Chapter  115:  Effects of Omega-3 Fatty Acids on Organ Transplantation

Technical Expert Panel

• William S. Harris, PhD

• Daniel Lauer/Missouri Professor of Metabolism and Vascular Research

• University of Missouri, School of Medicine, Kansas City

• Co-Director, Lipid and Diabetes Research Center

• Mid America Heart Institute at Saint Luke's Hospital

• Kansas City, Missouri

• Ronald Perrone, MD

• Professor of Medicine

• Tufts University School of Medicine

• Associate Chief, Division of Nephrology

• Tufts-New England Medical Center

• Boston, Massachusetts

• John A. Jarcho, MD

• Clinical Assistant Professor of Medicine

• Harvard Medical School

• Associate Physician Division of Cardiology

• Brigham and Women's Hospital

• Boston, Massachusetts

• J. Wesley Alexander, M.D.

• Technical Expert, for the American Society of Transplant Surgeons and the American Society for Transplantation

• Professor of Surgery

• Department of Surgery

• University of Cincinnati Medical Center

• Cincinnati, Ohio

• Alice H. Lichtenstein, DSc

• Stanley N. Gershoff Professor of Nutrition Science and Policy

• Gerald J. & Dorothy R. Friedman School of Nutrition Science & Policy

• Director and Senior Scientist, Cardiovascular Nutrition Laboratory

• Jean Mayer USDA Human Nutrition Research Center on Aging

• Tufts University

• Boston, Massachusetts

• Patricia J. Kehn, MS

• Technical Expert and Representative, National Institute of Allergy and Infectious Disease

• Div. of Allergy, Immunology & Transplantation

• National Institute of Allergy and Infectious Disease

• Bethesda, Maryland

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.

Figure 1.1

Classical omega-3 and omega-6 fatty acid synthesis (more...)

Figure 1.1

.

   Classical omega-3 and omega-6 fatty acid synthesis pathways and the role of omega-3 fatty acid in regulating health/disease markers

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 1β (IL1β), and tumor necrosis factor α (TNFα) - 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

Estimates of the mean±standard error of the (more...)

Table 1.1

Estimates of the mean±standard error of the mean (SEM) intake of linoleic acid (LA), alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) in the United States population, based on analyses of a single 24-hour dietary recall of NHANES III data

	Grams/day		% Kcal/day
	Mean±SEM	Median (range) a	Mean±SEM	Median (range)a
LA (18:2 n-6)	14.1±0.2	9.9 (0 – 168)	5.79±0.05	5.30 (0 – 39.4)
ALA (18:3 n-3)	1.33±0.02	0.90 (0 – 17)	0.55±0.004	0.48 (0 – 4.98)
EPA (20:5 n-3)	0.04±0.003	0.00 (0 – 4.1)	0.02±0.001	0.00 (0 – 0.61)
DHA (22:6 n-3)	0.07±0.004	0.00 (0 – 7.8)	0.03±0.002	0.00 (0 –2.86)

a

The distributions are not adjusted for the over-sampling of Mexican Americans, non-Hispanic African-Americans, children ≤5 years old, and adults ≥ 60 years old in the NHANES III dataset.

Table 1.2

Mean, range, median, and standard error of the mean (more...)

Table 1.2

Mean, range, median, and standard error of the mean (SEM) of usual daily intakes of linoleic acid (LA), total omega-3 fatty acids (n-3 FA), alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) in the US population, based on CSFII data (1994-1996, 1998)

	Grams/day
	Mean±SEM	Median±SEM
LA (18:2 n-6)	13.0±0.1	12.0±0.1
Total n-3 FA	1.40±0.01	1.30±0.01
ALA (18:3 n-3)	1.30±0.01	1.21±0.01
EPA (20:5 n-3)	0.028	0.004
DPA (22:5 n-3)	0.013	0.005
DHA (22:6 n-3)	0.057±0.018	0.046±0.013

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.

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.

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.

Analytic Framework

Figure 2.1

Analytic framework for omega-3 fatty acid intervention (more...)

Figure 2.1

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   Analytic framework for omega-3 fatty acid intervention and transplantation outcomes

Figure 2.1

1. What type of organ transplantation did the participants receive?

2. What were the interventions?

3. What were the outcomes of interest (intermediate and clinical outcomes)?

4. 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

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.

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.

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.

Summary of Studies Found

Figure 3.1

Summary of study selection processes. RCTs indicates (more...)

Figure 3.1

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   Summary of study selection processes. RCTs indicates randomized-controlled trials; non-RCT Indicates non-randomized-controlled trials

Figure 3.2

Random Effects Model Meta-Analysis of Graft Survival (more...)

Figure 3.2

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   Random Effects Model Meta-Analysis of Graft Survival in Randomized-Controlled Trials in Kidney Transplant Patients

Figure 3.3

Random Effects Model Meta-Analysis of Proportion of (more...)

Figure 3.3

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   Random Effects Model Meta-Analysis of Proportion of Patients with an Acute Rejection Episode within First Month of Kidney Transplantation in Randomized-Controlled Trials

Figure 3.4

Random Effects Model Meta-Analysis of the Proportion (more...)

Figure 3.4

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   Random Effects Model Meta-Analysis of the Proportion of Patients with an Acute Rejection Episode Within One Year of Kidney Transplantation in Randomized-Controlled Trials

Figure 3.1

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}

Table 3.1

Effects of Fish oil on Graft Survival in Randomized-Controlled (more...)

Table 3.1

Effects of Fish oil on Graft Survival in Randomized-Controlled Trials in Kidney Transplant Patients

Author, Year	Fish oil EPA+DHA (g/d)	Placebo or Control Arm	Treatment Duration	Fish oil		Control		RR	Treatment Started (Post-transplant)	Qualityb
				Event	Total	Event	Total	(95% CI)		Summary	Jadad	Allocation Conceal
Homan van der Heide, 1992	3.0	Coconut oil	1 mo	39	40	47	48	1	Day 3	B	3	Un
								(0.93–1.06)
Homan van der Heide, 1993	3.0	Coconut oil	1 yr	30	31	28	32	1.11	Day 3	B	3	Un
								(0.96–1.28)
Kooijmans-Coutinho, 1996	3.0	Coconut oil	1 yr	20	24	20	23	0.96	Day 3	B	5	In
								(0.75–1.22)
Santos, 2000	3.0	Placebo	1 yr	15	15	15	15	1	Day 2	B	2	Un
								(0.88–1.13)
Berthoux, 1992	2.7	No placebo	1 yr	11	14	11	15	1.07	Day 3	C	1	Un
								(0.71–1.61)
Busnach, 1998	2.6	Olive oil	9 mo	17	19	19	21	0.99	Day 1	B	3	Un
								(0.80–1.22)
Maachi, 1995	2.5	No placebo	1 yr	35	40	35	40	1	Day 3	C	1	Un
								(0.85–1.18)
Hernandez, 2002	1.9	Soy oil	3 mo a	39	45	36	40	0.96	Day 2	B	3	Un
								(0.83–1.12)
Random effects model meta-analysis:				206	228	211	234	1.00
Total patients =								(0.96–1.05)

Yr = year(s); mo = month(s); RR = Relative risk of fish oil arm to placebo/controlled arm; CI = confidence interval; Event = Number of survived grafts

a

Treatment stopped at 3 months with follow-up results observed at 1 year

b

Ad = adequate allocation concealment; In = inadequate allocation concealment; Un = allocation concealment unclear. See Methods.

