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REVIEW |
Division of Nephrology, Department of Medicine, University of California Davis, Davis, and Department of Veterans Affairs Northern California Health Care System, Mather, California.
Correspondence to Dr. George A. Kaysen, Division of Nephrology, University of California, Davis, TB 136, Davis, CA 95616. Phone: 916-734-3774; Fax: 530-752-3791; E-mail: gakaysen{at}ucdavis.edu
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Abstract |
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 Top Abstract IntroductionMalnutrition in Renal DiseaseCauses of InflammationInflammation as a Cause...Inflammation as a Cause...Relationship between...References |
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) or acute-phase proteins (C-reactive protein and
serum amyloid A), however, has been found to be associated with vascular
disease in the general population as well as in dialysis patients. The process
of inflammation, also called the acute-phase response, additionally causes
loss of muscle mass and changes in plasma composition—decreases in serum
albumin, prealbumin, and transferrin levels, also associated with
malnutrition. Inflammation alters lipoprotein structure and function as well
as endothelial structure and function to favor atherogenesis and increases the
concentration of atherogenic proteins in serum, such as fibrinogen and
lipoprotein (a). Inflammation in dialysis patients is episodic. The causes are
likely to be multifactorial and include vascular access infection,
less-than-sterile dialysate, dialysate back leak, and nonbiocompatible
membranes in addition to clinically apparent infection. In addition,
proinflammatory compounds, such as advanced glycation end products, accumulate
in renal failure, and defense mechanisms against oxidative injury are reduced,
contributing to inflammation and to its effect on the vascular
endothelium. |
Introduction |
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A number of risk factors that provide a rationale for the remarkable prevalence of vascular disease in the dialysis patient population were recently identified. Among these, inflammation has been identified as an epidemiologically important risk factor for cardiovascular disease in the general population (4). Inflammation strongly predicts all-cause (5,6) and cardiovascular (6) mortality rates among the dialysis patient population. Additionally, levels of homocysteine, a factor that is known to promote atherogenesis in patients with normal renal function (7), are markedly increased among patients with renal failure (8). Oxidative stress (9) and postsynthetic modification of proteins, leading to accumulation of advanced glycation end products (AGE) (10), are additional risk factors that put patients with renal failure at increased risk of vascular injury and may play a role in the initiation of the inflammatory response.
It has been widely accepted by the nephrology community that malnutrition, as defined by reduced levels of serum albumin (1,3) or prealbumin (11) or by anthropometric markers of malnutrition, predicts poor outcomes. The relationship between malnutrition and vascular disease was initially obscure. It is now recognized, however, that inflammation is responsible for serologic or anthropometric evidence of malnutrition in this population (12). The biochemical basis for the apparent malnutrition among patients with inflammation is the fact that most of the serum proteins whose concentrations are decreased in response to protein malnutrition, i.e., prealbumin (13), transferrin (14), retinol-binding protein (15), and albumin, are negative acute-phase proteins (16). Their synthetic rates are decreased in response to inflammation, making their use as unambiguous markers of nutritional status problematic. Indeed, serum albumin concentrations vary inversely with those of positive acute-phase proteins, such as C-reactive protein (CRP), serum amyloid A (SAA) (17), and fibrinogen (18), and those of cytokines that modulate the synthesis of all of these proteins (19).
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Malnutrition in Renal Disease |
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The same relationships between nutritional markers and inflammation remain when renal function deteriorates, necessitating dialysis therapy. At that point, however, levels of cytokines (19) and acute-phase proteins increase, as does the fraction of the population that exhibits evidence of inflammation (21).
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Causes of Inflammation |
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Causes of Inflammation Related to Renal Failure
Postsynthetic Modification of Proteins. Renal failure itself may
possibly contribute to inflammation as a result of the accumulation of
proinflammatory compounds or products of metabolism. AGE such as pentosidine
are normally associated with diabetes mellitus
(22), and levels of advanced
lipoxidation end products are also increased in the plasma of patients with
renal failure, irrespective of their blood glucose levels. Levels of these
substances are increased in diabetes mellitus, generally as a consequence of
prolonged hyperglycemia. They result from the reaction of glucose and other
carbohydrates with protein, specifically with lysine, via nonenzymatic
glycation and oxidation (glycoxidation) of proteins. In diabetes mellitus,
these substances are thought to play a role in the progression of renal
disease (23).
