Next Article in Journal
Probiotic Microorganisms Inhibit Epithelial Cell Internalization of Botulinum Neurotoxin Serotype A
Next Article in Special Issue
High Uric Acid Ameliorates Indoxyl Sulfate-Induced Endothelial Dysfunction and Is Associated with Lower Mortality among Hemodialysis Patients
Previous Article in Journal
QuEChERS Purification Combined with Ultrahigh-Performance Liquid Chromatography Tandem Mass Spectrometry for Simultaneous Quantification of 25 Mycotoxins in Cereals
Previous Article in Special Issue
Fibroblast Growth Factor-23—A Potential Uremic Toxin
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Modified Lipids and Lipoproteins in Chronic Kidney Disease: A New Class of Uremic Toxins

CarMeN, INSERM U1060, INRA U1397, INSA de Lyon, Université Claude Bernard Lyon 1, University of Lyon, F-69621 Villeurbanne, France
Hospices Civils de Lyon, Department of Nephrology, Hôpital E. Herriot, F-69003 Lyon, France
Author to whom correspondence should be addressed.
Toxins 2016, 8(12), 376;
Received: 3 November 2016 / Revised: 9 December 2016 / Accepted: 12 December 2016 / Published: 16 December 2016
(This article belongs to the Special Issue Novel Issues in Uremic Toxicity)


Chronic kidney disease (CKD) is associated with an enhanced oxidative stress and deep modifications in lipid and lipoprotein metabolism. First, many oxidized lipids accumulate in CKD and were shown to exert toxic effects on cells and tissues. These lipids are known to interfere with many cell functions and to be pro-apoptotic and pro-inflammatory, especially in the cardiovascular system. Some, like F2-isoprostanes, are directly correlated with CKD progression. Their accumulation, added to their noxious effects, rendered their nomination as uremic toxins credible. Similarly, lipoproteins are deeply altered by CKD modifications, either in their metabolism or composition. These impairments lead to impaired effects of HDL on their normal effectors and may strongly participate in accelerated atherosclerosis and failure of statins in end-stage renal disease patients. This review describes the impact of oxidized lipids and other modifications in the natural history of CKD and its complications. Moreover, this review focuses on the modifications of lipoproteins and their impact on the emergence of cardiovascular diseases in CKD as well as the appropriateness of considering them as actual mediators of uremic toxicity.

1. Introduction

Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease as these patients develop accelerated atherosclerosis [1,2,3,4,5,6,7]. The main mechanisms underlying this increased CV risk in this population are oxidative stress [8], accumulation of uremic toxins [9], dyslipidemia and phosphocalcic metabolism disorders. Enhanced oxidative stress and uremic environment can strongly modify circulating lipids and lipoproteins leading to profound alterations of their biological properties. Indeed, lipid peroxidation by-products such as malondialdehyde (MDA) are increased and are negatively correlated with the glomerular filtration rate in CKD. Large amounts of oxidized lipids, such as F2α-isoprostanes are associated with CKD progression [10].
Renal dysfunction is also associated with many perturbations in lipoprotein metabolism leading to dyslipidemia and accumulation of atherogenic particles [11]. Lipoprotein metabolism is complex and is associated with multisite regulations (involving liver, colon, plasma, macrophages and endothelial cells) that can be individually affected by CKD. Post-translational modifications such as carbamylation, glycation or oxidation particularly affect circulating lipoproteins (both on their protidic or lipidic fraction) leading to altered behaviors in the cardiovascular system. These particular modifications of lipid metabolism in CKD are a novel way of explaining the failure of statins in the prevention of cardiovascular diseases in hemodialysis patients [12,13].
According to the European Uremic Toxin Work Group (EuTox,, uremic toxins are defined as accumulated solutes, normally excreted by the kidneys, that interact negatively with biological functions [9]. Even if some lipids and lipoproteins are neither excreted by the kidneys in normal conditions nor accumulated in CKD, their modifications and altered metabolism unambiguously change their interactions with biological functions and especially cardiovascular physiology. This review will explain why in CKD, some lipids and lipoproteins can be considered as uremic toxins.

2. Uremic Lipoproteins, Evidences of Toxicity

2.1. Dyslipidemia in CKD, A Unique Phenotype

CKD is associated with dyslipidemia associating hypertriglyceridemia, elevated LDL cholesterol, an accumulation of ApoB containing lipoproteins, increased concentrations of lipoprotein(a) particles and low HDL levels [14,15]. Many recent reviews analyzed this dyslipidemia in detail [11,14,16,17,18]. Dyslipidemia in CKD is unique for many reasons. First, cardiovascular (CV) diseases are the leading cause of mortality in CKD patients. Number of cardiovascular events has been strongly correlated with GFR decline [1] and despite constant improvement of renal suppletion therapies, such as hemodialysis, this cardiovascular mortality remains at the forefront [19]. Traditional strategies for cardiovascular prevention, including the prescription of statins, failed in some CKD populations. Even if post hoc analysis of large prospective studies sketched a potential benefit in early stages of CKD [20,21,22], this positive effect is diminished in advanced stages (4 and 5), either on intima/media thickness [23] or cardiovascular mortality and related events, as shown by 4D [12] and AURORA [13] studies. Recent meta-analysis from the Cochrane Collaboration confirmed this observation in dialysis patients [24] but also suggested its interest for CKD patients who did not require hemodialysis [25] or transplant recipients [26]. However, beyond its effects on CV mortality, statins exhibited beneficial effects for impeding renal failure progression [27,28]. Indeed, statins can modulate intracellular pathways of inflammatory and fibrogenic responses and inhibit the proliferation of mesangial and renal tubular epithelial cells [27,29]. Moreover, recent data corroborate their importance in lipid control to prevent the progression of CKD. The increase of one standard deviation of TG level and TG/HDL-cholesterol ratio was correlated with an increased risk of developing CKD. Additionally, increases of HDL-cholesterol level, LDL-cholesterol/ApoB and HDL-cholesterol/ApoAI ratios seemed to be protective [30].

2.2. Very Low Density, Intermediate Density Lipoproteins (VLDL, IDL) and Chylomicrons

An earlier report suggested that triglyceride-rich lipoproteins (TGRL), including chylomicrons, VLDL and their remnants, accumulate in CKD [31]. Okubo et al. found that ApoB48 levels, composed of chylomicrons and their remnants, are inversely correlated with GFR levels and increased proteinuria [32]. ApoB48 levels were also found elevated in ESRD diabetic patients [33]. In transplantation, ApoB gene polymorphism was associated with poor cardiovascular outcomes in patients presenting deletion of a part of ApoB signal peptide [34].
TGRL, chylomicrons and VLDL, deliver lipids to peripheral cells. After delivering their triglycerides cargos, these lipoproteins are converted into IDL and LDL or are removed by the liver. Chylomicrons and nascent VLDL need apolipoprotein C and E (ApoC, E) for their maturation. These proteins are delivered by HDL-2. In CKD, HDL metabolism is impaired and HDL-3 are not maturated into HDL-2 due to a lecithin-cholesterol acyl-transferase (LCAT) deficiency [35,36,37]. ApoE and ApoC are necessary for binding and activation of lipoprotein lipase (LPL) respectively and such defect leads to a reduced release of triglycerides in peripheral tissues and leads to an accumulation of TGRL. Moreover, significant evidence showed that peripheral LPL is lacking in CKD [38,39,40].
In normal conditions, VLDL and chylomicrons are transformed into IDL and chylomicrons remnants after lipolysis in peripheral tissue. Then, part of IDL and remnants are removed by the liver via LDL receptor protein (LRP) that has been found to be downregulated in CKD [41]. The other part of IDL is transformed into LDL by the removal of their triglycerides by the hepatic lipase and enrichment in cholesteryl esters from HDL-2 by cholesteryl-ester transfer protein (CETP). As previously described, lack of HDL-2 impedes this phenomenon and leads to the accumulation of highly pro-atherogenic IDLs [42]. Moreover, there is a downregulation of hepatic lipase expression in CKD [43,44,45]. A part of VLDL is removed by their binding on VLDL-receptor in myocytes and adipocytes. The expression of this receptor is also down-regulated in CKD [46,47] (Figure 1).

2.3. Low Density Lipoproteins (LDL)

As LDL remains the main target of cardiovascular prevention strategies, their metabolism in CKD was the focus of numerous works. Patients in early stages of CKD commonly exhibit elevated LDL-cholesterol level [48]. Uncommonly, ESRD patients and particularly HD patients have normal or reduced LDL cholesterol and total cholesterol levels and interestingly, an inversed association has been found between cholesterol level and mortality in those patients [49,50,51]. Beyond LDL-cholesterol level itself, CKD leads to various structural modifications of lipids and proteins that make up LDL particles.
Oxidized-LDLs (oxLDL) result from the action of enzymatic and non-enzymatic pathways of oxidative stress. Several levels of oxidation from electronegative (minimally modified) to extensively oxidized LDL can coexist in the bloodstream and lead to the activation of several pathways involved in atherosclerosis through their binding to scavenger receptors [52]. In CKD, there is substantial evidence that those oxLDL accumulate, especially in HD patients [53,54,55,56]. oxLDL concentration was shown to increase after an HD session [56]. Moreover, oxLDL are correlated with left ventricular hypertrophy in pediatric HD patients [57] and with the intensity of peripheral arterial disease [58]. Oxidized epitopes of LDL can activate immunity and then lead to the formation of antibodies directed against oxLDL. OxLDL/antibodies against oxLDL ratio was also correlated with carotid atherosclerosis and cardiovascular events in HD patients [59].
As stated above, CKD is associated with an enhanced MPO activity that plays a substantial role in the generation of post translational modification derived products (PTMDPs). Indeed, serum MPO levels have been correlated with mortality in an HD cohort [60] and with oxLDL levels [61]. MPO can promote LDL modifications through several mechanisms. First, reaction between HOCl generated by MPO and tyrosine residues of ApoB100 creates 3-chlorotyrosine, found in atherosclerotic lesions [62] and well-known for their pro-atherogenic properties through their binding with lectin-like oxidized LDL receptor 1 (LOX-1) [52,63]. Interestingly, 3-chlorotyrosine levels were found to be higher in HD patients compared to healthy volunteers [64]. Secondly, MPO can also catalyze the generation of reactive nitrogen species (RNS) and create pro-atherogenic nitrosilated-LDL [65]. Thirdly, MPO catalyzed the addition of thiocyanate to the LDL (derived from the decomposition of urea) and leads to the formation of carbamylated-LDL (cLDL) [66,67]. These cLDL have potent pro-atherogenic effects such as the transformation of macrophages into foam cells [68] through their binding to the pro-atherogenic CD36 receptor [69] (upregulated in CKD [70]) and associated with endothelial toxicity [71,72] and platelet aggregation [73] through LOX-1 [74]. cLDL levels are raised by chronic uremia and were linked with atherosclerosis in CKD [75,76].

2.4. High Density Lipoproteins (HDL)

Accelerated atherosclerosis in CKD patients and relative failure of statins in advanced stages of CKD demonstrate that traditional cardiovascular risk factors are not at the forefront. A recent focus on HDL quality rather than quantity revealed a potential role of HDL dysfunction in the set-up of cardiovascular disease in CKD.
HDL metabolism is impaired in CKD. In normal physiological conditions, ApoA1 and A2 are released into the circulation by the liver. These proteins are loaded with cholesterol and phospholipids to form nascent HDL. In CKD, ApoA1 and A2 levels are decreased [77,78]. Then, nascent HDL binds to the ABCA-1 receptor on circulating macrophages and activates cholesterol ester hydrolase allowing their loading with cholesterol. AcetylCoA acyl transferase (ACAT) limits this reverse efflux of cholesterol from macrophages by catalyzing the esterification of intracellular cholesterol. In CKD, modifications of ApoA1 limit HDL binding on macrophages [79] and upregulation of hepatic ACAT-2 in CKD [37,80] participates in the observed impaired cholesterol efflux. After its uptake, free cholesterol is esterified into cholesteryl esters by lecithin cholesterol acyl transferase (LCAT), which is transferred to the core of the lipoprotein. Nascent HDL are then transformed into discoid HDL-3 and then into spherical HDL-2 enriched in cholesterol. In CKD, LCAT level and activity are impaired [35,36,37], leading to the accumulation of HDL-3 and reduced level of HDL-2, especially in HD patients [81]. The latter, in normal conditions, enrich VLDL and chylomicrons with ApoC and E, essential for their normal metabolism (see above). Moreover, cholesterol ester transfer protein (CETP) transfers triglycerides in exchange for cholesterol from TGRL to HDL and LDL resulting in TG-enriched HDL-2 and LDL species. There is no evidence of deficit of CETP in CKD but as HDL-2 level is lowered, its activity may suffer. Then, HDL is cleared from their cholesterol content by their binding with hepatic SR-B1 receptor and the cycle starts again (Figure 1).
Beyond a dysfunctional metabolism, HDL is also a major target for oxidative stress and post-translational modifications. As stated above, CKD leads to a modification of ApoA1, impairing its binding on ABCA-1 [79]. As MPO activity is enhanced in CKD, MPO-modified ApoA1 results in decreased reverse cholesterol efflux and a reduced binding with ABCA-1 receptor [82,83]. Moreover, MPO leads to the increased formation of 3-chlorotyrosine, an oxidation product of MPO, in HDL and impairs LCAT and paraoxonase activities and then anti-inflammatory proprieties of HDL [84]. MPO-modified HDL are also potentially involved in the generation of foam cells in atherosclerotic lesions through the activation of SR-B1 in macrophages [85] and increase of pro-inflammatory secretion activity and adhesion molecules expression in endothelial cells [86]. These MPO-modified HDL exhibit impaired anti-apoptotic properties in endothelial cells [86]. Interestingly, high levels of oxidized HDL are correlated to increased cardiovascular mortality in HD patients [87] as well as to HDL anti-inflammatory index elaborated by Kalantar-Zadeh et al. [88]. Recent analysis of HDL proteome showed an association of acute phase protein serum amyloid A with CKD-HDL that may participate in impaired biological functions [89,90].
Normal HDL are known to be anti-atherogenic thanks to several properties [17]. First, HDL induces a reverse cholesterol transport from circulating macrophages. This property is well known to be atheroprotective [91]. In CKD, this function is dramatically impaired as CKD-HDL have reduced capacities of inducing this efflux [81,89,92,93,94]. Even in a pediatric CKD cohort, the deeper was CKD, the lower was the cholesterol efflux [95]. Moreover, restoration of renal function by transplantation is associated with an enhancement of these capacities without retrieving normal-HDL levels [92]. Nevertheless, Kopecky et al. sowed the seeds of doubt by showing that cholesterol efflux levels capacity in diabetic HD patients is not a prognostic marker of cardiovascular events [96].
Secondly, normal HDL increases the production of nitric oxide through the activation of eNOS in endothelial cells resulting in a vasorelaxant phenotype. In CKD, evidences show that HDL from CKD children lose their protective effect as the production of NO by endothelial cells is significantly reduced with HDL [95]. CKD-HDL can probably induce the uncoupling of eNOS from endothelial cells as the superoxide production in endothelial cells is significantly enhanced with CKD-HDL [95].
Thirdly, normal HDL inhibits the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1), which prevent the attachment of circulating monocytes to endothelial cells. In CKD, HDL promotes an enhanced expression of VCAM-1 and ICAM-1 on endothelial cells [93,95]. Moreover, CKD-HDL upregulates the expression of pro-inflammatory mediators such as monocyte chemoattractant protein-1 (MCP-1), interleukin-1ß (IL-1ß) and tumor necrosis factor α (TNF-α) [93,94].
Normal HDL exhibit anti-apoptotic effects on endothelial cells through the downregulation of caspase-3 activity [97]. CKD-HDL inhibits endothelial cell proliferation [93]. Finally, normal HDL has anti-oxidative properties thanks to PON1 and GPX enzymes on its surface. PON1 was firstly recognized as a hydrolytic enzyme for various toxic organophosphates. Mainly expressed in the liver and the kidney, this enzyme exhibited anti-oxidant properties against lipid peroxidation as it binds to HDL and in a minor part to VLDL [98]. Thus, this enzyme is considered as the main anti-oxidant enzyme bound to HDL. PON1 activity is lowered in CKD [99,100,101]. GPX is another important anti-oxidant enzyme at HDL surface. Its activity and expression on HDL are lowered in CKD [35].

