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n-3 Polyunsaturated Fatty Acids for the Management of Patients With Chronic Kidney Disease

2017; Elsevier BV; Volume: 27; Issue: 3 Linguagem: Inglês

10.1053/j.jrn.2017.02.003

1532-8503

My Svensson, Juan Jesús Carrero,

Cholesterol and Lipid Metabolism

Related Articles, p. 161 and p. 169The Irish playwright George Bernard Shaw (1856-1950) once wrote: “No diet will remove all the fat from your body because the brain is entirely fat. Without a brain, you might look good, but all you could do is run for public office.” He was not right in one thing: the brain is just about 60% fat. And of that percentage, the biggest portion comes from n-3 polyunsaturated fatty acids (PUFAs). Related Articles, p. 161 and p. 169 n-3 PUFA constitutes a family of healthy dietary fats predominantly found in fatty fish (eicosapentaenoic acid and docosahexaenoic acid) but also present, for instance, in walnuts, canola, or flax seeds (α-linolenic acid [ALA]). ALA is an essential fatty acid that cannot be synthesized endogenously by mammals and must be derived from the diet. Both eicosapentaenoic acid and docosahexaenoic acid can be synthesized from dietary ALA via elongation and desaturation endogenously, but the efficiency of this conversion is very poor and must be considered essential as well. The evidence that n-3 PUFA intake can reduce coronary heart disease mortality and to a lesser extent stroke mortality in the general population is consistent.1Mozaffarian D. Rimm E.B. Fish intake, contaminants, and human health: evaluating the risks and the benefits.Jama. 2006; 296: 1885-1899Crossref PubMed Scopus (1541) Google Scholar Mechanisms behind this effect may involve the capacity of n-3 PUFA of reducing triglycerides and cholesterol levels, inhibiting platelet aggregation, as well as anti-inflammatory, antiproliferative and vasodilatory properties by reducing the availability of arachidonic acid, leukotriene, and cytokine production as well as increasing prostaglandin-I3 production.2Lee J.H. O'Keefe J.H. Lavie C.J. Harris W.S. Omega-3 fatty acids: cardiovascular benefits, sources and sustainability.Nat Rev Cardiol. 2009; 6: 753-758Crossref PubMed Scopus (161) Google Scholar, 3Calder P.C. Marine omega-3 fatty acids and inflammatory processes: effects, mechanisms and clinical relevance.Biochim Biophys Acta. 2015; 1851: 469-484Crossref PubMed Scopus (995) Google Scholar The importance of dietary fat in a healthy and balanced diet is well recognized by current cardiovascular prevention guidelines; the American Heart Association4Krauss R.M. Eckel R.H. Howard B. et al.AHA Dietary Guidelines: revision 2000: A statement for healthcare professionals from the Nutrition Committee of the American Heart Association.Circulation. 2000; 102: 2284-2299Crossref PubMed Scopus (1402) Google Scholar recommends total fat not to exceed 30% of dietary energy, and the European Society of Cardiology5Perk J. De Backer G. Gohlke H. et al.European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts).Eur Heart J. 2012; 33: 1635-1701Crossref PubMed Scopus (3083) Google Scholar lowers that threshold down to 10%. Both guidelines recommend progressively replacing saturated fat by PUFA, via limiting the intake of meat and fast foods and consuming fish at least twice weekly, one of which should be fatty fish. It has been estimated that >40% of total dietary energy intake in patients with advanced chronic kidney disease (CKD) and undergoing dialysis comes from fat and mainly from unhealthy saturated fat.6Luis D. Zlatkis K. Comenge B. et al.Dietary quality and adherence to dietary recommendations in patients undergoing hemodialysis.J Ren Nutr. 2016; 26: 190-195Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 7Therrien M. Byham-Gray L. Denmark R. Beto J. Comparison of dietary intake among women on maintenance dialysis to a Women's Health Initiative cohort: results from the NKF-CRN Second National Research Question Collaborative Study.J Ren Nutr. 2014; 24: 72-80Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 8Khoueiry G. Waked A. Goldman M. et al.Dietary intake in hemodialysis patients does not reflect a heart healthy diet.J Ren Nutr. 2011; 21: 438-447Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 