Saint Louis University School of Medicine, Division of Nephrology, St Louis, Missouri, USA
Keywords: fatty acids; fish oil; end-stage renal disease; blood pressure; vascular access
Introduction
-3 Fatty acids, derived from fish oil, are well established as essential nutrients in developing humans and adults [1]. However, their role as therapeutic agents in the management of progressive renal disease, atherosclerosis, and hypertension has only recently received attention [2]. For example, in patients with IgA nephropathy fish oil-enriched diets may retard progression of chronic renal insufficiency [3]. Moreover, these agents may confer specific benefits in end-stage renal disease (ESRD) including a reduction in blood pressure and vascular disease in light of recent data illuminating the cell biology of
-3 fatty acids (see below).
Nomenclature of -3 fatty acids
Fatty acids with double bonds more distal than the sixth carbon from the (methyl) end of the parent hydrocarbon cannot be synthesized by humans and, therefore, must be ingested in the diet (Figure 1
). For example, linolenic acid, an essential fatty acid found in plant oil, possesses an unsaturated carboncarbon bond at position 6, hence this fatty acid is classified as an
-6 fatty acid.
-linolenic acid, an
-3 fatty acid present in marine oils and in chloroplasts of green leaves, possesses an unsaturated carboncarbon bond at position 3. Elongation and further desaturation of
-linolenic acid occurs in vivo to yield eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the principle
-3 fatty acids in humans. Marine oils derived from fish are rich sources of EPA and DHA. Importantly, the abundance of
-6 fatty acids in the conventional Western diet may interfere with the formation of EPA and DHA by competing for the desaturase and elongase enzymes necessary for their generation [4]. The latter observation is important since simply increasing the dietary intake of
-3 fatty acids may not engender a change in the tissue fatty acid composition and, accordingly, the behaviour of cells or tissues in vivo.
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Cell biology of -3 fatty acids
-3 fatty acids are incorporated into the lipid bilayer of virtually all cells, resulting in a change in the physical characteristics of the cell membrane such as membrane fluidity [5] (Figure 2
). As a result, the function of protein receptors embedded in the cell membrane may be transformed, eliciting changes in receptor-mediated intracellular signalling events [6]. For example,
-3 fatty acids have been shown to inhibit smooth muscle cell proliferation in response to various mitogens [7]. Interestingly, recent studies have demonstrated that diets enriched with
-3 fatty acids inhibit neointima formation after mechanical vascular injury in carotid arteries of nonhuman primates [8]. In addition,
-3 fatty acids directly inhibit endothelial synthesis of platelet-derived growth factor [9]. Furthermore,
-3 fatty acid supplementation has been shown to limit the synthesis of a variety of inflammatory cell cytokines including tumour necrosis factor-
and interleukins 1 and 6 [1012].
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The relative incorporation of -3 fatty acids into the cell membrane is an important determinant of the biological effects engendered by dietary fatty acid manipulations. For example, recent studies from our laboratory suggest a dose-response relationship between cell growth and the membrane fatty acid composition conferred by manipulation of the cell fatty acid microenvironment [15]. Thus, chronic exposure of mesangial cells to >20 µg/ml of EPA was necessary to induce sufficient membrane remodelling to suppress cell growth. Similar dose-dependent effects have been observed in vascular smooth muscle cells (unpublished observations). Therefore, the precise cell membrane phospholipid fatty acid composition appears to play a pivotal role in modulating cell division. Moreover, these studies underscore the importance of characterizing the membrane lipid composition, induced by fatty acid manipulations, in relation to a particular biological response. The latter is of great importance since extrapolation of in vitro findings to in vivo models of disease must be tempered by knowledge of the obligatory dose and/or tissue composition necessary to evoke a response.
