Diyaliz hastalarında inflamasyon nedenleri ve muhtemel tedavi seçenekleri

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Introduction
Inflammation may contribute to the progressive loss
of kidney function by promoting endothelial dysfunction and glomerular damage. Low-grade inflammation
is indeed present at early stages of chronic kidney disease (CKD), and it is believed that the reduction of
renal function per se runs parallel with an increase in
the inflammatory response (1,2) also after starting renal
replacement therapy (3-5). Patients with CKD stage 3-
5 are at risk for progression of kidney disease and development of ESRD. In one study it has been suggested
that most patients with stage 3-5 will die of cardiovascular complications prior to the development of endstage renal disease (ESRD) (2). Chronic inflammation
may indeed be one of the causes of the increased mortality and morbidity observed in this population (6-8),
especially because of its association to atherogenesis and
cardiovascular events, which account for approximately
50% of the deaths among patients undergoing dialysis
therapy. Recent epidemiologic data show that upon
commencement of dialysis therapy, 40% to 75% of
patients already have manifestations of cardiovascular
disease (CVD) (9). Some studies have shown that there
is a high prevalence of acute-phase inflammation
*Department of Nephrology, Gülhane Military Medical Faculty
Reprint request: Dr. Mahmut Ýlker Yýlmaz, Department of Nephrology,
Gülhane Military Medical Faculty, Etlik-06018, Ankara
E-mail: mahmutiyilmaz@yahoo.com
Date submitted: April 11, 2007
Accepted: May 24, 2007
DERLEME/REVIEW ARTICLE Gülhane Týp Dergisi 2007; 49: 271-276
© Gülhane Askeri Týp Akademisi 2007
Summary
Cardiovascular morbidity and mortality are increased in
patients with chronic kidney disease and especially dialysis.
In patients with uremia, inflammation starts long before
renal replacement therapy. Besides the other important
parameters such as malnutrition and atherosclerosis,
inflammation is one of the most important causes of morbidity and mortality in uremic patients. An association
between cardiovascular mortality and morbidity and
inflammation in both chronic kidney disease and dialysis
patients has been demonstrated by a lot of studies in the
past. Inflammation in patients with renal failure who have
not yet begun dialysis and in patients receiving dialysis has
shown increased levels of inflammatory markers, such as Creactive protein, interleukin-6, tumor necrosis factoralpha. In this review, it is tried to discuss both possible
causes of inflammation and possible therapeutic strategies
in dialysis patients.
Key words: Hemodialysis, inflammation, peritoneal dialysis, therapeutic options
Özet
Diyaliz hastalarýnda inflamasyon nedenleri ve muhtemel
tedavi seçenekleri
Kronik böbrek hastalarý ve özellikle diyaliz hastalarýnda
kardiyovasküler morbidite ve mortalite artmýþtýr. Üremili
hastalarda inflamasyon, renal replasman tedavisinden uzun
süre önce baþlamaktadýr. Malnütrisyon ve ateroskleroz gibi
önemli parametrelerin yanýnda inflamasyon, üremik hastalardaki mortalite ve morbiditenin en önemli nedenlerinden
birisidir. Kardiyovasküler mortalite ve morbidite ile inflamasyon arasýndaki iliþki, hem kronik böbrek hastalarý hem
de diyaliz hastalarýnda geçmiþte yapýlan pek çok çalýþma ile
gösterilmiþtir. Henüz diyalize baþlamamýþ olanlar ve halen
diyalize girmekte olan böbrek yetmezliklilerde C-reaktif protein, interlökin-6 ve tümör nekrozis faktör-alfa gibi inflamasyon belirteçlerinde artýþlar gösterilmiþtir. Bu derlemede
diyaliz hastalarýndaki inflamasyonun hem muhtemel nedenleri, hem de muhtemel tedavi stratejileri tartýþýlmaya
çalýþýlmýþtýr.
Anahtar kelimeler: Hemodiyaliz, inflamasyon, periton diyalizi, terapötik seçenekler272 · Aralýk 2007 · Gülhane TD Yýlmaz
including CRP and IL-6 and oxidative stress, both of
which are associated with the high rate of cardiovascular mortality and morbidity (2,10). Several studies have
shown that IL-6 levels may be the most reliable predictor of CVD and mortality (11,12). However, because
CRP is cheaper to analyze, this more readily available
inflammatory biomarker may be used in clinical practice to evaluate the presence and degree of inflammation. The present review aims to summarize our present understanding of the factors of this chronic inflammatory state in the dialysis population.
