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Foley RN Clinical epidemiology of cardiovascular disease in chronic kidney disease. They contribute to cardiovascular events via inhibiting endothelial NO production and promoting superoxide production.

Maggi et al. showed that LDL isolated from CKD patients is more susceptible to in vitro peroxidation than LDL from healthy subjects [ 59 ]. In lipid peroxidation, acrolein, thiobarbituric acid reactive substance TBARS , 4-hydroxynonenal, and malondialdehyde are produced [ 60 ]. There was a significant elevation in malondialdehyde levels in CKD patients with cardiovascular disease compared to CKD patients without cardiovascular disease, further suggesting that oxidative stress potentiates artherosclerosis in CKD [ 61 ].

Anemia is regarded as a nearly universal complication of CKD. While the rate of red blood cell production is reduced in CKD, shortened red blood cell life span also contributes to renal anemia. Increased peroxidation in CKD due to oxidative stress can lead to a profound modification of cellular structures and function, impairing erythrocytes.

Serum levels of MDA in erythrocytes are higher in HD patients, as shown in previous studies, along with severe vitamin deficiency, thus explaining the shortened lifespan of erythrocytes in CKD patients [ 62 ].

In a study with consecutive HD patients, serum levels of MDA, protein carbonyls, and 4-hydroxynonenal were inversely proportional to hemoglobin levels.

The correction of renal anemia by epoetin subsequently reduced the serum levels of aldehydic lipid peroxidation products [ 63 ].

Another study revealed that antioxidant therapy improved the renal anemia in CKD patients while reducing their requirement for erythropoiesis-stimulating agents ESAs [ 64 , 65 ]. In recent years, intravenous IV iron supplementation has been increasingly recognized as a therapy for anemia in CKD patients.

The key component of this treatment is to enhance the efficacy of erythropoiesis-stimulating agents ESAs by reducing the requirement for ESAs, increasing hemoglobin levels and improving the cost-effectiveness of ESA treatment [ 65 ].

However, since iron is a cellular transition element and its ionic forms participate in electron transfer reactions, it can also produce free radicals. Our prospective cohort study showed that iron supplementation was associated with a lower risk of all-cause mortality in CKD patients [ 66 ].

The general benefits of iron treatment revealed in other studies included achieving target hemoglobin levels, reducing hospitalization and improving survival [ 67 , 68 , 69 ]. The clinical decision to use IV iron therapy should be based on a risk-benefit analysis [ 52 ].

Under conditions of oxidative stress, ROS tend to modify the function of proteins directly via the formation of oxidized amino acids. ROS can also react with other substrates to form potent pro-oxidant species, such as AGEs. AGEs promote the alteration of vascular structure and function while further enhancing oxidative stress and inflammation.

Besides, the presence of AGEs in β2-microglobulin deposits in long-term HD patients suggests that protein denaturation from oxidative stress might increase the risk for amyloidosis [ 68 ].

Nutritional status decline is highly prevalent in CKD and is usually associated with high rates of morbidity and mortality. For CKD patients, the International Society of Renal Nutrition and Metabolism ISRNM had proposed a common nomenclature and diagnostic criteria for protein-energy wasting syndrome PEW , a condition of concurrent losses of protein and energy stores with cachexia as the end stage [ 70 ].

While there are many contributing factors of PEW in CKD, such as decreased intake, anabolism, and other comorbidities, increased oxidative stress in CKD is being considered one of the major causes. Increased oxidative signaling is associated with muscle insulin resistance, atherosclerosis, and muscle wasting [ 71 , 72 ].

Upregulation of NADPH oxidases in CKD creates signals to induce muscle insulin resistance [ 73 ]. Elevated inflammatory markers in CKD is also associated with loss of muscle mass [ 73 ].

Besides, there is increased oxidation of protein, lipid, and DNA due to depletion of dietary antioxidants, protein stores, and systemic inflammation in CKD [ 71 , 72 ]. As oxidative stress in CKD leads to a chronic inflammatory state, the coordination between polymorphonuclear leukocytes PMNLs , lymphocytes, and antigen-presenting cells APCs can be impaired, leading to decline in host defense responses.

Uremia disrupts the priming of immune cells and enhances apoptosis of PMNLs [ 74 , 75 ]. Besides, as demonstrated in vitro, monocytes from HD patients have characteristics of senescent cells, suggesting an increased susceptibility to apoptosis [ 76 ].

Terminal differentiation of monocyte-derived dendritic cells in CKD stage IV patients is also affected [ 77 ]. Lim et al. has shown that dendritic cells, when exposed in uremic microenvironments, exhibited decreased endocytosis and impaired maturation [ 78 ]. To combat oxidative stress and its clinical consequences in CKD patients, the use of antioxidants is vigorously promoted.

The two primary goals of antioxidative stress management are to slow the progression of CKD and to reduce its clinical consequences, such as atherosclerosis.

Table 2 summarizes the relevant clinical studies on antioxidant therapies discussed here. Ivanovski et al. demonstrated that treatment with N -acetylcysteine NAC , which is a precursor to the antioxidant glutathione, can reduce nitrosative oxidative stress and atheromatous plaque progression in a murine model of CKD-accelerated atherosclerosis [ 79 ].

