|Year : 2016 | Volume
| Issue : 1 | Page : 88-93
|Evaluation of administration of oral N-acetylcysteine to reduce oxidative stress in chronic hemodialysis patients: A double-blind, randomized, controlled clinical trial
Heshmatollah Shahbazian1, Shokouh Shayanpour2, Ali Ghorbani2
1 Chronic Kidney Disease Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
2 Department of Nephrology, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
Click here for correspondence address and email
|Date of Web Publication||15-Jan-2016|
| Abstract|| |
This study was designed to assess the efficacy of N-acetylcysteine (NAC) on the reduction of oxidative stress in chronic hemodialysis (HD) patients through measurement of total serum anti-oxidant capacity. In this randomized, double-blind, controlled clinical trial, the efficacy and safety of NAC in reduction of oxidative stress was evaluated in 40 chronic HD patients. The study was conducted at the HD Department of the Golestan Hospital, Ahvaz, Iran. Data were analyzed using SPSS version 19. Paired samples test showed that the mean score of the serum level of total anti-oxidant capacity (TAC) increased from 26.39 ± 17.03 to 33.26 ± 18.8 (Pvalue = 0.01) and from 24.02 ± 16.47 to 25.38 ± 17.04 (P = 0.1) in the NAC and placebo groups, respectively. Difference in the mean TAC changes between groups was statistically significant (P= 0.042). In our study, NAC administration could reduce oxidative stress in chronic HD patients. No major side-effects were observed.
|How to cite this article:|
Shahbazian H, Shayanpour S, Ghorbani A. Evaluation of administration of oral N-acetylcysteine to reduce oxidative stress in chronic hemodialysis patients: A double-blind, randomized, controlled clinical trial. Saudi J Kidney Dis Transpl 2016;27:88-93
|How to cite this URL:|
Shahbazian H, Shayanpour S, Ghorbani A. Evaluation of administration of oral N-acetylcysteine to reduce oxidative stress in chronic hemodialysis patients: A double-blind, randomized, controlled clinical trial. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2020 Feb 28];27:88-93. Available from: http://www.sjkdt.org/text.asp?2016/27/1/88/174084
| Introduction|| |
Patients with chronic renal failure (CRF) of various etiologies are prone to atherosclerosis. ,, Cardiovascular events are the most common cause of mortality in end-stage renal disease (ESRD) patients. , Recently, a couple of cardiovascular disease (CVD) risk factors have been recognized, including oxidative stress.  Oxidative stress is a situation in which an imbalance occurs between produced free radicals and anti-oxidative defence.  This imbalance causes oxygen radicals, nitrogen and/or free hydroxyl to cause oxidation of biomolecules of cells and, finally, to structural and functional changes. ,,,,
Oxidative stress and pro-inflammatory status are more common in chronic kidney disease (CKD) patients than healthy persons and are accentuated after initiation of hemodialysis (HD) because of incompatible membranes and/or the loss of anti-oxidative molecules. ,,, Increasing levels of stress biomarkers and reduction of serum anti-oxidant capacity occur early, in the beginning of the third stage of CKD. ,,
In human beings, the anti-oxidant defense system consists of enzymatic anti-oxidant, including dismutase superoxide, catalase, glutathione peroxidase and non-enzymatic antioxidants (hydrophilic and lipophilic). The hydrophilic branch includes uric acid, ascorbic acid, bilirubin, albumin and flavonoids. The lipophilic branch consists of α-tocopherol, ubquinol and carotenoids. ,,,,,, Therapeutic antioxidants include N-acetylcysteine (NAC) and barodoxolone. ,,,
NAC is a composition with a sulfhydryl moiety and has a potent anti-oxidant effect. Also, it is the precursor of glutathione that reduces oxidative stress by increasing the level of serum anti-oxidants. ,
Direct measurement of reactive oxidative species (ROS) is very difficult, sophisticated and practically impossible because of their diminutive amount in the free form and short half-lives. ,
Therefore, to assess the status of oxidative stress, the following two methods are applied instead of direct measurement of ROS and reactive nitrogen species: measurement of oxidative stress biomarkers, as discussed above, and measurement of serum anti-oxidant capacity, which falls in case of oxidative situation because of consumption. 
