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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 1  |  Page : 311-316

Effect of omega-3 on tumor necrosis factor-α in children on hemodialysis


1 Pediatrics Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
2 Clinical Pathology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt
3 Pediatric Department, Shebin El-Kom Teaching Hospital, Shebin El-Kom, Egypt

Date of Submission11-Jul-2017
Date of Acceptance01-Sep-2017
Date of Web Publication17-Apr-2019

Correspondence Address:
Eman H Dawood
Pediatric Department, Shebin El-Kom Teaching Hospital, Shebin El-Kom, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_475_17

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  Abstract 


Objectives
The aim of this study was to assess the effect of high-dose omega-3 supplementation on tumor necrosis factor-α (TNF-α) in children on long-term hemodialysis.
Background
Patients who are on hemodialysis have elevated serum levels of inflammatory markers. Giving high doses of omega-3 supplementation results in significant decrease in TNF-α (one of the inflammatory markers).
Patients and methods
This study was conducted at a pediatric dialysis unit in Menoufia University hospital, and included 26 patients from January 2015 to April 2015. The study commenced after approval of the local institutional ethical committee of Menoufia University hospital and obtaining written consents from all the participants in our study.
Results
The mean age of the 26 patients was 13.4 years (range: 8–17 years). There were 13 (50%) males and (50%) females. The comparison of the studied variables before and after supplementation with omega-3 fatty acids showed that there were statistically high significant differences between the level of TNF-α before (147.62 ± 13.57 mg/dl) and after (79.73 ± 16.884 mg/dl) supplementation with omega-3 fatty acid (P < 0.001).
Conclusion
The use of omega-3 caused significant decrease in serum levels of TNF-α in children on hemodialysis, and omega-3 may need to be taken in larger doses to exert its anti-inflammatory effect.

Keywords: children, chronic kidney disease, hemodialysis, omega-3, tumor necrosis factor--α


How to cite this article:
El-mashad GM, El Gebaly SI, Montaser BF, Dawood EH. Effect of omega-3 on tumor necrosis factor-α in children on hemodialysis. Menoufia Med J 2019;32:311-6

How to cite this URL:
El-mashad GM, El Gebaly SI, Montaser BF, Dawood EH. Effect of omega-3 on tumor necrosis factor-α in children on hemodialysis. Menoufia Med J [serial online] 2019 [cited 2019 Aug 25];32:311-6. Available from: http://www.mmj.eg.net/text.asp?2019/32/1/311/256118




  Introduction Top


Chronic kidney disease (CKD) is usually asymptomatic, but it is detectable, and tests for CKD are simple and freely available. There is evidence that treatment can prevent or delay the progression of CKD, reduce or prevent the development of complications, and reduce the risk of cardiovascular disease. However, CKD is often unrecognized because there are no specific symptoms, and it is often not diagnosed or diagnosed at an advanced stage. The classification of CKD has evolved over time. In 2004, the Department of Health's National service framework for renal services adopted the 2002 US National Kidney Foundation Kidney Disease Outcomes Quality Initiative classification of CKD. This classification divides CKD into five stages and uses the combination of an index of kidney function, the glomerular filtration rate (GFR), and markers of kidney damage to define the stages. Stages 3–5 were defined by a GFR less than 60 ml/min/1.73 m 2, with or without markers of kidney damage, on at least 2 separate occasions separated by a period of at least 90 days. Stages 1 and 2 were defined by the presence of markers of kidney damage including albuminuria, urine sediment abnormalities, electrolyte and other abnormalities caused by tubular disorders, abnormalities detected by histology, structural abnormalities detected by imaging, and a history of kidney transplantation [1].

The basis for the management of advanced chronic kidney disease is the seamless integration of renal replacement therapy [hemodialysis (HD), peritoneal dialysis, and transplantation), with evidence-based medical treatment of its complications [2].

HD should be initiated when one or more of the following are present: symptoms or signs attributable to kidney failure (serositis acid–base or electrolyte abnormalities, pruritis), inability to control volume status or blood pressure, a progressive deterioration in nutritional status refractory to dietary intervention, or cognitive impairment. This often but not invariably occurs in the GFR range between 5 and 10 ml/min/1.73 m 2 [3].

