al’s recent observa-
tion that type I IL-1 receptor is expressed in human
hypothalamus [28].
SLEEP DISORDERS
Sleep disorders have been reported to be high among
uremic patients on hemodialysis treatment, likely con-
tributing to the impaired quality of life experienced by
many of these patients. By using a sleep questionnaire,
Walker, Fine, and Kryger demonstrated the presence
of sleep disturbance or daytime sleepiness in 45 of 54
hemodialysis patients (83.3%) evaluated, and causes
were secondary to delayed sleep onset and frequent
awakening in 46.3 and 35.2% of patients, respectively
[29]. Moreover, symptoms of mild or severe restless legs
were reported by 57.4% of patients. The data reviewed
in this study support the hypothesis that immune-active
molecules, such as cytokines, may induce profound alter-
ations in several neurotransmitters in the brain. The fre-
quent sleeping during hemodialysis and the abnormal
sleep patterns of patients are rather speculative corre-
lates of increased cytokine production. It has been dem-
onstrated that IL-1␤ and TNF-␣ are involved in physio-
logic sleep regulation [30] and may induce slow-wave
sleep. There is a daily rhythm of TNF-␣ and IL-1␤
mRNA expression in the central nervous system, with
the highest levels occurring during peak sleep periods.
Moreover, IL-1␤ and TNF-␣ are part of a larger bio-
chemical cascade involved in sleep regulation; other
somnogenic substances in this cascade include growth
hormone-releasing hormone and NO. Thus, we may hy-
pothesize that an alteration in cytokine production (for
example, overproduction) directly or via an increased
synthesis of other somnogenic substances, such as NO,
may explain the altered sleep pattern observed in chronic
hemodialyzed patients, particularly in those treated with
bioincompatible membranes [31].
HYPOTENSION
The incidence of a symptomatic reduction in blood
pressure during hemodialysis ranges from 15 to 50% of
dialysis sessions [32].
Hypotension and cardiovascular instability are the most
frequent side effects of dialysis, occurring both chroni-
cally in long-term hemodialysis patients and acutely dur-
ing dialytic sessions, and have been related to induction
of IL-1 and TNF-␣ synthesis in monocytes [24]. More-
over, it has been proposed that hypotensive responses
to hemodialysis may result from cytokine-induced syn-
thesis of NO, a potent vasodilator in vitro and in vivo,
within vascular smooth muscle cells and endothelial cells
[33]. Particularly, it has been demonstrated that acetate
can directly activate human monocytes to produce IL-1
[34], and Amore et al found that acetate-containing dial-
ysate up-regulated inducible NO synthase (iNOS) gene
expression and NO production in endothelial cells as
compared with acetate-free buffers [35]. In contrast,
Noris et al demonstrated that plasma from patients dia-
lyzed with acetate-free biofiltration (AFB), a technique
using a buffer-free dialysate, postdilution with a sterile
bicarbonate solution, and a polyacrylonitrile dialyzer,
did not stimulate endothelial NO synthesis as compared
with plasma from patients treated with acetate dialysate
[36]. Moreover, plasma IL-1␤ was greater after acetate
 Pertosa et al: Hemodialysis and cytokine production S-107

dialysis than after AFB, corresponding to a more pro-

nounced intradialytic decrease in systolic blood pressure
in patients treated with acetate buffer than in those
treated with AFB. These data are consistent with the
possibility that cytokines, released in excessive amounts
during acetate dialysis, may contribute to hemodynamic
instability, via an increased production of NO by mono-
cytes and endothelial cells. Moreover, the interaction
between bioincompatible complement-activating mem-
branes and PBMCs can induce iNOS expression and
enzyme activity, most likely mediated by an increase
production of IL-1␤ and TNF-␣, contributing to the de-
velopment of hypotension in dialyzed patients [3].