NAC pretreatment was shown to reduce endothelial dysfunction due to uremic toxins by decreasing ROS-induced expression of NF-κB [ 80 ]. In a mouse model of diabetic nephropathy, NAC reduced renal MDA levels [ 81 ].

Possible beneficial effects of NAC were shown by an increase in hematocrit and decreases in 8-isoprostane and ox-LDL in HD patients on NAC therapy [ 82 ]. Besides, Tepel et al.

However, the role of NAC in long-term therapy to reduce oxidative stress complications in CKD patients might be limited due to reduced clearance of NAC in these patients [ 84 ]. Two of the most commonly known antioxidants are vitamins C and E.

Vitamin E can protect cell membranes from lipid peroxidation, and vitamin C can directly scavenge ROS superoxide anions and hydroxyl radical. A number of small clinical studies have reported that the administration of vitamins E and C can help reduce levels of oxidative stress biomarkers.

Morimoto et al. reported that polysulfone membranes coated with vitamin E exerted antioxidant activity via reducing ADMA in HD patients [ 85 ]. The goal of vitamin E supplementation is to increase α-tocopherol levels in plasma membranes, as it is a compound with the highest bioavailability in the class of vitamin E.

In CKD patients, serum α-tocopherol levels are markedly decreased, suggesting an increased need for α-tocopherol in this population [ 86 ].

In terms of clinical benefits, α-tocopherol supplementation has been shown to reduce the risk of cardiovascular diseases and to increase erythrocyte antioxidants [ 87 ].

The Secondary Prevention with Antioxidants of Cardiovascular Disease in End-Stage Renal Disease SPACE study by Boaz et al. In the Anti-Oxidant Therapy in Chronic Renal Insufficiency ATIC Study [ 89 ], a treatment strategy comprising pravastatin, vitamin E and decreasing homocysteine in order to combat oxidative stress resulted in a significant decline in common carotid intima-media thickness and an improvement in brachial artery flow-mediated dilatation and urinary albumin excretion.

These outcomes implied that an active treatment strategy could be useful in safely reducing the burden of cardiovascular events in CKD via targeting oxidative stress. In addition, Takouli et al. reported that vitamin E-coated acetate dialysis membranes have reduced biomarker levels of oxidative stress and inflammation [ 90 ].

A vitamin E-coated dialysis membrane comprises a multilayer membrane with lipid-soluble α-tocopherol on the blood surface side, which allows direct free radical scavenging. demonstrated that the use of a vitamin E-bound dialysis membrane can reduce lymphocyte 8-OH-dG levels and preserve plasma vitamin E concentration, suggesting a reduction in oxidative stress [ 91 ].

Existing preclinical and clinical studies have established that oxidative stress plays an important role in CKD. In addition to being an important pathogenic mechanism, oxidative damage is further complicated by uremic status, the dialysis system, and concomitant comorbidities related to CKD patients.

Anemia, malnutrition, and other systemic inflammatory processes are associated with oxidative stress. Several clinical biomarkers have been helpful in investigating the degree of oxidative stress in CKD, but their clinical application remains to be further investigated.

Various therapeutic strategies have emerged, such as the antioxidants vitamins E and C. Current clinical evidence seems promising, but large-scale, randomized controlled trials with long-term follow-up periods will be required to reach a definitive decision on management options.

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Abstract Over generation of reactive molecules leads to oxidative stress which is a causative agent of many diseases occurrence including kidney disease.

Oxidative stress at kidney tissue induces the cellular signaling pathways which may activate construction of growth and pro-inflammatory mediators, finally, lead to glomerulosclerosis and renal fibrosis. Both enzymatic and low molecular weight antioxidants are able to ameliorate these injurious impacts.

Therefore, antioxidants are chemoprotective agents that neutralize cellular macromolecules oxidative damages. Numerous components are recognized to exert antioxidative properties that are originated from medicinal plants and have been administering as resourceful therapeutic approach in various diseases such as kidney failure.

Therefore, we summarized the nephron-protective effects of several medicinal plants which are recently investigated at clinical trials.

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DM is supported by the Clinical Research Fund of UZ Leuven, by the Fund for Scientific Research G0BN, and by a research grant from the European Society for Pediatric Nephrology. FJ is a Fellow of the Fonds National de la Recherche Scientifique.

Department of Microbiology and Immunology, Laboratory of Nephrology, KU Leuven — University of Leuven, , Leuven, Belgium. Department of Nephrology, Dialysis and Renal Transplantation, University Hospitals Leuven, , Leuven, Belgium.

Department of Nephrology, Sahlgrenska University Hospital, Gothenburg, Sweden. Department of Pharmaceutical and Pharmacological Sciences, Pharmaceutical Analysis, KU Leuven — University of Leuven, , Leuven, Belgium.

Department of Development and Regeneration, Laboratory of Pediatrics, PKD Group, KU Leuven — University of Leuven, , Leuven, Belgium. Department of Pediatric Nephrology, University Hospitals Leuven, , Leuven, Belgium. Division of Nephrology, Department of Internal Medicine, University of Liège Hospital ULg CHU , Liège, Belgium.

