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NDT Advance Access published online on April 24, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn180
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


The effect of n-3 fatty acids on lipids and lipoproteins in patients treated with chronic haemodialysis: a randomized placebo-controlled intervention study

My Svensson1, Erik B. Schmidt2, Kaj A. Jørgensen3 and Jeppe H. Christensen1

1 Department of Nephrology 2 Department of Cardiology, Center for cardiovascular research, Aalborg Hospital 3 Department of Renal medicine C, Skejby Hospital, Aarhus University Hospital, Aarhus, Denmark

Correspondence and offprint requests to: My Svensson, Department of Nephrology, Aalborg Hospital, Aarhus University Hospital, Hobrovej 18-20, Aalborg 9100, Denmark. Tel: +45-99326610; Fax: +45-99326108; E-mail: my_svensson{at}hotmail.com



   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Discussion
 References
 
Background. Patients with end-stage renal disease (ESRD) have an increased mortality, mainly due to cardiovascular disease (CVD). ESRD is accompanied by several lipid abnormalities, which may be responsible for part of the increased risk of CVD in this population. n-3 polyunsaturated fatty acids (PUFA) lower plasma triglycerides in patients with normal renal function. The aim of the present study was to examine the effect of n-3 PUFA on serum lipid and lipoproteins in patients treated with chronic haemodialysis (HD).

Methods. In a double-blind randomized placebo-controlled design, patients with documented CVD, treated with HD for a minimum of 6 months, were randomized to treatment with n-3 PUFA or a control treatment (olive oil). A dietary intake of n-3 PUFA was assessed with a dietary questionnaire. Plasma lipids and lipoproteins and the content of n-3 PUFA in serum phospholipids were measured at baseline and after 3 months.

Results. Two hundred and six patients were included. Serum phospholipid levels of n-3 PUFA were significantly higher in patients reporting a high fish intake compared to patients reporting a low fish intake. After 3 months, a significant decrease was seen in serum triglycerides in the n-3 PUFA group compared to the control group (P = 0.01). No significant effect was seen on total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, Lp(a) or apoB.

Conclusion. In patients treated with HD, consumption of fish increases levels of n-3 PUFA. Additional supplementation with n-3 PUFA for 3 months further increases levels of n-3 PUFA and lowers serum triglycerides, but does not significantly affect other plasma lipids or lipoproteins.

Keywords: dialysis; lipids; lipoproteins; n-3 fatty acids



   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Discussion
 References
 
In patients with end-stage renal disease (ESRD) changes in lipid metabolism occur, creating a complex form of dyslipidaemia [1]. Elevated levels of serum triglycerides, increased levels of Lp(a) and low high-density lipoprotein (HDL) cholesterol are part of the uraemic dyslipidaemia [2,3]. While levels of low-density lipoprotein (LDL) cholesterol tend to be normal or near normal, other modifications of LDL cholesterol develop in relation to ESRD, such as a prolonged half-life of LDL cholesterol [4], increased oxidation of LDL cholesterol [5] and a high frequency of atherogenic small dense LDL particles [6]. In addition to the uraemic dyslipidaemia, patients with ESRD have a very high incidence of cardiovascular disease (CVD) [7], which may partly be explained by these lipid abnormal- ities [8].

A considerable amount of data show beneficial effects from n-3 polyunsaturated fatty acids (PUFA) as prevention of CVD [9–11]. Furthermore, supplementation with n-3 PUFA is known to lower serum triglycerides in patients with normal renal function [12], and we have previously shown that n-3 PUFA lower serum triglycerides and increase HDL in pre-dialysis patients [13]. In patients treated with chronic haemodialyis (HD), there is a lack of randomized intervention trials to address the effect of n-3 PUFA on lipids and lipoproteins [14]. The aim of the present study was to evaluate the effect of the dietary fish intake and treatment with n-3 PUFA on plasma lipids and lipoproteins in patients treated with chronic HD.



   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Discussion
 References
 
Study objectives
We investigated the hypothesis that treatment with n-3 PUFA would reduce serum triglycerides and increase HDL cholesterol, in patients treated with chronic HD.

