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Omega-3 fatty acids, fish oil, alpha-linolenic acid

Natural Standard® Patient Monograph, Copyright © 2007 (www.naturalstandard.com). Commercial distribution prohibited. This monograph is intended for informational purposes only, and should not be interpreted as specific medical advice. You should consult with a qualified healthcare provider before making decisions about therapies and/or health conditions.

ARTICLE SECTIONS

Background
Synonyms
Evidence
Dosing
Safety
Methodology
Selected references

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Background

Dietary sources of omega-3 fatty acids include fish oil and certain plant/nut oils. Fish oil contains both docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), while some nuts (English walnuts) and vegetable oils (canola, soybean, flaxseed/linseed, olive) contain alpha-linolenic acid (ALA).

There is evidence from multiple large-scale population (epidemiologic) studies and randomized controlled trials that intake of recommended amounts of DHA and EPA in the form of dietary fish or fish oil supplements lowers triglycerides, reduces the risk of death, heart attack, dangerous abnormal heart rhythms, and strokes in people with known cardiovascular disease, slows the buildup of atherosclerotic plaques (“hardening of the arteries”), and lowers blood pressure slightly. However, high doses may have harmful effects, such as an increased risk of bleeding. Although similar benefits are proposed for alpha-linolenic acid, scientific evidence is less compelling, and beneficial effects may be less pronounced.

Some species of fish carry a higher risk of environmental contamination, such as with methylmercury.

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Synonyms

#945;-linolenic acid (ALA, C18:3n-3), alpha-linolenic acid, cod liver oil, coldwater fish, docosahexaenoic acid (DHA, C22:6n-3), eicosapentaenoic acid (EPA, C20:5n-3), fish oil fatty acids, fish body oil, fish liver oil, fish extract, halibut oil, long chain polyunsaturated fatty acids, mackerel oil, marine oil, menhaden oil, n-3 fatty acids, n-3 polyunsaturated fatty acids, omega fatty acids, omega-3 oils, polyunsaturated fatty acids (PUFA), salmon oil, shark liver oil, w-3 fatty acids.

Should not be confused with omega-6 fatty acids.

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Evidence

These uses have been tested in humans or animals. Safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider.

Uses based on scientific evidence
Grade*
Hypertriglyceridemia (fish oil / EPA plus DHA)

There is strong scientific evidence from human trials that omega-3 fatty acids from fish or fish oil supplements (EPA + DHA) significantly reduce blood triglyceride levels (1; 2; 3; 4; 5; 6). Benefits appear to be dose-dependent, with effects at doses as low as 2 grams of omega-3 fatty acids per day. Higher doses have greater effects, and 4 grams per day can lower triglyceride levels by 25-40%. Effects appear to be additive with HMG-CoA reductase inhibitor (“statin”) drugs such as simvastatin (7), pravastatin (8; 9), and atorvastatin (10). The effects of fish oil on hypertriglyceridemia are similar in patients with or without diabetes (5), and in those with kidney disease receiving dialysis. It is not clear how fish oil therapy compares to other agents used for hypertriglyceridemia, such as fibrates (like gemfibrozil of fenofibrate) or niacin/nicotinic acid. Fish oil supplements also appear to cause small improvements in high-density lipoprotein (“good cholesterol”) by 1-3%. However, increases (worsening) in low-density lipoprotein levels (LDL/”bad cholesterol”) by 5-10% are also observed. Therefore, for individuals with high blood levels of total cholesterol or low-density lipoprotein, significant improvements will likely not be seen, and a different treatment should be selected. It is not clear if alpha-linolenic acid significantly affects triglyceride levels, and there is conflicting evidence in this area. The American Heart Association, in its 2003 recommendations, reports that supplementation with 2-4 grams of EPA + DHA each day can lower triglycerides by 20-40% (11). Because of the risk of bleeding from omega-3 fatty acids (particularly at doses greater than 3 grams per day), a physician should be consulted prior to starting treatment with supplements. C-Reactive Protein (CRP) levels : The data on fish oils and CRP is mixed (12; 13). While omega-3 fatty acids from both plants (ALA) and fish (EPA+DHA) have been shown to reduce CRP in some studies, others have failed to show an effect. There is growing evidence that reducing CRP is beneficial towards favorable cardiovascular outcomes, although additional research is pending in this area. Although statin drugs, weight reduction, smoking cessation, and COX-2 inhibitors all appear to reduce CRP, the evidence regarding fish oil remains equivocal.
A

Secondary cardiovascular disease prevention (fish oil / EPA plus DHA)

Several well-conducted randomized controlled trials report that in people with a history of heart attack, regular consumption of oily fish (200-400 grams of fish each week equal to 500-800mg of daily omega-3 fatty acids) or fish oil/omega-3 supplements (containing 850-1800mg of EPA + DHA) reduces the risk of non-fatal heart attack, fatal heart attack, sudden death, and all-cause mortality (death due to any cause) (14; 15; 16; 17; 18; 19; 11). Most patients in these studies were also using conventional heart drugs, suggesting that the benefits of fish oils may add to the effects of other therapies. Benefits have been reported after 3 months of use, and after up to 3.5 years of follow-up. Benefits of supplements may not occur in populations that already consume large amounts of dietary fish (20). Multiple mechanisms have been proposed for the beneficial effects of omega-3 fatty acids. These include reduced triglyceride levels, reduced inflammation, slightly lowered blood pressure, reduced blood clotting, reduced tendency of the heart to develop abnormal rhythms, and diminished buildup of atherosclerotic plaques in arteries of the heart. Experiments suggest that omega-3 fatty acids may reduce platelet derived growth factor (PDGF), decrease platelet aggregation, inhibit the expression of vascular adhesion molecules, and stimulate relaxation of endothelial cells in the walls of blood vessels (21). The American Heart Association, in its 2003 recommendations, suggests that people with known coronary heart disease take in approximately 1 gram of EPA and DHA (combined) each day (11). This may be obtained from eating fish, or from fish oil capsule supplements. Because of the risk of bleeding from omega-3 fatty acids (particularly at doses greater than 3 grams per day), a physician should be consulted prior to starting treatment with supplements.
A

High blood pressure

Multiple human trials report small reductions in blood pressure with intake of omega-3 fatty acids (22; 23; 24; 25; 26; 27; 28). Reductions of 2-5 mmHg have been observed, and benefits may be greater in those with higher blood pressures. Effects appear to be dose-responsive (higher doses have greater effects) (23). DHA may have greater benefits than EPA (29). However, intakes of greater than 3 grams of omega-3 fatty acids per day may be necessary to obtain clinically relevant effects, and at this dose level, there is an increased risk of bleeding. Therefore, a physician should be consulted prior to starting treatment with supplements. Other approaches are known to have greater effects on blood pressure, such as salt reduction, weight loss, exercise, or antihypertensive drug therapy. Therefore, although omega-3 fatty acids do appear to have effects in this area, their role in the management of high blood pressure is limited.
A

Primary cardiovascular disease prevention (fish intake)

Several large studies of populations (“epidemiologic” studies) report a significantly lower rate of death from heart disease in men and women who regularly eat fish (30; 31; 32; 33; 34; 35; 36; 37; 38; 39). Other epidemiologic research reports no such benefits (40; 41; 42). It is not clear if reported benefits only occur in certain groups of people, such as those at risk of developing heart disease. Overall, the evidence suggests benefits of regular consumption of fish oil (43; 44; 45). However, well-designed randomized controlled trials which classify people by their risk of developing heart disease are necessary before a firm conclusion can be drawn (46). The American Heart Association, in its 2003 recommendations, suggests that all adults eat fish at least two times per week (11). In particular, fatty fish are recommended, including mackerel, lake trout, herring, sardines, albacore tuna, and salmon.
B

Rheumatoid arthritis (fish oil)

Multiple randomized controlled trials report improvements in morning stiffness and joint tenderness with the regular intake of fish oil supplements for up to three months (47; 48; 49; 50; 51; 52; 53; 54; 55; 56; 57; 58; 59; 60; 61; 62). Benefits have been reported as additive with anti-inflammatory medications such as NSAIDs (like ibuprofen or aspirin). However, because of weaknesses in study designs and reporting, better research is necessary before a strong favorable recommendation can be made. Effects beyond three months of treatment have not been well evaluated.
B

Protection from cyclosporine toxicity in organ transplant patients

There are multiple studies of heart transplant and kidney transplant patients taking cyclosporine (Neoral®), who were administered fish oil supplements. The majority of trials report improvements in kidney function (glomerular filtration rate, serum creatinine) (63; 64; 65; 66; 67; 68; 69; 70; 71; 72), and less hypertension (high blood pressure) (63; 73; 74) compared to patients not taking fish oil. Although several recent studies report no benefits on kidney function (75; 76; 77; 78; 79), the weight of scientific evidence favors the beneficial effects of fish oil. No changes have been found in rates of rejection or graft survival.
B

Secondary cardiovascular disease prevention (#945;-linolenic acid [ALA])

Several randomized controlled trials have examined the effects of alpha-linolenic acid in people with a history of heart attack. Although some studies suggest benefits (18; 80; 80; 39), others do not (81; 82; 83). Weaknesses in some of this research make results difficult to interpret, such as the use of other foods that may also be beneficial. Additional research is necessary before a conclusion can be drawn in this area.
C

Primary cardiovascular disease prevention (#945;-linolenic acid [ALA])

Several large studies of populations (“epidemiologic” studies) report a significantly reduced risk of fatal or non-fatal heart attack in men and women who regularly consume foods high in #945;-linolenic acid (39; 84; 85). Other epidemiologic research reports no such benefits (42; 83). Although the existing research is compelling, weaknesses in this research make results difficult to interpret, such as the use of other foods that may also be beneficial, or effects of risk factors for heart disease such as smoking. Additional research is necessary before a conclusion can be drawn in this area. The American Heart Association, in its 2003 recommendations, suggests that in addition to eating fish at least two times per week, all adults should consume plant-derived sources of omega-3 fatty acids, such as tofu/soybeans, walnuts, flaxseed oil, and canola oil (11).
C

Stroke prevention

Several large studies of populations (“epidemiologic” studies) have examined the effects of omega-3 fatty acid intake on stroke risk. Some studies suggests benefits (86; 87; 88), while others do not (80; 89; 90; 91). Effects are likely on ischemic or thrombotic stroke risk, and very large intakes of omega-3 fatty acids (“Eskimo” amounts) may actually increase the risk of hemorrhagic (bleeding) stroke (92). At this time, it is unclear if there are benefits in people with or without a history of stroke, or if effects of fish oil are comparable to other treatment strategies. Multiple mechanisms have been proposed for the beneficial effects of omega-3 fatty acids. These include reduced triglyceride levels, reduced inflammation, slightly lowered blood pressure, reduced blood clotting, and diminished buildup of atherosclerotic plaques in blood vessels. Experiments suggest that omega-3 fatty acids may reduce platelet derived growth factor (PDGF), decrease platelet aggregation, inhibit the expression of vascular adhesion molecules, and stimulate relaxation of endothelial cells in the walls of blood vessels (21).
C

Atherosclerosis

Some research reports that regular intake of fish or fish oil supplements reduces the risk of developing atherosclerotic plaques in the arteries of the heart (93; 94; 95), while other research reports no effects (96). Additional evidence is necessary before a firm conclusion can be drawn in this area.
C

Prevention of restenosis after coronary angioplasty (PTCA)

Several randomized controlled trials have evaluated whether omega-3 fatty acid intake reduces blockage of arteries in the heart following balloon angioplasty (percutaneous transluminal coronary angioplasty/PTCA). Some research has reported small significant benefits (97; 98), while other investigations have not found benefits (99; 100; 101). The evidence in this area remains inconclusive.
C

Prevention of graft failure after heart bypass surgery

There is limited study of the use of fish oils in patients after undergoing coronary artery bypass grafting (CABG). Initial research suggests possible small benefits in reducing blood clot formation in vein grafts (102; 103). Additional evidence is necessary before a firm conclusion can be drawn in this area.
C

Angina pectoris

Preliminary studies report reductions in angina associated with fish oil intake (104; 105). Better research is necessary before a firm conclusion can be drawn.
C

Cardiac arrhythmias (abnormal heart rhythms)

There is promising evidence that omega-3 fatty acids may decrease the risk of cardiac arrhythmias (106; 107; 108). This is one proposed mechanism behind the reduced number of heart attacks in people who regularly ingest fish oil or EPA + DHA. Additional research is needed in this area specifically before a firm conclusion can be reached.
C

Cancer prevention

Several population (epidemiologic) studies report that dietary omega-3 fatty acids or fish oil may reduce the risk of developing breast, colon, or prostate cancer (109; 110; 111; 112; 113; 114; 115). Randomized controlled trials are necessary before a clear conclusion can be drawn.
C

Colon cancer

Omega-3 fatty acids are commonly taken by cancer patients (116). Although preliminary studies report that growth of colon cancer cells may be reduced by taking fish oil, effects on survival or remission have not been measured adequately.
C