Multiple causes of chronic inflammation in ESRD
The reasons for the increased risk of persistent lowgrade inflammation in ESRD patients appear to be
complex and include a variety of both non-dialysis
related and dialysis related factors that stimulate the
inflammatory response by activating the production of
interleukin 1 (IL-1), IL-6, TNF-α and interferon-γ
(IFN-γ) by macrophages (13). In addition, the impaired
immune response characterized by hyporesponsive
neutrophils and T-cells present in CKD patients also
contributes to the low-grade inflammation seen in
ESRD. The combination of an impaired immune
response coupled with a persistent immune stimulation
might have an important role in low-grade inflammation and altered cytokine balance which are present in
ESRD (13).
Figure 1. Possible non-dialysis and dialysis related causes of
inflammation in ESRD patients
Dialysis-unrelated factors
Residual renal function
A reduction of kidney function per se is associated
with an inflammatory response in both mild and
advanced renal failure, suggesting that differences in
residual renal function may contribute to this "uremic
inflammation", perhaps through the retention of circulating cytokines (13). As the failing heart produces large
quantities of pro-inflammatory cytokines, volume overload and/or congestive heart failure may also link
inflammation to reduced residual renal function (13).
Not surprisingly, strong interrelations between inflammation, residual renal function and cardiac hypertrophy
are found in peritoneal dialysis (PD) patients (14).
Chronic inflammation can be related to uremic conditions and explained by reduced excretion of cytokines
(10,15). The catabolic effects of hemodialysis procedure
are well documented (16,17), indicating modest
changes in selected cytokine concentration before and
after the hemodialysis session, with the use of bioincompatible membranes (18,19). Caglar et al. have
hypothesized that the hemodialysis procedure indeed
induces an acute inflammatory reaction, which is further exacerbated during the 2-hour period following
completion of the hemodialysis session (17). Carrero et
al. have recently observed that during the first year of
dialysis, CRP concentrations decreased significantly in
hemodialysis (HD), but not in PD patients, suggesting
that dialysis procedures might exert different effects on
inflammation (20). The reason for this finding is still
unclear, but it could be speculated that frequent
heparinization may hamper pro-inflammatory status in
HD patients (20).
Infectious complications
Infections are common in CKD and dialysis patients
possibly as a consequence of impaired humoral and cellular immunity and vascular access (21). The prevalence
of tuberculosis, for instance, is higher in dialysis
patients, and wasting syndromes may be the result of
Mycobacterium tuberculosis infection. Other inflammatory
diseases, including systemic lupus, rheumatoid arthritis
and other malignancies usually accompany CKD or
dialysis patients. Dialysis patients who have diabetes
with foot infection are also one of the other sources of
infection (21,22). Periodontitis, a chronic bacterial
infection of the oral cavity, has for instance been associated with renal insufficiency and related to elevated
CRP values in HD populations (23,24).
Intercurrent clinical events
Intercurrent clinical events including infections, surgical interventions and inflammatory or injurious conditions may be related to inflammation. In one study
neither the type of dialyzer nor bacterial quality of the
Peritonitis
Bioincompatible
membranes
Access site
infection
Uremic
retention
Thrombosed
fistula or graft
Unpure
dialysate
Acidosis
Dialysis-related
causes of
inflammation
Dialysis-unrelated
causes of
inflammation
INFLAMMATION
Infectious
complications
Residual
renal
function
Volume
overload
Intercurrent
clinical eventsCilt 49 · Sayý 4 · Gülhane TD Inflammation in dialysis patients · 273
dialysate predicted CRP values in HD patients (25).
Whether changes in CRP values, which are associated
with intercurrent clinical events, influence the long
term prognosis of chronic HD patients is unknown.
Volume overload
Overhydration is frequent in patients with renal failure and may contribute to inflammation. Extracellular
volume control besides contributing to cardiovascular
morbidity and hypertension is closely related to patient
survival in PD patients. Extracellular fluid volume
expansion is believed to increase inflammation (26,27),
and adequate control of extracellular volume has prevented loss of residual renal function and reduced cardiovascular mortality and morbidity (28).