Study design
The present study was part of a trial, which was designed to investigate the clinical effect of n-3 PUFA as secondary prevention against cardiovascular events and death [15]. In brief, patients with documented CVD, treated with chronic HD for at least 6 months, were eligible for inclusion. Patients were recruited at 11 hospital-based dialysis centres in Denmark, between November 2002 and May 2003. Exclusion criteria were active malignant disease, patients participating in other trials and patients with a documented poor compliance. After informed consent, the primary investigator randomly assigned patients to treatment with n-3 PUFA or a control treatment. The randomization was done according to a computer-generated allocation sequence where patients were given the next consecutive number. The allocation sequence was generated by GM pack (Hadsund, Denmark) and kept at GM pack until the database was closed in September 2005. All patients, investigators and monitors were blinded for treatment throughout the trial. The duration of the study was 3 months, and patients were evaluated with clinical examination and blood samples at baseline and after 3 months of treatment.

Dietary evaluation of a fish intake
To estimate the dietary fish intake, all patients were evaluated with a dietary questionnaire. Patients were scored according to their intake of fish at lunch and dinner with 1 = never eating fish, 2 = eating fish once a month, 3 = eating fish twice a month, 4 = eating fish once a week, 5 = eating fish two to three times per week and 6 = eating fish every day, thus giving a minimum of 2 and a maximum of 12 points. For further analysis, patients were divided into three groups according to a low fish intake (score 2–5), a moderate fish intake (score 6–8) and a high fish intake (score 9–12).

Treatment
n-3 PUFA was administered as two capsules of Omacor (omega-3-acid ethyl esters 90) daily, with a content of 45% of eicosapentaenoic acid (EPA) and 37.5% of docosahexaenoic acid (DHA), in total 1.7 g of n-3 PUFA. The control treatment consisted of identical soft gelatine capsules with olive oil in a concentration of 77%. Patients receiving treatment with n-3 PUFA had a washout period of at least 4 weeks before inclusion. Pronova Biocare (Sandefjord, Norway) provided both the Omacor capsules and the control capsules.

Blood sampling and laboratory methods
Blood was drawn immediately before the patients’ usual dialysis session. Due to logistic reasons and time of dialysis session, only the patients attending dialysis in the morning were evaluated with fasting blood samples. Levels of serum total cholesterol, HDL and triglycerides were measured enzymatically by standard methods (Hitachi 991, Roche Diagnostics, NY, USA) in the hospital laboratory, Aalborg Hospital. LDL cholesterol levels were calculated according to the Friedewald formula. Analysis of serum phospholipids was performed in our lipid research laboratory as previously described in detail [15]. In brief, total lipids were extracted from serum, and phospholipids were separated from other lipid classes. The fatty acid composition was analysed by gas chromatography using a Chrompack CP-9002 gas chromatograph (Varian, Middleburg, The Netherlands). This approach permits quantification of fatty acids methyl esters with 14–24 carbon atoms and separation of several trans fatty acids. Interassay variation was 3.5% for EPA and 2.8% for DHA.

Statistical analysis
Continuous data were reported as mean ± SD, except for Lp(a) that was reported as median (inter-quartile range). All P values were two-tailed, and all confidence levels were computed to a 95% level. P < 0.05 were considered statistically significant. Analysis for trend was done using variance-weighted least squares. Regarding the effect of intervention, the Student's t-test was used to compare the mean difference between groups for variables normally distributed, while the Mann–Whitney test was used for variables not normally distributed. The statistical software used was the Statistical Package of Social Sciences, Version 11 (SPSS Inc., Chicago, IL, USA) and Stata version 9.1.



   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Discussion
 References
 
Two hundred and six patients were randomized to treatment with n-3 PUFA or matching control treatment. The two groups were comparable regarding baseline characteristics (Table 1).