9Luttrell K.J. Beto J.A. Tangney C.C. Selected nutrition practices of women on hemodialysis and peritoneal dialysis: observations from the NKF-CRN Second National Research Question Collaborative Study.J Ren Nutr. 2014; 24: 81-91Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Notwithstanding, current guidelines for renal nutrition management make little emphasis on the potential health benefits of improving dietary fat quality. Observational studies from distant parts of the globe consistently show that dialysis patients, compared to their general populations, have a very low consumption of fish and of n-3 PUFA, with a subsequent lower proportion of n-3 PUFA in plasma, red blood cells, and tissue.10Friedman A.N. 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: 451-458Crossref PubMed Scopus (30) Google Scholar This is true also in societies where dietary fish intake is high, like Japan.11Shoji T. Kakiya R. Hayashi T. et al.Serum n-3 and n-6 polyunsaturated fatty acid profile as an independent predictor of cardiovascular events in hemodialysis patients.Am J Kidney Dis. 2013; 62: 568-576Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar During the last decade, numerous observational studies analyzing the correlates of fish intake or n-3 PUFA content in plasma of dialysis patients have reported associations of a higher intake and improved survival, lower cardiovascular risk, improved metabolic, inflammatory, and antioxidant profile, as well as better quality of life.12Huang X. Sjogren P. Arnlov J. et al.Serum fatty acid patterns, insulin sensitivity and the metabolic syndrome in individuals with chronic kidney disease.J Intern Med. 2014; 275: 71-83Crossref PubMed Scopus (31) Google Scholar, 13Huang X. Stenvinkel P. Qureshi A.R. et al.Essential polyunsaturated fatty acids, inflammation and mortality in dialysis patients.Nephrol Dial Transpl. 2012; 27: 3615-3620Crossref PubMed Scopus (45) Google Scholar, 14Friedman A. Moe S. Review of the effects of omega-3 supplementation in dialysis patients.Clin J Am Soc Nephrol. 2006; 1: 182-192Crossref PubMed Scopus (103) Google Scholar Interventional studies addressing the effects of n-3 PUFA supplementation in CKD patients suggest capacity to reduce triglyceride levels; halter CKD progression; and possibly improve systemic inflammation, oxidative stress, and uremic pruritus (some recent examples found in Esaki et al.15Esaki S. Iwahori M.T. Takagi Y. et al.Effects of a novel nutritional formula enriched with eicosapentaenoic acid and docosahexaenoic acid specially developed for tube-fed hemodialysis patients.J Ren Nutr. 2017; 27: 127-131Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar and Jorgensen et al.16Jorgensen H.S. Eide I.A. Hartmann A. et al.Plasma n-3 polyunsaturated fatty acids and bone mineral density in renal transplant recipients.J Ren Nutr. 2016; 26: 196-203Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar). Small sample sizes, potentially inadequate study designs, and short intervention periods render overall evidence, however, inconclusive.17Huang X. Lindholm B. Stenvinkel P. Carrero J.J. Dietary fat modification in patients with chronic kidney disease: n-3 fatty acids and beyond.J Nephrol. 2013; 26: 960-974Crossref PubMed Scopus (28) Google Scholar In this issue of the Journal, two studies add to the growing evidence supporting salutary effects of n-3 PUFA in the dietary management of CKD. Ateya et al.18Ateya A.M. Sabri N.A. El Hakim I. Shaheen S.M. Effect of omega-3 fatty acids on serum lipid profile and oxidative stress in pediatric patients on regular hemodialysis: A randomized placebo-controlled study.J Ren Nutr. 2017; 27: 169-174Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar present a 1:1 RCT examining the effect of n-3 PUFA supplementation on lipids and oxidative stress in 50 pediatric patients undergoing dialysis. Patients were randomly assigned to receive 750 mg/day of n-3 PUFA or placebo for 16 weeks. They report that antioxidant defenses improved in the n-3 PUFA group illustrated in the study by significant increases against placebo in the levels of glutathione peroxidase and superoxide dismutase. These antioxidant effects are in line with previous interventions in adult dialysis patients.19Bouzidi N. Mekki