Effects of omega-3 on lipid profile and inflammation markers in peritoneal dialysis patients

Abstract

Introduction: Cardiovascular complications are the main cause of mortality in patients with end-stage renal disease (ESRD). Peritoneal dialysis (PD) patients generally have a more atherogenic serum lipid profile. Although statins are the cornerstone of lipid-lowering therapy, there is an important role of fibrates in the treatment of hypertriglyceridemia. Fibrates increased the risk of rhabdomyolysis. ESRD patients are at risk for inadequate omega-3 intake as a result of renal dietary recommendations. In the general population omega-3 fatty acids play an important modulatory role in lipid regulation, immune and inflammatory responses, progression of arteriosclerosis, and cardiovascular disease. Aim: To evaluate the effect of oral omega-3 administration on plasma lipid levels and inflammatory markers in PD patients. Patients and methods: Fifteen adult and stable PD patients who did not receive omega-3 or fibrates treatment before were included in the study. All subjects followed the usual dialysis diet and regimen and continued with the same cholesterol-lowering statins. The patients were treated with daily oral 2.4 g docosahexaenoic acid and 1 g eicosapentaenoic acid supplementation in three divided doses with meals for 8 weeks. Triglycerides, LDL-C, HDL-C, and inflammation markers were evaluated before the administration of omega-3 and at 8 weeks. Results: Triglyceride levels were decreased significantly (p = 0.001). Total, HDL and LDL cholesterol levels were not affected. ESR, CRP, IL-6, TNF-α, 4-hydroxynonenal, and malondialdehyde levels reduced insignificantly. Conclusions: This short-term pilot study demonstrated the efficacy, safety, and well tolerability of omega-3 in the treatment of hypertriglyceridemia in PD patients.

Keywords:

• omega-3
• triglycerides
• lipid profile
• inflammation markers
• peritoneal dialysis

INTRODUCTION

Chronic kidney disease (CKD) is associated with substantially increased risk for cardiovascular morbidity and mortality.¹ Cardiovascular complications are the main cause of mortality in patients with end-stage renal disease (ESRD).² Approximately 40% of deaths among dialysis patients in the United States are due to cardiovascular causes.³ Premature atherosclerotic coronary heart disease (CHD) in patients with CKD is driven by multiple risk factors, including traditional, uremic, and “novel” risk factors.^4–11 Traditional risk factors include dyslipidemia, hypertension, diabetes mellitus, insulin resistance, and smoking.¹¹ Uremic risk factors include anemia, phosphate (PO₄⁻³)retention, hyperparathyroidism, vascular calcification, uremic toxins, hyperhomocysteinemia, and volume overload.¹¹ “Novel” risk factors include inflammatory, oxidative stress, sympathetic activation, endothelial dysfunction, and carbamylation of proteins.¹¹ Compared with hemodialysis patients, peritoneal dialysis (PD) patients generally have a more atherogenic serum lipid profile which may be related partially to peritoneal glucose absorption.¹² Given the strong evidence of risk reduction and the benefits of lipid-lowering treatment in the nondialysis population, the emerging consensus is that dialysis patients should be treated aggressively for dyslipidemia to a low density lipoprotein cholesterol (LDL-C) goal below 100 mg/dL.¹³ Although statins are the cornerstone of lipid-lowering therapy for most patients with CKD, there is an important role of fibrates in the treatment of hypertriglyceridemia.¹⁴ Fibrates that renally metabolized require both adjustments in dose and very careful monitoring due to the increased risk of rhabdomyolysis.¹⁴ Because the body is unable to synthesize an appreciable amount of omega-3 fatty acids, they are obtained primarily from dietary sources (i.e., they are “essential” fatty acids) especially fatty fish (salmon, bluefish, mackerel, arctic char, and swordfish).¹⁵ There is strong evidence from human trials that omega-3 fatty acids from fish or fish oil supplements [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] significantly decrease cardiovascular mortality, dampen the inflammatory and atherosclerotic processes, and improve blood pressure and lipid status.^16,17 ESRD patients are at risk for inadequate omega-3 intake because dialysis patients may find foodstuffs less palatable as a result of alterations in taste, renal dietary recommendations do not encourage fish consumption, PD is believed to upregulate oxidative mechanisms that ultimately lead to breakdown of fatty structure and loss of biologic function.^18,19 Studies in the general population suggested that omega-3 fatty acids play an important modulatory role in lipid regulation, inflammatory responses, progression of arteriosclerosis and cardiovascular disease, and improvement of statins effectiveness.^19–21 On the basis of the above laboratory and clinical data, it was suggested that omega-3 supplementation may offer a host of benefits to PD patients.¹⁵ Therefore, the aim of this study was to evaluate the effects of oral omega-3 administrations on plasma lipid levels and inflammatory markers in PD patients.

