Original Article
Effect of Dietary Fish Oil on Renal Function and Rejection in Cyclosporine-Treated Recipients of Renal Transplants
N Engl J Med 1993; 329:769-773September 9, 1993
- Abstract
Background
Dietary fish oil exerts effects on renal hemodynamics and the immune response that may benefit renal-transplant recipients treated with cyclosporine. To evaluate this possibility, we studied the effect of fish oil on renal function, blood pressure, and the incidence of acute rejection episodes in cyclosporine-treated recipients of renal transplants.
Methods
In a randomized, double-blind trial, 33 recipients of first cadaveric kidney transplants who were treated with cyclosporine and prednisolone ingested 6 g of fish oil daily during the first postoperative year (the fish-oil group), whereas another 33 renal-graft recipients treated with cyclosporine and prednisolone ingested 6 g of coconut oil daily for three months, after which time it was stopped (the control group).
Results
One year after transplantation, the fish-oil group had higher median values than the controls for glomerular filtration rate (53 vs. 40 ml per minute per 1.73 m2, P = 0.038) and effective renal plasma flow (214 vs. 178 ml per minute per 1.73 m2, P = 0.023) and lower mean arterial pressure (103 vs. 118 mm Hg, P = 0.0011). The cyclosporine doses in the two groups were similar. The cumulative number of rejection episodes was 20 in the controls, as compared with 8 in the fish-oil group (P = 0.029). One-year graft survival also tended to be better in the fish-oil group (97 vs. 84 percent, P = 0.097).
Conclusions
The daily administration of 6 g of fish oil during the first postoperative year has a beneficial effect on renal hemodynamics and blood pressure in renal-transplant recipients treated with cyclosporine. Although the fish-oil group had significantly fewer rejection episodes than the control group, graft survival at one year was not significantly better in the fish-oil group.
Media in This Article
Figure 1
Median Glomerular Filtration Rate 1, 3, 6, and 12 Months after Renal Transplantation in the Two Study Groups.Figure 2
Median Effective Renal Plasma Flow 1, 3, 6, and 12 Months after Renal Transplantation in the Two Study Groups.Article Activity
- Article
Cyclosporine has many side effects, the most important being nephrotoxicity1,2. The drug causes a dose-dependent, initially reversible decrease in the glomerular filtration rate and the effective renal plasma flow,3-5 often accompanied by an increase in blood pressure6 due to afferent arteriolar vasoconstriction7,8. The production of thromboxane A2,9 leukotriene C4, and leukotriene D4 10 is increased in cyclosporine-induced renal dysfunction. Thus, cyclosporine appears to disturb the balance in production between vasodilatory and vasoconstrictive eicosanoids. We previously demonstrated that in renal-transplant recipients with stable renal function, cyclosporine-induced renal dysfunction could be at least partly corrected by dietary supplementation with fish oil11.
Fish oil enhances the immunosuppressive effects of cyclosporine in rats with heart transplants12,13 and inhibits delayed hypersensitivity in the same animals13. Independently of cyclosporine, fish oil reduces the generation of cytokines such as interleukin-1,14,15 interleukin-2,15 interleukin-6,14,15 and tumor necrosis factor14,15 in both humans and rats. On the basis of these considerations, we investigated the effect of dietary supplementation with fish oil on renal function, blood pressure, and the incidence of acute rejection episodes in renal-transplant recipients treated with cyclosporine.
Methods
Study Design
The study was a randomized and initially double-blind comparison between a dietary regimen of 6 g of fish oil daily (30 percent eicosapentaenoic acid [C20:5, n-3] and 20 percent docosahexaenoic acid [C22:6, n-3] as their ethyl esters, with 1 IU of vitamin E per gram as an antioxidant) and a regimen of 6 g of coconut oil daily (containing medium-chain saturated fatty acids [63 percent C8:0 and 36 percent C10:0], with 1 IU of vitamin E per gram and 0.25 percent fish-flavor perfume, to make the coconut oil smell like fish oil). Fish oil and coconut oil were provided by Aerofako (Amersfoort, the Netherlands) in 0.5-g capsules made by Kortman Intradal (Amersfoort), and four capsules of the assigned treatment were given three times a day with meals.