Groupe Interdisciplinaire de Génoprotéomique Appliquée GIGA , Cardiovascular Science, University of Liège, Liège, Belgium. You can also search for this author in PubMed Google Scholar.

Correspondence to Kristien Daenen. Reprints and permissions. Daenen, K. et al. Oxidative stress in chronic kidney disease. Pediatr Nephrol 34 , — Download citation.

Received : 21 December Revised : 03 June Accepted : 14 June Published : 13 August Issue Date : 01 June Anyone you share the following link with will be able to read this content:.

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Am J Clin Nutr — Article CAS PubMed Google Scholar Download references. Funding DM is supported by the Clinical Research Fund of UZ Leuven, by the Fund for Scientific Research G0BN, and by a research grant from the European Society for Pediatric Nephrology.

Author information Author notes Kristien Daenen and Asmin Andries contributed equally to this work. View author publications. Ethics declarations Conflict of interest The authors declare that they have no conflict of interest.

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Among the various endogenous defences against ROS, glutathione homeostasis is critical for a cellular redox environment.

Glutathione-linked enzymatic defences of this family include Gpx, glutathione-S-transferase GST , glutaredoxins Grx , thioredoxins Trx , and peroxiredoxins Prx [ 51 ].

Many of these proteins are known to interact with each other, forming redox networks that have come under investigation for their contribution to dysfunctional oxidant pathways. Mitochondrial-specific isoforms of these proteins also exist and include Grx2, Grx5, Trx2 and Prx3 [ 52 - 54 ], which may be more critical for cell survival compared to their cystolic counterparts [ 50 ].

Mitochondrial dysfunction, resulting in depleted ATP synthesis, has the potential to reduce the redox control of glutathione since the rate of glutathione synthesis is ATP-dependent [ 55 ]. Intracellular synthesis of glutathione from amino acid derivatives glycine, glutamic acid and cysteine accounts for the majority of cellular glutathione compared with extracellular glutathione uptake [ 56 ].

Antioxidant networks in which there is interplay, crosstalk and synergism to efficiently and specifically scavenge ROS, may also exist.

If this is the case, these antioxidant networks could be harnessed to develop poly-therapeutic antioxidant supplements to combat oxidant-related pathologies, like CKD and CVD.

The role of oxidative stress in upstream transcriptional gene regulation is becoming increasingly recognised. Not only does this provide insight into the physiological role of oxidative stress, but presents regulatory systems that are possibly prone to deregulation. Furthermore, these sites present targets for pharmacological intervention.

Peroxisome proliferator-activated receptors PPARs are members of the nuclear hormone receptor superfamily of ligand-dependant transcription factors which have been shown to alter during CKD and CVD [ 57 - 59 ]. They have important roles in the transcriptional regulation of cell differentiation, lipid metabolism, glucose homeostasis, cell cycle progression, and inflammation.

Peroxisome proliferator gamma coactivator PGCα , in association with PPARγ activation, leads to a variety of cellular protective responses including mitochondrial biogenesis [ 57 ]. PPARγ regulation in chronic disease is increasingly recognised, with oxidative stress as the unifying initiating feature.

Omega-3 polyunsaturated fatty acids PUFA reduce inflammation in kidney tubular epithelial cells by upregulating PPARγ [ 60 ].

Nrf2 is a nuclear transcription factor that is suppressed in the cytoplasm by the physical binding of Keap1 preventing its translocation into the nucleus. Nrf2 is activated by a loss of Keap1 binding by alterations in cellular redox status, such as increased ROS, by-products of oxidative damage, and reduced antioxidant capacity, thereby promoting its transcriptional response at the ARE [ 63 ].

The ARE is a vital component of the promoter regions of genes encoding detoxifying, antioxidant, and glutathione-regulatory enzymes such as quinone-reductase, glutathione-peroxidases, glutathione-reductase, thioredoxins and thioredoxin-reductase, peroxiredoxins, gamma-glutamyl cysteine, heme-oxygenase-1 HO-1 , CAT, SOD metallothionein and ferritin [ 64 - 67 ].

Important to note is that by-products of oxidative damage such a 4-hydroxynoneal and J-isoprostanes act as endogenous activators of Nrf2 [ 68 , 69 ]. Recent pharmacological protocols have allowed the modulation of this pathway to enhance the capabilities of cells to combat oxidative stress and inflammation [ 70 ].

Chronic diseases of the kidney possess various commonalities to chronic disease of the cardiovascular system which can be linked through pathways controlled by oxidative stress, as shown in Figure 1. Vascular, cellular and biochemical factors all contribute. Increased serum uric acid levels hyperuricaemia can arise from increased purine metabolism, increasing age and decreased renal excretion, and have harmful systemic effects.

Hyperuricaemia is associated with an increased risk for development and progression of CKD. Hyperuricemia is also a risk factor associated with coronary artery disease [ 71 ], left ventricular hypertrophy [ 72 ], atrial fibrillation [ 73 ], myocardial infarction [ 74 ] and ischemic stroke [ 75 ].