PATIENTS AND METHODS

Fifteen adult, stable PD patients, on continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) for at least 3 months, with Kt/V > 1.7, without history of malignancy, hypersensitivity to oil fish or known fish allergy, bleeding disorders or coagulopathy and who were not treated with an anticoagulation, omega-3, or fibrate therapy were included in the study. The characteristics of the study population were summarized in Table 1.

Table 1.  Characteristics of the study population

Age	69.7 ± 8.6
Male/female	8/7
CAPD/APD	8/7
Dialysis duration (months)	32.2
Underlying cause:
Diabetes mellitus	6
Chronic glomerulonephritis	3
Unknown	3
Focal segmental glomerulosclerosis	1
Adult polycystic kidney disease	2

CGN, chronic glomerulonephritis;

CAPD, continuous ambulatory peritoneal dialysis; APD, automated peritoneal dialysis.

Patients with a history of peritonitis in the past 6 months were excluded from the study. No subjects suffered from peritonitis during the study period. All subjects followed the usual dialysis diet and PD regimen. All patients received cholesterol-lowering simvastatin and continued with the same dosage during the study period. Patients did not receive sevelamer before and during the study. The study protocol was approved by the local ethics committee and all patients signed a written informed consent before participating in the study. All study patients received daily oral 2.4 g DHA and 1 g EPA supplementation in three divided doses with meals for 8 weeks. Grimsgaard et al. used 4.0 g/dL DHA and 3.8 g/dL EPA in healthy patients.²² All diabetic patients received 2 L icodextrin bag as a night dwell in CAPD subjects and as a daytime dwell in APD subjects. All patients enrolled in the study had serum albumin levels ≥ 3.5 g/dL and did not receive amino acid dialysis solution. The daily glucose load was stable during the study period. At baseline and 4 and 8 weeks blood samples were drawn for complete blood count (CBC), bleeding time (BT), prothrombin time (PT), partial thromboplastin time (PTT), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), bilirubin, albumin, creatine phosphokinase (CPK), fibrinogen, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), IL-6, TNF-α, HNE (4-hydroxynonenal), and MDA (malondialdehyde). C-reactive protein assay on the ARCHITECT cSystem™ and AEROSET system, Abbott Laboratories, Abbott Park, Illinois, USA was used to determine CRP levels. Human IL-6 ELISA, Bender Medsystems, Vienna, Austria was used to determine IL-6 levels. Human TNF-α/TNFSF1A Immunoassay, R&D Systems, Minneapolis, Minnesota, USA, was used to determine TNF-α levels. OxiSelect™ HNE-His Adduct ELISA Kit, Cell Biolabs, Inc., San Diego, California, USA, was used to determine HNE levels. OxiSelect™ MDA Adduct ELISA Kit, Cell Biolabs, Inc., was used to determine MDA levels. HbA_1c levels were determined at baseline. In statistical analysis, qualitative variables were described by incidences and percents, quantitative variables were described by means and standard deviations, paired t-test was used to examine the effects of omega-3 on lipid profile and inflammatory markers, Wilcoxon signed ranks test was used to compare nondiabetic to diabetic patients, CAPD to APD patients, and males to females.