Infant eye / brain development

It has been suggested that fatty acids, particularly DHA, may be important for normal neurologic development. Fatty acids are added to some infant formulas. Several studies have examined the effects of DHA on development of vision in preterm infants (117; 118; 119; 120; 121; 122; 123). Short-term benefits have been reported compared to formulas without DHA, although these benefits may not be meaningful in the long-term. Well-designed research is necessary before a clear conclusion can be reached.
C

Ulcerative colitis

It has been suggested that effects of omega-3 fatty acids on inflammation may be beneficial in patients with ulcerative colitis when added to standard therapy, and several studies have been conducted in this area (124; 125; 126; 127; 128; 129; 130; 131; 132; 133; 134; 135). Although results have been promising, the majority of trials are small and not well designed. Therefore, better research is necessary before a clear conclusion can be drawn.
C

Crohn’s disease

It has been suggested that effects of omega-3 fatty acids on inflammation may be beneficial in patients with Crohn’s disease when added to standard therapy, and several studies have been conducted in this area (136; 137; 126; 138). Results are conflicting, and no clear conclusion can be drawn at this time.
C

IgA nephropathy

There are conflicting results from several trials in this area (139; 140; 141; 142; 143; 144; 145).
C

Nephrotic syndrome

There is not enough reliable evidence to form a clear conclusion in this area (146; 147).
C

Lupus erythematosus

There is not enough reliable evidence to form a clear conclusion in this area (148; 149; 150).
C

Psoriasis

Several studies in this area do not provide enough reliable evidence to form a clear conclusion (151; 152; 153; 154; 155; 156; 157; 158; 159; 160; 161; 162).
C

Eczema

Several studies of EPA for eczema do not provide enough reliable evidence to form a clear conclusion (163; 164; 165).
C

Asthma

Several studies in this area do not provide enough reliable evidence to form a clear conclusion, with some studies reporting no effects (166; 167; 168; 169; 170; 171), and others finding benefits (172; 173; 174; 175; 176; 177; 178). Because most studies have been small without clear descriptions of design or results, the results cannot be considered conclusive (179).
C

Preeclampsia

Several studies of fish oil do not provide enough reliable evidence to form a clear conclusion in this area (180; 181; 182; 183; 184; 185; 186).
C

Schizophrenia

There is promising preliminary evidence from several randomized controlled trials in this area (187; 188; 189; 190). Additional research is necessary before a firm conclusion can be reached (191).
C

Bipolar disorder

Several studies in this area do not provide enough reliable evidence to form a clear conclusion (192; 193; 194).
C

Depression

Several studies in this area do not provide enough reliable evidence to form a clear conclusion (195; 196; 197). Promising initial evidence (198; 199; 200; 201; 202) requires confirmation with larger, well-designed trials.
C

Dysmenorrhea (painful menstruation)

It has been suggested that anti-inflammatory or prostaglandin-mediated mechanisms associated with omega-3 fatty acids may play a role in the management of dysmenorrhea. There is preliminary evidence suggesting possible benefits of fish oil/omega-3 fatty acids in patients with dysmenorrhea (203; 204; 205). Additional research is necessary before a firm conclusion can be reached.
C

Cystic fibrosis

A small amount of research in this area does not provide enough reliable evidence to form a clear conclusion (206; 207; 208; 209; 210; 211; 212; 213).
C

Diabetes

Although slight increases in fasting blood glucose levels have been noted in patients with type 2 (“adult onset”) diabetes, the available scientific evidence suggests that there are no significant long-term effects of fish oil in patients with diabetes, including no changes in progression of diabetic nephropathy (kidney disease), albuminuria (protein in the urine), or hemoglobin A 1c levels (214; 5). Most studies in this area are not well designed. The effects of fish oil on hypertriglyceridemia are similar in patients with or without diabetes (5).
D

Hypercholesterolemia

Although fish oil is able to reduce triglycerides, beneficial effects on blood cholesterol levels have not been demonstrated. Fish oil supplements appear to cause small improvements in high-density lipoprotein (“good cholesterol”) by 1-3%. However, increases (worsening) in low-density lipoprotein levels (“bad cholesterol”) by 5-10% are also observed (dose-dependent with effects likely to occur at 1 gram per day or greater of omega-3 fatty acids). Therefore, for individuals with high blood levels of total cholesterol or low-density lipoprotein, significant improvements will likely not be seen, and a different treatment should be selected. Fish oil does not appear to affect C-reactive protein (CRP) levels (12). Several randomized trials in patients with familial hypercholesterolemia yield conflicting results (215; 216; 217; 218; 219).
D

Transplant rejection prevention (kidney and heart)

There are multiple studies of heart transplant and kidney transplant patients taking cyclosporine (Neoral®), who were administered fish oil supplements. The majority of trials report improvements in kidney function (glomerular filtration rate, serum creatinine) (63; 64; 65; 66; 67; 68; 69; 70; 71; 72), and less hypertension (high blood pressure) (63; 73; 74) compared to patients not taking fish oil. However, several recent studies report no benefits on kidney function (75; 76; 77; 78; 79), and no changes have been found in rates of rejection or graft survival.
D

Appetite / weight loss in cancer patients

There is preliminary evidence that fish oil supplementation does not improve appetite or prevent weight loss in cancer patients (220; 221; 222; 223; 224; 225; 226).
D

Key to grades
A Strong scientific evidence for this use
B Good scientific evidence for this use
C Unclear scientific evidence for this use
D Fair scientific evidence against this use (it may not work)
F Strong scientific evidence against this use (it likely does not work)

Grading rationale

Uses based on tradition or theory

The below uses are based on tradition or scientific theories. They often have not been thoroughly tested in humans, and safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider.

Acute myocardial infarction (heart attack), acute respiratory distress syndrome (ARDS), age related macular degeneration, aggressive behavior, agoraphobia, AIDS, allergies, Alzheimer’s disease, anticoagulation, antiphospholipid syndrome, attention deficit hyperactivity disorder (ADHD), anthracycline-induced cardiac toxicity, autoimmune nephritis, bacterial infections, Behcet’s syndrome, bipolar disorder (227), bone density improvement (228), borderline personality disorder (229), breast cysts, breast tenderness, cartilage destruction, chronic fatigue syndrome, chronic obstructive pulmonary disease, cirrhosis, common cold, congestive heart failure, critical illness, Crohn’s disease (230), dementia (231), dermatomyositis, diabetic nephropathy, diabetic neuropathy, dyslexia, dyspraxia, exercise performance enhancement, fibromyalgia, gallstones, gingivitis, glaucoma, glomerulonephritis, glycogen storage diseases, gout, hay fever, headache, hepatorenal syndrome, hypoxia, ichthyosis, immunosuppression, kidney disease prevention, kidney stones, leprosy, leukemia, malaria, male infertility, mastalgia (breast pain), memory enhancement, menopausal symptoms, menstrual cramps, methotrexate toxicity (232), multiple sclerosis, myopathy, neuropathy, night vision enhancement, obesity, omega-3 fatty acid deficiency, osteoarthritis, osteoporosis, otitis media (ear infection), panic disorder, peripheral vascular disease (233; 234), postpartum depression (235; 236), postviral fatigue syndrome, pregnancy nutritional supplement, premature birth prevention, premenstrual syndrome, prostate cancer prevention, protection from isotretinoin drug toxicity, Raynaud’s phenomenon, Refsum’s syndrome, retinitis pigmentosa (237; 238), Reye’s syndrome, seizure disorder (239), suicide prevention (235), systemic lupus erythematosus (240; 241; 150), tardive dyskinesia, tennis elbow, ulcerative colitis (242), urolithiasis (bladder stones), vision enhancement, weight loss (243).

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Dosing

The below doses are based on scientific research, publications, traditional use, or expert opinion. Many herbs and supplements have not been thoroughly tested, and safety and effectiveness may not be proven. Brands may be made differently, with variable ingredients, even within the same brand. The below doses may not apply to all products. You should read product labels, and discuss doses with a qualified healthcare provider before starting therapy.

Standardization:

General : For fish oil supplements, dosing should be based on the amount of EPA and DHA (omega-3 fatty acids) in a product, not on the total amount of fish oil. Supplements vary in the amounts and ratios of EPA and DHA. A common amount of omega-3 fatty acids in fish oil capsules is 0.18 grams (180mg) of EPA and 0.12 grams (120mg) of DHA. Five grams of fish oil contains approximately 0.17-0.56 grams (170 to 560mg) of EPA and 0.072-0.31 grams (72-310mg) of DHA. Different types of fish contain variable amounts of omega-3 fatty acids, and different types of nuts or oil contain variable amounts of #945;-linolenic acid.

Amounts of seafood necessary to provide 1 gram of DHA + EPA (based on USDA Nutrient Data Laboratory information): cod (Pacific): 23 ounces; haddock: 15 ounces; catfish: 15-20 ounces; flounder/sole: 7 ounces; shrimp: 11 ounces; lobster: 7.5-42.5 ounces; sardines: 2-3 ounces; crab: 8.5 ounces; cod (Atlantic): 12.5 ounces; clams: 12.5 ounces; scallops: 17.5 ounces; trout: 3-3.5 ounces; salmon: 1.4-4.5 ounces; herring: 1.5-2 ounces; oysters: 2.5-8 ounces; tuna (fresh): 2.5-12 ounces; tuna (canned, light): 12 ounces; tuna (canned, white): 4 ounces; halibut: 3-7.5 ounces; mackerel: 2-8.5 ounces. Cod liver oil: 5 grams; standard fish body oil: 3 grams; omega-3 fatty acid concentrate: 2 grams.

Amounts of #945;-linolenic acid in nuts and vegetable oils (based on USDA Nutrient Data Laboratory information): canola oil: 1.3 grams/tbsp; flaxseed/linseed oil: 8.5 grams/tbsp; flaxseeds: 2.2 grams/tbsp; olive oil: 0.1 grams/tbsp; soybean oil: 0.9 grams/tbsp; walnut oil: 1.4 grams/tbsp; walnuts (English): 0.7 grams/tbsp.

Calories : Fish oils contain approximately 9 calories per gram of oil.

Vitamin E : Fish oil taken for many months may cause a deficiency of vitamin E, and therefore vitamin E is added to many commercial fish oil products.

Adults (18 years and older):

Average dietary intake of omega-3/omega-6 fatty acids : Average Americans consume approximately 1.6 grams of omega-3 fatty acids each day, of which about 1.4 grams (~90%) comes from #945;-linolenic acid, and only 0.1-0.2 grams (~10%) from EPA and DHA. In Western diets, people consume roughly 10 times more omega-6 fatty acids than omega-3 fatty acids. These large amounts of omega-6 fatty acids come from the common use of vegetable oils containing linoleic acid (for example: corn oil, evening primrose oil, pumpkin oil, safflower oil, sesame oil, soybean oil, sunflower oil, walnut oil, wheatgerm oil). Because omega-6 and omega-3 fatty acids compete with each other to be converted to active metabolites in the body, benefits can be reached either by decreasing intake of omega-6 fatty acids, or by increasing omega-3 fatty acids.

Recommended daily intake of omega-3 fatty acids (healthy adults) : For healthy adults with no history of heart disease, the American Heart Association recommends eating fish at least two times per week (11). In particular, fatty fish are recommended, such as anchovies, bluefish, carp, catfish, halibut, herring, lake trout, mackerel, pompano, salmon, striped sea bass, tuna (albacore), and whitefish. It is also recommended to consume plant-derived sources of #945;-linolenic acid, such as tofu/soybeans, walnuts, flaxseed oil, and canola oil (11). The World Health Organization and governmental health agencies of several countries recommend consuming 0.3-0.5 grams of daily EPA + DHA and 0.8-1.1 grams of daily #945;-linolenic acid (11).

Hypertriglyceridemia : The effects of omega-3 fatty acid intake on triglyceride-lowering is dose-responsive (higher doses have greater effects). Benefits are seen at doses less than 2 grams per day of omega-3 fatty acids from EPA and DHA, although higher doses may be necessary in people with marked hypertriglyceridemia (>750mg/dL). The American Heart Association, in its 2003 recommendations, reports that supplementation with 2-4 grams of EPA + DHA each day can lower triglycerides by 20-40% (11). Effects appear to be additive with HMG-CoA reductase inhibitor (“statin”) drugs such as simvastatin (Zocor®) (7), pravastatin (Pravachol®) (8; 9), and atorvastatin (Lipitor®) (10). Because of the risk of bleeding from omega-3 fatty acids (particularly at doses greater than 3 grams per day), a physician should be consulted prior to starting treatment with supplements.

Heart disease (secondary prevention) : In people with a history of heart attack, regular consumption of oily fish (200-400 grams of fish each week equal to 0.5-0.8 grams [500-800mg] of daily omega-3 fatty acids) or fish oil/omega-3 supplements (containing 0.85-1.8 grams [850-1800mg] of EPA + DHA) appears to reduce the risk of non-fatal heart attack, fatal heart attack, sudden death, and all-cause mortality (death due to any cause). The American Heart Association, in its 2003 recommendations, suggests that people with known coronary heart disease consume approximately 1 gram of EPA and DHA (combined) each day (11). This may be obtained from eating fish or from fish oil capsule supplements. Because of the risk of bleeding from omega-3 fatty acids (particularly at doses greater than 3 grams per day), a physician should be consulted prior to starting treatment with supplements.

