Cu/Zn-superoxide dismutase (Cu/Zn-SOD) is an enzyme that is ubiquitously present in the cytoplasm and causes dismutation of superoxide radicals, which are produced by nicotinamide adenine dinucleotide phosphate oxidase and xanthine oxidase, into hydrogen peroxide (H2O2) and molecular oxygen (O2). The copper and zinc ions in Cu/Zn-SOD play essential roles in enzyme activity and structure stability, respectively. Several studies have reported that levels of Cu/Zn-SOD are high in patients on hemodialysis and this is closely related to end-stage renal failure. However, there are very few reviews that summarize the significance of Cu/Zn-SOD. In this brief review, we reconsider the significance of Cu/Zn-SOD levels in dialysis patients.
2. High Levels of Serum Cu/Zn-SOD in Hemodialysis Patients
Several reports have shown that levels of Cu/Zn-SOD are higher in the serum of hemodialysis patients than in serum of healthy volunteers  -  . Such high levels are related to decrease in renal excretion with low renal function  . Moreover, Akiyama et al. reported that Cu/Zn-SOD mRNA levels were also high in the white blood cells of these patients, thus leading to increased Cu/Zn-SOD production  . On the other hand, Futenma et al. examined Cu/Zn-SOD isomers using gel column chromatography and revealed that despite a decrease in tetramers or octamers of Cu/Zn-SOD, there was a marked increase in Cu/Zn- SOD levels in hemodialysis patients owing to an increase in monomers of Cu/ Zn-SOD that are immunologically active but enzymatically inactive  . Thus, both immune status and enzymatic activities may be important for Cu/Zn-SOD measurements in hemodialysis patients.
3. Factors Affecting Serum Cu/Zn-SOD Levels in Hemodialysis Patients
Serum Cu/Zn-SOD levels are related to many factors           . Pawlak et al. found that serum Cu/Zn-SOD levels in peritoneal dialysis and hemodialysis patients are associated with several factors, such as age, creatinine clearance, dialysis period, arteriosclerosis (medial intima complex thickening, malondialdehyde modified low-density lipoprotein), vascular injury, hemostasis, coagulation, vascular repair, angiogenesis (thrombomodulin, vascular endothelial growth factor, von Willebrand factor, urokinase-type plasminogen activator, plasmin/antiplasmin, matrix metalloproteinases, tissue inhibitors of metalloproteinases, tissue factor pathway inhibitor, tissue factor), inflammation (vascular cell adhesion molecule-1, tumor necrosis factor-alpha, macrophage inflammatory proteins, monocyte chemoattractant protein, Regulated on Activation, Normal T-cell Expressed and Secreted), hepatitis, and hepatocyte growth factor. In these reports, the increase of serum Cu/Zn-SOD levels is related to the decrease of kidney function with aging and arteriosclerosis. Moreover, infection, vascular puncture, and hemostasis may be related to the increase in serum Cu/Zn-SOD levels in peritoneal dialysis and hemodialysis patients. Cu/Zn-SOD is primarily used as an antioxidant marker. However, as it is associated with numerous factors in hemodialysis patients, it may serve as a complex marker for arteriosclerosis, vascular, and inflammatory conditions. The onset of arteriosclerotic disease and vascular infection are especially poor prognostic factors in dialysis patients and such complex marker is important, thus necessitating further study.
4. Agents Reducing Serum Cu/Zn-SOD Levels in Hemodialysis Patients
Two reports have revealed the agents reducing serum Cu/Zn-SOD. Washio et al. reported that serum Cu/Zn-SOD and leukocyte Cu/Zn-SOD mRNA levels decreased in hemodialysis patients who were administered vitamin E or who were treated with vitamin E-coated dialyzer membranes  . Vitamin E, an antioxidant agent, might suppress Cu/Zn-SOD production in the blood cells. Pawlak et al. reported that erythropoiesis-stimulating agent (ESA) treatment caused a decrease in Cu/Zn-SOD levels in peritoneal dialysis patients with diabetes  . It is important to investigate such agents that decrease serum Cu/Zn-SOD levels as it is a complex marker indicating arteriosclerosis as well as vascular and inflammatory conditions.
Cu/Zn-SOD is the antioxidant marker as well as a complex marker indicating arteriosclerosis, vascular, and inflammatory conditions. Thus, further studies on serum Cu/Zn-SOD levels are necessary to improve the life-span of hemodialysis patients.
We would like to thank Editage (www.editage.jp) for English language editing.
