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      The effect of steroid pretreatment of deceased organ donors on liver allograft function: A blinded randomized placebo-controlled trial

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          Abstract

          Background & Aims

          Brain death-associated inflammatory response contributes to increased risk of impaired early liver allograft function, which might be counterbalanced by steroid pretreatment of the organ donor. The aim of this randomized controlled trial was to elucidate whether steroid pretreatment of liver donors improves early liver allograft function, prevents rejection and prolongs survival.

          Methods

          A placebo-controlled blinded randomized clinical trial was performed in three different centers in Austria and Hungary between 2006 and 2008. Ninety deceased organ donors received either 1000 mg of methylprednisolone or placebo 6 h before recovery of organs. The primary end point was the concentration slope of transaminases within the first week. The secondary end point included survival and biopsy-confirmed acute rejection (BCAR) within 3 years after transplantation.

          Results

          Of the 90 randomized donors, 83 recipients were eligible for study. The trajectories of ALT and AST were not different between treatments ( p = 0.40 and p = 0.13, respectively). Eight subjects died in the steroid and 13 in the placebo group within 3 years after engraftment (RR = 0.63 95% CI [0.29, 1.36], p = 0.31). Eleven recipients experienced biopsy-confirmed rejection (BCAR) in the steroid and 11 in the placebo group (RR = 1.02 95% CI [0.50, 2.10], p = 1.00). No effect modification could be identified in the predefined strata of donor age, sex, cold ischemic time, and cause of donor death.

          Conclusions

          Steroid pretreatment of organ donors did not improve outcomes after liver transplantation.

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          Most cited references16

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          High survival rates of kidney transplants from spousal and living unrelated donors.

          In the United States, increasing numbers of persons are donating kidneys to their spouses. Despite greater histoincompatibility, the survival rates of these kidneys are higher than those of cadaveric kidneys. We examined the factors influencing the high survival rates of spousal-donor kidneys. Kidney-transplant data from the United Network for Organ Sharing Renal Transplant Registry were used to calculate graft-survival rates with Kaplan-Meier analysis. The three-year survival rates were 85 percent for kidneys from 368 spouses, 81 percent for kidneys from 129 living unrelated donors who were not married to the recipients, 82 percent for kidneys from 3368 parents, and 70 percent for 43,341 cadaveric kidneys. The three-year survival rate for wife-to-husband grafts was 87 percent, which was the same as for husband-to-wife grafts if the wife had never been pregnant. If the wife had previously been pregnant, the three-year graft-survival rate was 76 percent (P = 0.40). The three-year graft-survival rate among recipients of spousal grafts who did not receive transfusions preoperatively was 81 percent, as compared with 90 percent for recipients who received 1 to 10 transfusions preoperatively (P = 0.008). The superior survival rate of grafts from unrelated donors could not be attributed to better HLA matching, white race, younger donor age, or shorter cold-ischemia times, but might be explained by damage due to shock before removal in 10 percent of the cadaveric kidneys. Spouses are an important source of living-donor kidney grafts because, despite poor HLA matching, the graft-survival rate is similar to that of parental-donor kidneys. This high rate of survival is attributed to the fact that the kidneys were uniformly healthy.
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            The utility of marginal donors in liver transplantation.

            The shortage of organs has led centers to expand their criteria for the acceptance of marginal donors. The combination of multiple marginal factors seems to be additive on graft injury. In this review, the utility of various marginal donors in patients requiring liver transplantation will be described, including older donors, steatotic livers, non-heart-beating donors, donors with viral hepatitis, and donors with malignancies. The pathophysiology of the marginal donor will be discussed, along with strategies for minimizing the ischemia reperfusion injury experienced by these organs. Finally, new strategies for improving the function of the marginal/expanded donor liver will be reviewed.
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              Brain death activates donor organs and is associated with a worse I/R injury after liver transplantation.

              The majority of transplants are derived from donors who suffered from brain injury. There is evidence that brain death causes inflammatory changes in the donor. To define the impact of brain death, we evaluated the gene expression of cytokines in human brain dead and ideal living donors and compared these data to organ function following transplantation. Hepatic tissues from brain dead (n = 32) and living donors (n = 26) were collected at the time of donor laparotomy. Additional biopsies were performed before organ preservation, at the time of transplantation and one hour after reperfusion. Cytokines were assessed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and cytometric bead array. Additionally, immunohistological analysis of tissue specimens was performed. Inflammatory cytokines including IL-6, IL-10, TNF-alpha, TGF-beta and MIP-1alpha were significantly higher in brain dead donors immediately after laparotomy compared to living donors. Cellular infiltrates significantly increased in parallel to the soluble cytokines IL-6 and IL-10. Enhanced immune activation in brain dead donors was reflected by a deteriorated I/R injury proven by elevated alanin-amino-transferase (ALT), aspartat-amino-transferase (AST) and bilirubin levels, increased rates of acute rejection and primary nonfunction. Based on our clinical data, we demonstrate that brain death and the events that precede it are associated with a significant upregulation of inflammatory cytokines and lead to a worse ischemia/reperfusion injury after transplantation.
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                Author and article information

                Journal
                J Hepatol
                J. Hepatol
                Journal of Hepatology
                Elsevier
                0168-8278
                June 2012
                June 2012
                : 56
                : 6
                : 1305-1309
                Affiliations
                [1 ]KH Elisabethinen, Linz, Austria
                [2 ]Department of Internal Medicine 3, Medical University of Vienna, Austria
                [3 ]Department of Transplantation, Medical University of Vienna, Austria
                [4 ]Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary
                Author notes
                [* ]Corresponding author. Address: Department of Internal Medicine 3, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria. Tel.: +43 1 40400 4390; fax: +43 1 40400 4392. rainer.oberbauer@ 123456meduniwien.ac.at
                [†]

                These authors contributed equally to this work.

                Article
                JHEPAT4125
                10.1016/j.jhep.2012.01.020
                3355301
                22326464
                e1779a2b-fa27-477f-9244-e049d3fd59f4
                © 2012 Elsevier B.V.

                This document may be redistributed and reused, subject to certain conditions.

                History
                : 17 October 2011
                : 12 January 2012
                : 23 January 2012
                Categories
                Research Article

                Gastroenterology & Hepatology
                ggt, glutamyl transpeptidase,bcar, biopsy-confirmed rejection,donor pretreatment,steroid,liver transplantation,ap, alkaline phosphatase,rai, reaction activity index,ast, aspartate transaminase,alt, alanine transaminase,alb, serum albumin,bil, total bilirubin,early liver allograft function

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