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FRONTIERS IN NEPHROLOGY
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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
JASN March 2004, 15 (3) 538-548; DOI: https://doi.org/10.1097/01.ASN.0000111744.00916.E6
George A. Kaysen
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Jason P. Eiserich
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Abstract

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

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-α 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

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. ⇓

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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.

  • © 2004 American Society of Nephrology

References

  1. ↵
    Yeun JY, Levine RA, Mantadilok V, Kaysen GA: C-Reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients. Am J Kidney Dis 35: 469–476, 2000
    OpenUrlPubMed
  2. ↵
    Bologa RM, Levine DM, Parker TS, Cheigh JS, Serur D, Stenzel KH, Rubin AL: Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients. Am J Kidney Dis 32: 107–114, 1998
    OpenUrlPubMed
  3. ↵
    Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C: Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 55: 648–658, 1999
    OpenUrlCrossRefPubMed
  4. ↵
    Pastan S, Soucie JM, McClellan WM: Vascular access and increased risk of death among hemodialysis patients. Kidney Int 62: 620–626, 2002
    OpenUrlCrossRefPubMed
  5. ↵
    Nassar GM, Ayus JC: Infectious complications of the hemodialysis access. Kidney Int 60: 1–13, 2001
    OpenUrlCrossRefPubMed
  6. ↵
    David S, Tetta C, Canino F, Gervasio R, Cambi V: Production of platelet activating factor by human neutrophils after backfiltration of endotoxin contaminated dialysate. ASAIO J 39: M773–M777, 1993
    OpenUrlCrossRefPubMed
  7. ↵
    Parker TF 3rd, Wingard RL, Husni L, Ikizler TA, Parker RA, Hakim RM: Effect of the membrane biocompatibility on nutritional parameters in chronic hemodialysis patients. Kidney Int 49: 551–556, 1996
    OpenUrlCrossRefPubMed
  8. ↵
    Stenvinkel P, Heimburger O, Lindholm B, Kaysen GA, Bergstron J: Are there two types of malnutrition in chronic renal failure? Evidence for relationships between malnutrition, inflammation and atherosclerosis (MIA syndrome). Nephrol Dial Transplant 15: 953–960, 2000
    OpenUrlCrossRefPubMed
  9. ↵
    Pecoits-Filho R, Heimburger O, Barany P, Suliman M, Fehrman-Ekholm I, Lindholm B, Stenvinkel P: Associations between circulating inflammatory markers and residual renal function in CRF patients. Am J Kidney Dis 41: 1212–1218, 2003
    OpenUrlCrossRefPubMed
  10. ↵
    Fried LF, Shlipak MG, Crump C, Bleyer AJ, Gottdiener JS, Kronmal RA, Kuller LH, Newman AB: Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals. J Am Coll Cardiol 41: 1364–1372, 2003
    OpenUrlCrossRefPubMed
  11. ↵
    Shlipak MG, Fried LF, Crump C, Bleyer AJ, Manolio TA, Tracy RP, Furberg CD, Psaty BM: Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. Circulation 107: 87–92, 2003
    OpenUrlAbstract/FREE Full Text
  12. ↵
    Muntner P, He J, Hamm L, Loria C, Whelton PK: Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States. J Am Soc Nephrol 13: 745–53, 2002
    OpenUrlAbstract/FREE Full Text
  13. ↵
    Longenecker JC, Coresh J, Powe NR, Levey AS, Fink NE, Martin A, Klag MJ: Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: The CHOICE study. J Am Soc Nephrol 13: 1918–1927, 2002
    OpenUrlAbstract/FREE Full Text
  14. ↵
    Fried LF, Shlipak MG Crump C, Bleyer AJ, Gottdiener JS, Kronmal RA, Kuller LH, Newman AB: Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals. J Am Coll Cardiol 41: 1364–1372, 2003
  15. ↵
    Jungers P, Massy ZA, Nguyen Koha T, Fumeron C, Labrunie M, Lacour B, Descamps-Latscha B, Man NK: Incidence and risk factors of atherosclerotic cardiovascular accidents in predialysis chronic renal failure patients: A prospective study. Nephrol Dial Transplant 12: 2597–2602, 1997
    OpenUrlCrossRefPubMed
  16. ↵
    Culleton BF, Larson MG, Wilson PWF, Evans JC, Parfrey PS, Levy D: Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. Kidney Int 56: 2214–2219, 1999
    OpenUrlCrossRefPubMed
  17. ↵
    Herbelin A, Urena P, Nguyen AT, Zingraff J, Descamps-Latscha B: Elevated circulating levels of interleukin-6 in patients with chronic renal failure. Kidney Int 39: 954–60, 1991
    OpenUrlCrossRefPubMed
  18. ↵
    Pereira BJ, Shapiro L, King AJ, Falagas ME, Strom JA, Dinarello CA: Plasma levels of IL-1 beta, TNF alpha and their specific inhibitors in undialyzed chronic renal failure, CAPD and hemodialysis patients. Kidney Int 45: 890–896, 1994
    OpenUrlCrossRefPubMed
  19. ↵