Dialysis-related causes of inflammation
Peritonitis
Peritonitis remains one of the most important complications of PD and contributes not only to the inflammatory status but also to the mortality of PD patients
(29). Bacterial infections usually occur by inoculation
through or around the catheter or by contamination of
dialysate, providing an additional inflammatory stimuli
(30).
Uremic retention
A number of compounds are retained in uremia and
such compounds often interact with the proinflammatory milieu, resulting in their oxidative modification
(31). A number of uremic retention solutes, such as
guanidine compounds, have shown to exert both proand anti-inflammatory effects on monocyte/macrophage function, which could altogether contribute to
CVD in this group of patients (32).
Unpure dialysate
The microbiological impurity of hemodialysis water
and dialysate might constitute a cause of chronic
inflammation in the dialysis population. Uremia and its
metabolic complications, together with the bioincompatibility of the components of the dialytic procedure
could contribute to higher cytokine concentrations.
Inflammation mediated by the cytokine response to
bacterial contamination of the dialysis fluid appears to
be an independent factor affecting the nutritional status
of HD patients (33).
Bioincompatible membranes
The type of membrane, its flux and the extent of
convective transport are additional factors that may
influence inflammation. Indeed, direct blood membrane specific interactions, the permeation of bacterial
products from the dialysate and the activation of the
complement because of these interactions have been
shown to stimulate cytokine production in the blood
stream, and high-flux membranes showed a better performance against cytokine-inducing substances from
the dialysate (34).
Access site infection
Vascular access site-related infections can also
increase inflammation in dialysis patients. Venous
catheters are associated with increased rates of infections as compared to other forms of vascular access (35).
Catheter related bacteremia may have various clinical
presentations, and stringent monitoring in this regard
can substantially minimize the global impact of vascular
access-related infection (36).
Thrombosed fistula or graft
The incidence of infections caused by the HD vascular access have shown to be higher when a central
venous catheter is used and lower when a native
arterivenous fistula is implanted (37). It has also been
shown that there is a higher infection rate when using a
graft than when using a native arteriovenous fistula and
that such infections are indeed contributors to the systemic inflammation (38). However, bacterial infections
in thrombosed grafts and fistulas tend to be silent,
which makes it difficult to diagnose (36), and further
research is warranted with regards to the detection and
management of infections derived from old thrombosed grafts.
Acidosis
Acidosis is a well known complication of uremia that
also contributes to inflammation. Consumption of
ammonium chloride in animal models increased the
excretion of urea nitrogen (34,39), and acidosis augmented the in vitro production of IL-6 and chemokine
(regulated upon activation, normal T cell expressed and
secreted) RANTES from smooth muscle cells, suggesting a direct contribution to chronic inflammatory uremic state (18).
Adipose tissue and malnutrition as causative inflammatory factors
Recent discoveries, notably of the adipokines leptin
and adiponectin, have revised the notion that adipocytes
are simply a storage depot for body energy. Instead, hormones secreted by the adipocytes (adipokines) act as
autogenic regulators of body fat depots, modulating274 · Aralýk 2007 · Gülhane TD Yýlmaz
gastrointestinal activities, metabolic changes and central
nervous mechanisms, and have been speculated to play
a central role in the development of complications often
observed in this group of patients, such as insulin resistance, CVD and sarcopenia (40). Furthermore, there are
intimate links among adipokines and pro-inflammatory
cytokines as well as between fat and muscle tissue (41).
Considering the dramatic effect that loss of renal function has on the clearance of these substances (13), the
systemic effects of adipokines in CKD patients may be
greater than those in the general population. It has been
estimated that about 20% of the circulating IL-6 originates from fat tissue and a significant amount of the circulating TNF-α comes from macrophages present in
the adipose tissue (42). As visceral fat appears to produce adipokines more actively than subcutaneous adipose tissue, visceral abdominal fat may be the main producer of IL-6. In accordance, in ESRD patients evaluated shortly before the start of renal replacement therapy
(RRT) Axelsson et al. found a significant association
between serum IL-6 and truncal fat, but not between
IL-6 and non-truncal fat (43).
On the other hand, protein-energy malnutrition
(PEM) is highly present in patients with CKD and is a
strong predictor of morbidity and mortality (44).