The study included 66 patients who had each received a first cadaveric renal transplant. The administration of oil began three days postoperatively, and after three months the code was broken. The 33 patients ingesting fish oil (the fish-oil group) continued to do so, whereas oil treatment was stopped in the 33 patients assigned to coconut oil (the control group). These patients served as controls for the remainder of the study. Clinical and laboratory evaluations were performed 1, 3, 6, and 12 months postoperatively.
Compliance
Compliance with fish-oil ingestion was determined by analyzing plasma cholesterol esters after the preparation of a plasma total-lipid extract and the isolation of the cholesterol ester fraction by amino propyl-silica chromatography; the fatty acid composition was determined by capillary gas chromatography16. These analyses were performed before and six months after transplantation. In the fish-oil group the median 20:5 n-3 content of the plasma cholesterol esters increased from 0.39 (range, 0.18 to 1.67) mole percent ([mole/mole]/100) initially to 4.7 (0.89 to 10.31) mole percent (P<0.001) at six months, whereas there was no change in the control group. These results indicate that compliance with fish-oil ingestion was good.
Immunosuppression and Diagnosis and Treatment of Rejection
In both study groups cyclosporine (Sandoz, Basel, Switzerland) was administered intravenously (3 mg per kilogram of body weight per day) for the first 72 hours after transplantation, starting 6 hours after the revascularization of the graft, followed by the oral administration of 10 mg of cyclosporine per kilogram per day for two weeks, after which the dose was adjusted to maintain whole-blood drug concentrations of 200 ng per milliliter. The patients also received 20 mg of prednisolone daily for the first two weeks after transplantation, after which the dose was reduced by 2.5 mg every two weeks to 10 mg per day, which was used as the maintenance dose.
Rejection was suspected when the serum creatinine concentration rose or did not improve for three consecutive days in the absence of excessive trough cyclosporine concentrations. The diagnosis of rejection was based on graft swelling and tenderness, fever, sodium retention, blood eosinophilia, and the results of serial renal ultrasonography; it was confirmed histologically in all patients by percutaneous renal biopsy before the start of antirejection treatment.
Episodes of rejection were treated with intravenous doses of 1 g of methylprednisolone (Solu-Medrol, Upjohn, Kalamazoo, Mich.) daily for three to six days. In patients resistant to methylprednisolone, rabbit antithymocyte globulin (Anti-Humaan Thymocyten Globuline, RIVM, Bilthoven, the Netherlands) was given intravenously in a dose of 4 mg per kilogram every other day for five doses.
Dietary Composition
During hospitalization, the patients followed a daily diet containing 3 g of sodium chloride and 2.5 liters of fluid. Their intake of protein, potassium, and fatty acid was not restricted. After discharge they were urged to continue restricting their sodium intake.
Concomitant Medication and Treatment of Hypertension
Patients taking nonsteroidal antiinflammatory drugs, including acetylsalicylic acid, were excluded from the study. In the case of persistent hypertension (diastolic blood pressure repeatedly exceeding 95 mm Hg), patients were treated with a beta1-adrenergic-antagonist drug, in combination with a diuretic if necessary, or a centrally acting vasodilatory agent such as clonidine. Calcium-channel blockers were used only for antihypertensive rescue therapy in view of their potential interfering effects on renal hemodynamics17,18 and possible enhancement of the immunosuppressive action of cyclosporine19.
Measurement of Renal Function and Mean Arterial Pressure
The glomerular filtration rate and the effective renal plasma flow were measured with 125I-labeled iothalamate and 131I-labeled hippuran, respectively19. The filtration fraction was calculated as the glomerular filtration rate divided by the effective renal plasma flow. A 24-hour urine collection was obtained for the measurement of protein excretion before each clearance study.
