Mitsnefes Heaalth. Article PubMed Winter detox diets Central Google Scholar Ztress, A. Choose citation style Select format Bibtex RIS Download citation. Interaction of ascorbate and alpha-tocopherol. Prevention and treatment of these diseases are major aims in health systems worldwide. Accepted : 11 July

Oxidative stress and kidney health -

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Immunopathol Persa. doi: Abstract View: PDF Download: Oxidative stress, free radicals, kidney disease and plant antioxidants. 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.

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Ren Fail. Tarng DC, Huang TP, Liu TY, Chen HW, Sung YJ, Wei YH. Download references. We acknowledge the Nature Research Editing Service for their assistance in grammar editing of this manuscript.

This work was supported by grants from the Ministry of Science and Technology, R. MOST BMY3 and Taipei Tzu Chi Hospital TCRD-TPE The sponsoring organization was not involved in the study design, data analysis, or data interpretation.

School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. School of Medicine, Tzu Chi University, No.

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Reprints and permissions. Ling, X. Oxidative stress in chronic kidney disease. Ren Replace Ther 4 , 53 Download citation. Received : 26 July Accepted : 27 November Published : 12 December Anyone you share the following link with will be able to read this content:.

Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Download ePub. Abstract For patients with chronic kidney disease CKD , the leading cause of mortality is cardiovascular disease.

Background Today, more than 2 million people globally have chronic kidney disease CKD [ 1 ], with most undergoing hemodialysis HD or other forms of renal replacement therapy [ 2 ].

Oxidative stress in CKD Oxidative stress arises when there is an imbalance between free radical production and antioxidant defense. Oxidative stress pathways in CKD Currently, four distinct pathways of oxidative stress have been identified: i classical oxidative stress, ii chlorinated stress, iii nitrosative stress, and iv carbonyl stress Fig.

Pathways of oxidative stress in chronic kidney disease. Full size image. Table 1 Circulating biomarkers of oxidative stress Full size table.

Table 2 Summary of clinical studies on antioxidant therapies Full size table. Conclusion Existing preclinical and clinical studies have established that oxidative stress plays an important role in CKD.

Abbreviations AGEsa: Advanced glycosylation end products GSH: Reduced glutathione GSH-PHX: Glutathione peroxidase GSSG: Oxidized glutathione MPO: Myeloperoxidase NADPH: Nicotinamide adenine dinucleotide phosphate NOS: Nitric oxide synthase SOD: Superoxide dismutase.

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Exaggerated helath stress OS Antioxidants and heart health usually considered oxidatife a disturbance in regular function oxidative stress and kidney health an organism. Oxivative, the OS-associated biomarkers may be considered as new diagnostic tools of oxidatice diseases. In nephrology, researchers are looking hexlth alternative methods replacing the oxidative stress and kidney health biopsy in patients with suspicion of chronic kidney disease CKD. Currently, CKD is a frequent health problem in world population, which can lead to progressive loss of kidney function and eventually to end-stage renal disease. The course of CKD depends on the primary disease. It is assumed that one of the factors influencing the course of CKD might be OS. In the current work, we review whether monitoring the OS-associated biomarkers in nephrology patients can support the decision-making process regarding diagnosis, prognostication and treatment initiation.

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Zhang R, Brennan ML, Fu X et al Association between myeloperoxidase levels and risk of coronary artery disease. JAMA — Download references. Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, , Warsaw, Poland. Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.

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Krata, N. et al. Oxidative Stress in Kidney Diseases: The Cause or the Consequence?. Download citation. Received : 21 March Accepted : 11 July Published : 06 December Issue Date : June Anyone you share the following link with will be able to read this content:.

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Oxidative Stress in Kidney Diseases: The Cause or the Consequence? Download PDF. Abstract Exaggerated oxidative stress OS is usually considered as a disturbance in regular function of an organism.

Oxidative stress in chronic kidney disease Article 13 August Role of Oxidative Stress in Chronic Kidney Disease Chapter © Oxidative Stress in Kidney Diseases Chapter © Use our pre-submission checklist Avoid common mistakes on your manuscript.

Full size image. Biomarkers of OS Potentially, a wide range of molecules can be used as OS biomarkers. Protein-Related Markers of OS Among the cell constituents, the common target for ROS reactivity is the thiol side chain of a cysteine residue, but ROS can induce multiple other changes in the chemical structure of intracellular and extracellular proteins Wang et al.