Additionally, uric acid synthesis can promote oxidative stress directly through the activity of xanthine oxidoreductase. This enzyme is synthesized as xanthine dehydrogenase, which can be converted to xanthine oxidase by calcium-dependant proteolysis [ 80 ] or modification of cysteine residues [ 81 ].

In doing so, the enzyme loses its capacity to bind NADH by alterations in its catalytic site and, instead, transfers electrons from O 2 , thereby generating O 2 - [ 82 ]. However, the role of uric acid in many conditions associated with oxidative stress is not clear and there are experimental and clinical data showing that uric acid also has a role in vivo as an anti-oxidant [ 83 ].

Chronic kidney disease and cardiovascular disease are unified by oxidative stress. Mutual risk factors influence the development and progression of CKD and CVD and can either be modifiable diabetes, obesity, metabolic syndrome, smoking or non-modifiable genetic predisposition, increasing age, acute injury.

Oxidative stress has been implicated in the majority of initiating factors. The kidney is a vital source of L-arginine which is a precursor for nitric oxide NO. A reduction in renal mass can therefore reduce the production of L-arginine and NO activity. NO is vital for regular vascular endothelial cell function, and decreased amounts have the potential to manifest into CVD [ 84 ].

Additionally, oxidized low density lipoprotein ox-LDL , a by-product of oxidative damage in human blood, plays a pivotal role in the pathogenesis of atherosclerosis [ 85 ]. There is also a possible link between CVD and CKD that is regulated by oxidative stress through a functional mitochondrial angiotensin system [ 86 ].

Angiotensin type II receptors were co-localised with angiotensin on the inner mitochondrial membrane of human mononuclear cells and mouse renal tubular cells. This system was found to modulate mitochondrial NO production and respiration. The current state of antioxidant therapies for CKD and CVD is one of promise, but not without controversy.

In vitro studies commonly identify agents that are able to detoxify harmful oxidants. However, these studies are criticised for their isolated, non-holistic, nature [ 87 , 88 ]. It is largely the positive pre-clinical results from in vivo studies, usually in rodents, which drive progress for applicability in chronic human disease, but even these show considerable discrepancies in translation into patients.

The following trials of antioxidants need then to be rigorous, identifying not only any positive patient outcomes, but also the underlying mechanism, and of course any deleterious outcome. Various approaches have been taken to reduce oxidative stress in models of CKD and accelerated CVD, ranging from reducing oxidant intake in food stuffs [ 93 , 94 ] to targeted polypharmaceutical compounds.

The benefit of rigorous review of outcome from antioxidant therapies in either CKD or CVD is that the primary and secondary outcomes related to both can be measured.

In the following section, some antioxidants used for CKD or CVD are reviewed, as shown in Figure 2. N-acetyl cysteine NAC acts as an essential precursor to many endogenous antioxidants involved in the decomposition of peroxides [ 95 ]. NAC attenuates oxidative stress from various underlying causes by replenishing intracellular glutathione stores.

Glutathione is synthesized in the body by three amino acids by the catalysing of intracellular enzymes gamma-glutamylcysteine synthetase and glutathione synthetase. L-glutamic acid and glycine are two precursors of glutathione that are biologically and readily available.

However, the limiting precursor to glutathione biosynthesis and the third amino acid, L-cysteine, is not readily available in a human diet.

Although the primary basis for NAC supplementation is to replenish cellular cysteine levels to maintain intracellular glutathione and thus redox control, the sulfhydral-thiol group of L-cysteine is also able to exert direct antioxidant effects by scavenging free radicals, and NAC may also exert its protective effects against 2,3,5-tris glutathion-S-yl -hydroquinone toxicity.

The results of NAC supplementation in kidney disease have been variable and largely dependent on the type and cause of kidney injury and also the timing of treatment. In cultured human proximal tubular epithelial cells, NAC reduced lipid peroxidation and maintained the mitochondrial membrane potential, thereby preventing apoptosis following H 2 O 2 administration [ 97 ].

Although NAC had no significant effect on markers of oxidative stress and inflammation in rats following unilateral ureteral obstruction [ 98 ], it reduced kidney malondialdehyde MDA levels in a diabetic mouse model [ 99 ].

The treatment of CKD patients with NAC with the aim of improving renal function and preventing ESKD has been largely disappointing, with no evidence of reduction in proteinuria [ , ]. However, NAC seems to exert the greatest antioxidant and anti-inflammatory properties when used against the greatest injury, such as in ESKD patients receiving either haemodialysis or peritoneal dialysis.

In those cases, NAC reduced serum 8-isoprostane and the inflammatory cytokine IL-6 [ , ]. A recent systemic review on antioxidant therapy in hemodialysis patients highlighted NAC as the most efficacious agent in decreasing oxidative stress [ ].

The effect of NAC on cardiovascular pathologies is less well investigated than CKD. Crespo et al. Endothelial dysfunction caused by uremic toxins such as indoxyl sulphate induced ROS-dependent expression of the pro-inflammatory and pro-oxidant nuclear factor-κB NF-κB , which was ameliorated by NAC pre-treatment [ ].