Blood pressure was measured with a Hawksley random-zero sphygmomanometer. Mean arterial blood pressure was calculated with the following formula:
(systolic pressure + 2 × diastolic pressure) divided by 3.
Delayed postoperative renal-graft function was defined as the number of postoperative days when the urine volume was less than 1000 ml in the absence of a fall in the serum creatinine concentration, with optimal hydration.
Measurement of Blood Cyclosporine Concentrations
Whole-blood cyclosporine concentrations were measured by radioimmunoassay with a monoclonal anticyclosporine antibody (Sandoz) eight hours after a dose of the drug.
Statistical Analysis
The results are expressed as median values and ranges, unless otherwise indicated. Unpaired results were compared by a Mann-Whitney U test, and paired results by a two-tailed Wilcoxon test. Dichotomous variables were compared by chi-square analysis. P values less than 0.05 were considered to indicate statistical significance.
Results
Characteristics of the Patients
Of the 66 patients who entered the study, 58 were studied for 12 months. In the fish-oil group, one patient lost the renal graft because of acute postoperative arterial thrombosis, one patient stopped taking fish oil because of its fishy aftertaste, and one patient declined to undergo renal-function tests during follow-up. In the control group, one patient lost the graft because of a technical failure, three patients lost their grafts because of therapy-resistant rejection, and one patient died of myocardial infarction. All patients with surviving grafts were included in the analysis of renal function and mean arterial pressure, whereas the analysis of graft survival included all patients.
The characteristics of the patients are shown in Table 1Table 1
Characteristics of the Recipients and Donors in the Two Study Groups.. The two groups were comparable, except that acute postoperative oliguria or anuria was significantly less frequent in the fish-oil group.Cyclosporine Concentrations
The dose and whole-blood trough concentrations of cyclosporine are shown in Table 2Table 2
Cyclosporine Doses and Whole-Blood Trough Concentrations in the Two Study Groups 1, 3, 6, and 12 Months Postoperatively.. The dose and bioavailability of cyclosporine were similar in both groups throughout the follow-up period.Renal Function and Renal Hemodynamics
The median glomerular filtration rate was significantly higher at 3, 6, and 12 months in the fish-oil group than in the control group (Figure 1Figure 1
Median Glomerular Filtration Rate 1, 3, 6, and 12 Months after Renal Transplantation in the Two Study Groups.). The median values for the effective renal plasma flow were comparable 1 month after the operation but were higher in the fish-oil group at 3, 6, and 12 months (Figure 2Figure 2Median Effective Renal Plasma Flow 1, 3, 6, and 12 Months after Renal Transplantation in the Two Study Groups.). The filtration fraction was significantly higher in the fish-oil group one month after transplantation and remained so thereafter. The median values at 12 months were 0.25 (range, 0.12 to 0.32) in the fish-oil group and 0.22 (range, 0.12 to 0.33) in the control group (P = 0.009). The median 24-hour urinary protein excretion at 12 months was 0.2 g (range, 0 to 1) in the fish-oil group and 2.0 g (range, 0 to 18.9) in the control group (P = 0.008).Blood Pressure and Its Treatment
Table 3Table 3
Mean Arterial Pressure and Percentage of Patients Requiring Antihypertensive Therapy in the Two Study Groups 1, 3, 6, and 12 Months after Transplantation. shows the mean arterial pressure for the two groups, as well as the percentage of patients in each group who required antihypertensive therapy during the study. The patients in the fish-oil group had a significantly lower mean arterial pressure at all times, and they required significantly less antihypertensive therapy.Incidence and Treatment of Acute Rejection Episodes
During the first month after transplantation, there were 6 episodes of acute rejection in the fish-oil group, as compared with 10 in the control group. During the second and third months after transplantation, there was only one acute rejection episode in the fish-oil group as compared with nine in the control group (P = 0.016). In months 4 through 6 there were no rejection episodes in either group, but between month 6 and the end of month 12 there was one 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 control group (8 vs. 20, P = 0.029). Also, the patients in the fish-oil group received less additional methylprednisolone than the controls (0.71 vs. 2.56 g per patient, P = 0.013). The amount of methylprednisolone used per rejection episode did not differ (3.8 vs. 4.5 g per episode, P = 0.12). The same was true of the number of acute rejection episodes that were resistant to steroid treatment (2 of 8 episodes in the fish-oil group vs. 5 of 20 in the control group, P = 0.45).