ANEMIA
Cytokines are well-known regulatory factors for eryth-
ropoiesis, especially in pathological conditions. Chronic
inflammatory diseases, characterized by high cytokine cir-
culating levels, are often associated with anemia caused
Fig. 1. Intracellular cross-talk between cytokine and erythropoietin
by a hyporesponsiveness to erythropoietin [37]. A sig- signaling pathways.
nificant percentage of uremic patients present erythro-
poietin resistance even in the absence of comorbid condi-
tions such as iron depletion, hyperparathyroidism, or
aluminum overload [38]. The presence of a deranged (Fig. 1). Tyrosine-phosphorylated STATs dimerize and
cytokine production in dialysis may suggest a role for migrate to the nucleus, where they can induce the expres-
these soluble mediators in the reduced response to eryth- sion of a variety of proinflammatory and cell-activating
ropoietin in this patient population. Goicoechea et al genes (Fig. 1) [41]. On the other hand, these transcription
demonstrated in uremic patients undergoing chronic he- factors can cause the up-regulation of a growing family of
genes encoding proteins known as suppressor of cytokine
modialysis a significant and direct correlation between
signaling (SOCS), which can interfere with JAK–STAT
the erythropoietin dose and the IL-6 and TNF-␣ produc-
interaction [42]. SOCS may thus inhibit the cytokine-
tion from stimulated and unstimulated cultured PBMCs
activating signal, turning on a negative feedback loop
[39]. Allen et al, using normal and uremic bone marrow
(Fig. 1). Noteworthy, SOCS activated from one cytokine
to test erythropoietin response in the presence of uremic
can inhibit the signal induced by a second cytokine acting
serum, recently reported a more direct and causal rela-
on the same cell [43]. Interestingly, erythropoietin induces
tionship between cytokine production and erythropoie-
erythroid cell proliferation interacting with a specific cell
tin resistance in hemodialysis [40]. They did not observe
surface receptor belonging to the cytokine receptor su-
any difference in erythropoietin response between nor-
perfamily and inducing the JAK-STAT pathway [44].
mal and uremic bone marrow. However, when bone mar-
Therefore, it is conceivable that SOCS expressed in re-
row was cultured with uremic serum, the erythropoietin
sponse to IL-1, TNF-␣, or IL-6 in erythroid cells can
effect on erythroid colony formation was clearly inhib-
switch off erythropoietin signaling and inhibit its prolif-
ited. The addition of specific anti–TNF-␣ and interferon-␥ erative effect on this cell line (Fig. 1).
(IFN-␥) antibodies to this system almost completely re-
stored erythropoietin response.
The increasing knowledge on intracellular events in- BONE DISEASE
duced by cytokines suggests that mechanisms underlying Patients with end-stage renal disease present with vari-
their ability to inhibit the erythropoietin effect are cur- ous debilitating forms of osteodystrophy characterized
rently present. Several of these inflammatory mediators either by high or low bone turnover. Alterations in para-
utilize Janus kinases (JAK) and the signal transducers thyroid hormone (PTH) and calcitriol production do not
and activators of transcription (STAT) proteins to modu- completely account for the observed abnormalities in
late gene expression in their target cells [41]. The differ- bone resorption/formation. Recent reports stress the role
ent JAK isoforms are activated upon receptor dimeri- of cytokines and their inhibitors in the process of bone
zation and phosphorylate one or more STAT proteins remodeling directly or modulating the expression and/or
S-108 Pertosa et al: Hemodialysis and cytokine production
the effects of PTH. It is well established that marrow cells
can modulate bone remodeling through local cytokine
release. Moreover, there is an increasing body of evi-
dence suggesting several cytokines as autocrine factors
regulating osteoblast/osteoclast cell functions. IL-6 is
physiologically produced by osteoblasts in response to
PTH and, interestingly, may induce osteoclastogenesis
and bone resorption [45, 46]. In mice, both acute neutral-
ization and chronic deficiency of IL-6 are associated with
markedly lower levels of biochemical markers of bone
resorption in response to PTH infusion when compared
with animals with normal IL-6 levels [47]. In addition to
IL-6, IL-1 and TNF-␣ may induce directly bone resorption
by stimulating the development of osteclast-like multinu-
cleated cells and by increasing the bone-resorbing activ-
ity of formed osteoclast [48]. Moreover, these two cyto-
kines may modulate the actions of calciotropic hormones
on osteoblast by inhibiting intracellular calcium release
and inositol trisphosphate production in a tyrosine ki-
nase-dependent manner [49].
Beside the direct effect on bone cells, cytokine may
modulate PTH production. Parathyroid cells express
IL-8 type B receptor and respond to IL-8 incubation
with a marked increase in PTH expression [50]. On the
other hand, IL-1 can induce an up-regulation of extracel-
lular calcium-sensing receptor mRNA while inhibiting
PTH secretion in cultured parathyroid tissue slices [51].
