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Bonis P, Chung M, Tatsioni A, et al. Effects of Omega-3 Fatty Acids on Organ Transplantation. Rockville (MD): Agency for Healthcare Research and Quality (US); 2005 Feb. (Evidence Reports/Technology Assessments, No. 115.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Effects of Omega-3 Fatty Acids on Organ Transplantation.

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4Discussion

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

Overview

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

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

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

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

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

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

Main Findings

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

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

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

No benefit on early or late rejection episodes or graft survival was detected in meta-analyses in kidney transplantation. However, 1 study suggested that the total number of rejection episodes was 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.

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