As increasing oxidative stress biomarker levels and reduction of serum anti-oxidant capacity are correlated with the extent of inflammation and the prevalence of atherosclerosis and CVD progression, ,, we attempted in this study to evaluate the efficacy and safety of NAC in reduction of oxidative stress in chronic HD patients through measurement of total serum anti-oxidant capacity.
| Materials and Methods|| |
This study is a randomized, double-blind, controlled clinical trial evaluating the efficacy and safety of NAC in reduction of oxidative stress in 40 chronic HD patients in the HD Department of the Golestan Hospital, Ahvaz, Iran. All patients were above 18 years old and were under HD treatment three times a week for at least three months.
Exclusion criteria were any acute illness during the study or in the past month, leading to hospitalization, known allergy to NAC, hepatic cirrhosis and/or elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT), use of vitamin E or vitamin C or any anti-oxidant, for two weeks before or through the study and presence of heart failure (ejection fraction <35%).
Patients who enrolled into the study were allocated to the intervention or control group randomly by a random number generator. The assignment was concealed using encoded cards placed in opaque envelopes. Drug prescription and randomization were conducted by a person who was unaware of the study and statistical analysis. Before prescribing NAC or placebo, the baseline total serum anti-oxidant capacities were measured by the enzymelinked immunosorbent assay method using a laboratory total anti-oxidant capacity (TAC) kit (Glory Company, Denver, CO, USA). Patients in the intervention group took 600 mg of NAC orally (Hexal brand), twice daily before meals. To control the appropriate use of medications, tablets were delivered to the patients weekly and participants gave back the used tablet sheets to be checked. In the control group, the patients took the placebo tablets twice daily as well. Placebo tablets were similar to NAC pills in shape, color, hardness and taste. Placebo tablets consisted of microcrystal cellulose, lactose, starch, sorbitol and powder. It looked like NAC solution after dissolving in 50 mL of water in terms of taste and physical characteristics.
Appropriate intake of placebo pills was controlled as in the NAC group. The study duration was six weeks. After six weeks, be-fore the last session of HD, the serum level of TAC was measured. [Figure 1] demonstrates the flow chart of the study.
Forty participants were enrolled into the study. All the patients took their tablets regularly. All participants completed the study; therefore, 40 patients were analyzed at the end of the trial. In this trial, we did not measure the oxidative stress biomarkers.
All participants gave a written informed consent. It was also cleared by the ethical committee of the Ahvaz Jundishapur University of Medical Sciences (Register code: ETH-511). The clinical trial registration code was IRCT 201201108679N1. Also, the proposal of this article was registered in Iranian clinical trials (IRCT 201201108679N1).
| Statistical Analysis|| |
The results were presented as mean ± SD. The Kolmogronov-Smirnov test was applied to test the normalcy of the data. The Paired ttest was used to compare the pre- and post-intervention findings. Student's T-test was used to compare the changes between groups. The level of significance was considered as 5%. Data were analyzed using SPSS version 19.
| Results|| |
A total of 40 participants were enrolled into the study. Twenty patients each were allocated to the treatment and control groups; there were eight males in the treatment group and ten males in the control group. The mean score of age in both groups was similar (43 ± 12 years for the treatment group and 43 ± 13 for the placebo group). The baseline characteristics of patients are shown in [Table 1]. The most common cause of ESRD was diabetes mellitus. The Kolmogorov-Smirnov test showed normalcy of variables in both groups before and at the end of the study (P >0.05).
The Paired samples test showed that the mean score of the serum level of TAC increased from 26.39 ± 17.03 to 33.26 ± 18.8 (P = 0.01) in the NAC group and from 24.02 ± 16.47 to 25.38 ± 17.04 (P = 0.1) in the placebo group. The difference in the mean TAC changes between groups was statistically significant (P = 0.042).
Sub-group analysis showed that the difference in change of mean TAC between groups in males was statistically significant (P = 0.012). In contrast, the post hoc sub-group analysis showed that a difference in change of the mean TAC between groups in females was not significant (P = 0.401).