K. Boukaddoum A. Dida N. Kaddous A. Bouchenak M. Effects of omega-3 polyunsaturated fatty-acid supplementation on redox status in chronic renal failure patients with dyslipidemia.J Ren Nutr. 2010; 20: 321-328Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Further, they observed a significant decrease in total cholesterol without any change in serum triglycerides. While it is well established that n-3 PUFA supplementation effectively lowers triglyceride levels,20Sorensen G.V. Svensson M. Strandhave C. Schmidt E.B. Jorgensen K.A. Christensen J.H. The effect of n-3 fatty acids on small dense low-density lipoproteins in patients with end-stage renal disease: a randomized placebo-controlled intervention study.J Ren Nutr. 2015; 25: 376-380Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar the daily dose in the study of Ateya et al. might be considered low to exert an effect. However, the simplest explanation for this lack of effect is perhaps that serum triglycerides were normal from the beginning in most patients. Further, randomization favored lower triglyceride levels in the placebo group (137.7 vs. 109.6 mg/dL at inclusion; intervention vs. placebo; P < .001). If we look beyond P values, there is a relative triglyceride reduction of 16% in those consuming n-3 PUFA as compared to a 4% reduction in the placebo group. Also in this issue of the Journal, Eide et al.21Eide I.A. Åsberg A. Svensson M. et al.Plasma levels of marine n-3 fatty acids are inversely correlated with proinflammatory markers sTNFR1 and IL-6 in renal transplant recipients.J Ren Nutr. 2017; 27: 161-168Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar examine the cross-sectional association between n-3 PUFA levels and inflammation in a cohort study including more than 800 renal transplant recipients. Strength of the study is the use of n-3 PUFA content in the phospholipid fraction of plasma as a more accurate reflection of long-term dietary fat intake.22Huang X. Sjogren P. Cederholm T. et al.Serum and adipose tissue fatty acid composition as biomarkers of habitual dietary fat intake in elderly men with chronic kidney disease.Nephrol Dial Transpl. 2014; 29: 128-136Crossref PubMed Scopus (18) Google Scholar The authors report a robust association between n-3 PUFA content and the levels of two mediators of inflammation, namely interleukin-6 and soluble tumor necrosis factor receptor 1. Such observations are consistent with the reported inflammatory-lowering effects of n-3 PUFA in intervention trials in end-stage renal disease patients.17Huang X. Lindholm B. Stenvinkel P. Carrero J.J. Dietary fat modification in patients with chronic kidney disease: n-3 fatty acids and beyond.J Nephrol. 2013; 26: 960-974Crossref PubMed Scopus (28) Google Scholar, 23Gharekhani A. Khatami M.R. Dashti-Khavidaki S. et al.Effects of oral supplementation with omega-3 fatty acids on nutritional state and inflammatory markers in maintenance hemodialysis patients.J Ren Nutr. 2014; 24: 177-185Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Also from this same cohort, the authors reported earlier that n-3 PUFA levels associated with protective effects against late rejection episodes, renal graft function, and graft survival with high marine n-3 PUFA intake.24Eide I.A. Jenssen T. Hartmann A. et al.The association between marine n-3 polyunsaturated fatty acid levels and survival after renal transplantation.Clin J Am Soc Nephrol. 2015; 10: 1246-1256Crossref PubMed Scopus (38) Google Scholar, 25Eide I.A. Jenssen T. Hartmann A. et al.Plasma levels of marine n-3 polyunsaturated fatty acids and renal allograft survival.Nephrol Dial Transpl. 2016; 31: 160-167Crossref PubMed Scopus (16) Google Scholar It was recently shown that kidney transplants with subclinical inflammation increase their interstitial fibrosis and experience a more rapid deterioration of graft function and survival.26Park W.D. Griffin M.D. Cornell L.D. Cosio F.G. Stegall M.D. Fibrosis with inflammation at one year predicts transplant functional decline.J Am Soc Nephrol. 