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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2014  |  Volume : 25  |  Issue : 1  |  Page : 66-72
The effect of treatment with N-acetylcysteine on the serum levels of C-reactive protein and interleukin-6 in patients on hemodialysis


1 Nephrology Department, Dr. Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
2 Urology Research Center, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
3 Nephrology Department, Islamic Azad University, Tehran Medical Branch, Tehran, Iran

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Date of Web Publication7-Jan-2014
 

   Abstract 

Patients with end-stage renal disease (ESRD) are at an increased risk of cardiovas­cular disease due to many factors including inflammation and oxidative stress. N-acetylcysteine (NAC) is a thiol-containing anti-oxidant with anti-inflammatory properties. We aimed to assess the effect of three months treatment with oral NAC on the plasma levels of inflammatory mediators like interleukin-6 (IL-6) and C-reactive protein (hs-CRP) in patients on hemodialysis (HD). Twenty-four patients (nine males and 15 females) on maintenance HD were recruited in the study. Their mean age was 55.3 years. All the patients received oral NAC (600 mg twice a day) for a period of three months. The serum levels of biomedical parameters and IL-6 and hs-CRP were measured at baseline and three months after initiation of treatment. A significant decrease in serum levels of hs-CRP (22.4 vs. 5.2), IL-6 (8.1 vs. 3.6), parathyroid hormone (iPTH) (257.2 vs. 158.8), ferritin (632.0 vs. 515.1) and erythrocyte sedimentation rate (ESR) (54.2 vs. 38.3) was observed following NAC treatment. Female subjects presented with a significantly higher change in serum levels of hs-CRP compared with males (23 vs. 5.4). In three subjects who were less than 40 years old, the hs-CRP and IL-6 levels showed an increase following NAC treatment. Our study found that short-term oral NAC treatment might result in the reduction of IL-6 and hs-CRP in patients who are on regular HD. This suggests that patients with ESRD may benefit from the anti-inflammatory effects of NAC.

How to cite this article:
Saddadi F, Alatab S, Pasha F, Ganji MR, Soleimanian T. The effect of treatment with N-acetylcysteine on the serum levels of C-reactive protein and interleukin-6 in patients on hemodialysis. Saudi J Kidney Dis Transpl 2014;25:66-72

How to cite this URL:
Saddadi F, Alatab S, Pasha F, Ganji MR, Soleimanian T. The effect of treatment with N-acetylcysteine on the serum levels of C-reactive protein and interleukin-6 in patients on hemodialysis. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2019 Nov 19];25:66-72. Available from: http://www.sjkdt.org/text.asp?2014/25/1/66/124489

   Introduction Top


Patients with end-stage renal disease (ESRD) are at increased risk of cardiovascular disease (CVD) and atherosclerosis. In fact, more than half of the mortality in patients with ESRD who are on hemodialysis (HD) is due to cardio­vascular events. There are some traditional risk factors including diabetes mellitus, hyper­tension and hyperlipidemia, which are involved in both progression of renal disease and in­creased cardiovascular events. However, the high prevalence of CVD in HD patients cannot be fully explained by only these traditional risk factors. It has been suggested that patients with ESRD are exposed to other non-traditio­nal uremia-related risk factors. These include anemia, altered calcium-phosphorus metabo­lism, increased homocystein levels, inflamma­tion, malnutrition and increased levels of oxidative stress. [1],[2] Of these risk factors, increased oxidative stress and inflammation are common and known to be among the mediators of car­diovascular complications in ESRD patients. It has been proposed that oxidative stress might be involved in the pathogenesis of many pro­cesses that eventually lead to atherogenesis and cardiovascular events such as hypertension [3],[4] and endothelial dysfunction. [5] Indeed, in ESRD patients, oxidative stress may lead to an immunodeficiency state characterized clinically by repeated episodes of infections, which in turn could aggravate the high inflammatory state that these patients already have. [6] On the basis of these considerations, targeting the oxidative stress could be an important and effective treatment strategy in ESRD patients. N-acetylcysteine (NAC) is a thiol-containing compound that serves as a precursor in the formation of the anti-oxidant gluthatione. It also stimulates the intracellular synthesis of glutathione and glutathione-S-transferase acti­vity. Moreover, the thiol group in NAC has the ability to reduce the free radicals. [7] In addition to its anti-oxidant properties, NAC has been shown to reduce the production of angiotensin II via inhibiting the angiotensin-converting enzyme activity, enhance the nitric oxide (NO)-dependent vasodilatation in L-Nitro-Arginine Methyl Ester (L-NAME)-treated rats [8] and re­duce systemic blood pressure in animals. [9] In view of these observations, we aimed to eva­luate whether treatment with NAC in patients with ESRD can also have an effect on the inflammatory state of these patients. To do this, the serum levels of inflammatory media­tors interleukin-6 (IL-6) and highly sensitive C-reactive protein (hs-CRP) were measured before and three months after NAC treatment.


