The emerging paradox has been that despite impressive success in short-term renal allograft survival, longer-term graft survival remains unchanged, which is primarily because of poor long-term survival of cadaveric kidneys. Kidney transplants from live donors have much better long-term survival. An important distinction between these two types of kidney transplants is the cold ischemia suffered by cadaveric kidneys, which has averaged approximately 24 h over the last two decades. With prolonged cold ischemia, graft function is delayed and graft loss is increased. Although attempts are currently being made in the US to reduce cold ischemia time, the interactions among cold ischemic injury, delayed graft function and outcomes are so complex that even relatively short cold ischemic time can be deleterious in the presence of other risk factors (1). Therefore, limiting cold ischemic injury remains an important goal. In this issue of the Journal, Yard et al. demonstrate in endothelial cells that a number of catecholamine-related compounds, particularly dopamine and dobutamine, confer protection against cold storage injury (2). Using the European transplant database, this group has also shown that kidneys of donors that had received catecholamines before kidney retrieval were likely to have improved allograft survival (3). The exact mechanism of catecholamine-related protection reported by these investigators remains unclear, but it is likely to involve antioxidant mechanisms. For instance, these compounds have been shown to induce heme oxygenase-1 (HO-1) in the endothelial cells. HO-1 is a 32-kDa microsomal protein that catalyzes the degradation of heme. In the process, either through ferritin induction, antioxidant bilirubin production, or the cellular effects of carbon monoxide, or through a combination of these effects, HO-1 exhibits antioxidant and antiapotoic properties. In several transplant models, preinduction of HO-1 by metalloporphyrins before cold ischemia has been shown to limit injury in the post-transplant period (4), and therefore any potential benefit from pretreating donors with catecholamines could arise from its ability to recruit HO-1. Another tantalizing possibility suggested by Yard et al.'s present data is that catecholamines may act as a direct scavenger of free radicals. A short incubation of endothelial cells with catecholamines in the presence of inhibitors of protein synthesis, thus preventing HO-1 protein synthesis, still afforded protection against a cold injury (2). Although somewhat counterintuitive, free radical production has been shown to be increased in cells and organs kept in the cold, and direct inclusion of antioxidants such as iron chelator deferoxamine in cold storage have been shown to reduce cold-induced cellular necrosis and apoptosis (5). Because of the steps involved in clinical transplantation, pretreating donors, preconditioning donor kidneys or modifying cold storage solutions can be carried out in a controlled fashion. Therefore, prospective controlled studies are required to inform us whether catecholamine-related compounds have a role in reducing cold ischemic allograft injury and related consequences. The author's related work is supported by NIH grant RO-1 DK-56835–01. The author is grateful to Dr John Jenkins and Dr Henry Barber at the University of Mississippi Medical Center for their critical evaluation of this editorial.
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Jul 15, 2006
Gérard Rifle + 2
Open Access