2010; 21: 1987-1997Crossref PubMed Scopus (174) Google Scholar Therefore, the hypothesis that n-3 PUFA may preserve or improve kidney function in these patients is worth addressing, not only because of the anti-inflammatory properties of n-3 PUFA, but also for their capacity to reduce fibroblast proliferation and collagen synthesis,27Priante G. Musacchio E. Valvason C. et al.Further insights about the beneficial effects of n-3 fatty acids in the early molecular events of renal fibrosis in vitro.J Nephrol. 2013; 26: 652-659Crossref PubMed Scopus (11) Google Scholar both of which are essential steps in the development and progression of renal fibrosis.28Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics.Kidney Int. 2006; 69: 213-217Abstract Full Text Full Text PDF PubMed Scopus (890) Google Scholar We may also fundament our speculation on observational studies in the community reporting that a high content of marine n-3 PUFA associates with better renal function29Gopinath B. Harris D.C. Flood V.M. Burlutsky G. Mitchell P. Consumption of long-chain n-3 PUFA, alpha-linolenic acid and fish is associated with the prevalence of chronic kidney disease.Br J Nutr. 2011; 105: 1361-1368Crossref PubMed Scopus (68) Google Scholar or on trials demonstrating that long-term supplementation with marine n-3 PUFA provides a small beneficial effect on kidney function in patients with myocardial infarction.30Hoogeveen E.K. Geleijnse J.M. Kromhout D. et al.Effect of omega-3 fatty acids on kidney function after myocardial infarction: the Alpha Omega Trial.Clin J Am Soc Nephrol. 2014; 9: 1676-1683Crossref PubMed Scopus (44) Google Scholar Finally, several trials in patients with diabetic nephropathy, lupus nephritis, or IgA nephropathy suggest a greater reduction in urine protein excretion after fish oil intake.31Miller 3rd, E.R. Juraschek S.P. Appel L.J. et al.The effect of n-3 long-chain polyunsaturated fatty acid supplementation on urine protein excretion and kidney function: meta-analysis of clinical trials.Am J Clin Nutr. 2009; 89: 1937-1945Crossref PubMed Scopus (67) Google Scholar We must admit that although hopeful and encouraging, the story of n-3 PUFA in CKD is, collectively, a half successful one. The three largest trials supplementing n-3 PUFA in dialysis patients show none or inconclusive results: first, in a randomized controlled trial from Denmark,32Svensson M. Schmidt E.B. Jorgensen K.A. Christensen J.H. N-3 fatty acids as secondary prevention against cardiovascular events in patients who undergo chronic hemodialysis: a randomized, placebo-controlled intervention trial.Clin J Am Soc Nephrol. 2006; 1: 780-786Crossref PubMed Scopus (135) Google Scholar 206 patients undergoing dialysis were randomly assigned to treatment with n-3 PUFA or placebo for 2 years to assess the impact of n-3 PUFA on the prevention of major (cardiovascular) end points; the primary study end point (composite of CV events and death) was negative (intervention vs. placebo hazard ratio 1.04; 95% confidence interval 0.72-1.48; P = 0.8), but the secondary end points suggested benefits for n-3 PUFA intake: the incidence of myocardial infarction was reduced by 70% and major coronary events by 60% against placebo. Second, another RCT from North America33Lok C.E. Moist L. Hemmelgarn B.R. et al.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: 1809-1816Crossref PubMed Scopus (109) Google Scholar settled to determine the effect of fish oil supplementation on synthetic HD graft patency and cardiovascular events. A total of 201 CKD stage 5 patients were randomly allocated to receive fish oil capsules or placebo on day 7 after graft creation during 12 months. Despite an impressive risk reduction of 22%, the proportion of participants experiencing graft thrombosis did not significantly differ between fish oil and placebo recipients (relative risk, 0.78; 95% CI, 0.60-1.03; P = .06). Secondary outcomes seemed again to be notably improved by fish oil supplementation, with the rates of graft patency and thrombosis being significantly reduced. Third, and published just a month ago, results from a third and larger multinational trial with the same objectives were reported34Irish A.B. Viecelli A.K. Hawley C.M. et al.Effect of fish oil supplementation and aspirin use on arteriovenous fistula failure in patients requiring hemodialysis: a randomized clinical trial.JAMA Intern Med. 2017; PubMed Google Scholar: the authors found no difference in arteriovenous fistula failure rates among 