Mortality is markedly elevated in HD patients. Between 30 and 50% of prevalent patients have elevated serum levels of inflammatory markers such as tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and interleukin-6 (IL-6). The presence of inflammation, chronic or episodic, has been found to be associated with increased mortality risk [4].

TNF is a member of a family of structurally related cytokines that signal through specific cell-surface receptors that also form a structurally related family of proteins. The TNF superfamily consists of more than 35 specific ligand-receptor pairs that play pivotal roles in many biological processes in mammalian cells, such as host defense, inflammation, apoptosis, autoimmunity, and development and organogenesis of the immune, ectodermal, and nervous systems [5].

The elevated levels of TNF-α in hemodialysis and renal transplant patients could be because of uremia, as impaired renal function may be one of the major factors associated with increased serum levels of TNF-α. Insulin resistance, volume overload, and obesity have been also proposed as important causes of elevated TNF-α levels in hemodialysis and renal transplant patients [6].

Dietary omega-3 polyunsaturated fatty acids (PUFA) have immunomodulatory effects that are thought to be anti-inflammatory based on human clinical and epidemiological studies. The first evidence of the important role of dietary intake of omega-3 polyunsaturated fatty acids in inflammation was derived from epidemiological observations of the low incidence of autoimmune and inflammatory disorders [7].

Omega-3 fatty acids are a group of fatty acids important for human health. There are three main types of omega-3 fatty acids: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and α-linolenic acid, which is converted in our bodies to EPA or DHA after consumption. High concentrations of omega-3 fatty acids are found in fish and plant oils, in addition to human milk and eggs from chickens fed a fishmeal diet. Consumption of omega-3 fatty acids from fish has been associated with a variety of beneficial effects, including a reduction in overall mortality. This is largely owing to protection against coronary heart disease, in part through lowered heart rate and blood pressure. Other beneficial effects associated with fish consumption include reduced risk of stroke, depression, and mental decline with aging. Current research also suggests that a deficit in omega-3 fatty acids could negatively affect brain development in a fetus [8].

This study was conducted for minimizing cardiovascular disease risks by reducing inflammation, decreasing oxidative stress, inhibiting platelet activity, and exerting antiarrhythmic effects. In addition, the modification of erythrocyte membrane fatty acid content by omega-3 PUFAs supplementation is an important process related to cardiovascular disease risk reduction which may help in the interpretation of clinical trials in general populations and patients with chronic kidney disease (CKD). Increasing erythrocyte membrane content of omega-3 PUFAs, and consequently the omega-3 index, and decreasing total saturated fatty acids, oleic acids, and amino acids may affect cellular function by changing transmembrane proteins and inflammatory mediators involved in cell signaling systems.


  Patients and Methods Top


This study was conducted in a pediatric dialysis unit at Menoufia University Hospital and included 26 patients with chronic kidney disease from January 2015 to April 2015.

The study commenced after approval of the local institutional ethical committee of Menoufia University hospital and obtaining written consents from all participants in our study.

All patients were daily treated with oral 2000 mg (omega-3 plus) containing 360 mg EPA and 240 mg DHA for 3 months.

Inclusion criteria

The inclusion criteria was as follows: patients with end-stage renal disease with a GFR less than 10 ml/min/1.73 m 2 with childhood onset of HD; their age being less than 18 years; on regular HD, having at least three sessions a week; and duration of HD of more than 3 months.

Exclusion criteria

Exclusion criteria were as follows: patient s having predialysis stages of CKD, patients on chronic peritoneal dialysis, patients on regular HD of less than 3 months, and those with primary (nonuremic) cardiovascular disease and metabolic disease (1 year of hyperparathyroidism).

The study design is a prospective one.

Patients were subjected to the following: full history taking; personal history; other important medical problems such as hypertension, cardiopulmonary, hepatobiliary, neurological, endocrinal systems or infection; dialysis duration; current prescription; current vascular access; and number of arteriovenous fistula used for HD.

Thorough clinical examination included recording of treatment parameters such as anthropometric measurements; vital signs, especially blood pressure; antihypertensive medications used; regional examination; and cardiac, chest, abdominal, and neurological examination.

