Summary
Evidence Report/Technology Assessment: Number 115
Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.
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Introduction / Reporting the Evidence / / Key Questions / Methods / Results / Future Research / Availability of Full Report / References
Authors: Bonis PA, Chung M, Tatsioni A, Sun Y, Kupelnick B, Lichtenstein A,
Perrone R, Chew P, DeVine D, Lau J.
Introduction
This evidence report has been prepared by the
Tufts-New England Medical Center (Tufts-NEMC) Evidence-based Practice Center (EPC)
concerning the health benefits of omega-3 fatty
acids on organ transplantation. These reports are
among several that address topics related to
omega-3 fatty acids, and that were requested and
funded by the Office of Dietary Supplements,
National Institutes of Health (NIH), through the
EPC program at the Agency for Healthcare
Research and Quality (AHRQ). Three EPCs—the Tufts-NEMC EPC, the Southern California
EPC (SCEPC), based at RAND, and the
University of Ottawa EPC—each produced
evidence reports. To ensure consistency of
approach, the three EPCs collaborated on selected
methodological elements, including literature
search strategies, rating of evidence, and data table
design.
The aim of the reports is to summarize the
current evidence on the health effects of omega-3
fatty acids (eicosapentaenoic acid [EPA; chemical
abbreviation: 20:5 n-3], docosahexaenoic acid
[DHA; 22:6 n-3], alpha-linolenic acid [ALA,
18:3 n-3], and docosapentaenoic acid [DPA, 22:5
n-3]) on the following:
- Cardiovascular disease.
- Cancer
- Child and maternal health.
- Eye health.
- Gastrointestinal diseases.
- Kidney diseases.
- Asthma.
- Autoimmune diseases.
- Immune-mediated diseases.
- Organ transplantation.
- Mental health.
- Neurological diseases and conditions.
In addition
to informing the research community and the
public on the effects of omega-3 fatty acids on
various health conditions, it is anticipated that the
findings of the reports will also be used to help
define the agenda for future research.
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Reporting the Evidence
This evidence report on omega-3 fatty acids
and organ transplantation is based on a systematic
review of the literature. The 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
AHRQ, and institutes at 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 SCEPC. The three EPCs
coordinated efforts to produce evidence reports 2
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 three EPCs agreed on a common definition of omega-3
fatty acids; however some variation that reflected different
topics and key questions was permitted in definitions and study
eligibility criteria.
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Key Questions
Nine key questions, which fall under five major categories,
are addressed in this report.
Graft-Related Outcomes
Question 1. What is the evidence that omega-3 fatty acid
supplementation reduced rejection episodes or graft failure in
patients (adults or children) who received an organ transplant?
Question 2. What is the evidence that omega-3 fatty acid
supplementation is renoprotective (improves glomerular
filtration rate or increases kidney size) or is protective against
primary kidney disease recurrence following kidney
transplantation?
Cardiovascular Disease-Related Outcomes
Question 3. What is the evidence that omega-3 fatty acid
supplementation lowers cardiovascular disease risk factors or
events in organ transplant recipients (adults or children)?
Infectious Outcomes
Question 4. What is the evidence that omega-3 fatty acid
supplementation reduces serious infectious complications
following organ transplantation?
All Outcomes
Question 5. What is the evidence that any benefits to organ
transplant recipients from omega-3 fatty acid supplementation
differ in different subsets of patients?
Question 6. What is the evidence that effects of omega-3
fatty acid supplementation on outcomes of interest vary
depending on the time of administration relative to
transplantation procedures (pre- or post-transplant)?
Effects on Immunosuppressive Agents and
Related Drugs
Question 7. What is the evidence in patients (adults or
children) who receive an organ transplant that the benefits of
omega-3 fatty acid supplementation interact with the
concomitant administration of various immunosuppressive
agents/drugs?
Question 8. What is the evidence in patients (adults or
children) who receive an organ transplant that serum levels of
immunosuppressive agents/drugs are altered by omega-3 fatty
acid supplementation?
Question 9. What is the evidence in patients (adults or
children) who receive an organ transplant that omega-3 fatty
acid supplementation can replace or reduce the need for other
more potent anti-inflammatory or immunosuppressive drugs
(such as steroids and non-steroidal anti-inflammatory drugs)?