RESULTS

Omega-3 supplementation for 8 weeks to PD patients decreased triglyceride levels (p = 0.001) (Table 2).

Table 2.  Effects of omega-3 on lipid profile and inflammatory markers in peritoneal dialysis patients

	At baseline	At 8 weeks	p-Value
Triglycerides	254.40 ± 132.08	210.093 ± 132.051	0.001
ESR	82.67 ± 22.19	78.33 ± 25.74	0.25
CRP	10.81 ± 10.13	10.42 ± 11.75	0.43
IL-6	5.20 ± 2.45	5.05 ± 2.62	0.38
TNF-α	12.46 ± 2.54	12.12 ± 2.47	0.23
HNE	6.08 ± 1.71	6.00 ± 1.56	0.38
MDA	9.04 ± 1.38	8.98 ± 1.57	0.46

MDA, malondialdehyde; 4-HNE, 4-Hydroxynonenal.

No difference was found between the basal and 8 weeks TG levels in nondiabetic and diabetic subjects, in CAPD and APD patients, and in males and females (Table 3).

Table 3.  Effects of omega-3 on TG levels in nondiabetic, diabetic, CAPD, APD, males, and females PD patients

	TG (baseline)	TG (8 weeks)	p	ΔTG (mg/dL)
Non-DM	267.86 ± 132.31	216.57 ± 107.57	0.008	51.3 ± 18.0
DM	242.63 ± 139.80	206.00 ± 158.55	0.03	49.9 ± 21.8
p	0.61	0.56		0.87
CAPD	291.6 ± 146.7	245.9 ± 164.8	0.04	45.7 ± 31.3
APD	222.4 ± 127.2	182.4 ± 105.4	0.02	44.3 ± 30.04
p	0.16	0.17		0.57
Males	258.1 ± 165.7	222.3 ± 172.9	0.03	35.8 ± 20.1
Females	250.1 ± 92.9	198.0 ± 75.6	0.008	32.9 ± 19.3
p	0.27	0.3		0.83

Omega-3 decreased triglyceride levels in nondiabetic (p = 0.008) and diabetic (p = 0.03) subjects, in CAPD (p = 0.04) and APD (p = 0.02) patients, and in males (p = 0.03) and females (p = 0.008) (Table 3).

Furthermore, no difference was found in the degree of reduction in TG levels (ΔTG mg/dL) in nondiabetic compared with diabetic subjects, in CAPD compared to APD patients, and males compared to females, Table 3.

The basal and 8 weeks HbA_1C levels were higher in diabetic compared to nondiabetic individuals (6.98 ± 1.92 vs. 5.07 ± 1.14, respectively, p = 0.03).

Omega-3 did not reduce significantly the inflammatory markers ESR, CRP, IL-6, TNF-α, HNE, and MDA at 8 weeks (Table 2). Although IL-6 levels were marginally lower in nondiabetic patients, all other inflammatory marker levels were similar in nondiabetic and diabetic subjects (Table 4).

Table 4.  Effects of omega-3 on inflammatory markers in nondiabetic and diabetic PD patients at baseline and 8 weeks

	ESR	CRP	IL-6	TNF-α	4-HNE	MDA
Non-DM0	80.0 ± 25.1	9.5 ± 11.1	3.6 ± 1.9	12.3 ± 3.3	5.5 ± 1.5	9.1 ± 1.8
DM0	85.7 ± 19.9	12.4 ± 9.5	6.8 ± 1.7	12.6 ± 1.5	6.8 ± 1.7	8.9 ± 1.4
p	0.42	0.22	0.05	0.35	0.06	0.43
Non-DM8W	75.6 ± 17.2	7.1 ± 6.3	4.0 ± 2.0	12.1 ± 2.8	5.5 ± 1.5	8.8 ± 1.9
DM8W	81.4 ± 33.8	14.3 ± 15.6	6.5 ± 2.9	12.2 ± 2.3	6.6 ± 1.5	9.1 ± 1.6
p	0.38	0.16	0.05	0.43	0.12	0.38

