| 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 2022 May 17];12:312-24. Available from: https://www.sjkdt.org/text.asp?2001/12/3/312/33555
| Introduction|| |
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,  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,  iron release by lactoferrin  or finally hypochlorite anion release by myeloperoxidase.  Thus, excessive deleterious ROS overproduction is strongly linked to an inflammatory process as reported in HD patients. 
In the normal course of events, cells and tissues have adequate antioxidative defences that protect against the entire spectrum of prooxidants  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, , 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.  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?:|| |
The imbalance between antioxidant defense mechanisms and overproduction of ROS is now well established in HD patients , 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. , More recently, Witko-Sarsat et al identified the presence of advanced oxidation protein products (AOPP) in the plasma of uremic patients.  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.  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. 
| What are the factors that contribute to oxidative stress in HD patients?|| |
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|| |
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.  Impairment in plasma , and erythrocyte  GPx have been also reported. By contrast, GSH-transferase, an enzyme with a seleniumindependant peroxidase activity, is highly over-expressed in CRF erythrocytes  suggesting an important role of selenium deficiency. Low levels of erythrocyte GSG and impairment in GPx activity both in red blood cells (RBC)  and platelets  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 , and polymorphonuclears (PMNs)  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.  Such effect, due to accumulation of high plasma uric acid concentrations, is well known as the "uric acid paradox".  Plasma vitamin E levels are normal despite impairment in erythrocyte and mononuclear cell content. ,,, Uremia is also associated with profound disturbances in the NO control system. Indeed, Vallance et al, have reported the increase in NO synthase inhibitors  while Arese et al, reported the increase of both NO synthase inhibitors and activators.  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.  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.  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. 
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|| |
Uremia is associated with several metabolic abnormalities including complex alterations of ROS production.  Ward et al, have recently shown that PMNs obtained from uremic patients were primed for superoxide anion production. , High levels of plasma homocysteine, which accumulates at the early stage of CRF,  could promote prooxidant state by interacting with H 2 O 2 . 
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;  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. , 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. 
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.  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.  In addition, endotoxin contaminants of dialysate may play a major role in the cytokine release during HD. ,, 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 , which could in turn upregulate NADPH oxidase. ,
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?|| |
Oxidative stress tends to be implicated in the development of long-term complications in HD patients such as anemia, amyloidosis, atherosclerosis and malnutrition.
Oxidative stress may partly explain the shortened RBC survival in HD. ,, Indeed MDA level, a marker of lipid peroxidation, is high in erythrocytes  and a severe impairment in vitamin E content , is observed. Moreover, life-span of RBC may be shortened by their reduced resistance to mechanical, osmotic or oxidative stress.  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.  Erythropoietin is also a contributing factor.
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.  The presence of AGEs in β2M amyloidosis deposit of long-term HD patients have been demonstrated by Miyata et al, [56,] suggesting that oxidative stress is, by its denaturating protein action, a pro-amyloidosis factor.
Atherogenesis, a recognized inflammatory disease, is strongly dependent on oxidative stress.  Presence of oxidized LDL, derived from lipid abnormalities and oxidative stress, plays a major role in the development and progression of atherosclerotic lesions. , 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.  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.  However, ex vivo LDL oxidability data, still debated, are reported as normal by some studies , or increased in other studies. , Recently, we have reported an enhanced LDL susceptibility to ex vivo oxidation associated with an impairment of HDL protection against LDL oxidability. 
Oxidative stress may also play a role in malnutrition as reported in the MIA syndrome  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. ,,
| Therapeutic insights of oxidative stress in HD patients|| |
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.  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.
Several antioxidant nutrients were proven to be effective in HD patients. , 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.  also, a Sparing effect on erythropoietin dosage has been shown by Taccone-Gallucci et al,  which was attributed to an increase in osmotic resistance of RBC. In addition, vitamin E supplementation could prevent HD-induced LDL oxidability , .