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Methods
Patient Population and Settings
The target population included adults or children
undergoing any form of organ transplantation.
Search Strategy
We conducted a comprehensive literature search to address
the key questions. 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 six 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
All abstracts identified through the literature search were
screened manually and in triplicate by three independent
investigators. Triplicate screening was performed because the
modest number of abstracts allowed us to gather additional
data for methodology research pertaining to the most efficient
method of abstract screening. Eligibility criteria were defined
broadly to include all studies (regardless of language of
publication, experimental design, or size) that evaluated any
potential source of omega-3 fatty acids in human subjects who
underwent organ transplantation, and reported any outcome.
Any abstract identified by any independent investigator was
retrieved for further review.
The full text of studies selected by the abstract screening
process was reviewed by three independent investigators.
Studies of any design (including controlled trials, cohort
studies, case series, and case reports), size, and language were
included provided that they reported any outcome in adults or
children undergoing organ transplantation who received
omega-3 fatty acids.
Studies were excluded if they focused on nonhuman
subjects, were review articles or other articles without primary
sources of data, focused on subjects who did not undergo organ
transplantation, did not use omega-3 fatty acids, or if the
amount of omega-3 fatty acids could not be quantified.
Acceptable sources of omega-3 fatty acids included fish oil,
vegetable oils containing ALA (i.e., canola, rapeseed, soybean,
flaxseed, linseed, walnut, mustard seed), Mediterranean diet, or
other sources where the quantity was reported explicitly.
Pharmaceutical companies and individuals in relevant countries
were contacted when a brand name of a fish oil supplement
was provided without a quantitative description of its
components.
The authors, study locations, and dates of all retrieved
studies were compared to identify duplicate reports of the same
subjects. Where there was any ambiguity, an attempt was made
to contact authors of the relevant publications. Duplicate
reports were included if they provided additional data; however,
subjects were included and accounted for only once.
Data Extraction Process
Electronic data extraction forms and a database were created
in a multi-step process during which the key study questions
were translated into a structure that was applicable to all types
of transplants and outcomes of interest. Frequent and regular
discussions helped to ensure use of uniform definitions. Thus,
multiple versions of the data extraction forms were tested by
several investigators on samples of the included studies, until a
final version was achieved. All investigators were trained on
how to complete the form to assure consistency among
extractors.
All studies were extracted by three 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:
- 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.
- All reported outcomes.
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.
Methodological Quality
As part of the overall omega-3 fatty acid project, the three
collaborating EPCs agreed to use the Jadad Score and adequacy
of random allocation concealment as elements to grade
individual randomized controlled trials.1,2 The EPCs also agreed
to permit inclusion of other quality elements that were
considered to be appropriate for a generic quality score.
There was consensus among the three EPCs that studies
should not be graded using a single, quantitative summary
score, since such scores are often arbitrary and unreliable.3 The
Jadad Score assesses the quality of randomized controlled trials
using three criteria:
- Adequacy of randomization.
- Double blinding.
- Dropouts.1
Studies fulfilling all three criteria
receive a maximum score of five points. In addition, adequacy
of allocation concealment was assessed using the criteria by
Schulz, et al., as "adequate," "inadequate," or "unclear."2
A limitation of the Jadad and Schulz scores is that they
address only some aspects of the methodological quality. These
scores do not include other elements of study quality, such as
potential biases due to reporting and analytic problems.
Furthermore, these scoring systems are applicable only to
randomized controlled trials.
Thus, to supplement these scores, a 3-category grading
system (A, B, C) was applied to each study. This grading system
has been used in most of the previous evidence reports from the
Tufts-NEMC EPC as well as in evidence-based clinical practice
guidelines.4 This system defines a generic grading system that is
applicable to varying study designs including randomized
controlled trials, cohort, and case-control studies. The
categories are defined as follows:
- Category A studies have the least bias and results are considered valid. This is a study that adheres mostly to the commonly held concepts of high quality including the following:
- A formal randomized study.
- Clear description of the population, setting, interventions, and comparison groups.
- Clear description of the content of the placebo used.
- Appropriate measurement of outcomes.
- Appropriate statistical and analytic methods and reporting.
- No reporting errors.
- Less than 20 percent dropout and clear reporting of dropouts.
- No obvious bias.