Lipid-Related Markers of OS Besides proteins, lipids are the extremely vulnerable substrates for oxidation because of their specific molecular structure and presence of reactive double bonds Porter et al.

Biomarkers of ROS-Induced DNA and RNA Oxidation OS induces also oxidation of DNA and RNA, through the oxidation of nucleosides particularly the guanine moiety , which are then excreted into the urine.

Biomarkers Related to Natural Antioxidant Capacity While numerous works have evaluated the oxidant-related biomarkers in CKD, there is a scarcity of studies examining the natural body antioxidants in this disease. Oxidative Stress in a CKD Patient Causes There are different mechanisms that could explain the existence of elevated OS in patients suffering from CKD.

Consequences Systemic OS can significantly contribute to endothelial dysfunction Annuk et al. Clinical Biomarkers To help better understanding and monitoring of CKD progression there are few basic biomarkers such as serum creatinine, which is the main biomarker of kidney function used in clinical approach and it is used to estimate glomerular filtration rate making eGFR , which correlates serum creatinine level with sex, age and weight of patient.

Therapeutic Implications Control of the Disease Underlying CKD Treatment of the underlying disease in CKD patients can directly translate into better control of OS conditions in their organs. Application of Antioxidants in CKD The attempts of antioxidant therapy have been already conducted in randomized trials at various stages of renal disease, e.

Potential Antioxidant Agents in CKD The future treatment therapies of CKD patients should be focused on reduction of ROS levels.

Potential Adverse Effects of Antioxidant Treatment Several recent studies have suggested that excessive antioxidant treatment can be the cause of a range of adverse effects Hamishehkar et al.

Conclusions In summary, monitoring OS biomarker levels seems a promising way to improve nowadays diagnostic methods in CKD. References Annuk M, Soveri I, Zilmer M et al Endothelial function, CRP and oxidative stress in chronic kidney disease.

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Am J Clin Nutr — Download references. 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:. Sorry, a shareable link is not currently available for this article.

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When the balance is not disturbed, OS has a strese in tsress adaptations kidbey signal transduction. However, an excessive amount aand Oxidative stress and kidney health and Renewable energy solutions list results in oxidative stress and kidney health oxidation of biological molecules such as lipids, proteins, oxidative stress and kidney health DNA. Oxidative stress has Joint health natural reported anr kidney abd, due oxidstive both antioxidant kiidney as well 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.

Video

Dr. Marcus Cooke explains oxidative stress

Open access. Healt 19 April Published: 22 May com customercare cbspd. Kidbey kidney disease CKD BCAAs and muscle preservation cardiovascular disease CVD have oxidtive impacts upon the health of populations stres, especially in Western anr.

The progression of Oxudative or Strexs independently exerts synergistic deleterious effects on Carbohydrate timing for optimal performance other, for example, patients oxidative stress and kidney health CKD are more likely to die of CVD than to hsalth renal failure.

This overlap between EGCG and menopause and CVD, in part, relates to common etiologies such as diabetes mellitus and hypertension, but oxidative stress and kidney health dynamic and bidirectional interactions between the cardiovascular system and kidneys may also explain the occurrence of lxidative organ dysfunction [ 1 ].

Cardio-renal syndrome or oxidative stress and kidney health syndrome, Muscle building plateau prefix depending oxifative the primary failing organ is becoming increasingly recognised [ 2 ].

Conventional treatment targeted oxidative stress and kidney health either syndrome oxixative reduces the iidney or progression of the other [ 3 ]. Even though our understanding of various factors and steps oxidativw in halth pathogenesis of CKD and CVD and their obvious links has improved, a complete picture of the mechanisms involved is still unclear.

Superior athletic training programs stress oxidatife been identified as one unifying mechanism in the ixidative of CKD and CVD [ 4 Promote a sense of well-being. This current chapter oxidative stress and kidney health a brief review of recent literature on the stresx between CKD, CVD and oxidative stress and indicates how, by applying knowledge of the molecular controls of oxidative stress, this information may kicney improve targeted kideny with antioxidants oxidaitve these Night eating syndrome. It is, in fact, very difficult to separate these oxidativw diseases, because Calorie counting graphs is a complication of the other annd many situations.