DISCUSSION

Cardiovascular complications were considered the leading cause of death in ESRD patients.^1,2 Dyslipidemia and inflammation play an important role in the development of premature atherosclerotic CHD.¹¹ PD patients generally have a more atherogenic serum lipid profile and elevated levels of inflammatory markers.¹² Statins that are considered as the cornerstone of cholesterol-lowering therapy in PD patients failed to reduce the triglyceride levels. Fibrates increased the risk of rhabdomyolysis.¹⁴ Although we have no conclusive data that the treatment of dyslipidemia in PD patients might contribute to reducing CV mortality, reducing triglyceride levels in this population is still challenging. In literature few studies were expressly addressed to the dyslipidemia in PD patients and the present study tries to fill this gap. The results of the present study revealed that omega-3 supplementation decreased triglyceride levels (p = 0.001). Moreover, omega-3 supplementation decreased triglyceride levels in nondiabetic (p = 0.008) and diabetic (p = 0.03) PD patients, in subjects on CAPD (p = 0.04) and APD (p = 0.02) modalities, and in males (p = 0.03) and in females (p = 0.008), (Table 3). The degree of reductions in TG levels (ΔTG mg/dL) was similar in nondiabetic compared with diabetic patients, in subjects on CAPD as well as on APD modalities, and males compared to females, (Table 3). Therefore, the reduction in TG levels was independent on the underlying cause of ESRD, PD modality, or gender. Omega-3 supplementation was well tolerated and was not associated with any significant adverse affects and may be used safely in the treatment of hypertriglyceridemia in PD patients. Omega-3 supplementation did not affect LDL-C levels. It may be because the patients continued to receive cholesterol-lowering statins during the study period. Eight weeks of omega-3 supplementation did not affect the HDL-C levels also. The statistically insignificant reduction in the levels of the plasma inflammatory markers at 8 weeks may be related to the short study period. Long-term studies are needed to verify the possible effects of omega-3 on the modulation of the inflammatory responses. Recently, Kelly et al. reported that DHA supplementation to hypertriglyceridemic men for 45 days did not alter the circulatory levels of the inflammatory markers, but at 91 days the levels of CRP and IL-6 were significantly reduced (p < 0.05).²³ Therefore, long-term omega-3 supplementation to hypertriglyceridemic PD patients may be efficient in reducing the circulatory levels of the inflammatory markers. Finally, Stirban et al.²⁴ have reported recently that 6 weeks of n–3 FA supplementation in subjects with type 2 diabetes mellitus improved postprandial microvascular function suggesting a protective vascular effect of n–3 FAs. The triglyceride-lowering properties of omega-3 fatty acids are well known; however, the mechanisms through which this effect is achieved are not completely understood.²⁵ One potential mechanism involves increased degradation of fatty acids in the liver (through enhancing β-oxidation), which decreases the amount of substrate available for triglyceride synthesis and incorporation into VLDL particles.²⁶ Omega-3 fatty acids may also lower triglyceride levels by enhancing triglyceride clearance from circulating VLDL particles through increased lipoprotein lipase activity.²⁷ This may be mediated through a reduction in apo CIII, which inhibits lipoprotein lipase activity.²⁸ Other proposed mechanisms to explain the triglyceride-lowering effects of omega-3 fatty acids include decreased activity of phosphatidic acid, phosphatase/phosphohydrolase, and diacylglycerol acyltransferase.²⁹

In conclusion, this short-term pilot study demonstrated the efficacy, safety, and well tolerability of omega-3 in the treatment of hypertriglyceridemia in PD patients. Therefore, omega-3 may contribute to the attenuation of the progression of arteriosclerosis and cardiovascular disease in this population. Other multicenter RCT studies are needed.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.