Cellular sites for antioxidant therapy targets in CKD and CVD. Inflammation, lipid peroxidation and reactive oxygen species ROS from mitochondrial, cytoplasmic and extracellular sources contribute to oxidative stress.

Vitamin E incorporates into the phospholipid bilayer halting lipid peroxidation chain reactions. Omega ω -3 fatty acids displace arachadonic acid in the cell membrane and thus reduce arachadonic acid-derived ROS, but also significantly reduce inflammation and subsequent fibrosis.

The cysteine residue of N-acetyl-cysteine NAC is a precursor for glutathione GSH synthesis, and the thiol group is able to scavenge ROS directly. Bardoxolone exerts transcriptional control by promoting nuclear translocation of Nrf2, facilitating antioxidant response element ARE binding that upregulates endogenous antioxidant enzyme activity.

Allopurinol inhibits xanthine oxidase-derived ROS and the damaging effects of hyperuricemia. Coenzyme Q 10 CoQ 10 enhances the efficacy of electron transport in the mitochondria, thereby reducing mitochondrial-derived ROS — it is also able to directly scavenge ROS.

L-carnitine enhances mitochondrial fatty acid synthesis and subsequent ATP production and thereby maintains cell health. L-arginine is a precursor for nitric oxide which restores endothelial function.

Vitamin E, or α-tocopherol, is a lipid-soluble antioxidant that incorporates into the plasma membrane of cells, thereby scavenging free radicals, mainly the peroxyl radical, and halting lipid peroxidation chain reactions [ ].

A benefit of α-tocopherol is its ability to restore its antioxidant capacity from its oxidized form following free radical scavenging, and incorporate back into the plasma membrane. Vitamin C ascorbic acid is able to directly reduce α-tocopherol [ - ], and intracellular glutathione and lipoic acid can restore α-tocopherol indirectly by restoring vitamin C [ ].

This is a prime example of a cellular antioxidant network prone to dysregulation. Administration of α-tocopherol to kidney proximal tubular cells in culture decreased cisplatin-induced ROS and increased cell viability [ ].

The beneficial effects of α-tocopherol are not limited to its antioxidant properties, and recently attention has focused on its blood oxygenising and endogenous cell signalling functions [ ]. Vitamin E foodstuffs primarily consist of α-tocotreinol, an isoform of α-tocopherol which has higher antioxidant efficacy in biological membranes.

Despite this, the uptake and distribution of α-tocotreinol is far less than α-tocopherol. Therefore, the basis of vitamin E supplementation is to enhance α-tocopherol levels in cell plasma membranes to prevent lipid peroxidation and resultant oxidative stress.

One drawback of α-tocopherol is that it takes several days of pre-treatment to exhibit antioxidant effects [ ]. Vitamin E therapy has been extensively researched for renal and cardiovascular benefits in human disease populations. Nevertheless, confounding reports mean there is a lack of consensus as to whether vitamin E therapy induces an overall benefit.

It is known that patients with CKD stage 4 display the largest decrease in serum α-tocopherol levels following a progressive decline from stage 1 indicating an increased need for α-tocopherol in the CKD population [ ]. Interestingly, within the same cohort of patients, a positive correlation of serum α-tocopherol levels and GFR was found [ ].

A large scale trial concluded that vitamin E supplementation to cardiovascular high-risk patients over 4. The results from the Selenium and Vitamin E Cancer Prevention Trial SELECT are of greater concern.

They suggest that vitamin E supplementation significantly increases the risk of prostate cancer for young healthy men [ ].

Most studies finding beneficial outcomes of α-tocopherol supplementation have largely focused on the ESKD dialysis populations compared to healthy controls and found a reduced risk of CVD, decreased oxidative stress and increased erythrocyte antioxidants SOD, Gpx and CAT [ - ].

The use of α-tocopherol in CKD patients is not without controversy. However, this study was highly criticized owing to a bias in data analysis and numerous methodological flaws [ - ]. The apparent lack of clarity surrounding vitamin E supplementation and associated renal and cardiovascular outcomes appears to stem largely from differences in trial design and failure to specify the form of tocopherol used.

The heart and kidneys contain the highest endogenous levels of co-enzymes Co Q 9 and CoQ 10 compared to all other organs [ , ]. This is likely due to the respective reliance on aerobic metabolism and high density of mitochondria in the intrinsic functioning cells from these organs.

It is imperative that endogenous CoQ 10 levels are maintained to ensure mitochondrial health, and this forms the rationale for CoQ 10 therapy. CoQ 10 is a fundamental lipid-soluble component of all cell membranes including those enclosing subcellular compartments.

The continual oxidation-reduction cycle, and existence of CoQ 10 in three different redox states, explains its actions as an important cellular redox modulator through its pro-oxidant and antioxidant actions. The fully oxidised form of CoQ 10 , or ubiquinone, is able to accept electrons, primarily from NADH, to become fully reduced ubiquinol - CoQ 10 -H 2.

The reduced form of CoQ 10 is able to give up electrons, thereby scavenging free radicals. The major antioxidant role of CoQ 10 is in preventing lipid peroxidation directly, and by interactions with α-tocopherol [ ].