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.

Table 3.2

Effects of Fish oil on Graft Survival in Randomized-Controlled (more...)

Table 3.2

Effects of Fish oil on Graft Survival in Randomized-Controlled Trials in Kidney Transplant Patients Who Received Delayed Treatment

Author, Year	Fish oil EPA+DHA (g/d)	Placebo or Control Arm	Treatment Duration	Fish oil		Control		RR	Treatment Started (Post-transplant)	Qualityb
				Event	Total	Event	Total	(95% CI)		Summary	Jadad	Allocation Conceal
Bennet, 1995	5.4	Corn oil	26 wks	22	22	50	50 a	0.99	16 weeks	B	3	Un
								(0.92–1.06)
	2.7	Corn oil	26 wks	18	18	50	50 a	0.98
								(0.91–1.06)
Castro, 1997	3	Simvastatin	3 mo	18	18	25	25	0.99	≥1 year	C	2	In
		10 mg/d						(0.94–1.03

Wks = weeks; mo = month(s); RR = Relative risk of fish oil arm to placebo/controlled arm; Event = Number of survived grafts

a

Data on high-dose and low-dose controls were combined.

b

Ad = adequate allocation concealment; In = inadequate allocation concealment; Un = allocation concealment unclear. See Methods.

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).

Table 3.3

Effects of Fish oil on the Proportion of Patients with (more...)

Table 3.3

Effects of Fish oil on the Proportion of Patients with an Acute Rejection Episode in Randomized-Controlled Trials in Kidney Transplant Patients Who Received Treatment Immediately after Transplant

Author, Year	Fish oil EPA+DHA (g/d)	Placebo or Control Arm	Treatment Duration	Fish Oil		Control		RR	Treatment Started (Post-transplant)	Qualityb
				Event	Total	Event	Total	(95% CI)		Summary	Jadad	Allocation Conceal
Homan van der Heide, 1992	3.0	Coconut oil	1 mo	15	40	12	48	1.50	Day 3	B	3	Un
								(0.80–2.82)
Kooijmans-Coutinho, 1996	3.0	Coconut oil	1 mo	11	25	11	25	1.00	Day 3	B	5	In
								(0.54–1.87)
Homan van der Heide 1990a	3.0	Coconut oil	1 mo	3	14	6	17	0.61	Day 3	B	3	Un
								(0.18–2.00)
Busnach, 1998	2.6	Olive oil	1 mo	3	17	2	19	1.68	Day 1	B	3	Un
								(0.32–8.88)
Hernandez, 2002	1.9	Soy oil	1 mo	16	45	12	40	1.19	Day 2	B	3	Un
								(0.64–2.19)
Random effects meta-analysis:				48	141	43	149	1.16
Total patients =								(0.83–1.63)
Kooijmans-Coutinho, 1996	3.0	Coconut oil	2–3 mo	13	23	3	24	4.52	Day 3	B	5	In
								(1.48–13.8)
Hernandez, 2002	1.9	Soy oil	2–3 mo	4	45	4	40	0.89	Day 2	B	3	Un
								(0.23–3.3)
Random effects meta-analysis:				17	68	7	64	2.04
Total patients =								(0.43–9.62)
Busnach, 1998	2.6	Olive oil	2–9 mo	0	17	1	19	-	Day 1	B	3	Un
Kooijmans-Coutinho, 1996	3.0	Coconut oil	3–12 mo	3	22	3	22	1.00	Day 3	B	5	In
								(0.23–4.42)
No meta-analysis performed for this group of data
Santos, 2000	3.0	Placebo	1 yr	4	15	6	15	0.67	Day 2	B	2	Un
								(0.23–1.89)
Berthoux, 1992	2.7	No placebo	1 yr	9	14	10	15	0.96	Day 3	C	1	Un
								(0.57–1.64)
Maachi, 1995	2.5	No placebo	1 yr	29	40	32	40	0.8	Day 3	C	1	Un
								(0.71–1.16)
Hernandez, 2002	1.9	Soy oil	3 mo a	20	45	19	40	0.94	Day 2	B	3	Un
								(0.59–1.48)
Random effects meta-analysis:				62	114	67	110	0.91
Total patients =								(0.75–1.11)

Yr = year(s); mo = month(s); RR = Relative risk of fish oil arm to placebo/controlled arm; Event = number of patients with at least one rejection episodes

a

Treatment was stopped at 3 months with follow-up results reported at 1 year

b

Ad = adequate allocation concealment; In = inadequate allocation concealment; Un = allocation concealment unclear. See Methods.

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.

Table 3.4

Effects of Fish oils on the Proportion of Patients (more...)

Table 3.4

Effects of Fish oils on the Proportion of Patients with an Acute Rejection Episode in Randomized-Controlled Trials in Kidney Transplant Patients Who Received Delayed Treatment

Author, Year	Fish oil EPA+DHA (g/d)	Placebo or Control Arm	Treatment Duration	Fish Oil		Control		RR	Treatment Started (Post-transplant)	Qualityc
				Event	Total	Event	Total	(95% CI)		Summary	Jadad	Allocation Conceal
Bennet, 1995	5.4	Corn oil	26 wks	2 b	22	2	50 a	2.27	16 weeks	B	3	Un
								(0.34–15.1)
	2.7	Corn oil	26 wks	0	18	2	50 a	0.54
								(0.03–10.7)
Urakaze 1989; Urakaze 1989	2.2	No treatment	6 mo	0	14	0	16	1.13	Mean 25 months	B	1	Un
								(0.02–53.7)

Wks = week(s); mo = month(s); RR = Relative risk of fish oil arm to placebo/controlled arm; Event = number of patients with at least one rejection episodes

a

Data on high-dose and low-dose controls were combined.

b

Authors stated that plasma EPA values in these 2 patients were not different from values in placebo, indicating noncompliance.

c

Ad = adequate allocation concealment; In = inadequate allocation concealment; Un = allocation concealment unclear. See Methods.

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 patients⁸³ 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}

Table 3.5

Effects of Fish Oil on Glomerular Filtration Rate (GFR) (more...)