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  		Table 1 Baseline characteristics of the 206 patients

 
Self-reported intake of n-3 PUFA
One patient was excluded from analysis due to the lack of dietary information. When patients were divided into groups after a self-reported intake of fish, levels of EPA and DHA were significantly higher in patients with a high fish intake compared to patients with a low or medium fish intake. This trend was seen for both fasting and non-fasting patients (Table 2). Furthermore, in fasting patients, the levels of HDL cholesterol were higher in patients with a high self-reported fish intake (P = 0.03), and serum triglycerides decreased with increasing fish intake, although not significant (P = 0.07) (Figure 1). In non-fasting patients, no significant differences were seen in plasma lipids and lipoproteins when comparing the patients according to a self-reported fish intake (Figure 2).


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  		Table 2 Plasma lipids and lipoprotein levels and n-3 PUFA content at baseline according to a self-reported fish intake

 

Figure 1
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  		Fig. 1 Self-reported fish consumption. Fasting patients.

 

Figure 2
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  		Fig. 2 Self-reported fish consumption. Non-fasting patients.

 
Intervention with n-3 PUFA
Sixteen patients changed the time of their dialysis session from morning to afternoon or from afternoon to morning, altering their fasting status. These patients were excluded from statistical analysis. Moreover, 25 patients were withdrawn due to various reasons, while 12 patients experienced a cardiovascular event and therefore completed the trial before the second visit (Figure 3). Patients eligible for final analysis (n = 152) did not significantly differ from patients not eligible for final analysis (n = 54), regarding baseline characteristics (data not shown).


Figure 3
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  		Fig. 3 Flow chart illustrating fasting and non-fasting patients.

 
All patients (n = 152)
Serum triglycerides decreased significantly in the n-3 PUFA group (1.84 ± 0.98 versus 1.63 ± 0.86), compared to the control group (1.89 ± 1.04 versus 2.07 ± 1.20), after 3 months of treatment (P = 0.01), while there were no significant changes in HDL cholesterol (Figure 4). Total cholesterol, LDL cholesterol, ApoB and Lp(a) were not affected by treatment (data not shown). Compliance evaluated from the content of EPA and DHA in serum phospholipids was satisfactory with a significant increase in EPA and DHA in the n-3 PUFA group, compared to unchanged values in the control group (Figure 4).


Figure 4
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  		Fig. 4 Levels of EPA and DHA before and after supplementation. All patients (n = 152).

 
Fasting patients (n = 73)
In the fasting patients, serum triglycerides did not change significantly after supplementation with n-3 PUFA (1.68 ± 0.9 versus 1.60 ± 1.0), but due to a significant increase in triglycerides in the control group (1.62 ± 0.8 versus 1.94 ± 1.0) the difference between groups was significant (P = 0.01). Other lipids and lipoproteins were largely unaffected by treatment (Table 3). EPA and DHA increased significantly in the n-3 PUFA group, confirming compliance.


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  		Table 3 Plasma lipid and lipoprotein levels before and after supplementation

 
Non-fasting patients (n = 79)
After supplementation with n-3 PUFA, a significant decrease in serum triglycerides was seen in the n-3 PUFA group (1.97 ± 0.98 versus 1.65 ± 0.76), and compared to the control group (2.16 ± 1.16 versus 2.20 ± 1.41) this difference was significant (P = 0.03). Total cholesterol, LDL cholesterol, HDL cholesterol, Lp(a) and ApoB were not affected by supplementation with n-3 PUFA (Table 3). Levels of EPA and DHA increased significantly after supplementation with n-3 PUFA.



   Discussion
Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
References
 
In the present study of patients treated with chronic HD, levels of EPA and DHA in serum phospholipids increased with increasing self-reported fish intake. In fasting patients, a higher fish intake was also associated with a more favourable lipid profile with higher HDL cholesterol and a tendency towards lower serum triglycerides. Treatment with n-3 PUFA for 3 months reduced serum triglycerides compared to a control treatment, but did not significantly affect other plasma lipids or lipoproteins.

The effects of n-3 PUFA on plasma lipids and lipoproteins in the general population are relatively well documented. n-3 PUFA lower serum triglycerides with ~20–30%, with a larger effect from higher doses [12,16]. A small increase in HDL cholesterol of 1–2% has also been reported [12]. In addition, previous reports have shown that supplementation with n-3 PUFA suppresses postprandial hypertriglyceridaemia both in patients with hyperlipidaemia and in healthy volunteers [17,18]. The mechanism by which n-3 PUFA reduce postprandial hypertriglyceridaemia might be through an increased lipoprotein lipase activity and increased chylomicron clearance, as previously demonstrated by Park and Harris [19], but also through suppression of VLDL secretion from the liver [20].