    Cavaillon JM, Poignet JL, Fitting C, Delons S: Serum interleukin-6 in long-term hemodialyzed patients. Nephron 60: 307–313, 1992
    OpenUrlPubMed
  20. ↵
    Libetta C, De Nicola L, Rampino T, De Simone W, Memoli B: Inflammatory effects of peritoneal dialysis: Evidence of systemic monocyte activation. Kidney Int 49: 506–511, 1996
    OpenUrlPubMed
  21. ↵
    Pereira BJ, Poutsiaka DD, King AJ, Strom JA, Narayan G, Levey AS, Dinarello CA: In vitro production of interleukin-1 receptor antagonist in chronic renal failure, CAPD and HD. Kidney Int 42: 1419–24, 1992
    OpenUrlPubMed
  22. ↵
    Ceballos-Picot I, Witko-Sarsat V, Merad-Boudia M, Nguyen AT, Thevenin M, Jaudon MC, Zingraff J, Verger C, Jungers P, Descamps-Latscha B: Glutathione antioxidant system as a marker of oxidative stress in chronic renal failure. Free Radic Biol Med 21: 845–853, 1996
    OpenUrlCrossRefPubMed
  23. ↵
    Martin-Mateo MC, Sanchez-Portugal M, Iglesias S, de Paula A, Bustamante J: Oxidative stress in chronic renal failure. Ren Fail 21: 155–167, 1999
    OpenUrlCrossRefPubMed
  24. ↵
    McGrath LT, Douglas AF, McClean E, Brown JH, Doherty CC, Johnston GD, Archbold GP: Oxidative stress and erythrocyte membrane fluidity in patients undergoing regular dialysis. Clin Chim Acta 235: 179–188, 1995
    OpenUrlCrossRefPubMed
  25. ↵
    Loughrey CM, Young IS, Lightbody JH, McMaster D, McNamee PT, Trimble ER: Oxidative stress in haemodialysis. QJM 87: 679–83, 1994
    OpenUrlPubMed
  26. ↵
    Miyata T, Wada Y, Cai Z, Iida Y, Horie K, Yasuda Y, Maeda K, Kurokawa K, van Ypersele de Strihou C: Implication of an increased oxidative stress in the formation of advanced glycation end products in patients with end-stage renal failure. Kidney Int 51: 1170–1181, 1997
    OpenUrlCrossRefPubMed
  27. ↵
    Odetti P, Cosso L, Pronzato MA, Dapino D, Gurreri G: Plasma advanced glycosylation end-products in maintenance haemodialysis patients. Nephrol Dial Transplant 10: 2110–113, 1995
    OpenUrlPubMed
  28. ↵
    Miyata T, van Ypersele de Strihou C, Kurokawa K, Baynes JW: Alterations in nonenzymatic biochemistry in uremia: Origin and significance of “carbonyl stress” in long-term uremic complications. Kidney Int 55: 389–399, 1999.
    OpenUrlCrossRefPubMed
  29. ↵
    Stein G, Busch M, Muller A, Wendt T, Franke C, Niwa T, Franke S: Are advanced glycation end products cardiovascular risk factors in patients with CRF? Am J Kidney Dis 41 [3 Suppl 1]: S52–S56, 2003.
    OpenUrlPubMed
  30. ↵
    Kalousova M, Zima T, Tesar V, Sulkova S, Fialova L: Relationship between advanced glycoxidation end products, inflammatory markers/acute-phase reactants, and some autoantibodies in chronic hemodialysis patients. Kidney Int Suppl 84: S62–S64, 2003.
  31. ↵
    Nestel PJ, Fidge NH, Tan MH: Increased lipoprotein-remnant formation in chronic renal failure. N Engl J Med 307: 329–333, 1982
    OpenUrlCrossRefPubMed
  32. ↵
    Ron D, Oren I, Aviram M, Better OS, Brook JG: Accumulation of lipoprotein remnants in patients with chronic renal failure. Atherosclerosis 46: 67–75, 1983
    OpenUrlCrossRefPubMed
  33. ↵
    Grutzmacher P, Marz W, Peschke B, Gross W, Schoeppe W: Lipoproteins and apolipoproteins during the progression of chronic renal disease. Nephron 50: 103–111, 1988
    OpenUrlPubMed
  34. ↵
    Fuh MM, Lee CM, Jeng CY, Shen DC, Shieh SM, Reaven GM, Chen YD: Effect of chronic renal failure on high-density lipoprotein kinetics. Kidney Int 37: 1295–1300, 1990
    OpenUrlPubMed
  35. ↵
    Kopple JD, Greene T, Chumlea WC, Hollinger D, Maroni BJ, Merrill D, Scherch LK, Schulman G, Wang SR, Zimmer GS: Relationship between nutritional status and the glomerular filtration rate: Results from the MDRD study. Kidney Int 57: 1688–1703, 2000
    OpenUrlCrossRefPubMed
  36. ↵
    Kaysen GA, Stevenson FT, Depner TA: Determinants of albumin concentration in hemodialysis patients. Am J Kidney Dis 29: 658–668, 1997
    OpenUrlPubMed
  37. ↵
    Pecoits-Filho R, Lindholm B, Stenvinkel P: The malnutrition, inflammation, and atherosclerosis (MIA) syndrome—The heart of the matter. Nephrol Dial Transplant 17 [Suppl 11]: 28–31, 2002
  38. ↵
    Stenvinkel P, Heimburger O, Jogestrand T: Elevated interleukin-6 predicts progressive carotid artery atherosclerosis in dialysis patients: Association with Chlamydia pneumoniae seropositivity. Am J Kidney Dis 39: 274–282, 2002
    OpenUrlPubMed
  39. ↵
    Heimburger O, Qureshi AR, Blaner WS, Berglund L, Stenvinkel P: Hand-grip muscle strength, lean body mass, and plasma proteins as markers of nutritional status in patients with chronic renal failure close to start of dialysis therapy. Am J Kidney Dis 36: 1213–1225, 2000
    OpenUrlCrossRefPubMed
  40. ↵