A 20% increase in TAC occurred in 13 patients in the treatment group (65%) and in two cases (10%) in the placebo group (P = 0.000). In this study, all the patients tolerated NAC well. The participants were followed-up for two weeks after the end of the study for assessing any complication. No side-effects including pruritus and urticaria were found in either group.
| Discussion|| |
Recent investigations have shown the role of oxidative stress in acceleration of atherosclerosis as well as therapeutic effect of antioxidants; oxidative stress causes tissue damage by free radicals. , Free radical atoms are groups that contain uncoupled electrons. They are very reactive and are able to bind to lipoproteins, nucleic acids, proteins and enzymes. ,, Free oxygen radicals produce reactive oxygen groups such as hydroxyl radicals of superoxide and peroxide ions. Binding of free radicals to nitric oxide (NO) in endothelium leads to its decreased ability to induce vasodilation. ,,, Thus, it is considered as a coronary ischemic agent. Nicotinamide adenine dinucleotide phosphate-oxidase and xanthine oxidase are two important sources of oxidative stress that, by producing high levels of oxidized lowdensity lipoprotein, leads to reduction of coronary blood flow. ,, In this way, it is important to protect the organism by keeping the level of anti-oxidants elevated. ,,
It has been shown that NAC therapy has protective effects against oxidative stress and in replenishing consumed glutathione. , Additionally, it has a protective effect on the liver and kidney and is used as an antidote in acetaminophen toxicity and contrast nephropathy. Its usage as a mucolytic is due to the free sulfhydryl moiety in its structure that can break glycoprotein bands in the mucus; hence, NAC can be considered as a supplement therapy for anti-oxidant increase for two reasons. , Firstly, its sulfhydryl group can neutralize the effects of reactive oxygen species (such as hydrogen peroxide, hypochloric acid and hydroxyl radicals) and, secondly, it can increase glutathione. , There are a large number of investigations on the effects of NAC on oxidative stress. In Trimarchi's clinical trial study, NAC decreased the malondialdehyde (MDA) level significantly in chronic HD patients.  The study, as compared with our investigation, had a shorter duration and lesser number of cases. Also, the dose of NAC was smaller. The study of Lazar et al showed that serum Aopps biomarker significantly decreased after 20 days of the administration of NAC. This study had no control group and sample size and duration of the study was also less than ours.  In the two studies by Thaha et al, they showed that NAC specifically increases circulation-dependent vasodilation and improves endothelial function. Also, intravenous administration of NAC during HD can reduce the level of asymmetric dimethyl arginine (ADMA). In both studies, NAC administration was intravenous and single dose. , Therefore, it was shorter than our study. En-Pi Tsai et al, in a clinical trial, suggested that intravenous NAC can normalize the homocysteine level in HD patients.  In their study as well, NAC was administered intravenously and at a single dose.  In another study by Karimzadeh et al, treatment with NAC decreased the plasma level of homocysteine but had no effect on the plasma level of MDA and enzymatic anti-oxidants. However, they had a smaller sample size and shorter duration as compared with our trial. Also, they did not have a control group. 
Swarnalatha et al showed that NAC as an oral supplement can decrease oxidative stress in HD patients and may improve the treatment of anemia. In this investigation, the dose was smaller but the duration was longer than our study.  The above-mentioned researches are consistent with our findings.
In our study, NAC administration was shown to reduce oxidative stress in chronic HD patients. No major side-effect was observed. Considering that oxidative stress is an important improving factor for anemia, inflammation and atherosclerosis in chronic HD patients, NAC as supplement therapy may be encouraging.  In this trial, we did not measure biomarkers of oxidative stress.
Source of Support
This study was a fellowship thesis of Shokouh Shayanpour and was supported by a grant from the Ahvaz Jundishapur University of Medical Sciences.
Conflict of Interest:
All authors declare that there is no conflict of interests.
| References|| |
Popolo A, Autore G, Pinto A, Marzocco S. Oxidative stress in patients with cardiovascular disease and chronic renal failure. Free Radic Res 2013;47:346-56.