The kidney normally plays an important role in the metabolism of AGE, which are processed by glomerular filtration followed by tubular uptake and metabolism (24). Because most of the pentosidine in blood is bound to high-molecular weight proteins such as albumin, dialysis has little effect on AGE concentrations (25). AGE may play a role in activating mononuclear cells, thus directly inciting an inflammatory response (24). Inflammation, however, can also play a role in the production of AGE (26). Although AGE and related compounds clearly can modify proteins, including the vascular endothelium (27) and lipoproteins (28), and thus could play a significant role in the development of vascular disease in patients with renal failure, it is not clear why the increased concentrations of these compounds that are observed for all dialysis patients would lead to activation of the acute-phase response or to hypoalbuminemia in only a fraction of dialysis patients.
Although oxidative stress and other postsynthetic modifications of proteins that occur in parallel with decreasing GFR may well explain a component of the inflammation observed for dialysis patients, they do not explain the large skews in the frequencies of increased levels of interleukin-6 (IL-6) (10) or acute-phase proteins (17,19) that were observed among the dialysis patient population (Figure 1A) or the wide temporal variability that we observed (Figure 1B) (29). These observations are more consistent with an episodic process either driving inflammation for this population as a whole or superimposed on a low level of inflammation.
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Oxidative injury and protein glycation have also been suggested to play a
role, although neither of these processes has been demonstrated to directly
increase either acute-phase protein levels or cytokine levels in dialysis
patients. However, levels of advanced oxidation products increase as GFR
decreases (30) and are closely
related to levels of the AGE pentosidine
(30). There is a correlation
between these products and cytokines, specifically IL-1 receptor antagonist,
tumor necrosis factor (TNF-), TNF soluble receptor 55, and TNF
soluble receptor 75, and these products are associated with evidence of
monocyte activation (30),
providing at least a theoretical link between advancing loss of renal function
and the onset of an inflammatory response.
Oxidative Stress. Renal failure reduces plasma antioxidant activity (31). The increase in oxidative stress is identified by an increase in malondialdehyde levels in red blood cell membranes and a reduction in levels of the reduced forms of glutathione. The loss of antioxidants (32), zinc, selenium, and vitamins C and E (33) occurs during renal failure or as a consequence of dialysis and may contribute to susceptibility to oxidative injury. Plasma glutathione peroxidase activity is also reduced in renal failure (34). Superoxide dismutase and glutathione peroxidase activities are decreased in plasma and in erythrocytes. Increased oxidative stress occurs even before dialysis is instituted. After initiation of dialysis, the opportunity for oxidative injury of circulating blood elements is also present (35). Dialysis does not reduce oxidative injury and may actually exacerbate oxidative stress (36). Increased oxidative stress leads to lipid peroxidation (37) and oxidative alteration of lipoproteins. Cell membranes are also subject to oxidative injury. Stenvinkel et al. (38) established that the decrease in the levels of reduced erythrocyte phospholipids in patients with pre-ESRD was greatest for patients judged to be malnourished, suggesting that there is a relationship between inflammation and oxidative injury.
Levels of IL-6, IL-1, and TNF- have been found to be significantly
increased in patients with renal failure, with no difference being observed
between patients undergoing longterm dialysis and patients who have not yet
undergone dialysis (39),
although others reported an increase primarily among patients undergoing
dialysis (40). The process of
dialysis provides multiple opportunities for exposure to stimuli that might
promote inflammation.
Dialysis Membranes or Techniques. Exposure of blood to bioincompatible dialysis membranes causes activation of circulating mononuclear cells (41) and has been implicated as a potential cause of inflammation induction within the population of patients with ESRD (42). Bioincompatible membranes, such as cellulosic membranes, activate white blood cells (43) and complement (44) and can even exert effects on residual renal function (45). Kaizu et al. (46) observed that dialysis membrane properties represented one factor that predicted serum IL-6 levels in their patients. Activation of cytokines occurred after dialysis using cellulose membranes (47), in contrast to biocompatible membranes (48).
