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J Am Soc Nephrol 15:538-548, 2004
© 2004 American Society of Nephrology

FRONTIERS IN NEPHROLOGY

The Role of Oxidative Stress–Altered Lipoprotein Structure and Function and Microinflammation on Cardiovascular Risk in Patients with Minor Renal Dysfunction

George A. Kaysen and Jason P. Eiserich

Division of Nephrology, Department of Medicine University of California Davis, Davis, California; and Department of Veteran’s Affairs Northern California Health Care System, Mather, California.

Correspondence to: Dr. George A. Kaysen, Chief, Division of Nephrology, One Shields Avenue, TB 136, University of California, Davis, Davis CA 95616. Phone: 530-752-4010; 530-752-3791; E-mail: gakaysen{at}ucdavis.edu


   Abstract
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Inflammation Mortality and...
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ABSTRACT. Cardiovascular disease is common in patients with chronic kidney disease (CKD). As renal function fails, many patients become progressively malnourished, as evidenced by reduced levels of albumin, prealbumin, and transferrin. Malnourished patients have increased levels of C reactive protein (CRP), interleukin-6 (IL-6), and concomitant cardiovascular disease when they reach end stage. Many diseases that cause CKD, diabetes, and hypertension are also associated with cardiovascular disease. Thus the direct effect of renal failure per se directly contributing to the inflammation–malnutrition–atherosclerosis paradigm is not completely established in early stages of CKD. Some aspects of progressive renal failure, however, cause changes in plasma composition and endothelial structure and function that favor vascular injury. As renal function fails, hepatic apo A-I synthesis decreases and HDL levels fall. HDL is an important antioxidant and defends the endothelium from the effects of cytokines. Inflammation causes further structural and functional abnormalities in HDL. Apolipoprotein C III (apo C III), a competitive inhibitor of lipoprotein lipase is increased in CKD. Serum triglyceride levels increase as a result of accumulation of intermediate-density lipoprotein (IDL) comprising VLDL and chylomicron remnants. These impede vascular relaxation and are associated with cardiovascular disease. Activation of the renin angiotensin axis is a component of many renal diseases and adaptation to loss of renal mass. Angiotensin II (AngII) activates NADPH oxidases, leading to production of the superoxide anion and decreased availability of nitric oxide (NO), further impairing vascular function. H2O2, produced as a consequence of superoxide dismutation, stimulates vascular cell proliferation and hypertrophy. Leukocyte-derived myeloperoxidase functions as an "NO Oxidase" in the inflamed vasculature and contributes to decreased NO bioavailability and compromised vascular reactivity. The changes in lipoprotein composition and structure as well as AngII-mediated alterations in endothelial function amplify the effect of subsequent inflammatory events.


   Inflammation Mortality and Malnutrition in Advancing Renal Failure
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 Abstract
 Inflammation Mortality and...
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The mortality rate of patients on dialysis is as great as from many malignancies. The leading cause of death is cardiovascular disease, and it is abundantly clear that inflammation is closely associated with cardiovascular risk in this population (1–3). Many aspects of dialysis treatment can contribute to inflammation, such as vascular access (4,5), back leak of dialysate (6), and exposure of blood to non-biologic surfaces (7). While the role of inflammation in patients who have yet been treated for end-stage renal disease (ESRD) is less well defined, as patients approach dialysis the prevalence of inflammation increases (8,9), and cytokine and acute phase protein levels are associated both with the prevalence of vascular disease in these patients as well as future progression of vascular disease (10). The role of inflammation in patients with early stages of chronic kidney disease (CKD) is less well described. While many of the diseases associated with progression of renal failure, diabetes, and hypertension to mention two are risk factors for development of vascular injury. Certain biochemical changes common to loss of renal function pre se, specifically alteration in lipoprotein structure and function and activation of the renin angiotensin system, are likely candidates for contributing to vascular injury. Fried et al. (10) found that serum creatinine level alone was an independent risk factor for cardiovascular mortality and morbidity, including stroke, congestive heart failure, and peripheral vascular disease, even with creatinine levels elevated to as low as >1.5 mg/dl in men and 1.3 mg/dl in women, consistent with the hypothesis that renal failure per se may be an independent risk factor for vascular disease. These same investigators, using the same definition for early mild renal failure, found that patients with this level of renal insufficiency had significantly increased levels of acute phase proteins (C-reactive protein, fibrinogen, interleukin-6 [IL-6]) as well as increased levels of factor VIIc, factor VIIIc, plasmin-antiplasmin complex, and D-dimer, even among patients with no cardiovascular disease at baseline, suggesting that even mild renal failure is associated with and possibly causes inflammation and vascular injury (11). However, once data were analyzed following stratification for preexisting cardiovascular disease, the observed differences among IL-6, CRP, and fibrinogen either failed to achieve significance or became only marginally significant, still leaving the question open as to whether the acute phase response, while associated with cardiovascular disease in these patients as in others, is increased, renal failure per se may have a less significant contribution to that inflammatory response and to the vascular disease. However the differences in the levels of clotting factors did remain highly significant even after adjustment, and it is likely that renal failure indeed does contribute risk (11).

