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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2001  |  Volume : 12  |  Issue : 3  |  Page : 312-324
Rationale for Antioxidant Supplementation in Hemodialysis Patients


1 Biochemistry Laboratory, Lapeyronie University Hospital, Montpellier, France
2 Nephrology Department, Lapeyronie University Hospital, Montpellier, France
3 Nephrology Department and Renal Research and Training Institute, Lapeyronie University Hospital, Montpellier, France

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   Abstract 

Oxidative stress, which results from an imbalance between reactive oxygen species (ROS) production and antioxidant defense mechanisms, is now a well recognized pathogenic process in hemodialysis (HD) patients that could be involved in dialysis-related pathologies such as accelerated atherosclerosis, amyloidosis and anemia. This review is aimed at evaluating the rationale for preventive intervention against oxidative damage during HD as well as the putative causal factors implicated in this imbalance. The antioxidant system is severely impaired in uremic patients and impairment increases with the degree of renal failure. HD further worsens this condition mainly by losses of hydrophilic unbound small molecular weight substances such as vitamin C, trace elements and enzyme regulatory compounds. Moreover, inflammatory state due to the hemo­incompatibility of the dialysis system plays a critical role in the production of oxidants contributing further to aggravate the pro-oxidant status of uremic patients. Prevention of ROS overproduction can be achieved by improvement of dialysis biocompatibility, a main component of adequate dialysis, and further complimented by antioxidant supplementation. This could be achieved either orally or via the extracorporeal circuit. Antioxidants such as vitamin E could be bound on dialyzer membranes. Alternatively, hemolipodialysis consisting of loading HD patients with vitamin C or E via an ancillary circuit made of vitamin E-rich liposomes may be used.

Keywords: Antioxidant, Atherosclerosis, Hemodialysis, Oxidative stress.

How to cite this article:
Morena M, Martin-Mateo M, Cristol JP, Canaud B. Rationale for Antioxidant Supplementation in Hemodialysis Patients. Saudi J Kidney Dis Transpl 2001;12:312-24

How to cite this URL:
Morena M, Martin-Mateo M, Cristol JP, Canaud B. Rationale for Antioxidant Supplementation in Hemodialysis Patients. Saudi J Kidney Dis Transpl [serial online] 2001 [cited 2021 Apr 19];12:312-24. Available from: https://www.sjkdt.org/text.asp?2001/12/3/312/33555

   Introduction Top


Oxidative stress clearly results from the imbalance between oxidative and anti­oxidative mechanisms [Figure - 1]. Oxidative mechanisms arise from the excessive production of deleterious oxidants including reactive oxygen species (ROS), reactive nitrogen species (RNS) and chlorinated compounds [Figure - 2]. Briefly, the acceptance by oxygen of one electron yields superoxide anion (O2°-). Such anion, continuously produced at a low rate as a byproduct of respiratory chain in the mitochondrial internal membrane, [1] could be overproduced by the NADPH oxidase complex in response to stimuli such as pro-inflammatory mediators, either soluble (C5a, interleukin-1 (IL-1), tumor necrosis factor (TNF)) or others, including platelet activating factor (PAF), bacteria, endotoxins and immunoglobulin G. Under the action of superoxide dismutase (SOD), hydrogen peroxide (H 2 O 2 ) could be produced; both oxidants can yield the highly injurious hydroxyl radical (OH°) under the catalytic effect of iron, the so­called Fenton Haber-Weiss reaction. Superoxide anion can also directly interact with nitric oxide (NO), a reactive nitrogen species, to produce peroxynitrite (ONOO - ), an injurious prooxidant compound. Moreover, H 2 O 2 , under the action of myeloperoxidase, an enzyme abundantly present in the azurophilic granules of leukocytes, can interact with halides to produce hypohalous acids; the latter could generate long-lived oxidants such as chloramines. Interestingly, the pro-inflammatory mediators which activate NADPH oxidase also upregulate NO production via iNO synthases induction, [2] iron release by lactoferrin [3] or finally hypo­chlorite anion release by myeloperoxidase. [4] Thus, excessive deleterious ROS over­production is strongly linked to an inflam­matory process as reported in HD patients. [5]