   Patients and Methods Top


Subjects

Twenty-four patients (nine males and 15 females), aged between 28 and 74 years, who were on maintenance HD for more than six months were enrolled in this interventional study. The participants were selected from patients who were referred to the dialysis ward of Baharloo or Dr. Shariati hospitals. These two hospitals are affiliated to the Tehran University of Medical Science, Tehran, Iran. The investigation was conducted during 2008 - 2009. The study protocol was approved by the ethics committee of the Tehran University of Medical Science and written consent was signed by all the participants before enrolling into the study. All the stages of this research were followed according to the Helsinki dec­laration of the world medical association. Patients with a history of smoking, evidence of malignancy, vasculitis, infection (active or within the last one month), hepatitis [abnormal liver function test (LFT)], cardiac disease (having symptoms and/or an abnormal electro-cardiography), respiratory disorders, uncon­trolled diabetes (HbA1C >7.5) and those re­ceiving lipid-lowering agents and immunosuppressive drugs in the last three months were excluded. Any patient who received statins, vitamin D supplements, aspirin, heparin and sevelamer and had a history of regular use of non-steroidal anti-inflammatory drugs (NSAIDs) during the last three months were also excluded from the study. Additionally, all study patients were strongly advised to not consume any nutritional material with known anti-oxidant effects. All the patients were routinely dialyzed for 4 h, three times weekly, using a biocompatible polysulfone membrane and bicarbonate buffer.

Compliance of the study patients was moni­tored in each dialysis session by asking about the consumption of the medication and coun­ting the remaining tablets. Demographic data including age, gender, weight and duration on dialysis were recorded. Oral NAC (600 mg, twice a day) (Zambon Pharmacy, Swiss) was given to all the subjects for a period of three months. The serum levels of blood urea ni­trogen (BUN), parathyroid hormone (iPTH), ferritin, albumin, calcium (Ca), phosphorus (Ph), hs-CRP, IL-6, cholesterol, triglycerides (TG), low-density lipoprotein (LDL) choles­terol, high-density lipoprotein (HDL) choles­terol and erythrocyte sedimentation rate (ESR) were measured before and three months after the initiation of therapy. The blood samples for measuring all the above-mentioned varia­bles were taken just before the initiation of dialysis.

Laboratory measurements Fasting blood samples were collected in coa­gulant-containing vacutainers in the morning. The blood was centrifuged within 1 h of col­lection and serum was separated. The collected serum samples were stored at -20°C until all the samples were ready to be assessed. The serum IL-6 and hs-CRP levels were measured by immunoassay (ELISA). The TG, total cho­lesterol, HDL cholesterol, LDL cholesterol and BUN levels were measured by a colori-metric method. Plasma levels of iPTH, ferritin and albumin were measured by the electro­luminescence method.


   Statistical Analysis Top


Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS, version 16, Chicago, IL, USA). Distribution was checked by one sample Kolmogorov-Smirnov test. Data are presented as mean (median; min. - max.). Because of the non-parametric distribution of some continuous data, Wilcoxon-Signed Ranks test was used to compare the data before and after intervention. The Spearman rho correlation was used to investigate the linear correlation between the variables. Independent t-test and Mann-Whitney U test were, respectively, used for comparison of age and laboratory parameters between the two genders. Differences were considered statistically significant at level of P ≤0.05.