All patients were followed for 3 months by routine monthly laboratory investigations of predialysis and postdialysis blood urea nitrogen (BUN), serum creatinine clearance, and serum total calcium and phosphorous levels, which were measured by standard methods on multichannel auto-analyzer (Hitachi Koki Co., Ltd., Japan). Predialysis complete blood count was done to detect hemoglobin, and hematocrit was measured by automated hematology counter (pentra80; HoribaABX, France). Arterial blood gases were measured by rabicount 480 (Bayer, Germany), and predialysis serum iron, iron-binding capacity, and serum ferritin were measured by standard methods on multichannel auto-analyzer (Hitachi). Parathyroid hormone was measured by minividas (Hemilumenesence, France), and TNF-α was measured using ELISA kit (Invitrogen Corporation, Carlsbad, California, USA).

Laboratory investigations were obtained from the A–V fistula immediately before the dialysis procedure at the beginning and after 3 months of the study.

All these laboratory investigations were done in clinical pathology department, Menoufia University Hospital.

Assessment of the efficiency of dialysis was done using single pool Kt/V formula:



Where, Ln is the natural logarithm; R, the predialysis BUN/postdialysis BUN; t the dialysis session length (h); UF, the ultra-filtration volume (l); and W, postdialysis weight (kg). Target Kt/V for urea was more than 1.3.

Sampling

Predialysis

Six ml of venous blood was obtained before dialysis from each patient during the insertion of the A–V fistula needles (in cases of A–V fistulae) or from the venous line of CVP (in cases of CVP) and was divided as follows: 1 ml of blood was put in a tube containing EDTA as anticoagulant for performing complete hemogram. Three ml blood was left to clot to obtain serum for performing predialysis BUN, serum creatinine level, and total calcium, phosphorus, sodium, and potassium examination. One ml of arterial blood was obtained for examination of predialysis arterial blood gases in a heparinized syringe. One ml was used for TNF-α assessment using ELISA kit (Invitrogen Corporation).

Statistical analysis

Data were collected in tables and then analyzed using SPSS, version 20 (SPSS Inc., Chicago, Illinois, USA).

P values less than 0.05 were considered statistically significant.

Two types of statistics were done:

Descriptive statistics

  1. Quantitative data were shown as mean, SD, and range.
  2. Qualitative data were expressed as frequency and percent.


Analytical statistics

Wilcoxon test was used to compare mean and SD of paired quantitative not normally distributed data.


  Results Top


Demographic data

[Table 1] shows the distribution of the studied patients regarding their age and sex. Their mean age was 13.4 years. The number of males as well as females was 13 (50%).
Table 1: Demographic data of the studied patients (n=26)

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Regarding height and weight distribution of the studied group, the mean height of the studied group was 129 cm. Overall, 21 (80.8%) patients had height below the third percentile and 20 (76.9%) patients had weight below the third percentile, as shown in [Table 2].
Table 2: Height and weight of the studied patients

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[Table 3] shows the different etiologies of renal failure in the studied group. They were obstructive uropathy in 10 (38.4%) patients, glomerulonephritis in five (19.2%) patients, cystic kidney diseases in two (7.7%) patients, cystinosis in in one (3.8%) patient, and unknown etiology in eight (30.7%) patients.
Table 3: Etiologies of renal failure of the studied patients

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[Table 4] shows the distribution of the studied patients regarding their duration of dialysis, which ranged from 1 to 6 year (3.94 ± 1.53).
Table 4: Duration of dialysis of the studied patients

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[Table 5] shows that there was no statistically significant difference between the total iron-binding capacity, serum iron, transferrin saturation, serum ferritin, hemoglobin level, platelet, parathyroid hormone, and albumin level count in the studied patients before and after supplementation of omega-3. The efficiency of dialysis before and after o mega-3 supplementation in the studied patients showed no significant difference. This table also shows that there was no statistically significant difference between the PO4, Ca, K, and Na in the studied patients before and after supplementation of omega-3.
Table 5: Iron profile before and after omega-3 supplementation of the studied patients

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[Table 6] shows TNF-α before and after omega-3 supplementation in the studied patients. This table shows that there were statistically significant decrease in the TNF-α level in the studied patients after supplementation of omega-3. P value is less than 0.001.
Table 6: TNF-α before and after omega-3 supplementation of the studied patients

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  Discussion Top


Many studies were done in adults with CRF on HD to evaluate the effect of omega-3 supplementation on the inflammatory markers; however, very little has been published about its effect in children.