Table 3.5

Effects of Fish Oil on Glomerular Filtration Rate (GFR) or Creatinine Clearance (Cr Cl) in Randomized-Controlled Trials

Author, Year	GFR or Cr Cl method	Treatment Started (Post-transplant)	N	Fish oil EPA+DHA (g/d)	N	Placebo or Control	Resultsa			Qualityb
							Base (ml/min/ (1.73m2))	Net Δ	P	Summary	Jadad	Allocation Conceal
			Kidney Transplant
Hernandez, 2002	EDTA	Day 2	45	1.9	40	Soy oil	50.8	+2.8	n.d.	B	3	Un
Santos, 2000	EDTA	Day 2	15	3.0	15	Placebo	ND	+4.1 c	n.d.	C	2	Un
Homan van der Heide, 1992	Cr Cl	Day 3	39	3.0	47	Coconut oil	ND	+4.0 d	n.d.	C	3	Un
Homan van der Heide, 1993	125I	Day 3	30	3.0	28	Coconut oil	42.0	+3.0	n.d.	B	3	Un
Kooijmans-Coutinho, 1996	125I	Day 3	14	3.0	17	Coconut oil	46.1	-1.0	n.d.	B	5	In
Homan van der Heide, 1990a	125I	Day 3	14	3.0	17	Coconut oil	ND	-4.0 c	n.d.	C	2	Un
Berthoux, 1992	Inulin	Day 3	14	2.7	15	No placebo	44.6 e	+0.2	n.d.	C	1	Un
Maachi, 1995	Inulin	Day 3	40	2.5	40	No placebo	47.5	+2.1	n.d.	C	1	Un
Bennett, 1995	DTPA	16 wks	22	5.4	50	Corn oil	68.0	-19.0	n.d.	B	3	Un
			18	2.7			73.0	-19.0	n.d.
Homan van der Heide, 1990b	125I	9 mo	11	3.0	10	Corn oil	56.0	+16.5	<.01	B	3	Un
Schut ,1993; Schut,1993; Schut ,1992; Levi, 1992	125I	1 yr	5	Fish oil: 3.0 + CsA	5	Corn oil + CsA	57.0	-10.0	n.d.	B	2	Un
			5	Fish oil: 3.0 +CsA & Pred	5	Corn oil + CsA + Pred	50.0	+3.0	n.d.
			5	Fish oil: 3.0 +Aza & Pred	4	Corn oil + Aza + Pred	62.0	+5.0	n.d.
			Heart Transplant
Andreassen, 1997	Cr Cl	Day 4	14	3.4	14	Corn oil	57.0	+7.0	n.d.	B	2	Un
Holm, 2001; Holm, 2001	Cockroft & Gaults	Mean 6 yrs (range 1–12 yrs)	21	3.4	20	Corn oil	ND	+5.0 f	n.d.	B	3	Un
			Liver Transplant
Badalamenti, 1995	Inulin	ND	13	3.6	13	Corn oil	71.0	+20.4	.05	B	3	Un

99m

ND = no data; n.d. = not done; NS = not significant; DTPA = Tc-diethylenetriaminepentaacetate; ¹²⁵I = ¹²⁵I-iothalamate; EDTA = [⁵¹Cr] EDTA; Inulin = Inulin clearance; wks = weeks; mo = months; yrs = years

a

Base = in treatment arm; Net Δ = Net difference in effect of omega-3 fatty acids and effect of control, see Methods; P = p-value of the net difference between treatment and control arms.

b

Ad = adequate allocation concealment; In = inadequate allocation concealment; Un = allocation concealment unclear. See Methods.

c

Only the difference after intervention between the 2 groups could be calculated due to lack of baseline data.

d

Only the difference after intervention between the 2 groups could be calculated due to lack of baseline data. Median values were used because mean values were not reported.

e

No baseline data were available; the 3-month measures served as baseline values.

f

Estimated from figure.

Table 3.6

Effects of Fish Oil on Glomerular Filtration Rate (GFR) (more...)

Table 3.6

Effects of Fish Oil on Glomerular Filtration Rate (GFR) in a Prospective Cohort Study in Kidney Transplant Recipients

Author, Year	GFR	Treatment Started (Post-transplant)	N	Fish oil EPA+DHA (g/d)	Resultsa			Quality
					Base (ml/min/ (1.73m2))	Δ	P W/in
Hansen 1995a	DTPA	Mean 16 (range 6–71) months	10	3.5	61.9	+2.2	NS	B

99m

ND = no data; n.d. = not done; NS = not significant; DTPA = Tc-diethylenetriaminepentaacetate

a

Base = Baseline level in treatment arm; Δ = difference of the effect at the end of the study to the baseline. P W/in = p-value for the change within group.

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 trial⁹⁰ 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

Table 3.7

Randomized-Controlled Trials of the Effects of Fish (more...)

Table 3.7

Randomized-Controlled Trials of the Effects of Fish Oil on Total Cholesterol (Duration: 12 weeks to 1 year)

Author, Year	Lipid lowering drugs	Treatment Started (Post-transplant)	N	Fish oil EPA+DHA (g/d)	N	Placebo or Control	Resultsa			Qualityb
							Base (mg/dl)	Net Δ	P	Summary	Jadad	Allocation Conceal
			Kidney Transplant
Busnach, 1998	ND	Day 1	21	2.6	21	Olive oil	202	-9	n.d.	B	3	Un
Santos, 2000	ND	Day 2	15	3.0	15	Placebo	155	-13	n.d.	B	2	Un
Hernandez, 2002	ND	Day 2	45	1.9	40	Soy oil	187	-28	n.d.	B	3	Un
Berthoux, 1992	ND	Day 3	14	2.7	15	No placebo	242c	-22	n.d.	C	1	Un
Maachi, 1995	ND	Day 3	40	2.5	40	No placebo	233c	-19	n.d.	C	1	Un
Yoa, 1994	ND	Mean 36 months	12	1.2	11	Olive oil	208	+8	n.d.	B	2	Un
			Heart Transplant
Andreassen, 1997	Methyl-prednisolone	Day 4	14	3.4	14	Corn oil	193	-28	NS	B	2	Un
Ventura, 1993	ND	Mean 3.5 months	10	3.0	6	Corn oil	275	-32	n.d.	B	3	Un
Holm, 2001	Statins	Mean 6 (range 1–12) years	21	3.4	20	Corn oil	267	0	NS	B	3	Un

ND = no data; n.d. = not done; NS = not significant

a

Base = Baseline level in treatment arm; Net Δ = Net difference in effect of omega-3 fatty acids and effect of control, see Methods; P = p-value of the net difference between treatment and control arms.

b

Ad = adequate allocation concealment; In = inadequate allocation concealment; Un = allocation concealment unclear. See Methods.

c

No baseline data were available; the 3-month measures served as baseline values.