High blood pressure : The effects of omega-3 fatty acids on blood pressure appear to be dose-responsive (higher doses have greater effects) (23). However, intakes of greater than 3 grams of omega-3 fatty acids per day may be necessary to obtain clinically relevant effects, and at this dose level, there is an increased risk of bleeding. Therefore, a physician should be consulted prior to starting treatment with supplements.

Rheumatoid arthritis : Clinical trials have used a range of doses, most commonly between 3 and 5 grams of EPA + DHA daily (1.7 to 3.8 grams of EPA, and 1.1 to 2.0 grams of DHA). Effects beyond three months of treatment have not been well evaluated.

Protection from cyclosporine toxicity in organ transplant patients : Studies have used 6 grams of fish oil per day for up to one year. Some research has started at 3 grams daily for six weeks, followed by 6 grams per day (70)). Up to 12 grams per day has been used.

Other : Omega-3 fatty acids are used for numerous other indications, although effective doses are not clearly established.

Children (younger than 18 years):

Omega-3 fatty acids are used in some infant formulas, although effective doses are not clearly established. Ingestion of fresh fish should be limited in young children due to the presence of potentially harmful environmental contaminants. Fish oil capsules should not be used in children except under the direction of a physician.

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Safety

The U.S. Food and Drug Administration does not strictly regulate herbs and supplements. There is no guarantee of strength, purity or safety of products, and effects may vary. You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare provider before starting a new therapy. Consult a healthcare provider immediately if you experience side effects.

Allergies

People with allergy or hypersensitivity to fish should avoid fish oil or omega-3 fatty acid products derived from fish. Skin rash has been reported rarely (205; 244). People with allergy or hypersensitivity to nuts should avoid alpha linolenic acid or omega-3 fatty acid products that are derived from the types of nuts to which they react.

Side Effects and Warnings

General : The U.S. Food and Drug Administration classifies intake of up to 3 grams per day of omega-3 fatty acids from fish as GRAS (Generally Regarded as Safe). Caution may be warranted, however, in diabetic patients due to potential (albeit unlikely) increases in blood sugar levels, patients at risk of bleeding, or in those with high levels of low-density lipoprotein (LDL). Fish meat may contain methylmercury and caution is warranted in young children and pregnant/breastfeeding women.

Bleeding : Intake of 3 grams per day or greater of omega-3 fatty acids may increase the risk of bleeding, although there is little evidence of significant bleeding risk at lower doses (245; 246; 247). Very large intakes of fish oil/omega-3 fatty acids (“Eskimo” amounts) may increase the risk of hemorrhagic (bleeding) stroke (92). High doses have also been associated with nosebleed and blood in the urine (147). Fish oils appear to decrease platelet aggregation and prolong bleeding time, increase fibrinolysis (breaking down of blood clots), and may reduce von Willebrand factor.

Environmental contamination : Potentially harmful contaminants such as dioxins, methylmercury, and polychlorinated biphenyls (PCBs) are found in some species of fish. Methylmercury accumulates in fish meat more than in fish oil, and fish oil supplements appear to contain almost no mercury. Therefore, safety concerns apply to eating fish but likely not to ingesting fish oil supplements. Heavy metals are most harmful in young children and pregnant/nursing women. For sport-caught fish, the U.S. Environmental Protection Agency recommends that intake be limited in pregnant/nursing women to a single 6-ounce meal per week, and in young children to less than 2 ounces per week. For farm-raised, imported, or marine fish, the U.S. Food and Drug Administration recommends that pregnant/nursing women and young children avoid eating types with higher levels of methylmercury (approximately 1 part per million, such as mackerel, shark, swordfish, or tilefish), and less than 12 ounces per week of other fish types. Women who might become pregnant are advised to eat 7 ounces or less per week of fish with higher levels of methylmercury (up to 1 part per million), or up to 14 ounces per week of fish types with approximately 0.5 parts per million (such as marlin, orange roughy, red snapper, or fresh tuna). Unrefined fish oil preparations may contain pesticides.

Gastrointestinal symptoms : Gastrointestinal upset is common with the use of fish oil supplements, occurring in up to 5 percent of patients in clinical trials, with nausea in up to 1.5 percent of patients (15; 25; 205; 244; 248; 8). Diarrhea may also occur, with potentially severe diarrhea at very high doses (249). There are also reports of increased burping (205), acid reflux/heartburn/indigestion (250), abdominal bloating (248), and abdominal pain (97). Fishy aftertaste is a common effect (248; 205). Gastrointestinal side effects can be minimized if fish oils are taken with meals and if doses are started low and gradually increased.

Blood pressure effects : Multiple human trials report small reductions in blood pressure with intake of omega-3 fatty acids (22; 23; 24; 25; 26; 27; 28). Reductions of 2-5 mmHg have been observed, and effects appear to be dose-responsive (higher doses have greater effects) (23). DHA may have greater effects than EPA (29). Caution is warranted in patients with low blood pressure or in those taking blood-pressure lowering medications.

Blood sugar levels/diabetes : Although slight increases in fasting blood glucose levels have been noted in patients with type 2 (“adult onset”) diabetes, the available scientific evidence suggests that there are no significant long-term effects of fish oil in patients with diabetes, including no changes in hemoglobin A 1c levels (214; 5). Limited reports in the 1980s of increased insulin needs in diabetic patients taking long-term fish oils may be related to other dietary changes or weight gain (251; 147).

Vitamin levels : Fish oil taken for many months may cause a deficiency of vitamin E, and therefore vitamin E is added to many commercial fish oil products. As a result, regular use of vitamin E-enriched products may lead to elevated levels of this fat-soluble vitamin. Fish liver oil contains the fat-soluble vitamins A and D, and therefore fish liver oil products (such as cod liver oil) may increase the risk of vitamin A or D toxicity.

Cholesterol levels : Increases (worsening) in low-density lipoprotein levels (“bad cholesterol”) by 5-10% are observed with intake of omega-3 fatty acids. Effects are dose-dependent with effects likely to occur at 1 gram per day or greater of omega-3 fatty acids.

Liver (hepatic) effects : Mild elevations in liver function tests (alanine aminotransferase) have been reported rarely (252).

Dermatologic effects : Skin rashes have been reported rarely (205; 244).

Neurologic/psychiatric effects : There are rare reports of mania in patients with bipolar disorder or major depression (253). Restlessness and formication (the sensation of ants crawling on the skin) have also been reported (244).

Calories : Fish oils contain approximately 9 calories per gram of oil.

Pregnancy and Breastfeeding

Potentially harmful contaminants such as dioxins, methylmercury, and polychlorinated biphenyls (PCBs) are found in some species of fish, and may be harmful in pregnant/nursing women. Methylmercury accumulates in fish meat more than in fish oil, and fish oil supplements appear to contain almost no mercury. Therefore, these safety concerns apply to eating fish but likely not to ingesting fish oil supplements. However, unrefined fish oil preparations may contain pesticides.

For sport-caught fish, the U.S. Environmental Protection Agency recommends that intake be limited in pregnant/nursing women to a single 6-ounce meal per week. For farm-raised, imported, or marine fish, the U.S. Food and Drug Administration recommends that pregnant/nursing women avoid eating types with higher levels of methylmercury (approximately 1 part per million, such as mackerel, shark, swordfish, or tilefish), and less than 12 ounces per week of other fish types.

Women who might become pregnant are advised to eat up to 7 ounces per week of fish with higher levels of methylmercury (up to 1 part per million), or up to 14 ounces per week of fish types with approximately 0.5 parts per million (such as marlin, orange roughy, red snapper, or fresh tuna).

It is not known if omega-3 fatty acid supplementation of women during pregnancy or breastfeeding is beneficial to infants. It has been suggested that high intake of omega-3 fatty acids during pregnancy, particularly DHA, may increase birth weight and gestational length (254). However, higher doses may not be advisable due to the potential risk of bleeding. Fatty acids are added to some infant formulas.

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Methodology

This patient information is based on a professional level monograph edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com). (THE NATURAL STANDARD RESEARCH COLLABORATION, 2007)

EFFECTS OF OMEGA-3 FATTY ACIDS ON ORGAN TRANSPLANTATION

Chapter 1. Introduction

This evidence report has been prepared by the Tufts-New England Medical Center (Tufts-NEMC) Evidence-based Practice Center (EPC) concerning the health benefits of omega-3 fatty acids on transplantation. These reports are among several that address topics related to omega-3 fatty acids, and that were requested and funded by the Office of Dietary Supplements, National Institutes of Health, through the EPC program at the Agency for Healthcare Research and Quality (AHRQ). Three EPCs – the Tufts-NEMC EPC, the Southern California EPC-RAND, and the University of Ottawa EPC – each produced evidence reports. To ensure consistency of approach, the 3 EPCs collaborated on selected methodological elements, including literature search strategies, rating of evidence, and data table design.

The aim of the reports is to summarize the current evidence on the health effects of omega-3 fatty acids (eicosapentaenoic acid [EPA; chemical abbreviation: 20:5 n-3], docosahexaenoic acid [DHA; 22:6 n-3], alpha-linolenic acid [ALA, 18:3 n-3], and docosapentaenoic acid [DPA, 22:5 n-3]) on the following: cardiovascular disease, cancer, child and maternal health, eye health, gastrointestinal diseases, kidney diseases, asthma, autoimmune diseases, immune-mediated diseases, organ transplantation, mental health, and neurological diseases and conditions. In addition to informing the research community and the public on the effects of omega-3 fatty acids on various health conditions, it is anticipated that the findings of the reports will also be used to help define the agenda for future research.

The focus of this report is on organ transplantation. In this chapter, the metabolism, physiological functions, and the sources of omega-3 fatty acids are discussed briefly. Subsequent chapters describe the methods used to identify and review studies related to omega-3 fatty acids and organ transplantation, findings related to the effects of omega-3 fatty acids on organ transplantation, and recommendations for future research in this area.

Background

Metabolism and Biological Effects of Essential Fatty Acids

Dietary fat is an important source of energy for biological activities in human beings. Dietary fat encompasses saturated fatty acids, which are usually solid at room temperature, and unsaturated fatty acids, which are liquid at room temperature. Unsaturated fatty acids can be divided further into monounsaturated and polyunsaturated fatty acids. Polyunsaturated fatty acids can be classified on the basis of their chemical structure into two groups: omega-3 (n-3) fatty acids and omega-6 (n-6) fatty acids. The omega-3 or n-3 notation indicates that the first double bond from the methyl end of the molecule is in the third position. The same principle applies to the omega-6 or n-6 notation. Despite their differences in structure, all fats contain the same amount of energy (9 kcal/g or 37 kJ/g).

Of all fats found in food, 2 — ALA and linoleic acid (LA, 18:2 n-6) — cannot be synthesized in the human body in adequate amount, yet are necessary for proper physiological functioning. For this reason, these 2 fats are classified as essential fatty acids. These essential fatty acids can be converted in the liver to what are commonly termed very long-chain polyunsaturated fatty acids, which have a higher number of carbon atoms and double bonds. The metabolic product of LA is arachidonic acid (AA, 20:4 n-6) and products of ALA are EPA and DHA. These very long-chain polyunsaturated fatty acids retain the omega type (n-3 or n-6) of the parent essential fatty acids.

ALA and LA comprise the majority of the total polyunsaturated fatty acids consumed in a typical North American diet. Typically, LA comprises 89% of the total polyunsaturated fatty acids consumed, while ALA comprises 9%. Smaller amounts of other polyunsaturated fatty acids make up the remainder. 1 Both ALA and LA are present in a variety of plant-based foods. For example, LA is present in high concentrations in many commonly used vegetable oils, including safflower, sunflower, soy, and corn oil. ALA, which is consumed in smaller quantities, is present in leafy green vegetables and in some commonly used vegetable oils, primarily canola and soybean oil. Some novelty oils, such as flaxseed oil, contain relatively high concentrations of ALA, but these oils are not commonly found in the food supply. Small amounts of AA come from animal products and EPA and DHA from cold-water fish.

The Institute of Medicine has recently established adequate intake levels (AI) for ALA and LA. Sufficient data were not available to establish recommended dietary allowances (RDA). The AIs for adults 19 and older are 1.1–1.6 g/day for ALA and 11–17 g/day for LA. 2 AI’s for ALA and LA differ by age and gender groups, and for special conditions such as pregnancy and lactation.

As shown in Figure 1.1, EPA and DHA can act as competitors for the same metabolic pathways as AA. In human studies, the analyses of fatty-acid compositions in both blood phospholipids and adipose tissue showed reciprocal relationship between EPA plus DHA and AA. The Institute of Medicine, due to lack of sufficient data, has not established either RDAs or AIs for AA, EPA or DHA. Dietary recommendations have been made for these very long chain fatty acids by other countries worldwide, however, these specific amounts vary widely among countries. 3 Furthermore, there remain numerous unanswered questions relating to the metabolic interrelationship between omega-3 and omega-6 fatty acid. For example, it remains unclear to what extend ALA is converted to EPA and DHA in humans and whether this conversion varies among aged groups or physiological states (i.e. pregnancy), and to what extent the intake of omega-6 fatty acids impacts on the conversion rate or alters the biological effects attributed solely to EPA and DHA. Without resolution of these 2 foundational questions, it remains difficult to fully understand the relative roles of omega-6 and omega-3 fatty acid in human health.

