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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2012  |  Volume : 23  |  Issue : 3  |  Page : 500-506
Effect of treatment with Omega-3 fatty acids on C-reactive protein and tumor necrosis factor-alfa in hemodialysis patients


1 Department of Internal Medicine, Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
2 Continuing Medical Education (CME) Center, Tabriz University of Medical Sciences, Tabriz, Iran
3 Department of Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
4 Department of Vital Statics, Faculty of Health and Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran

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Date of Web Publication7-May-2012
 

   Abstract 

C-reactive protein (CRP), a strong independent risk marker of cardiovascular disease (CVD), and tumor necrosis factor-alfa (TNF-α), a known pro-inflammatory cytokine, are elevated and have damaging effects in patients with chronic renal failure (CRF). Omega-3 fatty acids play an important modulatory role in inflammatory responses. The aim of this study is to review the alterations in serum levels of TNF-α, CRP and other parameters caused by omega-3 supplementation in dialysis patients. The clinical trial was performed in 37 patients with end-stage renal disease undergoing dialysis in hemodialysis centers of three university hospitals in Tabriz. Blood samples were obtained from the study patients for hemoglobin, albumin, ferritin, triglyceride, total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL)-cholesterol, TNF-α and high specific-CRP (hs-CRP) measurement. The patients received 3 g omega-3 per day for 2 months. The side-effects noticed were nausea, diarrhea and dyspepsia and undesired drug smell. The difference noted in hemoglobin, albumin, ferritin, CRP, triglyceride, total, LDL and HDL-cholesterol before and after supplementation with omega-3 fatty acid was not statistically significant (P > 0.05). However, the use of omega-3 decreased the serum levels of TNF-α significantly. We conclude that the use of 3 g of omega-3 per day caused significant decrease in serum levels of TNF-α in the dialysis population, and its use is recommended in such patients.

How to cite this article:
Tayyebi-Khosroshahi H, Houshyar J, Dehgan-Hesari R, Alikhah H, Vatankhah AM, Safaeian AR, Zonouz NR. Effect of treatment with Omega-3 fatty acids on C-reactive protein and tumor necrosis factor-alfa in hemodialysis patients. Saudi J Kidney Dis Transpl 2012;23:500-6

How to cite this URL:
Tayyebi-Khosroshahi H, Houshyar J, Dehgan-Hesari R, Alikhah H, Vatankhah AM, Safaeian AR, Zonouz NR. Effect of treatment with Omega-3 fatty acids on C-reactive protein and tumor necrosis factor-alfa in hemodialysis patients. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2019 Aug 24];23:500-6. Available from: http://www.sjkdt.org/text.asp?2012/23/3/500/95769

   Introduction Top


Atherosclerosis is a major complication that determines the morbidity and mortality in dialysis patients. The causative factors of atherosclerosis in dialysis patients are complicated, but atherogenic lipoproteins that accumulate in plasma could be related. [1],[2] Inflammation is believed to play a critical role in the evolution of atherosclerosis. [3] An association with C-reactive protein (CRP) levels has also been reported in these patients. [1],[4] CRP, a strong independent risk marker of cardiovascular disease (CVD), is elevated in a large proportion of patients with chronic renal failure (CRF). [5],[6] High sensitivity C-reactive protein (hs-CRP) is a marker of low-grade sustained inflammation, [7] and its serum concentration is inversely related to plasma n-3 fatty acid levels. [7],[8] Tumor necrosis factor alfa (TNF-α) is a known pro-inflammatory cytokine. It has been reported that TNF-α has some damaging effects on different body tissues, specially in CRF patients.[9],[10]

Omega-3 (n-3) fatty acids play an important modulatory role in the immune and inflamematory responses, [7],[9],[11],[12],[13],[14] the progression of arteriosclerosis, vascular reactivity, cell membrane function and gene expression. [11] Omega-3 fatty acids have cardioprotective effects, [15],[16],[17] which may be partly attributed to their anti-inflammatory properties. [5],[6] Supplementation with omega-3 had a favorable effect on inflammatory and nutritional parameters in hemodialysis (HD) patients. [18] A dietary regime with medium-dose (2.4 g/d) omega-3 intake may slow atherosclerosis in HD patients. [18] Increased intake of omega-3 has a beneficial effect on systemic inflammation in men [19] and inverse association with serum CRP in women. [20] Omega-3 can modulate TNF-α-induced endothelial cell activation and inflammation. [9],[10],[21]