In addition to the two classic variants of renal osteodys-
trophy, amyloid bone disease is the third form of hemodi-
alysis-related bone pathology. The incidence of amyloid
bone disease is much greater in patients dialyzed with
cellulosic membranes than with biocompatible filters
[52]. Cellulosic membrane may indeed induce an in-
creased synthesis of ␤2-microglobulin via complement
system activation and cytokine release. Particularly IL-1,
TNF-␣, and IL-6 have been shown to stimulate ␤2-micro-
globulin release by leukocyte and endothelial cells [53].
MALNUTRITION
Malnutrition is often present in hemodialyzed patients,
and several reports have demonstrated the adverse effect
of malnutrition on their morbidity and mortality [54].
Patients undergoing chronic hemodialysis show evidence
of accelerated protein catabolism primarily because of
a significant loss of amino acid induced by the dialysis
procedure [55]. Experimental data suggest that the dial-
ysis procedure per se leads to enhanced catabolism, as
well as a direct loss of plasma amino acids and proteins
into the dialysate [56]. In addition, several studies suggest
a role for cellulosic membranes in enhancing active ca-
tabolism, most likely through an increased release of
proinflammatory cytokines [57]. Indeed, cytokines such
as IL-1, TNF-␣, and particularly IL-6 appear to play a
central role in both the loss of skeletal muscle proteins
and the utilization of exogenously administered nutrients
[58]. IL-1 is well known to act directly on the hypothala-
mus, causing anorexia [58]. The role of TNF-␣ in neopla-
sia-induced cachexia is well established, and there is now
evidence of the involvement of TNF-␣, formerly known
as cachectin, in uremia-associated malnutrition. Indeed,
its plasma concentration correlates with biochemical
signs of protein catabolism in hemodialysis patients
[57, 58]. Finally, Kaizu et al reported that hemodialyzed
patients with a high plasma IL-6 concentration presented
a lower albumin levels and a significantly higher weight
loss over a three-year period than patients with low
plasma IL-6 [59]. Moreover, the circulating IL-6 concen-
tration was inversely correlated with serum albumin,
cholinesterase, and midarm muscle area. Furthermore,
a direct correlation between cell content of IL-1 receptor
antagonist and some nutritional parameters, such as
body mass index, anthropometry-derived arm muscle
area, serum cholesterol, and triglycerides, was found in
16 patients dialyzed with reprocessed cellulose dialyzers
[60]. These findings suggest a direct correlation between
nutrition and cytokine production and that malnutrition
could depress cytokine production and potentially con-
tribute to reduced immune responsiveness in patients on
chronic hemodialysis.
IMMUNOLOGIC DYSFUNCTION
There is an increasing body of evidence that uremic
patients on dialysis present an increased susceptibility to
infections. Particularly the use of cellulosic membranes is
associated with dysfunction of phagocytic cells, natural
killer cells, and other immunologic alterations, including
altered cytokine production and complement system ac-
tivation [61]. Indeed, bacterial infections are the most
common cause for hospitalization and the second most
common cause for death [62]. The presence of a pro-
found defect in lymphocyte and monocyte function in
uremia is further suggested by the observation of an
extended survival of skin allografts, a marked decreased
cutaneous responsiveness to a broad panel of antigens
and, finally, a reduced seroconversion after vaccination
[63]. A growing interest has been recently focused on
the relationships between cytokine plasma levels and/or
production by immune cells and the dysfunction of
phagocytes, natural killers and T lymphocytes often ob-
served in hemodialysis patients [21]. Although the physi-
ologic role of circulating cytokines is unknown, it is con-
ceivable that a proinflammatory milieu characterized by
high cytokine plasma levels may influence specific and
tightly regulated cellular processes in leukocytes, induc-
ing an inappropriate cellular and/or humoral immune
response. Since individual cytokines have multiple syner-
gistic and antagonistic actions on different cellular tar-
gets, cytokine combinations may exert immunologic ef-
 Pertosa et al: Hemodialysis and cytokine production
fects not foreseeable based on the actions of the single
cytokine. Moreover, the presence of high circulating lev-
els of soluble receptors or binding proteins, reported in
patients on hemodialysis, may further complicate the
scenario [21]. However, it should be considered that cyto-
kines exert their major physiologic and pathophysiologic
effects as autocrine or paracrine factors. Therefore, the
altered intracellular processing and local release of a
cytokine may be more relevant in the pathogenesis of the
uremic immune dysfunction than its increased circulating
levels. Insufficient or delayed cytokine release may de-
crease the immune reaction and, consequently, increases
the risk of infection. We and others have recently re-
ported that contact of circulating mononuclear cells with
complement-activating membranes results in the in-
creased gene expression for an array of different cyto-
kines, including IL-6, MCP-1, and IL-8, without a corre-
sponding increased translation into protein [23]. As a
consequence, mononuclear cells of uremic patients on
dialysis are chronically activated, although they cannot
completely demonstrate their activated phenotype. There-
fore, uremic monocytes may easily become exhausted
and subsequently refractory to any further stimulation.
