A series of experiments using cardiac transplants in rats showed that a variety of amino acids and lipids when added to the diet in relatively high concentrations increased the survival of allografts when given with a short course of several immunosuppressive drugs in subtherapeutic doses. A prospectively randomized clinical trial was then done in patients with renal transplants which showed that the administration of nine grams of arginine and 30 ml of canola oil reduced the incidence of rejection significantly (p=0.01) during the posttransplant period between 30 days and 3 years. It also reduced the incidence of biopsy-proven calcineurin inhibitor toxicity (35.3% vs. 9.2%, p=0.002), sepsis (18.9% vs. 6.5%, p=0.05), new onset diabetes (14.5% vs. 2.3%, p=0.04) and cardiac events (17.1% vs. 4.6%, p=0.05). In a subsequent study in kidney transplant patients, some patients were treated with arginine and fish oil rather than arginine and canola oil. Fifty-four patients had blood samples performed preoperatively and postoperatively and 49 of these patients also had plasma amino acid profiles. When the concentration of omega-3 fatty acids in red blood cells was <6%, rejection rate was 18.5% compared to no rejections when the percentage of omega-3 fatty acids was >6% (p=0.01). An inverse relationship was seen with the omega-6 fatty acids and similar findings were seen with omega-3:omega 6 ratio and concentrations of docosahexaenoic acid and eicosapentaenoic acid independently. The concentration of omega-3 fatty acids in the red blood cell membranes have no significant relationship to the development of new onset diabetes mellitus, nor did the concentration of arginine. However, ornithine, the metabolic product of arginine, was significantly associated with prevention of new onset diabetes after transplant.

It is now evident that a combination of arginine and omega-3 fatty acids provides a more powerful effect than either alone, possibly through the development of myeloid-derived suppressor cells (MDSC). A proposed definitive prospective, placebo-controlled clinical trial of the use of arginine and fish oil is planned for the United States in the near future, but no studies have been done in liver transplant patients. It is highly probable that this simple, inexpensive and nontoxic therapeutic modality will have the same beneficial effects in hepatic transplantation that it has in kidney transplants.