However, although omega-3 fatty acids have anti-inflammatory properties, [7] the results about the effect of omega-3 on the levels of inflammatory markers are still unclear. In one study on heart transplant recipients, there was a rise in the TNF-α levels in the omega-3 group, but not in the placebo group; [10] in another study, there was a significant decrease in the levels of all inflammatory markers (TNF-α, IL-6, hs-CRP and ferritin) in HD patients who were administered omega-3. [14] The effect of omega-3 on CRP also is controversial despite the significant decrease in CRP described in some studies. In the study of Madsen et al, there was no significant difference in hs-CRP levels between omega-3-treated and placebo groups. [5]

Despite the potential for diverse clinical applications, omega-3 supplementation is neither routinely recommended nor used in the dialysisdependent population. This is probably related, in part, to a general lack of familiarity with the biochemical and clinical effects of omega-3 therapy. [11] This study was conducted to further evaluate the effect of omega-3 supplementation on inflammatory markers such as CRP and TNF-α in chronic HD patients.


   Materials and Methods Top


This is a multi-center clinical trial performed on end-stage renal disease patients undergoing dialysis in HD centers in three university hospitals in Tabriz. The inclusion criteria included: presence of CRF requiring dialysis, age >15 years and inclination to participate in the study. The exclusion criteria included: history of acute inflammatory disease, history of malignancy and dialysis duration of less than 3 months.

All the study patients were visited by an internal ward resident. Forty-five patients fulfilled the inclusion criteria and were enrolled into the study. All patients signed the informed consent at the beginning of the study. Blood samples were obtained from the patients before starting the dialysis sessions. The sampled blood was tested for hemoglobin (Hb), albumin (Alb), ferritin, triglyceride (TG), total cholesterol and low-density lipoprotein (LDL) and high-density lipoprotein (HDL)-cholesterol. The blood was then centrifuged for measurement of TNF-α and hs-CRP. Serum was stored at -80°C.

All the study patients received 3 g of omega-3 fatty acid per day (1 g omega-3 Pearl three-times a day). The drug was manufactured at the Tabriz Zahravi Pharmacy. The patients were followed-up for two months and were evaluated periodically for the appearance of complications as well as correct usage of the drug. Five patients discontinued the drug because of personal reasons and were excluded from the study. Three other patients were also excluded: one died and two underwent kidney transplantation. Thus, a total of 37 patients completed the study.

After two months of follow-up, all the blood tests performed earlier were repeated. For detection of TNF-α, we used ab ELISA kit of Human TNF-α, Lot: 41881009 and Ref: BMS225/4 manufactured by Austria Bender Med Systems. The results were reported as pg/mL. hs-CRP was measured by immunoturbidometry, using a kit made by Iran Pars-Azmoon manufacture. The results were reported as mg/L.


   Statistical Analysis Top


The results are expressed as means ± SD. The collected data were analyzed by SPSS-15 statistical software using Paired t-test or Wilcoxon Signed - Rank test. P-values less than 0.05 were considered statistically significant.


   Results Top


Overall, 45 patients met the inclusion criteria and were enrolled into the study. However, eight patients had to be excluded during follow-up and 37 patients completed the study. Of the 37 patients, 25 were male (67.6%) and 12 were female (32.4%). The mean age of the study patients was 48.83 years (range: 15-63 years). The average duration on HD before the study was 43.1 months. Among the studied cases, 21.6% had diabetes mellitus (DM) and all had adequate control of their blood sugar levels. There were no other comorbid states in the study patients. The mean hs-CRP level was 6.45 ± 4.86 mg/L before supplementation, which decreased to 5.79 ± 4.42 mg/L after supplementation with omega-3 (P = 0.441). The mean TNF-α level was 6.91 ± 15.25 pg/mL before supplementation, which decreased to 2.35 ± 8.02 pg/mL after supplementation with omega-3 (P = 0.038).

