Does Ischemia-Reperfusion Injury After Solid Organ Transplantation Damage Native Organs?

CORRESPONDENCE Ischemia-reperfusion injury (IRI) is an unfortunate consequence of organ transplantation. During ischemia, macrophages and endothelial cells generate reactive oxygen species, nicotinamide adenine dinucleotide phosphate, nuclear factor-κB, nitric oxide synthases, and other proinflammatory cytokines. After blood reintroduces oxygen to the ischemic cells, the reactive oxygen species and cytokines activate neutrophils and alveolar macrophages further damaging cellular proteins, DNA, and plasma membranes. The damaged cells release allopeptides, glycolipids, and damage-associated molecular pattern molecules which are intracellular lipids and proteins that initiate and perpetuate the noninfectious inflammatory response. The allopeptides, damage-associated molecular pattern molecules, and glycolipids enter the circulation and are presented as foreign peptides or bind to the toll-like receptors on resident dendritic cells (DC), where an immune response is initiated. The triggered DCs interact with and activate natural killer (NK), NK T cells, and T cells (1). The activated lymphocytes release cytokines, activating other inflammatory cells, especially granulocytes and macrophages. This appears to be a mixed adaptive or innate immune response, and primary, secondary, and tertiary lymph organs, including the liver, augment IRI (Fig. 1).FIGURE 1: Schematic diagram of potentially important events leading to a systemic inflammatory response syndrome after organ transplantation. ROS, reactive oxygen species; NF-κB, nuclear factor-κB; NOS, nitric oxide synthases; DAMPS, damage-associated molecular pattern molecules; NK, natural killer.In this issue of Transplantation, Rancan et al. (2) confirmed previous studies demonstrating that IRI within the lung allograft might damage nontransplanted organs, namely, the liver, using a swine autotransplantation model. In addition, they showed that preconditioning with sevoflurane, a volatile anesthetic, attenuated these effects. Although these authors showed that lung IRI induced a proinflammatory cytokine response by measuring RNA and protein levels in the liver, they did not report an increase in liver enzymes, histologic evidence of leukocytes infiltration, or hepatocyte injury or apoptosis. Multiple studies have shown that volatile anesthetics can reduce the IRI in transplanted organs; however, no study has shown that it reduces the downstream effects outside the transplanted organ. In 2011, Casanova et al. (3) were the first to show that sevoflurane decreased the inflammatory response and oxidative stress in an ischemia-reperfusion swine auto lung transplant model. Volatile anesthetics may be protective in several ways. First, they decrease the Na, K-ATPase, and sodium channel activities within the cells of the lung decreasing their metabolic needs; and second, they decrease the tumor necrosis factor-α–induced microvascular endothelial permeability. Further studies are needed to determine if sevoflurane inhibits DC or NK-cell function. We analyzed the last 100 patients transplanted at our center to see if liver dysfunction was a notable downstream effect of lung transplantation. Surprisingly, posttransplant liver function testing was not routine so we were unable to determine if there was liver damage, even if transient, after transplantation. To further investigate, we reached out to the lung transplant programs at Duke University Medical Center in the United States (L. Snyder), University of Toronto Medical Center in Canada (S. Keshavjee), St Vincent’s Hospital in Australia (A. Glanville), University Hospital Zurich in Switzerland (A. Boehler), and Hospital Foch in France (M. Stern). The other centers followed liver function immediately after transplantation and only noted episodes of ischemic hepatitis from operative complications. In addition, none noted significant long-term issues with liver dysfunction other than associated with azole antifungal therapy or pretransplant underlying liver disease. Several factors may contribute to the absence of clinically significant native organ inflammation after lung transplantation in humans. First, all transplants are done using a volatile anesthetic, such as isoflurane or sevoflurane. Second, all transplants use high-dose corticosteroids before implantation, and the corticosteroids downregulate the ischemia-reperfusion inflammatory cascade by decreasing the numbers of circulating and organ-resident DCs, inhibiting interleukin-2 and tumor necrosis factor-α production and inhibiting a host of other proinflammatory mechanisms (4). Third, many centers use an induction agent at the time of transplant. Alemtuzumab and antithymocyte globulin suppress DC function and deplete a broad number of cell types, including most lymphocytes, which are thought to play a role in IRI. Additionally, basiliximab prevents the interleukin-2–induced differentiation and proliferation of NK-cells (5). Lastly, fluids and blood products may dilute transaminase levels in blood, making it harder to detect a signal. Hopefully, with the growing use of ex vivo lung perfusion, IRI will decrease. Glimpses of this are seen with a lower incidence of primary graft dysfunction (Cypel M, et al. Am J Transplant 2009;9:2262–9). The IRI is an unwanted consequence of lung transplantation, leading to primary graft dysfunction, earlier onset bronchiolitis obliterans, and increased mortality. Clinically, most of the effects seem to be contained within the allograft. However, there is no compelling reason to believe that the systemic inflammatory response induced by organ transplantation would remain limited to the more vulnerable transplanted organ. In addition, native organ injury after IRI may be transplant organ-dependent as some transplanted organs receive 100% of the cardiac output, such as the lungs, while other organs, such as the kidneys, only receive 10 to 15%. Clinicians should remain vigilant for “innocent bystander” injury to additional organs with the liver and kidney being two of the most susceptible ones.

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