Marine n-3 polyunsaturated fatty acids in renal transplantation

To date, no observational studies and only small randomized controlled trials (RCTs) (42, 53-72) have studied the effects of marine n-3 PUFAs in RTRs (Table 2). Meta-analyses of these studies reported a significant reduction in plasma triglyceride levels, a minor reduction of diastolic blood pressure and slightly increased plasma high-density lipoprotein (HDL) cholesterol levels in patients who received marine n-3 PUFA supplements compared with controls (73-75). The effect of marine n-3 PUFA supplementation on renal graft function is unclear (73, 74). Due to a low number of events, meta-analyses of RCTs could not evaluate effects of marine n-3 PUFAs on mortality and graft loss incidence (7 deaths and 45 graft losses out of 846 patients) and acute rejection rates were not significantly different in the interventional group compared with the control group (73, 74).

Marine n-3 PUFAs might possibly improve patient survival in RTRs through various cardio-protective effects (Table 1). Uremic dyslipidemia is characterized by high triglyceride and low HDL cholesterol levels (76). Although renal transplantation improve lipid profiles (76), dyslipidemia is common in RTRs (22). Statin therapy, which primarily lower low-density lipoprotein (LDL) cholesterol, has been reported to lower the risk of major cardiovascular events in RTRs (77). At our center, three out of four RTRs receive statin therapy at one year post transplantation (20). A triglyceride-lowering effect of marine n-3 PUFAs has been repeatedly shown in various patient populations (37), also in patients on statin therapy (78).

Only a small cross-over study has investigated the additional effect of marine n-3 PUFA supplementation to statin therapy in RTRs and found that the combined treatment lowered triglyceride levels more efficiently than statins alone (72).

Patients with ESRD suffer a particularly high risk of sudden cardiac death (SCD) (79), and SCD is still prevalent after renal transplantation (22). Marine n-3 PUFAs lower resting heart rate and increase heart rate variability, which might reduce the risk of arrhythmias and SCD (44). To our knowledge, no previous study has investigated the relationship between marine n-3 PUFAs and heart rate in renal transplantation.

Marine n-3 PUFAs may possibly exert beneficial effects on renal grafts. EPA competes with n-6 PUFA arachidonic acid (AA) as substrate in the cyclooxygenase and lipoxygenase pathways. The cyclooxygenase pathway produces the prostaglandin hormones that initiate the inflammation process (30). Prostaglandins synthesized from EPA, as opposed to AA, are not pro-inflammatory (30). Specialized pro-resolving lipid mediators (protectins and resolvins),

synthesized from marine n-3 PUFAs in the cyclooxygenase pathway, reduce lymphocyte infiltration and inflammatory cytokine production (80). Another branch of the

cyclooxygenase pathway leads to synthesis of the vasoactive hormone thromboxane. AA derived thromboxane cause vasoconstriction, as opposed to thromboxane synthesized from EPA (30). Calcineurin inhibitors reduce blood flow into the glomeruli, which might reduce renal graft function (81). This side-effect might be counteracted by EPA (30, 42).

In the lipoxygenase pathway, EPA derived leukotrienes not only reduce vascular and bronchial constriction, but also the ability of leukocytes to detect cytokines, thereby reducing mitigation of leukocytes towards inflamed areas (30).

Inflammation causes release of both inflammatory and pro-fibrotic cytokines (31). Pro-inflammatory cytokines stimulate fibroblasts to synthesize and deposit proteins that intrude between cells (31). This process, called fibrosis, obliterates normal tissue structure and change the environment surrounding the cells, therefore also their function and increase the risk of cell death (31). Progressive fibrosis in the renal graft will eventually lead to graft failure (82). Marine n-3 PUFAs have been found to reduce fibroblast proliferation and collagen synthesis (31), which are essential steps in development and progression of fibrosis (83). Finally, EPA may exert immunomodulatory effects through upregulation of regulatory T-lymphocytes (33). These cells modulate the immune system to maintain tolerance to antigens and thereby not only reduce the tendency to reject a renal graft, but also reduce chronic low-grade inflammation (33). Anti-inflammatory effects of marine n-3 PUFAs are scarcely studied in RTRs (64).

Hypertension may cause renal damage (84). Marine n-3 PUFA supplementation has been found to lower blood pressure in both non-transplant and transplant populations (26, 55, 85).

Since the endothelium regulates vascular tone and permeability, endothelium dysfunction will impair renal function (86). Marine n-3 PUFAs may improve endothelial function (87). In renal transplantation, no interventional study has investigated the effects of marine n-3 PUFAs on arterial stiffness or endothelial function to date.