Table 3.8

Randomized- and non-Randomized-Controlled Trials of (more...)

Table 3.8

Randomized- and non-Randomized-Controlled Trials of the Effects of Fish Oil vs. Other Lipid-Lowering Drugs on Total Cholesterol (Duration: 3 to 6 months)

Author, Year	Lipid lowering drugs	Treatment Started (Post-transplant)	Cohorts			Resultsa				Qualityb
			N	Source	Dose	Base (mg/dl)	Δ	P W/in	P Btw	Summary	Jadad	Allocation Conceal
			Kidney Transplant
Castro, 1997	None	≥ 1 year	18	Fish oil	EPA+DHA = 3.0 g/d	266	-26	<.001	n.d.	C	2	In
			25	Simvastatin	10 mg/d	271	-43	<.001
Rodriguez, 1997	None	40.3 mo	18	Fish oil	EPA+DHA = 3.0 g/d	272	-34	<.001	<0.01	B	2	Un
		50.9 mo	16	Lovastatin	20 mg/d	278	-57	<.001
			Heart Transplant
Barbir, 1992	ND	ND	44	Fish oil	EPA+DHA = 3.0 g/d	286	0	n.d.	.0003	C	1	Un
			43	Bezafibrate	400 mg/day	278	-33	n.d.

ND = no data; n.d. = not done; NS = not significant; mo = months

a

Base = Baseline level in treatment arm; Δ = difference of the effect at the end of the study to the baseline. P W/in = p-value for the difference within the group. P Btw = p-value for the net difference between the study arms.

b

Ad = adequate allocation concealment; In = inadequate allocation concealment; Un = allocation concealment unclear. See Methods.

Table 3.9

Prospective Cohort Studies of the Effects of Omega-3 (more...)

Table 3.9

Prospective Cohort Studies of the Effects of Omega-3 Fatty Acids on Total Cholesterol (Duration: 8 weeks to 6 months)

Author, Year	Lipid lowering drugs	Treatment Started (Post-transplant)	Cohorts				Resultsa			Quality
			N	Source	g/d		Base (mg/dl)	Δ	P W/in
			Kidney Transplant
Sweny, 1993; Sweny, 1989	ND	Mean 58 (range 13–132) months	14	Fish oil	EPA+DHA	0.06 g/kg BW/d	291	+18	NS	C
Grekas, 2001	Pravastatin 20 mg/d	Mean 8.7 years	30	Fish oil	EPA+DHA	0.30	229	-42	<.02	C
			Heart Transplant
Salen, 1994	ND	n.d.	41	French Mediterranean diet	ALA	0.39	317	-39	.005	C

ND = no data; n.d. = not done; NS = not significant; ALA = alpha-linolenic acid dosage

a

Base = Baseline level in treatment arm; Δ = difference of the effect at the end of the study to the baseline. P W/in = p-value for the change within the group.

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)

Table 3.10

Randomized-Controlled Trials of the Effects of Fish (more...)

Table 3.10

Randomized-Controlled Trials of the Effects of Fish Oil on High-Density Lipoprotein (HDL) (Duration: 12 weeks to 1 year)

Author, Year	Lipid lowering drugs	Treatment Started (Post-transplant)	N	Fish oil EPA+DHA (g/d)	N	Placebo or Control	Resultsa			Qualityb
							Base (mg/dl)	Net Δ	P	Summary	Jadad	Allocation Conceal
			Kidney Transplant
Santos, 2000	ND	Day 2	15	3.00	15	Placebo	36.0	+7.0	n.d.	B	2	Un
Busnach, 1998	ND	Day 1	21	2.55	21	Olive oil	45.7	+14.0	n.d.	B	3	Un
Bennett, 1995	ND	16 weeks	22	5.40	50	Corn oil	58.0	+1.0	n.d.	B	3	Un
			18	2.70			59.0	+4.0	n.d.
Yoa, 1994	ND	Mean 36 months	12	1.20	11	Olive oil	62.0	-1.0	n.d.	B	2	Un
			Heart Transplant
Andreassen, 1997	ND	Day 4	14	3.4	14	Corn oil	30.0	+2.0	NS	B	2	Un
Ventura, 1993	ND	Mean 3.5 months	10	3.0	6	Corn oil	47.0	-2.0	n.d.	B	3	Un
Holm, 2001; Holm, 2001	ND	Mean 6 (range 1–12) years	21	3.4	20	Corn oil	50.3	+7.7	NS	B	3	Un

ND = no data; n.d. = not done; NS = not significant;

a

Base = Baseline level in treatment arm; Net Δ = Net difference in effect of omega-3 fatty acids and effect of control, see Methods; P = p-value of the net difference between treatment and control arms.

b

Ad = adequate allocation concealment; In = inadequate allocation concealment; Un = allocation concealment unclear. See Methods.

Table 3.11

Randomized-Controlled Trials of the Effects of Fish (more...)

Table 3.11

Randomized-Controlled Trials of the Effects of Fish Oil vs. Other Lipid-Lowering Drugs on High-Density Lipoprotein (HDL) (Duration: 3 to 6 months)

Author, Year	Lipid lowering drugs	Treatment Started (Post-transplant)	Cohorts			Resultsa				Qualityb
			N	Source	Dose	Base (mg/dl)	Δ	PW/in	P Btw	Summary	Jadad	Allocation Conceal
			Kidney Transplant
Castro, 1997	None	≥1 year	18	Fish oil	EPA+DHA = 3.0 g/d	63.0	-10.0	<.01	n.d.	C	2	In
			25	Simvastatin	10 mg/d	58.0	-2.0	NS
Rodriguez, 1997	None	40.3 mo	18	Fish oil	EPA+DHA = 3.0 g/d	48.1	+1.1	NS	NS	B	2	Un
		50.9 mo	16	Lovastatin	20 mg/d	60.2	+0.1	NS
			Heart Transplant
Barbir, 1992	ND	n.d.	44	Fish oil	EPA+DHA = 3.0 g/d	41.4	0	n.d.	.0023	C	1	Un
			43	Bezafibrate	400 mg/day	40.6	+12.2	n.d.

ND = no data; n.d. = not done; NS = not significant; mo = months

a

Base = Baseline level in treatment arm; Δ = difference of the effect at the end of the study to the baseline. P W/in = p-value for the difference within the group. P Btw = p-value for the net difference between the study arms.

b

Ad = adequate allocation concealment; In = inadequate allocation concealment; Un = allocation concealment unclear. See Methods.

Table 3.12

Prospective Cohort Studies of the Effects of Omega-3 (more...)

