Kareem Abu-Elmagd

Intestinal transplant registry report: global activity and trends.

The Registry has gathered information on intestine transplantation (IT) since 1985. During this time, individual centers have reported progress but small case volumes potentially limit the generalizability of this information. The present study was undertaken to examine recent global IT activity. Activity was assessed with descriptive statistics, Kaplan–Meier survival curves and a multiple variable analysis. Eighty‐two programs reported 2887 transplants in 2699 patients. Regional practices and outcomes are now similar worldwide. Current actuarial patient survival rates are 76%, 56% and 43% at 1, 5 and 10 years, respectively. Rates of graft loss beyond 1 year have not improved. Grafts that included a colon segment had better function. Waiting at home for IT, the use of induction immune‐suppression therapy, inclusion of a liver component and maintenance therapy with rapamycin were associated with better graft survival. Outcomes of IT have modestly improved over the past decade. Case volumes have recently declined. Identifying the root reasons for late graft loss is difficult due to the low case volumes at most centers. The high participation rate in the Registry provides unique opportunities to study these issues.

Preformed and de novo donor specific antibodies in visceral transplantation: long-term outcome with special reference to the liver.

Despite improvement in early outcome, rejection particularly chronic allograft enteropathy continues to be a major barrier to long‐term visceral engraftment. The potential role of donor specific antibodies (DSA) was examined in 194 primary adult recipients. All underwent complement‐dependent lymphocytotoxic crossmatch (CDC‐XM) with pre‐ and posttransplant solid phase HLA–DSA assay in 156 (80%). Grafts were ABO‐identical with random HLA‐match. Liver was included in 71 (37%) allografts. Immunosuppression was tacrolimus‐based with antilymphocyte recipient pretreatment in 150 (77%). CDC‐XM was positive in 55 (28%). HLA–DSA was detectable before transplant in 49 (31%) recipients with 19 continuing to have circulating antibodies. Another 19 (18%) developed de novo DSA. Ninety percent of patients with preformed DSA harbored HLA Class‐I whereas 74% of recipients with de novo antibodies had Class‐II. Gender, age, ABO blood‐type, cold ischemia, splenectomy and allograft type were significant DSA predictors. Preformed DSA significantly (p < 0.05) increased risk of acute rejection. Persistent and de novo HLA–DSA significantly (p < 0.001) increased risk of chronic rejection and associated graft loss. Inclusion of the liver was a significant predictor of better outcome (p = 0.004, HR = 0.347) with significant clearance of preformed antibodies (p = 0.04, OR = 56) and lower induction of de novo DSA (p = 0.07, OR = 24). Innovative multifaceted anti‐DSA strategies are required to further improve long‐term survival particularly of liver‐free allografts.

Sanguineous normothermic machine perfusion improves hemodynamics and biliary epithelial regeneration in donation after cardiac death porcine livers

The effects of normothermic machine perfusion (NMP) on the postreperfusion hemodynamics and extrahepatic biliary duct histology of donation after cardiac death (DCD) livers after transplantation have not been addressed thoroughly and represent the objective of this study. Ten livers (5 per group) with 60 minutes of warm ischemia were preserved via cold storage (CS) or sanguineous NMP for 10 hours, and then they were reperfused for 24 hours with whole blood in an isolated perfusion system to simulate transplantation. In our experiment, the arterial and portal vein flows were stable in the NMP group during the entire reperfusion simulation, whereas they decreased dramatically in the CS group after 16 hours of reperfusion (Pu2009<u20090.05); these findings were consistent with severe parenchymal injury. Similarly, significant differences existed between the CS and NMP groups with respect to the release of hepatocellular enzymes, the volume of bile produced, and the levels of enzymes released into bile (Pu2009<u20090.05). According to histology, CS livers presented with diffuse hepatocyte congestion, necrosis, intraparenchymal hemorrhaging, denudated biliary epithelium, and submucosal bile duct necrosis, whereas NMP livers showed very mild injury to the liver parenchyma and biliary architecture. Most importantly, Ki‐67 staining in extrahepatic bile ducts showed biliary epithelial regeneration. In conclusion, our findings advance the knowledge of the postreperfusion events that characterize DCD livers and suggest NMP as a beneficial preservation modality that is able to improve biliary regeneration after a major ischemic event and may prevent the development of ischemic cholangiopathy in the setting of clinical transplantation. Liver Transpl 20:987–999, 2014.