[Table 1] shows the comparison of the studied variables before and after supplementation with omega-3 fatty acids. There was no statistically significant difference in the levels of Hb, Alb, ferritin, hs-CRP, triglyceride, total, LDL and HDL cholesterol before and after supplementation with omega-3 fatty acids (P >0.05). However, analysis showed that the use of omega-3 decreased the serum levels of TNF-α significantly [Table 1].
Table 1: The comparison of studied variables before and after the supplementation with omega-3.

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   Discussion Top


Omega-3 fatty acids contain two or more double bonds ("polyunsaturated"), one of which is located three carbon positions from the methyl terminus ("omega-3" or "n-3"). [11],[22] Because the body is unable to synthesize omega-3 fatty acids in appreciable amounts, they are obtained primarily from dietary sources (i.e., they are "essential" fatty acids). [11] Recently, the American Heart Association established evidence-based recommendations for intake of omega-3 fatty acids. [11],[23] Dietary omega-3 fatty acids have anti-inflammatory properties. For example, their inclusion in the diet in the form of n-3-polyunsaturated fatty acids (PUFA)-rich fish oil reduces the symptoms in patients with severe inflammatory disease. [24]

In our study, there was significant reduction of TNF-α level after two months of omega-3 administration in HD patients. Likewise, n-3 PUFAs can also reduce the production of inflammatory cytokines, such as TNF-α, interleukin-1 and interleukin-6. [25] Dietary omega-3 fatty acids decrease the production of these classic inflammatory cytokines as well as the expression of adhesion molecules involved in inflammatory interactions between leukocytes and endothelial cells. [26] It is reported that pathologic levels of the pro-inflammatory cytokine TNF-α are associated with muscle wasting, exerted through inhibition of myogenic differentiation and enhanced apoptosis.[9] Omega-3 has a protective action against the damaging effects of TNF-α.[9]

Cardiovascular disease (CVD) is the leading cause of mortality in patients with CRF. CRP, a strong independent risk marker of CVD, and TNF-α are elevated in a large proportion of patients with CRF. Omega-3 fatty acids have cardioprotective effects, which may be partly attributed to their anti-inflammatory properties. [27] Treatment with omega-3 for two years significantly reduced the number of myocardial infarctions (MI) in HD patients with established CVD. [28],[29] Supplementation with omega-3 is associated with a reduction in cardiovascular events through its hypo-triglyceridemic, anti-aggregatory and anti-inflammatory properties. [3],[30] Omega-3 fatty acids have shown promise in modifying a host of disease processes involving the inflammatory pathways, arteriosclerosis and cardiovascular disease, cardiac dysrhythmias and lipid regulation. [11],[31],[32] At the molecular level, omega-3 appears to act by reducing leukocytosis, systemic inflammation and oxidative stress. [33] Hypertriglyceridemia and associated high circulating free fatty acids are important risk factors for atherosclerosis. [21] The utility of omega-3 in post-MI patients is possibly derived through its triglyceride lowering effect. [17],[34] Studies of omega-3 supplementation in dialysis patients describe salutary effects on triglyceride levels, dialysis access patency and, perhaps, uremic pruritus and oxidative stress. [11]

Because cell membrane fatty acids play an important role in signal transduction, omega-3 fatty acids are capable of modifying gene expression. It is believed that the dramatic lipid altering effects of omega-3 fatty acids are mediated via this mechanism. [11],[35] By mediating cell membrane function and structure and the synthesis of lipid mediators such as eicosanoids, omega-3 fatty acids may cause multiple health benefits to dialysis patients. [11]

Despite the potential for diverse clinical applications, omega-3 supplementation is neither routinely recommended nor used in the dialysis-dependent population. This is probably related in part to a general lack of familiarity with the biochemical and clinical effects of omega-3 therapy. [11] There are a number of reasons for inadequate levels of omega-3 in the dialysis population: (a) foodstuffs containing omega-3 may be less palatable for these patients, (b) fish consumption may be limited by social dietary habits, (c) formal renal dietary recommendations that encourage fish consumption do not exist and (d) consumption of the omega-3 parent fatty acid may potentially be reduced as a result of kidney disease-related dietary potassium restriction. [11],[36]