Patients arrive at ESRD with significant cardiovascular risk factors (12) and once on dialysis die at a more rapid rate than would be predicted by their Framingham risks alone (12,13). The prevalence of cardiovascular disease is significantly elevated in both men and women with mild to moderate renal failure (14,15), although not all investigators have found an increased relative risk contributed by mild renal failure pre se; in a study of the Framingham population, Culleton et al. (16) found that the risks for cardiovascular disease could be accounted for by other known risk factors.

Some investigators have found significantly elevated serum levels of IL-6, IL-1, and TNF-{alpha} in patients with renal failure with no difference observed between long-term dialyzed and as yet undialyzed patients (17,18), while others found an increase primarily in dialyzed patients (19–21). Increased oxidative stress (22–25) and the accumulation of post synthetically modified proteins, advanced glycation end products (26,27) and products of carbonyl stress (28), normally cleared by the kidney, have been proposed as sources for increased inflammation in patients not yet on dialysis. No clear evidence has been found, however, to link these products with cardiovascular risk in patients with renal failure (29,30). Thus it remains possible that the same risk factors that cause atherogenesis are responsible for progression of renal failure, and the association between inflammation and progressive CKD is simply another manifestation of co morbidities. There is a basis however to challenge this hypothesis.

Both hypertension and disorders in lipoprotein composition (31–33) and metabolism (34) have been recognized consequences of progressive renal failure, laying the foundation for increased prevalence of vascular disease in patients reaching end stage regardless of etiology. Additionally, activation of the renin angiotensin axis (RAA) has the potential to confer additional risk of vascular disease and to cause patients with renal failure to be especially susceptible to the adverse effects of inflammation. Inflammation may also increase in conjunction with progression of CKD and interact with alteration in lipoprotein metabolism to synergistically augment cardiovascular risk.

Evidence of Inflammation Associated with Progressive Renal Failure
Malnutrition is associated with declining GFR (35), but the relationship between inflammation and malnutrition that is so well established now in the ESRD patient population (36,37) has not been as well characterized in patients with early renal failure. Clearly work by Muntner et al. (12) establish that the malnutrition inflammation atherosclerosis (MIA) paradigm is in place before the implementation of renal replacement therapy. IL-6 levels before the onset of dialysis correlate with incident intimal media thickness of the carotid artery and also predict future change in intimal media thickness (38). These studies have been carried out either in patients already on dialysis or in patients just before the onset of dialysis treatment (39,40). The presence of malnutrition, whether defined by subjective global assessment (SGA) or serum albumin or pre-albumin concentration at the time that dialysis is initiated, are powerful predictors of death within the first year of renal replacement therapy (41–43).

Links between Inflammation and Vascular Injury
It has recently been recognized that there is a very tight linkage between "malnutrition" and vascular disease in both the ESRD patient population (1–3) and in other populations (44–46). While this remains an association and debate continues between whether inflammation reflects vascular injury or instead is a cause of vascular injury, there are multiple mechanisms whereby the inflammatory response can both alter blood lipids (47,48), the vascular endothelium (49,50), and plasma protein composition in such a way as to favor and promote vascular injury. Alterations in lipoprotein composition associated with renal failure reduce defense mechanisms that would mitigate the effects of inflammation on vascular structure.