Ubiquinol is able to donate a hydrogen atom and thus quench peroxyl radicals, preventing lipid peroxidation chain reactions. CoQ 10 and α-tocopherol co-operate as antioxidants through the actions of CoQ 10 -H 2 restoring α-tocopheroxyl back to α-tocopherol [ , ].

However, the reactivity of α-tocopherol with peroxy radicals far exceeds that of ubiquinol with peroxyl radicals, suggesting that, in vivo , ubiquinols do not act as antioxidants but regenerate the antioxidant properties of α-tocopherols [ ].

This is in accordance with in vivo studies investigating the effects of CoQ 10 supplementation which have primarily found a limited antioxidant capacity.

Nonetheless, many in vitro studies demonstrate antioxidant properties of CoQ 10 in single cells, and benefits of CoQ 10 supplementation in humans are attributed to its ability to maintain efficient mitochondrial energy metabolism and thus prevent mitochondrial dysfunction, rather than act as a direct cellular antioxidant.

CoQ 10 supplementation in vivo reduced protein oxidation in skeletal muscle of rats but had no effect on mitochondrial H 2 O 2 production in the kidney [ ]. Recently, CoQ 10 supplementation improved left ventricular diastolic dysfunction and remodelling and reduced oxidative stress in a mouse model of type 2 diabetes [ ].

CoQ 10 supplementation in CVD patients also receiving statin therapy is becoming increasingly popular due to the CoQ 10 -inhibitory actions of statins. CoQ 10 levels decrease with age, but there are no studies measuring endogenous CoQ 10 levels in CKD or CVD patients and this could prove vital in the identification of population where CoQ 10 therapy may have beneficial outcomes.

Inflammation and fibrosis are causes, as well as consequences, of oxidative stress [ , ]. Direct targeting of inflammatory and fibrotic pathways with more specific modifying compounds presents a way to indirectly decrease oxidative stress in chronic pathologies.

Long chain omega-3 PUFA, including docosahexanoic acid DHA and eicosapentanoic acid EPA , have been investigated in a large range of in vitro and in vivo models and found to possess anti-inflammatory properties.

Recently, omega-3 fatty acid treatment of peripheral blood mononuclear cells from pre-dialysis CKD patients reduced the inflammatory markers IL-6, IL-1β, tumor necrosis factor TNF -α and C-reactive protein to levels observed in healthy subjects [ ].

DHA and EPA incorporate into the phospholipid bilayer of cells where they displace arachidonic acid. Arachidonic acid can generate ROS through the COX2 and xanthine oxidase inflammatory pathways.

Furthermore, chemoattractants derived from EPA are less potent that those derived from arachidonic acid [ , ]. Recently, in vitro studies determined that EPA and DHA attenuated TNF-α-stimulated monocyte chemoattractant protein MCP -1 gene expression by interacting with ERK and NF-κB in rat mesangial cells [ ].

Earlier evidence had shown that EPA and DHA inhibit NF-κB expression by stimulating PPARs in human kidney-2 cells in vitro [ 60 ].

Recently, a highly beneficial outcome of fish oil supplementation was found with heart failure patients with co-morbid diabetes [ ]. Clinical studies have found fish oil treatment modulates lipid levels [ , ], and has anti-thrombotic [ , ] and anti-hypertensive effects due to its vascular and endothelial actions [ ].

Allopurinol treatment aims is to inhibit xanthine oxidase to decrease serum uric acid and its associated toxic effects. Allopurinol and its metabolite, oxypurinol, act as competitive substrates for xanthine oxidase.

They enhance urinary urate excretion and block uric acid reabsorption by urate transporters in the proximal tubule, thereby facilitating enhanced uric acid excretion [ - ]. Allopurinol treatment of diabetic mice attenuated hyperuricaemia, albuminuria, and tubulointerstitial injury [ ]. Interventional studies of use of allopurinol in renal disease have shown improved uric acid levels, GFR, cardiovascular outcomes and delayed CKD progression.

Allopurinol given to ESKD patients on hemodialysis reduced the risk of CVD by decreasing serum low density lipoproteins, triglycerides and uric acid [ ].

Large, long-term interventional studies investigating kidney function in the CKD, and CVD, populations are needed to fully determine if allopurinol is cardio- and reno-protective via anti-oxidant mechanisms.

A different approach has been investigated by modulating pathways that respond to oxidative stress, rather than targeting ROS by directly increasing endogenous antioxidants. Bardoxolone methyl is a triterperoid derived from natural plant products that has undergone oleanolic acid-based modification [ ].

Its mechanism of action is largely unknown, however, it induces an overall antioxidative protective effect with anti-inflammatory and cytoprotective characteristics [ , ]. Bardoxolone methyl administered to mice ameliorated ischemia-reperfusion induced acute kidney injury by Nrf2-dependant expression of HO-1 and PPARγ [ ].

Its mechanism may also reside in regulating mitochondrial biogenesis given the involvement of PPARγ. Concurrent benefits to CVD will undoubtedly also be measured. Carnitine is an essential cofactor required for the transformation of free fatty acids into acylcarnitine and its subsequent transport into the mitochondria for β-oxidation [ ].

