CKD:Macronutrients: LC n-3 PUFA Nutritional Supplements for AV Graft and Fistula Patency and Kidney Allograft Survival (2020)
Click here to see the explanation of recommendation ratings (Strong, Fair, Weak, Consensus, Insufficient Evidence) and labels (Imperative or Conditional). To see more detail on the evidence from which the following recommendations were drawn, use the hyperlinks in the Supporting Evidence Section below.
CKD: LC n-3 PUFA Nutritional Supplements for AV Graft and Fistula Patency for Maintenance Hemodialysis
In adults with CKD 5D on maintance himodialysis (MHD), we suggest not routinely prescribing fish oil to improve primary patency rates in patients with AV grafts (2B) or fistulas (2A).
CKD: LC n-3 PUFA Nutritional Supplements for Kidney Allograft Survival
In posttransplantation adults, we suggest not routinely prescribing LC n-3 PUFA to reduce the number of rejection episodes or improve graft survival (2D).
Risks/Harms of Implementing This Recommendation
Adverse effects of capsule-based supplementation may lead to gastrointestinal side effects like stomach upset and eructation (though the latter can be masked by different formulations). Theoretical risks like bleeding have not been borne out in clinical trials.
Conditions of Application
All treatment should be individualized according to a patient's preferences, health history and co-morbidities as well as clinical judgement.
Potential Costs Associated with Application
- LC n-3 PUFA supplementation considerations will differ depending on whether the intervention is diet-based or capsule-based.
- For dietary interventions the goal of supplementation must be clearly defined. If it is to raise blood levels of α-linolenic acid then supplementation should focus on soybean, flaxseed, and other oils as well as meat and dairy products. If it is to raise EPA or DHA blood/tissue levels then the primary dietary sources must be sardine, mackerel, salmon and other high-content marine-based foods. Potential limitations to dietary supplementation include their relatively high cost and difficulty in achieving high daily intake. In addition, the source and processing method will influence LC n-3 PUFA foodstuff content. For example, farmed fish typically (but not always) has lower LC n-3 PUFA compared to wild fish, while frying fish could alter the n-3/n-6 ratio which may be of clinical significance (Strobel, et al. 2012).
- Capsule-based supplementation involves a set of different considerations. While dozens of commercial LC n-3 PUFA supplements are available, quality control is often lacking (Kleiner, et al. 2015).This makes precise dosing recommendations difficult. An alternative route is to have the patient obtain supplements via physician prescription (e.g. icosapent ethyl, omega-3 ethyl esters). For either option cost could be an issue. Achieving high dose supplementation will be easier with capsules then through dietary consumption. Adverse effects of capsule-based supplementation may lead to gastrointestinal side effects like stomach upset and eructation (though the latter can be masked by different formulations). Theoretical risks like bleeding have not been borne out in clinical trials.
- LC n-3 PUFA content is listed on the website of the National Institutes of Health (NIH 2018) (https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/).
Long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) include eicosapentaenoic (EPA) and docosapentaenoic and docohexaenoic acids (DHA), both of which are obtained primarily from dietary sources like cold-water fish (i.e. fish oil), or linoleic acid, which is derived from flaxseed or certain other vegetable oils. In recent decades LC n-3 PUFA have demonstrated protean biologic effects that mediate eicosanoid production, cell membrane physiology, signal transduction, metabolism, apoptosis, oxidation, and inflammation. Accordingly, they have been tested in a variety of medical conditions. Of particular interest has been their putative effects on cardiac membrane stabilization leading to possible reduction of malignant arrhythmias and sudden cardiac death. Patients with CKD have been documented to have some of the lowest [IA1] [FAN2] blood levels of LC n-3 PUFA on record178 thus making them potentially very suitable candidates for supplementation interventions. In fact, LC n-3 PUFA supplementation has been studied as possible therapy for a number of conditions commonly observed in patients with CKD including dyslipidemia, hemodialysis access failure, cardiovascular disease and death, as well as for their immunomodulatory effects in patients with kidney allografts.
Previous studies have suggested that LC n-3 PUFA, in particular those derived from fish oil, have anti-proliferative, anti-oxidant, and vasodilatory effects. This was the impetus for the four RCTs that examined whether LC n-3 PUFA supplementation could improve patency of arteriovenous grafts (AVG) or fistulas (AVF) in patients on MHD. Of the three RCTs (Lok et al 2012, Bowden et al 2007, Schmitz et al 2002) studying AV graft survival, the two smallest (using 0.96-1.76 g/d EPA and 0.6-0.96 g/d DHA) had mixed results with one showing no benefit at six months (n=29)(Bowden, et al. 2007) and the other (n=24) reporting higher primary patency rates compared to placebo group at 1 year (p<0.03) (Scmitz et al 2002). The third and much larger trial (n=201) noted a borderline statistically significant improvement in the loss of native patency at one year 0.78 [0.60-1.03](p=0.064) after providing 1.6 g/d EPA and 0.8g/d DHA (Lok, et al. 2012). While the overall results are not clearly positive they do suggest at a possible beneficial effect. However, by far the largest study in this field (n=567), which examined patency rates in new AVF at 12 months (Irish et al 2017), reported that fish oil 4 g/d (1.84 g/d EPA and 1.52 g/d DHA) had no benefit. When data was pooled from the three trials studying patency rates no benefit was observed heterogeneity of results was high (I2=72.19%).