Changes in Lipoprotein Concentration and Composition: HDL
HDL plays an important role in mechanism against atherosclerosis. In addition to being a component of the reverse cholesterol transport system, HDL serves both as an antioxidant, reducing oxidized LDL (51,52), and decreases the expression of adhesion molecules by vascular endothelial cells induced by cytokines (53,54). HDL levels decrease progressively as renal function fails (55), in part due to decreased synthesis (56) resulting from downregulation of apo A-I gene expression by the liver (57) (Figure 1). HDL structure is also deranged (58). Apo A-I, an important activator of lecithin:cholesterol acyltransferase (LCAT) is decreased. LCAT esterifies cholesterol and is necessary for HDL maturation. Maturation of HDL is thus severely impaired (59). Apo C-III, a competitive inhibitor of the activity of lipoprotein lipase (LPL), is increased (58) (Figure 1). LPL is the principal enzyme necessary for lipolysis of triglycerides and is necessary for VLDL and chylomicron catabolism on the vascular endothelium. Increased apo C III levels correlate with increased triglyceride levels in patients with renal failure (58). This is accompanied by, and perhaps causes an increase in intermediate density lipoprotein (IDL) remnants of very low–density lipoprotein (VLDL) and chylomicrons (55,60). High triglyceride levels and low levels of HDL also predict progression of renal failure (61) as well as cardiovascular disease (62), the lipoprotein composition that parallels loss of renal function (63) (Figure 1).



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  		Figure 1. (A) Apo A-I synthesis is decreased, resulting in decreased synthesis of high-density lipoprotein (HDL) and reduced HDL levels. When inflammation is present, serum amyloid A secretion increases, displacing Apo A-I from HDL, decreasing its capacity as a reducing agent. In conjunction with increased myeloperoxidase (MPO) release, this causes oxidized LDL to accumulate and bind to the endothelium. Lecithin cholesterol ester transferase (LCAT), an enzyme activated by Apo A-I that esterifies free cholesterol and is necessary for maturation of HDL, is reduced. Levels of paroxynase (PON) and aryl hydrocarbon hydrolase enzymes utilized by HDL in reducing oxidative injury are also reduced. HDL thus fails to block cytokine-mediated expression of endothelial-derived adhesion molecules sICAM and e-Selectin. Neutrophils are activated, releasing myeloperoxidase-oxidizing LDL, allowing it to be taken up more easily on the endothelium. Apo C III delivered by HDL to very low-density lipoprotein (VLDL) is increased. (B) Derangements in lipoprotein metabolism in CKD. Increased apo C III delivery to VLDL impairs VLDL lipolysis, increasing levels of highly atherogenic remnant particles taken up by their receptor, the lipoprotein-like receptor (LRP) found both on the endothelium and in liver. Highly atherogenic small dense LDL also accumulates and Lp(a) synthesis is increased as a function of GFR.

 

In inflamed individuals without renal failure, HDL levels also decrease (47) and the apo A-I that normally composes about half of the proteins in HDL is replaced by SAA (47,64,65). This form of HDL is chemoattractive to macrophages as well as the vascular endothelium and has reduced capacity to reduce oxidized LDL (47,64,65). Inflammation alters HDL structure and function to remove these antiinflammatory properties by reducing the levels of aryl hydrocarbon hydrolase and paroxynase (63,64,66). Thus inflammation and the changes in HDL metabolism that occur in renal failure, presumably independently of inflammation, are synergistic in reducing this important defense mechanism against the effects of further inflammation and produce a positive feedback loop.

LDL is therefore more likely to be oxidized during an inflammatory event because of a decreased ability of HDL to protect it and as a consequence of increased action of myeloperoxidase, an abundantly expressed enzyme of activated neutrophils that chlorinates a tyrosine residue on apo B100 (Figure 1). HDL also normally suppresses the effects of cytokines on their induction of adhesion molecules by endothelial cells (53). Inflammation alters HDL structure and function to decrease these antiinflammatory properties (64,65). Inflammation would be anticipated to cause a decrease in HDL as well as an increase in triglyceride levels. These same characteristics predict cardiovascular disease in women (67) and are closely associated with markers of inflammation, including serum amyloid A levels. This specific acute phase protein directly affects HDL levels (48) and function as well as triglyceride content, suggesting that inflammation may play not only a role in vascular disease, but may also provide a link between progression of renal disease and the lipoprotein abnormalities associated with progression.