JAK2 V617F mutation in patients with catastrophic intra-abdominal thromboses.

Catastrophic intra-abdominal thrombosis can result from a variety of prothrombotic states, including polycythemia vera and essential thrombocythemia, both of which are frequently associated with an acquired mutation (V617F) in the JAK2 gene. To assess the prevalence and clinical implications of this mutation in the setting of intra-abdominal thrombosis, JAK2 V617F genotyping was performed in 42 patients who had catastrophic intra-abdominal thromboses resulting in visceral transplants. The prevalence of V617F was compared with that of other prothrombotic states for which molecular testing is routinely performed. V617F mutations were detected in 7 patients (17%), who were not distinguishable on the basis of their peripheral blood cell counts. The median posttransplantation survival of V617F+ patients was 17.5 months, compared with 116.4 months for the V617F- patients (ratio, 6.6; 95% confidence interval, 6.3-7.0). These results highlight the diagnostic usefulness of JAK2 V617F testing in this setting and underscore the clinical significance of a positive result.

Ex Vivo Normothermic Machine Perfusion Is Safe, Simple, and Reliable: Results From a Large Animal Model

Introduction. Normothermic machine perfusion (NMP) is an emerging preservation modality that holds the potential to prevent the injury associated with low temperature and to promote organ repair that follows ischemic cell damage. While several animal studies have showed its superiority over cold storage (CS), minimal studies in the literature have focused on safety, feasibility, and reliability of this technology, which represent key factors in its implementation into clinical practice. The aim of the present study is to report safety and performance data on NMP of DCD porcine livers. Materials and Methods. After 60 minutes of warm ischemia time, 20 pig livers were preserved using either NMP (n = 15; physiologic perfusion temperature) or CS group (n = 5) for a preservation time of 10 hours. Livers were then tested on a transplant simulation model for 24 hours. Machine safety was assessed by measuring system failure events, the ability to monitor perfusion parameters, sterility, and vessel integrity. The ability of the machine to preserve injured organs was assessed by liver function tests, hemodynamic parameters, and histology. Results. No system failures were recorded. Target hemodynamic parameters were easily achieved and vascular complications were not encountered. Liver function parameters as well as histology showed significant differences between the 2 groups, with NMP livers showing preserved liver function and histological architecture, while CS livers presenting postreperfusion parameters consistent with unrecoverable cell injury. Conclusion. Our study shows that NMP is safe, reliable, and provides superior graft preservation compared to CS in our DCD porcine model.

EBV-Specific CD8+ T Cell Reactivation in Transplant Patients Results in Expansion of CD8+ Type-1 Regulatory T Cells

Posttransplantation lymphoproliferative disorders (PTLD) are life‐threatening complications of solid organ transplantation, triggered by EBV infection in chronically immunosuppressed (IS) patients. Our goal is to establish DC‐based protocols for adoptive immunotherapy of refractory PTLD, while understanding how the immunosuppressive drug environment may subvert DC‐EBV‐specific T cell interactions. Type‐1 CD8+ T cells are critical for efficient immune surveillance and control of EBV infection, whereas type‐2 or Treg/type‐3 responses may provide an environment conductive to disease progression. We have recently reported that chronic IS inhibits DC function in transplant patients. Here, we have analyzed the comparative ability of mature, type‐1 polarized DCs (i.e. DC1) generated from quiescent transplant patients or healthy controls, to boost type‐1 EBV‐specific CD8+ T cells in vitro. Our results show that unlike healthy controls, where DC1 loaded with MHC class I EBV peptides preferentially reactivate specific type‐1 CD8+ T cells, DC1 generated from transplant patients reactivate EBV‐specific CD8+ T cells that produce both IFN‐γ and IL‐10, up‐regulate FOXP3 mRNA, and suppress noncognate CD4+ T‐cell proliferation via cell–cell contact. These data support a novel regulatory pathway for anti‐EBV T‐cell‐mediated responses in IS transplant patients, with implications for the design of adoptive immunotherapies in this setting.

Immunologic challenges in small bowel transplantation.