In the normal course of events, cells and tissues have adequate antioxidative defences that protect against the entire spectrum of prooxidants [6] both in preventing and repairing the damage caused by oxidants. Antioxidants are classified as enzymatic and non-enzymatic substances. Among non-enzymatic antioxidants, vitamin E or tocopherol and vitamin C or ascorbic acid constitute two of the main important defences against ROS and lipid peroxidation, [6],[7] which act synergistically [Figure - 3]. Reduced glutathione (GSH), uric acid, flavonoids, glucose and bilirubin are also considered as non-enzymatic antioxidants. GSH is able to detoxify free radicals leading to the formation of oxidized glutathione form (GSSG).

Enzymatic antioxidants also provide an efficient scavenging function. Indeed, O2° - ­ is dismutated by the enzyme SOD, a metalloprotein with three different isoenzymes containing copper/zinc or manganese. [6] Two other different enzymes, namely GPx and catalase, metabolize H 2 O 2 in H 2 O. GPx is a seleno protein which detoxifies hydroperoxides and thus acts additively with vitamin E/C in preventing lipid peroxidation.

The purpose of this work is to focus on; i) oxidative stress evidenced in HD patients (factors that contribute to impaired anti­oxidant defenses, and to increase oxidant generation) and ii) prophylaxis/treatment based on antioxidant supplementation to restore "antioxidant state".


   What are the evidences of an oxidative stress in HD patients?: Top


The imbalance between antioxidant defense mechanisms and overproduction of ROS is now well established in HD patients [8],[9] and evidenced by the presence of several oxidative stress markers. Indeed, malonyldialdehyde (MDA), a lipid peroxi­dation product, was noted to be signi­ficantly increased in HD patients. [8],[10] More recently, Witko-Sarsat et al identified the presence of advanced oxidation protein products (AOPP) in the plasma of uremic patients. [11] Interestingly, AOPP levels increased with progression of chronic renal failure (CRF) but were significantly higher in dialysis patients. Also, AOPP levels were found closely related to advanced glycation end products (AGEs) and monocyte activation markers in dialysis patients. Moreover, the authors found that AOPP and AGEs were capable of triggering the oxidative burst of ex vivo human monocytes. [12] Finally, AOPP was identified as a new marker of oxidative stress and a potent trigger of the monocyte respiratory burst in chronic renal failure and dialysis patients.

Recently, 8 hydroxy 2'-deoxyguanosine (8-OH dG) of leukocyte DNA has been identified as a surrogate marker of oxidative stress in HD patients, as reported by Tarng et al. [13]


   What are the factors that contribute to oxidative stress in HD patients? Top


Pro-oxidative state of HD patients results from two groups of factors: uremia­associated metabolic abnormalities and hemodialysis-associated procedure per se that may interact on the same pathways.


   Impairment in antioxidant defense mechanisms Top


Uremia-induced factors

There is increasing evidence suggesting that the oxygen radical scavenger system is severely impaired in uremic patients and gradually altered with the degree of renal failure. Main disturbance concerns the glutathione/GPx/selenium complex. Selenium is significantly decreased in uremic patients. [14] Impairment in plasma [15],[16] and erythrocyte [17] GPx have been also reported. By contrast, GSH-transferase, an enzyme with a selenium­independant peroxidase activity, is highly over-expressed in CRF erythrocytes [18] suggesting an important role of selenium deficiency. Low levels of erythrocyte GSG and impairment in GPx activity both in red blood cells (RBC) [19] and platelets [20] which is independent of dialysis, have been observed in early stages of renal insufficiency, showing that defense mechanism impairment is at least in part independent of the dialysis procedure.

SOD activity is significantly impaired in red blood cells [21],[22] and polymorphonuclears (PMNs) [23] probably due to a deficient zinc level. By contrast, catalase has been reported as increased.