Hypertriglyceridemia and Intermediate Density Lipoprotein (IDL)
Progressive renal failure is associated with increased levels of highly atherogenic remnant particles (31,32). Remnant particles simulate endothelium-dependent arterial contraction (68) and induce even a greater uptake of cholesterol by macrophages than does oxidized LDL (69). Of interest is one factor that plays an important role in production of IDL particles is apo C III (70), a lipoprotein lipase inhibitor (71) that is characteristically increased in renal failure (72). IDL is an independent risk factor in patients with renal failure (73) and is a more important predictor that total lipid levels (55)

The correlation between serum triglycerides and increased cardiovascular risk in this population suggests that increased remnant particles (74) (also known as IDL) are a likely factor (75,76). Remnants are products of metabolism of VLDL and chylomicrons (CM) that are normally cleared rapidly by the liver. If they instead accumulate they carry potent risk for vascular injury (77). Remnant particles are indeed increased in the nephrotic syndrome (78,79) and in renal failure (31,32), providing another potential cause for vascular injury.

LDL also activates the RAA (80), inducing AngII levels and upregulating the angiotensin type I (AT1) receptor. Through this mechanism, LDL augments synthesis of the superoxide anion (02-), providing a direct link between lipids as a cause of oxidative injury. The additional contribution of the RAA will be reviewed subsequently.

Lp(a)
Lp(a) is a powerful risk factor for vascular disease in most populations (81,82). The tight link between isoform, a genetically encoded characteristic, and serum concentration is not found in all racial groups (83). It remains unclear as to whether it is the isoform or the concentration of Lp(a) that confers vascular risk (84). This point is especially important because Lp(a) levels increase as renal failure progressively deteriorates (85,86) and the increase that occurs exclusively in the high molecular weight isoform subfraction. Thus the clinical effect of changes in Lp(a) in renal failure will depend largely on whether it is isoform or concentration that confers risk. Lp(a) also increases as a consequence of protienuria in nephrotic patients (87) exclusively as a result of increased synthesis (88). This increase is isoform independent.

Proteinuria is an independent risk factor both for progression of renal injury and for vascular disease in both the diabetic and nondiabetic hypertensive patient population (89). How this might occur is multifactorial. Proteinuria is observed with greater prevalence in patients with isolated systolic hypertension (90); in this context, it could simply be a marker both for a risk factor for vascular disease as well as for renal injury. Proteinuria may reflect general injury to the vascular endothelium (91–93). When proteinuria is excessive, there are alterations in plasma protein composition and lipoprotein composition that are themselves associated with vascular disease (87,88).

Angiotensin II
The adaptation to loss of renal mass recruits local changes in renal hemodynamics that involve the RAA (94), a subject well beyond the scope of this review. Hypertension in the 5/8-nephrectomized rat is mediated at least in part by inactivation of NO mediated by superoxide generated as a result of AngII (95). AngII activates vascular NAD(P)H-oxidase (96, 97), which in turn generate superoxide anion (O2-). The superoxide anion has recently been found to be responsible for consumption of NO, reducing its bioavailability (98). Inactivation of NO then in turn leads to increased smooth muscle cell hypertrophy, proliferation, and increased extracellular matrix formation (97). AngII also induces IL-6 synthesis through a lipoxygenase-mediated mechanism and thus can directly augment inflammation (99). Both early atherosclerosis and renal vascular disease are associated with endothelial dysfunction characterized by lack of responsiveness of the vasculature to acetylcholine (100) affected in response to AngII (101).

Vascular dysfunction can be partially normalized by repair of unilateral renal artery obstruction (102), and this is accompanied by evidence of decreased oxidative stress. Before angioplasty, infusion of ascorbate augmented the response of forearm blood flow to acetylcholine, suggesting that oxidative stress was at least in part responsible for the abnormal endothelial response. After angioplasty, the effect of infusion of ascorbate was abolished.