Several factors administered intravenously (e.g. selenium) have been shown to be effective and, clinically well tolerated. [31, Interestingly, plasma and erythrocyte selenium content as well as GPx activity were significantly increased in these cases tending towards normalization. ,,
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. , 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.  In vitro studies showed that hemolipodialysis technique was associated with a dramatic reduction in oxidative stress markers including AOPP and MDA. , 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. , 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. , Cytokine production decreased and additionally, impairment of monocyte sequestration and T cell activation were also reported by Girndt et al.  The use of such membrane reduced the dysmorphic erythrocyte percentage,  the hemolysis  and reduced the erythrocyte MDA level.  Use of vitamin E-bound membrane was accompanied with a significant reduction of AGEs  and carbonyl group formation  and a diminution in β2-microglobulin level.  Anti-oxidized LDL autoantibodies were significantly decreased with vitamin E membrane treatment as reported by Mune et al and Miyazaki et al. , These data are in total agreement with our findings concerning a potential effect of vitamin Ebound membrane on prevention of HDinduced LDL hyperoxidability.  Moreover, use of this dialyzer significantly reduced the percentage of aortic calcification index.  In addition, prevention of endothelial dysfunction induced by HD was observed by Miyazaki et al. 
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.
| References|| |
|1.||Crastes de Paulet A, Cristol JP, Toreilles J. Membrane lipids as a preferential target for oxidative processes. In: Paoletti R (Eds) Oxidative Processes and Antioxidants, Raven Press, Ltd New-York 1994:73-96. |
|2.||Thiemermann C. Nitric oxide and septic shock. Gen Pharmacol 1997;29(2):159-66. |
|3.||Britigan BE, Edeker BL. Pseudomonas and neutrophil products modify transferrin and lactoferrin to create conditions that favor hydroxyl radical formation. J Clin Invest 1991;88:1092-102. [PUBMED] [FULLTEXT]|
|4.||Johnson K, Nauseef W. Molecular biology of MPO. Peroxidases in chemistry and biology 1991; Volume II; Everse J and Everse KE Eds, CRC press, Boca Raton: 63-81. |
|5.||Lonnemann G, Linnenweber S, Burg M, Koch KM. Transfer of endogenous pyrogens across artificial membranes? Kidney Int Suppl 1998;66:S43-6. [PUBMED] |
|6.||Rice-Evans C, Gopinathan V. Oxygen toxicity, free radicals and antioxidants in human disease: Biochemical implications in atherosclerosis and the problems of premature neonates. In: Apps DK, Tripton KF: Essays in Biochemistry. London, Portland Press 1995:39-63. |
|7.||Rice-Evans CA, Diplock AT. Current status of antioxidant therapy. Free Radic Biol Med 1993;15:77-96. [PUBMED] |
|8.||Loughrey CM, Young IS, Lightbody JH, McMaster D, McNamee PT, Trimble ER. Oxidative stress in haemodialysis. Q J Med 1994;87(11):679-83. |
|9.||Canaud B, Cristol J, Morena M, LerayMoragues H, Bosc J, Vaussenat F. Imbalance of oxidants and antioxidants in haemodialysis patients. Blood Purif 1999;17(2-3):99-106. |
|10.||Cristol JP, Maggi MF, Bosc JY, et al. Oxidative stress and chronic renal insufficiency: what can be a prophylactic approach? C R Seances Soc Biol Fil 1997;191(4):603-16. |
|11.||Witko-Sarsat V, Friedlander M, CapeillereBlandin C, et al. Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int 1996;49(5):1304-13. |
|12.||Witko-Sarsat V, Friedlander M, Nguyen Khoa T, et al. Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure. J Immunol 1998;161(5):2524-32. |
|13.||Tarng DC, Huang TP, Liu TY, Chen HW, Sung YJ, Wei YH. Effect of vitamin Ebonded membrane on the 8-hydroxy 2'deoxyguanosine level in leukocyte DNA of hemodialysis patients. Kidney Int 2000;58(2):790-9. |