   Results Top


In this interventional study, 24 patients who were on regular HD for at least six months were recruited. The mean age of the parti­cipants was 55.3 years. The median duration on dialysis was five years, with minimum of seven months and a maximum of 21 years. Four patients had previous kidney transplan­tation. The underlying cause of chronic kidney disease (CKD) in these patients is shown in [Table 1]. No major side-effects, except slight itching, were reported following administra­tion of NAC. Evaluation of the laboratory data revealed that serum levels of hs-CRP, IL-6, PTH, ferritin and ESR were significantly lo­wer following NAC treatment [Table 2]. There was also a slight, although not significant, dec­rease in serum TG level after NAC treatment. When the mean of changes in laboratory parameters were separately analyzed in the two sexes, we found a significant reduction in hs-CRP levels in female subjects compared with male participants. The median decrease of hs-CRP in females was 23 units, while it was only 5.4 units in male subjects (P = 0.04). Separate evaluation of IL-6 concentration in male and female subjects did not show a significant difference.
Table 1: Underlying causes of chronic kidney disease in the study subjects.

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Table 2: Biochemical characteristics of the study subjects before and after N-acetylcysteine treatment.

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A significant reverse correlation was seen between the amount of change in hs-CRP (hs-CRP) and patient's age (r = -0.58, P = 0.003); however, such a correlation was not observed for IL-6 (r = -0.14, P = 0.513). One interesting finding of this study was that in subjects in whom age was under 40 years, hs-CRP increased by a mean of 5 units (mini­mum of 4.2 units and maximum of 19 units) after NAC treatment. However, in patients 40 years or older, a decrease in hs-CRP of 23 units was observed following NAC treatment (P = 0.002). In all three patients who were under 35 years, the serum levels of hs-CRP increased after NAC treatment. A similar pat­tern of results was observed for IL-6 levels after treatment. Patients under 40 years old showed a mean of 1.6 units increase in the IL-6 levels, and subjects 40 years or older presented with a 6.1 units' decrease following NAC treatment (P = 0.04). The age-related distribution of change in hs-CRP levels ( hs-CRP) is presented in [Figure 1]. Multivariate analysis adjusted for age and sex showed that the hs-CRP levels before intervention was a significant predictor of the amount of change after treatment with the adjusted partial corre­lation coefficient of -0.96 and P <0.001. Age had a marginal effect (r = -0.40, and P = 0.05). The IL-6 and hs-CRP levels did not signi­ficantly correlate with the duration on dialysis.
Figure 1: Age-related distribution of change in the serum high-sensitive C-reactive protein (hs-CRP) levels.

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   Discussion Top


Cardiovascular disease and, as a consequence, cardiovascular mortality are considerably higher in patients with CKD, and accounts for approximately 50% of all deaths in these patients. Although the exact contribution of atheroscle­rosis to CVD in patients with CKD is unclear, but it seems that atherosclerosis remains the main cause. Several lines of evidence pre­sent that IL-6, not just as a marker of atherosclerosis but also as a pro-atherogenic cytokine, can contribute to this process through various metabolic, endothelial and coagulant mechanisms. [10],[11],[12] On the other hand, the in­flammatory biomarker, hs-CRP, has been pro­posed as a marker to assess the cardiovascular risk. [13] Moreover, in vitro studies have indi­cated that CRP activates a number of pro­cesses involved in the inflammatory reaction. An induction in the expression of adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1), inter-cellular adhesion molecule-1 (ICAM-1), E-selectin in human endothelial cells and monocytes chemo-attractant protein-1 (MCP-1) in human monocytes, following CRP exposure, has been reported. [14] In line with these observations, it seems rational to evaluate the levels of these two inflammatory mediators as the indicators of cardiovascular risk. We found that NAC therapy could pro­duce a significant reduction in the plasma levels of hs-CRP and IL-6. In a study by Gosset et al, [15] NAC was shown to inhibit the production of IL-6 from alveolar macrophages by a mechanism independent of glutathione metabolism. Indeed, oxidants such as hydro­gen peroxide have been previously shown to activate nuclear factor-KB and IL-6 in cultured monocytes and endothelial cells. [16],[17] Taken together, it is possible that attenuation of levels of IL-6 by NAC treatment seen in this study is related at least partially to the anti-oxidative stress effects of NAC. Accordingly, Nascimento et al showed a reduction of cir­culating levels of IL-6 eight weeks after the­rapy with oral NAC in 30 patients who were on regular peritoneal dialysis. [18]