Uremia-induced disturbance is observed at a much lower intensity in the non-enzymatic systems. Total plasma anti-oxidant capacity is frequently higher in CRF patients than in healthy volunteers. [15] Such effect, due to accumulation of high plasma uric acid concentrations, is well known as the "uric acid paradox". [24] Plasma vitamin E levels are normal despite impairment in erythrocyte and mononuclear cell content. [22],[25],[26],[27] Uremia is also associated with profound disturbances in the NO control system. Indeed, Vallance et al, have reported the increase in NO synthase inhibitors [28] while Arese et al, reported the increase of both NO synthase inhibitors and activators. [29] The clinical consequences of NO pathway alterations in uremia-associated oxidative stress remains to be determined.

Hemodialysis related losses of antioxidant

Hemodialysis is a non-selective process clearing solute solely based on molecular weight, a sieving property of the membrane and protein bound capacity. Consequently, HD, particularly modalities using highly permeable membranes, induces solute losses including both waste products and essential substances including antioxidants. Therefore, it appears that increased dialysis efficiency and enlarged spectrum of solute removal by convective clearance, two highly desirable options for improving dialysis adequacy, enhance also antioxidant losses thereby impairing oxygen radical scavenging capacities.

Hemodialysis losses of antioxidant pathways appear particularly relevant with hydrophilic and unbound small molecular weight substances such as vitamins. Loss of vitamin C in hemodiafiltration, splitting diffusive and convective modality named paired filtration dialysis, has been recently evaluated. Following results of this study, it was reported that vitamin C losses averaged 66 mg per session, two-thirds through diffusive and one-third through convective pathways. [30] Koenig et al, in a recent work assessing antioxidant status of HD patients, found that selenium concentration in plasma was decreased while it was normal in erythrocytes. [31] Curiously, they were unable to detect any selenium loss in the dialysate. Hemodialysis could also affect the NO system. It has been shown that NO synthase active compounds (inhibitors or activators) can be removed differently by convective or diffusive processes. [32]

The HD losses of hydrophilic antioxidants, trace elements or regulatory compounds enhance the abnormalities of the enzymatic pathway or hydrophobic antioxidants induced by uremia.

All these findings allow one to conclude that impairment in enzymatic antioxidants is due to uremia while HD is mainly responsible for non-enzymatic antioxidant losses. This suggests that HD, far from improving oxidative stress, worsens the same. This deleterious effect is, in turn, enhanced by overproduction of ROS linked to inflammatory state.


   Overproduction of reactive oxygen species Top


Uremia-associated factors

Uremia is associated with several metabolic abnormalities including complex alterations of ROS production. [15] Ward et al, have recently shown that PMNs obtained from uremic patients were primed for superoxide anion production. [33],[34] High levels of plasma homocysteine, which accumulates at the early stage of CRF, [35] could promote prooxidant state by interacting with H 2 O 2 . [36]

Hemodialysis-induced factors (membranes, LPS, Cytokine)

Hemo-incompatibility of the dialysis system resulting in chronic inflammation plays a critical role in the production of free oxygen radical species. HD-related oxidative stress relies upon two major components of the dialysis system: one is the dialyzer membrane; [37] the other is the microbial contamination and the pyrogen content of the dialysate.

Contribution of the dialyzer membrane in the production of free oxygen radicals has been studied in acute HD conditions by comparing cellulosic (cuprophane) and synthetic (polysulfone) membranes. [38],[39] More recently, Chen et al, have shown that basal blood levels of superoxide anion were higher in chronic HD patients as compared to healthy subjects and further increased after each HD session. [34]

Indirect evidences also exist, showing that trace amounts of endotoxin in dialysate is a potent trigger of the ROS species production via the activation of PMN leukocytes. DeLeo et al, demonstrated in a recent work, that neutrophils harvested from normal human volunteers exposed to bacterial lipopolysaccharide upregulate NADPH oxidase assembly. In this work, it was shown that lipopolysaccharide (LPS) had a "priming" effect on the respiratory burst of neutrophils. [40] LPS pre-treatment increased superoxide generation (O2° - ) nearly ten fold in response to fMLP.

