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Recommendations Summary

CKD: Macronutrients: LC n-3 PUFA Nutritional Supplements for Lipid Profile (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.


  • Recommendation(s)

    CKD: LC n-3 PUFA Nutritional Supplements for Lipid Profile, Maintenance Hemodialysis

    In adults with CKD 5D on MHD, we suggest that 1.3-4 g/d LC n-3 PUFA may be prescribed to reduce triglycerides and LDL cholesterol (2C) and raise HDL levels (2D).

    Rating: Weak
    Conditional

    CKD: LC n-3 PUFA Nutritional Supplements for Lipid Profile, Peritoneal Dialysis

    In adults with CKD 5D on PD,  it is reasonable to consider prescribing 1.3-4 g/d LC n-3 PUFA to improve the lipid profile (OPINION).

    Rating: Consensus
    Conditional

    CKD: LC n-3 PUFA Nutritional Supplements for Lipid Profile, Non-dialyzed

    In adults with CKD 3-5, we suggest prescribing ~2g/d LC n-3 PUFA to lower serum triglyceride levels (2C).

    Rating: Weak
    Conditional

    • 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.
      • There is no need to routinely monitor dietary LC n-3 PUFA intake other than in the context of general dietary counselling. An exception would be if the patient is specifically instructed to consume greater dietary quantities of LC n-3 PUFA.

    • Conditions of Application

      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 wide heterogeneity in in terms of the absolute and relative amounts of n-3 PUFA supplemented, the type of placebo used, and the study duration, making it more difficult to provide conclusive evidence for or against the use of LC n-3 PUFA as a treatment option. 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.178, 211

      Implementation considerations

      •  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 (Kris-Ehterton et al 2002). 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.212
      • 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.213 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 (https://ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional/).

    • Potential Costs Associated with Application

      • LC n-3 PUFA supplementation considerations will differ depending on whether the intervention is diet-based or capsule-based.
      • Potential limitations to dietary supplementation include their relatively high cost and difficulty in achieving high daily intake.

    • Recommendation Narrative

      Rationale/Background
      Long chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) include eicosapentaenoic (EPA), docosapentaenoic and docohexaenoic acids (DHA), all 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 record blood levels of LC n-3 PUFA on record (Friedman, et al. 2012) 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.

      Lipid Profiles
      Aside from with HDL, there were no signals suggesting that LC n-3 PUFA improved circulating plasma lipids. Nineteen separate RCTs (though one without a true control groupGuebre-Egziabher et al 2005) addressed the impact of LC n-3 PUFA supplementation on lipid levels. Thirteen studied patients on MHD (Tayebi-Khosroshahi et al 2013; Saifullah et al 2007; Kooshki et al 2011; Lemos et al 2012; Sorensen et al 2015; Bowden et al 2009 and Daud et al 2012, Poulia et al 2011; Ewers et al 2009; An et al 2012 (included patients on PD also); Khajehdehi et al 2000; Taziki et al 2007 and Khalatbari et al 2013),   four studies patients with CKD 2-5 (Svensson et al 2004, Mori et al 2009, Bouzidi et al 2010, Guebre-Egziabher et al 2013), and two studied patients with CKD with kidney allografts (Bennett et al 1995; Ramezani et al 2011). The studies ranged greatly in terms of the type of supplement (seventeen with fish oil, two with flaxseed oil or ground flaxseed (2 g/d oil in Lemos et al 2012 and 40g/d seed in Khalatbari et al 2013) and duration (3-6 months). Additionally, amount and reporting of dosing was inconsistent. Studies reporting amount of specific LC n-3 PUFAs described doses ranging form 0.42-1.8g/d EPA and 0.25-0.82g/d DHA. The specific amounts of EPA and DHA were not clear in several studies (Bennett et al, Ewers et al, Khajehdehi et al, Sorrenson et al, Taybei-Khosroshahi et al, Guebre-Egziabher et al).

      Triglycerides
      Eighteen RCTs studied the impact of LC n-3 PUFA on serum triglycerides. Seven of the thirteen trials studying patients with MHD found no effect (An et al 2012; Bowden et al 2009; Daud et al 2012; Ewers et al 2009; Poulia et al 2011; Saifullah et al 2007; Tayebi-Khosrashahi, et al. 2013) and six reported a reduction in levels (Lemos et al 2012; Khalatbari et al 2013; Khajehdehi et al 2000; Kooshki et al 2011; Sorensen et al 2015; Taziki et al 2007). In a pooled analysis of twelve of these studies,   LC n-3 PUFA supplementation lowered triglyceride levels by an average (95% CI) of -33.78 (-63.21, -4.36) mg/dL as compared to placebo/controls, though heterogeneity was high (I2=92.36%, p<0.001). While outcomes did not appear to be related to study quality or duration, triglyceride lowering tended to be associated with using lower doses of LC n-3 PUFA (0.42-0.96 g/d EPA and 0.24-0.6 g/d DHA daily)), flaxseed oil (2g/day) or ground flaxseed (40g/day), a counterintuitive finding.  Interestingly, positive results were more consistent in pre-dialysis patients (Svensson et al 2004; Mori et al 2009; Bouzidi et al 2010; Guebre-Egziabher et al 2005) where fish oil supplementation (1.8 g/d total or 0.46-1.44 g/d EPA with 0.25-0.96 g/d DHA) for 8-12 weeks consistently lowered triglycerides.