Maesaka JK, Sodam B, Palaia T, et al. Prostaglandin D2 synthase: Apoptotic factor in alzheimer plasma, inducer of reactive oxygen species, inflammatory cytokines and dialysis dementia. J Nephropathol 2013;2:166-80.
Hambali Z, Ahmad Z, Arab S, Khazaai H. Oxidative stress and its association with cardiovascular disease in chronic renal failure patients. Indian J Nephrol 2011;21:21-5.
Mohamed BA, Yang W, Litt H, Rosas SE. Valvular calcification, inflammation, and mortality in dialysis patients. J Heart Valve Dis 2013;22:584-90.
Nasri H. Elevated serum parathyroid hormone is a heart risk factor in hemodialysis patients. J Parathyroid Dis 2013;1:13-4.
Solati M, Mahboobi HR. Paraoxonase enzyme activity and dyslipidemia in chronic kidney disease patients. J Nephropathol 2012;1:123-5.
Gupta K, Mahajan R. Coronary risk factors in maintenance hemodialysis patients: Who is the culprit - Hemodialysis or chronic renal failure? Int J Appl Basic Med Res 2011;1:11-4.
Yildiz G, Aydin H, Mağden K, Yilmaz A, Hür E, Candan F. Influence of single hemodialysis session on serum paraoxonase-1, arylesterase activity, total oxıdant status and total antioxidant status. Minerva Med 2014;105:79-87.
Rafieian-Kopaei M, Nasri H. Serum lipoprotein (a) and atherosclerotic changes in hemodialysis patients. J Renal Inj Prev 2013; 2:47-50.
Günal SY, Ustündağ B, Günal Aİ. The assessment of oxidative stress on patients with chronic renal failure at different stages and on dialysis patients receiving different hypertensive treatment. Indian J Clin Biochem 2013; 28:390-5.
Rafiean-Kopaie M, Nasri H. Impact of inflammation on anemia of hemodialysis patients who were under treatment of recombinant human erythropoietin. J Renal Inj Prev 2013;2: 93-5.
Celik G, Capraz I, Yontem M, Bilge M, Unaldi M, Mehmetoglu I. The relationship between the antioxidant system, oxidative stress and dialysis-related amyloidosis in hemodialysis patients. Saudi J Kidney Dis Transpl 2013;24: 1157-64.
Tamadon MR. Secondary hyperparathyroidism and chronic kidney disease. J Parathyroid Dis 2013;1:15-6.
Sung CC, Hsu YC, Chen CC, Lin YF, Wu CC. Oxidative stress and nucleic acid oxidation in patients with chronic kidney disease. Oxid Med Cell Longev 2013;2013:301982.
Gobe GC, Morais C, Vesey DA, Johnson DW. Use of high-dose erythropoietin for repair after injury: A comparison of outcomes in heart and kidney. J Nephropathol 2013;2:154-65.
Puchades MJ, Saez G, Muñoz MC, et al. Study of oxidative stress in patients with advanced renal disease and undergoing either hemodialysis or peritoneal dialysis. Clin Nephrol 2013;80:177-86.
Nasri H. Association of Ca×PO4 product with levels of serum C-reactive protein in regular hemodialysis patients. J Renal Inj Prev 2012; 1:55-9.
Coaccioli S, Standoli ML, Biondi R, et al. Open comparison study of oxidative stress markers between patients with chronic renal failure in conservative therapy and patients in haemodialysis. Clin Ter 2010;161:435-9.
Ghorbani A, Jasemi-Zergani F. Ticlopidine to prevent primary arteriovenous fistula failure in hemodialysis patients; a randomized controlled trial. J Renal Inj Prev 2013;2:109-11.
Galli F, Piroddi M, Annetti C, Aisa C, Floridi E, Floridi A. Oxidative stress and reactive oxygen species. Contrib Nephrol 2005;149: 240-60.
Spasovski D. Renal markers for assessment of renal tubular and glomerular dysfunction. J Nephropharmacol 2013;2:23-5.
Morena M, Delbosc S, Dupuy AM, Canaud B, Cristol JP. Overproduction of reactive oxygen species in end-stage renal disease patients: A potential component of hemodialysis-associated inflammation. Hemodial Int 2005;9:37-46.