Table 2. Marine n-3 polyunsaturated fatty acids in renal transplantation. Studies performed to date. Panel A: Study characteristics.

Ref Yr First author Country

Base-line*

Dur-ation

Dose

EPA+DHA Placebo

Sample size

Lost#

%

(53) 89 Urakaze Japan 2yr 26w 2.2 g/day None 30 0

(54) 90 van der Heide Netherlands 3d 4w 3.0 g/day Coconut oil 31 0 (55) 90 van der Heide Netherlands 36w 12w 3.0 g/day Corn oil 21 14 (56) 92 van der Heide Netherlands 3d 4w 3.0 g/day Coconut oil 88 0 (57) 93 van der Heide Netherlands 3d 52w 3.0 g/day Coconut oil 66 9

(58) 92 Berthoux France 3d 52w 2.7 g/day None 32 9

(59) 94 Corda France 12w 27w 1.2 g/day Olive oil 23 0

(60) 95 Bennett US 16w 26w 2.7 g/day† Corn oil 90 32

(61) 95 Maachi France 3d 52w 2.4 g/day None 80 2

(62) 96

Kooijmans-

Coutinho Netherlands 3d 12w 3.0 g/day Coconut oil 50 9

(42) 98 Busnach Italy 1d 52w 2.6 g/day‡ Olive oil 42 0

(63) 00 Santos Portugal 2d 52w 3.0 g/day Unknown 60 0

(64) 02 Hernandez Spain 2d 12w 1.9 g/day Soy oil 91 0

(65) 89 Sweny UK 14 pts with chronic rejection. Marine n-3 PUFA, no placebo.

(66) 93 Schut Netherlands Cross-over, 29 pts. Marine n-3 PUFA 16w, corn oil 16w.

(67) 95 Hansen Denmark 18 pts + 9 healthy controls, both received marine n-3 PUFA 10w.

(68) 04 Singer Israel Parenteral marine n-3 PUFA to 8 donors and their recipients.

(69) 13 Sabbatini Italy 26 pts received diet rich in fatty fish vs no dietary advice Three studies have compared the effects of marine n-3 PUFAs vs statins after renal transplantation:

(70) 97 Castro Portugal 1yr 12w 3.0 g/day Simvastatin 43 0

(71) 97 Rodriguez Spain 26w 26w 3.0 g/day Lovastatin 34 6

(72) 01 Grekas Greece Cross-over, 24 pts. Pravastatin vs pravastatin + marine n-3 PUFA.

Abbreviations: yr: year, d: days, w: weeks, pts: patients, vs: versus, EPA: eicosapentaenoic acid, DHA:

docosahexaenoic acid. *: After time of transplantation. #: Lost to follow-up. †: Some patients received 5.4 g EPA+DHA / day. ‡: Some patients received 5.1 g EPA+DHA / day.

Table 2 continued. Panel B: Results.

Effects (interventional group compared with placebo group) on lipids, blood pressure, cyclosporine A trough levels and renal graft function (53) 0 / 0 0 / 0 0 / 0 No effect on triglyceride level, BP or graft function

(54) 0 / 0 0 / 0 3 / 6 No effect on BP, graft function or CyA level

(55) Lower BP, better graft function, no effect on CyA level

(56) 0 / 0 1 / 1 15 / 12 No effect on BP, graft function or CyA level

Better graft function, lower triglyceride levels, no effect on CyA or cholesterol levels

(62) 1 / 3 4 / 3 24 / 14 No effect on lipids, BP, graft function or CyA levels

(42) 2 / 0 2 / 2 3 / 3*

Better graft function, lower triglyceride and higher HDL cholesterol levels, no effect on total cholesterol or CyA levels

(63) 0 / 0 0 / 0 5 / 8 No effect on lipids, BP, graft function or CyA levels

(64) 0 / 0 6 / 4 20 / 19

Lower total cholesterol levels, no effects on triglycerides, BP, graft function or CyA levels. Effects on cytokines presented in section 9.6 (65)

Better graft function, lower triglyceride levels, no effect on cholesterol levels

(66) No effect on BP or graft function

(67) Lower BP, no effect on graft function or CyA levels

(68) No effect on graft function

(69) Lower triglyceride and cholesterol levels, no effect on graft function (70) 0 / 0 0 / 0 No difference in lipid levels between the groups

(71) 0 / 0 0 / 0

Lower triglyceride levels in the marine n-3 PUFA group and lower cholesterol levels in the statin group

(72) Lower triglyceride levels in the combined treatment group

I: Interventional group. P: Placebo group. BP: Blood pressure. CyA: Cyclosporine A. *: Patients, not episodes.

5.2 Marine n-3 polyunsaturated fatty acids in patients with chronic kidney disease