    Stenvinkel P, Lindholm B, Heimburger M, Heimburger O: Elevated serum levels of soluble adhesion molecules predict death in pre-dialysis patients: association with malnutrition, inflammation, and cardiovascular disease. Nephrol Dial Transplant 15: 1624–1630, 2000
    OpenUrlCrossRefPubMed
  41. ↵
    Avram MM, Goldwasser P, Erroa M, Fein PA: Predictors of survival in continuous ambulatory peritoneal dialysis patients: The importance of prealbumin and other nutritional and metabolic markers. Am J Kidney Dis 23: 91–98, 1994
    OpenUrlPubMed
  42. ↵
    Sreedhara R, Avram MM, Blanco M, Batish R, Avram MM, Mittman N: Prealbumin is the best nutritional predictor of survival in hemodialysis and peritoneal dialysis. Am J Kidney Dis 28: 937–942, 1996
    OpenUrlPubMed
  43. ↵
    Chertow GM, Johansen KL, Lew N, Lazarus JM, Lowrie EG: Vintage, nutritional status, and survival in hemodialysis patients. Kidney Int 57: 1176–1181, 2000
    OpenUrlCrossRefPubMed
  44. ↵
    Koenig W, Sund M, Frohlich M, Fischer HG, Lowel H, Doring A, Hutchinson WL, Pepys MB: C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992, Circulation 99: 237–242, 1999
    OpenUrlAbstract/FREE Full Text
  45. ↵
    Harris TB, Ferrucci L, Tracy RP, Corti MC, Wacholder S, Ettinger WH Jr., Heimovitz H, Cohen HJ, Wallace R: Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med 106: 506–512, 1999
    OpenUrlCrossRefPubMed
  46. ↵
    Muir KW, Weir CJ, Alwan W, Squire IB, Lees KR: C-reactive protein and outcome after ischemic stroke. Stroke 30: 981–985, 1999
    OpenUrlAbstract/FREE Full Text
  47. ↵
    Van Lenten BJ, Hama SY, de Beer FC, Stafforini DM, McIntyre TM, Prescott SM, La Du BN, Fogelman AM, Navab M: Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures. J Clin Invest 96: 2758–2767, 1995
  48. ↵
    Artl A, Marsche G, Lestavel S, Sattler W, Malle E: Role of serum amyloid A during metabolism of acute-phase HDL by macrophages. Arterioscler Thromb Vasc Biol 20: 763–772, 2000
    OpenUrlAbstract/FREE Full Text
  49. ↵
    Jager A, van Hinsbergh VW, Kostense PJ, Emeis JJ, Nijpels G, Dekker JM, Heine RJ, Bouter LM, Stehouwer CD: Increased levels of soluble vascular cell adhesion molecule 1 are associated with risk of cardiovascular mortality in type 2 diabetes: the Hoorn study. Diabetes 49: 485–491, 2000
    OpenUrlAbstract
  50. ↵
    Hwang SJ, Ballantyne CM, Sharrett AR, Smith LC, Davis CE, Gotto AM Jr, Boerwinkle E: Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study. Circulation 96: 4219–4225, 1997
    OpenUrlAbstract/FREE Full Text
  51. ↵
    Mackness MI, Arrol S, Abbott C, Durrington PN: Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase. Atherosclerosis 104: 129–135, 1993
    OpenUrlCrossRefPubMed
  52. ↵
    Bielicki JK, Forte TM: Evidence that lipid hydroperoxides inhibit plasma lecithin: Cholesterol acyltransferase activity. J Lipid Res 40: 948–954, 1999
    OpenUrlAbstract/FREE Full Text
  53. ↵
    Cockerill GW, Huehns TY, Weerasinghe A, Stocker C, Lerch PG, Miller NE, Haskard DO: Elevation of plasma high-density lipoprotein concentration reduces interleukin-1-induced expression of E-selectin in an in vivo model of acute inflammation. Circulation 103: 108–112, 2001
    OpenUrlAbstract/FREE Full Text
  54. ↵
    Cockerill GW, Saklatvala J, Ridley SH, Yarwood H, Miller NE, Oral B, Nithyanathan S, Taylor G, Haskard DO: High-density lipoproteins differentially modulate cytokine-induced expression of E-selectin and cyclooxygenase-2. Arterioscler Thromb Vasc Biol 19: 910–917, 1999
    OpenUrlAbstract/FREE Full Text
  55. ↵
    Shoji T, Nishizawa Y, Kawagishi T, Tanaka M, Kawasaki K, Tabata T, Inoue T, Morii H: Atherogenic lipoprotein changes in the absence of hyperlipidemia in patients with chronic renal failure treated by hemodialysis. Atherosclerosis 131: 229–236, 1997
    OpenUrlCrossRefPubMed
  56. ↵
    Fuh MM, Lee CM, Jeng CY, Shen DC, Shieh SM, Reaven GM, Chen YD: Effect of chronic renal failure on high-density lipoprotein kinetics. Kidney Int 37: 1295–1300, 1990
  57. ↵
    Vaziri ND, Deng G, Liang K: Hepatic HDL receptor, SR-B1 and Apo A-I expression in chronic renal failure. Nephrol Dial Transplant 14: 1462–1466, 1999
    OpenUrlCrossRefPubMed
  58. ↵
    Atger V, Duval F, Frommherz K, Drueke T, Lacour B: Anomalies in composition of uremic lipoproteins isolated by gradient ultracentrifugation: Relative enrichment of HDL in apolipoprotein C-III at the expense of apolipoprotein A-I. Atherosclerosis 74: 75–83, 1988
    OpenUrlCrossRefPubMed
  59. ↵
    Miida T, Miyazaki O, Hanyu O, Nakamura Y, Hirayama S, Narita I, Gejyo F, Ei I, Tasaki K, Kohda Y, Ohta T, Yata S, Fukamachi I, Okada M: LCAT-dependent conversion of prebeta1-HDL into alpha-migrating HDL is severely delayed in hemodialysis patients. J Am Soc Nephrol 14: 732–738, 2003
    OpenUrlAbstract/FREE Full Text
  60. ↵
