The Combined Organ Effect

Robert J. Stratta, MD


November 24, 2008

The Combined Organ Effect: Protection against Rejection?

Rana A, Robles S, Russo MJ, et al
Ann Surg. 2008;248:871-879

The authors performed a retrospective analysis of United Network for Organ Sharing (UNOS) data on patients receiving deceased-donor transplants between January 1, 1994 and October 6, 2005. Exclusions included living-donor transplants, pediatric recipients (except intestinal transplants, where all ages were included), retransplants, and patients with insufficient follow-up. All patients were observed until death, retransplantation, or date of last known follow-up visit. A total of 133,416 patients were included in the analysis. Rates of acute rejection for allografts cotransplanted with a donor-specific primary liver (976 liver-kidney), heart (207 heart-kidney, 27 heart-liver), or kidney (210 kidney-heart, 1054 kidney-liver) were significantly lower in combined transplants compared with rejection rates in primary liver (n = 31,529), heart (n = 17,381), or kidney (n = 65,468) transplant recipients, respectively. Combined transplants involving the intestine or pancreas were not associated with lower rates of acute rejection. In addition, a decreased rate of acute rejection was reported in interval kidney-heart transplants when both allografts shared ≥1 HLA antigen. Finally, decreased rates of acute rejection were noted in double-lung AND double-kidney transplants compared with their respective single-organ counterparts. The authors concluded that these findings not only support the notion that the liver has immunoprotective properties against rejection, but also extend this observation to include kidney and heart allografts when used in combined transplants as well as interval transplants in the setting of shared-HLA antigens and double transplants involving the same organ.


A provocative and intriguing phenomenon in transplantation is the hierarchy of acute rejection that may occur not only with different organ transplants, but also when multiple organs are transplanted either sequentially from different donors or simultaneously from the same donor. A number of theories have been offered to explain this observation, including variations in antigen presentation, antigen load, immune recognition, and even partial tolerance. It is generally believed that the liver is the most tolerogenic of the solid organs that are currently transplanted and that any other organ that is cotransplanted with the liver is "protected" from rejection. In addition, in simultaneous kidney-pancreas transplantation, the kidney appears to have an immunoprotective effect on the pancreas, analogous to the immunoprotective effect of the heart on the lung in combined heart-lung transplantation. This study attempts to validate these clinical observations and take them a step further by suggesting that heart and kidney allografts may also be highly protective of another organ transplanted either simultaneously or subsequently. In addition, double-kidney and double-lung transplants may have lower rates of acute rejection than single-kidney or single-lung transplants, respectively. Possible explanations for these findings include closer follow-up and monitoring of dual- or sequential-organ recipients, the ability to use 1 organ as a marker for rejection in either organ, the presence of chronic immunosuppression at the time of subsequent transplantation in patients receiving an interval (second or sequential) transplant, passenger leukocytes and microchimerism, the induction of suppressor T cells, immune diversion or creation of an antigen "sink" in which 1 organ diverts the immune system away from the second organ, immune paralysis due to high antigen loads, and partial tolerance induced by the liver's ability to reduce the level of lymphocytotoxic antibodies and to release soluble class I antigens. Elucidation of the mechanisms of the immunoprotective effect of allografts in combined transplants may provide insights into the search for innovative strategies to reduce allograft rejection and the quest to achieve complete operational tolerance.



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