This hypothesis is further supported by the observation
of an impaired endotoxin-induced IL-1, TNF-␣, and IL-6
release from PBMCs of hemodialysis patients. By exam-
ining the Th1 and Th2 cytokine profiles in 22 stable
hemodialyzed patients and 22 healthy controls, Daichou
et al demonstrated that the T-cell activity was signifi-
cantly retarded in uremic patients as compared with nor-
mal controls [64]. Furthermore, they showed that the
production of IL-2, which is involved in cell-mediated
immune responses, and IL-4 and IL-10, which affect hu-
moral immunity, were significantly lower in patients than
in controls. Finally, an increased production of IL-12 by
macrophages and IFN-␥ by Th1 cells, as well as elevated
plasma levels of soluble IL-2 receptor, was observed in
uremic patients as compared with controls. They con-
cluded that the balance of Th1- and Th2-type responses
is altered in hemodialyzed patients, contributing to the
immune dysfunction in these patients. Other authors
also demonstrated an alteration of Th1 and Th2 cells
network. Memoli et al demonstrated that cultured
PBMCs harvested from uremic patients dialyzed with a
cuprophan membrane spontaneously release a greater
amount of IL-12 than PBMCs from normal controls and
nondialyzed uremic patients, whereas under mitogen
stimulation, IL-12 supernatant levels were significantly
lower than controls [65]. In contrast, the use of a less com-
plement-activating membrane, such as PMMA mem-
brane, normalized IL-12 release from PBMCs. IL-12 pro-
motes the differentiation of cytokine-producing Th1
cells, likely by inducing the IFN-␥ gene expression in
both T cells and natural killer cells and IFN-␥ plays an
important role in the resistance to infection [66]. An
S-109
altered PBMC IL-12 production may determine an im-
munodeficiency state in hemodialyzed patients. Indeed,
the authors hypothesize that an altered IL-12 release
may contribute to a depressed cell-mediated immune
response in these patients, by inducing a shift toward a
Th2 cell response [65]. Thus, the use of poor biocompati-
ble membranes, by recurrently activating mononuclear
cells or altering Th1/Th2 balance, may contribute to
down-regulation of the synthesis and release of different
immunoregulatory cytokines and may play a role in cell-
mediated immunodeficiency of dialyzed uremic patients.
CONCLUSIONS
In summary, bioincompatible dialytic treatment may
induce an inappropriate monocyte activation and cyto-
kine production, which, in turn, mediate some of the
immune and metabolic dysfunction associated with he-
modialysis. Activation of immunocompetent cells during
the hemodialysis session results in acute and long-term
adverse effects. Clinical alterations resulting from cyto-
kine production and release include fever, cardiovascular
instability, sleep disorders, and increased muscle protein
catabolism. Altered cytokine release also contributes to
the immunodeficiency of dialysis patients and increases
the morbidity and mortality of these patients [67]. Recent
studies support the hypothesis that hemodialysis with
synthetic and less complement-activating membranes
may normalize monocyte function [23] and improve im-
munologic parameters by reducing the circulating levels
of proinflammatory cytokines, thus contributing to ame-
lioration of the survival of hemodialysis patients [68].
ACKNOWLEDGMENTS
We thank Terumo (Japan) and Bieffe (Italy) for technical and
financial support.
Reprint requests to Giovanni Pertosa, M.D., Division of Nephrology,
Department of Emergency and Transplantation, University of Bari,
Policlinico, Bari, Italy.
E-mail: g.pertosa@nephro.uniba.it
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