One notable finding of this study was that the magnitude of decrease of hs-CRP levels, after NAC treatment, was significantly higher in female patients compared with men. Gene­rally, females have higher serum CRP levels than males. This difference has been shown by several researchers. [19],[20],[21],[22] In a population-based study performed by Marquesvidal et al on more than 6000 Swedish subjects of both gen­ders, aged between 35 and 75 years, the serum CRP levels showed a significant reverse corre­lation with male gender, and male subjects had generally higher levels of CRP compared with female subjects. [19] Although the mechanism for this observation is unknown, some investi­gators have suggested that sex hormones can have an effect on the serum levels of CRP and other inflammatory mediators probably by me­chanisms involving IL-6. [23] We observed that this trend of higher levels of CRP in females was present even in ESRD patients. After NAC treatment, the mean of decrease in the hs-CRP concentration was significantly higher in females; this may reflect the finding that higher levels of hs-CRP were presented before treatment in this group.

In three patients who were below 35 years old (two females and one male), an augmenta­tion of hs-CRP levels following NAC therapy was observed. The underlying cause of ESRD in these patients included systemic lupus erythematosus, hemolytic uremic syndrome and glomerulonephritis in one patient each. As shown previously, the serum levels of inflam­matory mediators including CRP is signifi­cantly associated with age. [24] In our study, however, due to the limitation in the number of patients, we could not investigate whether the lack of response to NAC therapy in these patients is related to their age, as all the three patients were under 35 years old, or the underlying cause of ESRD. We should men­tion that there are other parameters including body mass index and nutritional factors that might affect the levels of CRP. However, the role of these factors remains controversial. For example, in a study by Nasri, no association was observed between albumin, as an indicator of nutritional status, and levels of CRP in HD patients, [25] while Quresh et al demonstrated that chronic HD patients with severe malnu­trition display higher levels of inflammatory mediators including CRP compared with their well-nourished control patients. [26] Whether these factors also contributed to the difference observed in our study needs further investi­gations.

In conclusion, we observed that NAC treat­ment in ESRD patients could have an anti-inflammatory effect as was evaluated by mea­suring the serum levels of hs-CRP and IL-6. Additionally, a significant decrease in serum Ca and PTH levels was noticed. We suggest that the ESRD patients may benefit from the anti-inflammatory and anti-oxidative stress effects of NAC. However, whether these effects could affect the cardiovascular outcome in these patients needs to be evaluated.


   Acknowledgment Top


This work was supported by a research grant from Tehran University of Medical Sciences. The authors would like to thank the staff of the laboratory for their technical assistance.


   Conflict of Interest Top


All the authors hereby declare and certify that they do not have any conflict of interest.

 
   References Top

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4.Vaziri ND, Ni Z, Oveisi F, Liang K. Enhanced nitric oxide inactivation and protein nitration by reactive oxygen species in chronic renal insufficiency. Hypertension 2002;39:135-41.  Back to cited text no. 4
    
5.Hasdan G, Benchetrit S, Rashid G, Rathaus M. Endothelial dysfunction and hypertension in 5/6 nephrectomized rats are mediated by vas­cular superoxide. Kidney Int 2002;61:586-90.  Back to cited text no. 5
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6.Descamps-Latscha B, Jungers P. New mole­cular aspects of chronic uraemia and dialysis related immunocompetent cell activation. Nephrol Dial Transplant 1996;11 Suppl 2: S121-4.  Back to cited text no. 6
    
7.Aruoma OI, Halliwell B, Hoey BM, Butler J. The antioxidant action of N-acetylcysteine: Its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med 1989;6:593-7.  Back to cited text no. 7
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8.Zicha J, Dobesová Z, Kunes J. Antihypertensive mechanisms of chronic captopril or N-acetylcysteine treatment in L-NAME hyperten­sive rats. Hypertens Res 2006;29:1021-7.  Back to cited text no. 8
    
