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Recommendations Summary

CKD:Macronutrients: LC n-3 PUFA Nutritional Supplements for AV Graft and Fistula Patency and Kidney Allograft Survival (2020)

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  • Recommendation(s)

    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).

    Rating: Fair

    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).

    Rating: Weak

    • 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/).

    • Recommendation Narrative

      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.

      Detailed Justification

      Hemodialysis Access
      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.

    • Minority Opinions

      Consensus reached.