Table 3.12

Prospective Cohort Studies of the Effects of Omega-3 Fatty Acids on High-Density Lipoprotein (HDL)

Author, Year	Lipid lowering drugs	Treatment Started (Post-transplant)	Cohorts				Resultsa			Quality
			N	Source	g/d		Base (mg/dl)	Δ	P W/in
			Kidney Transplant
Grekas, 2001	Pravastatin 20 mg/d	Mean 8.7 yrs	30	Fish oil	EPA+DHA	0.3	46.0	+3.0	NS	C
			Heart Transplant
Salen, 1994	ND	n.d.	41	French Mediterranean diet	ALA	0.39	54.1	+0.8	NS	C

ND = no data; n.d. = not done; NS = not significant

a

Base = Baseline level in treatment arm; Δ = difference of the effect at the end of the study to the baseline. P W/in = p-value for the change within the group.

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)

Table 3.13

Randomized-Controlled Trials of the Effects of Fish (more...)

Table 3.13

Randomized-Controlled Trials of the Effects of Fish Oil on Low-Density Lipoprotein (LDL) (12 weeks to 1 year)

Author, Year	Lipid lowering drugs	Treatment Started (Post-transplant)	N	Fish oil EPA+DHA(g/d)	N	Placebo or Control	Resultsa			Qualityb
							Base (mg/dl)	Net Δ	P	Summary	Jadad	Allocation Conceal
			Kidney Transplant
Santos, 2000	ND	Day 2	15	3.00	15	Placebo	100	+13	n.d.	B	2	Un
Bennett, 1995	ND	16 weeks	22	5.40	50	Corn oil	133	0	n.d.	B	3	Un
			18	2.70			176	-3	n.d.
			Heart Transplant
Ventura, 1993	ND	Mean 3.5 months	10	3.0	6	Corn oil	185	-22	n.d.	B	3	Un
Holm, 2001 ; Holm, 2001	ND	Mean 6 (range 1–12) years	21	3.4	20	Corn oil	170	0	NS	B	3	Un

ND = no data; n.d. = not done; NS = not significant

a

Base = Baseline level in treatment arm; Net Δ = Net difference in effect of omega-3 fatty acids and effect of control, see Methods; P = p-value of the net difference between treatment and control arms.

b

Ad = adequate allocation concealment; In = inadequate allocation concealment; Un = allocation concealment unclear. See Methods.

Table 3.14

Randomized- and non-Randomized-Controlled Trials of (more...)

Table 3.14

Randomized- and non-Randomized-Controlled Trials of the Effects of Fish Oil vs. Other Lipid-Lowering Drugs on Low-Density Lipoprotein (LDL) (Duration: 3 to 6 months)

Author, Year	Lipid lowering drugs	Treatment Started (Post-transplant)	Cohorts			Resultsa				Qualityb
			N	Source	Dose	Base (mg/dl)	Δ	P W/in	P Btw	Summary	Jadad	Allocation Conceal
			Kidney Transplant
Castro, 1997	None	≥1 year	18	Fish oil	EPA+DHA = 3.0 g/d	162	-4	NS	n.d.	C	2	In
			25	Simvastatin	10 mg/d	177	-33	<.01
Rodriguez, 1997	None	40.3 mo	18	Fish oil	EPA+DHA = 3.0 g/d	105	-7	NS	<.01	B	2	Un
		50.9 mo	16	Lovastatin	20 mg/d	121	-42	<.01
			Heart Transplant
Barbir, 1992	ND	n.d.	44	Fish oil	EPA+DHA = 3.0 g/d	201	0	n.d.	.0002	C	1	Un
			43	Bezafibrate	400 mg/day	193	-35	n.d.

ND = no data; n.d. = not done; NS = not significant; mo = months

a

Base = Baseline level in treatment arm; Δ = difference of the effect at the end of the study to the baseline. P W/in = p-value for the difference within the group. P Btw = p-value for the net difference between the study arms.

b

Ad = adequate allocation concealment; In = inadequate allocation concealment; Un = allocation concealment unclear. See Methods.

Table 3.15

Prospective Cohort Studies of the Effects of Omega-3 (more...)

Table 3.15

Prospective Cohort Studies of the Effects of Omega-3 Fatty Acids on Low-Density Lipoprotein (LDL) (Duration: 8 weeks to x months)

Author, Year	Lipid lowering drugs	Treatment Started (Post-transplant)	Cohorts				Resultsa
			N	Source	g/d		Base (mg/dl)	Δ	P W/in	Quality
			Kidney Transplant
Grekas, 2001	Pravastatin 20 mg/d	Mean 8.7 yrs	30	Fish oil	EPA+DHA	0.3	151	-27	<.03	C
			Heart Transplant
Salen, 1994	ND	n.d	41	French Meditteranean diet	ALA	0.39	240	-35	.004	C

ND = no data; n.d. = not done; NS = not significant

a

Base = Baseline level in treatment arm; Δ = difference of the effect at the end of the study to the baseline. P W/in = p-value for the change within the group.

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

Table 3.16

Randomized-Controlled Trials of the Effects of Fish (more...)

Table 3.16

Randomized-Controlled Trials of the Effects of Fish Oil on Triglycerides (Duration: 12 weeks to 1 year)

Author, Year	Lipid lowering drugs	Treatment Started (Post-transplant)	N	Fish oil EPA+DHA(g/d)	N	Placebo or Control	Resultsa			Qualityb
							Base (mg/dl)	Net Δ	P	Summary	Jadad	Allocation Conceal
			Kidney Transplant
Busnach, 1998	ND.	Day 1	21	2.6	21	Olive oil	208	-107	n.d.	B	3	Un
Santos, 2000	ND	Day 2	15	3.0	15	Placebo	150	+46	n.d.	B	2	Un
Hernandez, 2002	ND	Day 2	45	1.9	40	Soy oil	203	-46	n.d.	B	3	Un
Berthoux, 1992	ND	Day 3	14	2.7	15	No Placebo	138c	-0.8	n.d.	C	1	Un
Maachi, 1995	ND	Day 3	40	2.5	40	No placebo	137	-25	n.d.	C	1	Un
Urakaze, 1989; Urakaze, 1989	ND	Mean 25 months	14	2.2	16	No placebo	148	-42	NS	B	1	Un
Yoa, 1994	ND	Mean 36months	12	1.2	11	Olive oil	133	+9	n.d.	B	2	Un
			Heart Transplant
Andreassen, 1997	ND	Day 4	14	3.4	14	Corn oil	181	-71	<.0.5	B	2	Un
Ventura, 1993	ND	Mean 3.5 months	10	3.0	6	Corn oil	157	-6	n.d.	B	3	Un
Holm, 2001; Holm, 2001	ND	Mean 6 (range 1–12 years	21	3.4	20	Corn oil	195	-62	.07	B	3	Un

ND = no data; n.d. = not done; NS = not significant

a

Base = Baseline level in treatment arm; Net Δ = Net difference in effect of omega-3 fatty acids and effect of control, see Methods; P = p-value of the net difference between treatment and control arms.

b

Ad = adequate allocation concealment; In = inadequate allocation concealment; Un = allocation concealment unclear. See Methods.

c

No baseline data were available; the 3-month measures served as baseline values.