In our study, there was an insignificant reduction of hs-CRP level in omega-3-treated patients that is comparable with the study of Madsen et al. Supra-physiologic doses of omega-3 (>3 g/d) in humans can reduce triglyceride levels by 25-30% and increase LDL and HDL levels by 5-10% and 1-3%, respect-tively. [11] However, only very limited data exist describing fatty acid levels in dialysis patients. Supplementation with low-dose omega-3 has a favorable effect on plasma lipid levels in patients on HD. [6] Bowden et al. demonstrated that consuming 960 mg/d of eicosapentanoic acid and 600 mg/d of DHA can lower CRP levels. [37] However, low-dose omega-3 fatty acids had no effect on the plasma hs-CRP levels. [38] One study showed that only high doses of omega-3 given for a long time can influence inflammation and atherosclerosis. [39]

Rasic-Milutinovic et al studied the effects of omega-3 fatty acid (2.4 g/d) given for eight-weeks in 35 patients with CRF on maintenance HD. There was a significant decrease in the levels of all inflammatory markers (P = 0.01 for TNF-α, P = 0.001 for IL-6, P = 0.001 for hs-CRP and P = 0.01 for ferritin). [14] Madsen et al performed a randomized, double-blind, placebo-controlled study. They found a trend toward a reduction in hs-CRP in the n-3 PUFA group, but there was no significant difference in hs-CRP levels when both groups were compared. [27] In our study, the difference in Hb, Alb, ferritin, hs-CRP, triglyceride, total LDL and HDL cholesterol before and after supplementation with omega-3 fatty acid was not statistically significant (P > 0.05). However, analysis showed that use of omega-3 decreased serum levels of TNF-α significantly.

Supplementation with omega-3 decreased serum-soluble TNF receptor p55 (sTNF-R p55) and CRP levels in patients with rheumatoid arthritis. [40],[41] Holm et al examined plasma levels of TNF-α and IL-10 in 45 heart transplant recipients before and after treatment with omega-3 fatty acids or placebo. The patients were randomized to receive omega-3 (3.4 g/day) or placebo for one year. In the omega-3 group, but not in the placebo group, there was a rise in the pro-inflammatory cytokine TNF-α, a decrease in the anti-inflammatory cytokine IL-10 and a rise in the TNF/IL-10 ratio, suggesting a net pro-inflammatory effect. [10] There was an insignificant reduction of triglyceride and LDL levels in dialysis patients at the end of our study. The Hb level was also slightly elevated at the end of this study.

When recommending omega-3 therapy, clinicians should be aware of any possible adverse effects or drug interactions that, although not necessarily clinically significant, may occur. [25] The most commonly reported adverse effects of fish oil supplements are a fishy after-taste and gastrointestinal complaints (e.g., nausea, dyspepsia). [11],[25],[42] The risk for increased bleeding times has been seen, primarily with >3 g/d fish oil, especially in patients who may be susceptible to increased bleeding (e.g., patients taking warfarin). [1],[34] Increase in serum glucose and LDL levels has also been seen with large doses of fish oil (e.g., >4.5 g/d). A more detailed discussion of these adverse effects can be found in the Food and Drug Administration ruling on menhaden oil. [11],[43] In this study, the omega-3 side-effects noticed included nausea, diarrhea and unfavorable drug smell. There were no hemorrhagic and/or any severe side-effects in our patients.


   Limitations Top


The major limitation of this study was the short duration of administration of omega-3 in HD patients and the small number of study patients.


   Conclusions Top


We conclude that the use of omega-3, 3 g per day, is well tolerated and has a positive effect at least in reduction of inflammation markers, which may have a role in causing CVD in dialysis patients. Further studies with larger numbers of patients and longer duration of treatment are recommended.


   Acknowledgment Top


We thank the Tabriz Zahravi Pharmacy Manufacture for sponsoring this study. We also thank the personnel of the HD centers of Tabriz Imam Reza, Sina and 29 th Bahman hospitals.

 
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Correspondence Address:
Hamid Tayyebi-Khosroshahi
Assistant Professor, Department of Internal Medicine, Imam Reza Hospital, Tabriz University of Medical Sciences, Tabriz
Iran
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