Indeed, PEM is reported to be present in as many as
37% to 48% of CKD patients, percentages that increase
once RRT starts (44). Usually, this deterioration of the
clinical nutritional status is characterized by a progressive weight loss, wasting of both fat and skeletal muscle
tissues and a reduction of serum proteins, including
albumin, pre-albumin and transferrin. Of these, muscle wasting (sarcopenia) is the one strongest and most
consistently associated with poor outcome (44).
Malnutrition and inflammation are often interrelated in
the clinical setting and also have additive effects on outcome (44). Kaizu et al. demonstrated that muscle mass
was inversely correlated to both IL-6 and CRP in HD
patients, even after adjustment for age and gender (45).
In a longitudinal study, the declining markers of muscle
mass during a 1-year period in HD were also associated
with higher IL-1β concentrations (46). Moreover, a
study from our group reported that patients who lost
lean body mass (LBM) after 1 year in PD had significantly elevated initial CRP levels than patients who
gained LBM (47). Although the mechanisms connecting inflammation to muscle wasting are not fully
understood, enhanced protein turnover seems to play a
central role, and Carrero et al. have recently reviewed
the ATP-ubiquitin-proteasome pathway, insulin resistance, resting energy expenditure and anorexia as plausible mechanisms supporting this connection to inflammatory biomarkers (20).
Polymorphonuclear leukocyte (PMNL) priming
When PMNL gets in contact with a stimulus/damage, it remains in a "primed" state. In the case of CKD
patients undergoing continuous ambulatory peritoneal
dialysis (CAPD) or HD these PMNL seem to be permanently "primed" (48,49). This PMNL priming is
believed to be one of the contributing causes to the systemic oxidative stress and chronic low-grade inflammation associated with renal failure (49). In the elderly
general population, absolute neutrophil and total white
blood cell counts have been associated with atherosclerotic risk factors (50), adverse cardiovascular outcomes
and all-cause mortality (51). This association has also
been described in ESRD patients, where both higher
neutrophil count and lower lymphocyte count were
independently associated with increased risk of death
(52,53). It is known that nutritional status can affect the
levels of leukocytes and that lymphopenia is a common
finding in malnourished patients (54). Thus, low lymphocyte count may reflect protein-calorie malnutrition
and therefore has additive effects on its risk of death
secondary to this co-morbid condition. Altogether, the
PMNL priming might underline the intimate association between malnutrition, inflammation and atherosclerosis (MIA syndrome) present in uremia.
Strategies for reducing chronic low-grade uremic inflammation
At a rudimentary level, reducing complications is
always about optimizing care. Thus, one obvious but
unfortunately often neglected strategy is the optimization of dialysis prescription. Specifically, volume overload should be avoided, water purity should be monitored, peritonitis should be prevented by stringent
hygienic regiments, and biocompatible dialysis solutions should be evaluated to see if they can contribute to
reducing inflammation in this group of patients.
Heparin has been shown to have anti-inflammatory
properties in renal patients, and a recent study has
shown decreasing systemic CRP when heparin is given
intraperitoneally to PD patients (55).
As interventions directed towards traditional risk factors have so far not proven to be very effective, controlled studies are needed to evaluate if various novel
pharmacological as well as non-pharmacological antiinflammatory treatment strategies, alone or in combination, may be more effective than traditional strategies.
To date, four classes of drugs; statins, angiotensin-con-Cilt 49 · Sayý 4 · Gülhane TD Inflammation in dialysis patients · 275
verting enzyme inhibitors, peroxisome proliferatorsactivated receptor agonists and natural antioxidants,
have been proposed as promising in dialysis patients.
Nutritional intervention may also be a potential strategy to reduce inflammation while ameliorating the
CKD. The anti-inflammatory properties of fish oil
(omega-3-fatty acids) show promise in preventing CVD
in the general population, but have not been tried in
ESRD. Also, vitamin E supplementation (using γ-tocopherol), genistein (antioxidant and anti-inflammatory
soy isoflavones) and anthocyanins (antioxidant
flavonoids from wine or berries) are currently in the
process of being evaluated.
Conclusion
Taken together, the present review aimed to emphasize the following key messages:
1. Low-grade inflammation is a common feature of
chronic kidney disease that is related to glomerular filtration rate.
2. Leukocyte priming may be a key mediator in
inducing a vicious circle of inflammation in CKD.
3. The inflammatory characteristics of uremic retention solute compounds need to be further elucidated.
Acknowledgment
Mahmut Ilker Yilmaz is supported by the ERA-EDTA.