      Total Cholesterol
      The literature did not suggest a beneficial effect of LC n-3 PUFA supplementation on total cholesterol. Eleven of thirteen studies in patients on MHD reported no effect (0.42-1.8 g/d EPA and 0.24-1.14 g/d DHA for 4 weeks fot 6 months) (Lemos et al 2012,  Khajehdehi et al 2000; Bowden et al 2009; Daud et al 2012; Ewers et al 2009, Kooshki et al 2011, Poulia et al 2011, Saifullah et al 2007, Sorensen et al 2015, Tayebi-Khososhahi et al 2013, Taziki et al 2007), while the two studies supplementing with flaxseed oil (2g/d for 120 days) (Lemos, et al. 2012) or ground flaxseed (40 g/d for 8 weeks) (Khalatbari, et al. 2013) noted a significant reduction in total cholesterol levels (though one study did not compare differences between groupsKhalatbari, et al. 2013). A pooled analysis of all 13 studies did not find any effect on mean total cholesterol, but did note a high level of heterogeneity in the data (I2=95.77%, p<0.001).  Three of four supplementation studies in pre-dialysis patients reported no effect on total cholesterol levels (Svensson, et all 2006; Mori, et al. 2009; Guebre-Egziabher, et al. 2005) while the fourth demonstrated a reduction at three months (p<0.05) with no difference between arms (Bouzidi, et al. 2010). Results could not be pooled for these four studies. While Ramezani et al. 2011 reported lower cholesterol levels in CKD patients with kidney allografts compared to placebo after 6 months of supplementation with 1.76 g/d EPA with 0.96 g/d of DHA in fish oil, Schmitz et al found no such benefit in a similar population.

      LDL Cholesterol
      Eight of twelve studies in patients on MHD found no benefit of supplementation (Lemos et al 2012; Daud et al 2012; Ewers et al 2009; Kooshki et al 2011; Saifullah et al 2007; Sorensen et al 2015; Tayebi-Khosroshahi et al 2013; Taziki et al 2007) while four reported a reduction in LDL (Lemos et al 2012; Khalatbari et al 2013; Khajehdehi et al 2000; Bowden et al 2009). Two of the four positive studies supplemented with fish oil (1.5g total in Khajehdehi et al 2000 and 0.96 g/d EPA with 0.6 g/d DHA in Bowden et al) while the other two used flaxseed oil or ground flaxseed,  with both latter studies observing a drop in LDL (Lemos, et al. 2012; Khalatbari, et al. 2013). Study quality or duration or the type of comparison group used did not influence the outcome. A pooled analysis of all twelve studies noted an improvement in LDL only when excluding the flaxseed-based supplement studies [mean difference (95% CI): -5.26 (-9.51, -1.00) mg/dL] and even then the result was clinically marginal. In pre-dialysis patients, four studies of 8-12 weeks length using fish oil found no effect on LDL (1.8g/d total in Guebre-Egziabher et al and 0.46-1.44g/d EPA with 0.25-0.96g/d DHA) (Svensson et al 2006; Mori et al 2009; Bouzidi et al 2010; Guebre-Egziabher et al 2005). In patients with CKD with kidney allografts, one study reported that  EPA “9g capsules” per day increased LDL levels (but a higher dose did not) while another study reported negative results (Bennett et al and Schmitz et al).

      HDL Cholesterol 
      Seventeen RCTs included HDL as an outcome. Though HDL may be influenced by physical activity, smoking status, and gender, the preponderance of these studies did not control for these factors. Of the twelve studies in patients on MHD six reported negative results (An et al 2012; Daud et al 2012; Ewers et al 2009; Kooshki et al 2011; Saifullah et al 2007; Tayebi-Khosroshahi et al 2013) and six found that HDL levels were increased (An et al 2012; Khalatbari et al 2013; Khajehdehi et al 2000; Bowden et al 2009; Sorensen et al 2015; Taziki et al 2007). Effects were not clearly influenced by study quality or duration. However, the positive studies tended to use lower doses of LC n-3 PUFA (0.72-0.96 g/d EPA with 0.42-0.6 g/d DHA), flaxseed oil (2g/day), or ground flaxseed (40g/day). In a pooled analysis of all twelve studies LC n-3 PUFA supplementation was found to raise HDL by a mean (95% CI) of 7.1 (0.52, 13.63) mg/dL. However, the heterogeneity was high overall. Results were mixed in the four trials of pre-dialysis patients, with two showing a benefit (Svensson et al 2004; Guebre-Egziabher et al 2005) and two reporting no effect (Mori et al 2009; Bouzidi et al 2010). Again, the outcome was not clearly influenced by quality of study, study duration or dosage, and results could not be pooled. Finally, the only study in CKD patients with kidney allografts showed no benefit (Bennett et al 1995).

    • Recommendation Strength Rationale

      The evidence supporting the recommendations is based on Grade III/Grade C, D evidence and consensus/expert opinion. The clinical impact of LC n-3 PUFA supplementation in patients with CKD was challenging to assess due to short study duration, modest sample size, and wide heterogeneity in terms of the absolute and relative amounts of n-3 PUFA supplemented, the type of placebo used, and the study duration. 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 (Friedman et al 2012,  Mozaffarian et al 2006).

    • Minority Opinions

      Consensus reached.