Other investigators have suggested that even dialysis with biocompatible membranes may pose risks for activation of the acute-phase response. Honkanen et al. (41) observed very rapid and similar increases in the levels of IL-1ß and the acute-phase protein SAA during 240 min of dialysis with cellulose, cellulose acetate, or polymethylmethacrylate membranes; the latter two types are biocompatible membranes. Cytokine production during in vitro dialysis of whole blood has been demonstrated (49), suggesting that interactions of circulating nuclear cells directly stimulate cytokine production. Dialysis also alters mononuclear cells so that they respond more vigorously to subsequent exposure to endotoxin (50). Therefore, dialysis with a variety of membranes is a potential source of inflammation, although most other investigators, including our group, failed to find convincing evidence of activation of the acute-phase response during dialysis with membranes other than cellulose membranes.
Reuse techniques and the number of times of reuse also may contribute to the interaction of blood with the dialyzer (51), leading to changes in protein loss and possibly changes in the acute-phase response. Pyrogenic reactions in the absence of septicemia are closely associated with reuse (52).
Dialysate Quality. The quality of water used to prepare the dialysate may also contribute to inflammation (53). Mounting evidence suggests that the use of less-than-sterile dialysate or back-leakage of lipopolysaccharide through the dialysis membranes can cause dialysis-related inflammation (54). Several groups recently prepared ultrapure, endotoxin-free water by membrane filtration of the dialysate and observed reduced levels of cytokines (55), which suggests either that monocytes may be activated by endotoxin that remains on the dialysate side of the membrane or that endotoxin can directly cross the dialysis membrane. This latter route may be of increased importance with the use of highly permeable membranes (56).
Neither the exposure of blood to dialysis membranes nor the use of less-than-ultrapure water in the dialysate can explain the inflammation variability observed within the dialysis population (Figure 1A). Furthermore, the acute-phase response also plays an important role in establishing albumin levels in patients undergoing continuous ambulatory peritoneal dialysis (57), a population exposed to neither lipopolysaccharide-containing dialysates nor dialysis membranes. Indeed, in our own patient population, CRP and SAA levels were significantly greater among patients undergoing peritoneal dialysis than among patients undergoing hemodialysis (57). Peritoneal dialysis may, however, carry its own special risk of exposure to mediators of inflammation. Exposure of the peritoneal membrane to plasticizers found in dialysates may be one source of inflammation among this population. Another potential source is transperitoneal access.
The majority of dialysis patients exhibit no evidence of activation of the inflammatory response, despite the fact that all patients are exposed to dialysis membranes and dialysates. The highly skewed distributions of CRP and SAA (Figure 1A) (17) and IL-6 (19) values within the hemodialysis patient population suggest that patient-specific processes, such as the type of vascular access, unrecognized infections, or variable responses to the dialyzer used, may play a role. Qureshi et al. (58) observed that patients with CRP levels of >20 µg/ml exhibited clinical evidence of infection, suggesting that patients with levels of acute-phase proteins or cytokines skewed to high values have clinical infections. However, Bologa et al. (19) specifically excluded patients with evidence of infection and observed that the distribution of IL-6 levels was similar to that we described for acute-phase proteins in hemodialysis patients (17).
Another significant issue is the variability of both cytokine and
acute-phase protein levels with time. Cross-sectional studies demonstrated a
strong correlation between CRP concentrations and albumin concentrations
(17,19)
and between CRP and IL-6 concentrations and mortality rates. Those
measurements were made at one time point. In longitudinal studies of 37
hemodialysis patients, we observed that levels of two acute-phase proteins,
i.e., CRP and 1-acid glycoprotein, varied significantly with
time, with no change in dialyzer type or treatment, suggesting that
non-dialysis-related processes might be responsible for altered expression of
the acute-phase response in these patients
(29). The variance in CRP
levels was 2 orders of magnitude greater than that for albumin or transferrin
(29). Therefore, factors other
than dialysis, which are specific to individual patients, might also be
responsible for initiating the inflammatory response. It is unclear what
specific process is responsible for activation of the acute-phase response in
dialysis patients; however, the process does not occur at all times in all
dialysis patients.
Infectious Causes of Inflammation
Infections occur commonly among hemodialysis patients. This population is
at increased risk of infection as a consequence of impaired humoral and
cellular immunity (59) and
vascular access, as discussed below.
In a longitudinal cohort study of the incidence of and risk factors for hospitalized cases of septicemia among diabetic and nondiabetic hemodialysis patients, using baseline data from the United States Renal Data System, it was reported that, during a 7-yr period, 11.1% of nondiabetic patients and 12.5% of diabetic patients experienced at least one episode of septicemia (60). Risk factors that predicted septicemia were low serum albumin levels and advancing age.