567 patients receiving fish or placebo within 12 months of fistula implantation (relative risk 1.03; 95% CI, 0.86-1.23; P = .78). While the scientific method demands proven effects, the science of nutrition works on the premise that without adequate nutrient supply, the body cannot survive. Surely, no RCT would be required to demonstrate this. Diet is much richer and complex than a single isolated nutrient, and n-3 PUFAs are involved in many critical functions of the body, including ATP synthesis, structural composition of membranes, intercellular signaling…etc. What becomes clear from current evidence is that we can only expect good things from healthy eating for the management of the metabolic complications of CKD.35Campbell K.L. Carrero J.J. Diet for the management of patients with chronic kidney disease; it is not the quantity, but the quality that matters.J Ren Nutr. 2016; 26: 279-281Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar That healthy eating should probably involve increased fish intake. In the absence of specific renal guidelines, intake of n-3 PUFA supplements or fatty fish in CKD patients should probably be advocated for cardioprotection. Natural n-3 PUFA sources (e.g. fatty fish) are preferred to supplements, but considerations are required on the amount of protein ingested or the protein/phosphate ratio of different species (Table 1). Wild fatty fish is preferred to farmed fish: The latter may contain lower amount of n-3 PUFA as this is naturally obtained from plankton37Henriques J. Dick J.R. Tocher D.R. Bell J.G. Nutritional quality of salmon products available from major retailers in the UK: content and composition of n-3 long-chain PUFA.Br J Nutr. 2014; 112: 964-975Crossref PubMed Scopus (54) Google Scholar; Further, farmed fish are often fed with flour and preparations rich in bioavailable phosphorus to promote rapid growth. This, together with the alleged elevated costs of fatty fish, may render n-3 PUFA supplements as an attractive alternative. Reported adverse effects associated to these have been minimal in CKD studies and generally limited to gastrointestinal complaints.38Friedman A.N. Omega-3 fatty acid supplementation in advanced kidney disease.Semin Dial. 2010; 23: 396-400Crossref PubMed Scopus (42) Google ScholarTable 1Estimated EPA + DHA Content as well as Phosphorus-to-Protein Ratio per 100 g of Selected Species of Wild Fatty FishFatty FishEPA + DHA (g)∗The Report of the Dietary Guidelines Advisory Committee on Dietary Guidelines for Americans, 2005 (health.gov).Protein (g)†Modified from Barril-Cuadrado et al.36Phosphorus (mg)†Modified from Barril-Cuadrado et al.36Phosphorus/Protein Ratio†Modified from Barril-Cuadrado et al.36Anchovy1.417.618210.34Mackerel1.815.415710.19Tuna1.522.023010.45Trout1.115.720813.24Salmon1.818.425013.58Sardine1.018.147526.24DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid.∗ The Report of the Dietary Guidelines Advisory Committee on Dietary Guidelines for Americans, 2005 (health.gov).† Modified from Barril-Cuadrado et al.36Barril-Cuadrado G. Puchulu M.B. Sanchez-Tomero J.A. Table showing dietary phosphorus/protein ratio for the Spanish population. Usefulness in chronic kidney disease.Nefrologia. 2013; 33: 362-371PubMed Google Scholar Open table in a new tab DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid. Plasma Levels of Marine n-3 Fatty Acids Are Inversely Correlated With Proinflammatory Markers sTNFR1 and IL-6 in Renal Transplant RecipientsJournal of Renal NutritionVol. 27Issue 3PreviewMarine n-3 polyunsaturated fatty acids (PUFAs) exert potential anti-inflammatory effects and might improve long-term outcomes after renal transplantation. We assessed associations between plasma phospholipid levels of marine n-3 PUFAs and plasma inflammatory biomarkers 10 weeks after renal transplantation. Full-Text PDF Effect of Omega-3 Fatty Acids on Serum Lipid Profile and Oxidative Stress in Pediatric Patients on Regular Hemodialysis: A Randomized Placebo-Controlled StudyJournal of Renal NutritionVol. 27Issue 3PreviewWe sought to evaluate the effects of omega-3 fatty acids supplementation on serum lipid profile and oxidative stress markers in pediatric patients with end-stage renal disease on regular hemodialysis (HD). Full-Text PDF