Saddadi F, Alatab S, Pasha F, Ganji MR, Soleimanian T. The effect of treatment with Nacetylcysteine on the serum levels of Creactive protein and interleukin-6 in patients on hemodialysis. Saudi J Kidney Dis Transpl 2014;25:66-72.
Purwanto B, Prasetyo DH. Effect of oral Nacetylcysteine treatment on immune system in continuous ambulatory peritoneal dialysis patients. Acta Med Indones 2012;44:140-4.
Rouhi H, Ganji F. Effects of N-acetyl cysteine on serum lipoprotein (a) and proteinuria in type 2 diabetic patients. J Nephropathol 2013; 2:61-6.
Ardalan MR, Sanadgol H, Nasri H, Baradaran A, Tamadon MR, Rafieian-Kopaei R. Impact of Vitamin D on the immune system in kidney disease. J Parathyroid Dis 2013;1:17-20.
Raj DS, Dominic EA, Pai A, et al. Skeletal muscle, cytokines, and oxidative stress in endstage renal disease. Kidney Int 2005;68:2338-44.
Nasri H. Impact of diabetes mellitus on parathyroid hormone in hemodialysis patients. J Parathyroid Dis 2013;1:9-11.
Cachofeiro V, Goicochea M, de Vinuesa SG, Oubiña P, Lahera V, Luño J. Oxidative stress and inflammation, a link between chronic kidney disease and cardiovascular disease. Kidney Int Suppl 2008;111:S4-9.
Mowlaie M, Nasri H. Close association of arterial plaques with left ventricular hypertrophy and ejection fraction in hemodialysis patients. J Nephropharmacol 2014;3:9-12.
Stenvinkel P, Ketteler M, Johnson RJ, et al. IL-10, IL-6, and TNF-alpha: Central factors in the altered cytokine network of uremia - The good, the bad, and the ugly. Kidney Int 2005;67:1216-33.
Trimarchi H, Mongitore MR, Baglioni P, et al. N-acetylcysteine reduces malondialdehyde levels in chronic hemodialysis patients - A pilot study. Clin Nephrol 2003;59:441-6.
Lazárová M, Stejskal D, Lacnák B, et al. The antioxidant acetylcysteine reduces oxidative stress by decreasing level of AOPPs. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2004;148:131-3.
Thaha M, Yogiantoro M, Tomino Y. Intravenous N-acetylcysteine during haemodialysis reduces the plasma concentration of homocysteine in patients with end-stage renal disease. Clin Drug Investig 2006;26:195-202.
Thaha M, Pranawa W, Yogiantoro M, Tomino Y. Intravenous N-acetyl cysteine during hemodialysis reduces asymmetric dimethyl arginine level in end-stage renal disease patients. Clin Nephrol 2008;69:24-32.
Tsai EP, Yang FL, Wang CH, Fang TC, Lee RP, Hsu BG. Effect of Intravenous N-acetyl cysteine on plasma total homocysteine and inflammatory cytokines during high flux hemodialysis. Tzu Chi Med J 2010;22:90-5.
Karimzadeh I, Khalili H, Dashti-Khavidaki S, et al. N-acetyl cysteine in prevention of amphotericininduced electrolytes imbalances: A randomized, double-blinded, placebo-controlled, clinical trial. Eur J Clin Pharmacol 2014;70:399-408.
Swarnalatha G, Ram R, Neela P, Naidu MU, Dakshina Murty KV. Oxidative stress in hemodialysis patients receiving intravenous iron therapy and the role of N-acetylcysteine in preventing oxidative stress. Saudi J Kidney Dis Transpl 2010;21:852-8.
Pezeshgi A, Parsamanesh N, Farhood G, Mahmoodi K. Evaluation of the protective effect of N-acetylcysteine on contrast media nephropathy. J Renal Inj Prev. 2015;4(4):109-112.
Department of Nephrology, Ahvaz Jundishapur University of Medical Sciences, Golestan Hospital, Ahvaz
| Article Access Statistics|
| Viewed||3748 |
| Printed||20 |
| Emailed||1 |
| PDF Downloaded||683 |
| Comments ||[Add] |