    Attman PO, Alaupovic P, Tavella M, Knight-Gibson C: Abnormal lipid and apolipoprotein composition of major lipoprotein density classes in patients with chronic renal failure. Nephrol Dial Transplant 11: 63–69, 1996
    OpenUrlPubMed
  61. ↵
    Samuelsson O, Mulec H, Knight-Gibson C, Attman PO, Kron B, Larsson R, Weiss L, Wedel H, Alaupovic P: Lipoprotein abnormalities are associated with increased rate of progression of human chronic renal insufficiency. Nephrol Dial Transplant 12: 1908–1915, 1997
    OpenUrlCrossRefPubMed
  62. ↵
    Halle M, Berg A, Baumstark MW, Konig D, Huonker M, Keul Joseph: Influence of mild to moderately elevated triglycerides on low density lipoprotein subfraction concentration and composition in healthy men with low high density lipoprotein cholesterol levels. Atherosclerosis 143: 185–192, 1999
    OpenUrlCrossRefPubMed
  63. ↵
    Shoji T, Ishimura E, Inaba M, Tabata T, Nishizawa Y: Atherogenic lipoproteins in end-stage renal disease. Am J Kidney Dis 38 [4 Suppl 1]: S30–S33, 2001
    OpenUrlPubMed
  64. ↵
    Pruzanski W, Stefanski E, de Beer FC, Ravandi A, Kuksis A: Comparative analysis of lipid composition of normal and acute-phase high density lipoproteins. J Lipid Res 41: 1035–1047, 2000
    OpenUrlAbstract/FREE Full Text
  65. ↵
    De Beer FC, Fagan EA, Hughes GRV, Mallya RK, Lanham JG, Pepys MB: Serum amyloid-A protein concentration in inflammatory diseases and its relationship to the incidence of reactive systemic amyloidosis. Lancet 2: 231–234, 1982
    OpenUrlPubMed
  66. ↵
    Pruzanski W, Stefanski E, Kopilov J, Kuksis A: Mitogenic effect of lipoproteins on human vascular smooth muscle cells: the impact of hydrolysis by gr II A phospholipase A(2). Lab Invest 81: 757–765, 2001
    OpenUrlPubMed
  67. ↵
    Ridker PM, Hennekens CH, Buring JE, Rifai N: C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342: 836–43, 2000
    OpenUrlCrossRefPubMed
  68. ↵
    Grieve DJ, Avella MA, Botham KM, Elliott J: Chylomicron remnants potentiate phenylephrine-induced contractions of rat aorta by an endothelium-dependent mechanism. Atherosclerosis 151: 471–480, 2000
    OpenUrlCrossRefPubMed
  69. ↵
    Whitman SC, Sawyez CG, Miller DB, Wolfe BM, Huff MW: Oxidized type IV hypertriglyceridemic VLDL-remnants cause greater macrophage cholesteryl ester accumulation than oxidized LDL. J Lipid Res 39: 1008–1020, 1998
    OpenUrlAbstract/FREE Full Text
  70. ↵
    Olin-Lewis K, Krauss RM, La Belle M, Blanche PJ, Barrett PH, Wight TN, Chait A: ApoC-III content of apoB-containing lipoproteins is associated with binding to the vascular proteoglycan biglycan. J Lipid Res 43: 1969–1977, 2002
    OpenUrlAbstract/FREE Full Text
  71. ↵
    Catapano AL: Activation of lipoprotein lipase by apolipoprotein C-II is modulated by the COOH terminal region of apolipoprotein C-III. Chem Phys Lipids 45: 39–47, 1987
    OpenUrlCrossRefPubMed
  72. ↵
    Atger V, Beyne P, Frommherz K, Roullet JB, Drueke T: Presence of Apo B48, and relative Apo CII deficiency and Apo CIII enrichment in uremic very-low density lipoproteins Ann Biol Clin (Paris) 47: 497–501, 1989
    OpenUrlPubMed
  73. ↵
    Shoji T, Nishizawa Y, Kawagishi T, Kawasaki K, Taniwaki H, Tabata T, Inoue T, Morii H: Intermediate-density lipoprotein as an independent risk factor for aortic atherosclerosis in hemodialysis patients. J Am Soc Nephrol 9: 1277–1284, 1998
    OpenUrlAbstract
  74. ↵
    Vaziri ND, Liang K: Down-regulation of tissue lipoprotein lipase expression in experimental chronic renal failure. Kidney Int; 50: 1928–1935, 1996
    OpenUrlCrossRefPubMed
  75. ↵
    Karpe F, Boquist S, Tang R, Bond GM, de Faire U, Hamsten A: Remnant lipoproteins are related to intima-media thickness of the carotid artery independently of LDL cholesterol and plasma triglycerides. J Lipid Res 42: 17–21, 2001
    OpenUrlAbstract/FREE Full Text
  76. ↵
    McNamara JR, Shah PK, Nakajima K, Cupples LA, Wilson PW, Ordovas JM, Schaefer EJ: Remnant-like particle (RLP) cholesterol is an independent cardiovascular disease risk factor in women: Results from the Framingham heart study. Atherosclerosis 154: 229–236, 2001
    OpenUrlCrossRefPubMed
  77. ↵
    Hirany S, O’Byrne D, Devaraj S, Jialal I: Remnant-like particle-cholesterol concentrations in patients with type 2 diabetes mellitus and end-stage renal disease. Clin Chem May 46: 667–672, 2000
    OpenUrl
  78. ↵
    Joven J, Simo JM, Vilella E, Camps J, Espinel E, Villabona C: Accumulation of atherogenic remnants and lipoprotein(a) in the nephrotic syndrome: Relation to remission of proteinuria. Clin Chem 41: 908–913, 1995
    OpenUrlAbstract/FREE Full Text
  79. ↵
    Kaysen GA, Mehendru L, Pan XM, Staprans I: Both peripheral chylomicron catabolism and hepatic uptake of remnants are defective in nephrosis. Am J Physiol 263: F335–F341, 1992.