Ferrucci and colleagues concluded that omega-3 fatty acids are beneficial in patients affected by diseases characterized by active inflammation. The total omega-3 fatty acids were independently associated with lower levels of proinflammatory markers (IL-6, IL-1, TNF-α, and CRP) and higher anti-inflammatory markers (soluble IL-6r, IL-10, and TGF-α) [9].

In our study, the mean age of the studied group was 13.4 ± 2.5 years and the mean weight was 32.9 ± 11 kg, whereas their mean height was 129 ± 24.5 cm. Overall, 80.8% of them had heights below the third percentile for age and sex. The sex distribution in the patients was equal number of males and females (50% each).

Shroff and colleagues recorded such results in their study carried out in a dialysis center. There were 98 children and 62% were boys, with a median age at the start of dialysis being 4.2 (range: birth to 16.2 years). In all, 55% of the children started dialysis at less than 5 years of age [10].

The reason for this variation in age of presentation from our patients may be because of screening, early detection of cases, and regular follow-up. Moreover, in this study, we found that chronic renal failure was more common in males than females owing to a predominance of males with renal dysplasia and obstructive uropathy causing chronic renal failure which can explain the variation of sex compared with our study.

In the present study, there was a significant decrease in body weight, height, and of the patients on dialysis. This is in agreement with the study of Kretzler and Allred [11], who stated that growth retardation is one of the major complications of a child with CKD which is believed to be multifactorial, including disturbed growth hormone, insulin-like growth factor-I function, nutritional status, acid–base balance, and bone mineralization.

Conversely, Cury and colleagues reported that, regarding the anthropometric characteristics of the population in their study, the sample was homogeneous in relation to the parameters of age, height, and BMI. There was a significant difference regarding weight. Although this study did not include the aim of evaluating nutritional status, it was found that the means of the groups were within the normal range for BMI. The discrepancy in results may be attributed to differences in the age of the studied populations [12].

In our study, the etiologies of renal failure were obstructive uropathy in 10 (38.4%) patients, glomerulonephritis in five (19.2%) patients, cystic kidney diseases in two (7.7%) patients, cystinosis in one (3.8%) patient, and unknown etiology in eight (30.7%) patients.

In the study by Sherif and colleagues, the underlying etiology of CKD was most commonly urological causes in 61 (51%) patients, followed by autosomal recessive polycystic kidney disease in eight (6.7%), hypodysplastic kidneys in five (4.2 steroid resistant nephrotic syndrome in seven (5.8%), lupus nephritisin in seven (5.8%), tubulopathies in seven (5.8%), and other rare etiologies in 12 (10%). The underlying cause was unknown in 12 (10%) children [13]. Overall, 30% of the patients were found to have unknown etiology in our study, which is in contrary to the aforementioned study, in which it was a smaller percentage.

These differences may be because of variable sophistication of diagnostic techniques. Therefore, precise diagnosis is important for prognostic reasons, and more effort should be allocated to determine the etiology of the unknown cases; detection of unknown cases may be because of the late age of presentation, in which case even investigation like renal biopsy is not helpful.

In our study, daily consumption of 2 g of omega-3 fatty acid for 3 months shows that there were statistically significant differences between the TNF-α level in the studied patients before and after supplementation of omega-3. P value is 0.001. This result is in agreement with Saifullah and colleagues, who showed that a supplementation of 1.3 g of oral EPA and DHA daily over a period of 3 months could modestly reduce CRP levels. However, a recent study using a larger dosage (2.08 g/day) but a shorter duration (10 weeks) showed no effects on serum systemic inflammatory markers (CRP, IL-6, TNF, oxidative stress biomarker malondialdehyde, and total antioxidant capacity) [14].

Moreover, in the study by Hamid and colleagues, there was significant reduction of TNF-α level after two months of 3 g of omega-3 administration in HD patients. Likewise, n-3 PUFAs can also reduce the production of inflammatory cytokines, such as TNF-α, IL-1, and IL-6. 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. It is reported that pathologic levels of the proinflammatory cytokine TNF-α are associated with muscle wasting, exerted through inhibition of myogenic differentiation and enhanced apoptosis. Omega-3 has a protective action against the damaging effects of TNF-α [15].