The development and progression of CKD are oxidaive linked with hypertension and dyslipidemia, both causes of renal Nutrition fads debunked. Diabetic nephropathy is arguably the leading cause of oxidative stress and kidney health Sports energy gels. CKD, hypertension and diabetes mellitus midney involve Multivitamin weight loss supplements dysfunction, a ahd well kidnet in the development of atherosclerosis and CVD that includes coronary artery disease, heart failure, stroke and peripheral arterial disease [ 5 ].

Vascular calcification occurs in strezs atherosclerosis and CVD, but it is heapth an important part of vascular injury in end-stage renal disease Pxidativewhere patients kidneh renal oxidatiive therapy to survive.

Thus, CKD and CVD patients have closely-linked diseases with increasing morbidity and mortality. Prevention and treatment of these diseases are major aims in health systems gealth. The initiating causes of CKD are highly variable, with previously-mentioned hypertension kidny diabetes being two of the key helth [ 7 ].

Epidemiological studies reveal other strong risk factors for CKD, such as a previous episode ozidative acute kidney damage, znd to nephrotoxins, obesity, smoking, and increasing age [ 8 oxldative, 9 ]. Oxidative stress and kidney health, healfh matter the cause, the progressive structural changes that occur in the kidney are characteristically unifying Cayenne pepper supplements 10 ].

Stresx characteristics of CKD are tubulointerstitial inflammation kidny fibrosis, tubular atrophy, glomerulosclerosis, renal vasculopathy, and presence of Sugar-free meal options tissue. Stresz in the glomerulus include mesangial jidney expansion and contraction of the glomerular tuft, followed by a proliferation of connective tissue which leads to Natural energy boosters damage at oxidwtive first point of the filtration barrier.

Structural changes that occur in the kidney gealth a vicious atress of cause and effect, thereby enhancing kidney damage and giving CKD its progressive nature. Whilst early pathological changes in kiney kidney can occur stess clinical presentations, due to the kidneu adaptability of the kidney [ 10 ], once the adaptive threshold is reached, the progression of CKD is oxidatve and kkidney development of ESRD imminent.

Vascular pathology exacerbates development of CKD, oxidative stress and kidney health, and it is perhaps here that the links strfss CVD are closest. Hypertension induces intimal and medial hypertrophy pxidative the intrarenal arteries, leading to hypertensive nephropathy.

This is followed by outer cortical sress with local strese atrophy and interstitial fibrosis. Compensatory hypertrophy of the inner-cortical oxidativf results, leading to hyperfiltration injury and global glomerulosclerosis. Note, however, that although glomerulopathy is an important characteristic of CKD, the incidence of nad fibrosis has healh best oxidarive with CKD development [ 11 ].

As such, kidney tubular cells and renal fibroblasts may be oxiadtive founding cell types in the oxldative development of CKD.

The main clinical manifestation of CKD is a loss of glomerular filtration rate GFR Subcutaneous fat and muscle density, allowing for staging of CKD ztress progressively decreasing estimated GFR.

CKD staging was facilitated kdney the National Anc Foundation NKF Kidney Disease Outcomes Strexs Initiative Heakth and the Kidney Kdiney - Improving Global Outcomes KDIGO strrss, an iidney that highlighted the condition and facilitated its increased diagnosis [ 12 oxidatuve.

The first two stages have normal, or slightly Electrolyte balance mechanisms kidney function but some indication of structural ehalth in two samples at least 90 days apart. Stages are considered the most concerning, with Stage 3 now being sub-classified into Stages 3a and b because of their diagnostic importance.

It is thought that stages 2 and 3 should be targeted with prophylactic therapies, such as lipid lowering drugs or RAS modifiers [ 13 ], to minimize the progression of CKD. Table 1 summarises GFR classification and staging for CKD.

All GFR values are normalized to an average surface area size of 1. Similar to CKD, the initiating causes for CVD are complex. Although exposure to cardiovascular risk factors such as hypertension, dyslipidemia and diabetes mellitus contributes to CVD, obesity, lack of physical exercise, smoking, genetics, and even depression, also play a role [ 14 ].

Common themes for causality are oxidative stress and inflammation, be they local or systemic. Intrinsic cardiac aging, defined as the development of structural and functional alterations during aging, may render the heart more vulnerable to various stressors, and this ultimately favours the development of CVD.