  80. ↵
    Park SY, Song CY, Kim BC, : Angiotensin II mediates LDL-induced superoxide generation in mesangial cells. Am J Physiol Renal Physiol 285: F909–F915, 2003
    OpenUrlCrossRefPubMed
  81. ↵
    Paultre F, Pearson TA, Weil HF, Tuck CH, Myerson M, Rubin J, Francis CK, Marx HF, Philbin EF, Reed RG, Berglund L: High levels of lp(a) with a small apo(a) isoform are associated with coronary artery disease in African American and white men. Arterioscler Thromb Vasc Biol 20: 2619–2624, 2000
    OpenUrlAbstract/FREE Full Text
  82. ↵
    Dahlen GH, Srinivasan SR, Stenlund H, Wattigney WA, Wall S, Berenson GS: The importance of serum lipoprotein (a) as an independent risk factor for premature coronary artery disease in middle-aged black and white women from the United States. J Intern Med 244: 417–424, 1998
    OpenUrlCrossRefPubMed
  83. ↵
    Carstens ME, Burgess LJ, Taljaard JJ: A simultaneous study of the metabolism of apolipoprotein B and albumin in nephrotic patients. Kidney Int 54: 2064–2080, 1998
    OpenUrlCrossRefPubMed
  84. ↵
    Geethanjali FS, Luthra K, Lingenhel A, Kanagasaba-Pathy AS, Jacob J, Srivastava LM, Vasisht S, Kraft HG, Utermann G: Analysis of the apo(a) size polymorphism in Asian Indian populations: association with Lp(a) concentration and coronary heart disease. Atherosclerosis 169: 121–130, 2003
    OpenUrlCrossRefPubMed
  85. ↵
    Kronenberg F, Kuen E, Ritz E, Junker R, Konig P, Kraatz G, Lhotta K, Mann JF, Muller GA, Neyer U, Riegel W, Reigler P, Schwenger V, Von Eckardstein A: Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure. J Am Soc Nephrol 11: 105–115, 2000
    OpenUrlAbstract/FREE Full Text
  86. ↵
    Sechi LA, Zingaro L, Catena C, Perin A, De Marchi S, Bartoli E: Lipoprotein(a) and apolipoprotein(a) isoforms and proteinuria in patients with moderate renal failure. Kidney Int 56: 1049–1057, 1999
    OpenUrlCrossRefPubMed
  87. ↵
    Wanner C, Rader D, Bartens W, Kramer J, Brewer HB, Schollmeyer P, Wieland H: Elevated plasma lipoprotein(a) in patients with the nephrotic syndrome. Ann Intern Med 119: 263–269, 1993
    OpenUrlCrossRefPubMed
  88. ↵
    De Sain-Van Der Velden MG, Reijngoud DJ, Kaysen GA, Gadellaa MM, Voorbij H, Stellaard F, Koomans HA, Rabelink TJ: Evidence for increased synthesis of lipoprotein(a) in the nephrotic syndrome. J Am Soc Nephrol 9: 1474–1481, 1998Aug.