2.5. Lipoprotein A (Lp(a))

Lp(a) is composed of a LDL-like particle bound with an apolipoprotein(a) (Apo(a)) on lysine residues of ApoB100. Apo(a) is secreted by the liver and contains a repetition of kringle-IV units. Genetic variants of Lp(a) and its concentration have been deeply correlated with coronary heart disease and cardiovascular morbidity [102,103,104,105]. As its concentration is closely associated with OxPL/ApoB, Lp(a) may play a role in OxPL clearance even though its role(s) still remain unclear. Lp(a) levels were found to be risk predictors of all-cause mortality in HD patients [106]. Lp(a) accelerates atherosclerosis in a mouse model of CKD [107]. Moreover, Lp(a) clearance is partly done by the kidney explaining why its clearance is lowered in hemodialysis patients even if its generation does not seem to be higher than in healthy subjects [108]. However, in Tzanatos et al. study, Lp(a) levels seems to be increased after an HD session [109] while no change was found in Bossola et al. study [56]. As HD seems to be ineffective for Lp(a) clearance, it can explain higher levels in ESRD patients as its generation is not increased in these patients. Unlike hemodialysis, nephrotic syndrome exhibits enhanced secretion of Lp(a) by the liver [110]. In a nutshell, CKD exhibits higher levels of Lp(a) than in healthy subjects (Table 1) and it accumulates with CKD [111] severity while it decreases with renal transplantation [112], Lp(a) is a prototype candidate to be classified as a uremic toxin.

3. Oxidative Stress/Non-Oxidative Modifications of Lipids and Lipoproteins in CKD

3.1. Oxidative Stress, Lipid Peroxidation and Antioxidant Defenses

Oxidative stress is defined as a lopsided balance of the pro/anti-oxidant state in favor of the pro-oxidant [129]. The origin of this stress is the formation of reactive oxygen species (ROS) like superoxide anion O2•−, hydroxyl radical OH or hydrogen peroxide H2O2. Major part of reactive oxygen species in our organism is produced by the mitochondrial respiratory chain [130], the NADPH oxidase [131,132] and 5-lipooxygenase enzyme [133]. Other enzymes such as xanthine oxidase or NO synthase [134] can also provide ROS in pathological conditions. ROS, by many intertwined reactions, produce free radicals in the presence of transition metal ions (Fe2+, Cu2+) or carbon-composed molecules like proteins, nucleic acids or lipids. Nitric oxide (NO) can also yield free radicals often referred to as reactive nitrogen species (RNS). NO is generated by NO synthases and plays many roles in the regulation of vascular tone, permeability and platelet adhesion. NO can rapidly react with O2•− to generate a more oxidized form of a nitric product: the peroxinitric ion (ONOO). The latter can easily react with proteins, lipids or nucleic acids, resulting in oxidized or nitrosylated forms.
As previously described, lipids can be affected by oxidative stress. First step of lipid peroxidation is the reaction of a free radical with a poly-unsaturated fatty acid (L). This reaction results in the formation of a lipid radical L. This radical can react with oxygen and create lipid peroxyl radicals (LOO). From this point, LOO can react with other lipids and create new lipid radicals and lipid hydroperoxide (LOOH). The degradation of lipid hydroperoxide provides new lipid radicals (LO, LOO) and aldehydes as stable end-products of lipid peroxidation process (malondialdehyde or MDA, 4-OH-2,3-alkenals). F2α-isoprostanes are end-products from the oxidation of arachidonic acid (i.e., 20:4 (n-6)). These three end-products are routinely used for in vivo evaluation of lipid peroxidation level [135,136]. However, there are other products of lipid peroxidation such as oxysterols and oxidized phospholipids that play a substantial role in the onset and progression of atherosclerosis and lipid dysmetabolism [137].
Under physiologic conditions, there is a basal rate of production of ROS as well as a limited production of oxidized molecules [138]. Nevertheless, this production of oxidants is balanced by a complex pattern of antioxidant mechanisms that protect the cells and tissues from oxidative damages. The protection from the ROS damage is permitted by antioxidant enzymes such as superoxide dismutase (SOD) which catalyses the dismutation of O2•− into H2O2, glutathione peroxidase (GPX) or catalase, which detoxifies H2O2 and other hydroperoxide containing molecules. Non-enzymatic antioxidants include reduced glutathione (GSH), which allows the scavenging of OH and acts as a substrate for GPX as well as ascorbic and uric acids that are scavengers of OH, singlet O2 and peroxyls radicals. Ferritin, ceruleoplasmin, transferrin, lactoferrin and metallothionein can also be regarded as antioxidant proteins as they trap transition metal ions and prevent ROS formation from Fenton reaction [133]. To prevent lipid peroxidation, aforementioned antioxidant molecules act together with several liposoluble antioxidants such as tocopherols, ubiquinol, flavonoids and carotenoids. Moreover, the protein paraoxonase-1 (PON1) from HDL is a major anti-oxidant preventing lipoproteins from oxidation although its exact mechanism remains unclear [98]. Some molecules such as tocopherols or curcumin, are considered as chain-breaking antioxidants, corresponding with their ability to intercept intermediary radicals during the lipid peroxidation process and then break the oxidative chain. Finally, albumin can be considered as a major antioxidant protein of the plasma. In fact, serum albumin can bind various ligands such as copper, iron, long chains fatty acids (LCFA), poly-unsaturated fatty acids (PUFAs) and cholesterol and prevent them from oxidative modifications [139]. It can also bind bilirubin [140,141] and inhibit lipid peroxidation as well as prevent damages of α-tocopherol [142] and bind homocysteine. Albumin also contains a reduced cysteine residue (Cys34) which can scavenge hydroxyl radicals [143]. Due to the large amount of albumin in the plasma, it represents the largest amount of thiols available in the circulation [144]. Albumin also scavenges hypochlorous acid (HOCl) responsible for chlorination of proteins mediated by myeloperoxidase.

3.2. Oxidative Stress in CKD

Substantial literature is available about the enhanced oxidative stress in CKD [145,146,147,148,149,150,151,152,153,154]. The unbalanced pro-oxidative state appears almost at the onset of CKD and increases as the glomerular filtration rate (GFR) declines [8]. There are multiple reasons for this enhanced oxidative stress and they are often intertwined.
As we will discuss later, antioxidant defenses are lowered in CKD leading to a higher sensitivity to oxidative stress induced by classical cardiovascular risk factors (hypertension, advanced age, diabetes and obesity [155]). Indeed, hypertension is well known to be a major state of oxidative stress [156,157]. Upregulation of NADPH oxidase via the activation of renin-angiotensin system (RAS) is well-recognized as a major provider of ROS in hypertension [157,158,159]. In CKD, RAS has been directly linked with enhanced oxidative stress and CKD progression through the up-regulation of pro-oxidative pathways (NF-kB, NADPH oxidase, cyclooxygenase 2, 12-lipooxygenase) by angiotensin II and its binding to angiotensin-1 receptor [159].
Most antioxidant defenses are lowered in CKD. However, some controversies still exist as many studies produced conflicting results. Total antioxidant status is decreased in CKD [160,161]. Nevertheless, the large range of techniques used for this determination and the numerous confounding factors in CKD make it difficult to interpret [8,162]. The determination of Superoxide dismutase (SOD) activity is prototypical. Some studies found a decreased SOD activity in CKD patient [163,164] while others reported a normal level of activity [165]. Surprisingly, SOD activity was even found to have increased in CKD [166]. As there are several isoforms of SOD (cytosolic, mitochondrial and extra-cellular), assays are difficult to extrapolate between all the different studies. As a matter of fact, SOD activity seems to be correlated with CKD stage and its activity is restored by several interventions in CKD patients (erythropoietin, vitamin E supplementation and kidney transplantation) [167,168]. Similar contradictory observations were reported for catalase activity (e.g., either lowered [169], normal [165,170] or increased [160]). Glutathione activity and concentration are lowered in CKD and are correlated with uremic toxins’ concentrations [171,172] and glomerular filtration rate (GFR). PON1 activity is lowered in CKD [98,99,100]; however, further studies are needed to fully understand its implication on lipid dysmetabolism and lipoprotein dysfunction [97,173] associated with CKD.

3.3. Post-Translational Modification Derived Products (PTMDPs) of Lipoprotein and Covalent Modifications of Lipids

Proteins and lipids are especially prone to oxidation and their irreversible oxidative modifications lead to a profound alteration of their biological functions. Carbonylation is the addition of compounds made from glycation and lipid peroxidation onto proteins. These residues can react with lysine and arginine residues and then create advanced glycation end products [174] (AGEs) and advanced lipoxidation end products [175] (ALEs). Proteins can also be carbonyled by direct oxidation by ROS [176]. 3-desoxyglucosone, D-arabinose, glyoxal can react with proteins and create AGEs as pentosidine and carboxy-methyl-lysine. Lipid peroxides of polyunsaturated fatty acids (PUFAs) such as 4-hydroxy-2-nonenal (4-HNE) and 4-hydroxy-2-hexenal (4-HHE) can also react with lysine, cysteine and histidine residues of proteins and create ALEs (Figure 2).
AGEs and ALEs have several biological effects involved in atherosclerosis [177]. AGEs have significant effects on lipids as they can make LDL more prone to oxidative modifications [178], increase glycated-LDL uptake from macrophages by scavenger-receptors and accelerate the formation of foam cells [179]. ALEs also exhibit several pro-inflammatory effects and are involved in the progression of atherosclerosis [180]. Both AGEs and ALEs were reported to accumulate in CKD [181,182,183,184,185].
Carbamylation is the fixation of isocyanic acid, derived from the decomposition of urea on amine groups of proteins. Protein carbamylation is associated with cardiovascular disease [186], mortality in CKD [187,188] and can also affect lipoproteins [75] and promote atherosclerotic complications [68,189] (Figure 3).
Myeloperoxydase (MPO) activity contributes to the formation of chlorinated [64] and nitrosilated [65] proteins or lipids that are correlated with poor cardiovascular outcomes [62,190]. Its activity can also lead to the oxidation and modification of lipoproteins and especially the adduction of thiocyanate produced from the decomposition of urea [67]. In CKD and especially in hemodialysis, this activity is enhanced [60,61,191,192]. Wada et al. showed that MPO expression is associated with aortic stenosis in hemodialysis (HD) patients [193].

4. Oxidized Lipids in CKD: Evidences of Toxicity

4.1. Cholesterol and Oxysterols

Cholesterol is a major component of cell membranes. Its presence in almost all of the cell membranes makes it a perfect target for ROS. There are four major products of ROS-mediated cholesterol oxidation: 7α,β-OOH-Cholesterol, 7α,β-OH-Cholesterol, 7-oxo-Cholesterol and 5,6-epoxy-Cholesterol. However, there are many other minor forms of oxysterols produced by non-radical pathways (5-α-OOH-Cholesterol, 6α,β-OOH-Cholesterol with singlet oxygen; 5,6β-epoxy-Cholesterol and ozone; 5,6-dichlorocholestane and HOCl from neutrophils) [194].
Oxysterols play a role in the set-up of atherosclerosis as several studies found them in fatty streaks, aortic or atherosclerotic plaques [195,196,197]. Oxysterols exhibited a pro-apoptotic effect on monocytes [198,199], vascular cells (smooth muscle cells [198,200], endothelial cells [198,201]) and hepatocytes [202]. Particularly, 7-oxo-cholesterol and 7α,β-OH-Cholesterol triggered the major toxic effect [198] but other products such as 5,6-ep-oxy-Cholesterol also showed a potential pro-apoptotic effect [201,203]. Other deleterious effects have been shown from various oxysterols including death of macrophages in latter stages of atherosclerosis [204], production of pro-inflammatory cytokines [205,206], LDL oxidation [207] and platelet aggregation [208]. Nevertheless, their role in the modification of cholesterol metabolism still remains unclear [194,209].
Oxysterols are metabolized by the liver and excreted as bile acids. In healthy subjects, oxysterols are found at very low plasma concentrations [210] (Table 1). These concentrations are significantly increased in CKD patients compared to a control population and especially in end-stage renal disease (ESRD) patients undergoing hemodialysis [113,114]. Moreover, Siems et al. reported an increase of their concentration after an HD session [114].

4.2. Oxidized Phospholipids

Phospholipids (PLs) are the main components of cell membranes and, as cholesterol, are more exposed to oxidative stress and ROS. They also make up the external layer of lipoproteins and are a preferential site of oxidative and covalent modifications. Oxidized phospholipids can be produced through several pathways. Peroxyl radicals are derived from the free-radical-dependent oxidation of PUFAs esterified into PLs. [211]. Nitration can happen on PLs and generate nitrated-PUFAs and PLs [212]. Halogenation by a direct action of HOCl or HOBr released by neutrophilic and eosinophilic cells can also modify PLs by the addition of halogenide and hydroxyl groups leading to halohydrins (chlorydrins [213] and bromohydrins [214]) residues on PLs. Indeed, MPO and eosinophilic peroxidase activities are increased in CKD [60,61,191,192]. Enzymatic pathways of oxidation are almost always associated with the activity of 12- and 15-lipoxygenases, leading to the formation of hydroperoxides residues on PLs either in cell membranes [215] or lipoproteins [216,217].
These oxidized PLs (Ox-PLs) exhibit several biological effects [218]. First, they play a role in enhanced cell expression of adhesion molecules. Ox-PLs are involved in the activation of β1-integrin/fibronectin [219,220] and P-selectin [221,222] pathways of adhesion. Ox-PLs can also increase the generation of ROS by the elevation of the activity of NADPH oxidase [223]. As PLs are key activators of blood coagulation and platelet activation, Ox-PLs can also modulate this phenomenon. Effects on blood coagulation are mitigated as Ox-PLs can exert opposite effects on several steps of the coagulation cascade even if a pro-coagulation tendency raises from these studies [224,225,226]. Ox-PLs have shown pro-aggregate properties on platelets and vascular cells [227,228,229,230]. Many others effects of Ox-PLs are described in the literature (smooth muscle cells, bone, pro-angiogenic properties…) [211,231].
Part of Ox-PLs biological activity results from their binding to CD-36 receptor (a class B scavenger receptor) [232,233]. This receptor is well-known for its implication in atherosclerosis [69] and its expression is increased in CKD patients [70].
Moreover, high OxPL/ApoB ratio has been related to severe coronary artery disease [102] in patients without CKD (mean level of about 0.20 and 0.15 for respectively <60 years and >60 years population). This ratio has been correlated with the presence and progression of carotid, femoral atherosclerosis and cardiovascular disease for a ratio value higger than 0.088 [103]. Interestingly, in ESRD patients undergoing HD, this mean ratio was found to be at 0.13 [56] (Table 1). Nevertheless, this ratio was not found to be associated with cardiovascular disease in hemodialysis patients [56,115]. Indeed, their concentration decreases after an HD session [56]. This decrease may partially explain the absence of association in HD patients. This ratio has been also associated with renal progression in systemic lupus erythematous patients [234].

4.3. Fatty Acid Peroxidation Products (FAPP)

Fatty acids represent an important source of energy in human body physiology. Most of the time, they are derived from triglycerides or phospholipids and can be either saturated or unsaturated. Poly unsaturated fatty acids (PUFAs) are more prone to oxidation, and especially in CKD.
Malondialdehyde (MDA) is the result of polyunsaturated fatty acid oxidation containing more than two double bounds. More than a simple marker of lipid peroxidation, it covalently binds to proteins and nucleic acids, interfering with their normal biological functions. Indeed, MDA binding with nucleic acids can form several toxic adducts [235] and induce frameshift mutations and base-pair substitutions [236] (Figure 2 and Figure 3). Furthermore, MDA can react with lysine amino group and generate lysine-lysine bounds [237]. On ApoB, these bounds were associated with atherosclerosis [238]. MDA can be assayed itself or detected as a derived product of its reaction with thiobarbituric acid (TBA) that produces thiobarbituric acid reactive species (TBARS) [239]. Several studies have shown that MDA is elevated in CKD and represents a good marker of increased oxidative stress [116,165,166,240,241,242,243,244]. Moreover, MDA (or TBARS) levels are correlated with GFR [241], creatinine levels [245] and intensity of renal damages [166]. Surprisingly, data on HD behavior of MDA concentration are controversial. In Kuchta et al. study, it was not affected by HD procedure [162]. In other reports, HD session triggered a significant decrease of the MDA concentration [116,117] but was found to increase in a Nigerian cohort [118]. As an evidence of toxicity and as a significant part of MDA is excreted in the urine [246], EuTox group has already classified MDA as an uremic toxin [9].
Polyunsaturated fatty acids can also generate other reactive lipid aldehydes such as acrolein and 4-hydroxy-2-alkenals [237]. The latter, and particularly, 4-hydroxy-2-nonenal (4-HNE) (a by-product of the peroxidation of n-6 PUFAs) and 4-hydroxy-2-hexenal (4-HHE) (a by-product of the peroxidation of n-3 PUFAs) can react with proteins by a Michael addition mechanism (Figure 2). These adducts can especially bind to histidine, cysteine and lysine residues [247]. These ALEs disrupt several biological functions such as Na+/K+ ATPases [248], mitochondrial functions (potential role in permeability transition [249] and membrane fluidity [250]). These adducts are also found in large amounts in human atherosclerotic lesions [251]. Furthermore, HNE-modified LDL can activate macrophages and increase the up-regulation of class A scavenger receptors involved in the transformation of these cells into foam cells [252]. 4-HNE adducts induce smooth muscle cell proliferation in aortas of rats by the upregulation of ERK1 and ERK2 pathways [253]. 4-HNE can also alter vascular permeability and trigger apoptosis of endothelial cells [254] and promote the adhesion of pro-inflammatory cells to the endothelium [255]. There is some evidence that 4-HNE accumulates in CKD and especially in ESRD patients [256]. In a study by Sommerburg et al., mean level of 4-HNE was 3 fold higher in HD patients compared to healthy controls [257]. Alhamdani et al. showed that alkanals, alkenals and 4-hydroxy-alkenals concentrations are increased in HD patients compared to controls [258] (Table 1). Interestingly, HD procedure tends to reduce the 4-HNE concentration in several reports [116,119,120]. However, as the major part of 4-HNE reacts with proteins and creates stable adducts (ALEs), this observed reduction can over-estimate the decrease of the overall pool of 4-HNE in an HD session. As a major proof of toxicity and as part of alkenals are excreted in the urine [121], EuTox group has already classified 4-hydroxy-2-alkenals as a uremic toxins [9]. To the best of our knowledge, there is only limited data in the literature regarding the levels of 4-HHE in patients although its cytotoxic effect on proximal tubular cells was demonstrated in vitro [259].