Priming effect of LPS is particularly relevant in HD since it has been shown that CD 14 expression was enhanced during the HD session. [41] In addition, endotoxin contaminants of dialysate may play a major role in the cytokine release during HD. [42],[43],[44] Indeed, the presence of LPS in the dialysate may activate blood monocytes/macro­phages through the dialyzer membrane contributing to IL-1, IL-6 and TNF-α induction [45],[46] which could in turn up­regulate NADPH oxidase. [47],[48]

Taking into account the potent activating role of unsubstituted cellulosic membrane on PMNs, it can be speculated that the endotoxin-contaminated dialysate is an amplifying factor of PMNs activation and oxygen reactive species production.


   What could be the role of oxidative stress in the long-term complications of HD patients? Top


Oxidative stress tends to be implicated in the development of long-term complica­tions in HD patients such as anemia, amyloidosis, atherosclerosis and mal­nutrition.

Anemia

Oxidative stress may partly explain the shortened RBC survival in HD. [49],[50],[51] Indeed MDA level, a marker of lipid peroxidation, is high in erythrocytes [52] and a severe impairment in vitamin E content [22],[52] is observed. Moreover, life-span of RBC may be shortened by their reduced resistance to mechanical, osmotic or oxidative stress. [53] Membrane lipids are generally considered the preferential targets for most oxidative stress, while lipid peroxidation results in profound structural and functional cellular alterations. Consumption of erythrocyte antioxidant is due to ROS overproduction scavenging.

Finally, iron overload is frequently associated with the intravenous iron supp­lementation and contributes to prooxidant state. [54] Erythropoietin is also a contributing factor.

Amyloidosis

Under oxidative stress, proteins are modified directly by ROS with the eventual formation of oxidized amino acids. Proteins are also modified indirectly with reactive carbonyl compounds formed by the auto­oxidation of carbohydrates and lipids, resulting in the formation of AGEs. [55] The presence of AGEs in β2M amyloidosis deposit of long-term HD patients have been demonstrated by Miyata et al, [56,][57] suggesting that oxidative stress is, by its denaturating protein action, a pro-amyloidosis factor.

Atherosclerosis

Atherogenesis, a recognized inflammatory disease, is strongly dependent on oxidative stress. [58] Presence of oxidized LDL, derived from lipid abnormalities and oxidative stress, plays a major role in the development and progression of atherosclerotic lesions. [59],[60] In addition to its endothelial dysfunctions, oxidized LDL exhibits pro-inflammatory actions including chemotactic effects, enhance the expression of macrophage colony stimulating factors and adhesive molecules. Oxidized LDL, after trapping by monocyte/macrophage scavenging receptors, leads to monocyte activation with subsequent generation of myeloperoxidase­dependent chlorinated oxidant products, playing a pivotal role in atherogenesis. [12] Maggi et al reported a significant increase of anti-oxidized LDL antibodies in CRF patients during the conservative treatment phase as compared to control subjects. [61] However, ex vivo LDL oxidability data, still debated, are reported as normal by some studies [62],[63] or increased in other studies. [61],[64] Recently, we have reported an enhanced LDL susceptibility to ex vivo oxidation associated with an impairment of HDL protection against LDL oxidability. [65]

Malnutrition

Oxidative stress may also play a role in malnutrition as reported in the MIA syndrome [66] consisting of malnutrition, inflammation and atherosclerosis which occurs in some patients with CRF. Stenvinkel et al, reported a close link between nutritional status, inflammatory markers and cardiovascular disease in CRF, with a central role played by pro­inflammatory cytokines generated during HD sessions. [66],[67],[68]


   Therapeutic insights of oxidative stress in HD patients Top


Improvement of dialysis biocompatibility tends to be a common target for adequate dialysis. Prevention of ROS overproduction linked to bio-incompatibility-induced inflammation might be completed by anti­oxidant supplementation. Indeed, supple­mentation of antioxidant product to restore the oxidative balance is a promising way of research. [69] These therapeutic approaches aim at preventing both oxidative stress­associated anemia and atherosclerosis and can be achieved either by oral or intravenous supplementation or by means of the extracorporeal circuit.