Table 3.17

Randomized- and non-Randomized-Controlled Trials of (more...)

Table 3.17

Randomized- and non-Randomized-Controlled Trials of the Effects of Fish Oil vs. Other Lipid-Lowering Drugs on Triglycerides (Duration: 3 to 6 months)

Author, Year	Lipid lowering drugs	Treatment Started (Post-transplant)	Cohorts			Resultsa				Qualityb
			N	Source	Dose	Base (mg/dl)	Δ	P W/in	P Btw	Summary	Jadad	Allocation Conceal
			Kidney Transplant
Castro, 1997	None	≥1 year	18	Fish oil	EPA+DHA = 3.0 g/d	203	-47	.02	n.d.	C	2	In
			25	Simvastatin	10 mg/d	180	-46	<.01
Rodriguez, 1997	None	Mean 40.3 mo	18	Fish oil	EPA+DHA = 3.0 g/d	261	-64	<.01	<.05	B	2	Un
		Mean 50.9 mo	16	Lovastatin	20 mg/d	235	-36	NS
			Heart Transplant
Barbir, 1992	ND	n.d.	44	Fish oil	EPA+DHA = 3.0 g/d	292	-96	n.d.	NS	C	1	Un
			43	Bezafibrate	400 mg/day	257	-85	n.d.

ND = no data; n.d. = not done; NS = not significant; mo = months

a

Base = Baseline level in treatment arm; Δ = difference of the effect at the end of the study to the baseline. P W/in = p-value for the difference within the group. P Btw = p-value for the net difference between the study arms.

b

Ad = adequate allocation concealment; In = inadequate allocation concealment; Un = allocation concealment unclear. See Methods.

Table 3.18

Prospective Cohort Studies of the Effects of Omega-3 (more...)

Table 3.18

Prospective Cohort Studies of the Effects of Omega-3 Fatty Acids on Triglycerides (Duration: 5 days to 6 months)

Author, Year	Lipid lowering drugs	Treatment Started (Post-transplant)	Cohorts				Resultsa			Quality
			N	Source	g/d		Base (mg/dl)	Δ	PW/in
			Kidney Transplant
Zolotarski, 2003	ND	Day 1	8	Fish oil	EPA+DHA	0.1 g/kg BW/d	159	11	NS	C
Sweny, 1993; Sweny, 1989	ND	Mean 58 (range 13–132) months	14	Fish oil	EPA+DHA	0.06 g/kg BW/d	278	-103	<.003	C
Grekas, 2001	Pravastatin 20 mg/d	Mean 8.7 yrs	30	Fish oil	EPA+DHA	0.3	169	-45	<.03	C
			Heart Transplant
Salen, 1994	ND	n.d.	41	French Mediterranean diet	ALA	0.39	317	-39	.005	C

ND = no data; n.d. = not done; NS = not significant; BW = body weight

a

Base = Baseline level in treatment arm; Δ = difference of the effect at the end of the study to the baseline. P W/in = p-value for the change within the group.

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

Table 3.19

Randomized-Controlled Trials of the Effects of Fish (more...)

Table 3.19

Randomized-Controlled Trials of the Effects of Fish Oil on Mean Arterial Blood Pressure (MAP)

Author, Year	Anti-hypertensive agents	Treatment Started (Post-transplant)	N	Fish oil EPA+DHA (g/d)	N	Placebo or Control	Resultsa			Qualityb
							Base (mmHg)	Net Δ	P	Summary	Jadad	Allocation Conceal
			Kidney Transplant
Santos, 2000	β-blockers plus diuretics (if needed) or centrally acting vasodilators; calcium channel blockers, or ACE inhibitors (2nd line)	Day 2	15	3.0	15	Placebo	101	+4.0	n.d.	B	2	Un
Hernandez, 2002	β-blockers, α-adrenergic antagonists, calcium channel blockers, diuretics as needed	Day 2	45	1.9	40	Soy oil	106	-1.7	n.d.	B	3	Un
Homan van der Heide, 1993	Diuretics, β-blockers, vasodilatory agent. calcium channel blockers as needed	Day 3	30	3.0	28	Coconut oil	100	-7.0	n.d.	B	3	Un
Homan van der Heide, 1992	ND	Day 3	39	3.0	47	Coconut oil	ND	-3.0 c	n.d.	C	3	Un
Kooijmans-Coutinho, 1996	β-blockers plus diuretics (if needed) or centrally acting vasodilators; calcium channel blockers (rescue Rx)	Day 3	20	3.0	18	Coconut oil	108	-3.5	n.d.	B	5	In
Homan van der Heide, 1990a	ND	Day 3	14	3.0	17	Coconut oil	ND	-1.0 c	n.d.	C	2	Un
Bennett, 1995	Calcium antagonists, ACE inhibitors	16 weeks	22	5.4	50	Corn oil	109	-9.7	n.d.	B	3	Un
			18	2.7			104	-5.0	n.d.
Homan van der Heide, 1990b	Diuretics, β-blockers	9 months	11	3.0	10	Corn oil	106	-10.5	<.01	B	3	Un
Urakaze, 1989; Urakaze, 1989	ND.	Mean 25 months	14	2.2	16	No placebo	104	-3.0	NS	B	1	Un
			Heart Transplant
Andreassen, 1997	Enalapril as needed	Day 4	14	3.4	14	Corn oil	93	-8.9	<.01	B	2	Un
Ventura, 1993	Calcium-channel blocker, ACE inhibitor, or both	Mean 3.5±1.5 months	10	3.0	6	Corn oil	120	-18.0	n.d.	B	3	Un
Holm, 2001; Holm, 2001	ACE, calcium antagonist, β-blockers, diuretics	Mean 6 (1–12) years	21	3.4	20	Corn oil	105	-6.7	.02	B	3	Un
			Liver Transplant
Badalamenti, 1995	ND	n.d.	13	3.6	13	Corn oil	101	-3.0	n.d.	B	3	Un

ND = no data; n.d. = not done; NS = not significant;

a

Base = Baseline level in treatment arm; Net Δ = Net difference in effect of omega-3 fatty acids and effect of control, see Methods; P = p-value of the net difference between treatment and control arms.

b

Ad = adequate allocation concealment; In = inadequate allocation concealment; Un = allocation concealment unclear. See Methods.

c

Only the difference after intervention between the 2 groups could be calculated due to lack of baseline data.