|14.||Bonomini M, Albertazzi A. Selenium in uremia. Artif Organs 1995;19(5):443-8. |
|15.||Hasselwander O, Young IS. Oxidative stress in chronic renal failure. Free Radic Res 1998;29:1-11. [PUBMED] |
|16.||Martin-Mateo MC, del Canto-Jafiez E, Barrero-Martinez MJ. Oxidative stress and enzyme activity in ambulatory renal patients undergoing continuous peritoneal dialysis. Ren Fail 1998;20(1):117-24. |
|17.||Canestrari F, Galli F, Giorgini A, et al. Erythrocyte redox state in uremic anemia: effects of hemodialysis and relevance of glutathione metabolism. Acta Haematol 1994;91(4):187-93. |
|18.||Galli F, Rovidati S, Benedetti S, et al. Over-expression of erythrocyte glutathione S-transferase in uremia and dialysis. Clin Chem 1999;45(10):1781-8. |
|19.||Ceballos-Picot I, Witko-Sarsat V, MeradBoudia M, et al. Glutathione antioxidant system as a marker of oxidative stress in chronic renal failure. Free Radic Biol Med 1996;21(6):845-53. |
|20.||Girelli D, Olivieri O, Stanzial AM, et al. Low platelet glutathione peroxidase activity and serum selenium concentration in patients with chronic renal failure: relations to dialysis treatments, diet and cardiovascular complications. Clin Sci Colch 1993;84(6):611-7. |
|21.||Paul JL, Sall ND, Soni T, et al. Lipid peroxidation abnormalities in hemodialyzed patients. Nephron 1993;64(1):106-9. |
|22.||Cristol JP, Bosc JY, Badiou S, et al. Erythropoietin and oxidative stress in hemodialysis: beneficial effects of vitamin E supplementation. Nephrol Dial Transplant 1997;12(11):2312-7. |
|23.||Shurtz-Swirski R, Mashiach E, Kristal B, Shkolnik T, Shasha S. Antioxidant enzymes activity in polymorphonuclear leukocytes in chronic renal failure. Nephron 1995;71:176-9. |
|24.||Nguyen-Khoa T, Massy ZA, Witko-Sarsat V, et al. Critical evaluation of plasma and LDL oxidant-trapping potential in hemodialysis patients. Kidney Int 1999;56(2):747-53. |
|25.||Pastor MC, Sierra C, Bonal J, Teixido J. Serum and erythrocyte tocopherol in uremic patients: effect of hemodialysis versus peritoneal dialysis. Am J Nephrol 1993;13:238-43. |
|26.||Galli F, Rovidati S, Chiarantini L, Campus G, Canestrari F, Buoncristiani U. Bioreactivity and biocompatibility of a vitamin E-modified multi-layer hemodialysis filter. Kidney Int 1998;54:580-9. |
|27.||Zima T, Janebova M, Nemecek K, Bartova V. Retinol and alpha-tocopherol in hemodialysis patients. Ren Fail 1998;20:505-12. |
|28.||Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 1992;339(8793):572-5. |
|29.||Arese M, Cristol JP, Bosc JY, et al. Removal of constitutive and inducible nitric oxide synthase-active compounds in a modified hemodiafiltration with on-line production of substitution fluid: the contribution of convection and diffusion. Int J Artif Organs 1996;19(8):704-11. |
|30.||Morena M, Cristol JP, Bosc JY, et al. Convective and diffusive losses of vitamin C during hemodiafiltration session: a contributive factor to oxidative stress in hemodialysis patients. Nephrol Dial Transplant 1998;13(6):A200. |
|31.||Koenig JS, Fischer M, Bulant E, Tiran B, Elmadfa I, Druml W. Antioxidant status in patients on chronic hemodialysis therapy: impact of parenteral selenium supplementation. Wien Klin Wochenschr 1997;109:13-9. [PUBMED] |
|32.||Arese M, Strasly M, Ruva C. Regulation of nitric oxide synthesis in uraemia. Nephrol Dial Transplant 1995;10:1386-97. |
|33.||Ward R, McLeish K. Polymorphonuclear leukocyte oxidative burst is enhanced in patients with chronic renal insufficiency. J Am Soc Nephrol 1994;5:1697-1702. |
|34.||Chen MF, Chang CL, Liou SY. Increase in resting levels of superoxide anion in the whole blood of uremic patients on chronic hemodialysis. Blood Purif 1998;16(5):290-300. |