So far, only few reliable data exist regarding the effects of n-3 PUFA on plasma lipids and lipoproteins in HD patients [14] as the majority of earlier studies in this population have been both underpowered and uncontrolled. A few small randomized controlled trials have examined the effect of n-3 PUFA on plasma lipids and lipoproteins, in patients treated with chronic HD. Khajehdehi et al. demonstrated a significant decrease in serum triglycerides and an increase in HDL cholesterol, after supplementation with 1.5 g n-3 PUFA, compared to corn oil, sesame oil or placebo in 60 HD patients [21]. A significant reduction in serum triglycerides was also seen after supplementation with 1.8 g n-3 PUFA in a Japanese study of 38 HD patients [22]. In contrast, Schmitz et al. showed no significant effect on serum triglycerides after supplementation with 3.2 g n-3 PUFA in 24 HD patients [23], and Donnelly et al. found no effect of 3.6 g n-3 PUFA on serum triglyceride levels in 13 HD patients [24]. We have previously demonstrated that treatment with 2.4 g n-3 PUFA for 8 weeks significantly lowered serum triglycerides and increased HDL cholesterol, compared to a control treatment in pre-dialysis patients [13].

In the present study, the effect of treatment with n-3 PUFA on serum triglycerides was larger in non-fasting patients than in fasting patients, a result that may depend on several factors. First, fasting status might be of importance. The present data support a postprandial effect of n-3 PUFA in this population, in line with previous data from other populations [17,18]. However, our measurements were not standardized according to the time and size of the patients’ last meal that might have influenced the results. Secondly, baseline levels of serum triglycerides might influence the results [12]. In fasting patients, serum triglyceride levels at baseline were lower than those in non-fasting patients, which might be an explanation for the lacking significant effect of n-3 PUFA in the fasting patients. Finally, some previous studies, reporting larger reductions in serum triglycerides after supplementation with n-3 PUFA, also used larger doses, suggesting a dose-dependent effect from n-3 PUFA [12,16]. A recent review with pooling of data from more than 2000 patients with normal kidney function showed a small but significant effect on serum triglycerides from supplementation with 0.4–2.4 g/day, no effect on serum triglycerides from doses between 2.5 g/day and 4.4 g/day, but a highly significant effect from supplementation with doses >4.5 g/day.

In fasting patients, we found that the difference between groups in serum triglycerides was due to a significant increase in triglycerides in the control group. To our knowledge, such an adverse effect from olive oil has not previously been described. In contrast, the Mediterranean diet, including several dietary changes with both large amounts of olive oil and several servings of fish, may improve the lipid profile [25].

Other factors might have influenced our results. The type of dialysis filter could be of importance as some smaller previous reports have shown a possible influence on lipid levels in HD patients. Another factor is the use of heparin, which might have a possible effect on lipid levels in HD patients. Unfortunately, we did not register these parameters in our study and we can therefore not rule out any possible difference between the groups that could somehow have affected our patients. However, the present study was randomized and possible differences in the dialysis treatment would presumably have been equally distributed between groups. In addition, recent reviews do not support an effect from either the type of filter or the use of heparin on lipid levels in HD patients [26,27].

Until now, there are relatively few data regarding levels of fatty acids in patients with ESRD. Some previous reports have shown generally reduced levels of n-3 PUFA in HD patients [28], while a recent report of fatty acid levels in 75 HD patients compared to a control group showed conflicting results [28]. The authors found lower plasma levels of EPA and DHA in HD patients compared to controls but the level of DHA in red blood cells was, in contrast, higher in HD patients. The present study did not include a healthy control group, and our results are not comparable to the study by Friedman et al., as levels of fatty acids were measured in different compartments. However, in contrast to the study by Friedman et al. that showed no clear association between fish consumption and levels of EPA and DHA, our results showed that self-reported consumption of fish reflected the actual level of EPA and DHA. Furthermore, an important finding from the present study is that additional treatment with n-3 PUFA led to further incorporation of EPA and DHA in HD patients.