Rejection Episodes and Graft Survival in Kidney Allografts
While LC n-3 PUFA have been reported to mediate the immunologic response they have not yet demonstrated any benefits on kidney allografts. Two RCTs (Maachi, et al. 1995; Bennett, et la. 1995) with differing study interventions (2.4 g/d EPA + DHA for one year, 9 vs 18 g/d EPA for 26 weeks) found no benefit on rejection episodes or a relationship between supplementation dose and rejection episodes (Bennett, et al. 1995). Supplementation using approximately 2.5 g/d EPA+DHA also did not influence graft survival (Maachi, et al. 1995; Berthoux, et al. 1992).
Recommendation Strength Rationale
The evidence supporting the recommendation on is based on Grade I to III /Grade A, B, D based on different outcomes and populations.
The clinical impact of LC n-3 PUFA supplementation in patients with CKD was challenging to assess due to short study durations, modest sample sizes, and broad heterogeneity in the composition of the supplements and the dosing strategies. Furthermore, baseline LC n-3 PUFA levels (either in blood or tissues) were not typically used to target populations that would most benefit. This is an important but often overlooked point because the putative benefits of LC n-3 PUFA supplementation may be inversely related to baseline blood or tissue concentrations.
- Risks/Harms of Implementing This Recommendation
The recommendations were created from the evidence analysis on the following questions. To see detail of the evidence analysis, click the blue hyperlinks below (recommendations rated consensus will not have supporting evidence linked).
What is the effect of omega 3 fatty acid supplementation on hemodialysis access in adults with CKD 5D on hemodialysis?
What is the effect of omega 3 fatty acid supplementation on rejection episodes and graft survival in adults with CKD who are non-dialyzed and post-transplant?
Bowden R, Wilson R, Gentile M, Ounpraseuth S, Moore P, Leutholtz B. Effects of omega-3 fatty acid supplementation on vascular access thrombosis in polytetrafluorethylene grafts. Journal of Renal Nutrition: the official journal of the Council on Renal Nutrition of the National Kidney Foundation 2007; 17:126-31
Irish A, Viecelli A, Hawley C, Hooi L, Pascoe E, Paul-Brent P, Badve S, Mori T, Cass A, Kerr P, Voss D, Ong L, Polkinghorne K. Effect of Fish Oil Supplementation and Aspirin Use on Arteriovenous Fistula Failure in Patients Requiring Hemodialysis: A Randomized Clinical Trial. JAMA Internal Medicine 2017; 177:184-193
Lok C, Moist L, Hemmelgarn B, Tonelli M, Vazquez M, Dorval M, Oliver M, Donnelly S, Allon M, Stanley K. Effect of fish oil supplementation on graft patency and cardiovascular events among patients with new synthetic arteriovenous hemodialysis grafts: a randomized controlled trial. JAMA 2012; 307:1809-16
Schmitz P, McCloud L, Reikes S, Leonard C, Gellens M. Prophylaxis of hemodialysis graft thrombosis with fish oil: double-blind, randomized, prospective trial. Journal of the American Society of Nephrology 2002; 13:184-90
Bennett W, Carpenter C, Shapiro M, Strom T, Hefty D, Tillman M, Abrams J, Ryan D, Kelley V. Delayed omega-3 fatty acid supplements in renal transplantation. A double-blind, placebo-controlled study. Transplantation 1995; 59:352-6
Berthoux F, Guerin C, Burgard G, Berthoux P, Alamartine E. One-year randomized controlled trial with omega-3 fatty acid-fish oil in clinical renal transplantation. Transplantation Proceedings 1992; 24:2578-82
Maachi K, Berthoux P, Burgard G, Alamartine E, Berthoux F. Results of a 1-year randomized controlled trial with omega-3 fatty acid fish oil in renal transplantation under triple immunosuppressive therapy. Transplantation Proceedings 1995; 27:846-9
References not graded in Academy of Nutrition and Dietetics Evidence Analysis Process
Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019;380(1):11-22.
Friedman AN, Yu Z, Tabbey R, et al. Low blood levels of long-chain n-3 polyunsaturated fatty acids in US hemodialysis patients: clinical implications. Am J Nephrol. 2012;36(5):451-458.
Kleiner AC, Cladis DP, Santerre CR. A comparison of actual versus stated label amounts of EPA and DHA in commercial omega-3 dietary supplements in the United States. J Sci Food Agric. 2015;95(6):1260-1267.
Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA. 2006;296(15):1885-1899.
National Institutes of Health. Omega-3 Fatty Acids: Fact Sheet for Health Professionals. 2018. https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/. Accessed 1/28/19.
Strobel C, Jahreis G, Kuhnt K. Survey of n-3 and n-6 polyunsaturated fatty acids in fish and fish products. Lipids Health Dis. 2012;11:144.