|35.||Huysmans K, Lins RL, Daelemans R, Zachee P, De Broe ME. Hypertension and accelerated atherosclerosis in end-stage renal disease. J Nephrol 1998;11(4):185-95. |
|36.||Bostom AG, Lathrop L. Hyperhomocysteinemia in end-stage renal disease: prevalence, etiology, and potential relationship to arteriosclerosis outcomes. Kidney Int 1997;52:10-20. [PUBMED] |
|37.||Ward RA, McLeish KR. Hemodialysis with cellulose membranes primes the neutrophil oxidative burst. Artif Organs 1995;19:801-7. [PUBMED] |
|38.||Cristol JP, Canaud B, Rabesandratana H, Gaillard I, Serre A, Mion C. Enhancement of reactive oxygen species production and cell surface markers expression due to haemodialysis. Nephrol Dial Transplant 1994;9:389-94. [PUBMED] [FULLTEXT]|
|39.||Descamps-Latscha B, Goldfarb B, Nguyen AT, et al. Establishing the relationship between complement activation and stimulation of phagocyte oxidative metabolism in hemodialyzed patients: a randomized prospective study. Nephron 1991;59:279-85. [PUBMED] |
|40.||DeLeo FR, Renee J, McCormick S, Nakamura M, Apicella M, Weiss JP. Neutrophils exposed to bacterial lipopolysaccharide upregulate NADPH oxidase assembly. J Clin Invest 1998;101(2):455-63. |
|41.||Nockher WA, Scherberich J. Monocyte cell-surface CD 14 expression and soluble CD 14 antigen in hemodialysis: evidence for chronic exposure to LPS. Kidney Int 1995;48:1469-76. |
|42.||Dinarello CA, Lonnemann G, Bingel M, Koch KM, Shaldon S. Biological conesquences of monocyte activation during hemodialysis. Contrib Nephrol 1987;59:1-9. |
|43.||Lonnemann G, Haubitz M, Schindler R. Hemodialysis-associated induction of cytokines. Blood Purif 1990;8:214-22. [PUBMED] |
|44.||Balakrishnan VS, Jaber BL, Natov SN, et al. Interleukin-1 receptor antagonist synthesis by peripheral blood mononuclear cells in hemodialysis patients. Kidney Int 1998; 54(6):2106-12. |
|45.||Knudsen PJ, Leon J, Ng AK, Shaldon S, Floege J, Koch KM. Hemodialysis-related induction of beta-2-microglobulin and interleukin-1 synthesis and release by mononuclear phagocytes. Nephron 1989; 53:188-93. [PUBMED] |
|46.||Kumano K, Yokota S, Nanbu M, Sakai T. Do cytokine-inducing substances penetrate through dialysis membranes and stimulate monocytes? Kidney Int Suppl 1993;41: S205-8. [PUBMED] |
|47.||Niwa Y, Ozaki Y, Kanoh T, Akamatsu H, Kurisaka M. Role of cytokines, tyrosine kinase, and protein kinase C on production of superoxide and induction of scavenging enzymes in human leukocytes. Clin Immunol Immunopathol 1996;79(3):303-13. |
|48.||Serfilippi G, Ferro TJ, Johnson A. Activation of protein kinase C mediates altered pulmonary vasoreactivity induced by tumor necrosis factor-alpha. Am J Physiol 1994;267:L282-90. [PUBMED] [FULLTEXT]|
|49.||Rice-Evans C, Omorphos SC, Baysal E. Sickle cell membranes and oxidative damage. Biochem J 1986;237:265-9. [PUBMED] [FULLTEXT]|
|50.||Weinstein T, Chagnac A, Korzets A, et al. Hemolysis in hemodialysis patients: evidence for impaired defence mechanisms against oxidative stress. Nephrol Dial Transplant 2000;15(6):883-7. |
|51.||Siems WG, Sommerburg O, Grune T. Erythrocyte free radical and energy metabolism. Clin Nephrol 2000;53(Suppl 1):S9-17. |
|52.||Gallucci MT, Lubrano R, Meloni C, et al. Red blood cell membrane lipid peroxidation and resistance to erythropoietin therapy in hemodialysis patients. Clin Nephrol 1999;52:239-45. [PUBMED] |
|53.||Eckardt KU. Pathophysiology of renal anemia. Clin Nephrol 2000;53(Suppl 1):S2-8. |
|54.||Delmas-Beauvieux MC, Combe C, Peuchant E, et al. Evaluation of red blood cell lipoperoxidation in hemodialyzed patients during erythropoietin therapy supplemented or not with iron. Nephron 1995;69:404-10. [PUBMED] |
|55.||Miyata T, van Ypersele de Strihou C, Kurokawa K, Baynes JW. Alterations in nonenzymatic biochemistry in uremia: origin and significance of "carbonyl stress" in long-term uremic complications. Kidney Int 1999;55(2):389-99. |