- Category B studies are susceptible to some bias, but not sufficient to invalidate the results. They do not meet all the criteria in category A because they have some
deficiencies, but none likely to cause major bias. The
study may be missing information, making it difficult to
assess limitations and potential problems.
- Category C studies have significant bias that may
invalidate the results. These studies have serious errors in
design, analysis, or reporting, and have large amounts of
missing information, or discrepancies in reporting.
In addition to applying these three grading systems,
additional comments relating to potential sources of bias and
other study limitations were recorded by each investigator
during the data extraction process. Such comments are
included in the evidence tables.
Statistical Analysis
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 areas of transplantation. The following 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 cyclosporine (CsA).
- Major outcomes for heart transplantation included posttransplant 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 one study in each category was identified.
As a general rule, when more than one 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 one 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.5
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 followup,
and 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 three 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-3Final - Omega-3Initial) -
(ControlFinal - ControlInitial).
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 percent
confidence interval (CI) or standard error of the net difference
to determine whether it was less than .05. We included any
reported P value less than 0.10. Those above 0.10 and those
reported as "non-significant" were described as "NS" (nonsignificant).
For measures expressed using standard or Systeme
International 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. For
dichotomous or categorical variables, the rates in the treatment
and control groups were expressed as relative risk and 95
percent CIs. Among these, there were sufficient, clinically
comparable data to combine the results of graft or patient
survival and rejection episodes in kidney transplantation. This
was accomplished using a random effects model meta-analysis.6
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Results
Search Results
The literature search identified 1,281 abstracts. From these,
and from the articles found in bibliographies, a total of 78
studies were ultimately selected for full-text screening (based
upon the initial abstract screening and review of the
bibliographies of retrieved studies including review articles).
Thirty-nine of these were rejected because they did not fulfill
inclusion criteria leaving 39 for inclusion. Careful additional
review of these studies revealed 8 that were duplicate reports of
the same patients leaving a total of 31 independent reports.
There were 23 kidney transplant studies with a total of 846
patients, 6 heart transplant studies with 233 patients, 1 liver
transplant study with 26 patients, and 1 bone marrow
transplant study with 17 patients. The study designs of the
qualifying studies include 21 randomized controlled trials
(RCTs), 2 non-RCTs, 6 prospective cohort studies, and 2 case
reports. Fish oil supplements were used in all but the heart
transplant studies.7 Since the biological effects of long-chain
omega-3 fatty acids (EPA and DHA) are different from ALA,
the results should be considered separately. As a result, the
findings of this report apply almost exclusively to fish oil
supplementation.
Twelve study authors of the largest controlled trials were
contacted (by telephone or E-mail or both) and, of them, five
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.
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.
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 seven deaths out of a total of
846 kidney transplant patients, all of which were reported in
three studies.8-10 A total of four patients died with a
functional graft within 1 year of transplant (one patient in the
fish oil group and three patients in the placebo group).8 One
patient died of myocardial infarction in the placebo group.9 In
a 9-month RCT, two patients in the fish oil group died due to
hemorrhagic shock from removal of native polycystic kidney
and intestinal infarction.10
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.8-16
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 1-year graft survival tended
to be better in the fish oil group, although results did not
achieve statistical significance.9 Two other RCTs showed no
statistically significant difference in 1-year graft and patient
survival rates between fish oil and placebo or control group.12,14
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. 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 percent CI 0.96, 1.05). There was no statistical
heterogeneity among studies.
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.8-12,14-20 The studies were all of low
or intermediate quality. In all but two studies (published in
three papers11,19,20), treatment had been initiated within 3 days
following transplantation. 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.
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.9 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 6 episodes of rejection in the
fish oil group compared with 10 in the control group at 1
month. In the second and third months, there was only 1 acute
rejection episode in the fish oil group compared with none 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 1 year (97 versus 84 percent, P = 0.097).
The other eight reports (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. Results for two 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.8,10 The pooled relative risk
of a rejection episode in those receiving fish oil
supplementation was 0.91 (95 percent CI 0.75, 1.11) in four
studies with a total of 224 subjects that reported the longest
followup (i.e., 1 year). There was no significant heterogeneity
among the studies. 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 six studies described a
variety of outcomes in a total of 233 heart transplant
recipients,7,21-25 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.
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).26
The study duration was only 2 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.27 A
separate report of the same patients 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.28
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?