    OpenUrlAbstract
  89. ↵
    Keane WF: Proteinuria: Its clinical importance and role in progressive renal disease. Am J Kid Dis 35: S97–S105, 2000
    OpenUrlPubMed
  90. ↵
    Cirillo M, Stellato D, Laurenzi M, Panarelli W, Zanchetti A, De Santo NG: Pulse pressure and isolated systolic hypertension: association with microalbuminuria. The GUBBIO Study Collaborative Research Group. Kidney Int 58: 1211–1218, 2000
    OpenUrlCrossRefPubMed
  91. ↵
    Cirillo M, Senigalliesi L, Laurenzi M, Alfieri R, Stamler J, Stamler R, Panarelli W, De Santo NG: Microalbuminuria in nondiabetic adults: Relation of blood pressure, body mass index, plasma cholesterol levels, and smoking: The Gubbio Population Study. Arch Intern Med 158: 1933–1939, 1998
    OpenUrlCrossRefPubMed
  92. ↵
    Jensen JS, Feldt-Rasmussen B, Strandgaard S, Schroll M, Borch-Johnsen K: Arterial hypertension, microalbuminuria, and risk of ischemic heart disease. Hypertension 35: 898–903, 2000
    OpenUrlAbstract/FREE Full Text
  93. ↵
    Bianchi S, Bigazzi R, Campese VM: Microalbuminuria in essential hypertension: significance, pathophysiology, and therapeutic implications. Am J Kidney Dis 34: 973–995, 1999
    OpenUrlCrossRefPubMed
  94. ↵
    Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM: Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. J Am Soc Nephrol 12: 1315–1325, 2001
    OpenUrlFREE Full Text
  95. ↵
    Hasdan G, Benchetrit S, Rashid G, Green J, Bernheim J, Rathaus M: Endothelial dysfunction and hypertension in 5/6 nephrectomized rats are mediated by vascular superoxide Kidney Int 61: 586–590, 2002
    OpenUrlCrossRefPubMed
  96. ↵
    Rodriquez-Puyol M, Griera-Merino M, Perez-Rivero G, Diez-Marques ML, Ruiz-Torres MP, Rodriguez-Puyol D: Angiotensin II induces a rapid and transient increase of reactive oxygen species. Antioxid Redox Signal 4: 869–875, 2002
    OpenUrlCrossRefPubMed
  97. ↵
    de Gasparo M: Antiogensin and nitric oxide interaction. Heart Fail Rev 7: 347–358, 2000
  98. ↵
    Gryglewski RJ, Palmer RM, Moncada S: Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature 320: 454–456, 1986
    OpenUrlCrossRefPubMed
  99. ↵
    Luchtefeld M, Drexler H, Schieffer B: 5-Lipoxygenase is involved in the angiotensin II-induced NAD(P)H-oxidase activation. Biochem Biophys Res Commun 308: 668–672, 2003
    OpenUrlCrossRefPubMed
  100. ↵
    Chade AR, Rodriguez-Porcel M, Grande JP, Krier JD, Lerman A, Romero JC, Napoli C, Lerman LO: Distinct renal injury in early atherosclerosis and renovascular disease. Circulation 106: 1165–1171, 2002
    OpenUrlAbstract/FREE Full Text
  101. ↵
    Sigmon DH, Beierwaltes WH: Renal nitric oxide and angiotensin II interaction in renovascular hypertension. Hypertension 22: 237–242, 1993
    OpenUrlAbstract/FREE Full Text
  102. ↵
    Higashi Y, Sasaki S, Nakagawa K, Matsuura H, Oshima T, Chayama K: Endothelial function and oxidative stress in renovascular hypertension. N Engl J Med 346: 1954–1962, 2002
    OpenUrlCrossRefPubMed
  103. ↵
    Chamseddine AH, Miller Jr FJ. gp91phox contributes to NADPH oxidase activity in aortic fibroblasts, but not smooth muscle cells. J Physiol Heart Circ PhysiolJul 10 2003[Epub ahead of print]
  104. ↵
    Touyz RM, Chen X, Tabet F, Yao G, He G, Quinn MT, Pagano PJ, Schiffrin EL: Expression of a functionally active gp91phox-containing neutrophil-type NAD(P)H oxidase in smooth muscle cells from human resistance arteries: regulation by angiotensin II. Circ Res 90: 1205–1213, 2002
    OpenUrlAbstract/FREE Full Text
  105. ↵
    Lassegue B, Clempus RE: Vascular NAD(P)H oxidases: Specific features, expression, and regulation. Am J Physiol Regul Integr Comp Physiol 285: R277–297, 2003
    OpenUrlCrossRefPubMed
  106. ↵
    Vaziri ND, Dicus M, Ho ND, Boroujerdi-Rad L, Sindhu RK: Oxidative stress and dysregulation of superoxide dismutase and NADPH oxidase in renal insufficiency. Kidney Int 63: 179–185, 2003
    OpenUrlCrossRefPubMed
  107. ↵
    Cheng G, Cao Z, Xu X, van Meir EG, Lambeth JD: Homologs of gp91phox: cloning and tissue expression of Nox3, Nox4, and Nox5. Gene 269: 131–140, 2001
    OpenUrlCrossRefPubMed
  108. ↵
    Shiose A, Kuroda J, Tsuruya K, Hirai M, Hirakata H, Naito S, Hattori M, Sakaki Y, Sumimoto H: A novel superoxide-producing NAD(P)H oxidase in kidney. J Biol Chem 276: 1417–1423, 2001
    OpenUrlAbstract/FREE Full Text
  109. ↵
    Geiszt M, Kopp JB, Varnai P, Leto TL: Identification of renox, an NAD(P)H oxidase in kidney. Proc Natl Acad Sci U S A 97: 8010–8014, 2000
    OpenUrlAbstract/FREE Full Text
  110. ↵
    Suh YA, Arnold RS, Lassegue B, Shi J, Xu X, Sorescu D, Chung AB, Griendling KK, Lambeth JD: Cell transformation by the superoxide-generating oxidase Mox1. Nature 401: 79–82, 1999