Kaplan-Meier estimates of graft survival are shown in Figure 3Figure 3
Kaplan-Meier Estimates of Graft Survival One Year after Renal Transplantation in the Two Study Groups.. One-year graft survival tended to be better in the fish-oil group (P = 0.097).The median length of hospitalization during the year was 21.5 days (range, 12 to 57) in the fish-oil group as compared with 28 days (range, 15 to 110) in the control group (P = 0.089). The mean number of second admissions was 0.4 (range, 0 to 2) in the fish-oil group as compared with 1.1 (range, 0 to 5) in the control group (P = 0.023), and the second hospitalizations were significantly shorter (median duration, 2 days [range, 0 to 47] in the fish-oil group vs. 11 days [range, 0 to 57] in the control group; P = 0.003).
Adverse Effects
One patient stopped taking fish oil because of pyrosis, swallowing problems, and the fishy aftertaste of the oil. One danger associated with the intake of large amounts of n-3 polyunsaturated fatty acids may be impaired hemostasis20. There was no difference in the incidence of postoperative hemorrhage between the two groups, however. Prothrombin time, activated partial-thromboplastin time, and bleeding time were determined before every percutaneous renal biopsy, and no differences were found between the two groups.
Discussion
We demonstrated that fish-oil supplementation improves renal function, lowers mean arterial pressure, and reduces the incidence of episodes of acute rejection during the year after transplantation in cyclosporine-treated recipients of renal allografts, although it did not significantly alter one-year graft survival. The characteristics of the patients in the two groups were comparable, except for delayed postoperative graft function. However, when the patients with postoperative oliguria or anuria were excluded, the results of the analyses were similar, indicating that differences in postoperative renal function did not influence the results.
As expected, the glomerular filtration rate in both groups increased with the length of time after transplantation. The group treated with fish oil tended, however, to have higher glomerular filtration rates one month after transplantation, and the values in this group were significantly higher at all subsequent times. The effective renal plasma flow tended to rise in the fish-oil group and to decrease in the control group. The filtration fraction was also higher in the patients treated with fish oil. Mean arterial pressure was significantly lower in the patients in the fish-oil group, even though fewer of them needed antihypertensive treatment.
We previously reported that the glomerular filtration rate increased in response to the administration of amino acid and dopamine in patients treated with cyclosporine and fish oil,21 indicating that their improved renal function was not due to the loss of renal reserve filtration capacity. These results suggest that fish oil-induced hyperfiltration, possibly with detrimental long-term effects, is unlikely. Furthermore, the patients treated with fish oil had significantly less proteinuria despite a higher filtration fraction.
These results cannot be explained by differences in daily doses of cyclosporine or in cyclosporine trough concentrations, since both were comparable in the two groups. The fish-oil treatment did not influence the bioavailability of cyclosporine, in contrast to the findings of a recent study in rats treated with large doses of cyclosporine22. Dietary supplements with n-3 polyunsaturated fatty acids have moderate effects on renal hemodynamics in patients with many clinical conditions23. Although we did not measure prostaglandins in our patients, the effect of fish oil on eicosanoid production probably played an important part in the improved hemodynamic measurements in the fish oil-treated patients.