This underlies its importance in the production of ATP for cellular energy. Acylcarnitine is also essential for the removal of toxic fat metabolism by-products. Carnitine is obtained primarily from food stuffs, however it can be synthesised endogenously from the amino acid L-lysine and methionine [ ].

L-carnitine supplementation primarily benefits ESRD patients on hemodialysis and their associated cardiovascular complications, especially anemia. This is primarily due to the well-described decrease in serum free carnitine in maintenance hemodialysis patients compared to non-dialysis CKD and healthy patients [ ].

L-carnitine supplementation offsets renal anemia, lipid abnormalities and cardiac dysfunction in hemodialysis patients [ ].

Other measures of cardiac morbidity such as reduced left ventricular ejection fraction and increased left ventricular mass also significantly improved following low dose L-carnitine supplementation [ ].

Benefits to the peripheral vasculature have also been demonstrated by L-carnitine through a mechanism thought to involve an associated decrease in homocysteine levels [ ]. Interestingly, oxidative stress is a major characteristic of hemodialysis patients [ ].

As well as the physiological role of L-carnitine in mitochondrial fatty acid synthesis, oxidant reducing capabilities have also been demonstrated and may underlie the health benefits of L-carnitine therapy in CKD and CVD.

Ye et al. They suggest that this anti-apoptotic mechanism may also explain the demonstrated reduction in morbidity from cardiomyopathies in L-carnitine supplemented hemodialysis patients. The premise of L-arginine supplementation is to maintain NO signalling and thereby maintain vascular endothelial cell function.

L-arginine is a physiological precursor to NO and its availability and transport determine the rate of NO biosynthesis. CKD patients most often present with atherosclerosis, thromboembolitic complications, and endothelial dysfunction, primarily due to altered endothelium-dependant relaxation factors [ ].

It is believed that the impaired NO synthesis, common in CKD individuals, contributes significantly to their disease pathogenesis [ ]. L-arginine synthesis occurs in the liver and kidney, with the kidney functioning to maintain homeostatic plasma levels since the liver processes NO from the diet [ ].

The addition of L-aspartic acid or L-glutamic acid with L-citrulline and arginirosuccinic acid synthase as the rate determining enzyme forms L-arginine [ ]. The proximal tubular cells account for the majority of kidney NO synthesis [ , ], thus kidney damage and atrophy, a primary corollary of CKD, results in decreased synthesis of L-arginine.

The majority of research demonstrates decreased levels of NO production in CKD and CVD patients [ - ]. However, some research suggests NO activity increases [ , ]. These disparate findings highlight the need to measure L-arginine levels in patients before commencing L-arginine supplementation.

Rajapaske et al. During a state of oxidative stress, L-arginine supplementation was shown to decrease MDA, myeloperoxidase and xanthine oxidase and increase glutathionine in both heart and kidney tissue from rats [ ]. As such, L-arginine supplementation represents an approach to restoring a dysregulation of NO signalling and subsequent endothelial dysfunction in both chronic kidney and heart diseases.

Compounds commonly used to alleviate oxidative stress exhibit different antioxidant actions, and so there exists the potential for different antioxidants to work together to improve whole cell and organ function through a targeted polypharmaceutical approach to decrease oxidative stress.

However, most clinical studies investigating the effects of combination antioxidants have demonstrated confounding results. Mosca et al. However, this trial only included healthy participants and cannot be extrapolated to the CKD and CVD populations.

In a murine model of diabetic nephropathy, a major cause of CKD with associated CVD, the beneficial effects of NAC, L-ascorbic acid vitamin C and α-tocopherol were demonstrated [ ]. Daily supplementation for 8 weeks decreased lipid peroxidation, BUN, serum creatinine and blood glucose, mainly due to a reduction in the inflammatory response induced by hyperglycemia.

In comparison, a prospective trial investigating oral supplementation of mixed tocopherols and α-lipoic acid in stage 3 and 4 CKD patients has revealed disappointing results.

Over 2 months, supplementation did not reduce biomarkers of oxidative stress F 2 -isoprostanes and protein thiol concentration or inflammation CRP and IL The short period of time 2 months of the intervention may explain this result and longer trials need to be carried out.

The inclusion of vitamin E in these interventions has polarized discussion on the outcomes, because of its negligible benefits when cardiovascular outcomes were measured [ 91 , 92 , ] and also because of contraindications, discussed previously.

Despite this, long-term treatment in with the antioxidants vitamin C, vitamin E, CoQ 10 and selenium has been shown to reduce multiple cardiovascular risk factors [ ]. Recently, multiple antioxidants in combination with L-arginine have shown promise in animal models of CKD and associated CVD.

CKD is a progressive disease with increasing incidence, having very little success in current conventional therapies once CKD reaches stage 4. Stages 2 and 3 are best to target to slow or stop further development of the disease. There is an almost inseparable connection between CKD and CVD, with many patients with CKD dying of the cardiovascular complications before renal failure reaches its fullest extent.

Oxidative stress and inflammation are closely interrelated with development of CKD and CVD, and involve a spiralling cycle that leads to progressive patient deterioration.