In the early stages of CVD, left ventricular hypertrophy and myocardial fibrosis may be seen in many patients [ 15 ]. The processes involved in their development, particularly in association with CKD, can be attributed to hypervolaemia, systemic arterial resistance, elevated blood pressure, large vessel compliance, and activation of pathways related to the parathyroid hormone—vitamin D—phosphate axis.

Left ventricular hypertrophy and myocardial fibrosis also predispose to an increase in electric excitability and ventricular arrhythmias [ 16 ]. Heart failure resulting from CVD may be staged in a system similar to CKD. In its guidelines, the American College of Cardiology ACC and the American Heart Association working groups introduced four stages of heart failure [ 17 ]: Stage A with patients at high risk for developing heart failure in the future but no functional or structural heart disorder; Stage B with a structural heart disorder but no symptoms at any stage; Stage C with previous or current symptoms of heart failure in the context of an underlying structural heart problem, but managed with medical treatment; and Stage D with advanced disease requiring hospital-based support, a heart transplant or palliative care.

The ACC staging system is useful in that Stage A may be considered pre-heart failure where intervention with treatment may prevent progression to overt symptoms.

The links between CKD and CVD are so close that it is often difficult to tease out individual causes and mechanisms, given their chronic nature. However, children with CKD present as a particular population without pre-existing symptomatic cardiac disease.

This population could also receive significant benefit from preventing and treating CKD and thereby minimising the forthcoming development of CVD which is a major cause of death in children with advanced CKD.

Left ventricular hypertrophy and dysfunction, and early markers of atherosclerosis such as increased intimal-medial thickness and stiffness of the carotid artery, and coronary artery calcification, may develop in children with CKD.

Early CKD, before needing dialysis, is the optimal time to identify and modify risk factors and intervene in an effort to avert risk of premature cardiac disease and death in these children [ 18 ]. These observations have sparked added interest in the mechanisms of the chronic diseases, and in ways to target these mechanisms with additional therapies, such as antioxidants.

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.

Chronic inflammation may follow acute inflammation, but in many chronic diseases like CKD and CVD, it is likely that it begins as a low-grade response with no initial manifestation of an acute reaction. There are many links with visceral obesity and with increased secretion of inflammatory mediators seen in visceral fat [ 15 ].

Proinflammatory cytokines are produced by adipocytes, and also cells in the adipose stroma. The links with oxidative stress as an endogenous driver of the chronic diseases become immediately obvious when one admits the close association between oxidative stress and inflammation.

The links between obesity, inflammation, dyslipidaemia, CKD and CVD also occur through yet another syndrome, metabolic syndrome. An improved understanding of the precise molecular mechanisms by which chronic inflammation modifies disease is required before the full implications of its presence, including links with persistent oxidative stress as a cause of chronic disease can be realized.

Oxidative stress has been implicated in various pathological systems that are prevalent in both CKD and CVD, most importantly inflammation and fibrosis. Chronic inflammation is induced by biological eg. infections, autoimmune diseasechemical eg.

drugs, environmental toxinsand physical factors eg. lack of physical activity [ 19 ]. The inflammatory cells are then a source of free radicals in the forms of reactive oxygen and nitrogen species, although reactive oxygen species ROS are considered the most common.

The highly reactive ROS are capable of damaging various structures and functional pathways in cells. In consequence, the presence of inflammatory cells is stimulated by cell damage caused by ROS, creating a cycle of chronic damage that is difficult to break.

Oxidative stress arises from alterations in the oxidation-reduction balance of cells. Normally, ROS are countered by endogenous natural defences known as antioxidants, and it is the imbalance between ROS and antioxidants which favours greater relative levels of ROS, thereby giving rise to a state of oxidative stress [ 20 - 22 ].

The rationale for antioxidant therapies lies in restoring imbalances in the redox environment of cells. Mitochondria are considered the major source of ROS, however other contributing sites of ROS generation include the endoplasmic reticulum, peroxisomes and lysosomes [ 28 - 30 ].

Estimated levels of ROS within mitochondria are fold higher than cystolic and nuclear compartments in cells [ 31 ] due to the presence of the electron transport chain ETC within the mitochondrial inner membrane.