Oral supplementations

Several antioxidant nutrients were proven to be effective in HD patients. [22],[29] Beneficial effects of oral vitamin E (500 mg/day for 6 months) supplementation has recently been reported by Cristol et al. These investigators showed: i) oxidative state improvement ii) anemia correction and iii) atherosclerosis prevention. [22] also, a Sparing effect on erythropoietin dosage has been shown by Taccone-Gallucci et al, [52] which was attributed to an increase in osmotic resistance of RBC. In addition, vitamin E supplementation could prevent HD-induced LDL oxidability [70],[71] .

Intravenous supplementation

Several factors administered intravenously (e.g. selenium) have been shown to be effective and, clinically well tolerated. [31,[72] Interestingly, plasma and erythrocyte selenium content as well as GPx activity were significantly increased in these cases tending towards normalization. [72],[73],[74]

Extracorporeal circuit

New strategies for improving oxidative stress conditions of HD patients are now proposed. Hemolipodialysis is an innovative concept that consists in loading HD patients with vitamin E and C via the extracorporeal circuit during a HD session. Hydrophilic vitamin C is transferred by the dialysate while lipophilic vitamin E is delivered by an ancillary circuit consisting in vitamin E­ rich liposomes. [75],[76] The presence of lipo­somes facilitates vitamin E transfer from dialysate to blood but also enhances the removal of hydrophobic toxins such as leucotrienes, PAF acether and hydro­peroxides which could contribute to the oxidative stress. [77] In vitro studies showed that hemolipodialysis technique was associated with a dramatic reduction in oxidative stress markers including AOPP and MDA. [78],[79] Vitamin E-bound hemo­dialyzer membrane, recently marketed, offers another interesting concept. For this purpose, vitamin E was bound to a cellulosic modified membrane bearing a polysulfone layer. [26],[80] In vitro and in vivo experiments offer promising results con­cerning prevention of i) bio-incompatibility phenomena ii) anemia iii) amyloidosis and iv) atherogenesis.

Treatment with vitamin E coated membrane restored phagocytic and bactericidal function of PMNs to normal range. [81],[82] Cytokine production decreased and additionally, impairment of monocyte sequestration and T cell activation were also reported by Girndt et al. [83] The use of such membrane reduced the dysmorphic erythrocyte percentage, [84] the hemolysis [85] and reduced the erythrocyte MDA level. [86] Use of vitamin E-bound membrane was accompanied with a significant reduction of AGEs [87] and carbonyl group formation [88] and a diminution in β2-microglobulin level. [89] Anti-oxidized LDL autoantibodies were significantly decreased with vitamin E membrane treatment as reported by Mune et al and Miyazaki et al. [90],[91] These data are in total agreement with our findings concerning a potential effect of vitamin E­bound membrane on prevention of HD­induced LDL hyperoxidability. [92] Moreover, use of this dialyzer significantly reduced the percentage of aortic calcification index. [90] In addition, prevention of endothelial dysfunction induced by HD was observed by Miyazaki et al. [91]

In conclusion, oxidative stress is a common feature in HD patients resulting from an imbalance between pro- and anti­oxidative mechanisms. This pro-oxidative state is due to several factors that are related to patient condition, uremia state, HD system and drug-associated. Further tissue damage and other deleterious consequences must be prevented for HD patients by appropriate measures. Preventive modalities include the use of highly biocompatible membrane, ultrapure dialysate and exogenous supplementation of antioxidant vitamins. Extracorporeal removal of ROS and oxidatively-modified substances is a new way of research. Correction of oxidative stress imbalance appears to be a basic requisite to prevent complications of long-term dialysis patients.

 
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Correspondence Address:
Bernard Canaud
Department of Nephrology, Renal Research and Training Institute, Lapeyronie University Hospital, 371, Ave. Doyen G. Giraud, 34295 Montpellier
France
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