4.4. F2-Isoprostanes

Arachidonic acid peroxidation generates F2-isoprostanes by a cyclo-oxygenase independent pathway [260,261,262]. Part of these isoprostanes is unesterified but a great majority remains esterified. 8-epi-PGF acts as an agonist/antagonist on platelet aggregation via Thromboxane A2 receptor (TxA2-R). Added at high concentrations, it directly induced platelet aggregation via TxA2-R whereas at low concentrations, it inhibited platelet aggregation. Thus, low amount of 8-epi-PGF acts as an antagonist of this receptor and inhibits platelet aggregation [263] induced by a TXA2 agonist. F2-isoprostanes promote endothelial cell proliferation and endothelin-1 secretion [264]. Moreover, these compounds have potential vasoconstrictive effects on smooth muscle cells [265]. Intra-arterial infusion of F2-isoprostanes led to a decrease in GFR and these effects were counteracted with TxA2-R antagonists [266]. Additionally, high containing-vitamin E diet in aged rats increased the GFR by 50% and reduced glomerular sclerosis concurrently with a reduction of F2-isoprostanes concentration [267]. Therefore, F2-Isoprostane accumulation may play a role in CKD progression [10], especially since its concentration is closely correlated with GFR [8,268]. In addition, F2-isoprostane concentrations are elevated in HD patients in several studies [119,122,123,124,125] compared with intra-studies control groups and data from the literature [269] (Table 1) making them suitable for classification as uremic toxins and particularly because their concentrations decrease after kidney transplantation [270,271]. Part of these F2-isoprostanes are cleared by the kidney [126,127] but an HD session seems to have no effect on their concentration [119,128].

5. Conclusions

CKD is associated with deep modifications in oxidative stress balance, lipid metabolism and turnover, which is responsible for an accumulation of various toxic forms of lipids and lipoproteins. EUtox defined a uremic toxin as an accumulated solute, normally excreted by the kidneys, that interacts negatively with biological functions. As these molecules accumulate in ESRD and exhibit many noxious effects on cell metabolism, CKD progression, cardiovascular system they can be regarded as uremic toxins even if they are not always excreted by the kidneys. Future efforts need to be concentrated on the enhancement of the removal of these lipids and the avoidance of their generation.


Figures were realized with Servier Medical Art under the terms of the Creative Commons Attributions 3.0 France license.

Author Contributions

N.F., C.O.S. and C.C. wrote the manuscript. C.O.S., C.C., E.L. and L.J. edited and revised the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.


ABCA-1ATP-biding cassette 1
ACATacetyl-CoA acetyltransferase-1
AGEsadvanced glycation end-products
ALEsadvanced lipoxidation end-products
ApoA/B/C/Eapolipoprotein A/B/C/E
CETPcholesterol-ester transfer protein
CKDchronic kidney disease
cLDLcarbamylated low-density lipoprotein
CVDcardiovascular disease
ESRDend-stage renal disease
EuToxEuropean uremic toxin work group
FAPPsfatty acid peroxidation products
GFRglomerular filtration rate
GPXgluthatione peroxidase
HDLhigh density lipoproteins
HOCLhypochlorous acid
ICAM-1intercellular adhesion molecule 1
IL-1ßinterleukine 1ß
LCATlecithin-cholesterol acyltransferase
LCFAlong chain fatty acids
LDLlow-density lipoproteins
LOX-1lectin-like oxidized lox density receptor 1
Lp(a)lipoprotein a
LRPLDL receptor protein
LVHleft ventricle hypertrophy
MCP-1monocyte chemoattractant protein 1
NOnitric oxide
oxPLsoxidized phospholipids
oxLDLoxidized low-density lipoproteins
PON1paraoxonase 1
PTMDPspost translational modification derived products
PUFAspolyunsaturated fatty acids
RASrenin-angiotensin system
RNSreactive nitrogen species
ROSreactive oxygen species
SODsuperoxide dismutase
SR-B1scavenger receptor class B member 1
TBARSthiobarbituric acid reactive species
TGRLtriglyceride-rich lipoproteins
TNF-αtumor necrosis factor α
TxA2-Rthromboxane A2 receptor
VCAM-1vascular cell adhesion molecule 1