    OpenUrlCrossRefPubMed
  111. ↵
    Sorescu D, Weiss D, Lassegue B, Clempus RE, Szocs K, Sorescu GP, Valppu L, Quinn MT, Lambeth JD, Vega JD, Taylor WR, Griendling KK: Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation 105: 1429–1435, 2002
    OpenUrlAbstract/FREE Full Text
  112. ↵
    Szocs K, Lassegue B, Sorescu D, Hilenski LL, Valppu L, Couse TL, Wilcox JN, Quinn MT, Lambeth JD, Griendling KK: Upregulation of Nox-based NAD(P)H oxidases in restenosis after carotid injury. Arterioscler Thromb Vasc Biol 22: 21–27, 2002
    OpenUrlAbstract/FREE Full Text
  113. ↵
    Sorescu D, Szocs K, Griendling KK: NAD(P)H oxidases and their relevance to atherosclerosis. Trends Cardiovasc Med 11: 124–131, 2001
    OpenUrlCrossRefPubMed
  114. ↵
    Lassegue B, Sorescu D, Szocs K, Yin Q, Akers M, Zhang Y, Grant SL, Lambeth JD, Griendling KK: Novel gp91(phox) homologues in vascular smooth muscle cells : nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways. Circ Res 88: 888–894, 2001
    OpenUrlAbstract/FREE Full Text
  115. ↵
    Gorin Y, Ricono JM, Kim NH, Bhandari B, Choudhury GG, Abboud HE: Nox4 mediates angiotensin II-induced activation of Akt/protein kinase B in mesangial cells. Am J Physiol Renal Physiol 285: F219–F229, 2003
    OpenUrlCrossRefPubMed
  116. ↵
    Mollnau H, Wendt M, Szocs K, Lassegue B, Schulz E, Oelze M, Li H, Bodenschatz M, August M, Kleschyov AL, Tsilimingas N, Walter U, Forstermann U, Meinertz T, Griendling K, Munzel T: Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res 90: E58–E65, 2002
  117. ↵
    Wingler K, Wunsch S, Kreutz R, Rothermund L, Paul M, Schmidt HH: Upregulation of the vascular NAD(P)H-oxidase isoforms Nox1 and Nox4 by the renin-angiotensin system in vitro and in vivo. Free Radic Biol Med 31: 1456–1464, 2001
    OpenUrlCrossRefPubMed
  118. ↵
    Daugherty A, Dunn JL, Rateri DL, Heinecke JW: Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J Clin Invest 94: 437–444, 1994
  119. ↵
    Zhang R, Brennan ML, Fu X, Aviles RJ, Pearce GL, Penn MS, Topol EJ, Sprecher DL, Hazen SL: Association between myeloperoxidase levels and risk of coronary artery disease. JAMA 286: 2136–2142, 2001
    OpenUrlCrossRefPubMed
  120. ↵
    Pecoits-Filho R, Stenvinkel P, Marchlewska A, et al: A functional variant of the myeloperoxidase gene is associated with cardiovascular disease in end-stage renal disease patients. Kidney Int Suppl 84: 172–176, 2003
    OpenUrlCrossRef
  121. ↵
    Makela R, Karhunen PJ, Kunnas TA, Ilveskoski E, Kajander OA, Mikkelsson J, Perola M, Penttila A, Lehtimaki T: Myeloperoxidase gene variation as a determinant of atherosclerosis progression in the abdominal and thoracic aorta: an autopsy study. Lab Invest 83: 919–25, 2003
    OpenUrlCrossRefPubMed
  122. ↵
    Kutter D, Devaquet P, Vanderstocken G, Paulus JM, Marchal V, Gothot A: Consequences of total and subtotal myeloperoxidase deficiency: risk or benefit ? Acta Haematol 104: 10–15, 2000
    OpenUrlCrossRefPubMed
  123. ↵
    Podrez EA, Schmitt D, Hoff HF, Hazen SL: Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro. J Clin Invest 103: 1547–60, 1999
    OpenUrlCrossRefPubMed
  124. ↵
    Savenkova ML, Mueller DM, Heinecke JW: Tyrosyl radical generated by myeloperoxidase is a physiological catalyst for the initiation of lipid peroxidation in low density lipoprotein. J Biol Chem 269: 20394–400, 1994
    OpenUrlAbstract/FREE Full Text
  125. ↵
    Hazen SL, Heinecke JW: 3-Chlorotyrosine, a specific marker of myeloperoxidase-catalyzed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima. J Clin Invest 99: 2075–2081, 1997
    OpenUrlCrossRefPubMed
  126. ↵
    Eiserich JP, Hristova M, Cross CE, Jones AD, Freeman BA, Halliwell B, van der Vliet A: Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 391: 393–397, 1998
    OpenUrlCrossRefPubMed
  127. ↵
    Abu-Soud HM, Hazen SL: Nitric oxide modulates the catalytic activity of myeloperoxidase. J Biol Chem 275: 5425–5430, 2000
    OpenUrlAbstract/FREE Full Text
  128. ↵
    Abu-Soud HM, Hazen SL: Nitric oxide is a physiological substrate for mammalian peroxidases. J Biol Chem 275: 37524–37532, 2000
    OpenUrlAbstract/FREE Full Text
  129. ↵
    Eiserich JP, Baldus S, Brennan ML, Ma W, Zhang C, Tousson A, Castro L, Lusis AJ, Nauseef WM, White CR, Freeman BA: Myeloperoxidase, a leukocyte-derived vascular NO oxidase. Science 296: 2391–2394, 2002
    OpenUrlAbstract/FREE Full Text
  130. ↵
    Baldus S, Eiserich JP, Mani A, Castro L, Figueroa M, Chumley P, Ma W, Tousson A, White CR, Bullard DC, Brennan ML, Lusis AJ, Moore KP, Freeman BA: Endothelial transcytosis of myeloperoxidase confers specificity to vascular ECM proteins as targets of tyrosine nitration. J Clin Invest 108: 1759–1770, 2001