Marine n-3 fatty acids inhibit the production of thromboxane A2 in humans24. Eicosapentaenoic acid apparently competes with arachidonic acid in the cyclooxygenase pathway, thus limiting the production of thromboxane A2 25. Two studies of the short-term effect of thromboxane synthetase-inhibiting agents in renal-transplant recipients treated with cyclosporine have recently been reported. In one study, renal function did not change when thromboxane B2 production decreased by 81 percent,26 whereas in the other study the glomerular filtration rate increased during a blockade of thromboxane B2 production27. The increase in the glomerular filtration rate in this study was similar to that found after dietary intervention with fish oil in another trial of comparable design11. Interestingly, the combination of a thromboxane A2-receptor antagonist and a leukotriene C4/D4-receptor antagonist inhibited the fall in effective renal plasma flow in cyclosporine-treated rats,10 whereas dietary fish-oil supplements decreased the generation not only of leukotriene B4, but also of leukotriene C4 28. Thus, the effect of cyclooxygenase and lipoxygenase metabolites derived from dietary fish oil on cyclosporine-induced renal dysfunction may contribute to the favorable hemodynamic results in patients treated with fish oil.
The fish oil-treated patients had a significantly lower cumulative incidence of acute rejection episodes during the first postoperative year. This observation may explain the tendency toward favorable graft survival in these patients. The greatest difference in the incidence of acute rejection occurred between days 30 and 90 after transplantation -- a fact that may be attributed to the time lag needed to incorporate n-3 polyunsaturated fatty acids into the phospholipids of various cell membranes29.
Dietary fish oil may have immune-modulating effects30,31. This hypothesis is concordant with the effects of fish oil on the cyclooxygenase and lipoxygenase pathways and the resulting changes in the generation of eicosanoids, all important compounds in the sequence of renal-allograft rejection32. A fish oil-induced change in the leukotriene profile has been associated with a marked reduction in the chemotactic properties of leukocytes,33 as well as with reduced production of tumor necrosis factor alpha and interleukin-114. Decreased production of thromboxane A2 may also influence the rejection process34,35.
In summary, fish oil in a daily dose of 6 g has a favorable effect on renal hemodynamics and on the incidence of acute rejection in renal-transplant recipients treated with cyclosporine during the first year after transplantation.
Presented in part at the 6th International Congress on Nutrition and Metabolism in Renal Disease, Harrogate, United Kingdom, August 26-30, 1991, and at the 24th annual meeting of the American Society of Nephrology, Baltimore, November 17-20, 1991.
Supported by a grant (C89.835) from the Dutch Kidney Foundation (Nier Stichting Nederland).
We are indebted to Aerofako BV, Amersfoort, the Netherlands, for providing the capsules of fish oil and coconut oil; to Mrs. E. Konneman-van Zalk, Mrs. G. Dankert-von Duelmen Krumpelmann, and Mrs. S. Vorderman for their technical support; to Dr. S. Meijer for his assistance in the determination of the glomerular filtration rate and the effective renal plasma flow; and to Mrs. I. Martini and Dr. F.A.J. Muskiet from the Clinical Chemical Laboratory, University Hospital, Groningen, for the determination of the plasma cholesterol esters.
Source Information
From the Renal Transplant Division, Department of Internal Medicine, University Hospital, Groningen (J.J.H.H., A.M.T.); the Department of Internal Medicine, de Weezenlanden Hospital, Zwolle (H.J.G.B.); the Department of Internal Medicine, Free University Hospital, Amsterdam (J.M.D.); and the Renal Transplant Division, Department of Internal Medicine, Academic Medical Center, Amsterdam (J.M.W.) -- all in the Netherlands.
Address reprint requests to Dr. Homan van der Heide at the Renal Transplant Division, Department of Internal Medicine, University Hospital Groningen, Oostersingel 59, 9713 EZ Groningen, the Netherlands.
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