  1. Go, A.S.; Chertow, G.M.; Fan, D.; McCulloch, C.E.; Hsu, C.-Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N. Engl. J. Med. 2004, 351, 1296–1305. [Google Scholar] [CrossRef] [PubMed]
  2. McCullough, P.A.; Agrawal, V.; Danielewicz, E.; Abela, G.S. Accelerated atherosclerotic calcification and Monckeberg’s sclerosis: A continuum of advanced vascular pathology in chronic kidney disease. Clin. J. Am. Soc. Nephrol. 2008, 3, 1585–1598. [Google Scholar] [CrossRef] [PubMed]
  3. Schiffrin, E.L.; Lipman, M.L.; Mann, J.F.E. Chronic kidney disease: Effects on the cardiovascular system. Circulation 2007, 116, 85–97. [Google Scholar] [CrossRef] [PubMed]
  4. Cozzolino, M.; Brancaccio, D.; Gallieni, M.; Slatopolsky, E. Pathogenesis of vascular calcification in chronic kidney disease. Kidney Int. 2005, 68, 429–436. [Google Scholar] [CrossRef] [PubMed]
  5. Moe, S.M.; Chen, N.X. Pathophysiology of vascular calcification in chronic kidney disease. Circ. Res. 2004, 95, 560–567. [Google Scholar] [CrossRef] [PubMed]
  6. Kovesdy, C.P.; Trivedi, B.K.; Anderson, J.E. Association of kidney function with mortality in patients with chronic kidney disease not yet on dialysis: A historical prospective cohort study. Adv. Chronic Kidney Dis. 2006, 13, 183–188. [Google Scholar] [CrossRef] [PubMed]
  7. Muntner, P.; He, J.; Astor, B.C.; Folsom, A.R.; Coresh, J. Traditional and nontraditional risk factors predict coronary heart disease in chronic kidney disease: Results from the atherosclerosis risk in communities study. J. Am. Soc. Nephrol. 2005, 16, 529–538. [Google Scholar] [CrossRef] [PubMed]
  8. Dounousi, E.; Papavasiliou, E.; Makedou, A.; Ioannou, K.; Katopodis, K.P.; Tselepis, A.; Siamopoulos, K.C.; Tsakiris, D. Oxidative stress is progressively enhanced with advancing stages of CKD. Am. J. Kidney Dis. 2006, 48, 752–760. [Google Scholar] [CrossRef] [PubMed]
  9. Duranton, F.; Cohen, G.; De Smet, R.; Rodriguez, M.; Jankowski, J.; Vanholder, R.; Argiles, A.; on behalf of the European Uremic Toxin Work Group. Normal and pathologic concentrations of uremic toxins. J. Am. Soc. Nephrol. 2012, 23, 1258–1270. [Google Scholar] [CrossRef] [PubMed]
  10. Cottone, S.; Mulè, G.; Guarneri, M.; Palermo, A.; Lorito, M.C.; Riccobene, R.; Arsena, R.; Vaccaro, F.; Vadalà, A.; Nardi, E.; et al. Endothelin-1 and F2-isoprostane relate to and predict renal dysfunction in hypertensive patients. Nephrol. Dial. Transplant. 2009, 24, 497–503. [Google Scholar] [CrossRef] [PubMed]
  11. Vaziri, N.D. Role of dyslipidemia in impairment of energy metabolism, oxidative stress, inflammation and cardiovascular disease in chronic kidney disease. Clin. Exp. Nephrol. 2014, 18, 265–268. [Google Scholar] [CrossRef] [PubMed]
  12. Wanner, C.; Krane, V.; März, W.; Olschewski, M.; Mann, J.F.E.; Ruf, G.; Ritz, E.; German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N. Engl. J. Med. 2005, 353, 238–248. [Google Scholar] [CrossRef] [PubMed]
  13. Fellström, B.C.; Jardine, A.G.; Schmieder, R.E.; Holdaas, H.; Bannister, K.; Beutler, J.; Chae, D.-W.; Chevaile, A.; Cobbe, S.M.; Grönhagen-Riska, C.; et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N. Engl. J. Med. 2009, 360, 1395–1407. [Google Scholar] [CrossRef] [PubMed]
  14. Barter, P. Lipoprotein metabolism and CKD: Overview. Clin. Exp. Nephrol. 2014, 18, 243–246. [Google Scholar] [CrossRef] [PubMed]
  15. Vaziri, N.D.; Norris, K. Lipid disorders and their relevance to outcomes in chronic kidney disease. Blood Purif. 2011, 31, 189–196. [Google Scholar] [CrossRef] [PubMed]
  16. Massy, Z.A. The role of lipids and uremic toxins in cardiovascular disease in CKD. Clin. Exp. Nephrol. 2014, 18, 255–256. [Google Scholar] [CrossRef] [PubMed]
  17. Vaziri, N.D. HDL abnormalities in nephrotic syndrome and chronic kidney disease. Nat. Rev. Nephrol. 2015, 12, 37–47. [Google Scholar] [CrossRef] [PubMed]
  18. Keane, W.F.; Tomassini, J.E.; Neff, D.R. Lipid Abnormalities in Patients with Chronic Kidney Disease: Implications for the Pathophysiology of Atherosclerosis. J. Atheroscler. Thromb. 2013, 20, 123–133. [Google Scholar] [CrossRef] [PubMed]
  19. Maduell, F.; Moreso, F.; Pons, M.; Ramos, R.; Mora-Macia, J.; Carreras, J.; Soler, J.; Torres, F.; Campistol, J.M.; Martinez-Castelao, A.; et al. High-efficiency postdilution online hemodiafiltration reduces all-cause mortality in hemodialysis patients. J. Am. Soc. Nephrol. 2013, 24, 487–497. [Google Scholar] [CrossRef] [PubMed]
  20. Sever, P.S.; Dahlöf, B.; Poulter, N.R.; Wedel, H.; Beevers, G. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): A multicentre randomised controlled trial. Lancet 2003, 361, 1149–1158. [Google Scholar] [PubMed]
  21. Tonelli, M.; Moye, L.; Sacks, F.M.; Kiberd, B. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Ann. Intern. Med. 2003, 138, 98–104. [Google Scholar] [CrossRef] [PubMed]
  22. Tonelli, M.; Moyé, L.; Sacks, F.M.; Cole, T.; Curhan, G.C.; Cholesterol and recurrent events trial investigators. Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease. J. Am. Soc. Nephrol. 2003, 14, 1605–1613. [Google Scholar] [CrossRef] [PubMed]
  23. Fathi, R.; Isbel, N.; Short, L.; Haluska, B.; Johnson, D.; Marwick, T.H. The effect of long-term aggressive lipid lowering on ischemic and atherosclerotic burden in patients with chronic kidney disease. Am. J. Kidney Dis. 2004, 43, 45–52. [Google Scholar] [CrossRef] [PubMed]
  24. Palmer, S.C.; Navaneethan, S.D.; Craig, J.C. HMG CoA reductase inhibitors (statins) for dialysis patients. Cochrane Database Syst. Rev. 2013. [Google Scholar] [CrossRef]
  25. Navaneethan, S.D.; Pansini, F.; Perkovic, V. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst. Rev. 2009. [Google Scholar] [CrossRef]
  26. Palmer, S.C.; Navaneethan, S.D.; Craig, J.C. HMG CoA reductase inhibitors (statins) for kidney transplant recipients. Cochrane Database Syst. Rev. 2014. [Google Scholar] [CrossRef]
  27. Oda, H.; Keane, W.F. Recent advances in statins and the kidney. Kidney Int. 1999, 56, 2–5. [Google Scholar] [CrossRef]
  28. Zoja, C.; Corna, D.; Rottoli, D.; Cattaneo, D.; Zanchi, C. Effect of combining ACE inhibitor and statin in severe experimental nephropathy. Kidney Int. 2002, 61, 1635–1645. [Google Scholar] [CrossRef] [PubMed]
  29. O’Donnell, M.P.; Kasiske, B.L.; Kim, Y.; Atluru, D.; Keane, W.F. Lovastatin inhibits proliferation of rat mesangial cells. J. Clin. Investig. 1993, 91, 83–87. [Google Scholar] [CrossRef] [PubMed]
  30. Bae, J.C.; Han, J.M.; Kwon, S.; Jee, J.H.; Yu, T.Y.; Lee, M.K.; Kim, J.H. LDL-C/apoB and HDL-C/apoA-1 ratios predict incident chronic kidney disease in a large apparently healthy cohort. Atherosclerosis 2016, 251, 170–176. [Google Scholar] [CrossRef] [PubMed]
  31. Nestel, P.J.; Fidge, N.H.; Tan, M.H. Increased lipoprotein-remnant formation in chronic renal failure. N. Engl. J. Med. 1982, 307, 329–333. [Google Scholar] [CrossRef] [PubMed]
  32. Okubo, M.; Hanada, H.; Matsui, M.; Hidaka, Y.; Masuda, D.; Sakata, Y.; Yamashita, S. Serum apolipoprotein B-48 concentration is associated with a reduced estimated glomerular filtration rate and increased proteinuria. J. Atheroscler. Thromb. 2014, 21, 974–982. [Google Scholar] [CrossRef] [PubMed]
  33. Hayashi, T.; Hirano, T.; Taira, T.; Tokuno, A.; Mori, Y.; Koba, S.; Adachi, M. Remarkable increase of apolipoprotein B48 level in diabetic patients with end-stage renal disease. Atherosclerosis 2008, 197, 154–158. [Google Scholar] [CrossRef] [PubMed]
  34. Cofan, M.; Cofan, F.; Campos, B.; Guerra, R.; Campistol, J.M.; Oppenheimer, F. Effect of apolipoprotein B polymorphism in kidney transplantation. Transplant. Proc. 2005, 37, 3794–3795. [Google Scholar] [CrossRef] [PubMed]
  35. Moradi, H.; Pahl, M.V.; Elahimehr, R.; Vaziri, N.D. Impaired antioxidant activity of high-density lipoprotein in chronic kidney disease. Transl. Res. 2009, 153, 77–85. [Google Scholar] [CrossRef] [PubMed]
  36. Shoji, T.; Nishizawa, Y.; Nishitani, H.; Yamakawa, M. Impaired metabolism of high density lipoprotein in uremic patients. Kidney Int. 1992, 41, 1653–1661. [Google Scholar] [CrossRef] [PubMed]
  37. Vaziri, N.D.; Liang, K.; Parks, J.S. Down-regulation of hepatic lecithin: Cholesterol acyltransferase gene expression in chronic renal failure. Kidney Int. 2001, 59, 2192–2196. [Google Scholar] [CrossRef] [PubMed]
  38. Vaziri, N.D.; Liang, K. Down-regulation of tissue lipoprotein lipase expression in experimental chronic renal failure. Kidney Int. 1996, 50, 1928–1935. [Google Scholar] [CrossRef] [PubMed]
  39. Vaziri, N.D.; Wang, X.Q.; Liang, K. Secondary hyperparathyroidism downregulates lipoprotein lipase expression in chronic renal failure. Am. J. Physiol. 1997, 273, 925–930. [Google Scholar]
  40. Vaziri, N.D.; Yuan, J.; Ni, Z.; Nicholas, S.B.; Norris, K.C. Lipoprotein lipase deficiency in chronic kidney disease is accompanied by down-regulation of endothelial GPIHBP1 expression. Clin. Exp. Nephrol. 2012, 16, 238–243. [Google Scholar] [CrossRef] [PubMed]
  41. Kim, C.; Vaziri, N.D. Down-regulation of hepatic LDL receptor-related protein (LRP) in chronic renal failure. Kidney Int. 2005, 67, 1028–1032. [Google Scholar] [CrossRef] [PubMed]
  42. Hirowatari, Y.; Homma, Y.; Yoshizawa, J.; Homma, K. Increase of electronegative-LDL-fraction ratio and IDL-cholesterol in chronic kidney disease patients with hemodialysis treatment. Lipids Health Dis. 2012, 11, 1. [Google Scholar] [CrossRef] [PubMed]
  43. Klin, M.; Smogorzewski, M.; Ni, Z.; Zhang, G. Abnormalities in hepatic lipase in chronic renal failure: Role of excess parathyroid hormone. J. Clin. Investig. 1996, 97, 2167–2173. [Google Scholar] [CrossRef] [PubMed]
  44. Liang, K.; Vaziri, N.D. Down-regulation of hepatic lipase expression in experimental nephrotic syndrome. Kidney Int. 1997, 51, 1933–1937. [Google Scholar] [CrossRef] [PubMed]
  45. Sato, T.; Liang, K.; Vaziri, N.D. Protein restriction and AST-120 improve lipoprotein lipase and VLDL receptor in focal glomerulosclerosis. Kidney Int. 2003, 64, 1780–1786. [Google Scholar] [CrossRef] [PubMed]
  46. Liang, K.; Vaziri, N.D. Acquired VLDL receptor deficiency in experimental nephrosis. Kidney Int. 1997, 51, 1933–1937. [Google Scholar] [CrossRef] [PubMed]
  47. Sato, T.; Liang, K.; Vaziri, N.D. Down-regulation of lipoprotein lipase and VLDL receptor in rats with focal glomerulosclerosis. Kidney Int. 2002, 64, 1780–1786. [Google Scholar] [CrossRef] [PubMed]
  48. Vaziri, N.D. Dyslipidemia of chronic renal failure: The nature, mechanisms, and potential consequences. Am. J. Physiol. Ren. Physiol. 2006, 290, 262–272. [Google Scholar] [CrossRef] [PubMed]
  49. DeGoulet, P.; LeGrain, M.; Reach, I.; Aime, F.; Devries, C.; Rojas, P.; Jacobs, C. Mortality risk factors in patients treated by chronic hemodialysis. Nephron 1982, 31, 103–110. [Google Scholar] [CrossRef] [PubMed]
  50. Lowrie, E.G.; Lew, N.L. Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am. J. Kidney Dis. 1990, 15, 458–482. [Google Scholar] [CrossRef]
  51. Liu, Y.; Coresh, J.; Eustace, J.A.; Longenecker, J.C.; Jaar, B.; Fink, N.E.; Tracy, R.P.; Powe, N.R.; Klag, M.J. Association between cholesterol level and mortality in dialysis patients: Role of inflammation and malnutrition. JAMA 2004, 291, 451–459. [Google Scholar] [CrossRef] [PubMed]
  52. Levitan, I.; Volkov, S. Oxidized LDL: Diversity, patterns of recognition, and pathophysiology. Antioxid. Redox 2010, 13, 39–75. [Google Scholar] [CrossRef] [PubMed]
  53. Ribeiro, S.; Faria, M.D.S.; Silva, G.; Nascimento, H.; Rocha-Pereira, P.; Miranda, V.; Vieira, E.; Santos, R.; Mendonça, D.; Quintanilha, A.; et al. Oxidized low-density lipoprotein and lipoprotein(a) levels in chronic kidney disease patients under hemodialysis: Influence of adiponectin and of a polymorphism in the apolipoprotein(a) gene. Hemodial. Int. 2012, 16, 481–490. [Google Scholar] [CrossRef] [PubMed]
  54. Samouilidou, E.C.; Karpouza, A.P.; Kostopoulos, V.; Bakirtzi, T.; Pantelias, K.; Petras, D.; Tzanatou-Exarchou, H.; Grapsa, E. Lipid abnormalities and oxidized LDL in chronic kidney disease patients on hemodialysis and peritoneal dialysis. Ren. Fail. 2012, 34, 160–164. [Google Scholar] [CrossRef] [PubMed]
  55. Lobo, J.; Santos, F.; Grosso, D.; Lima, R.; Barreira, A.L.; Leite, M., Jr.; Mafra, D.; Abdalla, D.S.P. Electronegative LDL and lipid abnormalities in patients undergoing hemodialysis and peritoneal dialysis. Nephron Clin. Pract. 2008, 108, 298–304. [Google Scholar] [CrossRef] [PubMed]
  56. Bossola, M.; Tazza, L.; Merki, E.; Giungi, S.; Luciani, G.; Miller, E.R.; Lin, E.B.; Tortorelli, A.; Tsimikas, S. Oxidized low-density lipoprotein biomarkers in patients with end-stage renal failure: Acute effects of hemodialysis. Blood Purif. 2007, 25, 457–465. [Google Scholar] [CrossRef] [PubMed]
  57. Drożdż, D.; Kwinta, P.; Sztefko, K.; Kordon, Z.; Drożdż, T.; Łątka, M.; Miklaszewska, M.; Zachwieja, K.; Rudziński, A.; Pietrzyk, J.A. Oxidative stress biomarkers and left ventricular hypertrophy in children with chronic kidney disease. Oxid. Med. Cell. Longev. 2016. [Google Scholar] [CrossRef] [PubMed]
  58. Takenaka, T.; Takahashi, K.; Kobayashi, T.; Oshima, E.; Iwasaki, S.; Suzuki, H. Oxidized low density lipoprotein (Ox-LDL) as a marker of atherosclerosis in hemodialysis (HD) patients. Clin. Nephrol. 2002, 58, 33–37. [Google Scholar] [CrossRef] [PubMed]
  59. Pawlak, K.; Myśliwiec, M.; Pawlak, D. Oxidized LDL to autoantibodies against oxLDL ratio—The new biomarker associated with carotid atherosclerosis and cardiovascular complications in dialyzed patients. Atherosclerosis 2012, 224, 252–257. [Google Scholar] [CrossRef] [PubMed]
  60. Kalantar-Zadeh, K.; Brennan, M.-L.; Hazen, S.L. Serum myeloperoxidase and mortality in maintenance hemodialysis patients. Am. J. Kidney Dis. 2006, 48, 59–68. [Google Scholar] [CrossRef] [PubMed]
  61. Kitabayashi, C.; Naruko, T.; Sugioka, K.; Yunoki, K.; Nakagawa, M.; Inaba, M.; Ohsawa, M.; Konishi, Y.; Imanishi, M.; Inoue, T.; et al. Positive association between plasma levels of oxidized low-density lipoprotein and myeloperoxidase after hemodialysis in patients with diabetic end-stage renal disease. Hemodial. Int. 2013, 17, 557–567. [Google Scholar] [CrossRef] [PubMed]
  62. Hazen, S.L.; Heinecke, J.W. 3-Chlorotyrosine, a specific marker of myeloperoxidase-catalyzed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima. J. Clin. Investig. 1997, 99, 2075–2081. [Google Scholar] [CrossRef] [PubMed]
  63. Pirillo, A.; Norata, G.D.; Catapano, A.L. LOX-1, OxLDL, and Atherosclerosis. Mediat. Inflamm. 2013, 2013, 1–12. [Google Scholar] [CrossRef] [PubMed]
  64. Himmelfarb, J.; McMenamin, M.E.; Loseto, G.; Heinecke, J.W. Myeloperoxidase-catalyzed 3-chlorotyrosine formation in dialysis patients. Free Radic. Biol. Med. 2001, 31, 1163–1169. [Google Scholar] [CrossRef]
  65. Podrez, E.A.; Schmitt, D.; Hoff, H.F.; Hazen, S.L. Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro. J. Clin. Investig. 1999, 103, 1547–1560. [Google Scholar] [CrossRef] [PubMed]
  66. Shiu, S.W.M.; Xiao, S.M.; Wong, Y.; Chow, W.S.; Lam, K.S.L.; Tan, K.C.B. Carbamylation of LDL and its relationship with myeloperoxidase in Type 2 diabetes mellitus. Clin. Sci. 2013, 126, 175–181. [Google Scholar] [CrossRef] [PubMed]
  67. Exner, M.; Hermann, M.; Hofbauer, R.; Hartmann, B.; Kapiotis, S.; Gmeiner, B. Thiocyanate catalyzes myeloperoxidase-initiated lipid oxidation in LDL. Free Radic. Biol. Med. 2004, 37, 146–155. [Google Scholar] [CrossRef] [PubMed]