Table 3.20

Prospective Cohort Studies and a non-Randomized-Controlled (more...)

Table 3.20

Prospective Cohort Studies and a non-Randomized-Controlled Trial of the Effects of Fish Oil on Mean Arterial Blood Pressure (MAP)

Author, Year	GFR or Cr Cl method	Treatment Started (Post-transplant)	N	Fish oil EPA+DHA (g/d)	Resultsa			Quality
					Base (mmHg)	Δ	P W/in
			Kidney Transplant
Hansen 1995a	ACE inhibitors, calcium antagonist, β-blockers, diuretics, hydralazine	Mean 16 (range 6–71) months	10	3.5	106	0	NS	B
Hansen 1995b	Diuretics, Diltiazem, β-blockers, ACE inhibitors	Mean 42±17 months	9	Fish oil: 3.5 + CsA	121	-2.0	n.d.	B
		Mean 149±44 months	9	Fish oil:3.5 + AzA	110	-7.0	<.05
			Heart Transplant
Fleischhauer, 1993	Diltiazem, Hydralazine, Enalapril, Captopril, Clonidine	1 to 6 years	7	5.7	116	-9.0	NS	C
			7	No fish oil	114	-5.0	NS

ND = no data; n.d. = not done; NS = not significant

a

Base = Baseline level in treatment arm; Δ = difference of the effect at the end of the study to the baseline. P W/in = p-value for the change within group.

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

All Outcomes

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

Net Differences in GFR and 95% Confidence Intervals (more...)

Figure 3.5

.

   Net Differences in GFR and 95% Confidence Intervals Across Randomized-Controlled Trials in Kidney Transplant Recipients who Received Fish Oil Supplementation at Various Intervals Post-Operatively

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 transplant⁷⁷ 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 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.

Table 3.21

Changes in Serum Levels of Cyclosporine (CsA) in Randomized-Controlled (more...)

Table 3.21

Changes in Serum Levels of Cyclosporine (CsA) in Randomized-Controlled Trials of Fish Oil Supplementation

Author, Year	Anti-Rejection Treatments	Treatment Started (Post-transplant)	N	Fish oil EPA+DHA (g/d)	N	Placebo or Control	Resultsa			Qualityb
							Base (ng/mL)	Net Δ	P	Summary	Jadad	Allocation Conceal
			Kidney Transplant
Kooijmans-Coutinho, 1996	Methylprednisolone	Day 3	14	3.0	17	Coconut oil	288	-49	n.d.	B	5	In
Homan van der Heide, 1993	Methylprednisolone	Day 3	30	3.0	28	Coconut oil	245	-37	n.d.	B	3	Un
Homan van der Heide, 1992	Methylprednisolone	Day 3	39	3.0	47	Coconut oil	ND	+22d	n.d.	C	3	Un
Santos, 2000	ND	Day 2	15	3.0	15	Placebo	ND	+20d	n.d.	C	2	Un
Homan van der Heide, 1990a	Methylprednisolone	Day 3	14	3.0	17	Coconut oil	ND	-4.0d	n.d.	C	2	Un
Berthoux, 1992	ND	Day 3	14	2.7	15	No placebo	433c	-29	n.d.	C	1	Un
Maachi, 1995	ND	Day 3	40	2.5	15	No placebo	438	+2.1	n.d.	C	1	Un
Hernandez, 2002	Methylprednisolone	Day 2	45	1.9	40	Soy oil	244	+0.5	n.d.	B	3	Un
Homan van der Heide, 1990b	ND	9 mo	11	3.0	10	Corn oil	90	-3.0	NS	B	3	Un
			Heart Transplant
Andreassen, 1997	Methylprednisolone	Day 4	14	3.4	14	Corn oil	342	+6.0	n.d.	B	2	Un
Barbir, 1992e	ND	ND	44	3.0	43	Bezafibrate 400 mg/d	199	+38	NS	C	1	Un

ND = no data; n.d. = not done; NS = not significant

a

Base = Baseline level in treatment arm; Net = Net difference in effect of omega-3 fatty acids and effect of control, see Methods; P = p-value of the net difference between treatment and control arms.

b

Ad = adequate allocation concealment; In = inadequate allocation concealment; Un = allocation concealment unclear. See Methods.

c

No baseline data were available; the 3-month measures served as baseline values.

d

Only the difference after intervention between the 2 groups could be calculated due to lack of baseline data.

e

Non-randomized controlled trial

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.

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.

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 reduced⁶⁴ 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.

MEDLINE AND EMBASE: Omega 3 and drugs with controlled trial filter

1. exp fatty acids, omega-3/

2. fatty acids, essential/

3. Dietary Fats, Unsaturated/

4. linolenic acids/

5. exp fish oils/

6. (n 3 fatty acid$ or omega 3).tw.

7. docosahexa?noic.tw,hw,rw.

8. eicosapenta?noic.tw,hw,rw.

9. alpha linolenic.tw,hw,rw.

10. (linolenate or cervonic or timnodonic).tw,hw,rw.

11. menhaden oil$.tw,hw,rw.

12. (mediterranean adj diet$).tw.

13. ((flax or flaxseed or flax seed or linseed or rape seed or rapeseed or canola or soy or soybean or walnut or mustard seed) adj2 oil$).tw.

14. (walnut$ or butternut$ or soybean$ or pumpkin seed$).tw.

15. (fish adj2 oil$).tw.

16. (cod liver oil$ or marine oil$ or marine fat$).tw.

17. (salmon or mackerel or herring or tuna or halibut or seal or seaweed or anchov$).tw.

18. (fish consumption or fish intake or (fish adj2 diet$)).tw.

19. diet$ fatty acid$.tw.

20. or/1–19

21. dietary fats/

22. (randomized controlled trial or clinical trial or controlled clinical trial or evaluation studies or multicenter study).pt.

23. random$.tw.

24. exp clinical trials/ or evaluation studies/

25. follow-up studies/ or prospective studies/

26. or/22–25

27. 21 and 26

28. (Ropufa or MaxEPA or Omacor or Efamed or ResQ or Epagis or Almarin or Coromega).tw.

29. (omega 3 or n 3).mp.

30. (polyunsaturated fat$ or pufa or dha or epa or long chain or longchain or lc$).mp.

31. 29 and 30

32. 20 or 27 or 28 or 31

33. follow up studies/

34. (follow up or followup).tw.

35. exp case-control studies/ or case control study/

36. (case adj20 control).tw.

37. exp longitudinal studies/ or longitudinal study/

38. longitudinal.tw.

39. exp cohort studies/ or cohort analysis/

40. cohort.tw.

41. (random$ or rct).tw.