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 immunoglobulin A (IgA)
nephropathy.29,30 The observation is potentially important since
some studies have found a benefit from fish oil
supplementation in IgA nephropathy in the non-transplant
setting.31,32
Eleven randomized-controlled trials in 14 publications and
one prospective cohort study reported the effects of fish oil
supplementation on GFR. 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 followup.9,12,15,33
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.8,9 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,9 GFR in the fish oil group increased
from 42 at 1 month to 45, to 49, and to 53 ml/min/1.73m2 at 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,8 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.9
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.15
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 nontransplant
setting.34 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.
Question 4. What is the evidence that omega-3 fatty acid
supplementation reduces serious infectious complications following
organ transplantation?
Infections are an important cause of morbidity and mortality
following all forms of organ transplantation. Animal and
limited human data suggest that supplementation with omega-3 fatty acids may modulate the host's ability to respond to
infections.35,36 However, no study included in this evidence
report described infectious outcomes. Thus, its benefit in the
transplant setting could not be determined.
Question 5. What is the evidence that any benefits to organ
transplant recipients from omega-3 fatty acid supplementation
differ in different subsets of patients?
Two controlled trials in kidney transplantation (with a total
of 53 patients in the fish oil group and 64 patients in the
coconut oil group), both from the same center, described
outcomes in patients with and without an episode of
rejection.17,18 In one of these reports, patients who had received
fish oil supplementation demonstrated a significantly better
recovery of renal function following an episode of
histologically-confirmed rejection.17 The authors concluded that
fish oil supplementation favorably influenced renal function in
the recovery phase following a rejection episode.
In an earlier report, the authors analyzed a subset of patients
without an episode of rejection during the course of study.18
Patients receiving fish oil had a significantly higher filtration
fraction, a significantly lower effective renal plasma flow (164
versus 262 mL/min per 1.73m2) and a significantly better
response of the GFR following amino acid infusion (15.3
versus 10.6 percent).
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)?
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. The data do not support a clear
relationship between the time in which the supplement was
begun and the treatment effect.
Question 7. What is the evidence in patients (adults or
children) who receive an organ transplant that the benefits of
omega-3 fatty acid supplementation interact with the concomitant
administration of various immunosuppressive agents/drugs?
No study in any of the types of transplantation provided a
detailed evaluation of the interaction between omega-3 fatty
acid supplementation and the various immunosuppressive
drugs, except for dosing of cyclosporine (discussed below).
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. Furthermore, no
study evaluated levels and dosages of all the
immunosuppressant drugs that were used concurrently.
The effect of fish oil supplementation on
immunosuppression was most fully described for CsA. Several
studies in kidney and heart transplantation reported trough and
total doses of CsA in patients who received or did not receive
omega-3 fatty acids. 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. A possible exception was one study
that suggested that fish oil supplementation may improve CsA
absorption and metabolism in kidney transplant patients.10
Question 9. What is the evidence in patients (adults or
children) who receive an organ transplant that omega-3 fatty acid
supplementation can replace or reduce the need for other more
potent anti-inflammatory or immunosuppressive drugs (such as
steroids and non-steroidal anti-inflammatory drugs)?
No study reported that fish oil supplementation reduced or
replaced the need for other more potent anti-inflammatory
drugs. Potential effects on CsA absorption are described above.
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 one study (and one 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 1 year 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.
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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 followup 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 followup studies in patients undergoing heart transplantation to determine whether there is a benefit on post-transplant coronary disease.
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Availability of Full Report
The full evidence report from which this summary was taken
was prepared for the Agency for Healthcare Research and
Quality (AHRQ) by the Tufts-New England Medical Center
Evidence-based Practice Center under Contract No. 290-02-0022. Printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295.
Requesters should ask for Evidence Report/Technology
Assessment No. 115, Effects of Omega-3 Fatty Acids on Organ Transplantation.
The Evidence Report is also online on the National Library of Medicine Bookshelf, or can be downloaded as a PDF File (2.3 MB). PDF Help.
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AHRQ Publication Number 05-E012-1
Current as of February 2005
Internet Citation:
Effects of Omega-3 Fatty Acids on Organ Transplantation. Summary, Evidence Report/Technology Assessment: Number 115. AHRQ Publication Number 05-E012-1, February 2005. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/o3orgsum.htm