|56.||Miyata T, Oda O, Inagi R, et al. Beta 2Microglobulin modified with advanced glycation end products is a major component of hemodialysis-associated amyloidosis. J Clin Invest 1993;92(3): 1243-52. |
|57.||Miyata T, Wada Y, Cai Z, et al. Implication of an increased oxidative stress in the formation of advanced glycation end products in patients with end-stage renal failure. Kidney Int 1997;51(4):1170-81. |
|58.||Ross R. Atherosclerosis- an inflammatory disease. N Engl J Med 1999;340(2):115-26. |
|59.||Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modifications of low density lipoproteins that increase its atherogenicity. N Engl J Med 1989;320:915-24. |
|60.||Esterbauer H, Gebicki J, Puhl H, Jurgens G. The role of lipid peroxidation and antioxidants in oxidative modification of LDL. Free Radic Biol Med 1992;13:341-90. |
|61.||Maggi E, Bellazzi R, Falaschi F, et al. Enhanced LDL oxidation in uremic patients: an additional mechanism for accelerated atherosclerosis? Kidney Int 1994;45:876-83. [PUBMED] |
|62.||Sutherland WH, Walker RJ, Ball MJ, Stapley SA, Robertson MC. Oxidation of low density lipoproteins from patients with renal failure or renal transplants. Kidney Int 1995;48:227-36. [PUBMED] |
|63.||Westhuyzen J, Saltissi D, Healy H. Oxidation of low density lipoprotein in hemodialysis patients: effect of dialysis and comparison with matched controls. Atherosclerosis 1997;129:199-205. [PUBMED] [FULLTEXT]|
|64.||Panzetta O, Cominacini L, Garbin U, et al. Increased susceptibility of LDL to in vitro oxidation in patients on maintenance hemodialysis: effects of fish oil and vitamin E administration. Clin Nephrol 1995;44(5):303-9. |
|65.||Morena M, Cristol JP, Dantoine T, Carbonneau MA, Descomps B, Canaud B. Protective effects of high-density lipoprotein against oxidative stress are impaired in haemodialysis patients. Nephrol Dial Transplant 2000;15(3):389-95. |
|66.||Stenvinkel P, Holmberg I, Heimburger O, Diczfalusy U. A study of plasmalogen as an index of oxidative stress in patients with chronic renal failure. Evidence of increased oxidative stress in malnourished patients. Nephrol Dial Transplant 1998;13(10): 2594-600. |
|67.||Stenvinkel P, Heimburger O, Lindholm B, Kaysen GA, Bergstrom J. Are there two types of malnutrition in chronic renal failure? Evidence for relationships between malnutrition, inflammation and atherosclerosis (MIA syndrome). Nephrol Dial Transplant 2000;15(7):953-60. |
|68.||Stenvinkel P, Heimburger O, Paultre F, et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int 1999;55(5):1899-911. |
|69.||Bohm V, Tiroke K, Schneider S, Sperschneider H, Stein G, Bitsch R. Vitamin C status of patients with chronic renal failure, dialysis patients and patients after renal transplantation. Int J Vitam Nutr Res 1997;67(4):262-6. |
|70.||Cristol JP, Badiou S, Bosc JY, et al. Vitamin E supplementation increases LDL resistance to ex vivo oxidation in hemodialysis patients. J Am Soc Nephrol (Abst) 1998;9:232A. |
|71.||Islam KN, O'Byrne D, Devaraj S, Palmer B, Grundy SM, Jialal I. Alpha-tocopherol supplementation decreases the oxidative susceptibility of LDL in renal failure patients on dialysis therapy. Atherosclerosis 2000;150(1):217-24. |
|72.||Hussein O, Rosenblat M, Refael G, Aviram M. Dietary selenium increases cellular glutathione peroxidase activity and reduces the enhanced susceptibility to lipid peroxidation of plasma and low-density lipoprotein in kidney transplant recipients. Transplantation 1997;63:679-85. [PUBMED] [FULLTEXT]|
|73.||Azoicai D, Ivan A, Bradatean M, et al. The importance of the use of selenium in the role of an antioxidant in preventing cardiovascular diseases. Rev Med Chir Soc Med Nat Iasi 1997;101(3-4):109-15. |