NAD(P)H Oxidase Family
Studies within the past several years have revealed that NAD(P)H oxidase family members are major sources of reactive oxygen species that appear to play a pivotal role in the progression of vascular disease. The leukocyte-derived NAD(P)H oxidase (gp91phox; now referred to as Nox2) was presumed to be the major source of reactive oxygen species production during inflammatory responses. However, Nox2 is now known to be expressed in non-phagocytic cells such as adventitial fibroblasts, smooth muscle cells from resistance arteries, and endothelial cells (103–105). Indeed, rodent models of chronic renal failure have revealed that Nox2 expression is elevated in both the liver and kidney, and this is associated with increases in arterial BP, and paralleled by decreases in the expression of the antioxidant enzymes Cu-, Zn-, and Mn-superoxide dismutase (SOD). It should be noted, however, that the cellular source of increased tissue Nox2 was not identified (i.e., leukocyte or endothelial cell) (106). More recently, novel gp91phox homologues, termed Nox1, Nox3, Nox4, and Nox5, have been identified in non-phagocytic cells in the vasculature and in the kidney (mesangial cells) (107–110). Indeed, Nox isoforms are upregulated in human atherosclerotic arteries (111) and in smooth muscle cells after experimental angioplasty (112). While it is commonly viewed that reactive oxygen species such as superoxide (O2-) and hydrogen peroxide (H2O2) elicit their pathologic effects in the vasculature by oxidatively modifying critical biomolecules (i.e., lipids and proteins), it is now clear that these oxygen-derived metabolites play more direct roles as signaling molecules regulating cellular functions as diverse as hypertrophy, proliferation, and cell migration.

AngII clearly plays a role in altering endothelial function and promotes oxidative injury both in animal models of renal failure (94) as well as in humans with renal vascular disease (101) and is a likely candidate to play a key role in early stages of renal disease. It is now relatively well-established that the hypertrophic and proliferative effects of AngII on vascular smooth muscle cells and mesangial cells are mediated by oxidants generated from Nox enzymes (113). Indeed, it has recently been demonstrated that reactive oxygen species produced from Nox isozymes play critical roles in the intracellular signaling pathways initiated by growth factors (i.e., PDGF) and AngII (114,115). Several studies have now determined the expression and functional characterization of Nox isozymes in AngII-dependent vascular injury models (116). In addition to serving as a redox-based signaling molecule, superoxide produced from Nox isozymes can rapidly scavenge NO and impair its vasodilatory functions (117). The role of oxidants produced by Nox enzymes early in the course of renal disease is as of yet not well understood and warrants further investigation. A better understanding of the extent to which oxidative signaling affects renal and cardiovascular dysfunction will aid in the development of appropriate targeted therapeutic strategies.

Myeloperoxidase
The leukocyte-derived enzyme myeloperoxidase (MPO) is abundantly expressed in neutrophils, monocytes, and tissue-associated macrophages, and it has been implicated as a potential causal factor in atherosclerosis. In fact, MPO is highly expressed in human atherosclerotic lesions (118). Recent studies have shown that circulating leukocyte levels of MPO are positively associated with increased risk of developing coronary artery disease (119). Supporting this notion, it was recently observed that a single nucleotide polymorphism (SNP) in the promoter region of the MPO gene that confers decreased expression of MPO is associated with a lower prevalence of cardiovascular disease in ESRD patients (120), and MPO gene variation has been demonstrated to be a determinant of atherosclerosis progression in the abdominal and thoracic aorta (121). Moreover, when a group of 100 totally or subtotally MPO-deficient individuals was compared with a normal reference population selected at random, a protective effect of the deficiency against cardiovascular disease was observed (122). What remains to be determined is whether MPO plays a major role in the early stages of renal disease.

The most commonly appreciated view of how MPO can play a damaging role is its production of reactive oxidizing and chlorinating species that damage important biomolecules. Indeed, this hemoprotein can oxidatively modify LDL (123) by catalyzing lipid peroxidation as well as oxidation and chlorination of protein tyrosine residues (124,125). Whereas MPO is typically viewed to contribute to inflammatory injury by catalyzing oxidative damage to critical biomolecules within the vasculature, more recent studies have revealed that it may contribute to vascular dysfunction in more subtle ways; that is, its interaction with the nitric oxide (NO) pathway. It has been demonstrated that NO can biphasically modulate the catalytic activity of MPO (126,127). Conversely, this implies that the functions of NO can be enzymatically regulated by MPO. Supporting this notion, NO has been found to be a substrate of mammalian heme peroxidases (128), and MPO has been shown to directly modulate vascular inflammatory responses by regulating NO bioavailability through its catalytic consumption (129). Acute inflammation results in the activation of leukocytes and the secretion of MPO into the blood. Once secreted from activated leukocytes, MPO binds with high affinity to endothelial cell surface heparan-sulfate proteoglycans, and undergoes further transcytosis to the basolateral extracellular matrix (130). Here, MPO is anatomically poised to intercept and oxidize endothelial cell-derived NO and block its signaling and vasodilatory functions (Figure 2), which are commonly compromised in renal patients. These observations have led to the view that MPO can serve as a "NO oxidase," and that this aberrant function of MPO may provide a mechanistic link to its positive association with cardiovascular disease. This may provide a mechanistic explanation for the growing concept that oxidative processes lead to the consumption of NO in renal dysfunction (131).