Metabolic Pathways of Omega-3 and Omega-6 Fatty Acids

Omega-3 and omega-6 fatty acids share a common pool of enzymes and go through the same oxidation pathways while being metabolized (Figure 1.1). Once ingested, ALA and LA can be elongated and desaturated into long-chain polyunsaturated fatty acids. LA can be converted into gamma-linolenic acid (GLA, 18:3 n-6), an omega-6 fatty acid that is a positional isomer of ALA. GLA, in turn, can be converted to the very long-chain omega-6 fatty acid, AA. ALA can be converted, to a lesser extent, to the very long-chain omega-3 fatty acids, EPA and DHA. However, the conversion from parent fatty acids into very long-chain polyunsaturated fatty acids occurs slowly in humans, and conversion rates nor the determinants thereof are not well understood. Meat is the primary food source of AA, while cold-water fish has traditionally been the primary food source of EPA and DHA.

The specific biological functions of fatty acids depend on the number and position of double bonds and the length of the acyl chain. Both EPA and AA are 20-carbon fatty acids and are precursors for the formation of prostaglandins, thromboxane, and leukotrienes — hormone-like agents that are members of a larger family of substances called eicosanoids. Eicosanoids are localized tissue hormones that seem to be one of the fundamental regulatory classes of molecules in higher forms of life. They do not travel in the blood, but are synthesized in the cells and regulate a large number of processes, including the movement of calcium and other substances into and out of cells, dilation and contraction of muscles, inhibition and promotion of clotting, regulation of secretions including digestive juices and hormones, and control of fertility, cell division, and growth. 4

As shown in Figure 1.1, AA is the precursor of a group of eicosanoids including series-2 prostaglandins and series-4 leukotrienes. EPA is the precursor to a group of eicosanoids including series-3 prostaglandins and series-5 leukotrienes. The series-2 prostaglandins and series-4 leukotrienes derived from AA are involved in accelerating platelet aggregation and enhancing vasoconstriction and the synthesis of inflammatory mediators in response to physiological stressors. The series-3 prostaglandins and series-5 leukotrienes that are derived from EPA are less physiologically potent than those derived from AA. More specifically, the series-3 prostaglandins are formed at a slower rate and work to attenuate excessive series-2 prostaglandins. Thus, adequate production of the series-3 prostaglandins, which are derived from EPA may protect against heart attack and stroke as well as certain inflammatory diseases like arthritis, lupus, and asthma. 4 In addition, animal studies, have demonstrated that EPA and DHA involved in cytoprotective activities may contribute to antiarrhythmic mechanisms. 5 Arrhythmias are a common cause of “sudden death” in heart disease.

In addition to affecting eicosanoid production as described above, EPA als affects lipoprotein metabolism and decreases the production of other compound from AA-genases including cytokines, interleukin 1? (IL1?), and tumor necrosis factor ? (TNF?) – that have proinflammatory effects. These compounds stimulate the production of collagenases and increase the expression of adhesion molecules necessary for leukocyte extravasation. 6 The mechanism responsible for the suppression of cytokine production by omega-3 fatty acids remains unknown, although suppression of eicosanoid production by omega-3 fatty acids may be involved. EPA can also be converted into the longer chain omega-3 form of docosapentaenoic acid (n-3 DPA), and then further elongated and oxygenated into DHA. EPA and DHA are frequently referred to as very long chain omega-3 fatty acids (and commonly known as “fish oil”). DHA, which is thought to be important for brain development and functioning, is present in significant amounts in a variety of food products, including fish, fish liver oils, fish eggs, and organ meats. Similarly, AA can convert into n-6 DPA.

Studies have reported that omega-3 fatty acids decrease triglycerides (Tg) and very low density lipoprotein (VLDL) in hypertriglyceridemic subjects, with a concomitant increase in high density lipoprotein (HDL). However, they appear to increase or have no effect on low density lipoprotein (LDL). Omega-3 fatty acids lowers plasma Tg by inhibiting VLDL and apolipoprotein B-100 synthesis. 7 Omega-3 fatty acids, in conjunction with transcription factors (small proteins that bind to the regulatory domains of genes), target the genes governing cellular Tg production and those activating oxidation of excess fatty acids in the liver. Inhibition of fatty acid synthesis and increased fatty acid catabolism reduce the amount of substrate available for Tg production. 8

Population Intake of Omega-3 Fatty Acids in the United States

The major source of EPA and DHA is dietary intake of fish and fish oil, and that of ALA is dietary intake of vegetable oils (principally canola and soybean), some nuts including walnuts, and dietary supplements. Two population-based surveys, the third National Health and Nutrition Examination (NHANES III) 1988-94 and the Continuing Food Survey of Intakes by Individuals (CSFII) 1994-98, are the main source of dietary intake data for the U.S. population. NHANES III collected information on the U.S. population aged ?2 months. Mexican Americans and non-Hispanic African-Americans, children ?5 years old, and adults ? 60 years old were over-sampled to produce more precise estimates for these population groups. There were no imputations for missing 24-hour dietary recall data. A total of 29,105 participants had complete and reliable dietary recall. Complete descriptions of the methods used and fuller analyses are available in the report Effects of Omega-3 Fatty Acids on Cardiovascular Disease, under “Methods: Method to Assess the Dietary Intake of Omega-3 Fatty Acids in the US population” and “Results: Population Intake of Omega-3 Fatty Acids in the United States”.

CSFII 1994-96, popularly known as the What We Eat in America survey, addressed the requirements of the National Nutrition Monitoring and Related Research Act of 1990 (Public Law 101–445) for continuous monitoring of the dietary status of the American population. In CSFII 1994-96, an improved data-collection method known as the multiple-pass approach for the 24-hour recall was used. Given the large variation in intake from day-to-day, multiple 24-hours recalls are considered to be the best suited for most nutrition monitoring and will produce stable estimates of mean nutrient intakes from groups of individuals. 9

In 1998, the Supplemental Children’s Survey, a survey of food and nutrient intake by children under age of 10, was conducted as the supplement to the CSFII 1994-96. The CSFII 1994-96, 1998 surveyed 20,607 people of all ages with over-sampling of low-income population (<130% of the poverty threshold). Dietary intake data by individuals of all ages were collected over 2 nonconsecutive days by use of two 1-day dietary recalls.

Table 1.1 reports the NHANES III survey mean intake ± the standard error of the mean (SEM), as well as, the median and range for each omega-3 fatty acid. Distributions of EPA, DPA, and DHA were skewed; therefore, the means and standard errors of the means should be used and interpreted with caution. Table 1.2 reports the CSFII survey mean and median intakes for each omega-3 fatty acid, along with SEMs, as reported in Dietary Reference Intakes by the Institute of Medicine. 2 Estimates of intake from these reports may underestimate total consumption since they do not include intake from dietary supplements and fortified foods.

Dietary Sources of Omega-3 Fatty Acids

Omega-3 fatty acids can be found in many different sources of food, including EPA and DHA from fish and shellfish, and ALA from some nuts and various plant oils. They are summarized on the USDA website http://www.nal.usda.gov/fnic/foodcomp (accessed November 3, 2003; Finfish and Shellfish Products: sr16fg15.pdf; Fats and Oils: sr16fg04.pdf; and Nut and Seed Products: sr16fg12.pdf). 10

Potential Benefits of Omega-3 Fatty Acids in Organ Transplantation

The multiple biological effects of omega-3 fatty acids and observations in non-transplant settings provided a rationale for clinical trials in organ transplantation. 11–13 The largest experience has been in kidney transplantation in which laboratory, animal and early human studies suggested that omega-3 fatty acid supplementation, mostly fish oil, had the potential to decrease cyclosporine (CsA) nephrotoxicity, decrease rejection, improve hyperlipidemia, and reduce hypertension. Other benefits had also been suggested such as improvement in risk factors for thrombosis, restoration of erythrocyte deformability, and blood viscosity. There is far less experience in other forms of organ transplantation, although the effects of omega-3 fatty acids have been evaluated in the setting of heart, liver and bone marrow transplantation where similar benefits had been anticipated.

Reduction in CsA nephrotoxicity

A major advance in organ transplantation was the introduction of cyclosporine (CsA), which greatly improved graft survival. However, CsA is associated with many side effects, especially nephrotoxicity. CsA causes a dose-dependent decrease in glomerular filtration rate (GFR), leading to afferent arteriolar vasoconstriction an increase in blood pressure. 14–16 These effects appear to be related to alteration in the production of vasodilatory and vasoconstrictive eicosanoids. In particular, CsA-induced kidney dysfunction is associated with increased production of thromboxane A2, leukotriene C4, and leukotriene D4. 17, 18

Kidney dysfunction occurring within the first few weeks after transplantation may be reversible. Possible causes include acute tubular necrosis, rejection, vascular thrombosis, urinary obstruction or leak, hemolytic-uremic syndrome, and CsA nephrotoxicity. Amelioration of CsA-induced vasoconstriction by omega-3 fatty acids would be clinically relevant. Of greater concern is chronic nephropathy, which is characterized by the development of diffuse interstitial fibrosis and progressive loss of kidney function. 19

Animal studies of cyclosporine nephrotoxicity demonstrated that supplementation with omega-3 fatty acids improved markers of nephrotoxicity while reducing tissue and urine concentrations of thromboxane A2. 20 Similar results have been observed in cell culture studies in which macrophages stimulated with CsA produced less thromboxane A2 when animal had been fed a diet enriched with fish oil. 21 Human studies also demonstrated that supplementation with fish oil reduced production of thromboxane A2. 22

Reduction in rejection

Several lines of evidence suggested that omega-3 fatty acids had the potential to reduce organ rejection following transplantation. Enhanced immunosuppressive effects of CsA and delayed hypersensitivity were observed in rats undergoing heart transplantation. 23, 24 Reduction in generation of pro-inflammatory products (such as interleukins-1, -2, and-6, and tumor necrosis factor alpha) had also been described in humans and animals. 25–28 Expression of these cytokines is increased in kidney allograft rejection. 29–34 Interleukin-1 and tumor necrosis factor alpha both stimulate the production of interleukin-6 (a primary mediator of the acute phase response) while also participating in B- and T-cell activation and maturation. 33–35 Tumor necrosis factor alpha and interleukin-1 also stimulate macrophages and increase the expression of the class II major histocompatability complex. 33, 34, 36

Hyperlipidemia

Hyperlipidemia is common following organ transplantation. 37 Atherosclerosis resulting from hyperlipidemia is associated with increased long-term morbidity and mortality related to heart and cerebrovascular disease, particularly following kidney transplantation. Data from the United Network for Organ Sharing suggest that overall 10-year patient survival following kidney transplantation is 58 and 77 percent, for recipients of deceased donor and living related allografts, respectively. 38 Cardiovascular disease remains the major cause of death with a functioning graft. 39

The most frequently observed form of hyperlipidemia is hypertriglyceridemia, although some patients have isolated hypercholesterolemia. Regardless of the type of transplant, the cause is multifactorial, but in large part related to the use of corticosteroids and other immunosuppressive agents such as CsA.

The potential effect of omega-3 fatty acid supplementation on lipid metabolism in the non-transplant setting has been reviewed in detail in a previous evidence report from the Tufts-NEMC EPC. 40 The available data suggested that there is a large, consistent benefit of omega-3 fatty acids only on triglyceride levels while small or inconsistent effects were found for a variety of other cardiovascular risk factors and markers of cardiovascular disease.

Hypertension

Hypertension is common following organ transplantation. Although its etiology is incompletely understood, it is generally agreed that CsA is a major contributor. Studies in bone marrow and heart transplantation (settings in which initial or baseline kidney dysfunction is less likely to be present and thus contribute to hypertension) demonstrated that the incidence of hypertension was below 10 percent prior to the introduction of CsA, compared with 33 to 60 percent following bone marrow transplantation and 70 to 100 percent following heart transplantation after CsA had been introduced. 41

A potential modest benefit of omega-3 fatty acids on blood pressure may result from favorable changes in the eicosanoid profile, helping to restore the balance between vasodilatory and vasoconstrictive eicosanoids. In a systematic review in the non-transplant setting conducted by the Tufts-NEMC EPC, 40 fish oil supplementation was associated with a mean net change in systolic and diastolic blood pressure of -2.1 mm Hg (95% confidence interval -3.2, -1.0) and -1.6 mm Hg (-2.2, -1.0), respectively. 42

Miscellaneous effects

A variety of other potential benefits from omega-3 fatty acid supplementation have been proposed in the non-transplant setting, all of which provided the basis for study in patients undergoing transplantation.