 Pawlak, K., Mysliwiec, M. and Pawlak, D. (2013) Oxidized Low-Density Lipoprotein (OxLDL) Plasma Levels and OxLDL to LDL Ratio—Are They Real Oxidative Stress Markers in Dialyzed Patients? Life Sciences, 92, 253-258.https://doi.org/10.1016/j.lfs.2012.12.002
 Pawlak, K., Mysliwiec, M. and Pawlak, D. (2012) The Alteration in Cu/Zn Superoxide Dismutase and Adhesion Molecules Concentrations in Diabetic Patients with Chronic Kidney Disease: The Effect of Dialysis Treatment. Diabetes Research and Clinical Practice, 98, 264-270.http://dx.doi.org/10.1016/j.diabres.2012.09.012
 Pawlak, K., Tankiewicz, J., Mysliwiec, M. and Pawlak, D. (2010) Systemic Levels of MMP2/TIMP2 and Cardiovascular Risk in CAPD Patients. Nephron Clinical Practice, 115, c251-c258.https://doi.org/10.1159/000313483
 Pawlak, K., Brzosko, S., Mysliwiec, M. and Pawlak, D. (2009) Kynurenine, Quinolinic Acid—The New Factors Linked to Carotid Atherosclerosis in Patients with End-Stage Renal Disease. Atherosclerosis, 204, 561-566.http://dx.doi.org/10.1016/j.atherosclerosis.2008.10.002
 Pawlak, K., Kowalewska, A., Mysliwiec, M. and Pawlak, D. (2009) Kynurenine and Its Metabolites—Kynurenic Acid and Anthranilic Acid Are Associated with Soluble Endothelial Adhesion Molecules and Oxidative Status in Patients with Chronic Kidney Disease. American Journal of the Medical Sciences, 338, 293-300. http://dx.doi.org/10.1097/MAJ.0b013e3181aa30e6
 Pawlak, K., Domaniewski, T., Mysliwiec, M. and Pawlak, D. (2009) Kynurenines and Oxidative Status Are Independently Associated with Thrombomodulin and Von Willebrand Factor Levels in Patients with End-Stage Renal Disease. Thrombosis Research, 124, 452-457.http://dx.doi.org/10.1016/j.thromres.2009.04.011
 Pawlak, K., Zolbach, K., Borawski, J., Mysliwiec, M., Kovalchuk, O., Chyczewski, L. and Pawlak, D. (2008) Chronic Viral Hepatitis C, Oxidative Stress and the Coagulation/Fibrinolysis System in Haemodialysis Patients. Thrombosis Research, 123, 166-170.http://dx.doi.org/10.1016/j.thromres.2008.02.012
 Pawlak, K., Pawlak, D. and Mysliwiec, M. (2007) Impaired Renal Function and Duration of Dialysis Therapy Are Associated with Oxidative Stress and Proatherogenic Cytokine Levels in Patients with End-Stage Renal Disease. Clinical Biochemistry, 40, 81-85.https://doi.org/10.1016/j.clinbiochem.2006.09.001
 Pawlak, K., Pawlak, D. and Mysliwiec, M. (2007) Serum Matrix Metalloproteinase-2 and Increased Oxidative Stress Are Associated with Carotid Atherosclerosis in Hemodialyzed Patients. Atherosclerosis, 190, 199-204.http://dx.doi.org/10.1016/j.atherosclerosis.2006.01.020
 Pawlak, K., Pawlak, D., Brzosko, S. and Mysliwiec, M. (2006) Carotid Atherosclerosis Is Associated with Enhanced Beta-Chemokine Levels in Patients on Continuous Ambulatory Peritoneal Dialysis. Atherosclerosis, 186, 146-151.http://dx.doi.org/10.1016/j.atherosclerosis.2005.07.003
 Pawlak, K., Pawlak, D. and Mysliwiec, M. (2006) Oxidative Stress Effects Fibrinolytic System in Dialysis Uraemic Patients. Thrombosis Research, 117, 517-522.http://dx.doi.org/10.1016/j.thromres.2005.05.001
 Akiyama, S., Inagaki, M., Tsuji, M., Gotoh, H., Gotoh, T., Gotoh, Y. and Oguchi, K. (2005) MRNA Study on Cu/Zn Superoxide Dismutase Induction by Hemodialysis Treatment. Nephron Clinical Practice, 99, c107-c114. https://doi.org/10.1159/000083928
 Pawlak, K., Pawlak, D. and Mysliwiec, M. (2005) Method of Dialysis Therapy and Selected Markers of Oxidative Stress and Endothelial Injury in Patients with Chronic Renal Failure. Polish Archives of Internal Medicine, 113, 21-26.