|74.||Temple KA, Smith AM, Cockram DB. Selenate-supplemented nutritional formula increases plasma selenium in hemodialysis patients. J Ren Nutr 2000;10(1):16-23. |
|75.||Wratten ML, Navino C, Tetta C, Verzetti G. Hemolipodialysis. Blood Purif 1999;17: 127-33. [PUBMED] [FULLTEXT]|
|76.||Sevanian A, Asatryan L, Ziouzenkova O. Low density lipoprotein (LDL) modification: basic concepts and relationship to atherosclerosis. Blood Purif 1999;17:66-78. [PUBMED] [FULLTEXT]|
|77.||Tetta C, Wratten M, Cristol JP, et al. The role of platelet-activating factor in the haemocompatibility of hemodialytic treatments. Int J Artif Organs 1998;21:693-8. [PUBMED] |
|78.||Wratten ML, Sereni L, Tropea F, Tetta C. Hemolipodialysis removes hydrophobic toxins and reduces oxidative stress in an in vitro model system. Nephrol Dial Transplant 1998;13:A184. |
|79.||Wratten ML, Sereni L, Tetta C. Hemolipodialysis attenuates oxidative stress and removes hydrophobic toxins. Artif Organs 2000;24:685-90. [PUBMED] [FULLTEXT]|
|80.||Buoncristiani U, Galli F, Rovidati S, Albertini MC, Campus G, Canestrari F. Oxidative damage during hemodialysis using a vitamin-E-modified dialysis membrane: a preliminary characterization. Nephron 1997;77(1):57-61. |
|81.||Shimazu T, Kondo S, Toyama K, et al. Effect of vitamin E-modified regenerative cellulose membrane on neutrophil superoxide anion radical production and lipid peroxidation. Contrib Nephrol 1999;127: 251-60. [PUBMED] |
|82.||Gaggi R, Santoro A, Melotti C, Di Stasio D, Parente R, Zucchelli P. A chemiluminescence assay for the detection of reactive oxygen species produced by human neutrophils: in vitro comparison of vitamin E-modified multilayer hemodialysis filter with a polysulfone dialyzer. Contrib Nephrol 1999;127:215-25. [PUBMED] |
|83.||Girndt M, Lengler S, Kaul H, Sester U, Sester M, Kohler H. Prospective crossover trial of the influence of vitamin E-coated dialyzer membranes on T-cell activation and cytokine induction. Am J Kidney Dis 2000;35(1):95-104. |
|84.||Calzavara P, De Angeli S, Gatto C, Dugo M, Puggia R, Calconi G. Morphologic evaluation of red blood cells using vitamin E-modified dialysis filters. Contrib Nephrol 1999;127:172-6. [PUBMED] |
|85.||Taccone-Gallucci M, Meloni C, Lubrano R, et al. Chronic haemolysis and erythrocyte survival in haemodialysis patients treated with vitamin E-modified dialysis filters. Contrib Nephrol 1999;127:44-8. [PUBMED] |
|86.||Sommerburg O, Sostmann K, Grune T, Ehrich JH. Oxidative stress in hemodialysis patients treated with a dialysis membrane which has alpha-tocopherol bonded to its surface. Biofactors 1999;10(2-3):121-4. |
|87.||Miyata T, Ueda T, Saitou A, Kurokawa K. Carbonyl stress and high-performance membrane. Kidney Dial 1999;47:20-3. |
|88.||Odetti P, Robaudo C, Valentini S, et al. Effect of a new vitamin E-coated membrane on glycoxidation during hemodialysis. Contrib Nephrol 1999;127:192-9. [PUBMED] |
|89.||Brancaccio D, Bellotti V, Losi B, et al. Effects of a vitamin E-modified dialyzer (Excebrane) on beta-2-microglobulin structure and removal. Contrib Nephrol 1999;127: 147-55. [PUBMED] |
|90.||Mune M, Yukawa S, Kishino M, et al. Effect of vitamin E on lipid metabolism and atherosclerosis in ESRD patients. Kidney Int Suppl 1999;71:S126-9. [PUBMED] |
|91.||Miyazaki H, Matsuoka H, Itabe H, et al. Hemodialysis impairs endothelial function via oxidative stress: effects of vitamin Ecoated dialyzer. Circulation 2000;101(9): 1002-6. |
|92.||Morena M, Cristol JP, Descomps B, Canaud B. Does vitamin E bound on dialysis membrane improve the LDL susceptibility to oxidation? Lesssons from an in vitro model. Contrib Nephrol 1999;127:128-38. |
Department of Nephrology, Renal Research and Training Institute, Lapeyronie University Hospital, 371, Ave. Doyen G. Giraud, 34295 Montpellier
Source of Support: None, Conflict of Interest: None
[Figure - 1], [Figure - 2], [Figure - 3]