There are few prospective data to assess the impact of lipid abnormalities as risk factors for CVD in patients treated with chronic HD [29]. The linear relationship that exists between cholesterol and mortality in the general population does not seem to apply to HD patients [30–32]. In contrast, a low serum cholesterol is associated with a high mortality, a relation that might be due to confounding from other factors such as inflammation and malnutrition [33]. In line with this, the beneficial effects of statins have not been proven in dialysis patients [34] as in the general population. Until now, the importance of elevated triglycerides as a cardiovascular risk factor has been uncertain. However, a meta-analysis with 260 000 individuals and more than 10 000 cases recently established that elevated triglycerides is a moderate and independent risk factor of CVD in the general population [35]. Moreover, the authors also conclude that this association seems to be independent of fasting status. Since then, another large study with almost 14 000 participants has been published [36]. The authors find a clear association between non-fasting triglycerides and an increased risk of myocardial infarction, ischaemic heart disease and death in a Danish cohort. As fasting samples might be difficult to obtain in HD patients, these findings open up the possibility of using non-fasting lipids in the HD population. Regarding the impact of serum triglycerides as a risk factor of CVD in patients with established chronic kidney disease, there are relatively few prospective data, although data from the ARIC study indicate that elevated serum triglycerides contribute to an equal risk as seen in the general population [37]. In HD patients, recent data report a similar U-shaped relation of triglycerides and mortality as seen with cholesterol [38], whilst in patients treated with peritoneal dialysis a more linear association between triglycerides and mortality has been demonstrated [39].

Finally, we consider that the effect of n-3 PUFA on serum triglycerides might be important, not only as a result of the actual reduction in serum triglycerides but also from changing the uraemic lipid profile towards a more normal and less atherogenic lipid profile. It has previously been shown that elevated serum triglycerides are closely related to the presence of small dense LDL particles both in data from the general population [40] and in dialysis patients [6]. Further research regarding the effect of n-3 PUFA on the more specific uraemic dyslipidaemia would be of interest.

Strengths and limitations
The strength of the present study is the design and a reliable confirmation of compliance with measurement of plasma phospholipids. Furthermore, treatment with n-3 PUFA was given in addition to other medication, which makes the results applicable in daily clinic. An obvious limitation of the present study is the relatively large number of patients who withdrew before the second visit, which might have biased the results. However, a comparison of baseline characteristics suggests that this subset of patients was the representative of the entire sample. We also recognize the limited number of patients and the relatively short duration of the study as possible limitations. Enrolling both fasting and non-fasting patients could also be seen as a limitation of the present study, although we believe that our data resemble daily clinic where fasting samples from HD patients might be difficult to obtain. Finally, the present study was performed as pre-defined secondary analyses of an end-point-driven study regarding the effect of n-3 PUFA as secondary prevention of CVD. The main study did not show a protective effect from supplementation of n-3 PUFA, compared with a control treatment as for the primary endpoint of cardiovascular events and death. The negative results from the main study obviously limit the possible use of n-3 PUFA as secondary prevention of CVD.

Summary and conclusion
The most important findings from the present study were that a self-reported fish intake is related to actual levels of EPA and DHA measured in serum phospholipids and that fish consumption might be related to a more favourable lipid profile. Treatment with n-3 PUFA reduces serum triglycerides with the largest effect observed in non-fasting patients but does not significantly affect HDL cholesterol, LDL cholesterol, total cholesterol, Lp(a) or ApoB. We conclude that consumption of fish or treatment with n-3 PUFA might be part of a CVD prevention strategy in patients treated with chronic HD.



   Acknowledgments
 
We thank A. Gorst-Rasmussen for statistical assistance and I. Aardestrup for laboratory assistance. The study was supported by grants from the Danish Heart Foundation, the Danish Kidney Foundation, the Research Foundation of Northern Jutland and Pronova Biocare.

Conflict of interest statement. We have no conflict of interest. We have had no involvements that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated.



   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 

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Received for publication: 14. 7.06
Accepted in revised form: 7. 3.08


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