The observation that an elevated level of leukotriene B4 was a risk factor for acute colonic graft versus host disease following bone marrow transplantation suggested that omega-3 fatty acid supplementation may help prevent this complication. 43
Dietary supplementation with fish oil improved endothelial function in hypercholesterolemic and atherosclerotic porcine models. 44–46 Endothelial dysfunction is known to be present in patients undergoing heart transplantation. 47, 48
CsA may decrease erythrocyte deformability, a mechanism that may contribute to its toxicity. Supplementation with fish oil had favorable effects on erythrocyte deformability in healthy subjects and those on dialysis. 49–51
Fish oil decreased whole blood viscosity in healthy subjects. 52–54
Chapter 2. Methods

Overview

This evidence report on omega-3 fatty acids and organ transplantation is based on a systematic review of the literature. The Tufts-New England Medical Center Evidence-based Practice Center (Tufts-NEMC EPC) held meetings and teleconferences with technical experts including a Technical Expert Panel (TEP) as well as individual experts in relevant areas of transplantation to identify specific issues central to this report. A comprehensive search of the medical literature was conducted to identify studies addressing the key questions. Evidence tables of study characteristics and results were compiled, and the methodological quality of the studies was appraised. Study results were summarized with qualitative reviews of the evidence, summary tables, and meta-analyses, as appropriate.

A number of individuals and groups supported the Tufts-NEMC EPC in preparing this report. The TEP served as our science partner. It included technical experts, representatives from the Agency for Healthcare Research and Quality (AHRQ), and institutes at the National Institutes of Health (NIH) to work with the EPC staff to refine key questions, identify important issues, and define parameters to the report. Additional domain expertise was obtained through local experts who joined the EPC.

The Tufts-NEMC EPC also worked in conjunction with EPCs at the University of Ottawa and the Southern California EPC-RAND. The 3 EPCs coordinated efforts to produce evidence reports on 10 topics related to omega-3 fatty acids over a 2-year period, with the goal of producing evidence reports with a uniform format. Evidence table layout, and study quality assessment were standardized. In addition, literature searches for all evidence reports were performed by the University of Ottawa EPC, using identical search terms for studies of omega-3 fatty acids. The 3 EPCs agreed on a common definition of omega-3 fatty acids; however some variation in definitions and study eligibility criteria were permitted that reflected different topics and key questions. The studies included are described below, under Full Article Inclusion Criteria.

Key Questions Addressed in this Report

Nine key questions are addressed in this report, which fall under 5 major categories.

Graft-Related Outcomes

Question 1. What is the evidence that omega-3 fatty acid supplementation reduced rejection episodes or graft failure in patients (adults or children) who received an organ transplant?

Question 2. What is the evidence that omega-3 fatty acid supplementation is renoprotective (improves glomerular filtration rate or increases kidney size) or is protective against primary kidney disease recurrence following kidney transplantation?

Cardiovascular Disease-Related Outcomes

Question 3. What is the evidence that omega-3 fatty acid supplementation lowers cardiovascular disease risk factors or events in organ transplant recipients (adults or children)?

Infectious Outcomes

Question 4. What is the evidence that omega-3 fatty acid supplementation reduces serious infectious complications following organ transplantation?

All Outcomes

Question 5. What is the evidence that any benefits to organ transplant recipients from omega-3 fatty acid supplementation differ in different subsets of patients?

Question 6. What is the evidence that effects of omega-3 fatty acid supplementation on outcomes of interest vary depending on the time of administration relative to transplantation procedures (pre- or post-transplant)?

Effects On Immunosuppressive Agents And Related Drugs

Question 7. What is the evidence in patients (adults or children) who receive an organ transplant that the benefits of omega-3 fatty acid supplementation interact with the concomitant administration of various immunosuppressive agents/drugs?

Question 8. What is the evidence in patients (adults or children) who receive an organ transplant that serum levels of immunosuppressive agents/drugs are altered by omega-3 fatty acid supplementation?

Question 9. What is the evidence in patients (adults or children) who receive an organ transplant that omega-3 fatty acid supplementation can replace or reduce the need for other more potent anti-inflammatory or immunosuppressive drugs (such as steroids and non-steroidal anti-inflammatory drugs)?

Analytic Framework

To guide our assessment of studies that examine the association between omega-3 fatty acids and transplantation outcomes, we developed an analytic framework that maps the specific linkages associating the populations of interest, the exposures, modifying factors, and outcomes of interest (Figure 2.1). The framework, depicted graphically below, presents the key components of the study questions:

What type of organ transplantation did the participants receive?
What were the interventions?
What were the outcomes of interest (intermediate and clinical outcomes)?
What were the study designs?
The analytic framework illustrates the chain of logic that evidence must support to link the intervention (exposure to omega-3 fatty acids) to improved clinical outcomes.

This report reviews the evidence addressing the associations or effects of omega-3 fatty acid supplementation in organ transplant recipients on graft-related, cardiovascular-disease related, infectious, and all other transplantation-related outcomes. Also examined are effects on immunosuppressive agents and related drugs.

The most important questions relating to omega-3 fatty acid supplementation pertain to their effects on clinical outcomes such as graft survival or cardiovascular events. However, some of these (such as cardiovascular events) are difficult to assess since they may not occur for many years after transplantation. As a result, established risk factors for such adverse outcomes (such as hyperlipidemia) are also relevant since they may provide a surrogate measure of potential treatment benefits. Thus, in addition to clinical events such as episodes of rejection and rates of graft survival, this report examines whether omega-3 fatty acid supplementation reduces the likelihood or severity of risk factors (such as hyperlipidemia, high blood pressure) for clinical events.

Some of these measures are potentially modified by various factors, including use of concomitant drugs (such as lipid lowering agents), demographic features (e.g., sex, age), baseline diet, the time in which treatment was begun relative to the transplant, and subject characteristics (e.g., baseline renal function). This report considers the potential influences of these factors on the observed results following omega-3 fatty acid supplementation.

The analytic framework does not directly address the level of evidence that is necessary to evaluate each of the effects. Large randomized controlled trials that are adequately blinded and otherwise free of substantial bias provide the best evidence to prove a causal relationship between intervention and outcome. Thus, the current analysis relies as much as possible on high quality, randomized controlled trials.

However, randomized controlled trials are not always available (or feasible), and may not be well-conducted or reported. Thus, other types of study designs must also be considered. Crossover trials have the advantage of controlling fully for bias due to differences between study arms but may introduce bias due to incomplete washout or an order effect. In addition, they are generally small and have a narrow range of subjects. Uncontrolled trials and observational studies provide lesser degrees of evidence that are usually hypothesis-generating regarding causality.

Literature Search Strategy

We conducted a comprehensive literature search to address the key questions (Appendix A.1, available electronically at http://www.ahrq.gov/clinic/epcindex.htm). Relevant studies were identified primarily through search strategies conducted in collaboration with the University of Ottawa EPC. The Tufts-NEMC EPC used the Ovid search engine to conduct preliminary searches on the MEDLINE database. The final searches used 6 databases including MEDLINE, MEDLINE In Process and Other Non-Indexed Citations, Embase, CAB abstracts, BIOSIS abstracts, and Central Cochrane Database of Systematic Reviews from 1966 to week 4 2003. Subject headings and text words were selected so that the same set could be applied to each of the different databases. Following the initial electronic search, tables of contents of major transplant and clinical specialty journals were hand searched during the period while this report was being completed until preparation of the final manuscript.

Additional sources of published and unpublished data were sought by contacting the TEP as well as authors of controlled trials identified in our initial search. Bibliographies of all retrieved studies (including review articles) were also examined.

Study Selection

Abstract Screening

All abstracts identified through the literature search were screened manually and in triplicate by three independent investigators. Triplicate screening was performed because the modest number of abstracts allowed us to gather additional data for methodology research pertaining to the most efficient method of abstract screening. Eligibility criteria were defined broadly to include all studies (regardless of language of publication, experimental design, or size) that evaluated any potential source of omega-3 fatty acids in human subjects who underwent organ transplantation, and reported any outcome. Any abstract identified by any independent investigator was retrieved for further review.

Full Article Inclusion Criteria

The full text of studies selected by the abstract screening process was reviewed by 3 independent investigators. Studies of any design (including controlled trials, cohort studies, case series and case reports), size, and language were included provided that they reported any outcome in adults or children undergoing organ transplantation who received omega-3 fatty acids.

Studies were excluded if they focused on nonhuman subjects, were review articles or other articles without primary sources of data, focused on subjects who did not undergo organ transplantation, did not use omega-3 fatty acids, or if the amount of omega-3 fatty acids could not be quantified. Acceptable sources of omega-3 fatty acids included fish oil, vegetable oils containing ALA (i.e., canola, rapeseed, soybean, flaxseed, linseed, walnut, mustard seed), Mediterranean diet, or other sources where the quantity was reported explicitly. Pharmaceutical companies and individuals in relevant countries were contacted when a brand name of a fish oil supplement was provided without a quantitative description of its components.

The authors, study locations, and dates of all retrieved studies were compared to identify duplicate reports of the same subjects. Where there was any ambiguity, an attempt was made to contact authors of the relevant publications. Duplicate reports were included if they provided additional data; however, subjects were included and accounted for only once.

Data Extraction Process

Electronic data extraction forms and a database were created in a multi-step process during which the key study questions were translated into a structure that was applicable to all types of transplants and outcomes of interest. Frequent and regular discussions helped to ensure use of uniform definitions. Thus, multiple versions of the data extraction forms were tested by several investigators on samples of the included studies, until a final version was achieved. All investigators were trained on how to complete the form to assure consistency among extractors.

All studies were extracted by 3 independent investigators to allow for future methodology research aimed at comparing double versus single data extraction. The extraction team included investigators skilled in foreign languages so that non-English studies could be included.

Study features extracted included the design, blinding, randomization method, allocation concealment method, country, funding source, duration, quantity and type of omega-3 fatty acids, eligibility criteria, control interventions, sample characteristics (and their comparability), reasons for withdrawals and all reported outcomes. (Appendix B, available electronically at http://www.ahrq.gov/clinic/epcindex.htm). In addition, each study was categorized based on study quality as described below.

Two investigators compared the results of the triplicate data extraction forms. Discrepancies were resolved by discussion and review of the original study until consensus was achieved for all data points.

Grading of the Evidence

Studies accepted in evidence reports have been designed, conducted, analyzed, and reported with varying degrees of methodological rigor and completeness. Deficiencies in any of these components can lead to biased reporting and interpretation of the results. While it is desirable to grade individual studies to highlight the degree of potential bias, the grading of study quality is not straightforward. Most factors commonly used in quality assessment of randomized controlled trials have not been sufficiently validated to be certain about their relationship to estimates of treatment effects. 55 Thus, there is still no uniform approach to grade studies. As a result, various EPCs have previously used different approaches to grade study quality.

Common Elements for Grading Methodological Quality of Randomized Controlled Trials in Evidence Reports

As part of the overall omega-3 fatty acid project, the 3 collaborating EPCs agreed to use the Jadad Score and adequacy of random allocation concealment as elements to grade individual randomized controlled trials. 56, 57 The EPCs also agreed to permit inclusion of other quality elements that were considered to be appropriate for a generic quality score.

There was consensus among the 3 EPCs that studies should not be graded using a single, quantitative summary score, since such scores are often arbitrary and unreliable. 58 The Jadad Score assesses the quality of randomized controlled trials using 3 criteria: adequacy of randomization, double blinding, and dropouts. 56 Studies fulfilling all three criteria receive a maximum score of 5 points. In addition, adequacy of allocation concealment was assessed using the criteria by Schulz et al, as “adequate,” “inadequate,” or “unclear”. 57

Generic Summary Quality Grade for Studies

A limitation of the Jadad and Schulz scores is that they address only some aspects of the methodological quality. These scores do not include other elements of study quality, such as potential biases due to reporting and analytic problems. Furthermore, these scoring systems are applicable only to randomized controlled trials.

Thus, to supplement these scores, a 3-category grading system (A, B, C) was applied to each study. This grading system has been used in most of the previous evidence reports from the Tufts-NEMC EPC as well as in evidence-based clinical practice guidelines. 59 This system defines a generic grading system that is applicable to varying study designs including randomized controlled trials, cohort, and case-control studies:

Category A studies have the least bias and results are considered valid. A study that adheres mostly to the commonly held concepts of high quality including the following: a formal randomized study; clear description of the population, setting, interventions and comparison groups; clear description of the content of the placebo used; appropriate measurement of outcomes; appropriate statistical and analytic methods and reporting; no reporting errors; less than 20% dropout; clear reporting of dropouts; and no obvious bias.
Category B studies are susceptible to some bias, but not sufficient to invalidate the results. They do not meet all the criteria in category A because they have some deficiencies, but none likely to cause major bias. The study may be missing information, making it difficult to assess limitations and potential problems.
Category C studies have significant bias that may invalidate the results. These studies have serious errors in design, analysis or reporting, have large amounts of missing information, or discrepancies in reporting.
In addition to applying these 3 grading systems, additional comments relating to potential sources of bias and other study limitations were recorded by each investigator during the data extraction process. Such comments are included in the evidence tables.