42. exp randomized controlled trials/ or randomized controlled trial/

43. exp random allocation/

44. exp double-blind method/ or double blind procedure/

45. exp single-blind method/ or single blind procedure/

46. randomized controlled trial.pt.

47. clinical trial.pt. or exp clinical trial/

48. (clin$ adj trial$).tw.

49. ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ti,ab.

50. exp placebos/ or placebo/

51. placebo$.tw.

52. exp research design/ or exp methodology/

53. exp evaluation studies/ or exp postmarketing surveillance/

54. exp prospective studies/ or prospective study/

55. exp comparative study/

56. or/33–55

57. exp glucocorticoids/ or exp glucocorticoids, synthetic/ or exp glucocorticoid/

58. (glucocorticoids or hydroxycorticosteroids or 11-hydroxycorticosteroids or corticosterone or hydrocortisone or 18-hydroxycorticosterone or tetrahydrocortisol or 17-hydroxycorticosteroids or cortisone or cortodoxone or hydroxypregnenolone or tetrahydrocortisone).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]

59. (glucocorticoids, synthetic or beclomethasone or betamethasone or betamethasone 17-valerate or clobetasol or desoximetasone or dexamethasone or dexamethasone isonicotinate or diflucortolone or flumethasone or fluocinolone acetonide or fluocinonide or fluocortolone or fluorometholone or fluprednisolone or flurandrenolone or melengestrol acetate or methylprednisolone or methylprednisolone hemisuccinate or paramethasone or prednisolone or prednisone or triamcinolone or triamcinolone acetonide).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]

60. exp immunosuppressive agents/ or exp immunosuppressive agent/

61. (immunosuppressive agents or 6-mercaptopurine or antilymphocyte serum or azaserine or azathioprine or busulfan or cladribine or coformycin or cyclophosphamide or cyclosporine or cyclosporins or cytarabine or ellipticines or fluorouracil or gliotoxin or ifosfamide or methotrexate or muromonab-cd3 or pentostatin or razoxane or sirolimus or tacrolimus or thalidomide or thiamphenicol or thioinosine or triamcinolone acetonide).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]

62. okt3.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]

63. fk506.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]

64. rs-61443.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]

65. mycophenolic acid.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]

66. rapamycin.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]

67. acyclovir.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]

68. or/57–67

69. 32 and 56 and 68

70. 69

71. limit 70 to human

72. 71

73. limit 72 to english language

74. 71 not 73

MEDLINE AND EMBASE: Omega3 and Transplant

1. exp fatty acids, omega-3/

2. fatty acids, essential/

3. Dietary Fats, Unsaturated/

4. linolenic acids/

5. exp fish oils/

6. (n 3 fatty acid$ or omega 3).tw.

7. docosahexa?noic.tw,hw,rw.

8. eicosapenta?noic.tw,hw,rw.

9. alpha linolenic.tw,hw,rw.

10. (linolenate or cervonic or timnodonic).tw,hw,rw.

11. menhaden oil$.tw,hw,rw.

12. (mediterranean adj diet$).tw.

13. ((flax or flaxseed or flax seed or linseed or rape seed or rapeseed or canola or soy or soybean or walnut or mustard seed) adj2 oil$).tw.

14. (walnut$ or butternut$ or soybean$ or pumpkin seed$).tw.

15. (fish adj2 oil$).tw.

16. (cod liver oil$ or marine oil$ or marine fat$).tw.

17. (salmon or mackerel or herring or tuna or halibut or seal or seaweed or anchov$).tw.

18. (fish consumption or fish intake or (fish adj2 diet$)).tw.

19. diet$ fatty acid$.tw.

20. or/1–19

21. dietary fats/

22. (randomized controlled trial or clinical trial or controlled clinical trial or evaluation studies or multicenter study).pt.

23. random$.tw.

24. exp clinical trials/ or evaluation studies/

25. follow-up studies/ or prospective studies/

26. or/22–25

27. 21 and 26

28. (Ropufa or MaxEPA or Omacor or Efamed or ResQ or Epagis or Almarin or Coromega).tw.

29. (omega 3 or n 3).mp.

30. (polyunsaturated fat$ or pufa or dha or epa or long chain or longchain or lc$).mp.

31. 29 and 30

32. 20 or 27 or 28 or 31

33. exp transplants/

34. exp transplantation immunology/

35. exp transplantation/

36. (posttransplant$ or pretransplant$ or pre transplant$ or post transplant$).tw.

37. transplant$.mp.

38. transplant$.hw.

39. tr.fs.

40. graft$.mp,hw.

41. exp graft rejection/

42. (allotransplant$ or xenotransplant$ or heterotransplant$ or autotransplant$ or isotransplant$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]

43. (allograft$ or xenograft$ or homograft$ or heterograft$ or autograft$ or isograft$).mp.

44. exp postoperative complications/ or exp postoperative complication/

45. or/33–44

46. 32 and 45

47. limit 46 to human

48. 47

49. limit 48 to english language

50. 48 not 49

Transplant Form Part I

Transplant Form Part II

Peer Reviewers

We gratefully acknowledge the following individuals who reviewed the initial draft of this Report and provided us with constructive feedback. Acknowledgments are made with the explicit statement that this does not constitute endorsement of the report.

• William M. Bennett, MD

• Medical Director

• Legacy Transplant Services

• 1015 NW 22nd Avenue

• Portland, OR 97210

• Bruce Bistrian, MD, PhD

• Professor of Medicine

• Harvard Medical School

• Beth Israel Deaconess Medical Center

• One Deaconess Road, Baker - 605

• Boston, MA 02215

• Philip Calder, MD

• Division of Human Nutrition

• School of Biological Sciences

• University of Southampton

• Bassett Crescent East

• Southampton SO16 7PX UK

• Sven O. E. Ebbesson, PhD

• Professor of Marine Biology and Neuroscience

• Institute of Marine Science

• 200 O'Neill Building

• University of Alaska, Fairbanks

• Fairbanks, Alaska 99775-1080

• R. Michael Hofmann, MD

• University of Wisconsin Medical School, Madison

• Department of Nephrology

• 3034 Fish Hatchery Rd Ste B

• Madison, WI 53713

Representative for the American Society of Transplantation

• John Scandling, MD

• Medical Director

• Adult Kidney and Pancreas Transplant Program

• Stanford University Medical Center

• 750 Welch Road, Suite 200

• Palo Alto, CA 94304-1509

• Artemis P. Simopoulos, MD

• President

• The Center for Genetics, Nutrition and Health

• 2001 S Street, NW, Suite 530

• Washington, DC 20009

• Elizabeth A. Yetley, Ph.D.

• Senior Nutrition Research Scientist

• Office of Dietary Supplements

• National Institutes of Health

• 6100 Executive Boulevard, Suite 3B01

• Bethesda MD 20892-7517