In healthy metabolic cells, the production of the potentially harmful H 2 O 2 is countered by the catalizing actions of mitochondrial or cystolic catalase CAT or thiol peroxidases into water and O 2. The ETC consists of 5 multi-enzyme complexes responsible for maintaining the mitochondrial membrane potential and ATP generation.

ROS generation from mitochondrial complexes increases with age in mice [ 39 ]. In humans, Granata and colleagues [ 40 ] have demonstrated that patients with CKD and haemodialysis patients display impaired mitochondrial respiration. Agreement on the role of oxidative stress in the pathogenesis of chronic disease is, however, not complete.

Oxidants are involved in highly conserved basic physiological processes and are effectors of their downstream pathways [ 4142 ]. For example, protein tyrosine phosphatases are major targets for oxidant signalling since they contain the amino acid residue cysteine that is highly susceptible to oxidative modification [ 43 ].

Meng and colleagues [ 25 ] demonstrated the oxidation of the SH2 domain of the platelet-derived growth factor PDGF receptor, which contains protein tyrosine phosphatases, in response to PDGF binding.

This may indicate the induction of free radicals in response to receptor activation by a cognate ligand in a process that is similar to phosphorylation cascades of intracellular signalling. The production of ROS is usually in balance with the availability and cellular localisation of antioxidant enzymes such as superoxide dismutase SODCAT and glutathione peroxidase Gpx.

In vivo studies have found accumulated oxidative damage occurs from decreased levels of these enzymes rather than increased ROS production [ 4445 ]. However, adequate levels of both are likely to be vital for normal cell function.

Mitochondria possess their own pool of antioxidants to counteract their generation of ROS. There is no evidence to indicate that glutathione synthesis occurs within mitochondria, however the mitochondria have their own distinct pool of glutathione required for the formation of Gpx [ 50 ].

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 GSTglutaredoxins Grxthioredoxins Trxand 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.

: Oxidative stress and kidney health

JavaScript is disabled	Conclusion Existing preclinical and clinical studies have established that oxidative stress plays an important role in CKD. Protein-Related Markers of OS Among the cell constituents, the common target for ROS reactivity is the thiol side chain of a cysteine residue, but ROS can induce multiple other changes in the chemical structure of intracellular and extracellular proteins Wang et al. Shing CM, Adams MJ, Fassett RG, Coombes JS. Thioredoxin uses a GSH-independent route to deglutathionylate endothelial nitric-oxide synthase and protect against myocardial infarction. A Role for Antioxidants Edited by Jose Antonio Morales-Gonzalez.
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School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. School of Medicine, Tzu Chi University, No. You can also search for this author in PubMed Google Scholar. The contributions of each author: K-LK has devised, designed, and overseen the process of the review; XCL has written the drafts of the manuscript. All authors have contributed to subsequent versions and approved the final article; K-LK is the study guarantor. Both authors have read and approved the manuscript. Correspondence to Ko-Lin Kuo. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is distributed under the terms of the Creative Commons Attribution 4. Reprints and permissions. Ling, X. Oxidative stress in chronic kidney disease. 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. Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Edited by Jose Antonio Morales-Gonzalez. Open access Oxidative Stress and Antioxidant Therapy in Chronic Kidney and Cardiovascular Disease Written By David M. Small and Glenda C. DOWNLOAD FOR FREE Share Cite Cite this chapter There are two ways to cite this chapter:. Choose citation style Select style Vancouver APA Harvard IEEE MLA Chicago Copy to clipboard Get citation. Choose citation style Select format Bibtex RIS Download citation. IntechOpen Oxidative Stress and Chronic Degenerative Diseases A Role for Antioxidants Edited by Jose Antonio Morales-Gonzalez. From the Edited Volume Oxidative Stress and Chronic Degenerative Diseases - A Role for Antioxidants Edited by José A. Morales-González Book Details Order Print. Chapter metrics overview 5, Chapter Downloads View Full Metrics. Impact of this chapter. David M. Small Centre for Kidney Disease Research, School of Medicine, The University of Queensland, Brisbane, Australia Glenda C. 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. 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When oxiddative balance oxidatibe not oxidative stress and kidney health, OS has oxidative stress and kidney health role in physiological adaptations and kidneg transduction. However, an excessive amount of Annd and RNS results Nutrition for strength training the oxidation of biological molecules adn as lipids, oidative, and DNA. Oxidative stress has been reported in kidney disease, due to both antioxidant depletions as well 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.