Applicability grades, used in other evidence reports related to omega-3 fatty acids, were not included. The grades were designed to address the relevance of a given study to a population of interest. Such a framework was not considered to be relevant in the current report since all studies focused on patients undergoing organ transplantation, which is already a narrowly defined population.

Reporting Results

Results that are included in this report were determined through discussions with members of the TEP as well as additional experts in transplantation. This process allowed us to focus on the major outcomes of interest (and methods for their measurement) that were relevant to the TEP key questions, were available in the identified literature, and relevant for specific area of transplantation. These endpoints are featured in the evidence tables, but all measured endpoints are also included.

Major outcomes for kidney transplantation included the post-transplant glomerular filtration rate (GFR), blood pressure, lipid profile, patient and graft survival, episodes of rejection, and dose and trough levels of CsA.
Major outcomes for heart transplantation included post-transplant hypertension, renal function, lipid levels, rejection episodes (including surrogate markers) and coronary disease (including surrogate markers).
All outcomes for other forms of transplant (i.e, bone marrow and liver) were included in the evidence tables since, as will be noted below, only 1 study in each category was identified.
As a general rule, when more than 1 time-point was reported for a specific outcome (e.g., glomerular filtration rate), the result representing the longest time point from study inception was included in the primary analysis. However, additional analyses were performed for questions that were of clinical interest or relevant to the TEP questions (e.g., examining the effects of fish oil supplementation on early versus late rejection).

Studies describing renal function after transplantation frequently described the results of more than 1 method to assess it. All methods are described in the evidence tables. However, the most rigorous method was highlighted and used for comparison across studies whenever available. In particular, direct measurement of the GFR with a radioisotope study or inulin clearance was considered to provide the best estimate of renal function compared with indirect methods (such as the calculated GFR) or serologic markers such as the plasma concentration of blood urea nitrogen or creatinine. 60

Important covariates and study characteristics were also featured. These included, for example, the doses and types of immunosuppressant medications, type of transplant (live donor versus cadaveric), specific time in which the omega-3 fatty acid was introduced relative to the transplant, duration of follow-up, concomitant use of antihypertensive medications and lipid lowering agents, all of which may have an influence on the major outcomes of interest.

Many of the outcomes of interest were continuous variables such as blood pressure, GFR, and lipid levels. For these outcomes, the summary tables describe 3 sets of data: the mean baseline level in the omega-3 fatty acid arm, the net change of the outcome, and the reported P values of the difference between the omega-3 fatty acid and the control arms. The net change of the outcome is the difference between the change in the omega-3 fatty acid arm and the change in the control arm:

Net change = (Omega-3 Final – Omega-3 Initial) – (Control Final – Control Initial).

While some studies reported adjusted and unadjusted within-arm and between-arm (net) differences, to maintain consistency across studies, we calculated the unadjusted net change using the above formula for all studies when the data were available. All exceptions and caveats are described in footnotes.

We included only the reported P values for the net differences. We did not calculate any P values, but, when necessary, used provided information on the 95% confidence interval or standard error of the net difference to determine whether it was less than .05. We included any reported P value less than .10. Those above .10 and those reported as “non-significant” were described as “NS” (non-significant) in the tables.

For measures expressed using standard or Systeme International (SI) units (e.g. lipid levels), the original units reported in the study were included in the evidence tables. However, all such measurements were converted to standard units in the summary and results tables to facilitate comparisons.

Uncontrolled trials were described (e.g. case reports), and, when within group comparisons were made, the within-group change was reported along with its associated P value.

Meta-analysis

For dichotomous or categorical variables, the rates in the treatment and control groups were expressed as a relative risk and 95% confidence intervals. Among these, there were sufficient, clinically comparable data to combine the results of graft or patient survival and rejection episodes in kidney transplantation. This was accomplished using a random effects model meta-analysis. 61

For rejection episodes, calculations were performed with the patient (not the rejection episode) as the unit of analysis (since individual patients could have had more than one rejection episode). Thus, the proportion of patients having a rejection episode at various time points (rather than the total number of rejection episodes) was compared across treatment groups.

Evidence and Summary Tables

The evidence is described in two complementary ways:

Evidence tables offer a detailed description of the studies that addressed each of the key questions. These tables provide information about the study design, patient characteristics, inclusion and exclusion criteria, interventions and comparison groups evaluated, and outcomes. Outcome data are reported in the units and metrics reported in the articles. Each study appears once regardless of how many interventions our outcomes were reported. Studies are ordered alphabetically by the first author.

Summary tables report succinctly using summary measures of the main outcomes. They include information regarding study size, intervention and control, study population, outcome measures, and methodological quality. These tables were developed by condensing information from the evidence tables. Outcome units and metrics are reported in standard units and as in common metrics, regardless of how these were reported in the articles. They are designed to facilitate comparisons and synthesis across studies. Studies reporting multiple outcomes may appear several times in summary tables.

Studies are grouped first according to the time of introduction of omega-3 fatty acids relative to the transplant and then by the dose of omega-3 fatty acids used. Controlled trials are featured separately from uncontrolled trials and case series.

Chapter 3. Results

This chapter summarizes results of our literature search and findings from the studies that passed our screening and selection process. We considered all types of transplants together in attempting to answer the key questions posed by the TEP whenever feasible. An example is the effect of omega-3 fatty acid supplementation on the pharmacokinetics of cyclosporine, an interaction that may be apparent regardless of the type of transplant. On the other hand, all key questions were also addressed with specific consideration of the different transplantation types (i.e., kidney, heart, bone marrow, and liver) since the potential effects may vary by transplant type and because there are clinical issues specific to each form of transplantation.

Summary of Studies Found

The literature search identified 1,281 abstracts. From these, and from the articles found in bibliographies, a total of 78 studies were ultimately selected for full-text screening (based upon the initial abstract screening and review of the bibliographies of retrieved studies including review articles). Thirty nine of these were rejected because they did not fulfill inclusion (See Reference List of Rejected Articles) criteria leaving 39 for inclusion. Careful additional review of these studies revealed 8 that were duplicate reports of the same patients leaving a total of 31 independent reports. There were 23 kidney transplant studies with a total of 846 patients, 6 heart transplant studies with 233 patients, 1 liver transplant study with 26 patients, and 1 bone marrow transplant study with 17 patients. The study designs of the qualifying studies include 21 RCTs, 2 non-RCTs, 6 prospective cohort studies and 2 case reports (Figure 3.1). Fish oil supplements were used in all but 1 heart transplant study in which a Mediterranean diet was used. 62 Since the biological effects of long-chain omega-3 fatty acids (EPA and DHA) are different from ALA, the results should be considered separately. As a result, the findings of this report apply almost exclusively to fish oil supplementation.

Twelve study authors of the largest controlled trials were contacted (by telephone or email or both) and, of them, 5 responded. None was aware of additional published or unpublished data. Similarly, the final list of included studies was considered to be complete after review by the TEP. One member of the TEP reported that he was involved in a pilot study involving omega-3 fatty acids in kidney transplantation that had not yet been completed; he provided a draft manuscript, which is described at the end of this chapter.

The studies are described in the evidence tables, which have been designed to feature key elements of the studies and allow for easy comparison across studies.

Quality of the Studies

Studies were generally small, and many had important methodological limitations as indicated by the quality measures in summary tables. Masking and methods of randomization were generally not well described. Even among studies in which masking of patients and caregivers was described, it is likely that patients and caregivers became unmasked since fish oil supplementation was frequently associated with a fishy taste and dyspeptic side-effects in the active intervention arm, especially early in the course of treatment. Many controlled trials did not use isocaloric treatments or fats with comparable fatty-acid profiles in the control group, potentially biasing comparisons, especially for cardiovascular outcomes. Furthermore, there was variability in the degree to which compliance was assessed.

Similarly, there was variability in the rigor with which endpoints were defined and measured. Important covariates (such as use of antihypertensive agents or the intensity of immunosuppression) were often not well described or uniformly applied even when the study considered outcomes that may have been confounded by these factors.

Summary results were potentially underpowered since very few controlled studies analyzed the statistical significance for net differences in effects. Most studies only analyzed differences between groups at various time points during the study.

Graft Related Outcomes

Question 1: What is the evidence that omega-3 fatty acid supplementation reduced rejection episodes or graft failure in patients (adults or children) who received an organ transplant?

Kidney Transplantation

Patient survival

There were 7 deaths out of a total of 846 kidney transplant patients, all of which were reported in 3 studies. 63–65 A total of 4 patients died with a functional graft within 1 year of transplant (1 patient in the fish oil group and 3 patients in the placebo group). 63 One patient died of myocardial infarction in the placebo group. 64 In a 9-month randomized controlled trial (RCT), 2 patients in the fish oil group died due to hemorrhagic shock from removal of native polycystic kidney and intestinal infarction. 65

Graft survival

A total of 10 RCTs, with 291 patients in the fish oil group and 312 patients in the placebo or control group, described graft survival among kidney transplant recipients. 28, 63–70 However, most studies did not perform quantitative, graft survival analyses underscoring the excellent overall results in kidney transplantation regardless of fish oil supplementation. One exception was a RCT in which one-year graft survival tended to be better in the fish oil group, although results did not achieve statistical significance. 64 Two other RCTs showed no statistically significant difference in one-year graft and patient survival rates between fish oil and placebo or control group. 28, 67

Fish oil supplementation was begun 3 days post-transplant in 7 of these 10 reports with a total of 228 and 234 subjects in the fish oil and control groups, respectively (Table 3.1). The studies were all of low or intermediate quality. The pooled relative risk of graft survival in those receiving fish oil supplementation was 1.00 (95% CI 0.96, 1.05). There was no statistical heterogeneity among studies.

In 2 studies, 66, 68 fish oil was begun at 16 weeks and over one year post-transplant. Thus, the enrolled patients would be expected to have relatively stable renal function compared to the studies in which treatment was begun within days after transplant. No benefit from fish oil treatment was observed in either study (Table 3.2).

Furthermore, all grafts and patients survived in 2 prospective cohort studies with a total of 42 kidney transplant recipients who received fish oil treatments at least 6 months post-transplant. 71, 72

Rejection Episodes

Acute rejection episodes were described at varying time points in a total of 11 controlled trials, including 297 patients in the fish oil group and 282 patients in the placebo or control group. 28, 63–67, 69, 70, 73–76 The studies were all of low or intermediate quality. In all but 2 studies (published in 3 papers 66, 75, 76 ), treatment had been initiated within 3 days following transplantation.

One study reported only total episodes of rejection according to treatment (rather than the proportion of patients having a rejection episode), noting a statistically significant reduction in the total number of rejection episodes in the group receiving fish oil. 64 However, it was not possible to tell whether these differences could have been accounted for by multiple episodes of rejection in a small number of patients (or even a single patient). The authors described six episodes of rejection in the fish oil group compared with 10 in the control group at one month. In the second and third months, there was only 1 acute rejection episode in the fish oil group compared with 9 in the control group (P=0.016). In months 4 through 6, there were no rejection episodes in either group. Between month 6 and 12, there was 1 rejection episode in each group. Thus, during the year after transplantation, the total number of acute rejection episodes was significantly lower in the fish oil group than in the controls (8 versus 20, P=0.029). These results did not translate into statistically significant improved graft survival at one year (97 versus 84 percent, P=0.097).

The other 8 randomized controlled trials (in which treatment was started within 3 days post-transplant) described the proportion of patients with at least one rejection episode. The results for “early” and “late” rejection (as defined above) were combined using a random effects model, which showed no significant benefit at any time point examined (Table 3.3). Results for 2 studies that reported rejection episodes between 2 to 9 and 3 to 12 months were not pooled since the time points reported combined “early” and “late” episodes together. 63, 65 The pooled relative risk of a rejection episode in those receiving fish oil supplementation was 0.91 (95% CI 0.75, 1.11) in four studies with a total of 224 subjects that reported the longest follow-up (i.e., 1 year). There was no significant heterogeneity among the studies. To allow for clinically meaningful comparisons across studies, rejection episodes were defined as being “early” (within the first 6 months of transplant) or “late” (after 6 months), corresponding with generally accepted clinical criteria.

In 2 studies published in 3 papers 66, 75, 76 fish oil supplementation was begun at 16 weeks and an average of 25 months post-transplant. No significant differences in acute rejection episodes were found in either study (Table 3.4).

Overall, either immediate or delayed supplementation with fish oil showed no benefit on graft survival among patients who had kidney transplants. No reduction in either early or late acute rejections was found with fish oil supplementation.

Heart Transplantation

Although 6 studies described a variety of outcomes in a total of 233 heart transplant recipients (see Evidence Table II). 62, 77–81 , the studies were small, had various designs, and there was little detailed information on rejection episodes or graft survival from which to derive inferences regarding the effect of omega-3 fatty acid supplementation.