9.Rauchová H, Pechánová O, Kunes J, Vokurková M, Dobesová Z, Zicha J. Chronic N-acetyl-cysteine administration prevents development of hypertension in N(omega)- nitro-L-arginine methyl ester-treated rats: The role of reactive oxygen species Hypertens Res 2005;28:475-82.  Back to cited text no. 9
    
10.Yudkin JS, Kumari M, Humphries SE, Mohamed-Ali V. Inflammation, obesity, stress and coronary heart disease: Is interleukin-6 the link? Atherosclerosis 2000;148:209-14.  Back to cited text no. 10
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11.Pigott R, Dillon LP, Hemingway IH, Gearing AJ. Soluble forms of E-selectin, ICAM-1 and VCAM-1 are present in the supernatants of cytokine activated cultured endothelial cells. Biochem Biophys Res Commun 1992;187: 584-9.  Back to cited text no. 11
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12.Elhage R, Clamens S, Besnard S, et al. Involvement of interleukin-6 in atherosclerosis but not in the prevention of fatty streak for­mation by 17 b-estradiol in apolipoprotein E-deficient mice. Atherosclerosis 2001;156:315-20.  Back to cited text no. 12
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13.Genest J. C-reactive protein: Risk factor, biomarker and/or therapeutic target? Can J Cardiol 2010;26 Suppl A:41-4A.  Back to cited text no. 13
    
14.Ridker PM. Inflammation, infection and cardiovascular risk. How good is the clinical evidence? Circulation 1998;97:1671-4.  Back to cited text no. 14
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15.Gosset P, Wallaert B, Tonnel AB, Fourneau C. Thiol regulation of the production of TNF-alpha, IL-6 and IL-8 by human alveolar macro-phages. Eur Respir J 1999;14:98-105.  Back to cited text no. 15
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16.Jain SK, Kannan K. Chromium chloride inhi­bits oxidative stress and TNF-alpha secretion caused by exposure to high glucose in cultured U937 monocytes. Biochem Biophys Res Commun 2001;289:687-91.  Back to cited text no. 16
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17.Kannan K, Jain SK. Oxidative stress and apoptosis. Pathophysiology 2000;7:153-63.  Back to cited text no. 17
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18.Nascimento MM, Suliman ME, Silva M, et al. Effect of oral N-acetylcysteine treatment on plasma inflammatory and oxidative stress mar­kers in peritoneal dialysis patients: A placebo-controlled study Perit Dial Int 2010;30:336-42.  Back to cited text no. 18
    
19.Marques-Vidal P, Bochud M, Bastardot F, et al. Levels and determinants of inflammatory biomarkers in a Swiss population-based sam­ple (CoLaus study). PLoS One 2011;6:e21002.  Back to cited text no. 19
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22.Lakoski SG, Cushman M, Criqui M, et al. Gender and C-reactive protein: Data from the Multiethnic Study of Atherosclerosis (MESA) cohort. Am Heart J 2006;152:593-8.  Back to cited text no. 22
    
23.Norouzi V, Seifi M, Fallah S, Korani M, Samadikuchaksaraei A. Effect of oral contra­ceptive therapy on homocysteine and C-reactive protein levels in women: An obser­vational study. Anadolu Kardiyol Derg 2011; 11:698-702.  Back to cited text no. 23
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24.Yamada S, Gotoh T, Nakashima Y, et al. Dis­tribution of serum C-reactive protein and its association with atherosclerotic risk factors in a Japanese population: Jichi Medical School Cohort Study. Am J Epidemiol 2001;153: 1183-90.  Back to cited text no. 24
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25.Nasri H, Serum C. Reactive protein in asso­ciation with various nutritional parameters in maintenance hemodialysis patients. Bratisl Lek Listy 2005;106:390-5.  Back to cited text no. 25
    
26.Qureshi AR, Alvestrand A, Danielsson A, et al. Factors predicting malnutrition in hemodialysis patients. A cross sectional study. Kidney Int 1998;53:773-82.  Back to cited text no. 26
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Correspondence Address:
Fereshteh Saddadi
Nephrology Department, Dr. Shariati Hospital, Tehran University of Medical Sciences, Tehran
Iran
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DOI: 10.4103/1319-2442.124489

PMID: 24434384

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