  68. Apostolov, E.O.; Ok, E.; Burns, S.; Nawaz, S.; Savenka, A.; Shah, S.V.; Basnakian, A.G. Carbamylated-oxidized LDL: Proatherosclerotic effects on endothelial cells and macrophages. J. Atheroscler. Thromb. 2013, 20, 878–892. [Google Scholar] [CrossRef] [PubMed]
  69. Park, Y.M. CD36, a scavenger receptor implicated in atherosclerosis. Exp. Mol. Med. 2014, 46, e99. [Google Scholar] [CrossRef] [PubMed]
  70. Chmielewski, M.; Bryl, E.; Marzec, L.; Aleksandrowicz, E.; Witkowski, J.M.; Rutkowski, B. Expression of scavenger receptor CD36 in chronic renal failure patients. Artif. Organs 2005, 29, 608–614. [Google Scholar] [CrossRef] [PubMed]
  71. Carracedo, J.; Merino, A.; Briceno, C.; Soriano, S.; Buendia, P.; Calleros, L.; Rodriguez, M.; Martin-Malo, A.; Aljama, P.; Ramirez, R. Carbamylated low-density lipoprotein induces oxidative stress and accelerated senescence in human endothelial progenitor cells. FASEB J. 2011, 25, 1314–1322. [Google Scholar] [CrossRef] [PubMed]
  72. Speer, T.; Owala, F.O.; Holy, E.W.; Zewinger, S.; Frenzel, F.L.; Stähli, B.E.; Razavi, M.; Triem, S.; Cvija, H.; Rohrer, L.; et al. Carbamylated low-density lipoprotein induces endothelial dysfunction. Eur. Heart J. 2014, 35, 3021–3032. [Google Scholar] [CrossRef] [PubMed]
  73. Holy, E.W.; Akhmedov, A.; Speer, T.; Camici, G.G.; Zewinger, S.; Bonetti, N.; Beer, J.H.; Lüscher, T.F.; Tanner, F.C. Carbamylated low-density lipoproteins induce a prothrombotic state via lox-1: Impact on arterial thrombus formation in vivo. J. Am. Coll. Cardiol. 2016, 68, 1664–1676. [Google Scholar] [CrossRef] [PubMed]
  74. Son, J.N.; Lho, Y.; Shin, S.; Kwon, S.-H.; Moon, K.C.; Ha, E. Carbamylated low-density lipoprotein increases reactive oxygen species (ROS) and apoptosis via lectin-like oxidized LDL receptor (LOX-1) mediated pathway in human umbilical vein endothelial cells. Int. J. Cardiol. 2011, 146, 428–430. [Google Scholar] [CrossRef] [PubMed]
  75. Apostolov, E.O.; Ray, D.; Savenka, A.V.; Shah, S.V.; Basnakian, A.G. Chronic Uremia Stimulates LDL Carbamylation and Atherosclerosis. J. Am. Soc. Nephrol. 2010, 21, 1852–1857. [Google Scholar] [CrossRef] [PubMed]
  76. Apostolov, E.O.; Basnakian, A.G.; Ok, E.; Shah, S.V. Carbamylated low-density lipoprotein: Nontraditional risk factor for cardiovascular events in patients with chronic kidney disease. J. Ren. Nutr. 2012, 22, 134–138. [Google Scholar] [CrossRef] [PubMed]
  77. Kamanna, V.S.; Kashyap, M.L.; Pai, R.; Bui, D.T. Uremic serum subfraction inhibits apolipoprotein AI production by a human hepatoma cell line. J. Am. Soc. Nephrol. 1994, 5, 193–200. [Google Scholar] [PubMed]
  78. Shah, G.M.; Lin, Z.L.; Kamanna, V.S.; Pai, R.; Bassa, B. Effect of serum subfractions from peritoneal dialysis patients on Hep-G2 cell apolipoprotein AI and B metabolism. Kidney Int. 1996, 50, 2079–2087. [Google Scholar] [CrossRef] [PubMed]
  79. Shao, B.; Oda, M.N.; Oram, J.F.; Heinecke, J.W. Myeloperoxidase: An inflammatory enzyme for generating dysfunctional high density lipoprotein. Curr. Opin. Cardiol. 2006, 21, 322–328. [Google Scholar] [CrossRef] [PubMed]
  80. Liang, K.; Vaziri, N.D. Upregulation of acyl-CoA: Cholesterol acyltransferase in chronic renal failure. Am. J. Physiol. Endocrinol. Metab. 2002, 283, 676–681. [Google Scholar] [CrossRef] [PubMed]
  81. Holzer, M.; Schilcher, G.; Curcic, S.; Trieb, M.; Ljubojevic, S.; Stojakovic, T.; Scharnagl, H.; Kopecky, C.M.; Rosenkranz, A.R.; Heinemann, A.; et al. Dialysis modalities and HDL composition and function. J. Am. Soc. Nephrol. 2015, 26, 2267–2276. [Google Scholar] [CrossRef] [PubMed]
  82. Hewing, B.; Parathath, S.; Barrett, T.; Chung, W.K.K.; Astudillo, Y.M.; Hamada, T.; Ramkhelawon, B.; Tallant, T.C.; Yusufishaq, M.S.S.; DiDonato, J.A.; et al. Effects of native and myeloperoxidase-modified apolipoprotein A-I on reverse cholesterol transport and atherosclerosis in mice. Arterioscler. Thromb. Vasc. Biol. 2014, 34, 779–789. [Google Scholar] [CrossRef] [PubMed]
  83. Shao, B.; Tang, C.; Sinha, A.; Mayer, P.S.; Davenport, G.D.; Brot, N.; Oda, M.N.; Zhao, X.-Q.; Heinecke, J.W. Humans with atherosclerosis have impaired ABCA1 cholesterol efflux and enhanced high-density lipoprotein oxidation by myeloperoxidase. Circ. Res. 2014, 114, 1733–1742. [Google Scholar] [CrossRef] [PubMed]
  84. Holzer, M.; Zangger, K.; El-Gamal, D.; Binder, V.; Curcic, S.; Konya, V.; Schuligoi, R.; Heinemann, A.; Marsche, G. Myeloperoxidase-derived chlorinating species induce protein carbamylation through decomposition of thiocyanate and urea: Novel pathways generating dysfunctional high-density lipoprotein. Antioxid. Redox Signal. 2012, 17, 1043–1052. [Google Scholar] [CrossRef] [PubMed]
  85. Holzer, M.; Gauster, M.; Pfeifer, T.; Wadsack, C.; Fauler, G.; Stiegler, P.; Koefeler, H.; Beubler, E.; Schuligoi, R.; Heinemann, A.; et al. Protein carbamylation renders high-density lipoprotein dysfunctional. Antioxid. Redox Signal. 2011, 14, 2337–2346. [Google Scholar] [CrossRef] [PubMed]
  86. Undurti, A.; Huang, Y.; Lupica, J.A.; Smith, J.D.; DiDonato, J.A.; Hazen, S.L. Modification of high density lipoprotein by myeloperoxidase generates a pro-inflammatory particle. J. Biol. Chem. 2009, 284, 30825–30835. [Google Scholar] [CrossRef] [PubMed]
  87. Honda, H.; Ueda, M.; Kojima, S.; Mashiba, S.; Michihata, T.; Takahashi, K.; Shishido, K.; Akizawa, T. Oxidized high-density lipoprotein as a risk factor for cardiovascular events in prevalent hemodialysis patients. Atherosclerosis 2012, 220, 493–501. [Google Scholar] [CrossRef] [PubMed]
  88. Kalantar-Zadeh, K.; Kopple, J.D.; Kamranpour, N.; Fogelman, A.M.; Navab, M. HDL-inflammatory index correlates with poor outcome in hemodialysis patients. Kidney Int. 2007, 72, 1149–1156. [Google Scholar] [CrossRef] [PubMed]
  89. Holzer, M.; Birner-Gruenberger, R.; Stojakovic, T.; El-Gamal, D.; Binder, V.; Wadsack, C.; Heinemann, A.; Marsche, G. Uremia Alters HDL Composition and Function. J. Am. Soc. Nephrol. 2011, 22, 1631–1641. [Google Scholar] [CrossRef] [PubMed]
  90. Mangé, A.; Goux, A.; Badiou, S.; Patrier, L.; Canaud, B.; Maudelonde, T.; Cristol, J.-P.; Solassol, J. HDL proteome in hemodialysis patients: A quantitative nanoflow liquid chromatography-tandem mass spectrometry approach. PLoS ONE 2012. [Google Scholar] [CrossRef] [PubMed]
  91. Khera, A.V.; Cuchel, M.; la Llera-Moya, M.; Rodrigues, A.; Burke, M.F.; Jafri, K.; French, B.C.; Phillips, J.A.; Mucksavage, M.L.; Wilensky, R.L.; et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N. Engl. J. Med. 2011, 364, 127–135. [Google Scholar] [CrossRef] [PubMed]
  92. Kopecky, C.; Haidinger, M.; Birner-Grunberger, R.; Darnhofer, B.; Kaltenecker, C.C.; Marsche, G.; Holzer, M.; Weichhart, T.; Antlanger, M.; Kovarik, J.J.; et al. Restoration of Renal Function Does Not Correct Impairment of Uremic HDL Properties. J. Am. Soc. Nephrol. 2015, 26, 565–575. [Google Scholar] [CrossRef] [PubMed]
  93. Kaseda, R.; Jabs, K.; Hunley, T.E.; Jones, D.; Bian, A.; Allen, R.M.; Vickers, K.C.; Yancey, P.G.; Linton, M.F.; Fazio, S.; et al. Dysfunctional high-density lipoproteins in children with chronic kidney disease. Metabolism 2015, 64, 263–273. [Google Scholar] [CrossRef] [PubMed]
  94. Yamamoto, S.; Yancey, P.G.; Ikizler, T.A.; Jerome, W.G.; Kaseda, R.; Cox, B.; Bian, A.; Shintani, A.; Fogo, A.B.; Linton, M.R.F.; et al. Dysfunctional high-density lipoprotein in patients on chronic hemodialysis. J. Am. Coll. Cardiol. 2012, 60, 2372–2379. [Google Scholar] [CrossRef] [PubMed]
  95. Shroff, R.; Speer, T.; Colin, S.; Charakida, M.; Zewinger, S.; Staels, B.; Chinetti-Gbaguidi, G.; Hettrich, I.; Rohrer, L.; O’Neill, F.; et al. HDL in children with ckd promotes endothelial dysfunction and an abnormal vascular phenotype. J. Am. Soc. Nephrol. 2014, 25, 2658–2668. [Google Scholar] [CrossRef] [PubMed]
  96. Kopecky, C.; Ebtehaj, S.; Genser, B.; Drechsler, C.; Krane, V.; Antlanger, M.; Kovarik, J.J.; Kaltenecker, C.C.; Parvizi, M.; Wanner, C.; et al. HDL cholesterol efflux does not predict cardiovascular risk in hemodialysis patients. J. Am. Soc. Nephrol. 2016, in press. [Google Scholar] [CrossRef] [PubMed]
  97. Kimura, T.; Sato, K.; Malchinkhuu, E.; Tomura, H.; Tamama, K.; Kuwabara, A.; Murakami, M.; Okajima, F. High-density lipoprotein stimulates endothelial cell migration and survival through sphingosine 1-phosphate and its receptors. Arterioscler. Thromb. Vasc. Biol. 2003, 23, 1283–1288. [Google Scholar] [CrossRef] [PubMed]
  98. Litvinov, D.; Mahini, H.; Garelnabi, M. Antioxidant and anti-inflammatory role of paraoxonase 1: Implication in arteriosclerosis diseases. N. Am. J. Med. Sci. 2012, 4, 523–532. [Google Scholar] [PubMed]
  99. Dantoine, T.F.; Debord, J.; Charmes, J.P.; Merle, L.; Marquet, P.; Lachatre, G.; Leroux-Robert, C. Decrease of serum paraoxonase activity in chronic renal failure. J. Am. Soc. Nephrol. 1998, 9, 2082–2088. [Google Scholar] [PubMed]
  100. Kennedy, D.J.; Tang, W.H.W.; Fan, Y.; Wu, Y.; Mann, S.; Pepoy, M.; Hazen, S.L. Diminished antioxidant activity of high-density lipoprotein-associated proteins in chronic kidney disease. J. Am. Heart Assoc. 2013. [Google Scholar] [CrossRef] [PubMed]
  101. Kotani, K.; Kimura, S.; Gugliucci, A. Paraoxonase-1 and ischemia-modified albumin in patients with end-stage renal disease. J. Physiol. Biochem. 2011, 67, 437–441. [Google Scholar] [CrossRef] [PubMed]
  102. Tsimikas, S.; Brilakis, E.S.; Miller, E.R.; McConnell, J.P.; Lennon, R.J.; Kornman, K.S.; Witztum, J.L.; Berger, P.B. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N. Engl. J. Med. 2005, 353, 46–57. [Google Scholar] [CrossRef] [PubMed]
  103. Tsimikas, S.; Kiechl, S.; Willeit, J.; Mayr, M.; Miller, E.R.; Kronenberg, F.; Xu, Q.; Bergmark, C.; Weger, S.; Oberhollenzer, F.; et al. Oxidized phospholipids predict the presence and progression of carotid and femoral atherosclerosis and symptomatic cardiovascular disease: Five-year prospective results from the Bruneck study. J. Am. Coll. Cardiol. 2006, 47, 2219–2228. [Google Scholar] [CrossRef] [PubMed]
  104. Tsimikas, S.; Hall, J.L. Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: A rationale for increased efforts to understand its pathophysiology and develop targeted therapies. J. Am. Coll. Cardiol. 2012, 60, 716–721. [Google Scholar] [CrossRef] [PubMed]
  105. Tsimikas, S.; Viney, N.J.; Hughes, S.G.; Singleton, W.; Graham, M.J.; Baker, B.F.; Burkey, J.L.; Yang, Q.; Marcovina, S.M.; Geary, R.S.; et al. Antisense therapy targeting apolipoprotein(a): A randomised, double-blind, placebo-controlled phase 1 study. Lancet 2015, 386, 1472–1483. [Google Scholar] [CrossRef]
  106. Kollerits, B.; Drechsler, C.; Krane, V.; Lamina, C.; März, W.; Dieplinger, H.; Ritz, E.; Wanner, C.; Kronenberg, F.; German Diabetes and Dialysis Study Investigators. Lipoprotein(a) concentrations, apolipoprotein(a) isoforms and clinical endpoints in haemodialysis patients with type 2 diabetes mellitus: Results from the 4D Study. Nephrol. Dial. Transplant. 2016, 31, 1901–1908. [Google Scholar] [CrossRef] [PubMed]
  107. Pedersen, T.X.; McCormick, S.P.; Tsimikas, S.; Bro, S.; Nielsen, L.B. Lipoprotein(a) accelerates atherosclerosis in uremic mice. J. Lipid Res. 2010, 51, 2967–2975. [Google Scholar] [CrossRef] [PubMed]
  108. Frischmann, M.E.; Kronenberg, F.; Trenkwalder, E.; Schaefer, J.R.; Schweer, H.; Dieplinger, B.; Koenig, P.; Ikewaki, K.; Dieplinger, H. In vivo turnover study demonstrates diminished clearance of lipoprotein(a) in hemodialysis patients. Kidney Int. 2007, 71, 1036–1043. [Google Scholar] [CrossRef] [PubMed]
  109. Tzanatos, H.A.; Agroyannis, B.; Chondros, C.; Kapetanaki, A.; Fourtounas, C.; Soubassi, L.; Kopelias, I. Cytokine release and serum lipoprotein (a) alterations during hemodialysis. Artif. Organs 2000, 24, 329–333. [Google Scholar] [CrossRef] [PubMed]
  110. De Sain-Van Der Velden, M.G.; Reijngoud, D.J.; Kaysen, G.A.; Gadellaa, M.M.; Voorbij, H.; Stellaard, F.; Koomans, H.A.; Rabelink, T.J. Evidence for increased synthesis of lipoprotein(a) in the nephrotic syndrome. J. Am. Soc. Nephrol. 1998, 9, 1474–1481. [Google Scholar] [PubMed]
  111. Kronenberg, F.; König, P.; Neyer, U.; Auinger, M.; Pribasnig, A.; Lang, U.; Reitinger, J.; Pinter, G.; Utermann, G.; Dieplinger, H. Multicenter study of lipoprotein(a) and apolipoprotein(a) phenotypes in patients with end-stage renal disease treated by hemodialysis or continuous ambulatory peritoneal dialysis. J. Am. Soc. Nephrol. 1995, 6, 110–120. [Google Scholar] [PubMed]
  112. Kronenberg, F. Causes and consequences of lipoprotein(a) abnormalities in kidney disease. Clin. Exp. Nephrol. 2014, 18, 234–237. [Google Scholar] [CrossRef] [PubMed]
  113. Boaz, M.; Iuliano, L.; Himmelfarb, J.; Matas, Z.; Micheletta, F.; McMonagle, E.; Friedman, V.; Natoli, S.; Gvirtz, G.; Biro, A.; et al. Baseline oxysterols and other markers of oxidative stress, inflammation and malnutrition in the Vitamin E and Intima media thickness Progression in End-stage Renal disease (VIPER) cohort. Nephron Clin. Pract. 2005, 100, 111–119. [Google Scholar] [CrossRef] [PubMed]
  114. Siems, W.; Quast, S.; Peter, D.; Augustin, W.; Carluccio, F.; Grune, T.; Sevanian, A.; Hampl, H.; Wiswedel, I. Oxysterols are increased in plasma of end-stage renal disease patients. Kidney Blood Press. Res. 2005, 28, 302–306. [Google Scholar] [CrossRef] [PubMed]
  115. Bossola, M.; Tazza, L.; Luciani, G.; Tortorelli, A.; Tsimikas, S. OxPL/apoB, lipoprotein(a) and OxLDL biomarkers and cardiovascular disease in chronic hemodialysis patients. J. Nephrol. 2011, 24, 581–588. [Google Scholar] [CrossRef] [PubMed]
  116. Samouilidou, E.; Grapsa, E. Effect of dialysis on plasma total antioxidant capacity and lipid peroxidation products in patients with end-stage renal failure. Blood Purif. 2003, 21, 209–212. [Google Scholar] [CrossRef] [PubMed]
  117. Núñez, J.M.; Ghais, Z.; Bustamante, J. Evaluation of oxidant-antioxidant balance in patients on maintenance haemodialysis: A comparative study of dialyzers membranes. Nephron Clin. Pract. 2010, 114, 67–73. [Google Scholar]
  118. Ajala, M.O.; Ogunro, P.S.; Odun, A. Effect of hemodialysis on total antioxidant status of chronic renal failure patients in government hospitals in Lagos Nigeria. Niger J. Clin. Pract. 2011, 14, 154–158. [Google Scholar] [PubMed]
  119. Wiswedel, I.; Peter, D.; Gardemann, A.; Carluccio, F.; Hampl, H.; Siems, W. Serum concentrations of F2-isoprostanes and 4-Hydroxynonenal in hemodialysis patients in relation to inflammation and renal anemia. Biomark. Insights 2008, 3, 419–428. [Google Scholar] [PubMed]
  120. Odetti, P.; Traverso, N.; Monacelli, F.; Menini, S.; Vazzana, J.; Tasso, B.; Pronzato, M.A.; Robaudo, C.; Deferrari, G. Vitamin E-coated filter decreases levels of free 4-hydroxyl-2-nonenal during haemodialysis sessions. Free Radic. Res. 2006, 40, 207–212. [Google Scholar] [CrossRef] [PubMed]
  121. Guichardant, M.; Bacot, S.; Moliere, P.; Lagarde, M. Hydroxy-alkenals from the peroxidation of n-3 and n-6 fatty acids and urinary metabolites. Prostaglandins Leukot. Essent. Fat. Acids 2006, 75, 179–182. [Google Scholar] [CrossRef] [PubMed]
  122. Handelman, G.J.; Walter, M.F.; Adhikarla, R.; Gross, J.; Dallal, G.E.; Levin, N.W.; Blumberg, J.B. Elevated plasma F2-isoprostanes in patients on long-term hemodialysis. Kidney Int. 2001, 59, 1960–1966. [Google Scholar] [CrossRef] [PubMed]