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  		Figure 2. Oxidative pathways that have a deleterious affect on vascular structure and function. (A) Angiotensin II (AngII) stimulates the upregulation of NAD(P)H oxidases in vascular smooth muscle cells, which results in the increased production of reactive oxygen species, including superoxide (O2-) and hydrogen peroxide (H2O2). Nitric oxide (NO) produced by vascular endothelial cells can be rapidly scavenged by O2- to form the potent oxidant and nitrating species peroxynitrite (ONOO-). This reaction reduces the amount of bioavailable NO and results in compromised vasodilation. H2O2 produced by smooth muscle cells functions as a mitogenic signal inducing cell growth (proliferation), hypertrophy, and cell migration (all hallmarks of vascular disease). (B) Leukocytes that become activated by proinflammatory stimuli adhere to vascular endothelial cells and undergo degranulation (secretion) of myeloperoxidase (MPO). MPO binds with high affinity to glycosaminoglycans (GAG) on the cell surface, followed by transcytosis across the endothelium, where it accumulates in the extracellular matrix. Here, MPO can catalytically consume NO (functioning as an NO oxidase) and impair the ability of NO to stimulate soluble guanylate cyclase (and cGMP production) in smooth muscle cells and thus its function as a vasodilator.

 
In addition it its capacity to catalytically consume NO, MPO can also transform nitrite (NO2-), a nonfunctional metabolite of NO, into the powerful oxidizing and nitrating species nitrogen dioxide (·NO2) (126,132,133) (Figure 2). The production of ·NO2 in the inflamed vasculature can convert LDL into an atherogenic form and induce nitration reactions on tyrosine forming 3-nitrotyrosine (126,134). In addition to serving as a marker or dosimeter of reactive nitrogen species, plasma 3-nitrotyrosine levels are positively associated with cardiovascular disease, and this can be suppressed by statin therapy (135). Since catalytically active MPO is released from neutrophils during hemodialysis in ESRD patients (136), the role that this enzyme may play in the accelerated vascular disease in patients with renal failure may be significant. In addition, since MPO serum levels have been shown to strongly predict risk in patients with acute coronary syndromes (137), the use MPO to serve as an early marker of renal dysfunction and predictor of vascular disease in this patient population requires further investigation.


   Summary
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 Abstract
 Inflammation Mortality and...
 Summary
References
 
Clearly patients with CKD have increased prevalence of both vascular disease and the malnutrition–inflammation–atherosclerosis syndrome as renal function deteriorates. Comorbidity may play a role in a component of this. Specific characteristics of loss of renal function are not associated with comorbidities, and the adaptation to loss of renal mass provided by the RAA axis and changing lipoprotein structure and function clearly impart risk of vascular disease and promote increased oxidation on the endothelium. These factors act synergistically. Low HDL levels are associated with endothelial dysfunction (138). HDL in part acts by stabilizing endothelial derived nitric oxide synthase (eNOS) (139). Increasing HDL levels restore NO-dependent endothelial reactivity (140). Thus patients with advancing renal failure who have increased prevalence of hypertension, decreased apo A-I and HDL levels, and activation of the RAA system are subjected to a summation of risk factors for vascular injury, even in the absence of inflammation. Therapy directed at reducing the activity of the RAA system, angiotensin-converting enzyme inhibitors or angiotensin receptor blocker agents, and strategies to increase HDL levels should be considered early in the course of CKD. Go


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  		Table 1. Effects of renal failure and inflammation on lipoprotein and endothelial structure and function
 

   Acknowledgments
 
This work was supported in part by the research service of the United States Department of Veterans Affairs, in part by a grant from the National Institutes of Health RO1 DK 50777, and in part by a gift from Dialysis Clinics Incorporated.


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