Given the complex nature of oxidative stress and its molecular pathways, antioxidants may need to be given as a polypharmacotherapy to target each aberrant pathway, with the aim of reducing the burden of these chronic diseases.

It is vital for the progression of antioxidant therapy research in CKD and CVD that measures of oxidative stress are compared with pathophysiological outcome in the diseases, especially in connection with antioxidant therapies that may be delivered with or without more conventional CKD therapies.

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gobe uq. Introduction Chronic kidney disease CKD and cardiovascular disease CVD have major impacts upon the health of populations worldwide, especially in Western societies. Table 1. Classification and description of the different stages of CKD.

Inflammation and chronic kidney and cardiovascular disease The circulating nature of many inflammatory mediators such as cytokines, and inflammatory or immune cells, indicates that the immune system can act as a mediator of kidney-heart cross-talk and may be involved in the reciprocal dysfunction that is encountered commonly in the cardio-renal syndromes.

Understanding oxidative stress Oxidative stress has been implicated in various pathological systems that are prevalent in both CKD and CVD, most importantly inflammation and fibrosis. Endogenous antioxidants — Metabolism or disease modifiers The production of ROS is usually in balance with the availability and cellular localisation of antioxidant enzymes such as superoxide dismutase SOD , CAT and glutathione peroxidase Gpx.

Oxidative stress and transcriptional control The role of oxidative stress in upstream transcriptional gene regulation is becoming increasingly recognised. CKD and CVD are unified by oxidative stress Chronic diseases of the kidney possess various commonalities to chronic disease of the cardiovascular system which can be linked through pathways controlled by oxidative stress, as shown in Figure 1.

N-acetylcysteine — An antioxidant with promise N-acetyl cysteine NAC acts as an essential precursor to many endogenous antioxidants involved in the decomposition of peroxides [ 95 ]. Vitamin E — An established antioxidant with controversial outcomes Vitamin E, or α-tocopherol, is a lipid-soluble antioxidant that incorporates into the plasma membrane of cells, thereby scavenging free radicals, mainly the peroxyl radical, and halting lipid peroxidation chain reactions [ ].

Coenzyme Q 10 - Maintaining mitochondrial health The heart and kidneys contain the highest endogenous levels of co-enzymes Co Q 9 and CoQ 10 compared to all other organs [ , ].

Omega-3 poly-unsaturated fatty acids — Inflammation and oxidative stress Inflammation and fibrosis are causes, as well as consequences, of oxidative stress [ , ]. Allopurinol — A xanthine oxidase inhibitor Allopurinol treatment aims is to inhibit xanthine oxidase to decrease serum uric acid and its associated toxic effects.

L-Carnitine — Improving cardiovascular health in dialysis Carnitine is an essential cofactor required for the transformation of free fatty acids into acylcarnitine and its subsequent transport into the mitochondria for β-oxidation [ ].

L-Arginine - Maintaining endothelial function The premise of L-arginine supplementation is to maintain NO signalling and thereby maintain vascular endothelial cell function.

Combination antioxidants Compounds commonly used to alleviate oxidative stress exhibit different antioxidant actions, and so there exists the potential for different antioxidants to work together to improve whole cell and organ function through a targeted polypharmaceutical approach to decrease oxidative stress.

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When the balance is not disturbed, Oxidativve has a role in uealth adaptations and signal transduction. However, odidative excessive amount of ROS and RNS results in the Collagen Types Explained of kindey molecules oxidative stress and kidney health as andd, proteins, and DNA. Oxidative stress and kidney health stress has kdney reported in hdalth disease, due to both sttress depletions as Mood-boosting superfood supplement as increased ROS production. The kidney is a highly metabolic organ, rich in oxidation reactions in mitochondria, which makes it vulnerable to damage caused by OS, and several studies have shown that OS can accelerate kidney disease progression. Also, in patients at advanced stages of chronic kidney disease CKDincreased OS is associated with complications such as hypertension, atherosclerosis, inflammation, and anemia. In this review, we aim to describe OS and its influence on CKD progression and its complications. We also discuss the potential role of various antioxidants and pharmacological agents, which may represent potential therapeutic targets to reduce OS in both pediatric and adult CKD patients. When the balance is not disturbed, Oxidative stress and kidney health has healtj role in physiological adaptations and signal transduction. Kidnsy, an excessive amount of Kidnej and RNS results Pycnogenol and migraine prevention the oxidation of biological molecules such as lipids, proteins, and DNA. Oxidative stress oxidative stress and kidney health been reported in kidney disease, due to both antioxidant depletions healrh well as kidne ROS production. The kidney is a highly metabolic organ, rich in oxidation reactions in mitochondria, which makes it vulnerable to damage caused by OS, and several studies have shown that OS can accelerate kidney disease progression. Also, in patients at advanced stages of chronic kidney disease CKDincreased OS is associated with complications such as hypertension, atherosclerosis, inflammation, and anemia. In this review, we aim to describe OS and its influence on CKD progression and its complications. We also discuss the potential role of various antioxidants and pharmacological agents, which may represent potential therapeutic targets to reduce OS in both pediatric and adult CKD patients.