Since the introduction of tacrolimus, small‐bowel and multivisceral transplantion has increased to 100–200/year in the United States. The intestine carries more passenger lymphocytes than other organs, and bidirectional trafficking of lymphocytes and other immunocytes begins as soon as the vascular clamp is released. Because of ischemia‐reperfusion injury and exposure to ligands for Toll‐like receptors from the lumen, the innate immune system of the graft is activated, causing inflammation which must be brought under control by regulatory cells. Inclusion of the liver in the allograft favors graft acceptance, but the mechanism of this effect has not been determined. Anti‐HLA and other anti‐donor antibodies clearly play a major role in determining the long‐term fate of the graft, as reflected in 5‐year graft survival. Development of new (de novo) HLA antibodies and/or increases in their titers or function—especially the ability to bind C1q and activate complement increase the risk of graft loss. Monitoring antidonor antibody production and the use of new therapies including complement inhibitors will contribute to increasing success of SBT.

Comparing Normothermic Machine Perfusion Preservation With Different Perfusates on Porcine Livers From Donors After Circulatory Death.

The utilization of normothermic machine perfusion (NMP) may be an effective strategy to resuscitate livers from donation after circulatory death (DCD). There is no consensus regarding the efficacy of different perfusates on graft and bile duct viability. The aim of this study was to compare, in an NMP porcine DCD model, the preservation potential of three different perfusates. Twenty porcine livers with 60u2009min of warm ischemia were separated into four preservation groups: cold storage (CS), NMP with Steen solution (Steen; XVIVO Perfusion Inc., Denver, CO), Steen plus red blood cells (RBCs), or whole blood (WB). All livers were preserved for 10u2009h and reperfused to simulate transplantation for 24u2009h. During preservation, the NMP with Steen group presented the highest hepatocellular injury. At reperfusion, the CS group had the lowest bile production and the worst hepatocellular injury compared with all other groups, followed by NMP with Steen; the Steen plus RBC and WB groups presented the best functional and hepatocellular injury outcomes, with WB livers showing lower aspartate aminotransferase release and a trend toward better results for most parameters. Based on our results, a perfusate that contains an oxygen carrier is most effective in a model of NMP porcine DCD livers compared with Steen solution. Specifically, WB‐perfused livers showed a trend toward better outcomes compared with Steen plus RBCs.

An international survey of cytomegalovirus prevention and treatment practices in intestinal transplantation.

Background Practice variation regarding cytomegalovirus (CMV) prevention and treatment across intestinal transplantation (IT) programs is unknown. Methods An electronic survey was sent to IT programs registered with the Intestinal Transplant Association. Proportions were analyzed for categorical variables; means and SDs were analyzed for continuous variables. Results Seventy-seven percent of IT programs responded to the survey. For CMV D+/R- recipients, 39.1% programs used universal prophylaxis (UP), 8.7% preemptive strategy (PE), and 52.2% hybrid strategy. For CMV R+ recipients, 45.8% programs used UP, 12.5% PE, 37.1% hybrid strategy, and 4.2% none. For CMV D-/R- recipients, 39.1% programs used UP, 21.7% PE, 26.1% hybrid strategy, and 13% none. Frequency of monitoring for PE was weekly 71.4% of programs, every 2 weeks 21.4%, and monthly 7.1%. For CMV viremia, syndrome and disease, the most common first-line agents used were ganciclovir (100% and 96.2%) and valganciclovir (23.1%) and the second-line agent was foscarnet (73.1% and 84.6%). Immunoglobulins were administered in 65.4% of the programs for pneumonia (69.2%), meningoencephalitis (50%), enteritis (46.2%), colitis (38.5%), syndrome (42.3%), viremia (30.8%), and resistant/refractory infections (11.5%). Conclusions Prophylaxis and hybrid strategy were the most commonly used. Treatment practices were consistent and mainly involved ganciclovir as first-line agent and foscarnet as second-line agent. The use of immunoglobulins appeared to be more common than in other allografts.

Intestinal transplantation: review of operative techniques.

The improvement of outcomes in intestinal transplantation (ITx) over the last two decades has been made possible through standardization in surgical techniques, improvements in immunosuppressive and induction protocols, and post‐operative patient care. From a surgical technical point of view, all different types of small bowel containing transplants can be categorized into three main prototypes, including isolated small bowel, liver–small bowel, and multivisceral transplantations. In this review, we describe these three main prototypes and discuss the most important technical modifications of each type, as well as donor and recipient procedures, and highlight the more recent operative technical topics of discussion in the literature.