 Pawlak, K., Pawlak, D. and Mysliwiec, M. (2005) Cu/Zn Superoxide Dismutase Plasma Levels as a New Useful Clinical Biomarker of Oxidative Stress in Patients with End-Stage Renal Disease. Clinical Biochemistry, 38, 700-705.https://doi.org/10.1016/j.clinbiochem.2005.02.009
 Pawlak, K., Pawlak, D. and Mysliwiec, M. (2005) Circulating Beta-Chemokines and Matrix Metalloproteinase-9/Tissue Inhibitor of Metalloproteinase-1 System in Hemodialyzed Patients—Role of Oxidative Stress. Cytokine, 31, 18-24.https://doi.org/10.1016/j.cyto.2004.12.020
 Pawlak, K., Pawlak, D. and Mysliwiec, M. (2004) Possible New Role of Monocyte Chemoattractant Protein-1 in Hemodialysis Patients with Cardiovascular Disease. American Journal of Nephrology, 24, 635-640. https://doi.org/10.1159/000082936
 Pawlak, K., Pawlak, D. and Mysliwiec, M. (2004) Extrinsic Coagulation Pathway Activation and Metalloproteinase-2/TIMPs System Are Related to Oxidative Stress and Atherosclerosis in Hemodialysis Patients. Thrombosis and Haemostasis, 92, 646-653.https://doi.org/10.1160/TH04-02-0128
 Pawlak, K., Pawlak, D. and Mysliwiec, M. (2004) Hepatitis Intensified Oxidative Stress, MIP-1BETA and RANTES Plasma Levels in Uraemic Patients. Cytokine, 28, 197-204.https://doi.org/10.1016/j.cyto.2004.07.007
 Schettler, V., Kühn, W., Kleinoeder, T., Armstrong, V.W., Oellerich, M., Müller, G.A. and Wieland, E. (2003) No Acute Impact of Haemodialysis Treatment on Free Radical Scavenging Enzyme Gene Expression in White Blood Cells. Journal of Internal Medicine, 253, 201-207.
 Pawlak, K., Borawski, J., Naumnik, B. and Mysliwiec, M. (2003) Relationship between Oxidative Stress and Extrinsic Coagulation Pathway in Haemodialyzed Patients. Thrombosis Research, 109, 247-251. http://dx.doi.org/10.1016/S0049-3848(03)00241-X
 Borawski, J., Pawlak, K., Naumnik, B. and Mysliwiec, M. (2002) Relations between Oxidative Stress, Hepatocyte Growth Factor, and Liver Disease in Hemodialysis Patients. Renal Failure, 24, 825-837.https://doi.org/10.1081/JDI-120015684
 Chen, M.F., Chang, C.L. and Liou, S.Y. (1998) Increase in Resting Levels of Superoxide Anion in the Whole Blood of Uremic Patients on Chronic Hemodialysis. Blood Purification, 16, 290-300.https://doi.org/10.1159/000014347
 Mimic-Oka, J., Simic, T., Ekmescic, V. and Dragicevic, P. (1995) Erythrocyte Glutathione Peroxidase and Superoxide Dismutase Activities in Different Stages of Chronic Renal Failure. Clinical Nephrology, 44, 44-48.
 Canestrari, F., Galli, F., Giorgini, A., Albertini, M.C., Galiotta, P., Pascucci, M. and Bossù, M. (1994) Erythrocyte Redox State in Uremic Anemia: Effects of Hemodialysis and Relevance of Glutathione Metabolism. Acta Haematologica, 91, 187-193. https://doi.org/10.1159/000204332
 Futenma, A., Yamada, H., Kitano, M., Miyai, H., Fukatsu, A. and Kato, K. (1993) Plasma Levels of Superoxide Dismutase and Its Isomers in Patients with Chronic Renal Disease. Nippon Jinzo Gakkai Shi, 35, 371-376.
 Washio, K., Inagaki, M., Tsuji, M., Morio, Y., Gotoh, H., Gotoh, Y. and Oguchi, K. (2012) Correlation between Leukocyte Membrane Lipid Peroxidation and Expression of Cu/Zn-Superoxide Dismutase mRNA in Hemodialysis Patients. Blood Purification, 33, 59-65.https://doi.org/10.1159/000333840
 Akiyama, S., Inagaki, M., Tsuji, M., Gotoh, H., Gotoh, T., Washio, K., Gotoh, Y. and Oguchi, K. (2005) Comparison of Effect of Vitamin E-Coated Dialyzer and Oral Vitamin E on Hemodialysis-Induced Cu/Zn-Superoxide Dismutase. American Journal of Nephrology, 25, 500-506. https://doi.org/10.1159/000088172
 Pawlak, K., Pawlak, D. and Mysliwiec, M. (2007) Erythropoietin Therapy Decreased Tissue Factor, Its Pathway Inhibitor, and Oxidative Stress in Peritoneal Dialysis Patients with Diabetes. Nephron Clinical Practice, 107, c20-c24. https://doi.org/10.1159/000106508