In 1 report, 2 patients (one in the treatment group and the other a control) died of “vascular rejection” at 7 and 8 weeks and were excluded from the analysis. 77 Graft survival was similar in both treatment groups (14 of 15 in those receiving fish oil supplementation and 14 of 15 in those receiving corn oil).
One episode of acute rejection was described in the control group in another study. 78 A 60-year-old patient with angiographic evidence of accelerated coronary disease died of congestive heart failure secondary to myocardial infarction in the fish oil group.
Similar graft survival was described for patients receiving fish oil supplementation (21 of 23) or corn oil (20 of 22) in another RCT. 80
All grafts survived in 41 transplant recipients in an open-label prospective cohort study of a Mediterranean diet, which is rich in ALA. 62
Two patients in the placebo group dropped out of a RCT due to acute rejection. 81
Other Transplants

A study of liver transplantation focused on the renal effects of fish oil supplementation in those with stable liver graft function (at least 6 months after transplant). 82 The study duration was only two months. No effects on rejection or graft survival were described.

A study in bone marrow transplant recipients focused on predictors of acute colonic graft versus host disease but did not present outcomes related to the success of the transplant. 43 A separate report of the same patients 83 found a significantly higher patient survival rate in the group that received fish oil supplementation and improvement in biochemical markers of the systemic inflammatory response. 83

Question 2: What is the evidence that omega-3 fatty acid supplementation is renoprotective (improves glomerular filtration rate or increases kidney size) or is protective against primary kidney disease recurrence following kidney transplantation?

Kidney transplantation

No study reported kidney size as a measure of renal function following transplantation or described primary disease recurrence following kidney transplantation. Two case reports suggested that fish oil supplementation improved proteinuria in patients who developed recurrent IgA nephropathy. 84, 85 The observation is potentially important since some studies have found a benefit from fish oil supplementation in IgA nepropathy in the non-transplant setting. 86, 87

Eleven randomized-controlled trials in 14 publications and 1 prospective cohort study reported the effects of fish oil supplementation on GFR (Table 3.5 & 3.6). No consistent benefit was observed in patients treated shortly after transplantation or those with stable renal function in whom treatment was started several months after transplantation, although there were exceptions. The magnitude of benefit suggested in trials with positive findings was modest, and, as noted above, did not translate into improved graft survival with up to 1-year of follow-up. 64, 67, 69, 88

Comparison of studies with positive and negative findings did not reveal any patient or study-related factors that could account for the heterogeneity. Two of the largest studies that reached disparate conclusions had almost identical designs. 63, 64 In both, there was improvement in the GFR during the 12-month observation period in treated and control patients. In the study with positive findings, 64 GFR in the fish oil group increased from 42 to 45, to 49, and to 53 ml/min/1.73m2 from at 1, 3, 6, and 12 months, respectively. Corresponding values in the control group were 32, 38, 41, and 40. The differences were statistically significant at the 3, 6, and 12 month time-points.

By contrast, in the study with the negative results, 63 GFR increased from 46.1 ml/min/1.73m2 at 1 month to 54.4 at 12 months in the fish oil group and from 43.2 to 52.5 in the control group at the same time points. Thus, in both studies there were similar degrees of improvement in both treated and control patients relative to baseline. The main difference between studies was the lower values of GFR at all time points in the control group in the study with the positive findings. 64 This may have been due to fewer episodes of rejection in the fish oil group. However, given the small size of the study, it is also possible that unmeasured factors contributed to relatively poor graft function in the control arm. On the other hand, lower baseline values of GFR or higher rates of rejection for the control group did not appear to account for the positive finding that was observed in a different trial. 69

Heart Transplantation

Renal function was also examined in studies of heart transplant recipients. Although the effect of fish oil supplementation on renal function in transplants other than kidney was not specifically requested in the key question above, it is useful to compare renal outcomes with fish oil supplementation in other forms of transplant.

Three controlled trials in 4 reports in heart transplantation, with a total of 79 patients in the fish oil group and 77 patients in the control group, described the effect of fish oil supplementation on renal function. 77, 78, 80, 89 Two of these reported both serum creatinine levels and GFR or creatinine clearance (Table 3.5).

In 1 report, measured creatinine clearance 6 months after transplant improved in both treated and control patients with an insignificantly higher value in the group randomized to fish oil supplementation. 77

No significant difference was observed in the calculated GFR in a second trial. 89 However, serum creatinine increased significantly in the control group but did not increase in the group receiving fish oil supplementation. The calculated GFR decreased in the placebo group while remaining unchanged in the fish oil group.

In a third trial, serum creatinine levels remained stable in a group receiving fish oil supplementation while they increased in a group receiving bezafibrate. 78 While the differences were statistically significant, serum creatinine alone is considered to be a poor measure of renal function.

Other Transplants

Renal function was evaluated in 1 controlled trial 90 in liver transplantation (Table 3.5). GFR increased by 33 percent in patients randomized to receive fish oil supplementation compared with no change in the corn oil group. The mean percent change was statistically significant (P=0.05).

Cardiovascular Disease-Related Outcomes

Question 3: What is the evidence that omega-3 fatty acid supplementation lowers cardiovascular disease risk factors or events in organ transplant recipients (adults or children)?

Several factors are well known to be associated with the risk of cardiovascular disease. These include serum lipoproteins, blood pressure, diabetes mellitus, and related metabolic disorders. Multiple studies have demonstrated that improvement or suppression of these factors can reduce the risk. The effects of omega-3 fatty acid supplementation on these risk factors have been reviewed in detail in the non-transplant setting. 40 A large, consistent benefit was found only for triglyceride levels. Little or no effect was found for a variety of other cardiovascular risk factors and markers of cardiovascular disease.

Kidney Transplantation

Cardiovascular risk factors evaluated in studies of kidney transplantation focused on the effects of fish oils on lipid profiles and on blood pressure.

Total Cholesterol

Changes in total cholesterol were described in 8 randomized controlled trials (a total of 186 and 147 patients in the fish oil and control groups, respectively) and 2 uncontrolled studies (a total of 44 patients in the fish oil group) (Table 3.7, 3.8; 3.9). The studies were all of low or intermediate quality. A lesser degree of increase in total cholesterol in the fish oil group compared with control was described in 1 controlled trial. 28 Total cholesterol increased from 187 to 234 mg/dL by month 3 in the fish oil group compared with 176 to 251 mg/dL in controls. Fish oil supplementation was less effective than simvastatin or lovastatin in 2 controlled trials. 68, 91

High-Density Lipoprotein (HDL)

Six controlled trials (with a total of 124 and 138 patients in the fish oil and control groups, respectively) and 1 uncontrolled trial included levels of HDL cholesterol as an endpoint. No significant benefit from fish oil supplementation was observed (Table 3.10, 3.11; 3.12)

Low-Density Lipoprotein (LDL)

Four controlled trials (with a total of 91 and 106 patients in the fish oil and control groups, respectively) and 1 uncontrolled study included levels of LDL cholesterol as an endpoint (Table 3.13, 3.14; 3.15). No significant benefit was observed in the controlled trials. Lovastatin was significantly more effective than fish oil in 1 study. 91

Triglycerides

Nine controlled trials (with a total of 200 and 199 patients in the fish oil and control groups, respectively) and 3 uncontrolled studies (with a total of 52 patients in the fish oil group) included triglycerides as an outcome (Table 3.16, 3.17; 3.18). While there were exceptions, in aggregate, the data support a benefit of fish oil in lowering serum triglyceride concentrations, which is consistent with observations made in the non-transplant setting. 40 One study comparing fish oil supplementation to lovastatin found the former to be more effective in reducing triglycerides. 91

Mean Arterial Blood Pressure

Nine controlled trials (with a total of 228 and 241 patients in the fish oil and control groups, respectively) and 2 uncontrolled studies (with a total of 28 patients in the fish oil group) evaluated changes in blood pressure following kidney transplantation (Table 3.19 & 3.20). There were potentially clinically important differences among reports in use of specific antihypertensive agents and criteria for introducing them, limiting direct comparisons. Nevertheless, no consistent benefit of fish oil supplementation on mean arterial blood pressure was observed.

Heart Transplantation

Several studies in heart transplant recipients evaluated cardiovascular risk factors post transplant (Table 3.7–3.20). The following summarizes the main findings in each study.

A statistically significant reduction in systolic and diastolic blood pressure and serum triglycerides levels was reported in 1 RCT. 77 A statistically significant correlation was found between the changes in systolic blood pressure and the dose of EPA and DHA. However, use of enalapril was also permitted in both groups. Data were insufficiently reported to determine whether the total dose of enalapril and proportion of patients receiving enalapril were similar across groups, raising the possibility of confounding.
Bezafibrate was significantly more effective than fish oil supplementation in lowering total cholesterol, HDL and LDL levels in a non-RCT. 78 No significant differences were observed in triglyceride levels.
No significant differences were observed in mean arterial pressure or heart rate in a controlled trial. 79 Patients receiving fish oil supplements showed a normal vasodilator response to acetylcholine infusion compared with control patients, who demonstrated a vasoconstrictor response. The authors concluded that fish oil supplementation significantly altered endothelium-dependent coronary vasodilation in heart transplant recipients, a group known to have endothelial dysfunction. Whether this change altered the natural history of atherosclerosis following transplant could not be determined.
No change in systolic or diastolic blood pressure compared with a significant increase in these parameters in the corn oil group was observed in a RCT. 89 A significant reduction in triglyceride levels was observed while no significant differences were found for total cholesterol, HDL, or LDL. The percentage of subjects who were considered to be normotensive at 12 months was significantly higher in the fish oil group (9 of 21 compared with 0 of 20). A significant correlation was observed between changed in systolic blood pressure and serum concentrations of EPA and DHA.
Patients received several additional antihypertensive drugs during the course of the study raising the possibility of confounding. However, the authors stated that all medications remained unchanged during the three months prior to the investigation and during the study.

A prospective cohort study of the French Mediterranean diet found a significant reduction in total cholesterol and LDL levels compared with pretreatment values. 62 However since total calories and percentage of saturated fats in the French Mediterranean diet were significantly decreased at the same time, the observed effects could not be solely attributed to ALA. No significant changes were observed in serum triglycerides or HDL, or weight. A significant reduction in platelet aggregation was also described.
In a RCT, a significant reduction in mean arterial pressure and systemic vascular resistance was described in a group receiving fish oil supplementation when results were compared with baseline. 81 Whether these changes were significant compared with the placebo group was not described, although no changes in those receiving corn oil were reported. The authors also reported a reduction in left ventricular mass compared with baseline values in the fish oil group.
Other Transplants

Lipid profiles were not reported in the studies of bone marrow and liver transplantation. 83, 90 . In the RCT of liver transplant, fish oil supplementation had no significant effect on mean arterial pressure compared to the placebo (Table 3.19).

Infectious Outcomes

Question 4. What is the evidence that omega-3 fatty acid supplementation reduces serious infectious complications following organ transplantation?

Infections are an important cause of morbidity and mortality following all forms of organ transplantation. Animal and limited human data suggest that supplementation with omega-3 fatty acids may modulate the host’s ability to respond to infections. 13, 92 However, no study included in this evidence report described infectious outcomes. Thus, its benefit in the transplant setting could not be determined.

All Outcomes

Question 5. What is the evidence that any benefits to organ transplant recipients from omega-3 fatty acid supplementation differ in different subsets of patients?

Kidney Transplantation

Two controlled trials in kidney transplantation (with a total of 53 patients in the fish oil group and 64 patients in the coconut oil group), both from the same center, described outcomes in patients with and without an episode of rejection. 73, 74 In 1 of these reports, patients randomized to the fish oil group demonstrated a significantly better recovery of renal function following an episode of histologically-confirmed rejection. 73 The authors concluded that fish oil supplementation favorably influenced renal function in the recovery phase following a rejection episode.

In an earlier report the authors analyzed a subset of patients without an episode of rejection during the course of study. 74 Patients receiving fish oil had a significantly higher filtration fraction, a significantly lower effective renal plasma flow (164 versus 262 mL/min per 1.73 m2) and a significantly better response of the GFR following amino acid infusion (15.3 versus 10.6 percent).

Other Transplants

Effects of omega-3 fatty acid supplementation on subsets of patients were not reported for heart, liver, or bone marrow transplantation.

Question 6. What is the evidence that effects of omega-3 fatty acid supplementation on outcomes of interest vary depending on the time of administration relative to transplantation procedures (pre- or post-transplant)?

Kidney Transplantation

All studies evaluated patients who received fish oil supplementation after transplant. While there was no individual study in which patients were randomly assigned to receive supplementation at different time points relative to the transplant, variability was observed across studies allowing for indirect comparisons.

Figure 3.5 depicts the net difference in GFR and 95% confidence intervals across studies in kidney transplant recipients who received supplementation at various intervals following the transplant. Higher values suggest better renal function in those who received fish oil supplementation. Confidence intervals could not be calculated for four studies in which the standard deviation was not reported. 64, 73, 74, 88 Nevertheless, the data do not support a clear relationship between the time in which the supplement was begun and the treatment effect.

The plotted data points represent the longest follow-up values considered in each report. Thus, it is possible that there may be differences in benefit related to the timing of supplementation at earlier time intervals following transplantation. However, even if such a relationship existed, the clinical significance is unclear since the benefit did not appear to be durable or (as noted above) translate into improved graft survival.