Implications for ESRD
Vascular access thrombosis
Despite impressive advances in the management of patients with ESRD, thrombosis of vascular access has remained a persistent problem since the inception of dialysis. Recent studies have indicated that more than 75% of all access grafts will require a salvage procedure to maintain patency within 2 years of placement [16]. While a number of strategies have been employed to limit the incidence of vascular access thrombosis, including the use of pharmacological agents such as warfarin and anti-platelet agents, inconsistent clinical results coupled with side effects has diminished enthusiasm for these approaches [17,18]. The favourable effects of fish oil on platelet aggregation and bleeding time, blood viscosity, and cytokine release should all prove useful in inhibiting thrombus formation within vascular access grafts. Furthermore, the inhibitory effects of -3 fatty acids on vascular smooth muscle cell proliferation may play a vital role in preventing the development of intimal hyperplasia at or near the venous anasthamosis. Thus, the use of diets enriched with
-3 fatty acids may offer a novel approach to the prevention of access thrombosis.
Based on these considerations, we conducted a study to test the hypothesis that diets enriched with fish oil decrease the incidence of thrombosis in newly constructed polytetrafluorethylene grafts. Twenty-four patients were randomized to 4000 mg of fish oil or 4000 mg of control oil. Patients began therapy within 2 weeks of graft placement and were followed for 12 months or until a thrombosis developed. The primary patency rate at 365 days was 14.9% in the control group compared with 75.6% in the fish oil group [19]. Interestingly, in our study the venous outflow pressure in patients receiving fish oil was significantly less than those receiving the control supplement, suggesting an important effect on venous outflow resistance. Companion studies from our laboratory have revealed a decrease in intimal hyperplasia in a rodent model of arterial injury following the administration of fish oil [20].
Other complications of ESRD
The ingestion of -3 fatty acids may also favourably influence other complications commonly associated with ESRD. A reduction in triglyceride and VLDL levels has been shown with diets enriched with
-3 fatty acids [21]. The latter findings may favourably influence the prevalence of atherosclerotic vascular disease [22]. Recent data obtained in rodents suggest that
-3 fatty acids may limit the size of myocardial infarcts and potently suppress cardiac arrhythmias [23]. Finally, we have recently observed a striking decrease in systolic and diastolic blood pressure in a cohort of dialysis patients receiving 3200 mg/day of
-3 fatty acids. While the beneficial effects of fish oil supplements on blood pressure have been previously reported in humans, we are unaware of such data in the setting of ESRD [24]. The mechanism(s) responsible for eliciting a fall in systemic blood pressure may include alterations in endothelial cell function, nitric oxide synthesis, and prostaglandin generation [1,2,13,14].
Adverse effects
Relatively few side effects have been observed in patients consuming diets enriched with fish oil. Most commonly, consumption of high doses of fish oil has been associated with gastrointestinal complaints (e.g. indigestion and a fishy aftertaste). Concerns regarding gastrointestinal haemorrhage (due to inhibition of platelet aggregation) have been unfounded. In contrast, fish oils appear to decrease gastric erosions and peptic ulcer disease caused by alcohol or aspirin [25]. Theoretically, incorporation of highly unsaturated fatty acids into tissue lipids would increase the likelihood of lipid peroxidation, however, chronic administration of fish oil may actually increase the expression of antioxidant enzymes and attenuate the expected increase in lipid free radical formation [26].
Future research
The impressive preliminary results using fish oil to prevent vascular access thrombosis and the accompanying favourable effects on systemic blood pressure and venous outflow resistance highlight the urgent need for additional investigations to establish the optimal dose and duration of fish oil therapy in this setting. Regardless, given the tolerability and limited risk associated with supplemental fish oil ingestion, we believe that this strategy will prove useful in the prevention of access thrombosis and possibly other co-morbid conditions observed in ESRD.
Acknowledgments
This work was supported by grants from the Missouri Kidney Program, the Baxter HealthCare Extramural Grant Program and the National Institute of Diabetes and Digestive and Kidney Disease (DK-52039).
Notes
Correspondence and offprint requests to: Paul G. Schmitz MD, Saint Louis University Health Sciences Center, Division of Nephrology, 3635 Vista Avenue, St Louis, MO 63110, USA. Email: schmitzp{at}slu.edu
References