Clinical infections from actively infected grafts, as well as old clotted grafts that do not exhibit signs of active inflammation (61), are also infectious sources of inflammation and may play a very significant role in individual cases. The detection of graft infections may require 111In white blood cell scans (61) or other procedures.
The prevalence of tuberculosis is increased among dialysis patients (62). Dialysis patients are also subject to other sources of infection, especially because of the prevalence of diabetes mellitus among this population. Indeed, diabetes mellitus was found to be a risk factor for inflammation in a cross-sectional study of 128 hemodialysis patients (58). Diabetes mellitus poses the risk of peripheral vascular disease and neuropathy, which are both risk factors for foot infections. Peritonitis presents an additional risk of infection for peritoneal dialysis patients (63). It was recently hypothesized that vascular disease itself may be infectious in origin (64). This is reviewed below.
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Inflammation as a Cause of Malnutrition |
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Inflammation as a Cause of Anemia |
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Relationship between Inflammation and Vascular Disease |
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It was recently established, in large cross-sectional studies, that even small increases in the levels of either cytokines or acute-phase proteins predicted vascular disease among populations of otherwise healthy-appearing adults (4). This observation was based on the assumption, although it was not explicitly stated, that CRP and IL-6 levels are characteristic for specific patients, as LDL levels are. The finding that even small increases in the levels of these markers of inflammation predicted future vascular events generated the term "microinflammatory state." Markers of inflammation have the same predictive values for dialysis patients (5,6); however, for such patients we know that inflammation is not characteristic for each patient but instead varies with time (29). Elevations in the levels of acute-phase proteins are not subtle, and the incidence of vascular disease is greatly increased. The relationship between inflammation and vascular disease in this population is strong enough to obscure other well known risk factors. Although total cholesterol (and LDL cholesterol) levels are powerful predictors of vascular disease in the general population, the inverse is true for dialysis patients (3).
The relationship between the variability of the acute-phase response and vascular disease in the dialysis patient population remains unknown. Several possibilities present themselves. One is that even a short period of inflammation may result in future vascular events. Inflammation clearly alters the plasma protein composition and both endothelial and lipoprotein structure and function to favor vascular injury, and the time between inflammation and vascular occlusive disease may not be short. After vascular injury occurs, it may be self-propagating, and the inflammatory cells (monocytes) involved in vascular injury may contribute to a chronic increase in the levels of acute-phase proteins and cytokines. We observed, however, that both cytokine and acute-phase protein levels decreased to baseline values after episodes of acute inflammation (29).
There are several ways in which inflammation can promote vascular injury, i.e., through alterations in lipoprotein structure and function, changes in the composition of plasma proteins, alterations in the vascular endothelium, and changes in the expression of specific ligands on the surfaces of platelets, neutrophils, and mononuclear cells.
Several acute-phase proteins are directly associated with vascular disease. One of these is fibrinogen (71). Fibrinogen levels are increased in the subset of patients with inflammation/malnutrition (12), and the levels of this protein, like those of CRP and other acute-phase proteins, vary with time among dialysis patients. Therefore, a specific episode of inflammation not only promotes alterations in the vascular adhesion of mononuclear cells but also increases the concentration of this coagulation factor in plasma. Levels of lipoprotein(a) are also increased among patients with ESRD and are correlated with both vascular injury (carotid artery intimal thickening) and inflammation/malnutrition (12), suggesting that this protein may also be regulated as part of the acute-phase response. Although the concentrations of lipoprotein(a) are generally genetically controlled, the levels of this lipoprotein increase in patients with renal failure (72), in conjunction with increased levels of acute-phase proteins; this increase is in turn associated with increased mortality rates for the hemodialysis patient population (73). This lipoprotein is highly atherogenic when its levels are genotypically increased. The increase in the dialysis patient population may be a component of the acute-phase response and may also contribute to vascular injury.
Apolipoprotein A-I is a negative acute-phase protein, and its synthetic rate is decreased during inflammation (74). SAA displaces apolipoprotein A-I from HDL and alters HDL structure and function (Figure 2), causing HDL to become adherent to the vascular endothelial surface (75). Paraoxonase activity is reduced, and HDL is then no longer capable of reducing oxidized LDL. Furthermore, HDL that has been thus altered acts as a chemoattractant to macrophages, serving as a bridge between them and the endothelial surface (Figure 2) (76).