Other Transplants

Omega-3 fatty acid supplementation was started after transplant in all heart transplant recipients ranging from as early as four days post transplant 77 to as late as six years after transplant. 89 In two studies, the specific time was not described. 62, 78 No study described a relationship between time of transplant and treatment effects. Similarly, no relevant data were described in the studies of liver and bone marrow transplantation.

Effects on Immunosuppressive Agents and Related Drugs

Question 7. What is the evidence in patients (adults or children) who receive an organ transplant that the benefits of omega-3 fatty acid supplementation interact with the concomitant administration of various immunosuppressive agents/drugs?

No study in any of the types of transplantation provided a detailed evaluation of the interaction between omega-3 fatty acid supplementation and the various immunosuppressive drugs, except for dosing of cyclosporine (discussed below).

One series of reports on kidney transplantation of the same patients in three separate publications 93–95 compared outcomes in patients treated with CsA versus those treated with azathioprine. The following observations were made:

Administration of fish oil was associated with significant improvement in fibrinolysis in patients receiving CsA but not azathioprine. 93
Erythrocyte deformability improved with fish oil in patients treated with CsA but not azathioprine. 94
No change in blood viscosity was apparent in CsA or azathioprine treated patients receiving fish oil despite the improvement in erythrocyte deformability noted in the CsA group. 95
Question 8. What is the evidence in patients (adults or children) who receive an organ transplant that serum levels of immunosuppressive agents/drugs are altered by omega-3 fatty acid supplementation?

Included studies used differing immunosuppressive protocols which varied in the choice of agent, target (and achieved) blood levels of CsA for induction and maintenance therapy, and use of concomitant immunosuppressive agents such as corticosteroids and anti-thymocyte globulin (see Evidence Table Ib, Evidence Table II ; III). Furthermore, no study evaluated levels and dosages of all the immunosuppressant drugs that were used concurrently.

The effect of fish oil supplementation on immunosuppression was most fully described for CsA. Several studies in kidney and heart transplantation reported trough and total doses of CsA in patients who received or did not receive omega-3 fatty acids (Table 3.21). Fish oil did not appear to have an effect on either of these measures. Considered together, these data provide evidence against a clinically significant interaction between CsA and fish oil.

However, the trough and total doses of CsA do not provide a complete picture of its pharmacokinetics. Another measure of the intensity to exposure to CsA is the area time-concentration curve, generally referred to as the “area under the curve” (AUC). The AUC is generally considered to be the most useful indicator to exposure to CsA, since it reflects the intra-and inter-patient variability among concentrations after dosing. 96

The AUC (as well as maximal concentration, minimal concentration) at 8 five-hour time points was evaluated in a RCT in kidney transplantation. 65 Study patients received quadruple immunosuppressive therapy, which included CsA, antilymphocyte globulin, azathioprine, and 6-methylprednisolone. After one year, patients who received fish oil had a significantly lower plasma creatinine concentration (1.26 versus 1.88 mg/dL) and higher peak CsA levels. CsA dosages were comparable. The AUC was higher in patients who received fish oil and they had less variance in the time to peak levels, although differences in these measures did not achieve statistical significance. The authors concluded that this pattern provided evidence for better CsA absorption and metabolism in kidney transplant patients receiving fish oil.

Question 9. What is the evidence in patients (adults or children) who receive an organ transplant that omega-3 fatty acid supplementation can replace or reduce the need for other more potent anti-inflammatory or immunosuppressive drugs (such as steroids and nonsteroidal anti-inflammatory agents)?

No study reported that fish oil supplementation reduced or replaced the need for other more potent anti-inflammatory drugs. Potential effects on CsA absorption are described above.

Unpublished Data

The frequency with which clinical trials of omega-3 fatty acid supplementation in transplantation have appeared in the literature has decreased in recent years. The last relevant publication described in this evidence report was in 2002.

No additional publications were encountered while preparing this report, and no members of the TEP were aware of unpublished data that had been presented in preliminary form. Only 1 unpublished manuscript was uncovered after contact with the TEP. 97 The manuscript has been submitted for publication but a preliminary version was provided by Dr. Wesley Alexander.

The report included 64 patients who were enrolled in 3 sequential pilot open-label studies designed to evaluate the effects of CsA dose and length of administration in a steroid-free protocol in kidney transplant recipients (cadaveric and live donor). All patients had been treated with thymoglobulin induction, sirolimus (rapamycin), mycophenolate mofetil (MMF), CsA, and immunonutrients (arginine and canola oil). The amount of ALA consumed was approximately 1.93 grams per day.

Corticosteroids were avoided in most patients while MMF was discontinued in 70 percent of patients by two years. Despite the reduction in these immunosuppressive drugs, only 15 rejection episodes were observed in the first two years, and none past 24 months. Combining all patients, 84 percent were rejection-free at one year while 70 percent of patients during the past three years were receiving monotherapy with sirolimus (rapamycin) and the dietary supplements. There were no late cardiac events or patients who developed diabetes mellitus.

These preliminary data suggest that the immunosuppressive protocols used combined with the immunonutrients may have long-term benefits in patients undergoing kidney transplant. However, the degree to which omega-3 fatty acid supplementation as canola oil contributed to these benefits is unclear.

Chapter 4. Discussion

This chapter summarizes the findings in this report and provides recommendations for future research.

Overview

Studies included in this report were based on a systematic review of 1,281 abstracts and 78 full-text articles. Additional data were sought by reviewing the bibliographies of retrieved citations (including review articles), through discussions with the TEP and other experts in the respective areas of transplantation, and contact with authors of major controlled trials. Inclusion criteria were defined broadly to be as comprehensive as possible. Primary sources of data published in any language reflecting any study design and reporting any outcomes were included provided that they focused on human subjects who underwent transplantation and who received a quantifiable amount of omega-3 fatty acids.

A total of 31 independent studies were included. Duplicate reports were also included if they provided additional data but subjects were counted only once.

The majority of studies (23) focused on kidney transplantation while six were in heart transplantation and one each was in liver and bone marrow transplantation. All but 1 study (in heart transplantation) used fish oil supplements. Publication dates spanned from 1989 to 2002. Members of the TEP, authors of the included studies, and experts in transplantation were unaware of any ongoing studies, with the exception of a report that summarized three pilot open-label studies; a draft was provided by a member of the TEP.

The relatively advanced age of the included studies (most having been conducted in the 1990s) weighs against their relevance since there continue to be major advances in all the respective areas of transplantation. In particular, most of the included trials did not use newer immunosuppressant agents (such as tacrolimus, mycophenolate mofetil and rapamycin (sirolimus)) that are commonly used in contemporary transplantation procedures. The anticipated benefits of fish oil supplementation on two of the major outcomes considered in this report (renal function and hypertension) had, at least in part, been based on the use of CsA as a primary means of immunosuppression. Benefits of fish oil supplementation in the setting of other potentially nephrotoxic immunosuppressant agents have not been as well characterized in either laboratory or human studies.

Furthermore, there was variable use of concomitant therapies that can also be effective for treatment of complications following transplantation (such as statins for treatment of hyperlipidemia and calcium channel blockers for treatment of hypertension in kidney transplant recipients). Thus, whether fish oil supplementation leads to an additive benefit or can replace the use of these medications could not be determined. However, it is likely that some of these drugs would be more effective than fish oil supplementation for some of these endpoints. Two controlled trials (both in kidney transplantation) compared the efficacy of statins with fish oil supplementation. 68, 91 Both found statins to be more effective for reducing total and LDL cholesterol while one 91 found fish oil supplementation to be slightly more effective for reducing triglycerides.

A major consideration for all evaluated studies was their small size, and methodological deficiencies. Masking and methods of randomization were generally not well reported, and there was variability in the rigor with which endpoints were defined and measured. Important covariates (such as use of antihypertensive agents or the intensity of immunosuppression) were often not sufficiently described or uniformly applied even when the study considered outcomes that may have been confounded by these factors.

Main Findings

Evidence was inconclusive regarding the benefits of omega-3 fatty acid supplementation (mostly fish oil) on any outcome evaluated in any form of transplantation. A possible exception was a reduction in triglyceride levels in patients who underwent kidney transplantation, an observation that is consistent with the effects of omega-3 fatty acid supplementation in the non-transplant setting. 40 There were no other consistent benefits on other major cardiovascular risk factors such as blood pressure or the development of diabetes mellitus.

A reduction in acute colonic graft versus host disease and a survival benefit was suggested in a small RCT in bone marrow transplantation. 83, 98 However, there have been no additional studies to confirm these observations raising concern as to whether the authors or other groups may not have been able to reproduce these results.

The benefit on renal function, suggested in several of the individual studies in kidney, heart, and liver transplantation, was inconsistent, and not clearly related to features of the specific study design or patient characteristics. At best, the improvement in GFR was modest, and did not translate into better graft survival or any other clinically important outcome with up to one-year of follow-up. Nevertheless, it is possible that a modest degree of benefit might translate into improved kidney outcomes with longer duration of follow-up. However, the available data do not provide guidance as to which, if any, patients, might benefit from such treatment.

No benefit on early or late rejection episodes or graft survival was detected in meta-analyses in kidney transplantation. However, 1 study suggested that the total number of rejection episodes was reduced 64 while in 2 others (also from the same group), recovery from rejection episodes appeared to be faster in those receiving fish oil supplementation. 73, 74

The available data suggest that fish oil supplementation does not cause a clinically important interaction with CsA. No significant changes in total doses of CsA or trough levels were observed in studies of kidney and heart transplant recipients. However, the most detailed single study evaluated CsA pharmacokinetics in the presence of fish oil concluded that the AUC was higher in patients who received fish oil and they had less variance in the time to peak levels. These differences did not achieve statistical significance. The authors concluded that this pattern provided evidence for better CsA absorption and metabolism in kidney transplant patients receiving fish oil. The clinical significance of these observations is unclear. Whether fish oil supplementation caused an interaction with any other immunosuppressive drug such as azathioprine could not be determined since no study attempted to describe such associations.

Limitations

The main limitation relates to the quantity and quality of the available evidence and its applicability to contemporary transplantation procedures. By far the largest experience has been in kidney transplantation. Varied inclusion criteria, study designs, outcome measures, assessment of compliance, and insufficient reporting limited detailed comparisons among studies with positive and negative findings, which may have permitted a better understanding of the heterogeneous results, especially for renal function.

All but 1 study (and 1 unpublished report) used fish oil as the source of omega-3 fatty acids. Thus, this report cannot address the effects of supplementation with ALA. Furthermore, there were insufficient data to determine the relationship between the background diet and the optimal ratio of omega-3 and omega-6 fatty acids on the outcomes of interest. All studies began omega-3 fatty acid supplementation after transplantation. Because it may take up to 3 weeks for supplementation to have an effect on the production of various cytokines, it is possible that supplementation prior to transplant could have an influence on the outcomes.

Some controlled trials in humans found a benefit of fish oil supplementation on renal function. This suggests that fish oil supplementation could possibly benefit a subset of patients. However, no clear patient or transplant-related characteristics emerged from careful comparisons of the studies to identify such patients. Furthermore, whether the magnitude of the observed changes would translate into clinically important outcomes (such as improved graft survival) is uncertain, especially since the study durations were generally 1year or less.

The applicability of the results to contemporary transplantation procedures is also unclear since most of the studies were performed several years ago, with some more than a decade old. The technology for all transplantation procedures continues to improve with a larger choice of immunosuppressive agents, a better understanding of how to use them, and the means to address the known complications of transplantation including some of the important outcomes (such as hyperlipidemia and hypertension) where the benefits of fish oil supplementation had been anticipated. Thus, whether fish oil supplementation could have a benefit in the setting of contemporary transplantation procedures is uncertain. A draft report of a study in kidney transplantation using contemporary protocols suggested a possible benefit in achieving complete steroid withdrawal but the precise contribution of the fish oil supplements in achieving this objective could not be determined.

Future Research

Future research with omega-3 fatty acid supplementation in transplantation might focus on the following objectives:

A more detailed understanding of factors associated with improvement in renal function with fish oil or ALA supplementation in all forms of transplantation.
Long-term follow-up studies on patients enrolled in the studies included in this report to determine whether any of the observed benefits were durable or translated into other improved outcomes.
Determination of whether fish oil supplementation could benefit treatment or prevention of IgA nephropathy following transplantation.
Additional studies in bone marrow transplantation where a benefit on acute colonic graft versus host disease and a survival benefit have been suggested.
Long-term follow-up studies in patients undergoing heart transplantation to determine whether there is a benefit on post-transplant coronary disease.
Long-term follow-up studies in patients undergoing kidney transplantation to determine whether there is a benefit on post-transplant cardiovascular events. (Tufts-New England Medical Center EPC, 2005)

Reference:

THE NATURAL STANDARD RESEARCH COLLABORATION. (2007). Omega-3 fatty acids, fish oil, alpha-linolenic acid [Electronic Version] from http://www.mayoclinic.com/health/fish-oil/NS_patient-fishoil.

Tufts-New England Medical Center EPC, B., Massachusetts,. (2005). Effects of Omega-3 Fatty Acids on Organ Transplantation [Electronic Version] from http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1a.chapter.86457.

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