    OpenUrlCrossRefPubMed
  131. ↵
    Thuraisingham RC, Yaqoob MM: Oxidative consumption of nitric oxide: A potential mediator of uremic vascular disease. Kidney Int Suppl 84: 29–32, 2003
    OpenUrlCrossRef
  132. ↵
    Baldus S, Eiserich JP, Brennan ML, Jackson RM, Alexander CB, Freeman BA: Spatial mapping of pulmonary and vascular nitrotyrosine reveals the pivotal role of myeloperoxidase as a catalyst for tyrosine nitration in inflammatory diseases. Free Radic Biol Med 33: 1010–1019, 2002
    OpenUrlCrossRefPubMed
  133. ↵
    Hazen SL, Zhang R, Shen Z, Wu W, Podrez EA, MacPherson JC, Schmitt D, Mitra SN, Mukhopadhyay C, Chen Y, Cohen PA, Hoff HF, Abu-Soud HM: Formation of nitric oxide-derived oxidants by myeloperoxidase in monocytes: pathways for monocyte-mediated protein nitration and lipid peroxidation in vivo. Circ Res 85: 950–958, 1999
    OpenUrlAbstract/FREE Full Text
  134. ↵
    Podrez EA, Schmitt D, Hoff HF, Hazen SL: Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro. J Clin Invest 103: 1547–1560, 1999
  135. ↵
    Shishehbor MH, Aviles RJ, Brennan ML, Fu X, Goormastic M, Pearce GL, Gokce N, Keaney JF Jr, Penn MS, Sprecher DL, Vita JA, Hazen SL: Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy. JAMA 289: 1675–1680, 2003
    OpenUrlCrossRefPubMed
  136. ↵
    Himmelfarb J, McMenamin ME, Loseto G, Heinecke JW: Myeloperoxidase-catalyzed 3-chlorotyrosine formation in dialysis patients. Free Radic Biol Med 31: 1163–1169, 2001
    OpenUrlCrossRefPubMed
  137. ↵
    Baldus S, Heeschen C, Meinertz T, et al. Myeloperoxidase Serum Levels Predict Risk in Patients With Acute Coronary Syndromes. Circulation[Epub ahead of print], 2003.
  138. ↵
    Kuvin JT, Patel AR, Sidhu M, Rand WM, Sliney KA, Pandian NG, Karas RH: Relation between high-density lipoprotein cholesterol and peripheral vasomotor function. Am J Cardiol 92: 275–279, 2003
    OpenUrlCrossRefPubMed
  139. ↵
    Ramet ME, Ramet M, Lu Q, Nickerson M, Savolainen MJ, Malzone A, Karas RH: High-density lipoprotein increases the abundance of eNOS protein in human vascular endothelial cells by increasing its half-life. J Am Coll Cardiol 41: 2288–2297, 2003
    OpenUrlCrossRefPubMed
  140. ↵
    Bisoendial RJ, Hovingh GK, Levels JH, Lerch PG, Andresen I, Hayden MR, Kastelein JJ, Stroes ES.: Restoration of endothelial function by increasing high-density lipoprotein in subjects with isolated low high-density lipoprotein. Circulation 107: 2944–2948, 2003
    OpenUrlAbstract/FREE Full Text
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Journal of the American Society of Nephrology: 15 (3)
Journal of the American Society of Nephrology
Vol. 15, Issue 3
1 Mar 2004
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The Role of Oxidative Stress–Altered Lipoprotein Structure and Function and Microinflammation on Cardiovascular Risk in Patients with Minor Renal Dysfunction
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The Role of Oxidative Stress–Altered Lipoprotein Structure and Function and Microinflammation on Cardiovascular Risk in Patients with Minor Renal Dysfunction
George A. Kaysen, Jason P. Eiserich
JASN Mar 2004, 15 (3) 538-548; DOI: 10.1097/01.ASN.0000111744.00916.E6

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The Role of Oxidative Stress–Altered Lipoprotein Structure and Function and Microinflammation on Cardiovascular Risk in Patients with Minor Renal Dysfunction
George A. Kaysen, Jason P. Eiserich
JASN Mar 2004, 15 (3) 538-548; DOI: 10.1097/01.ASN.0000111744.00916.E6
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    • Inflammation Mortality and Malnutrition in Advancing Renal Failure
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More in this TOC Section

  • Polycystic Kidney Disease
  • Genotype–Phenotype Correlations in Autosomal Dominant and Autosomal Recessive Polycystic Kidney Disease
  • Role of Primary Cilia in the Pathogenesis of Polycystic Kidney Disease
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  • Indoxyl Sulfate-Induced Endothelial Dysfunction in Patients with Chronic Kidney Disease via an Induction of Oxidative Stress
  • Impact of Age and Overt Proteinuria on Outcomes of Stage 3 to 5 Chronic Kidney Disease in a Referred Cohort
  • Relationships among Renal Function Loss within the Normal to Mildly Impaired Range, Arterial Stiffness, Inflammation, and Oxidative Stress
  • Chronic Kidney Disease: Effects on the Cardiovascular System
  • Kidney in Early Atherosclerosis
  • Reduced Agonist-Induced Endothelium-Dependent Vasodilation in Uremia Is Attributable to an Impairment of Vascular Nitric Oxide
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