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Inflammation also alters the expression of soluble vascular cell adhesion molecule-1 (77) and soluble intercellular adhesion molecule-1, i.e., adhesion molecules that promote monocyte binding to endothelial cells and are associated with vascular disease (78).
P-selectin levels are increased during acute inflammation, increasing the
adherence of platelets to the endothelium. P-selectin (platelets) and
E-selectin (endothelial cells) are surface glycoproteins that mediate
leukocyte rolling on the endothelial surface, a step that immediately precedes
adhesion. P-selectin is able to initiate the cascade of events that increases
cell adherence and leukocyte infiltration into injured tissues, by first
promoting leukocyte rolling along the vascular endothelium
(79). P-selectin levels are
increased by hemodynamic stress
(80) and are regulated by
TNF- during inflammation
(81). Therefore, inflammation
also alters the expression of endothelial adhesion molecules that favor the
attachment of mononuclear cells and neutrophils, which then initiate oxidative
bust activity and further the inflammatory response, contributing to increased
oxidative modification of lipids and proteins. Patients with renal failure
have a decreased antioxidative reserve, as described above, and thus are less
likely than others to be able to prevent this process from becoming
self-perpetuating.
Effects of Inflammation and Oxidation of Lipoproteins
During inflammation, SAA is incorporated into HDL and displaces
apolipoprotein A-I. The triglyceride content of HDL is thus increased
(Figure 2). Both paraoxonase
and platelet-activating factor-acetyl hydrolase are thought to play a role in
preventing the peroxidation of other lipoproteins, including LDL. The
activities of both paraoxonase and platelet-activating factor-acetyl hydrolase
are reduced. Paraoxonase activity remains suppressed long after levels of the
acute-phase proteins have returned to normal after a single episode of minor
surgical stress (82).
Paraoxonase plays an important role in preventing the oxidation of HDL.
Oxidative modification of LDL has been implicated in atherogenesis
(83). This interaction between
acute inflammation and lipoprotein structure (specifically HDL structure)
provides one link between accelerated vascular disease and inflammation among
patients with ESRD. Inflammation itself can directly yield lipoprotein
oxidation, in addition to removing potential defense mechanisms against
lipoprotein oxidation.
The leukocyte enzyme myeloperoxidase oxidatively modifies LDL via the oxidative nitration of tyrosine and other modifications of the tyrosine residue (Figure 2) (84). Both ascorbate and probucol inhibit the myeloperoxidase-catalyzed oxidation of LDL, providing the possibility for therapeutic intervention. Ceruloplasmin carries copper and is an acute-phase protein whose concentrations increase during inflammation. It also acts as an oxidant for lipoproteins during acute inflammation.
In the absence of inflammation, the antioxidant activity of HDL is usually normal in hemodialysis patients (85), although total HDL levels are reduced. Reductions in HDL particle size are linked to insulin resistance and accompany reductions in LDL particle size and hypertriglyceridemia.
The predictors of death resulting from cardiovascular causes are low HDL cholesterol levels and high triglyceride/HDL ratios. Indeed, patients with the lowest total cholesterol levels, not those with the highest LDL levels, succumb to vascular disease (3). The combined effects of inflammation and oxidative injury on lipoprotein structure and function may provide some insight into this apparent contradiction.
Inflammation among patients with renal failure is common and may present with markers of malnutrition, e.g., reduced albumin or prealbumin levels, decreased muscle mass, or high Subjective Global Assessment scores. Inflammation contributes to both anemia and erythropoietin resistance. Inflammation predicts death, including death resulting from cardiovascular causes, and is likely to explain the relationship between malnutrition and death resulting from cardiovascular causes among this population. The cause of inflammation is likely to be multifactorial and, although it may reflect underlying vascular disease, inflammation is also a potent factor causing vascular injury. This effect is most likely mediated by changes in lipoprotein structure and function, alterations in endothelial function, adhesion to mononuclear cells and platelets, and alteration of the composition of plasma proteins to promote hemostasis and improve host defenses, with the unwanted consequences being vascular injury and death.
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Acknowledgments |
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