Conversely, the study by Erika and colleagues shows that there was no significant difference discovered between groups regarding IL-6 (P = 0.453) and TNF-α (P = 0.242) after fish oil supplementation. A significant difference was discovered for IL-1β (P = 0.050) with lower levels in the FO group. After dietary supplementation of 2.4 g/day (1400 mg EPA + 1000 mg DHA) or placebo (safflower oil) for 8 weeks [16].

This study shows that there was no statistically significant difference between complete blood count, serum levels of parathyroid hormone, iron, iron saturation, serum ferritin, and total calcium, phosphorous, potassium, sodium, and albumin levels before the start of the study and after 3 months of supplementation of omega-3 at the end of the study.

However, in the study by Zulfitri and colleagues, 63 eligible patients agreed to participate. The two intervention groups received 30 ml of liquid protein supplement plus either 2.4 gm omega-3 (1800 mg EPA + 600 mg DHA) or a placebo, three times per week after their routine dialysis session for 6 months. Serum albumin, plasma lipid, and other indicators of nutritional and inflammatory status were measured. For the omega-3 group, serum albumin was marginally higher after 6 months as compared with baseline (P = 0.07). The observed increase in CRP in the placebo group over 6 months was not apparent in the omega-3 group, although BMI and hemoglobin were unaffected by the intervention [17].

Moreover, the study by Elshafie and colleagues, which was conducted in 23 children with end-stage renal disease undergoing dialysis in the pediatric HD unit of Menoufia University hospitals, showed similar results. The patients received 1 g of omega-3 per day for 3 months. The differences found in hemoglobin, parathyroid hormone, ferritin, CRP, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol before and after supplementation with omega-3 fatty acid were not statistically significant (P > 0.05) [18].


  Conclusion Top


The use of omega-3 caused significant decrease in serum levels of TNF-α in children on HD, and omega-3 may be needed to be taken in a larger doses to exert its anti-inflammatory effect.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Keystone E, Ware CF. Tumor Necrosis factor and anti-tumor necrosisfactor therapies. J Rheumatol 2010; 37:27–39.  Back to cited text no. 5
    
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Shroff R, Rees L, Trompeter R, Hutchinson C, Ledermann S. Long-term outcome of chronic dialysis in children. Pediatr Nephrol 2006; 21:257–264.  Back to cited text no. 10
    
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Kretzler M, Allred L. Notch inhibition reverses kidney failure. Nat Med 2008; 14:246–247.  Back to cited text no. 11
    
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Cury JL, Brunetto AF, Aydos RD. Negative effects of chronic kidney failure on lung function and functional capacity. Br J Phys Ther 2010; 14:91–98.  Back to cited text no. 12
    
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El Desoky S, Farag YM, Safdar E, Shalaby MA, Singh AK, Kari JA. Prevalence of hyperparathyroidism, mineral and bone disorders in children with advanced chronic kidney disease. Indian J Pediatr 2016; 83:420–425.  Back to cited text no. 13
    
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Saifullah A, Watkins BA, Saha C, Li Y, Moe SM, Friedman AN. Oral fish oil supplementation raises blood omega-3 levels and lowers C-reactive protein in haemodialysis patients – A pilot study. Nephrol Dialysis Transpl 2007; 22:3561–3567.  Back to cited text no. 14
    
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Tayyebi-Khosroshahi H, Houshyar J, Dehgan-Hesari R, Alikhah H, Vatankhah A-M, Safaeian A-R, et al. 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; 23:50.  Back to cited text no. 15
    
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Deike E, Bowden RG, Moreillon JJ, Griggs JO, Wilson RL, Cooke M, et al. The effects of fish oil supplementation on markers of inflammation in chronic kidney disease patients. J Renal Nutr 2012; 22:572–577.  Back to cited text no. 16
    
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Daud Z, Tubie B, Adams J, Quainton T, Osia R, Tubie S, et al. Effects of protein and omega-3 supplementation, provided during regular dialysis sessions, on nutritional and inflammatory indices in hemodialysis patients. Vasc Health Risk Manag 2012;8:187–195.  Back to cited text no. 17
    
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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