  123. Ikizler, T.A.; Morrow, J.D.; Roberts, L.J.; Evanson, J.A.; Becker, B.; Hakim, R.M.; Shyr, Y.; Himmelfarb, J. Plasma F2-isoprostane levels are elevated in chronic hemodialysis patients. Clin. Nephrol. 2002, 58, 190–197. [Google Scholar] [CrossRef] [PubMed]
  124. Himmelfarb, J.; Phinney, S.; Ikizler, T.A.; Kane, J.; McMonagle, E.; Miller, G. Gamma-tocopherol and docosahexaenoic acid decrease inflammation in dialysis patients. J. Ren. Nutr. 2007, 17, 296–304. [Google Scholar] [CrossRef] [PubMed]
  125. Kamgar, M.; Zaldivar, F.; Vaziri, N.D.; Pahl, M.V. Antioxidant therapy does not ameliorate oxidative stress and inflammation in patients with end-stage renal disease. J. Natl. Med. Assoc. 2009, 101, 336–344. [Google Scholar] [CrossRef]
  126. Harman, S.M.; Liang, L.; Tsitouras, P.D.; Gucciardo, F.; Heward, C.B.; Reaven, P.D.; Ping, W.; Ahmed, A.; Cutler, R.G. Urinary excretion of three nucleic acid oxidation adducts and isoprostane F(2)alpha measured by liquid chromatography-mass spectrometry in smokers, ex-smokers, and nonsmokers. Free Radic. Biol. Med. 2003, 35, 1301–1309. [Google Scholar] [CrossRef] [PubMed]
  127. Morrow, J.D.; Zackert, W.E.; Yang, J.P.; Kurhts, E.H.; Callewaert, D.; Dworski, R.; Kanai, K.; Taber, D.; Moore, K.; Oates, J.A.; et al. Quantification of the major urinary metabolite of 15-F2t-isoprostane (8-iso-PGF2α) by a stable isotope dilution mass spectrometric assay. Anal. Biochem. 1999, 269, 326–331. [Google Scholar] [CrossRef] [PubMed]
  128. Morena, M.; Jaussent, I.; Chalabi, L.; Bargnoux, A.-S.; Dupuy, A.-M.; Badiou, S.; Rakic, C.; Thomas, M.; Canaud, B.; Cristol, J.-P. Biocompatibility of heparin-grafted hemodialysis membranes: Impact on monocyte chemoattractant protein-1 circulating level and oxidative status. Hemodial. Int. 2010, 14, 403–410. [Google Scholar] [CrossRef] [PubMed]
  129. Bonomini, F.; Tengattini, S.; Fabiano, A.; Bianchi, R. Atherosclerosis and oxidative stress. Histol. Histopathol. 2008, 23, 381–390. [Google Scholar] [PubMed]
  130. Cadenas, E.; Davies, K.J.A. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic. Biol. Med. 2000, 29, 222–230. [Google Scholar] [CrossRef]
  131. Vignais, P.V. The superoxide-generating NADPH oxidase: Structural aspects and activation mechanism. Cell. Mol. Life Sci. 2002, 59, 1428–1459. [Google Scholar] [CrossRef] [PubMed]
  132. De Minicis, S.; Bataller, R.; Brenner, D.A. NADPH oxidase in the liver: Defensive, offensive, or fibrogenic? Gastroenterology 2006, 131, 272–275. [Google Scholar] [CrossRef] [PubMed]
  133. Novo, E.; Parola, M. Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis Tissue Repair 2008, 1, 1. [Google Scholar] [CrossRef] [PubMed]
  134. Lambeth, J.D. Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy. Free Radic. Biol. Med. 2007, 43, 332–347. [Google Scholar] [CrossRef] [PubMed]
  135. Grotto, D.; Santa Maria, L.D.; Boeira, S.; Valentini, J.; Charão, M.F.; Moro, A.M.; Nascimento, P.C.; Pomblum, V.J.; Garcia, S.C. Rapid quantification of malondialdehyde in plasma by high performance liquid chromatography-visible detection. J. Pharm. Biomed. Anal. 2007, 43, 619–624. [Google Scholar] [CrossRef] [PubMed]
  136. Guichardant, M.; Chantegrel, B.; Deshayes, C.; Doutheau, A.; Moliere, P.; Lagarde, M. Specific markers of lipid peroxidation issued from n-3 and n-6 fatty acids. Biochem. Soc. Trans. 2004, 32, 139–140. [Google Scholar] [CrossRef] [PubMed]
  137. Smith, L.L.; Johnson, B.H. Biological activities of oxysterols. Free Radic. Biol. Med. 1989, 7, 285–332. [Google Scholar] [CrossRef]
  138. Finkel, T.; Holbrook, N.J. Oxidants, oxidative stress and the biology of ageing. Nature 2000, 48, 239–247. [Google Scholar] [CrossRef] [PubMed]
  139. Peters, T.J. All about Albumin; Academic Press, Inc.: San Diego, CA, USA, 1996. [Google Scholar]
  140. Jacobsen, C. Lysine residue 240 of human serum albumin is involved in high-affinity binding of bilirubin. Biochem. J. 1978, 171, 453–459. [Google Scholar] [CrossRef] [PubMed]
  141. Neužil, J.; Stocker, R. Bilirubin attenuates radical-mediated damage to serum albumin. FEBS Lett. 1993, 331, 281–284. [Google Scholar] [CrossRef]
  142. Neužil, J.; Stocker, R. Free and albumin-bound bilirubin are efficient co-antioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation. J. Biol. Chem. 1994, 269, 16712–16719. [Google Scholar] [PubMed]
  143. Gutteridge, J.M.C. Antioxidant properties of the proteins caeruloplasmin, albumin and transferrin. A study of their activity in serum and synovial fluid from patients with rheumatoid arthritis. Biochim. Biophys. Acta 1986, 869, 119–127. [Google Scholar] [CrossRef]
  144. Oettl, K.; Stauber, R.E. Physiological and pathological changes in the redox state of human serum albumin critically influence its binding properties. Br. J. Pharmacol. 2007, 151, 580–590. [Google Scholar] [CrossRef] [PubMed]
  145. Del Vecchio, L.; Locatelli, F.; Carini, M. What we know about oxidative stress in patients with chronic kidney disease on dialysis—Clinical effects, potential treatment, and prevention. Semin. Dial. 2011, 24, 56–64. [Google Scholar] [CrossRef] [PubMed]
  146. Tucker, P.S.; Dalbo, V.J.; Han, T.; Kingsley, M.I. Clinical and research markers of oxidative stress in chronic kidney disease. Biomarkers 2013, 18, 103–115. [Google Scholar] [CrossRef] [PubMed]
  147. Lahera, V.; Goicoechea, M.; de Vinuesa, S.G.; Oubiña, P.; Cachofeiro, V.; Gómez-Campderá, F.; Amann, R.; Luño, J. Oxidative stress in uremia: The role of anemia correction. J. Am. Soc. Nephrol. 2006, 17, S174–S177. [Google Scholar] [CrossRef] [PubMed]
  148. Ratliff, B.B.; Abdulmahdi, W.; Pawar, R.; Wolin, M.S. Oxidant mechanisms in renal injury and disease. Antioxid. Redox Signal. 2016, 25, 119–146. [Google Scholar] [CrossRef] [PubMed]
  149. Chao, C.-T.; Chiang, C.-K. Uremic toxins, oxidative stress, and renal fibrosis: An interwined complex. J. Ren. Nutr. 2015, 25, 155–159. [Google Scholar] [CrossRef] [PubMed]
  150. Modaresi, A.; Nafar, M.; Sahraei, Z. Oxidative stress in chronic kidney disease. Iran. J. Kidney Dis. 2015, 9, 165–179. [Google Scholar] [PubMed]
  151. Popolo, A.; Autore, G.; Pinto, A.; Marzocco, S. Oxidative stress in patients with cardiovascular disease and chronic renal failure. Free Radic. Res. 2013, 47, 346–356. [Google Scholar] [CrossRef] [PubMed]
  152. Libetta, C.; Sepe, V.; Esposito, P.; Galli, F.; Dal Canton, A. Oxidative stress and inflammation: Implications in uremia and hemodialysis. Clin. Biochem. 2011, 44, 1189–1198. [Google Scholar] [CrossRef] [PubMed]
  153. Vaziri, N.D. Oxidative stress in uremia: Nature, mechanisms, and potential consequences. Semin. Nephrol. 2004, 24, 469–473. [Google Scholar] [CrossRef] [PubMed]
  154. Himmelfarb, J.; Stenvinkel, P.; Ikizler, T.A.; Hakim, R.M. The elephant in uremia: Oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int. 2002, 62, 1524–1538. [Google Scholar] [CrossRef] [PubMed]
  155. Ramos, L.F.; Shintani, A.; Ikizler, T.A.; Himmelfarb, J. Oxidative stress and inflammation are associated with adiposity in moderate to severe CKD. J. Am. Soc. Nephrol. 2008, 19, 593–599. [Google Scholar] [CrossRef] [PubMed]
  156. Higashi, Y.; Sasaki, S.; Nakagawa, K.; Matsuura, H.; Oshima, T.; Chayama, K. Endothelial function and oxidative stress in renovascular hypertension. N. Engl. J. Med. 2002, 346, 1954–1962. [Google Scholar] [CrossRef] [PubMed]
  157. Touyz, R.M. Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension: What is the clinical significance? Hypertension 2004, 44, 248–252. [Google Scholar] [CrossRef] [PubMed]
  158. Zalba, G.; San José, G.; Moreno, M.U.; Fortuño, M.A.; Fortuño, A.; Beaumont, F.J.; Díez, J. Oxidative stress in arterial hypertension: Role of NAD(P)H oxidase. Hypertension 2001, 38, 1395–1399. [Google Scholar] [CrossRef] [PubMed]
  159. Moh, A.; Sakata, N.; Takebayashi, S.; Tateishi, K.; Nagai, R.; Horiuchi, S.; Chihara, J. Increased production of urea hydrogen peroxide from Maillard reaction and a UHP-Fenton pathway related to glycoxidation damage in chronic renal failure. J. Am. Soc. Nephrol. 2004, 15, 1077–1085. [Google Scholar] [CrossRef] [PubMed]
  160. Fatouros, I.G.; Pasadakis, P.; Sovatzidis, A. Acute exercise may exacerbate oxidative stress response in hemodialysis patients. Nephron Clin. Pract. 2008, 109, 55–64. [Google Scholar] [CrossRef] [PubMed]
  161. Coaccioli, S.; Standoli, M.L.; Biondi, R.; Panaccione, A.; Landucci, P.; Del Giorno, R.; Paladini, A.; Standoli, M.; Puxeddu, A. Open comparison study of oxidative stress markers between patients with chronic renal failure in conservative therapy and patients in haemodialysis. Clin. Ter. 2010, 161, 435–439. [Google Scholar] [PubMed]
  162. Kuchta, A.; Pacanis, A.; Kortas-Stempak, B.; Çwiklińska, A.; Ziętkiewicz, M.; Renke, M.; Rutkowski, B. Estimation of oxidative stress markers in chronic kidney disease. Kidney Blood Press. Res. 2011, 34, 12–19. [Google Scholar] [CrossRef] [PubMed]
  163. Biasioli, S.; Schiavon, R.; Petrosino, L.; Cavallini, L.; De Fanti, E.; Zambello, A.; Borin, D.; Targa, L. Do different dialytic techniques have different atherosclerotic and antioxidant activities? ASAIO J. 2001, 47, 516–521. [Google Scholar] [CrossRef] [PubMed]
  164. Shurtz-Swirski, R.; Mashiach, E.; Kristal, B.; Shkolnik, T.; Shasha, S.M. Antioxidant enzymes activity in polymorphonuclear leukocytes in chronic renal failure. Nephron 1995, 71, 176–179. [Google Scholar] [CrossRef] [PubMed]
  165. Atamer, A.; Kocyigit, Y.; Ecder, S.A.; Selek, S.; Iihan, N. Effect of oxidative stress on antioxidant enzyme activities, homocysteine and lipoproteins in chronic kidney disease. J. Nephrol. 2008, 21, 924–930. [Google Scholar] [PubMed]
  166. Kuo, H.-T.; Kuo, M.-C.; Chiu, Y.-W.; Chang, J.-M.; Guh, J.-Y.; Chen, H.-C. Increased glomerular and extracellular malondialdehyde levels in patients and rats with focal segmental glomerulosclerosis. Eur. J. Clin. Investig. 2005, 35, 245–250. [Google Scholar] [CrossRef] [PubMed]
  167. Inal, M.; Kanbak, G.; Sen, S.; Akyüz, F.; Sunal, E. Antioxidant status and lipid peroxidation in hemodialysis patients undergoing erythropoietin and erythropoietin-vitamin E combined therapy. Free Radic. Res. 1999, 31, 211–216. [Google Scholar] [CrossRef] [PubMed]
  168. Vural, A.; Yilmaz, M.I.; Caglar, K.; Aydin, A.; Sonmez, A.; Eyileten, T.; Acikel, C.; Gulec, B.; Kozak, O.; Oner, K. Assessment of oxidative stress in the early posttransplant period: Comparison of cyclosporine A and tacrolimus-based regimens. Am. J. Nephrol. 2005, 25, 250–255. [Google Scholar] [CrossRef] [PubMed]
  169. Ongajooth, L.; Ongajyooth, S.; Likidlilid, A.; Chantachum, Y.; Shayakul, C.; Nilwarangkur, S. Role of lipid peroxidation, trace elements and anti-oxidant enzymes in chronic renal disease patients. J. Med. Assoc. Thail. 1996, 79, 791–800. [Google Scholar] [PubMed]
  170. Romeu, M.; Nogues, R.; Marcas, L.; Sánchez-Martos, V.; Mulero, M.; Martinez-Vea, A.; Mallol, J.; Giralt, M. Evaluation of oxidative stress biomarkers in patients with chronic renal failure: A case control study. BMC Res. Notes 2010, 3, 20. [Google Scholar] [CrossRef] [PubMed]
  171. Rutkowski, P.; Malgorzewicz, S.; Slominska, E. Interrelationship between uremic toxicity and oxidative stress. J. Ren. Nutr. 2006, 16, 190–193. [Google Scholar] [CrossRef] [PubMed]
  172. Rutkowski, P.; Słominska, E.M.; Szołkiewicz, M.; Aleksandrowicz, E.; Smolenski, R.T.; Wołyniec, W.; Renke, M.; Wisterowicz, K.; Swierczynski, J.; Rutkowski, B. Relationship between uremic toxins and oxidative stress in patients with chronic renal failure. Scand. J. Urol. Nephrol. 2007, 41, 243–248. [Google Scholar] [CrossRef] [PubMed]
  173. Ikeda, Y.; Suehiro, T.; Itahara, T.; Inui, Y.; Chikazawa, H.; Inoue, M.; Arii, K.; Hashimoto, K. Human serum paraoxonase concentration predicts cardiovascular mortality in hemodialysis patients. Clin. Nephrol. 2007, 67, 358–365. [Google Scholar] [CrossRef] [PubMed]
  174. Weiss, M.F.; Erhard, P.; Kader-Attia, F.A.; Wu, Y.C. Mechanisms for the formation of glycoxidation products in end-stage renal disease. Kidney Int. 2000, 57, 2571–2585. [Google Scholar] [CrossRef] [PubMed]
  175. Miyata, T.; Kurokawa, K. Advanced glycation and lipoxidation end products role of reactive carbonyl compounds generated during carbohydrate and lipid metabolism. J. Am. Soc. Nephrol. 2000, 11, 1744–1752. [Google Scholar] [PubMed]
  176. Stadtman, E.R.; Levine, R.L. Free radical-mediated oxidation of free amino acids and amino acid residues in proteins. Amino Acids 2003, 25, 207–218. [Google Scholar] [CrossRef] [PubMed]
  177. Basta, G.; Schmidt, A.M.; De Caterina, R. Advanced glycation end products and vascular inflammation: Implications for accelerated atherosclerosis in diabetes. Cardiovasc. Res. 2004, 63, 582–592. [Google Scholar] [CrossRef] [PubMed]
  178. Bucala, R.; Mitchell, R.; Arnold, K.; Innerarity, T.; Vlassara, H.; Cerami, A. Identification of the major site of Apolipoprotein B modification by advanced glycosylation end products blocking uptake by the low density lipoprotein receptor. J. Biol. Chem. 1995, 270, 10828–10832. [Google Scholar] [PubMed]
  179. Klein, R.L.; Laimins, M.; Lopes-Virella, M.F. Isolation, characterization, and metabolism of the glycated and nonglycated subfractions of low-density lipoproteins isolated from Type I diabetic patients and nondiabetic subjects. Diabetes 1995, 44, 1093–1098. [Google Scholar] [CrossRef] [PubMed]
  180. Negre Salvayre, A.; Coatrieux, C.; Ingueneau, C.; Salvayre, R. Advanced lipid peroxidation end products in oxidative damage to proteins. Potential role in diseases and therapeutic prospects for the inhibitors. Br. J. Pharmacol. 2008, 153, 6–20. [Google Scholar] [CrossRef] [PubMed]
  181. Kalousova, M.; Zima, T.; Tesař, V.; Štípek, S.; Sulková, S. Advanced glycation end products in clinical nephrology. Kidney Blood Press. Res. 2004, 27, 18–28. [Google Scholar] [CrossRef] [PubMed]
  182. Kalousova, M.; Zima, T.; Tesař, V.; Lachmanová, J. Advanced glycation end products and advanced oxidation protein products in hemodialyzed patients. Blood Purif. 2003, 20, 531–536. [Google Scholar] [CrossRef]
  183. Schinzel, R.; Münch, G.; Heidland, A.; Sebekova, K. Advanced glycation end products in end-stage renal disease and their removal. Nephron 2001, 87, 295–303. [Google Scholar] [CrossRef] [PubMed]
  184. Canaud, B.; Cristol, J.P.; Morena, M.; Leray-Moragues, H.; Bosc, J.Y.; Vaussenat, F. Imbalance of oxidants and antioxidants in haemodialysis patients. Blood Purif. 1999, 17, 99–106. [Google Scholar] [CrossRef] [PubMed]
  185. Locatelli, F.; Canaud, B.; Eckardt, K.U.; Stenvinkel, P.; Wanner, C.; Zoccali, C. Oxidative stress in end-stage renal disease: An emerging threat to patient outcome. Nephrol. Dial. Transplant. 2003, 18, 1272–1280. [Google Scholar] [CrossRef] [PubMed]
  186. Verbrugge, F.H.; Tang, W.; Hazen, S.L. Protein carbamylation and cardiovascular disease. Kidney Int. 2015, 88, 474–478. [Google Scholar] [CrossRef] [PubMed]
  187. Koeth, R.A.; Kalantar-Zadeh, K.; Wang, Z.; Fu, X.; Tang, W.H.W.; Hazen, S.L. Protein carbamylation predicts mortality in ESRD. J. Am. Soc. Nephrol. 2013, 24, 853–861. [Google Scholar] [CrossRef] [PubMed]
  188. Berg, A.H.; Drechsler, C.; Wenger, J.; Buccafusca, R.; Hod, T.; Kalim, S.; Ramma, W.; Parikh, S.M.; Steen, H.; Friedman, D.J.; et al. Carbamylation of serum albumin as a risk factor for mortality in patients with kidney failure. Sci. Transl. Med. 2013, 5. [Google Scholar] [CrossRef] [PubMed]
  189. Mehta, J.L.; Basnakian, A.G. Interaction of carbamylated LDL with LOX-1 in the induction of endothelial dysfunction and atherosclerosis. Eur. Heart J. 2014, 35, 2996–2997. [Google Scholar] [CrossRef] [PubMed]
  190. Nicholls, S.J. Myeloperoxidase and cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 2005, 25, 1102–1111. [Google Scholar] [CrossRef] [PubMed]
  191. Rutgers, A.; Heeringa, P.; Kooman, J.P.; van der Sande, F.M.; Cohen Travaert, J.W. Peripheral blood myeloperoxidase activity increases during hemodialysis. Kidney Int. 2003, 64, 760–762. [Google Scholar] [CrossRef] [PubMed]
  192. Stenvinkel, P. Statin treatment and diabetes affect myeloperoxidase activity in maintenance hemodialysis patients. Clin. J. Am. Soc. Nephrol. 2006, 1, 281–287. [Google Scholar] [CrossRef] [PubMed]
  193. Wada, S.; Sugioka, K.; Naruko, T.; Kato, Y.; Shibata, T.; Inoue, T.; Inaba, M.; Ohsawa, M.; Yoshiyama, M.; Ueda, M. Myeloperoxidase and progression of aortic valve stenosis in patients undergoing hemodialysis. J. Heart Valve Dis. 2013, 22, 640–647. [Google Scholar] [PubMed]
  194. Murphy, R.C.; Johnson, K.M. Cholesterol, reactive oxygen species, and the formation of biologically active mediators. J. Biol. Chem. 2008, 283, 15521–15525. [Google Scholar] [CrossRef] [PubMed]
  195. Brown, A.J.; Jessup, W. Oxysterols and atherosclerosis. Atherosclerosis 1999, 142, 1–28. [Google Scholar] [CrossRef]
  196. Hodis, H.N.; Crawford, D.W.; Sevanian, A. Cholesterol feeding increases plasma and aortic tissue cholesterol oxide levels in parallel: Further evidence for the role of cholesterol oxidation in atherosclerosis. Atherosclerosis 1991, 89, 117–126. [Google Scholar] [CrossRef]
  197. Garcia-Cruset, S.; Carpenter, K.L.; Guardiola, F.; Stein, B.K.; Mitchinson, M.J. Oxysterol profiles of normal human arteries, fatty streaks and advanced lesions. Free Radic. Res. 2001, 35, 31–41. [Google Scholar] [CrossRef] [PubMed]
  198. Lizard, G.; Monier, S.; Cordelet, C.; Gesquière, L.; Deckert, V.; Gueldry, S.; Lagrost, L.; Gambert, P. Characterization and comparison of the mode of cell death, apoptosis versus necrosis, induced by 7β-hydroxycholesterol and 7-ketocholesterol in the cells of the vascular wall. Arterioscler. Thromb. Vasc. Biol. 1999, 19, 1190–1200. [Google Scholar] [CrossRef] [PubMed]
  199. Shibata, N.; Glass, C.K. Macrophages, oxysterols and atherosclerosis. Circulation 2010, 74, 2045–2051. [Google Scholar] [CrossRef]
  200. Nishio, E.; Watanabe, Y. Oxysterols induced apoptosis in cultured smooth muscle cells through CPP32 protease activation and bcl-2 protein downregulation. Biochem. Biophys. Res. Commun. 1996, 226, 928–934. [Google Scholar] [CrossRef] [PubMed]
  201. Lemaire, S.; Lizard, G.; Monier, S.; Miguet, C.; Gueldry, S.; Volot, F.; Gambert, P.; Néel, D. Different patterns of IL-1beta secretion, adhesion molecule expression and apoptosis induction in human endothelial cells treated with 7α-, 7β-hydroxycholesterol, or 7-ketocholesterol. FEBS Lett. 1998, 440, 434–439. [Google Scholar] [CrossRef]
  202. O’Callaghan, Y.C.; Woods, J.A.; O’Brien, N.M. Oxysterol-induced cell death in U937 and HepG2 cells at reduced and normal serum concentrations. Eur. J. Nutr. 1999, 38, 255–262. [Google Scholar] [CrossRef] [PubMed]
  203. Lizard, G.; Deckert, V.; Dubrez, L.; Moisant, M.; Gambert, P.; Lagrost, L. Induction of apoptosis in endothelial cells treated with cholesterol oxides. Am. J. Pathol. 1996, 148, 1625–1638. [Google Scholar] [PubMed]
  204. Maxfield, F.R.; Tabas, I. Role of cholesterol and lipid organization in disease. Nature 2005, 438, 612–621. [Google Scholar] [CrossRef] [PubMed]
  205. Prunet, C.; Montange, T.; Véjux, A.; Laubriet, A.; Rohmer, J.F.; Riedinger, J.M.; Athias, A.; Lemaire Ewing, S.; Néel, D.; Petit, J.M.; et al. Multiplexed flow cytometric analyses of pro- and anti-inflammatory cytokines in the culture media of oxysterol-treated human monocytic cells and in the sera of atherosclerotic patients. Cytom. Part A 2006, 69A, 359–373. [Google Scholar] [CrossRef] [PubMed]
  206. Lemaire-Ewing, S.; Prunet, C.; Montange, T.; Vejux, A.; Berthier, A.; Bessède, G.; Corcos, L.; Gambert, P.; Néel, D.; Lizard, G. Comparison of the cytotoxic, pro-oxidant and pro-inflammatory characteristics of different oxysterols. Cell. Biol. Toxicol. 2005, 21, 97–114. [Google Scholar] [CrossRef] [PubMed]
  207. Rosenblat, M.; Aviram, M. Oxysterol-induced activation of macrophage NADPH-oxidase enhances cell-mediated oxidation of LDL in the atherosclerotic apolipoprotein E deficient mouse: Inhibitory role for vitamin E. Atherosclerosis 2002, 160, 69–80. [Google Scholar] [CrossRef]
  208. Selley, M.L.; McGuiness, J.A.; Ardlie, N.G. The effect of cholesterol oxidation products on human platelet aggregation. Thromb. Res. 1996, 83, 449–461. [Google Scholar] [CrossRef]
  209. Olkkonen, V.M.; Lehto, M. Oxysterols and oxysterol binding proteins: Role in lipid metabolism and atherosclerosis. Ann. Med. 2009, 36, 562–572. [Google Scholar] [CrossRef]
  210. Iuliano, L.; Micheletta, F.; Natoli, S.; Ginanni Corradini, S.; Iappelli, M.; Elisei, W.; Giovannelli, L.; Violi, F.; Diczfalusy, U. Measurement of oxysterols and alpha-tocopherol in plasma and tissue samples as indices of oxidant stress status. Anal. Biochem. 2003, 312, 217–223. [Google Scholar] [CrossRef]
  211. Bochkov, V.N.; Oskolkova, O.V.; Birukov, K.G.; Levonen, A.-L.; Binder, C.J.; Stöckl, J. Generation and biological activities of oxidized phospholipids. Antioxid. Redox Signal. 2010, 12, 1009–1059. [Google Scholar] [CrossRef] [PubMed]
  212. Radi, R.; Beckman, J.S.; Bush, K.M.; Freeman, B.A. Peroxynitrite-induced membrane lipid peroxidation: The cytotoxic potential of superoxide and nitric oxide. Arch. Biochem. Biophys. 1991, 288, 481–487. [Google Scholar] [CrossRef]
  213. Jerlich, A.; Pitt, A.R.; Schaur, R.J.; Spickett, C.M. Pathways of phospholipid oxidation by HOCl in human LDL detected by LC-MS. Free Radic. Biol. Med. 2000, 28, 673–682. [Google Scholar] [CrossRef]
  214. Carr, A.C.; Winterbourn, C.C.; van den Berg, J.J. Peroxidase-mediated bromination of unsaturated fatty acids to form bromohydrins. Arch. Biochem. Biophys. 1996, 327, 227–233. [Google Scholar] [CrossRef] [PubMed]
  215. Kuhn, H.; Belkner, J.; Wiesner, R.; Brash, A.R. Oxygenation of biological membranes by the pure reticulocyte lipoxygenase. J. Biol. Chem. 1990, 265, 18351–18361. [Google Scholar] [PubMed]
  216. Belkner, J.; Wiesner, R.; Rathman, J.; Barnett, J.; Sigal, E.; Kuhn, H. Oxygenation of lipoproteins by mammalian lipoxygenases. Eur. J. Biochem. 1993, 213, 251–261. [Google Scholar] [CrossRef] [PubMed]
  217. Heydeck, D.; Upston, J.M.; Viita, H.; Ylä-Herttuala, S.; Stocker, R. Oxidation of LDL by rabbit and human 15-lipoxygenase: Prevalence of nonenzymatic reactions. J. Lipid Res. 2001, 42, 1082–1088. [Google Scholar] [PubMed]
  218. Berliner, J.A.; Leitinger, N.; Tsimikas, S. The role of oxidized phospholipids in atherosclerosis. J. Lipid Res. 2009, 50, 207–212. [Google Scholar] [CrossRef] [PubMed]
  219. Cole, A.L.; Subbanagounder, G.; Mukhopadhyay, S.; Berliner, J.A.; Vora, D.K. Oxidized phospholipid-induced endothelial cell/monocyte interaction is mediated by a cAMP-dependent R-Ras/PI3-kinase pathway. Arterioscler. Thromb. Vasc. Biol. 2003, 23, 1384–1390. [Google Scholar] [CrossRef] [PubMed]
  220. Li, R.; Mouillesseaux, K.P.; Montoya, D.; Cruz, D.; Gharavi, N.; Dun, M.; Koroniak, L.; Berliner, J.A. Identification of prostaglandin E2 receptor subtype 2 as a receptor activated by OxPAPC. Circ. Res. 2006, 98, 642–650. [Google Scholar] [CrossRef] [PubMed]
  221. Vora, D.K.; Fang, Z.T.; Liva, S.M.; Tyner, T.R.; Parhami, F.; Watson, A.D.; Drake, T.A.; Territo, M.C.; Berliner, J.A. Induction of P-selectin by oxidized lipoproteins. Separate effects on synthesis and surface expression. Circ. Res. 1997, 80, 810–818. [Google Scholar] [CrossRef] [PubMed]
  222. Dever, G.J.; Benson, R.; Wainwright, C.L.; Kennedy, S.; Spickett, C.M. Phospholipid chlorohydrin induces leukocyte adhesion to ApoE−/− mouse arteries via upregulation of P-selectin. Free Radic. Biol. Med. 2008, 44, 452–463. [Google Scholar] [CrossRef] [PubMed]
  223. Rouhanizadeh, M.; Hwang, J.; Clempus, R.E.; Marcu, L.; Lassègue, B.; Sevanian, A.; Hsiai, T.K. Oxidized-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine induces vascular endothelial superoxide production: Implication of NADPH oxidase. Free Radic. Biol. Med. 2005, 39, 1512–1522. [Google Scholar] [CrossRef] [PubMed]
  224. Weinstein, E.A.; Li, H.; Lawson, J.A.; Rokach, J.; FitzGerald, G.A.; Axelsen, P.H. Prothrombinase acceleration by oxidatively damaged phospholipids. J. Biol. Chem. 2000, 275, 22925–22930. [Google Scholar] [CrossRef] [PubMed]
  225. Safa, O.; Hensley, K.; Smirnov, M.D.; Esmon, C.T.; Esmon, N.L. Lipid oxidation enhances the function of activated protein C. J. Biol. Chem. 2001, 276, 1829–1836. [Google Scholar] [CrossRef] [PubMed]
  226. Bochkov, V.N.; Mechtcheriakova, D.; Lucerna, M.; Huber, J.; Malli, R.; Graier, W.F.; Hofer, E.; Binder, B.R.; Leitinger, N. Oxidized phospholipids stimulate tissue factor expression in human endothelial cells via activation of ERK/EGR-1 and Ca++/NFAT. Blood 2002, 99, 199–206. [Google Scholar] [CrossRef] [PubMed]
  227. Haserück, N.; Erl, W.; Pandey, D.; Tigyi, G.; Ohlmann, P.; Ravanat, C.; Gachet, C.; Siess, W. The plaque lipid lysophosphatidic acid stimulates platelet activation and platelet-monocyte aggregate formation in whole blood: Involvement of P2Y1 and P2Y12 receptors. Blood 2004, 103, 2585–2592. [Google Scholar] [CrossRef] [PubMed]
  228. Marathe, G.K.; Zimmerman, G.A.; Prescott, S.M.; McIntyre, T.M. Activation of vascular cells by PAF-like lipids in oxidized LDL. Vascul. Pharmacol. 2002, 38, 193–200. [Google Scholar] [CrossRef]
  229. Subbanagounder, G.; Leitinger, N.; Shih, P.T.; Faull, K.F.; Berliner, J.A. Evidence that phospholipid oxidation products and/or platelet-activating factor play an important role in early atherogenesis: In vitro and In vivo inhibition by WEB 2086. Circ. Res. 1999, 85, 311–318. [Google Scholar] [CrossRef] [PubMed]
  230. Tokumura, A.; Sumida, T.; Toujima, M.; Kogure, K.; Fukuzawa, K. Platelet-activating factor (PAF)-like oxidized phospholipids: Relevance to atherosclerosis. Biofactors 2000, 13, 29–33. [Google Scholar] [CrossRef] [PubMed]
  231. Deigner, H.-P.; Hermetter, A. Oxidized phospholipids: Emerging lipid mediators in pathophysiology. Curr. Opin. Lipidol. 2008, 19, 289–294. [Google Scholar] [CrossRef] [PubMed]
  232. Podrez, E.A. Identification of a novel family of oxidized phospholipids that serve as ligands for the macrophage scavenger receptor CD36. J. Biol. Chem. 2002, 277, 38503–38516. [Google Scholar] [CrossRef] [PubMed]
  233. Hazen, S.L. Oxidized phospholipids as endogenous pattern recognition ligands in innate immunity. J. Biol. Chem. 2008, 283, 15527–15531. [Google Scholar] [CrossRef] [PubMed]
  234. Frostegård, J.; Svenungsson, E.; Wu, R.; Gunnarsson, I.; Lundberg, I.E.; Klareskog, L.; Hörkkö, S.; Witztum, J.L. Lipid peroxidation is enhanced in patients with systemic lupus erythematosus and is associated with arterial and renal disease manifestations. Arthritis Rheum. 2005, 52, 192–200. [Google Scholar] [CrossRef] [PubMed]
  235. Marnett, L.J. Lipid peroxidation—DNA damage by malondialdehyde. Mutat. Res. 1999, 424, 83–95. [Google Scholar] [CrossRef]
  236. VanderVeen, L.A.; Hashim, M.F.; Shyr, Y.; Marnett, L.J. Induction of frameshift and base pair substitution mutations by the major DNA adduct of the endogenous carcinogen malondialdehyde. PNAS 2003, 100, 14247–14252. [Google Scholar] [CrossRef] [PubMed]
  237. Uchida, K. Role of reactive aldehyde in cardiovascular diseases. Free Radic. Biol. Med. 2000, 28, 1685–1696. [Google Scholar] [CrossRef]
  238. Palinski, W.; Ord, V.A.; Plump, A.S.; Breslow, J.L.; Steinberg, D.; Witztum, J.L. ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum. Arterioscler. Thromb. Vasc. Biol. 1994, 14, 605–616. [Google Scholar] [CrossRef]
  239. Del Rio, D.; Stewart, A.J.; Pellegrini, N. A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress. Nutr. Metabol. Cardiovasc. Dis. 2005, 15, 316–328. [Google Scholar] [CrossRef] [PubMed]
  240. De Vecchi, A.F.; Bamonti, F.; Novembrino, C.; Ippolito, S.; Guerra, L.; Lonati, S.; Salini, S.; Aman, C.S.; Scurati-Manzoni, E.; Cighetti, G. Free and total plasma malondialdehyde in chronic renal insufficiency and in dialysis patients. Nephrol. Dial. Transplant. 2009, 24, 2524–2529. [Google Scholar] [CrossRef] [PubMed]
  241. Yilmaz, M.I.; Saglam, M.; Caglar, K.; Cakir, E.; Sonmez, A.; Ozgurtas, T.; Aydin, A.; Eyileten, T.; Ozcan, O.; Acikel, C.; et al. The determinants of endothelial dysfunction in CKD: Oxidative stress and asymmetric dimethylarginine. Am. J. Kidney Dis. 2006, 47, 42–50. [Google Scholar] [CrossRef] [PubMed]
  242. Capusa, C.; Stoian, I.; Rus, E.; Lixandru, D.; Barbulescu, C.; Mircescu, G. Does dialysis modality influence the oxidative stress of uremic patients? Kidney Blood Press. Res. 2012, 35, 220–225. [Google Scholar] [CrossRef] [PubMed]
  243. Caimi, G.; Carollo, C.; Montana, M.; Iatrino, R.; Bondì, B.; Lo Presti, R. Nitric oxide metabolites, leukocyte activation markers and oxidative status in dialyzed subjects. Blood Purif. 2009, 27, 194–198. [Google Scholar] [CrossRef] [PubMed]
  244. Dirican, M.; Sarandol, E.; Serdar, Z.; Ocak, N.; Dilek, K. Oxidative status and prevalent cardiovascular disease in patients with chronic renal failure treated by hemodialysis. Clin. Nephrol. 2007, 68, 144–150. [Google Scholar] [CrossRef] [PubMed]
  245. Bober, J.; Kedzierska, K.; Kwiatkowska, E.; Stachowska, E.; Gołembiewska, E.; Mazur, O.; Staniewicz, Z.; Ciechanowski, K.; Chlubek, D. Does oxidative stress affect the activity of the sodium-proton exchanger? Ann. Acad. Med. Stetin. 2010, 56, 5–12. [Google Scholar] [PubMed]
  246. Esterbauer, H.; Schaur, R.J.; Zollner, H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic. Biol. Med. 1991, 11, 81–128. [Google Scholar] [CrossRef]
  247. Petersen, D.R.; Doorn, J.A. Reactions of 4-hydroxynonenal with proteins and cellular targets. Free Radic. Biol. Med. 2004, 37, 937–945. [Google Scholar] [CrossRef] [PubMed]
  248. Siems, W.G.; Hapner, S.J.; Van Kuijk, F.J. 4-Hydroxynonenal inhibits Na(+)-K(+)-ATPase. Free Radic. Biol. Med. 1996, 20, 215–223. [Google Scholar] [CrossRef]
  249. Kristal, B.S.; Park, B.K.; Yu, B.P. 4-Hydroxyhexenal is a potent inducer of the mitochondrial permeability transition. J. Biol. Chem. 1996, 271, 6033–6038. [Google Scholar] [PubMed]
  250. Chen, J.J.; Yu, B.P. Alterations in mitochondrial membrane fluidity by lipid peroxidation products. Free Radic. Biol. Med. 1994, 17, 411–418. [Google Scholar] [CrossRef]
  251. Uchida, K.; Itakura, K.; Kawakishi, S.; Hiai, H.; Toyokuni, S.; Stadtman, E.R. Characterization of Epitopes Recognized by 4-Hydroxy-2-nonenal Specific Antibodies. Arch. Biochem. Biophys. 1995, 324, 241–248. [Google Scholar] [CrossRef] [PubMed]
  252. Hoff, H.F.; O’Neil, J.; Chisolm, G.M.; Cole, T.B.; Quehenberger, O.; Esterbauer, H.; Jürgens, G. Modification of low density lipoprotein with 4-hydroxynonenal induces uptake by macrophages. Arterioscler. Thromb. Vasc. Biol. 1989, 9, 538–549. [Google Scholar] [CrossRef]
  253. Ruef, J.; Rao, G.N.; Li, F.; Bode, C.; Patterson, C.; Bhatnagar, A.; Runge, M.S. Induction of Rat Aortic Smooth Muscle Cell Growth by the Lipid Peroxidation Product 4-Hydroxy-2-Nonenal. Circulation 1998, 97, 1071–1078. [Google Scholar] [CrossRef] [PubMed]
  254. Herbst, U.; Toborek, M.; Kaiser, S.; Mattson, M.P.; Hennig, B. 4-Hydroxynonenal induces dysfunction and apoptosis of cultured endothelial cells. J. Cell. Physiol. 1999, 181, 295–303. [Google Scholar] [CrossRef]
  255. Go, Y.-M.; Halvey, P.J.; Hansen, J.M.; Reed, M.; Pohl, J.; Jones, D.P. Reactive aldehyde modification of thioredoxin-1 activates early steps of inflammation and cell adhesion. Am. J. Pathol. 2007, 171, 1670–1681. [Google Scholar] [CrossRef] [PubMed]
  256. Piroddi, M.; Bartolini, D.; Ciffolilli, S.; Galli, F. Nondialyzable uremic toxins. Blood Purif. 2013, 35, 30–41. [Google Scholar] [CrossRef] [PubMed]
  257. Sommerburg, O.; Grune, T.; Hampl, H.; Riedel, E.; van Kuijk, F.J.; Ehrich, J.H.; Siems, W.G. Does long-term treatment of renal anaemia with recombinant erythropoietin influence oxidative stress in haemodialysed patients? Nephrol. Dial. Transplant. 1998, 13, 2583–2587. [Google Scholar] [CrossRef] [PubMed]
  258. Alhamdani, M.S.S.; Al-Kassir, A.H.A.M.; Jaleel, N.A.; Hmood, A.M.; Ali, H.M. Elevated levels of Alkanals, alkenals and 4-ho-alkenals in plasma of hemodialysis patients. Am. J. Nephrol. 2006, 26, 299–303. [Google Scholar] [CrossRef] [PubMed]
  259. Bae, E.H.; Cho, S.; Joo, S.Y.; Ma, S.K.; Kim, S.H.; Lee, J.; Kim, S.W. 4-Hydroxy-2-hexenal-induced apoptosis in human renal proximal tubular epithelial cells. Nephrol. Dial. Transplant. 2011, 26, 3866–3873. [Google Scholar] [CrossRef] [PubMed]
  260. Morrow, J.D.; Hill, K.E.; Burk, R.F.; Nammour, T.M.; Badr, K.F.; Roberts, L.J., 2nd. A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Proc. Natl. Acad. Sci. USA 1990, 87, 9383–9387. [Google Scholar] [CrossRef] [PubMed]
  261. Roberts, L.J., II; Morrow, J.D. Measurement of F2-isoprostanes as an index of oxidative stress in vivo. Free Radic. Biol. Med. 2000, 28, 505–513. [Google Scholar] [CrossRef]
  262. Roberts, L.J., II; Fessel, J.P. The biochemistry of the isoprostane, neuroprostane, and isofuran pathways of lipid peroxidation. Chem. Phys. Lipids 2004, 128, 173–186. [Google Scholar] [CrossRef] [PubMed]
  263. Morrow, J.D.; Minton, T.A.; Roberts, L.J. The F2-isoprostane, 8-epi-prostaglandin F2α, a potent agonist of the vascular thromboxane/endoperoxide receptor, is a platelet thromboxane/endoperoxide receptor antagonist. Prostaglandins 1992, 44, 155–163. [Google Scholar] [CrossRef]
  264. Yura, T.; Fukunaga, M.; Khan, R.; Nassar, G.N.; Badr, K.F. Free-radical-generated F2-isoprostane stimulates cell proliferation and endothelin-1 expression on endothelial cells. Kidney Int. 1999, 56, 471–478. [Google Scholar] [CrossRef] [PubMed]
  265. Fukunaga, M.; Makita, N.; Roberts, L.J.; Morrow, J.D.; Takahashi, K.; Badr, K.F. Evidence for the existence of F2-isoprostane receptors on rat vascular smooth muscle cells. Am. J. Physiol. 1993, 264, 1619–1624. [Google Scholar]
  266. Takahashi, K.; Nammour, T.M.; Fukunaga, M.; Ebert, J.; Morrow, J.D.; Roberts, L.J., 2nd; Hoover, R.L.; Badr, K.F. Glomerular actions of a free radical-generated novel prostaglandin, 8-epi-prostaglandin F2 alpha, in the rat. Evidence for interaction with thromboxane A2 receptors. J. Clin. Investig. 1992, 90, 136–141. [Google Scholar] [CrossRef] [PubMed]
  267. Reckelhoff, J.F.; Kanji, V.; Racusen, L.C.; Schmidt, A.M.; Yan, S.D.; Morrow, J.; Roberts, L.J.; Salahudeen, A.K. Vitamin E ameliorates enhanced renal lipid peroxidation and accumulation of F2-isoprostanes in aging kidneys. Am. J. Physiol. 1998, 274, 767–774. [Google Scholar]
  268. Cottone, S.; Lorito, M.C.; Riccobene, R.; Nardi, E. Oxidative stress, inflammation and cardiovascular disease in chronic renal failure. J. Nephrol. 2008, 21, 175–179. [Google Scholar] [PubMed]
  269. Lee, C.-Y.J.; Huang, S.H.; Jenner, A.M.; Halliwell, B. Measurement of F2-isoprostanes, hydroxyeicosatetraenoic products, and oxysterols from a single plasma sample. Free Radic. Biol. Med. 2008, 44, 1314–1322. [Google Scholar] [CrossRef] [PubMed]
  270. Ramezani, M.; Nazemian, F.; Shamsara, J.; Koohrokhi, R.; Mohammadpour, A.H. Effect of Ω-3 fatty acids on plasma level of 8-isoprostane in kidney transplant patients. J. Ren. Nutr. 2011, 21, 196–199. [Google Scholar] [CrossRef] [PubMed]
  271. Simmons, E.M.; Langone, A.; Sezer, M.T.; Vella, J.P.; Recupero, P.; Morrow, J.D.; Ikizler, T.A.; Himmelfarb, J. Effect of renal transplantation on biomarkers of inflammation and oxidative stress in end-stage renal disease patients. Transplantation 2005, 79, 914–919. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Main modifications of lipoprotein metabolism induced by chronic kidney disease (CKD). CKD induces a deep modification in lipoprotein metabolism resulting in the accumulation of pro-atherogenic particles such as intermediary density lipoprotein (IDL) and triglyceride-rich lipoproteins (TGRL). Main modifications are listed below: In CKD, ApoA1 and A2 levels are decreased resulting in low level of circulating high density lipoprotein (HDL) (❶). In CKD, modifications of ApoA1 decrease HDL binding to macrophages and participate in the observed impaired cholesterol efflux (❷). Nascent HDL are transformed into discoid HDL-3 and then spherical HDL-2 enriched in cholesterol by the action of lecithin-cholesterol acyltransferase (LCAT). In CKD, LCAT level and activity are impaired (❸), leading to the accumulation of HDL-3 and reduced level of HDL-2 (❹). Thus, low HDL-2 concentration result in less transfer of triglycerides from TGRL to HDL-2 by cholesterol-ester transfer protein (CETP). Moreover, HDL-2 fail to enrich very-low density lipoprotein (VLDL) and chylomicrons with ApoC and E, essential for the binding and activation of lipoprotein lipase (LPL) respectively and such defect, associated with evidence of peripheral LPL lacking in CKD, leads to a reduced release of triglycerides into peripheral tissues and leads to an accumulation of TGRL (❺). IDL and remnants accumulate in CKD because of a down-regulation of LDL receptor protein (LRP) (❻), the lower level of CETP (❹) and the down-regulation of hepatic lipase (HL) expression (❼). A part of VLDL accumulates because of the down-regulation of the VLDL-receptor (VLDL-R) in myocytes and adipocytes (❽). Abbreviations: refer to abbreviation section.
Figure 1. Main modifications of lipoprotein metabolism induced by chronic kidney disease (CKD). CKD induces a deep modification in lipoprotein metabolism resulting in the accumulation of pro-atherogenic particles such as intermediary density lipoprotein (IDL) and triglyceride-rich lipoproteins (TGRL). Main modifications are listed below: In CKD, ApoA1 and A2 levels are decreased resulting in low level of circulating high density lipoprotein (HDL) (❶). In CKD, modifications of ApoA1 decrease HDL binding to macrophages and participate in the observed impaired cholesterol efflux (❷). Nascent HDL are transformed into discoid HDL-3 and then spherical HDL-2 enriched in cholesterol by the action of lecithin-cholesterol acyltransferase (LCAT). In CKD, LCAT level and activity are impaired (❸), leading to the accumulation of HDL-3 and reduced level of HDL-2 (❹). Thus, low HDL-2 concentration result in less transfer of triglycerides from TGRL to HDL-2 by cholesterol-ester transfer protein (CETP). Moreover, HDL-2 fail to enrich very-low density lipoprotein (VLDL) and chylomicrons with ApoC and E, essential for the binding and activation of lipoprotein lipase (LPL) respectively and such defect, associated with evidence of peripheral LPL lacking in CKD, leads to a reduced release of triglycerides into peripheral tissues and leads to an accumulation of TGRL (❺). IDL and remnants accumulate in CKD because of a down-regulation of LDL receptor protein (LRP) (❻), the lower level of CETP (❹) and the down-regulation of hepatic lipase (HL) expression (❼). A part of VLDL accumulates because of the down-regulation of the VLDL-receptor (VLDL-R) in myocytes and adipocytes (❽). Abbreviations: refer to abbreviation section.
Toxins 08 00376 g001
Figure 2. Major reactive lipid aldehydes derived from poly unsaturated fatty acids (PUFAs) oxidation. Malondialdehyde (MDA) results from the oxidation of various polyunsaturated fatty acids containing more than two double bounds. MDA binds with nucleic acids or lysine amino-groups and creates toxic adducts called advanced peroxidation lipid end products (ALEs). On ApoB, these adducts were associated with atherosclerosis. 4-hydroxy-2-nonenal (4-HNE) and 4-hydroxy-2-hexenal (4-HHE) result respectively from the oxidation of ω6 PUFAs and ω3 PUFAs. They can react with proteins by a Michael addition mechanism and create ALEs. These ALEs disrupt several biological functions and lead to the formation of atherosclerosis and foam cells. Abbreviations: refer to abbreviation section.
Figure 2. Major reactive lipid aldehydes derived from poly unsaturated fatty acids (PUFAs) oxidation. Malondialdehyde (MDA) results from the oxidation of various polyunsaturated fatty acids containing more than two double bounds. MDA binds with nucleic acids or lysine amino-groups and creates toxic adducts called advanced peroxidation lipid end products (ALEs). On ApoB, these adducts were associated with atherosclerosis. 4-hydroxy-2-nonenal (4-HNE) and 4-hydroxy-2-hexenal (4-HHE) result respectively from the oxidation of ω6 PUFAs and ω3 PUFAs. They can react with proteins by a Michael addition mechanism and create ALEs. These ALEs disrupt several biological functions and lead to the formation of atherosclerosis and foam cells. Abbreviations: refer to abbreviation section.
Toxins 08 00376 g002
Figure 3. Main effects of oxidized lipids and lipoproteins in chronic kidney disease (CKD). CKD is associated with increased oxidative stress, which promotes covalent modifications of lipids and lipoproteins. Lipid products of this unbalanced metabolism are oxidized phospholipids (oxPLs), fatty acid peroxidation products (FAPPs), oxysterols and F2-isoprostanes. Posttranslational modification derived products (PTMDPs) are the result of an enhanced myeloperoxidase (MPO) activity in CKD, an increased carbamylation and a massive production of advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs). ALEs are derived from lipid aldehydes issued from peroxidation of fatty acids (FAPPs). MPO catalyzes the nitrosilation on phospholipids to create oxPLs (❶). MPO are also involved in carbamylation process by the addition of thiocyanate on proteic residues (❷). Lipoproteins are also modified in CKD. First, triglyceride-rich lipoproteins (TGRL) have an impaired metabolism leading to their accumulation. Low-density lipoproteins (LDL) exhibit large amount of toxic oxidized (oxLDL) and carbamylated (cLDL) forms in CKD. These modifications lead to impaired functions and promote the progression of cardiovascular disease (CVD) especially in hemodialysis (HD) patients. High density lipoproteins (HDL) are also modified in CKD. Their whole metabolism is impaired and this dysregulation leads to many pro-atherosclerotic effects. MPO and carbamylation are greatly responsible for lipoproteins’ modifications and dysfunctions (❸) so are FAPP products that generate ALEs, especially on apolipoproteins A and B (ApoB) (❹). Abbreviations: refer to abbreviation section.
Figure 3. Main effects of oxidized lipids and lipoproteins in chronic kidney disease (CKD). CKD is associated with increased oxidative stress, which promotes covalent modifications of lipids and lipoproteins. Lipid products of this unbalanced metabolism are oxidized phospholipids (oxPLs), fatty acid peroxidation products (FAPPs), oxysterols and F2-isoprostanes. Posttranslational modification derived products (PTMDPs) are the result of an enhanced myeloperoxidase (MPO) activity in CKD, an increased carbamylation and a massive production of advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs). ALEs are derived from lipid aldehydes issued from peroxidation of fatty acids (FAPPs). MPO catalyzes the nitrosilation on phospholipids to create oxPLs (❶). MPO are also involved in carbamylation process by the addition of thiocyanate on proteic residues (❷). Lipoproteins are also modified in CKD. First, triglyceride-rich lipoproteins (TGRL) have an impaired metabolism leading to their accumulation. Low-density lipoproteins (LDL) exhibit large amount of toxic oxidized (oxLDL) and carbamylated (cLDL) forms in CKD. These modifications lead to impaired functions and promote the progression of cardiovascular disease (CVD) especially in hemodialysis (HD) patients. High density lipoproteins (HDL) are also modified in CKD. Their whole metabolism is impaired and this dysregulation leads to many pro-atherosclerotic effects. MPO and carbamylation are greatly responsible for lipoproteins’ modifications and dysfunctions (❸) so are FAPP products that generate ALEs, especially on apolipoproteins A and B (ApoB) (❹). Abbreviations: refer to abbreviation section.
Toxins 08 00376 g003
Table 1. Concentrations of plasma oxidized lipids and lipoproteins in control and CKD patients.
Table 1. Concentrations of plasma oxidized lipids and lipoproteins in control and CKD patients.
NormalCKDClearanceHD BehaviorReferences
Oxysterols (Total)Liver metabolismGenerated during HD session[113,114]
7-ketocholesterol, nM32.3 ± 16.742.2 ± 30.1 δ
7β-OH-cholesterol, nM14.4 ± 7.742.6 ± 24.1 δ
Oxidized PhospholipidsEnzymatic detoxificationReduced after HD session[56,103,115]
OxPL/ApoB ratio, AU0.068 ± 0.070.138 * ± 0.170 *
PUFAs Aldehydes [7,9,23,116,117,118]
Malondialdehyde (MDA), μg/L257.7 ± 81.7388.8 ± 21.6 δEnzymatic detoxification Renal excretionControversial (decrease, no change and increase)
4-hydroxy-decenal, μg/L10.3 ± 7.136.6 ± 22.3 δEnzymatic detoxification, rennal excretion4-HNE: Reduced after HD session
4-hydroxy-2-hexenal (4-HHE), μg/L25.1 ± 9.963.8 ± 25.3 δ
4-hydroxy-2-nonenal (4-HNE), μg/L16.4 ± 9.0117.3 ± 47.7 δ
4-hydroxy-octenal, μg/L10.7 ± 3.627.8 ± 13.8 δ
Arachidonic Acid By-Products of Lipid PeroxidationRenal excretion, Enzymatic detoxificationNo change[119,122,123,124,125,126,127,128]
Total F2-isoprostanes, pg/mL *162 ± 73270 ± 10 δ
Unesterified F2-isoprostanes, pg/mL37.6 ± 17.296.2 ± 48.8 δ
Esterified F2-isoprostanes, pg/mL146.8 ± 58.4220.4 ± 154.8 δ
Lipoprotein Products
ApoB48 level, mg/L3.7 ± 2.319.3 ± 13.9 δ [33]
Oxidized LDL, mg/L0.22 ± 0.051.92 ± 0.29 δAccumulation in atherosclerotic lesionsIncreased after HD session[53,54,55,56]
3-chlorotyrosine, μmol/mol of tyrosine<0.33.5 ± 0.5 δ--[64]
Lp(a) level, mg/dL18.4 ± 22.823.4 ± 34.6 δRenal and hepatic clearanceNo changes or increased after HD session[56,109,110,111]
Data are expressed as means ± SD. * computed from the data available in the original article, δ p < 0.05 vs. control; Lp(a): lipoprotein A, PUFAs: polyunsaturated fatty acids.

Share and Cite

MDPI and ACS Style

Florens, N.; Calzada, C.; Lyasko, E.; Juillard, L.; Soulage, C.O. Modified Lipids and Lipoproteins in Chronic Kidney Disease: A New Class of Uremic Toxins. Toxins 2016, 8, 376.

AMA Style

Florens N, Calzada C, Lyasko E, Juillard L, Soulage CO. Modified Lipids and Lipoproteins in Chronic Kidney Disease: A New Class of Uremic Toxins. Toxins. 2016; 8(12):376.

Chicago/Turabian Style

Florens, Nans, Catherine Calzada, Egor Lyasko, Laurent Juillard, and Christophe O. Soulage. 2016. "Modified Lipids and Lipoproteins in Chronic Kidney Disease: A New Class of Uremic Toxins" Toxins 8, no. 12: 376.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop