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Este mes en... American Journal of Transplantation

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Este mes en... American Journal of Transplantation:

  • Kidney paired donation program versus global kidney exchange in India
    We read with interest the recent article on global kidney exchange (GKE) to overcome financial incompatibility in developing country for living kidney transplantation. Authors proposed that enabling GKE will overcome “poverty barrier” in developing countries and “immunologic barrier” in developed countries. The need for renal replacement therapy in India is staggering; only 2% of patients with renal failure were managed with kidney transplantation2. This article is protected by copyright. All rights reserved.
  • Comment: Kidney exchange to overcome financial barriers to kidney transplantation
    Rees et al. have shown the feasibility of global kidney exchange (GKE) to overcome financial cost and address the current shortage of organs for transplantation. Wiseman and Gill, question their interpretation of definition of “financial incompatibility”. The authors1 do not factor in the well documented cognitive and emotional aspects of kidney transplantation. Particularly, relevant to kidney transplantation is how patients calculate risk and the emotional turmoil characterised by anxiety and fear which are directly correlated to post-transplant adherence. This article is protected by copyright. All rights reserved.
  • Living Donor Uterus Transplantation: A Single Center's Observations and Lessons Learned from Early Setbacks to Technical Success
    Uterus transplantation is a vascularized composite allograft transplantation. It allows women who do not have a uterus to become pregnant and deliver a baby. In this paper we analyze the first 5 cases of Living Donor Uterus Transplantation performed in the US. The first 3 recipients lost their uterus grafts at day 14, 12 and 6 after transplant. Vascular complications, related to both inflow and outflow problems, were identified as the primary reason for the graft losses. Two recipients, 6 and 3 months post-transplant have functioning grafts with regular menstrual cycles. Ultimate success will be claimed only after a live birth. This paper is an in-depth analysis of evaluation, surgical technique and follow-up of these five living donor uterus transplants. The lessons learned were instrumental in allowing us to evolve from failure to technical and functional success. We aim to share our conclusions and build on the knowledge in the evolving field of uterus transplantation. This article is protected by copyright. All rights reserved.
  • Deciphering tacrolimus-induced toxicity in pancreatic β-cells
    β-cell transcription factors like: FoxO1, MafA, PDX-1, NeuroD, are dysfunctional in type 2 diabetes (T2DM). PTDM resembles T2DM and reflects interaction between pre-transplant insulin resistance and immunosuppressants, mainly calcineurin inhibitors. We evaluated the effect of tacrolimus, cyclosporine-A and metabolic stressors (glucose+palmitate) on insulinoma β-cells (INS-1) in vitro and in pancreata of obese and lean Zucker rats. Cells were cultured for five days with 100μM palmitate and 22mM glucose; cyclosporin-A (250ng/mL) or tacrolimus (15ng/mL) were added the last 48h. Glucose+palmitate increased nuclear FoxO1 and decreased nuclear MafA. Tacrolimus on top of glucose+palmitate magnified these changes in nuclear factors whereas cyclosporin-A did not. On top of glucose+palmitate, both drugs reduced insulin content and tacrolimus also affected insulin secretion. Tacrolimus withdrawal or conversion to cyclosporin-A restored these changes. Similar results were observed in pancreata of obese animals on calcineurin inhibitors. Tacrolimus and cyclosporin-A, on top of glucose+palmitate induced a comparable inhibition of calcineurin-NFAT. Thus, tacrolimus potentiates glucolipotoxicity in β-cells, possibly by sharing common pathways of β-cell dysfunction. Tacrolimus-induced β-cell dysfunction is potentially reversible. The inhibition of calcineurin-NFAT pathway may contribute to the diabetogenic effect of calcineurin inhibitors but does not explain the stronger of tacrolimus compared with cyclosporine-A. This article is protected by copyright. All rights reserved.
  • Considering tangible benefit for interdependent donors: Extending a risk-benefit framework in donor selection
    From its infancy, live donor transplantation has operated within a framework of acceptable risk to donors. Such a framework presumes that risks of living donation are experienced by the donor while all benefits are realized by the recipient, creating an inequitable distribution that demands minimization of donor risk. We suggest that this risk-tolerance framework ignores tangible benefits to donor. A previously proposed framework more fully considers potential benefits to the donor and argues that risks and benefits must be balanced. We expand on this approach, and posit that donors sharing a household with and/or caring for a potential transplant patient may realize tangible benefits that are absent in a more distantly related donation (e.g. cousin, non-directed). We term these donors, whose wellbeing is closely tied to their recipient, “interdependent donors.” A flexible risk-benefit model that combines risk assessment with benefits to interdependent donors will contribute to donor evaluation and selection that more accurately reflects what is at stake for donors. In so doing, a risk-benefit framework may allow some donors to accept greater risk in donation decisions. This article is protected by copyright. All rights reserved.
  • Prevention of the Osmotic Demyelination Syndrome after Liver Transplantation: A Multidisciplinary Perspective
    The osmotic demyelination syndrome (ODS) is a serious neurologic condition that occurs in the setting of rapid correction of hyponatremia. It presents with protean manifestations, from encephalopathy to the “locked-in” syndrome. ODS can complicate liver transplantation (LT), and its incidence may increase with the inclusion of serum sodium as a factor in the Model for End-Stage Liver Disease score. A comprehensive understanding of risk factors for the development of ODS in the setting of LT, along with recommendations to mitigate the risk of ODS, are necessary. The literature to date on ODS in the setting of LT was reviewed. Major risk factors for the development of ODS include severe pre-transplant hyponatremia (Serum sodium [SNa] < 125 mEq/L), the magnitude of change in SNa pre- vs. post-transplant, higher positive intraoperative fluid balance, and the presence of postoperative hemorrhagic complications. Strategies to reduce the risk of ODS include correcting hyponatremia pre-transplant via fluid restriction and/or ensuring an appropriate rate of increase from the preoperative SNa via close attention to fluid and electrolyte management both during and after surgery. Multidisciplinary management involving transplant hepatology, nephrology, neurology, surgery, and anesthesiology/critical care is key to performing LT safely in patients with hyponatremia. This article is protected by copyright. All rights reserved.
  • Blood chimerism in dizygotic monochorionic twins during five years observation
    Dizygotic monochorionic twin pregnancies can result in blood chimerism due to in utero twin-to-twin exchange of stem cells. In this case, we examined the proportion of allogeneic red blood cells (RBCs) by flow cytometry and the proportion of allogeneic nucleated cells by digital PCR at seven months and again at five years. We found an increase in the proportion of allogeneic cells from 63% to 89% in one twin, and a similar increase in autologous cells in the other twin from 57% to 84%. A paradigm for stem cell therapy could be modelled on this case: induction of tolerance and chimerism by antenatal transfusion of donor stem cells. The procedure would hold the promise of transplantation and tolerance induction without myelo-ablative conditioning for inheritable benign hematological diseases like sickle cell disease and thalassemia. This article is protected by copyright. All rights reserved.
  • Rat hindlimb cryopreservation and transplantation – A step towards “organ banking”
    In 2016 over 5 million reconstructive procedures were performed in the USA. The recent successes of clinical vascularized composite allotransplantations (VCA), hand and face transplantations included, established the tremendous potential of these life-enhancing reconstructions. Nevertheless, Due to limited availability and lifelong immunosuppression, application is limited. Long term banking of composite transplants may increase the availability of esthetically compatible parts with partial or complete HLA matching, reducing the risk of rejection and the immunosuppressive burden. The study purpose was to develop efficient protocols for the cryopreservation and transplantation of a complete rodent limb. Directional freezing is a method in which a sample is cooled at a constant velocity linear temperature gradient enabling precise control of the process and ice crystal formation. Vitrification is an alternative cryopreservation method in which the sample solidifies without the formation of ice crystals. Testing both methods on a rat hindlimb composite tissue transplantation model, we found reliable, reproducible and stable ways to preserve composite tissue. We believe that with further research and development cryopreservation may lead to composite tissue “banks”. This may lead to a paradigm shift from few and far apart emergent surgeries to wide scale, well planned, and better controlled elective surgeries. This article is protected by copyright. All rights reserved.
  • Reply to Comment on the Article “OPTN/SRTR 2015 Annual Data Report: Pancreas”
    The OPTN/SRTR Annual Data Report surveys all solid-organ transplants, and deceased donor recovery and transplant economics, and attempts to maintain methodological consistency across chapters. We include multivisceral transplants in each organ-specific chapter, unless otherwise noted in a figure caption, as the most practical approach for including all transplants in the survey. This article is protected by copyright. All rights reserved.
  • Effect of Empagliflozin on Tacrolimus-induced Pancreas Islet Dysfunction and Renal Injury
    An inhibitor of sodium glucose co-transporter type 2 (SGLT-2) is recommended in type 2 diabetes mellitus (DM) but its use is still undetermined in Tacrolimus (TAC)-induced DM. We evaluated the effect of empagliflozin (Em) on TAC-induced pancreatic islet dysfunction and renal injury in experimental model of TAC-induced DM and in vitro. TAC induced a two-fold increase in SGLT-2 expression, while Em decreased SGLT-2 expression and further increased urinary glucose excretion compared to the TAC group. Em reduced hyperglycemia and increased plasma insulin level, pancreatic islet size and glucose-stimulated insulin secretion (GSIS) compared to the TAC group. In kidney, Em alleviated TAC-induced renal dysfunction and decreased albumin excretion and histological injury compared with the TAC group. Increased oxidative stress and apoptotic cell death by TAC was remarkably decreased with Em in serum, pancreatic and renal tissues. In vitro study, TAC decreased cell viability and increased reactive oxygen species (ROS) production in both insulin secreting beta cell derived (INS-1) and human kidney-2 (HK-2) cell lines. Addition of Em increased cell viability and decreased ROS production in HK-2 but not in INS-1 cell lines. This suggests that Em is effective in controlling TAC-induced hyperglycemia and has direct protective effect on TAC-induced renal injury. This article is protected by copyright. All rights reserved.
  • Histological evolution of BK virus associated nephropathy: Importance of integrating clinical and pathological findings
    Long term clinicopathological studies of BK-associated nephropathy (PyVAN) are not available. We studied 206 biopsies (71 patients), followed 3.09±1.46y after immunosuppression reduction. The biopsy features (% SV40+staining and inflammation +/- acute rejection) were correlated with viral load dynamics and serum creatinine to define the clinicopathological status (PyVCPS). Incidence of acute rejection was 28% in the 2ndbiopsy and 50% subsequently (25% mixed TCMR+AMR; rejection overall affected 38% of patients (>50% AMR). Graft loss was 15.4% (0.8-5.3y after PyVAN); 76% had complete viral clearance (mean 28weeks). The only predictors of graft loss were acute rejection (TCMR p=0.008, any type p=0.07), and increased “t” and “ci” in the 2ndbiopsy (p=0.006 and 0.048). Higher peak viremia correlated with poorer viral clearance (p=.002). Presumptive and proven PyVAN had similar presentation, evolution and outcome. Late PyVAN (>2 years,9.8%) justifies BK viremia evaluation at any point with graft dysfunction and/or biopsy evaluation. This study describes the histological evolution of PyVAN and corresponding clinicopathological correlations. Although the pathological features overall reflect the viral and immunological interactions, the PyVAN course remains difficult to predict based on any single feature. Appropriate clinical management requires repeat biopsies and determination of the PyVCPS at relevant time points, for corresponding personalized immunosuppression adjustment. This article is protected by copyright. All rights reserved.
  • A Transplant Specific Quality Initiative – Introducing TransQIP: a joint effort of the ASTS and ACS
    In an attempt to improve surgical quality in the field of transplantation, the American College of Surgeons (ACS) and American Society and Transplant Surgeons have initiated a national quality improvement program in transplantation. This transplant specific quality improvement program, called TransQIP, has been built from the ground up by transplant surgeons and captures detailed information on donor and recipient factors as well as transplant specific outcomes. It is built upon the existing ACS/NSQIP infrastructure and is designed to capture 100% of liver and kidney transplants performed at participating sites. TransQIP has completed its alpha pilot and will embark upon its beta phase at approximately 30 centers in the spring of 2017. Going forward, we anticipate TransQIP will help satisfy Centers for Medicare and Medicaid Services (CMS) requirements for a quality improvement program, surgeon requirements for maintenance of certification and qualify as a clinical practice improvement activity under the Merit-Based Incentive Payment System (MIPS). Most importantly, we believe TransQIP will provide insight into surgical outcomes in transplantation that will allow the field to provide better care to our patients. This article is protected by copyright. All rights reserved.
  • The Resurgence of Xenotransplantation
    There has been an upsurge of interest in xenotransplantation in recent years. This resurgence can attributed to a combination of factors. First, there has been a dramatic improvement in efficacy in several preclinical models, with maximum xenograft survival times increasing to 950 days for islets, 945 days for hearts, and 310 days for kidneys. Second, the rapid development of genome editing technology (particularly the advent of CRISPR/Cas9) has revolutionized the capacity to generate new donor pigs with multiple protective genetic modifications; what once took many years to achieve can now be performed in months, with much greater precision and scope. Third, the spectre of porcine endogenous retrovirus (PERV) has receded significantly. There has been no evidence of PERV transmission in clinical trials and preclinical models, and improved screening methods and new options for the treatment or even elimination of PERV are now available. Balancing these positive developments are several remaining challenges, notably the heavy and often clinically inapplicable immunosuppression required to prevent xenograft rejection. Nonetheless, the potential for xenotransplantation as a solution to the shortage of human organs and tissues for transplantation continues to grow. This article is protected by copyright. All rights reserved.
  • Improved Time to Notification of Impending Brain Death and Increased Organ Donation using an Electronic Clinical Decision Support System
    Early referral of patients to an organ procurement organization (OPO) may positively impact donation outcomes. We implemented an electronic clinic decision support (CDS) system to automatically notify our OPO of children meeting clinical triggers indicating impending brain death. Medical records of all patients who died in a pediatric critical care unit or were referred for imminent death for three years prior to installation of the initial CDS (pre-CDS) and for one year after implementation of the final CDS (post-CDS) were reviewed. Mean time to OPO notification decreased from 30.2 hours pre-CDS to 1.7 hours post-CDS (p=0.015). Notification within one hour of meeting criteria increased from 36% pre-CDS to 70% post-CDS (p=0.003). Although an increase in donor conversion from 50% pre-CDS to 90% post-CDS did not reach statistical significance (p=0.0743), there were more organ donors post-CDS (11 of 24 deaths) than pre-CDS (7 of 57 deaths; p=0.002). Positive outcomes were achieved with the use of a fully automated CDS system while simultaneously realizing few false positive notifications, low costs, and minimal workflow interruption. Use of an electronic clinical decision support system in a pediatric hospital setting improved timely OPO notification and was associated with increased organ donation. This article is protected by copyright. All rights reserved.
  • Risk of thyroid cancer among solid organ transplant recipients
    Solid organ transplant recipients have an elevated incidence of thyroid cancer. We evaluated a wide range of potential risk factors in a cohort of 229,300 U.S. solid organ transplant recipients linked with 15 stage/regional cancer registries (1987-2012). Incidence rate ratios (IRRs) were adjusted for age, sex, race/ethnicity, transplanted organ, year of transplant, and time since transplant. Hazards ratios (HRs) for death and/or graft failure were adjusted for age, sex, race/ethnicity, transplanted organ, and year of transplant. Following transplant, 356 thyroid cancers were diagnosed. Thyroid cancer incidence was 2.50-fold higher in transplant recipients than the general population (95%CI 2.25-2.77). Among recipients of different organs, kidney recipients had the highest incidence of thyroid cancer (IRR=1.26, 95%CI 1.03-1.53). Elevated thyroid cancer incidence was associated with cholestatic liver disease/cirrhosis as an indication for liver transplant (IRR=1.69, 95%CI 1.09-2.63), hypertensive nephrosclerosis as an indication for kidney transplant (IRR=1.41, 95%CI 1.03-1.94), and longer prior dialysis among kidney recipients (5+ versus <1 year, IRR=1.92, 95%CI 1.32-2.80;P-trend<0.01). Post-transplant diagnosis of thyroid cancer was associated with modestly increased risk of death (HR=1.33, 95%CI 1.02-1.73). Overall, our results suggest that end-stage organ disease and longer duration of dialysis may contribute to higher thyroid cancer incidence in transplant recipients. This article is protected by copyright. All rights reserved.
  • Depletion-resistant CD4 T cells enhance thymopoiesis during lymphopenia
    Lymphoablation is routinely used in transplantation, and its success is defined by the balance of pathogenic versus protective T cells within reconstituted repertoire. While homeostatic proliferation and thymopoiesis may both cause T cell recovery during lymphopenia, the relative contributions of these mechanisms remain unclear. The goal of this study was to investigate the role of the thymus during T cell reconstitution in adult allograft recipients subjected to lymphoablative induction therapy. Compared to euthymic mice, thymectomized heart allograft recipients demonstrated severely impaired CD4 and CD8 T cell recovery and prolonged heart allograft survival after lymphoablation with murine anti-thymocyte globulin (mATG). The injection with agonistic anti-CD40 mAb or thymus transplantation only partially restored T cell reconstitution in mATG treated thymectomized mice. Following mATG depletion, residual CD4 T cells migrated into the thymus following lymphoablation and enhanced thymopoiesis. Conversely, depletion of CD4 T cells prior to lymphoablation inhibited thymopoiesis at the stage of CD4-CD8-CD44hiCD25+ immature thymocytes. This is the first demonstration that the thymus and peripheral CD4 T cells cooperate to ensure optimal T cell reconstitution following lymphoablation. Targeting thymopoiesis through manipulating functions of depletion-resistant helper T cells may thus improve therapeutic benefits and minimize risks of lymphoablation in clinical settings. This article is protected by copyright. All rights reserved.
  • Geographic Disparities in Liver Availability: Accidents of geography or consequences of poor social policy?
    Recently, a redistricting proposal intended to equalize MELDs recommended expanding liver sharing to mitigate geographic variation in liver transplantation. Yet, it is unclear whether variation in liver availability is arbitrary and a disparity requiring rectification, or whether it reflects differences in access to care. We evaluate the proposal's claim that organ supply is an “accident of geography” by examining the relationship between local organ supply and the uneven landscape of social determinants and policies that contribute to differential death rates across the United States. We show that higher mortality leading to greater availability of organs may partly result from disproportionate risks incurred at the local-level. Disparities in public safety laws, healthcare infrastructure, and public funding may influence the risk of death and subsequent availability of deceased donors. These risk factors are disproportionately prevalent in regions with high organ supply. Policies calling for organ redistribution from high-supply to low-supply regions may exacerbate existing social and health inequalities by redistributing the single benefit (greater organ availability) of greater exposure to environmental and contextual risks (e.g. violent death, healthcare scarcity). Variation in liver availability may not be an “accident of geography”, but rather a byproduct of disadvantage. This article is protected by copyright. All rights reserved.
  • Post-Transplant Lymphoproliferative Disorder Following Clinical Islet Transplantation: Report of the First Two Cases
    We report the first two cases of post-transplant lymphoproliferative disorder (PTLD) in recipients of islet transplants worldwide. First, a 44-year old recipient of 3 islet infusions developed PTLD 80 months after his initial transplant, presenting with abdominal pain and diffuse terminal ileum thickening on imaging. He was treated with surgical excision, reduction of immunosuppression and rituximab. Seven months later he developed central nervous system PTLD, presenting with vertigo and diplopia; immunosuppression was discontinued, resulting in graft loss, and he was given high-dose methotrexate and consolidative autologous stem cell transplant. He remains in remission 37 months after initial diagnosis. Second, a 58-year old female recipient of 2 islet infusions developed PTLD 24 months after initial islet infusion, presenting with pancytopenia secondary to extensive bone marrow involvement. Immunosuppression was discontinued, resulting in graft loss, and she received rituximab and chemotherapy, achieving complete remission. Both cases were monomorphic B-cell PTLD subtype by histology and negative for EBV in tissue or blood. These cases document the first occurrences of this rare complication in islet transplant, likely secondary to prolonged, intensive immunosuppression, and highlight the variable clinical manifestations of PTLD. Further studies are needed to determine incidence rate and risk factors in islet transplantation. This article is protected by copyright. All rights reserved.
  • Vascularized Composite Allograft (VCA) Donation and Transplantation: A Survey of Public Attitudes in the United States
    Vascularized composite allograft (VCA) transplantation has emerged as a groundbreaking surgical intervention to return identity and function following traumatic injury, congenital deformity, or disfigurement. While public attitudes toward traditional organ/tissue donation are favorable, little is known about attitudes toward VCA donation and transplantation. A survey was conducted of 1,485 U.S. residents in August 2016 to assess VCA donation attitudes. Participants also completed the Revised Health Care System Distrust Scale. Most respondents were willing to donate hands/forearms (67.4%) and legs (66.8%), and almost half (48.0%) were willing to donate the face. Three-quarters (74.4%) of women were willing to donate the uterus; 54.4% of men were willing to donate the penis. VCA donation willingness was more likely among whites and Hispanics (p<0.001), registered organ/tissue donors (p<0.001), and those with less healthcare system distrust (p<0.001) and media exposure to VCA transplantation (p=0.003). Many who opposed VCA donation expressed concerns about psychological discomfort, mutilation, identity loss, and the reaction of others to seeing familiar body parts on a stranger. Attitudes toward VCA donation are favorable overall, despite limited exposure to VCA messaging and confusion about how VCA donation occurs. These findings may help guide the development and implementation of VCA public education campaigns. This article is protected by copyright. All rights reserved.
  • About the opt-out system, live transplantation and information to the public on organ donation in Spain … Y olé!
    We have read with interest Sharif's letter regarding our publication on the strategies developed in Spain to progress towards self-sufficiency in transplantation.1 The recognition of the efforts made along the years to achieve high levels of deceased donation (43.4 donors pmp in 2016), well summarized by his ‘Viva España’, is highly appreciated. This article is protected by copyright. All rights reserved.
  • HLA mismatching favoring host-versus-graft NK cell activity via KIR3DL1 is associated with improved outcomes following lung transplantation
    Chronic lung allograft dysfunction (CLAD) is linked to rejection and limits survival following lung transplantation. HLA-Bw4 recipients of HLA-Bw6 grafts have enhanced host-versus-graft (HVG) NK cell activity mediated by KIR3DL1 ligand. Because natural killer (NK) cells may promote tolerance by depleting antigen-presenting cells, we hypothesized improved outcomes for HLA-Bw4 recipients of HLA-Bw6 grafts. We evaluated differences in acute cellular rejection (ACR) and CLAD-free survival across 252 KIR3DL1+ recipients from UCSF. For validation, we assessed survival and freedom from BOS, retransplantation, or death in 12,845 non-KIR typed recipients from the UNOS registry. Cox proportional hazards models were adjusted for age, gender, ethnicity, transplant type, and HLA mismatching. HVG-capable subjects in the UCSF cohort had a decreased risk of CLAD or death (HR 0.57, 95% CI 0.36-0.88) and decreased early lymphocytic bronchitis. The HVG effect was not significant in subjects with genotypes predicting low KIR3DL1 expression. In the UNOS cohort, HVG-capable subjects had a decreased risk of BOS, retransplant, or death (HR 0.95, 95% CI 0.91-0.99). Survival improved with the higher affinity Bw4-80I ligand and in Bw4 homozygotes. Improved outcomes in HVG-capable recipients are consistent with a protective NK cell role. Augmentation of NK activity could supplement current immunosuppression techniques. This article is protected by copyright. All rights reserved.
  • Normothermic Ex Vivo Kidney Perfusion Following Static Cold Storage -NDASH- Brief, Intermediate, or Prolonged Perfusion for Optimal Renal Graft Reconditioning?
    Normothermic ex vivo kidney perfusion (NEVKP) demonstrated superior results compared to hypothermic storage in donation after circulatory death (DCD) kidney transplantation. It is unknown whether an optimal perfusion time exists following hypothermic storage to allow for the recovery of renal grafts from cold ischemic injury. In a porcine model of DCD kidney autotransplantation, the impact of initial static cold storage (SCS) (8h) followed by various periods of NEVKP recovery was investigated: group A) 8hSCS only (control), group B) 8hSCS+1hNEVKP (brief NEVKP), group C) 8hSCS+8hNEVKP (intermediate NEVKP), and group D) 8hSCS+16hNEVKP (prolonged NEVKP). All grafts were preserved and transplanted successfully. One animal in group D) was sacrificed and excluded by postoperative day 3 due to hind limb paralysis, but demonstrated good renal function. Postoperative graft assessment during 8 days follow up demonstrated lowest levels of peak serum creatinine for intermediate (C) and prolonged NEVKP (D) (p=0.027). Histological assessment on day 8 demonstrated a significant difference in tubular injury (p=0.001) with highest values for group B. These results suggest that longer periods of NEVKP following SCS are feasible and safe for postponing surgical transplant procedure and superior to brief NEVKP reducing the damage caused during cold ischemic storage of renal grafts. This article is protected by copyright. All rights reserved.
  • BK virus nephropathy: histological evolution by sequential pathology
    Reactivation of BK virus in renal allografts causes a destructive chronic infection. This single-centre, retrospective, cohort study describes the evolution of BK virus allograft nephropathy (BKVAN) from 63 kidneys (n=61 patients) using sequential histopathology (n=454 biopsies, averaging 7.8±2.6/kidney) followed for 60.1 months. Uninfected protocol biopsies formulated time-matched control Banff scores (n=975). This article is protected by copyright. All rights reserved.
  • Chronic allograft deterioration -NDASH- a clinical reality in vascularized composite allotransplantation
    The first successful transplantation of a vascularized composite tissue allotransplantation (VCA)-NDASH- a hand -NDASH- was achieved in 1998. However, it was not until the first partial face transplant was performed in France in 2005 that the world first witnessed with fascination the vast implications of vascularized composite allotransplantation (VCA). Since then, there have been over 107 upper extremities and 35 face transplantations, with the longest follow up of 18 years for hand transplantation (1), and 10 years for face transplantation. Given the facts that the average half life of a kidney transplant is about 10 years, and the numbers of VCA are so small, the true half life of VCA remains subject to speculation. This article is protected by copyright. All rights reserved.
  • A memory B cell crossmatch assay for quantification of donor-specific memory B cells in the peripheral blood of HLA-immunized individuals
    Humoral responses against mismatched donor HLA are routinely measured as serum HLA antibodies, which are mainly produced by bone-marrow residing plasma cells. Individuals with a history of alloimmunization but lacking serum antibodies may harbor circulating dormant memory B cells, which may rapidly become plasma cells upon antigen re-encounter. Currently available methods to detect HLA-specific memory B cells are scarce and insufficient in quantifying the complete donor-specific memory B cell response due to their dependence on synthetic HLA molecules. Here we present a highly sensitive and specific tool for quantifying donor-specific memory B cells in peripheral blood of individuals using cell lysates covering the complete HLA class I and class II repertoire of an individual. Using this ELISPOT assay, we found a median frequency of 31 HLA class I and 89 HLA class II-specific memory B cells per million IgG producing cells directed at paternal HLA in peripheral blood samples of women (n=22) with a history of pregnancy using cell lysates from spouses. The donor-specific memory B cell ELISPOT can be utilized in HLA diagnostic laboratories as a cross-match assay to quantify donor-specific memory B cells in patients with a history of sensitizing events. This article is protected by copyright. All rights reserved.
  • Prolonged cold ischemia time results in local and remote organ dysfunction in a murine model of vascularized composite transplantation
    Vascularized composite allotransplantation (VCA) is a viable reconstructive option for complex tissue defects. Although grafts with large muscular component may be uniquely susceptible to ischemia/reperfusion (I/R) syndrome, the safe cold ischemia time in VCA has not been established. We investigated the effects of cold ischemia on innate immune response and recipient survival in a murine orthotopic hindlimb transplantation model. Surprisingly, mice receiving grafts exposed to 6h or longer of cold storage demonstrated reduced survival and massive elevations in serum creatinine, BUN and creatine kinase, as compared to 1h of cold storage recipients. This was accompanied by progressive increase in macrophage and neutrophil cell infiltration in muscle biopsies, altered platelet endothelial cell adhesion molecule-1 (PECAM-1) expression and ultimate renal injury. Multiplex immunoassay analysis identified 21 cytokines in serum and 18 cytokines in muscle biopsies that are likely essential in the complex response to I/R-triggered injury in VCA. In conclusion, this study in a mouse model of orthotopic hindlimb transplantation, is the first to document that prolonged cold ischemia triggers progressive I/R injury with vascular endothelial damage, and may lead to irrecoverable local and remote organ damage. These experimental findings are important in guiding future therapies for human VCA recipients This article is protected by copyright. All rights reserved.
  • Cum hoc sed non propter hoc
    We are thankful to Carter and colleagues for their interest in our recently published paper (1). Analyzing the cases of 42 pancreas islet recipients from the GRAGIL network, we confirmed that pancreas islet grafting is an HLA-sensitizing event. In our cohort, ∼1/3 of islet graft recipients developed alloantibodies directed against mismatched HLA molecules expressed by the graft. This article is protected by copyright. All rights reserved.
  • Incidence and predictors of cancer following kidney transplantation in childhood
    Cancer risk is increased substantially in adult kidney transplant recipients, but the long-term risk of cancer in childhood recipients is unclear. Using the Australian and New Zealand Dialysis and Transplant Registry, the overall and site-specific incidences of cancer after transplantation in childhood recipients were compared with population-based data using standardized incidence ratios (SIR). Among 1734 childhood recipients (median age 14 years, 57% male, 85% white), 289 (16.7%) developed cancer (196 non-melanoma skin cancers, 143 non-skin cancers) over a median follow-up of 13.4 years. The 25-year cumulative incidences of any cancer were 27% (95% confidence intervals, 24-30%), 20% (17-23%) for non-melanoma skin cancer and 14% (12-17%) for non-skin cancer (including melanoma). The SIR for non-skin cancer was 8.23 (6.92-9.73), with the highest risk for post-transplant lymphoproliferative disease (SIR 45.80, 32.71-62.44) and cervical cancer (29.4, 95%CI 17.5-46.5). Increasing age at transplantation (adjusted hazard ratio [aHR] per year 1.10, 95%CI 1.06-1.14), white race (aHR 3.36, 95%CI 1.61-6.79) and having a functioning transplant (aHR 2.27, 95%CI 1.47-3.71) were risk factors for cancer. Cancer risk, particularly for viral related cancers, is increased substantially after kidney transplantation during childhood. This article is protected by copyright. All rights reserved.
  • The Influence of End-of-Life Care on Organ Donor Potential
    Many patients with acute devastating brain injury die outside intensive care units and could go unrecognized as potential organ donors. We conducted a prospective observational study in seven hospitals in the Netherlands to define the number of unrecognized potential organ donors outside intensive care units, and to identify the effect that end-of-life care has on organ donor potential. Records of all patients who died between January 2013 and March 2014 were reviewed. Patients were included if they died within 72 hours after hospital admission outside the intensive care unit due to devastating brain injury, and fulfilled the criteria for organ donation. Physicians of included patients were interviewed using a standardized questionnaire regarding logistics and medical decisions related to end-of-life care. Of the 5,170 patients screened, we found 72 additional potential organ donors outside intensive care units. Initiation of end-of-life care in acute settings and lack of knowledge and experience in organ donation practices outside intensive care units can result in under-recognition of potential donors equivalent to 11-34% of the total pool of organ donors. Collaboration with the intensive care unit and adjusting the end-of-life path in these patients is required to increase the likelihood of organ donation. This article is protected by copyright. All rights reserved.
  • Novel magnetic resonance imaging for assessment of bronchial stenosis in lung transplant recipients
    Bronchial stenosis in lung transplant recipients is a common disorder that adversely affects clinical outcomes. It is evaluated by spirometry, CT scan and bronchoscopy with significant limitations. We hypothesize that magnetic resonance imaging (MRI) employing both ultrashort echo time (UTE) scans and hyperpolarized (HP) 129Xe gas can offer structural and functional assessment of bronchial stenosis seen after lung transplantation. Six patients with lung transplantation-related bronchial stenosis underwent HP 129Xe MRI and UTE MRI. Three patients subsequently underwent airway stent placement and had repeated MRI at 4 week follow up. HP 129Xe MRI depicted decreased ventilation distal to the stenotic airway. After airway stent placement, MRI showed that low-ventilation regions had decreased (35% vs. 27.6%, P =0.006) and normal-ventilation regions increased (17.9% vs 27.6%, P = 0.04) in the stented lung. Improved gas transfer was also seen on 129Xe MRI. There was a good correlation between UTE MRI and independent bronchoscopic airway diameter assessment (Pearson correlation coefficient = 0.92). This pilot study shows that UTE and HP 129Xe MRI are feasible in patients with bronchial stenosis related to lung transplantation, and may provide structural and functional airway assessment to guide treatment. These conclusions need to be confirmed by larger studies. This article is protected by copyright. All rights reserved.
  • Urinary Markers of Fibrosis and Risk of Cardiovascular Events and Death in Kidney Transplant Recipients: the FAVORIT Trial
    Cardiovascular risk remains high in kidney transplant recipients (KTRs) despite improved kidney function after transplant. Urinary markers of kidney fibrosis and injury may help to reveal mechanisms of this risk. In a case-cohort study among stable KTRs who participated in the FAVORIT trial, we measured 4 urinary proteins known to correlate with kidney tubulointerstitial fibrosis on biopsy (urine alpha 1 microglobulin [α1m], monocyte chemoattractant protein-1 [MCP-1], procollagen type I [PINP] and type III [PIIINP] N-terminal amino peptide) and evaluated associations with cardiovascular disease (CVD) events (N=300) and death (N=371). In adjusted models, higher urine α1m (hazard ratio [HR] per doubling of biomarker 1.40 [95% CI 1.21, 1.62]), MCP-1 (HR 1.18 [1.03, 1.36]), and PINP (HR 1.13 [95% CI 1.03, 1.23]) were associated with CVD events. These 3 markers were also associated with death (HR per doubling α1m 1.51 [95% CI 1.32, 1.72]; MCP-1 1.31 [95% CI 1.13, 1.51]; PINP 1.11 [95% CI 1.03, 1.20]). Higher concentrations of urine α1m, MCP-1, and PINP may identify KTRs at higher risk for CVD events and death. These markers may identify a systemic process of fibrosis involving both the kidney and cardiovascular system, and give new insights into mechanisms linking the kidney with CVD. This article is protected by copyright. All rights reserved.
  • B Cell Receptor Genes Associated with Tolerance Identify a Cohort of Immunosuppressed Patients with Improved Renal Allograft Graft Function
    We previously reported that two B cell receptor genes, IGKV1D-13 and IGKV4-1, were associated with tolerance following kidney transplantation. To assess the potential utility of this “signature” we conducted a prospective, multicenter study to determine the frequency of patients predicted tolerant within a cohort of patients deemed to be candidates for immunosuppressive minimization. At any single time point 25 – 30% of patients were predicted to be tolerant, while 13.7% consistently displayed the tolerance “signature” over the two-year study. We also examined the relationship of the presence of the tolerance “signature” on drug usage and graft function. Contrary to expectations, the frequency of predicted tolerance was increased in patients receiving tacrolimus and reduced in those receiving corticosteroids, MMF, or Thymoglobulin as induction. Surprisingly, patients consistently predicted to be tolerant displayed a statistically and clinically significant improvement in eGFR that increased over time following transplantation. These findings indicate that the frequency of patients consistently predicted to be tolerant is sufficiently high to be clinically relevant and confirm recent findings by others that immunosuppressive agents impact putative biomarkers of tolerance. The association of a B cell-based “signature” with graft function suggests that B cells may contribute to the function/survival of transplanted kidneys. This article is protected by copyright. All rights reserved.
  • The Effects of Center Volume on Mortality in Pediatric Heart Transplantation- The Rest of the Story
    Paul Harvey was an American radio commentator in the latter part of the twentieth century. He would present vignettes and would finish them with the tag line “now you know the rest of the story”. In this issue Rana, et al (1) have analyzed the effects of center transplant volume on outcomes with pediatric heart transplantation. Instead of focusing on outcomes after transplantation, their primary aim was to analyze center volume effects on waitlist mortality- the rest of the story. This article is protected by copyright. All rights reserved.
  • Allo-HLA Cross-Reactivities of CMV-, FLU- and VZV-Specific Memory T Cells Are Shared by Different Individuals
    Virus-specific T cells can recognize allogeneic HLA (allo-HLA) through TCR cross-reactivity. The allospecificity often differs per individual (“private cross-reactivity”), but can also be shared by multiple individuals (“public cross-reactivity”). However, only a few examples of the latter have been described. Since these could facilitate alloreactivity prediction in transplantation, we aimed to identify novel public cross-reactivities of human virus-specific CD8+ T cells directed against allo-HLA by assessing their reactivity in mixed-lymphocyte reactions. Further characterization was done by studying TCR usage with primer-based DNA sequencing, cytokine production with enzyme-linked immunosorbent assays (ELISAs), and cytotoxicity with 51Chromium-release assays. We identified three novel public allo-HLA cross-reactivities of human virus-specific CD8+ T cells. CMV B35/IPS CD8+ T cells cross-reacted with HLA-B51 and/or HLA-B58/B57 (23% of tetramer-positive individuals), FLU A2/GIL CD8+ T cells with HLA-B38 (90% of tetramer-positive individuals) and VZV A2/ALW CD8+ T cells with HLA-B55 (two unrelated individuals). Cross-reactivity was tested against different cell types including endothelial and epithelial cells. All cross-reactive T cells expressed a memory phenotype, emphasizing the importance for transplantation. We conclude that public allo-HLA cross-reactivity of virus-specific memory T cells is not uncommon, which may create novel opportunities for alloreactivity prediction and risk estimation in transplantation. This article is protected by copyright. All rights reserved.
  • BK polyomavirus-specific 9mer CD8 T-cell responses correlate with clearance of BK viremia in kidney transplant recipients: First report from the Swiss Transplant Cohort Study (STCS)
    BK polyomavirus (BKPyV) causes premature kidney transplant (KT) failure in 1-15% of patients. Since antivirals are lacking, most programs screen for BKPyV-viremia and, if positive, reduce immunosuppression. To evaluate the relationship of viremia and BKPyV-specific immunity, we examined prospectively cryopreserved plasma and PBMCs at T0, T6, and T12 months post-transplant from 28 viremic KT patients and 68 non-viremic controls matched for the transplantation period. BKPyV-IgG seroprevalence was comparable between cases (89.3%) and controls (91.2%;p=0.8635), but cases had lower antibody levels (p=0.022) at T0. Antibody levels increased at T6 and T12, but were not correlated with viremia clearance. BKPyV-specific T-cell responses to pools of overlapping 15mers (15mP) or immunodominant CD8 9mers (9mP) from the early viral gene region were not different between cases and controls at T0. However, clearance of viremia was associated with stronger 9mP-responses at T6 (p=0.042) and T12 (p=0.048), whereas 15mP-responses were not informative (T6 p=0.359; T12 p=0.856). BKPyV-specific T-cells could be expanded in vitro from all patients post-transplant permitting identification of 78 immunodominant 9mer-epitopes including 50 new ones across different HLA-classI. Thus, 9mP-responses may be a novel marker of reconstituting CD8 T-cell function that warrant further study as complement of plasma BKPyV-loads for guiding immunosuppression reduction. This article is protected by copyright. All rights reserved.
  • Cytoprotective And Antioxidant Effects of Steen Solution on Human Lung Spheroids and Human Endothelial Cells
    Respiratory diseases represent a major healthcare burden worldwide. Lung transplantation (LTx) is the gold-standard for end-stage patients, strongly limited by shortage of available/suitable donor lungs. Normothermic ex vivo lung perfusion (EVLP) has significantly increased the number of lungs suitable for transplantation. Steen solution is used for EVLP, but the mechanisms involved in its beneficial properties remain to be clarified. We investigated the effects of Steen solution in an in vitro protocol of cold starvation and normothermic recovery (CS/NR) on human lung spheroids, named pneumospheres (PSs), containing epithelial/basal cells, and on endothelial HUVEC cells. Steen solution significantly preserved PSs viability, reduced ROS release by PSs and HUVECs, decreased NADPH-oxidase activity in PSs, and reduced inflammatory cytokines expression levels in HUVECs. Steen solution was able to specifically reduce NOX2 isoform activation, particularly in PSs, as detected by soluble-NOX2 peptide and p47-phosphorylation. Interestingly, a specific NOX2-inhibitor could partly mimic the pro-survival effect of Steen on PSs. We provide the first evidence that Steen solution can preserve lung epithelial/progenitor cells viability partially through NOX2-downregulation, and exert anti-oxidant effects on parenchymal cells, with consequent ROS reduction. These results suggest that NOX2 inhibition might be an additional strategy to reduce cellular damage during LTx procedures. This article is protected by copyright. All rights reserved.
  • Pretransplant Numbers of CD16+ Monocytes as a Novel Biomarker to Predict Acute Rejection After Kidney Transplantation: A Pilot Study
    Acute rejection is one of the major immunological determinants of kidney graft function and survival. Early biomarkers to predict rejection are lacking. Emerging evidence reveals a crucial role for the monocyte/macrophage lineage cells in the pathogenesis of rejection. We hypothesized that higher pretransplant numbers of proinflammatory CD16+ monocytes can predict rejection. The study cohort consisted of 104 kidney transplant recipients (58 with no rejection and 46 with biopsy-proven rejection) and 33 healthy persons. Posttransplant median follow-up time was 14.7 mo (interquartile range 0.3–34 mo). Pretransplantation blood samples were analyzed by flow cytometry for monocyte immunophenotypes. Groups were compared by Cox regression models for the occurrence of acute rejection. We documented a significantly increased absolute number of pretransplant CD16+ monocytes in patients who developed biopsy-proven rejection after transplantation compared with those with no rejection (hazard ratio [HR] 1.60, 95% CI 1.28–2.00, p < 0.001) and healthy persons (HR 1.47, 95% CI 1.18–1.82, p < 0.001). In parallel, significantly fewer absolute numbers of CD16− monocytes were observed at pretransplant time points in rejectors versus nonrejectors (HR 0.74, 95% CI 0.58–0.94, p < 0,014). A higher pretransplant number of CD16+ monocytes is significantly associated with a higher risk of acute rejection after kidney transplantation.
  • The Medication Level Variability Index (MLVI) Predicts Poor Liver Transplant Outcomes: A Prospective Multi-Site Study
    Nonadherence to immunosuppressant medications is a leading cause of poor long-term outcomes in transplant recipients. The Medication Level Variability Index (MLVI) provides a vehicle for transplant outcome risk-stratification through continuous assessment of adherence. The MALT (Medication Adherence in children who had a Liver Transplant) prospective multi-site study evaluated whether MLVI predicts late acute rejection (LAR). Four hundred pediatric (1–17-year-old) liver transplant recipients were enrolled and followed for 2 years. The a-priori hypothesis was that a higher MLVI predicts LAR. Predefined secondary analyses evaluated other outcomes such as liver enzyme levels, and sensitivity analyses compared adolescents to pre-adolescents. In the primary analysis sample of 379 participants, a higher prerejection MLVI predicted LAR (mean prerejection MLVI with LAR: 2.4 [3.6 standard deviation] versus without LAR, 1.6 [1.1]; p = 0.026). Fifty-three percent of the adolescents with MLVI>2 in year 1 had LAR by the end of year 2, as compared with 6% of those with year 1 MLVI≤2. A higher MLVI was significantly associated with all secondary outcomes. MLVI, a marker of medication adherence that uses clinically derived information, predicts LAR in pediatric liver transplant recipients.
  • Reciprocity to Increase Participation of Compatible Living Donor and Recipient Pairs in Kidney Paired Donation
    Inclusion of compatible living donor and recipient pairs (CPs) in kidney paired donation (KPD) programs could increase living donor transplantation. We introduce the concept of a reciprocity-based strategy in which the recipient of a CP who participates in KPD receives priority for a repeat deceased donor transplant in the event their primary living donor KPD transplant fails, and then we review the practical and ethical considerations of this strategy. The strategy limits prioritization to CPs already committed to living donation, minimizing the risk of unduly influencing donor behavior. The provision of a tangible benefit independent of the CP's actual KPD match avoids many of the practical and ethical challenges with strategies that rely on finding the CP recipient a better-matched kidney that might provide the CP recipient a future benefit to increase KPD participation. Specifically, the strategy avoids the potential to misrepresent the degree of future benefit of a better-matched kidney to the CP recipient and minimizes delays in transplantation related to finding a better-matched kidney. Preliminary estimates suggest the strategy has significant potential to increase the number of living donor transplants. Further evaluation of the acceptance of this strategy by CPs and by waitlisted patients is warranted.
  • Comment on the Article “OPTN/SRTR 2015 Annual Data Report: Pancreas”
  • Cytotoxicity of Natural Killer Cells Activated Through NKG2D Contributes to the Development of Bronchiolitis Obliterans in a Murine Heterotopic Tracheal Transplant Model
    Bronchiolitis obliterans after lung transplantation is a major cause of postoperative mortality in which T cell–mediated immunity is known to play an important role. However, the exact contribution of natural killer (NK) cells, which have functions similar to CD8+ T cells, has not been defined. Here, we assessed the role of NK cells in murine bronchiolitis obliterans through heterotopic tracheal transplantations and found a greater percentage of NK cells in allografts than in isografts. Depletion of NK cells using an anti-NK1.1 antibody attenuated bronchiolitis obliterans in transplant recipients compared with controls. In terms of NK cell effector functions, an improvement in bronchiolitis obliterans was observed in perforin-KO recipient mice compared to wild type (WT). Furthermore, we found upregulation of NKG2D-ligand in allografts and demonstrated the significance of this using grafts expressing Rae-1, a murine NKG2D-ligand, which induced severe bronchiolitis obliterans in WT and Rag-1 KO recipients. This effect was ameliorated by injection of anti-NKG2D blocking antibody. Together, these results suggest that cytotoxicity resulting from activation of NK cells through NKG2D leads to the development of murine bronchiolitis obliterans.
  • Hemodialysis Clinic Social Networks, Sex Differences, and Renal Transplantation
    This study describes patient social networks within a new hemodialysis clinic and models the association between social network participation and kidney transplantation. Survey and observational data collected between August 2012 and February 2015 were used to observe the formation of a social network of 46 hemodialysis patients in a newly opened clinic. Thirty-two (70%) patients formed a social network, discussing health (59%) and transplantation (44%) with other patients. While transplant-eligible women participated in the network less often than men (56% vs. 90%, p = 0.02), women who participated discussed their health more often than men (90% vs. 45.5%, p = 0.02). Patients in the social network completed a median of two steps toward transplantation compared with a median of 0 for socially isolated patients (p = 0.003). Patients also completed more steps if network members were closely connected (β = 2.23, 95% confidence interval [CI] 0.16–4.29, p = 0.03) and if network members themselves completed more steps (β = 2.84, 95% CI 0.11–5.57, p = 0.04). The hemodialysis clinic patient social network had a net positive effect on completion of transplant steps, and patients who interacted with each other completed a similar number of steps.
  • Nosocomial BK Polyomavirus Infection Causing Hemorrhagic Cystitis Among Patients With Hematological Malignancies After Hematopoietic Stem Cell Transplantation
    BK polyomavirus (BKPyV) is recognized as a pathogen that causes diseases such as hemorrhagic cystitis and nephritis after allogeneic hematopoietic stem cell transplantation (HSCT) or renal transplantation. BKPyV-associated disease is thought to occur through reactivation under immunosuppression. However, the possibility of its nosocomial transmission and the clinical significance of such transmission have not been elucidated. During a 6-month period, nine adult patients (median age: 47 years) who had hematological disorders and who were treated with HSCT (n = 7) or chemotherapy (n = 2) in a single hematology department developed hemorrhagic cystitis due to BKPyV infection. The polymerase chain reaction products of BKPyV DNA obtained from each patient were sequenced. Of the nine patients, six had subtype I, 2 had subtype IV, and 1 had subtype II or III. In the alignment of sequences, four and two of the six subtype I strains were completely homologous (100%). These results strongly suggest that BKPyV has the potential to cause nosocomial infection within a medical facility, especially among recipients of HSCT. Further studies are clearly warranted to elucidate the route(s) of BKPyV transmission in order to establish optimal infection control.
  • Novel Application of Localized Nanodelivery of Anti–Interleukin-6 Protects Organ Transplant From Ischemia–Reperfusion Injuries
    Ischemia–reperfusion injury (IRI) evokes intragraft inflammatory responses, which markedly augment alloimmune responses against the graft. Understanding the mechanisms underlying these responses is fundamental to develop therapeutic regimens to prevent/ameliorate organ IRI. Here, we demonstrate that IRI results in a marked increase in mitochondrial damage and autophagy in dendritic cells (DCs). While autophagy is a survival mechanism for ischemic DCs, it also augments their production of interleukin (IL)-6. Allograft-derived dendritic cells (ADDCs) lacking autophagy-related gene 5 (Atg5) showed higher death rates posttransplantation. Transplanted ischemic hearts from CD11cCre/Atg5 conditional knockout mice showed marked reduction in intragraft expression of IL-6 compared with controls. To antagonize the effect of IL-6 locally in the heart, we synthesized novel anti–IL-6 nanoparticles with capacity for controlled release of anti–IL-6 over time. Compared with systemic delivery of anti–IL-6, localized delivery of anti–IL-6 significantly reduced chronic rejection with a markedly lower amount administered. Despite improved allograft histology, there were no changes to splenic T cell populations, illustrating the importance of local IL-6 in driving chronic rejection after IRI. These data carry potential clinical significance by identifying an innovative, targeted strategy to manipulate organs before transplantation to diminish inflammation, leading to improved long-term outcomes.
  • Response to “Normothermic Machine Perfusion: A New World Deserving Careful Exploration”
  • “White-Out” After Lung Transplantation: A Multicenter Cohort Description of Late Acute Graft Failure
    Graft failure represents a leading cause of mortality after organ transplantation. Acute late-onset graft failure has not been widely reported. The authors describe the demographics, CT imaging–pathology findings, and treatment of patients presenting with the latter. A retrospective review was performed of lung transplant recipients at two large-volume centers. Acute late-onset graft failure was defined as sudden onset of bilateral infiltrates with an oxygenation index <200 without identifiable cause or concurrent extrapulmonary organ failure. Laboratory, bronchoalveolar lavage (BAL), radiology, and histology results were assessed. Between 2005 and 2016, 21 patients were identified. Median survival was 19 (IQR 13–36) days post onset. Twelve patients (57%) required intensive care support at onset, 12 (57%) required mechanical ventilation, and 6 (29%) were placed on extracorporeal life support. Blood and BAL analysis revealed elevated neutrophilia, with CT demonstrating diffuse ground-glass opacities. Transbronchial biopsy samples revealed acute fibrinoid organizing pneumonia (AFOP), organizing pneumonia, and diffuse alveolar damage (DAD). Assessment of explanted lungs confirmed AFOP and DAD but also identified obliterative bronchiolitis. Patients surviving to discharge without redo transplantation (n = 2) subsequently developed restrictive allograft syndrome. This study describes acute late-onset graft failure in lung allograft recipients, without known cause, which is associated with a dismal prognosis.
  • Regulatory B Cell-Dependent Islet Transplant Tolerance Is Also Natural Killer Cell Dependent
    Immunologic tolerance to solid organ and islet cell grafts has been achieved in various rodent models by using antibodies directed at CD45RB and Tim-1. We have shown that this form of tolerance depends on regulatory B cells (Bregs). To elucidate further the mechanism by which Bregs induce tolerance, we investigated the requirement of natural killer (NK) and NKT cells in this model. To do so, hyperglycemic B6, μMT, Beige, or CD1d−/− mice received BALB/c islet grafts and treatment with the tolerance-inducing regimen consisting of anti-CD45RB and anti-TIM1. B6 mice depleted of both NK and NKT cells by anti-NK1.1 antibody and mice deficient in NK activity (Beige) did not develop tolerance after dual-antibody treatment. In contrast, transplant tolerance induction was successful in CD1d−/− recipients (deficient in NKT cells), indicating that NK, but not NKT, cells are essential in B cell–dependent tolerance. In addition, reconstitution of Beige host with NK cells restored the ability to induce transplant tolerance with dual-antibody treatment. Transfer of tolerance by B cells from tolerant mice was also dependent on host Nk1.1+ cells. In conclusion, these results show that regulatory function of B cells is dependent on NK cells in this model of transplantation tolerance.
  • Safety and Outcomes in 100 Consecutive Donation After Circulatory Death Liver Transplants Using a Protocol That Includes Thrombolytic Therapy
    Donation after circulatory death (DCD) liver transplantation (LT) reportedly yields inferior survival and increased complication rates compared with donation after brain death (DBD). We compare 100 consecutive DCD LT using a protocol that includes thrombolytic therapy (late DCD group) to an historical DCD group (early DCD group n = 38) and a cohort of DBD LT recipients (DBD group n = 435). Late DCD LT recipients had better 1- and 3-year graft survival rates than early DCD LT recipients (92% vs. 76.3%, p = 0.03 and 91.4% vs. 73.7%, p = 0.01). Late DCD graft survival rates were comparable to those of the DBD group (92% vs. 93.3%, p = 0.24 and 91.4% vs. 88.2%, p = 0.62). Re-transplantation occurred in 18.4% versus 1% for the early and late DCD groups, respectively (p = 0.001). Patient survival was similar in all three groups. Ischemic-type biliary lesions (ITBL) occurred in 5%, 3%, and 0.2% for early DCD, late DCD, and DBD groups, respectively, but unlike in the early DCD group, in the late DCD group ITBL was endoscopically managed and resolved in each case. Using a protocol that includes a thrombolytic therapy, DCD LT yielded patient and graft survival rates comparable to DBD LT.
  • Complement Alternative Pathway Deficiency in Recipients Protects Kidney Allograft From Ischemia/Reperfusion Injury and Alloreactive T Cell Response
    Despite the introduction of novel and more targeted immunosuppressive drugs, the long-term survival of kidney transplants has not improved satisfactorily. Early antigen-independent intragraft inflammation plays a critical role in the initiation of the alloimmune response and impacts long-term graft function. Complement activation is a key player both in ischemia/reperfusion injury (IRI) as well as in adaptive antigraft immune response after kidney transplantation. Since the alternative pathway (AP) amplifies complement activation regardless of the initiation pathways and renal IR injured cells undergo uncontrolled complement activation, we speculated whether selective blockade of AP could be a strategy for prolonging kidney graft survival. Here we showed that Balb/c kidneys transplanted in factor b deficient C57 mice underwent reduced IRI and diminished T cell–mediated rejection. In in vitro studies, we found that fb deficiency in T cells and dendritic cells conferred intrinsic impaired alloreactive/allostimulatory functions, respectively, both in direct and indirect pathways of alloantigen presentation. By administering anti-fB antibody to C57 wt recipients in the early post Balb/c kidney transplant phases, we documented that inhibition of AP during both ischemia/reperfusion and early adaptive immune response is necessary for prolonging graft survival. These findings may have implication for the use of AP inhibitors in clinical kidney transplantation.
  • Origin of Enriched Regulatory T Cells in Patients Receiving Combined Kidney–Bone Marrow Transplantation to Induce Transplantation Tolerance
    We examined tolerance mechanisms in patients receiving HLA-mismatched combined kidney–bone marrow transplantation (CKBMT) that led to transient chimerism under a previously published nonmyeloablative conditioning regimen (Immune Tolerance Network study 036). Polychromatic flow cytometry and high-throughput sequencing of T cell receptor-β hypervariable regions of DNA from peripheral blood regulatory T cells (Tregs) and CD4 non-Tregs revealed marked early enrichment of Tregs (CD3+CD4+CD25highCD127lowFoxp3+) in blood that resulted from peripheral proliferation (Ki67+), possibly new thymic emigration (CD31+), and, in one tolerant subject, conversion from non-Tregs. Among recovering conventional T cells, central memory CD4+ and CD8+ cells predominated. A large proportion of the T cell clones detected in posttransplantation biopsy specimens by T cell receptor sequencing were detected in the peripheral blood and were not donor-reactive. Our results suggest that enrichment of Tregs by new thymic emigration and lymphopenia-driven peripheral proliferation in the early posttransplantation period may contribute to tolerance after CKBMT. Further, most conventional T cell clones detected in immunologically quiescent posttransplantation biopsy specimens appear to be circulating cells in the microvasculature rather than infiltrating T cells.
  • Chemotherapy and Transplantation: The Role of Immunosuppression in Malignancy and a Review of Antineoplastic Agents in Solid Organ Transplant Recipients
    It is estimated that solid organ transplant recipients have a two- to fourfold greater overall risk of malignancy than the general population. Some of the most common malignancies after transplant include skin cancers and posttransplant lymphoproliferative disorder. In addition to known risk factors such as environmental exposures, genetics, and infection with oncogenic viruses, immunosuppression plays a large role in the development of cancer through the loss of the immunosurveillance process. The purpose of this article is to explain the role of immunosuppression in cancer and to review the classes of chemotherapeutics. The field of anticancer drugs is continually expanding and developing, with limited data on use in transplant recipients. This article aims to provide information on class review, adverse effects, dose adjustments, and drug interactions that are pertinent to the care of transplant recipients.
  • Cancer in Solid Organ Transplant Recipients: There Is Still Much to Learn and Do
  • Determinants of the Magnitude of Interaction Between Tacrolimus and Voriconazole/Posaconazole in Solid Organ Recipients
    Administration of azole antifungals to tacrolimus-treated solid organ recipients results in a major drug–drug interaction characterized by increased exposure to tacrolimus. The magnitude of this interaction is highly variable but cannot currently be predicted. We performed a retrospective analysis of 126 solid organ recipients (95 lung, 31 kidney) co-treated with tacrolimus and voriconazole (n = 100) or posaconazole (n = 26). Predictors of the change in tacrolimus dose-corrected trough concentrations (C/D) between baseline and tacrolimus–azole co-therapy were assessed using linear mixed modeling. Patients were genotyped for relevant polymorphisms in CYP3A4, CYP3A5, MDR1, CYP2C19, POR, and UGT1A4. Tacrolimus C/D increased by a factor 5.0 ± 2.7 (range 1.0–20.2) for voriconazole and 4.4 ± 2.6 (range 0.9–18.0) for posaconazole, suggesting that a 66% dose reduction is insufficient for the majority of patients. Change in C/D was blunted in CYP3A5 expressors (estimated effect: -43%, p = 0.017) and affected by hematocrit (+8% per %, p = 0.004), baseline C/D (-14% per 100% increase, p < 0.001), and age (+1%, p = 0.008). However, the final model explained only 22% of interindividual variability in C/D change. In conclusion, CYP3A5 genotype and several clinical variables were identified as modulators of the tacrolimus–azole interaction, but these did not permit accurate predictions in individual patients.
  • Obituary of Thomas E. Starzl, MD, PhD
  • Improving the Diagnostic Criteria for Primary Liver Graft Nonfunction in Adults Utilizing Standard and Transportable Laboratory Parameters: An Outcome-Based Analysis
    Current diagnostic criteria for primary nonfunction (PNF) of liver grafts are based on clinical experience rather than statistical methods. A retrospective, single-center study was conducted of all adults (n = 1286) who underwent primary liver transplant (LT) 2000–2008 in our center. Laboratory variables during the first post LT week were analyzed. Forty-two patients (3.7%) had 2-week graft failure. Transplant albumin, day-1 aspartate aminotransferase (AST), day-1 lactate, day-3 bilirubin, day-3 international normalized ratio (INR), and day-7 AST were independently associated with PNF on multivariate logistic regression. PNF score =(0.000280*D1AST)+ (0.361*D1 Lactate)+(0.00884*D3 Bilirubin)+(0.940*D3 INR)+(0.00153*D7 AST)-(0.0972*TxAlbumin)-4.5503. Receiver operating curve analysis showed the model area under receiver operating curve (AUROC) of 0.912 (0.889–0.932) was superior to the current United Kingdom (UK) PNF criteria of 0.669 (0.634–0.704, p < 0.0001). When applied to a validation cohort (n = 386, 34.4% patients), the model had AUROC of 0.831 (0.789–0.867) compared to the UK early graft dysfunction criteria of 0.674 (0.624–0.721). The new model performed well after exclusion of patients with marginal grafts and when modified to include variables from the first three post-LT days only (AUROC of 0.818, 0.776–0.856, p = 0.001). This model is superior to the current UK PNF criteria and is based on statistical methods. The model is also applicable to recipients of all types of grafts (marginal and nonmarginal).
  • Laparoscopic Biopsies in Pancreas Transplantation
    As there is no precise laboratory test or imaging study for detection of pancreas allograft rejection, there is increasing interest in obtaining pancreas tissue for diagnosis. Pancreas allograft biopsies are most commonly performed percutaneously, transcystoscopically, or endoscopically, yet pancreas transplant surgeons often lack the skills to perform these types of biopsies. We have performed 160 laparoscopic pancreas biopsies in 95 patients. There were 146 simultaneous kidney–pancreas biopsies and 14 pancreas-only biopsies due to pancreas alone, kidney loss, or extraperitoneal kidney. Biopsies were performed for graft dysfunction (89) or per protocol (71). In 13 cases, an additional laparoscopic procedure was performed at the same operation. The pancreas diagnostic tissue yield was 91.2%; however, the pancreas could not be visualized in eight cases (5%) and in 6 cases the tissue sample was nondiagnostic (3.8%). The kidney tissue yield was 98.6%. There were four patients with intraoperative complications requiring laparotomy (2.5%) with two additional postoperative complications. Half of all these complications were kidney related. There were no episodes of pancreatic enzyme leak and there were no graft losses related to the procedure. We conclude that laparoscopic kidney and pancreas allograft biopsies can be safely performed with very high tissue yields.
  • Predicting Primary Nonfunction of Liver Transplants With Laboratory Values: Can It Be Done?
  • Mortality Risk Factors Among Patients With Cirrhosis and a Low Model for End-Stage Liver Disease Sodium Score (≤15): An Analysis of Liver Transplant Allocation Policy Using Aggregated Electronic Health Record Data
    Although the Model for End-Stage Liver Disease sodium (MELD Na) score is now used for liver transplant allocation in the United States, mortality prediction may be underestimated by the score. Using aggregated electronic health record data from 7834 adult patients with cirrhosis, we determined whether the cause of cirrhosis or cirrhosis complications was associated with an increased risk of death among patients with a MELD Na score ≤15 and whether patients with the greatest risk of death could benefit from liver transplantation (LT). Over median follow-up of 2.3 years, 3715 patients had a maximum MELD Na score ≤15. Overall, 3.4% were waitlisted for LT. Severe hypoalbuminemia, hepatorenal syndrome, and hepatic hydrothorax conferred the greatest risk of death independent of MELD Na score with 1-year predicted mortality >14%. Approximately 10% possessed these risk factors. Of these high-risk patients, only 4% were waitlisted for LT, despite no difference in nonliver comorbidities between waitlisted patients and those not listed. In addition, risk factors for death among waitlisted patients were the same as those for patients not waitlisted, although the effect of malnutrition was significantly greater for waitlisted patients (hazard ratio 8.65 [95% CI 2.57–29.11] vs. 1.47 [95% CI 1.08–1.98]). Using the MELD Na score for allocation may continue to limit access to LT.
  • Orthogonal Comparison of Molecular Signatures of Kidney Transplants With Subclinical and Clinical Acute Rejection: Equivalent Performance Is Agnostic to Both Technology and Platform
    We performed orthogonal technology comparisons of concurrent peripheral blood and biopsy tissue samples from 69 kidney transplant recipients who underwent comprehensive algorithm-driven clinical phenotyping. The sample cohort included patients with normal protocol biopsies and stable transplant (sTx) function (n = 25), subclinical acute rejection (subAR, n = 23), and clinical acute rejection (cAR, n = 21). Comparisons between microarray and RNA sequencing (RNA-seq) signatures were performed and demonstrated a strong correlation between the blood and tissue compartments for both technology platforms. A number of shared differentially expressed genes and pathways between subAR and cAR in both platforms strongly suggest that these two clinical phenotypes form a continuum of alloimmune activation. SubAR is associated with fewer or less expressed genes than cAR in blood, whereas in biopsy tissues, this clinical phenotype demonstrates a more robust molecular signature for both platforms. The discovery work done in this study confirms a clear ability to detect gene expression profiles for sTx, subAR, and cAR in both blood and biopsy tissue, yielding equivalent predictive performance that is agnostic to both technology and platform. Our data also provide strong biological insights into the molecular mechanisms underlying these signatures, underscoring their logistical potential as molecular diagnostics to improve clinical outcomes following kidney transplantation.
  • Effect of the Anti-C1s Humanized Antibody TNT009 and Its Parental Mouse Variant TNT003 on HLA Antibody–Induced Complement Activation—A Preclinical In Vitro Study
    The classic pathway (CP) of complement is believed to significantly contribute to alloantibody-mediated transplant injury, and targeted complement inhibition is currently considered to be a promising approach for preventing rejection. Here, we investigated the mode of action and efficacy of the humanized anti-C1s monoclonal antibody TNT009 and its parental mouse variant, TNT003, in preclinical in vitro models of HLA antibody–triggered CP activation. In flow cytometric assays, we measured the attachment of C1 subcomponents and C4/C3 split products (C4b/d, C3b/d) to HLA antigen–coated flow beads or HLA-mismatched aortic endothelial cells and splenic lymphocytes. Anti-C1s antibodies profoundly inhibited C3 activation at concentrations >20 μg/mL, in both solid phase and cellular assays. While C4 activation was also prevented, this was not the case for C1 subcomponent attachment. Analysis of serum samples obtained from 68 sensitized transplant candidates revealed that the potency of inhibition was related to the extent of baseline CP activation. This study demonstrates that anti-C1s antibodies TNT009 and TNT003 are highly effective in blocking HLA antibody–triggered complement activation downstream of C1. Our results provide the foundation for clinical studies designed to investigate the potential of TNT009 in the treatment or prevention of complement-mediated tissue injury in sensitized transplant recipients.
  • Inferior Outcomes on the Waiting List in Low-Volume Pediatric Heart Transplant Centers
    Low case volume has been associated with poor outcomes in a wide spectrum of procedures. Our objective was to study the association of low case volume and worse outcomes in pediatric heart transplant centers, taking the novel approach of including waitlist outcomes in the analysis. We studied a cohort of 6482 candidates listed in the Organ Procurement and Transplantation Network for pediatric heart transplantation between 2002 and 2014; 4665 (72%) of the candidates underwent transplantation. Candidates were divided into groups according to the average annual transplantation volume of the listing center during the study period: more than 10, six to 10, three to five, or fewer than three transplantations. We used multivariate Cox regression analysis to identify independent risk factors for waitlist and posttransplantation mortality. Of the 6482 candidates, 24% were listed in low-volume centers (fewer than three annual transplantations). Of these listed candidates in low-volume centers, only 36% received a transplant versus 89% in high-volume centers (more than 10 annual transplantations) (p < 0.001). Listing at a low-volume center was the most significant risk factor for waitlist death (hazard ratio [HR] 4.5, 95% confidence interval [CI] 3.5–5.7 in multivariate Cox regression and HR 5.6, CI 4.4–7.3 in multivariate competing risk regression) and was significant for posttransplantation death (HR 1.27, 95% CI 1.0–1.6 in multivariate Cox regression). During the study period, one-fourth of pediatric transplant candidates were listed in low-volume transplant centers. These children had a limited transplantation rate and a much greater risk of dying while on the waitlist.
  • Filtration Markers, Cardiovascular Disease, Mortality, and Kidney Outcomes in Stable Kidney Transplant Recipients: The FAVORIT Trial
    Cystatin C and beta-2-microglobulin (B2M) are filtration markers associated with adverse outcomes in nontransplant populations, sometimes with stronger associations than for creatinine. We evaluated associations of estimated glomerular filtration rate from cystatin C (eGFRcys), B2M (eGFRB2M), and creatinine (eGFRcr) with cardiovascular outcomes, mortality, and kidney failure in stable kidney transplant recipients using a case–cohort study nested within the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial. A random subcohort was selected (N = 508; mean age 51.6 years, median transplant vintage 4 years, 38% women, 23.6% nonwhite race) with enrichment for cardiovascular events (N = 306; 54 within the subcohort), mortality (N = 208; 68 within the subcohort), and kidney failure (N = 208; 52 within the subcohort). Mean eGFRcr, eGFRcys, and eGFRB2M were 46.0, 43.8, and 48.8 mL/min/1.73m2, respectively. After multivariable adjustment, hazard ratios for eGFRcys and eGFRB2M <30 versus 60+ were 2.02 (95% confidence interval [CI] 1.09–3.76; p = 0.03) and 2.56 (1.35–4.88; p = 0.004) for cardiovascular events; 3.92 (2.11–7.31) and 4.09 (2.21–7.54; both p < 0.001) for mortality; and 9.49 (4.28–21.00) and 15.53 (6.99–34.51; both p < 0.001) for kidney failure. Associations persisted with additional adjustment for baseline eGFRcr. We conclude that cystatin C and B2M are strongly associated with cardiovascular events, mortality, and kidney failure in stable kidney transplant recipients.
  • Radiological Analysis of Unused Donor Lungs: A Tool to Improve Donor Acceptance for Transplantation?
    Despite donor organ shortage, a large proportion of possible donor lungs are declined for transplantation. Criteria for accepting/declining lungs remain controversial because of the lack of adequate tools to aid in decision-making. We collected, air-inflated, and froze a large series of declined/unused donor lungs and subjected these lung specimens to CT examination. Affected target regions were scanned by using micro-CT. Lungs from 28 donors were collected. Two lungs were unused, six were declined for non–allograft-related reasons (collectively denominated nonallograft declines, n = 8), and 20 were declined because of allograft-related reasons. CT scanning demonstrated normal lung parenchyma in only four of eight nonallograft declines, while relatively normal parenchyma was found in 12 of 20 allograft-related declines. CT and micro-CT examinations confirmed the reason for decline in most lungs and revealed unexpected (unknown from clinical files or physical inspection) CT abnormalities in other lungs. CT-based measurements showed a higher mass and density in the lungs with CT alterations compared with lungs without CT abnormalities. CT could aid in the decision-making to accept or decline donor lungs which could lead to an increase in the quantity and quality of lung allografts.
  • Outcomes of Pediatric Kidney Transplantation in Recipients of a Previous Non-Renal Solid Organ Transplant
    Children who receive a non-renal solid organ transplant may develop secondary renal failure requiring kidney transplantation. We investigated outcomes of 165 pediatric kidney transplant recipients who previously received a heart, lung, or liver transplant using data from 1988 to 2012 reported to the United Network for Organ Sharing. Patient and allograft survival were compared with 330 matched primary kidney transplant (PKT) recipients. Kidney transplantation after solid organ transplant (KASOT) recipients experienced similar allograft survival: 5- and 10-year graft survival was 78% and 60% in KASOT recipients, compared to 80% and 61% in PKT recipients (p = 0.69). However, KASOT recipients demonstrated worse 10-year patient survival (75% KASOT vs. 97% PKT, p < 0.001). Competing risks analysis indicated that KASOT recipients more often experienced graft loss due to patient death (p < 0.001), whereas allograft failure per se was more common in PKT recipients (p = 0.01). To study more recent outcomes, kidney transplants performed from 2006 to 2012 were separately investigated. Since 2006, KASOT and PKT recipients had similar 5-year graft survival (82% KASOT vs. 83% PKT, p = 0.48), although 5-year patient survival of KASOT recipients remained inferior (90% KASOT vs. 98% PKT, p < 0.001). We conclude that despite decreased patient survival, kidney allograft outcomes in pediatric KASOT recipients are comparable to those of PKT recipients.
  • Improved Fetal Hemoglobin With mTOR Inhibitor–Based Immunosuppression in a Kidney Transplant Recipient With Sickle Cell Disease
    Fetal hemoglobin induction is a key point in the management of sickle cell disease (SCD). We report the case of a kidney transplant recipient with SCD who was treated with everolimus, a mammalian target of rapamycin inhibitor. At 10 months after initiating therapy, the patient's fetal hemoglobin level was dramatically increased (from 4.8% to 15%) and there was excellent tolerance to treatment.
  • The First Transplant Surgeon: The Flawed Genius of Nobel Prize Winner, Alexis Carrel, edited by David Hamilton. World Scientific, London, 2017. 587 pages
  • Improving the Outcomes of Organs Obtained From Controlled Donation After Circulatory Death Donors Using Abdominal Normothermic Regional Perfusion
    The use of donation after circulatory death (DCD) has increased significantly during the past decade. However, warm ischemia results in a greater risk for transplantation. Indeed, controlled DCD (cDCD) was associated with inferior outcomes compared with donation after brain death. The use of abdominal normothermic regional perfusion (nRP) to restore blood flow before organ recovery in cDCD has been proposed as better than rapid recovery to reverse the effect of ischemia and improve recipients’ outcome. Here, the first Spanish series using abdominal nRP as an in situ conditioning method is reported. A specific methodology to avoid restoring circulation to the brain after death determination is described. Twenty-seven cDCD donors underwent abdominal nRP during at least 60 min. Thirty-seven kidneys, 11 livers, six bilateral lungs, and one pancreas were transplanted. The 1-year death-censored kidney survival was 91%, and delayed graft function rate was 27%. The 1-year liver survival rate was 90.1% with no cases of ischemic cholangiopathy. Transplanted lungs and pancreas exhibited primary function. The use of nRP may represent an advance to increase the number and quality of grafts in cDCD. Poor results in cDCD livers could be reversed with nRP. Concerns about restoring brain circulation after death are easily solved.
  • Reply to “Representing Subnormothermic Machine Perfusion in Fatty Livers: The Complete Picture?”
  • Donor Specificity but Not Broadness of Sensitization Is Associated With Antibody-Mediated Rejection and Graft Loss in Renal Allograft Recipients
    Panel-reactive antibodies are widely regarded as an important immunological risk factor for rejection and graft loss. The broadness of sensitization against HLA is most appropriately measured by the “calculated population-reactive antibodies” (cPRA) value. In this study, we investigated whether cPRA represent an immunological risk in times of sensitive and accurate determination of pretransplantation donor-specific HLA antibodies (DSA). Five hundred twenty-seven consecutive transplantations were divided into four groups: cPRA 0% (n = 250), cPRA 1–50% (n = 129), cPRA 51–100% (n = 43), and DSA (n = 105). Patients without DSA were considered as normal risk and received standard immunosuppression without T cell–depleting induction. Patients with DSA received an enhanced induction therapy and maintenance immunosuppression. Surveillance biopsies were performed at 3 and 6 months. Median follow-up was 5.7 years. Among the three cPRA groups, there were no differences regarding the 1-year incidence of ABMR (p = 0.16) and TCMR (p = 0.75). The 5-year allograft survival rates were similar and around 87% (p = 0.28). The estimated glomerular filtration rate at last follow-up was 50–53 mL/min (p = 0.45). On multivariable Cox proportional hazard analysis, the strongest independent predictor for ABMR and (death-censored) graft survival was pretransplantation DSA. cPRA were not predictive for ABMR, TCMR, or (death-censored) graft survival. We conclude that with current DSA assignment, the broadness of sensitization measured by cPRA does not imply an immunological risk.
  • Thrombalexin: Use of a Cytotopic Anticoagulant to Reduce Thrombotic Microangiopathy in a Highly Sensitized Model of Kidney Transplantation
    Early activation of coagulation is an important factor in the initiation of innate immunity, as characterized by thrombotic microangiopathy (TMA). In transplantation, systemic anticoagulation is difficult due to bleeding. A novel “cytotopic” agent, thrombalexin (TLN), combines a cell-membrane-bound (myristoyl tail) anti-thrombin (hirudin-like peptide [HLL]), which can be perfused directly to the donor organ or cells. Thromboelastography was used to measure time to clot formation (r-time) in both rhesus and human blood, comparing TLN versus HLL (without cytotopic tail) versus negative control. Both TLN- and HLL-treated rhesus or human whole blood result in significantly prolonged r-time compared to kaolin controls. Only TLN-treated human endothelial cells and neonatal porcine islets prolonged time to clot formation. Detection of membrane-bound TLN was confirmed by immunohistochemistry and fluorescence activated cell sorter. In vivo, perfusion of a nonhuman primate kidney TLN-supplemented preservation solution in a sensitized model of transplantation demonstrated no evidence of TLN systemically. Histologically, TLN was shown to be present up to 4 days after transplantation. There was no platelet deposition, and TMA severity, as well as microvascular injury scores (glomerulitis + peritubular capillaritis), were less in the TLN-treated animals. Despite promising evidence of localized efficacy, no survival benefit was demonstrated.
  • The Effect of Cortex/Medulla Proportions on Molecular Diagnoses in Kidney Transplant Biopsies: Rejection and Injury Can Be Assessed in Medulla
    Histologic assessment of kidney transplant biopsies relies on cortex rather than medulla, but for microarray studies, the proportion cortex in a biopsy is typically unknown and could affect the molecular readings. The present study aimed to develop a molecular estimate of proportion cortex in biopsies and examine its effect on molecular diagnoses. Microarrays from 26 kidney transplant biopsies divided into cortex and medulla components and processed separately showed that many of the most significant differences were in glomerular genes (e.g. NPHS2, NPHS1, CLIC5, PTPRO, PLA2R1, PLCE1, PODXL, and REN). Using NPHS2 (podocin) to estimate proportion cortex, we examined whether proportion cortex influenced molecular assessment in the molecular microscope diagnostic system. In 1190 unselected kidney transplant indication biopsies (Clinicaltrials.govNCT01299168), only 11% had <50% cortex. Molecular scores for antibody-mediated rejection, T cell–mediated rejection, and injury were independent of proportion cortex. Rejection was diagnosed in many biopsies that were mostly or all medulla. Agreement in molecular diagnoses in paired cortex/medulla samples (23/26) was similar to biological replicates (32/37). We conclude that NPHS2 expression can estimate proportion cortex; that proportion cortex has little influence on molecular diagnosis of rejection; and that, although histology cannot assess medulla, rejection does occur in medulla as well as cortex.
  • Donor-Specific Antibodies—The Devil Is in the Detail
  • Normothermic Machine Perfusion: A New World Deserving Careful Exploration
  • Reply to “Fluctuation Does Not Mean Variability: A Pharmacokinetic Point of View”
  • Impact of CXCR4/CXCL12 Blockade on Normal Plasma Cells In Vivo
    Plasma cells (PCs) are a major source of alloantibody in transplant patients and are resistant to current therapy. Because receptor–ligand interactions in stromal microenvironments play important roles in the localization, development, and survival of normal PCs, we hypothesized that interfering with CXCR4/CXCL12 interactions with plerixafor might cause PC depletion and enhance the efficacy of the proteasome inhibitor bortezomib. PCs in mouse spleen, bone marrow, and peripheral blood demonstrated CXCR4 expression. We then treated with plerixafor in doses ranging from 240 μg/kg in a single dose to a 1-mg/kg daily dose for 10 days. CXCR4/CXCL12 blockade with plerixafor resulted in increased mobilization of PCs into the peripheral blood. Splenectomy completely abrogated this effect, suggesting that all plerixafor-mobilized cells were from the spleen. The total number of PCs in the spleen and marrow remained constant despite treatment with plerixafor. Bortezomib caused a reduction in PCs, but adding plerixafor did not increase killing. We conclude that CXCR4/CXCL12 interactions are important for the retention of a subpopulation of PCs in the spleen, but this interaction has minimal effect on PCs in the marrow. The lack of enhancement of bortezomib-mediated depletion suggests that factors other than CXCR4/CXCL12 interactions are responsible for drug resistance.
  • Viva España—Lessons From the Spanish Organ Donation System
  • Allosensitization Following Bone Graft
    It is recognized that patients may become sensitized to donor-specific HLA antigens as a result of previous antigenic exposures, classically through previous transplantation, pregnancy, or blood transfusion. We present an unusual case of a patient who unexpectedly developed a range of anti-HLA antibodies following orthopedic surgery where a bone graft was deployed intraoperatively. We describe the case of a 52-year-old man awaiting a renal transplantation, undergoing elective orthopedic surgery requiring a small-volume bone graft. His postoperative antibody profile was found to be substantially changed compared to his previous negative samples, with the presence of HLA-DR, DQ, and DP specificities, at levels that would be likely to give a positive flow cytometry crossmatch and therefore according to local procedures required listing as unacceptable antigens for organ allocation. We perform a literature review of all previous cases of allosensitization following bone graft. This case is the first to demonstrate allosensitization following minor surgery with ;low-volume bone graft. Previous evidence is very limited and pertains only to massive osteochondral surgery for trauma or malignancy, and is confounded by potential concomitant blood transfusion. Clinicians should be aware of the risk of allosensitization where bone grafts are used.
  • Mobile Health in Solid Organ Transplant: The Time Is Now
    Despite being in existence for >40 years, the application of telemedicine has lagged significantly in comparison to its generated interest. Detractors include the immobile design of most historic telemedicine interventions and the relative lack of smartphones among the general populace. Recently, the exponential increase in smartphone ownership and familiarity have provided the potential for the development of mobile health (mHealth) interventions that can be mirrored realistically in clinical applications. Existing studies have demonstrated some potential clinical benefits of mHealth in the various phases of solid organ transplantation (SOT). Furthermore, studies in nontransplant chronic diseases may be used to guide future studies in SOT. Nevertheless, substantially more must be accomplished before mHealth becomes mainstream. Further evidence of clinical benefits and a critical need for cost-effectiveness analysis must prove its utility to patients, clinicians, hospitals, insurers, and the federal government. The SOT population is an ideal one in which to demonstrate the benefits of mHealth. In this review, the current evidence and status of mHealth in SOT is discussed, and a general path forward is presented that will allow buy-in from the health care community, insurers, and the federal government to move mHealth from research to standard care.
  • The Road to HLA Antibody Evaluation: Do Not Rely on MFI
    Technological advances in HLA laboratory testing undoubtedly improved the sensitivity and specificity of HLA antibody assessment but not without introducing a set of challenges regarding data interpretation. In particular, the introduction of solid-phase single-antigen bead (SAB) antibody assessment brought the belief that mean fluorescence intensity (MFI) was a quantifiable value. As such, MFI levels heavily influenced HLA antibody reporting, monitoring, and clinical practice. However, given that SAB testing was neither intended for nor approved to be quantifiable, is the use of MFI in current clinical and laboratory practice valid? What, if anything, does this numerical value actually reveal about the pathogenic potential of the antibody? What are the pitfalls and caveats associated with reporting MFI? Herein, we travel the road to HLA antibody assessment and explore the reliability of MFI values to make clinical decisions.
  • Hemoglobin-Based Oxygen Carrier Rescues Double-Transplant Patient From Life-Threatening Anemia
    This case describes a 46-year-old male recipient of a kidney–pancreas transplant who is Jehovah's Witness. Early in the postoperative period, he was found to have splenic vein thrombosis requiring heparin infusion. Two days later, he developed severe symptomatic anemia (hemoglobin <6 g/dL). Standard medical therapy for bloodless surgical patients with severe anemia was instituted. Nevertheless, the patient's hemoglobin concentration continued to decline to critical levels (2 g/dL). Because he was Jehovah's Witness, transfusion of allogeneic blood products was not an option, prompting use of a hemoglobin-based oxygen carrier (HBOC). After approval by the U.S. Food and Drug Administration and the local institutional review board, 12 U of HBOC-201 were transfused over a period of 8 days. Two weeks later, the patient's hemoglobin levels had increased to 6.8 g/dL. The patient's overall clinical condition improved, and he was discharged home. This case describes the first use of HBOC transfusion in a double solid organ transplant patient. HBOC may represent a viable option in patients with severe symptomatic anemia when allogeneic blood transfusion is not an option.
  • Prophylactic Ureteric Stents in Renal Transplant Recipients: A Multicenter Randomized Controlled Trial of Early Versus Late Removal
    Prophylactic ureteric stenting in renal transplantation reduces major urological complications; however, morbidity is related to the indwelling duration of a stent. We aimed to determine the optimal duration for stents in this clinical setting. Patients (aged 2–75 years) from six UK hospitals who were undergoing renal transplantation were recruited and randomly assigned to either early stent removal at 5 days (without cystoscopy) or late removal at 6 weeks after transplantation (with cystoscopy). The primary outcome was a composite of stent-related complications defined as pain, visible hematuria, migration, fragmentation, and urinary tract infections (UTIs) within 3 mo of transplantation. Between May 2010 and Nov 2013, we randomly assigned 227 participants, with 205 included in the final analysis of the primary outcome. Stent-related complications were significantly higher in the late versus early stent removal groups (36 of 126 [28.6%] vs. 6 of 79 [7.6%]; p < 0.001). The majority of stent complications consisted of UTIs, with an incidence of 31 of 126 (24.6%) in the late group compared with 6 of 79 (7.6%) in the early group (p = 0.004). We found early stent removal on day 5 significantly reduced stent-related complications and improved quality of life in the first 3 mo after transplantation (ISRCTN09184595).
  • Fluctuation Does Not Mean Variability: A Pharmacokinetic Point of View
  • Cytomegalovirus-Responsive CD8+ T Cells Expand After Solid Organ Transplantation in the Absence of CMV Disease
    Cytomegalovirus (CMV) is a major cause of morbidity and mortality in solid organ transplant recipients. Approximately 60% of adults are CMV seropositive, indicating previous exposure. Following resolution of the primary infection, CMV remains in a latent state. Reactivation is controlled by memory T cells in healthy individuals; transplant recipients have reduced memory T cell function due to chronic immunosuppressive therapies. In this study, CD8+ T cell responses to CMV polypeptides immediate-early-1 and pp65 were analyzed in 16 CMV-seropositive kidney and heart transplant recipients longitudinally pretransplantation and posttransplantation. All patients received standard of care maintenance immunosuppression, antiviral prophylaxis, and CMV viral load monitoring, with approximately half receiving T cell–depleting induction therapy. The frequency of CMV-responsive CD8+ T cells, defined by the production of effector molecules in response to CMV peptides, increased during the course of 1 year posttransplantation. The increase commenced after the completion of antiviral prophylaxis, and these T cells tended to be terminally differentiated effector cells. Based on this small cohort, these data suggest that even in the absence of disease, antigenic exposure may continually shape the CMV-responsive T cell population posttransplantation.
  • Assessment of Tocilizumab (Anti–Interleukin-6 Receptor Monoclonal) as a Potential Treatment for Chronic Antibody-Mediated Rejection and Transplant Glomerulopathy in HLA-Sensitized Renal Allograft Recipients
    Extending the functional integrity of renal allografts is the primary goal of transplant medicine. The development of donor-specific antibodies (DSAs) posttransplantation leads to chronic active antibody-mediated rejection (cAMR) and transplant glomerulopathy (TG), resulting in the majority of graft losses that occur in the United States. This reduces the quality and length of life for patients and increases cost. There are no approved treatments for cAMR. Evidence suggests the proinflammatory cytokine interleukin 6 (IL-6) may play an important role in DSA generation and cAMR. We identified 36 renal transplant patients with cAMR plus DSAs and TG who failed standard of care treatment with IVIg plus rituximab with or without plasma exchange. Patients were offered rescue therapy with the anti–IL-6 receptor monoclonal tocilizumab with monthly infusions and monitored for DSAs and long-term outcomes. Tocilizumab-treated patients demonstrated graft survival and patient survival rates of 80% and 91% at 6 years, respectively. Significant reductions in DSAs and stabilization of renal function were seen at 2 years. No significant adverse events or severe adverse events were seen. Tocilizumab provides good long-term outcomes for patients with cAMR and TG, especially compared with historical published treatments. Inhibition of the IL-6–IL-6 receptor pathway may represent a novel approach to stabilize allograft function and extend patient lives.
  • Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial
    SIMCER was a 6-mo, multicenter, open-label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low-exposure tacrolimus discontinued by month 4 (n = 93) or to tacrolimus-based therapy (n = 95), both with basiliximab induction and enteric-coated mycophenolate sodium with or without steroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1 vs. −13.3 mL/min per 1.73 m2 for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3–21.3]; p < 0.001). Mean eGFR at week 24 was 95.8 versus 76.0 mL/min per 1.73 m2 for everolimus versus tacrolimus (p < 0.001). Treatment failure (treated biopsy-proven acute rejection [BPAR; rejection activity index score >3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p = 0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p = 0.026); the rate of treated BPAR was 8.9% versus 2.2% (p = 0.055). Sixteen everolimus-treated patients (17.8%) and three tacrolimus-treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI-based immunosuppression but more frequent BPAR.
  • BET Proteins: An Approach to Future Therapies in Transplantation
    In order to develop new efficient therapies for organ transplantation, it is essential to acquire a comprehensive knowledge of the molecular mechanisms and processes, such as immune activation, chronic inflammation, and fibrosis, which lead to rejection and long-term graft loss. Recent efforts have shed some light on the epigenetic regulation associated with these processes. In this context, the bromo and extraterminal (BET) family of bromodomain proteins (BRD2, BRD3, BRD4, and BRDT) have emerged as major epigenetic players, connecting chromatin structure with gene expression changes. These proteins recognize acetylated lysines in histones and master transcription factors to recruit regulatory complex and, finally, modify the transcriptional program. Recent studies indicate that BET proteins are essential in the NF-kB-mediated inflammatory response, during the activation and differentiation of Th17-immune cells, and in profibrotic processes. Here, we review this new body of data and highlight the efficiency of BET inhibitors in several models of diseases. The promising results obtained from these preclinical models indicate that it may be time to translate these outcomes to the transplantation field, where epigenetics will be of increasing value in the coming years.
  • Proteasome Inhibitor Carfilzomib-Based Therapy for Antibody-Mediated Rejection of the Pulmonary Allograft: Use and Short-Term Findings
    We present this observational study of lung transplant recipients (LTR) treated with carfilzomib (CFZ)-based therapy for antibody-mediated rejection (AMR) of the lung. Patients were considered responders to CFZ if complement-1q (C1q)-fixing ability of their immunodominant (ID) donor-specific anti-human leukocyte antibody (DSA) was suppressed after treatment. Treatment consisted of CFZ plus plasma exchange and immunoglobulins. Fourteen LTRs underwent CFZ for 20 ID DSA AMR. Ten (71.4%) of LTRs responded to CFZ. DSA IgG mean fluorescence intensity (MFI) fell from 7664 (IQR 3230–11 874) to 1878 (653–7791) after therapy (p = 0.001) and to 1400 (850–8287) 2 weeks later (p = 0.001). DSA C1q MFI fell from 3596 (IQR 714–14 405) to <30 after therapy (p = 0.01) and <30 2 weeks later (p = 0.02). Forced expiratory volume in 1s ( FEV1) fell from mean 2.11 L pre-AMR to 1.92 L at AMR (p = 0.04). FEV1 was unchanged after CFZ (1.91 L) and subsequently rose to a maximum of 2.13 L (p = 0.01). Mean forced expiratory flow during mid forced vital capacity (25–75) (FEF25–75) fell from mean 2.5 L pre-AMR to 1.95 L at AMR (p = 0.01). FEF25–75 rose after CFZ to 2.54 L and reached a maximum of 2.91 L (p = 0.01). Responders had less chronic lung allograft dysfunction or progression versus nonresponders (25% vs. 83%, p = 0.04). No deaths occurred within 120 days and 7 patients died post CFZ therapy of allograft failure. Larger prospective interventional studies are needed to further describe the benefit of CFZ-based therapy for pulmonary AMR.
  • Face Transplantation: Partial Graft Loss of the First Case 10 Years Later
    Ten years after the first face transplantation, we report the partial loss of this graft. After two episodes of acute rejection (AR) occurred and completely reversed in the first posttransplantation year, at 90 months posttransplantation the patient developed de novo class II donor-specific antibodies, without clinical signs of AR. Some months later, she developed several skin rejection episodes treated with steroid pulses. Despite rapid clinical improvement, some months later the sentinel skin graft underwent necrosis. Microscopic examination showed intimal thickening, thrombosis of the pedicle vessel, and C4d deposits on the endothelium of some dermal vessels of the facial graft. Flow magnetic resonance imaging of the facial graft showed a decrease of the distal right facial artery flow. Three steroid pulses of 500 mg each, followed by intravenous immunoglobulins (2 g/kg), five sessions of plasmapheresis, and three cycles of bortezomib 1.3 mg/m2, were administered. Despite rescue therapy with eculizumab, necrosis of the lips and the perioral area occurred, which led to surgical removal of the lower lip, labial commissures, and part of the right cheek in May 2015. In January 2016, the patient underwent conventional facial reconstruction because during the retransplantation evaluation a small-cell lung carcinoma was discovered, causing the patient's death in April 2016.
  • Association of Clinical Events With Everolimus Exposure in Kidney Transplant Patients Receiving Low Doses of Tacrolimus
    A key objective in the use of immunosuppression after kidney transplantation is to attain the optimal balance between efficacy and safety. In a phase 3b, multicenter, randomized, open-label, noninferiority study, the incidences of clinical events, renal dysfunction, and adverse events (AEs) were analyzed at 12 months in 309 de novo renal transplant recipients receiving everolimus (EVR), low-dose tacrolimus (LTac), and prednisone. Cox proportional hazard regression modeling was used to estimate the probability of clinical events at specified combinations of time-normalized EVR and Tac trough concentrations. At 12 months, the highest incidence of treated biopsy-proven acute rejection (tBPAR) and graft loss occurred most often in patients with EVR trough concentration <3 ng/mL (64.7% and 10.5%, respectively). At 1 month and 12 months, increasing EVR levels were associated with fewer tBPAR events (both p < 0.0001). Low estimated glomerular filtration rate (eGFR) and decreased eGFR occurred more often in patients with lower EVR and higher Tac levels. AEs were most often observed in patients with EVR levels <3 ng/mL. This study supports maintaining an EVR trough concentration of 3–8 ng/mL, when combined with LTac, to achieve balanced efficacy and safety in renal transplant recipients. Trial registration: NCT01025817.
  • Erratum
  • OPO Strategies to Prevent Unintended Use of Kidneys Exported for High PRA (>98% cPRA) Recipients
    Since the advent of the Kidney Allocation System (KAS), matched candidates with high (>98%) panel reactive antibody (hPRA) are given priority over local candidates with lower PRA. This often leads to exporting of kidneys. Data for these kidneys are not detailed on routine reports. Twenty-two organ procurement organizations prospectively submitted data from August 2015 to July 2016, describing allocation practices of kidneys to hPRA patients and outcomes of these kidneys. Five hundred twenty out of 6924 procured kidneys were exported for hPRA recipients. Of these, 402 (77.3%) were transplanted into the intended recipient (IR); 100 (19.2%) were transplanted into unintended recipients (UR), and 18 (3.5%) were discarded. The most common reason for use in an UR was a positive crossmatch (XM) (63%). The most common reasons for discard were donor quality (44%) and ischemic time (39%). Prior to kidney export, when tissue crossmatching was done, 96.2% of the kidneys went to the IR, versus 80.7% following virtual CM, versus 56.7% when no crossmatching was performed (p < 0.0001). A significant number of kidneys exported for hPRA patients are not being used in the IR or are being discarded. The most common reason for this is positive tissue XM. We report that unintended use of the kidney was minimized when tissue was shipped and XM results were known prior to exporting the kidney.
  • Role of Intrinsic (Graft) Versus Extrinsic (Host) Factors in the Growth of Transplanted Organs Following Allogeneic and Xenogeneic Transplantation
    In our studies of life-supporting α-1,3-galactocyltransferase knockout (GalT-KO) pig-to-baboon kidneys, we found that some recipients developed increased serum creatinine with growth of the grafts, without histological or immunological evidence of rejection. We hypothesized that the rapid growth of orthotopic pig grafts in smaller baboon recipients may have led to deterioration of organ function. To test this hypothesis for both kidneys and lungs, we assessed whether the growth of outbred (Yorkshire) organ transplants in miniature swine was regulated by intrinsic (graft) or extrinsic (host environment) factors. Yorkshire kidneys exhibited persistent growth in miniature swine, reaching 3.7 times their initial volume over 3 mo versus 1.2 times for miniature swine kidneys over the same time period. Similar rapid early growth of lung allografts was observed and, in this case, led to organ dysfunction. For xenograft kidneys, a review of our results suggests that there is a threshold for kidney graft volume of 25 cm3/kg of recipient body weight at which cortical ischemia is induced in transplanted GalT-KO kidneys in baboons. These results suggest that intrinsic factors are responsible, at least in part, for growth of donor organs and that this property should be taken into consideration for growth-curve–mismatched transplants, especially for life-supporting organs transplanted into a limited recipient space.
  • Justifying Nonstandard Exception Requests for Pediatric Liver Transplant Candidates: An Analysis of Narratives Submitted to the United Network for Organ Sharing, 2009–2014
    Nonstandard exception requests (NSERs), for which transplant centers provide patient-specific narratives to support a higher Model for End-stage Liver Disease/Pediatric End-stage Liver Disease score, are made for >30% of pediatric liver transplant candidates. We describe the justifications used in pediatric NSER narratives 2009–2014 and identify justifications associated with NSER denial, waitlist mortality, and transplant. Using United Network for Organ Sharing data, 1272 NSER narratives from 1138 children with NSERs were coded for analysis. The most common NSER justifications were failure-to-thrive (48%) and risk of death (40%); both associated with approval. Varices, involvement of another organ, impaired quality of life, and encephalopathy were justifications used more often in denied NSERs. Of the 25 most prevalent justifications, 60% were not associated with approval or denial. Waitlist mortality risk was increased when fluid overload or “posttransplant complication outside standard criteria” were cited and decreased when liver-related infection was noted. Transplant probability was increased when the narrative mentioned liver-related infections, and fluid overload for children <2 years old; it decreased when “posttransplant complications outside standard criteria” and primary sclerosing cholangitis were cited. This analysis provides novel insight and suggests targets for future consideration in outcomes research and exception criteria. Changes in the allocation system are needed to ensure equity and optimize outcomes for all pediatric candidates.
  • A Tale of Two Pathways: Renewing the Promise of Anti-CD40L Blockade
  • Donor Preconditioning After the Onset of Brain Death With Dopamine Derivate n-Octanoyl Dopamine Improves Early Posttransplant Graft Function in the Rat
    Heart transplantation is the therapy of choice for end-stage heart failure. However, hemodynamic instability, which has been demonstrated in brain-dead donors (BDD), could also affect the posttransplant graft function. We tested the hypothesis that treatment of the BDD with the dopamine derivate n-octanoyl-dopamine (NOD) improves donor cardiac and graft function after transplantation. Donor rats were given a continuous intravenous infusion of either NOD (0.882 mg/kg/h, BDD+NOD, n = 6) or a physiological saline vehicle (BDD, n = 9) for 5 h after the induction of brain death by inflation of a subdural balloon catheter. Controls were sham-operated (n = 9). In BDD, decreased left-ventricular contractility (ejection fraction; maximum rate of rise of left-ventricular pressure; preload recruitable stroke work), relaxation (maximum rate of fall of left-ventricular pressure; Tau), and increased end-diastolic stiffness were significantly improved after the NOD treatment. Following the transplantation, the NOD-treatment of BDD improved impaired systolic function and ventricular relaxation. Additionally, after transplantation increased interleukin-6, tumor necrosis factor TNF-α, NF-kappaB-p65, and nuclear factor (NF)-kappaB-p105 gene expression, and increased caspase-3, TNF-α and NF-kappaB protein expression could be significantly downregulated by the NOD treatment compared to BDD. BDD postconditioning with NOD through downregulation of the pro-apoptotic factor caspase-3, pro-inflammatory cytokines, and NF-kappaB may protect the heart against the myocardial injuries associated with brain death and ischemia/reperfusion.
  • Successful Renal Transplantation in Small Children With a Completely Thrombosed Inferior Vena Cava
    In small children with end-stage renal disease, an adult-sized kidney transplant is the best option. However, in the face of a completely thrombosed inferior vena cava (IVC), such transplants can be challenging, given the difficulty of achieving adequate renal venous outflow and the risk of graft thrombosis. Using a new technique to anastomose the renal vein to the right hepatic vein/IVC junction, we successfully implanted an adult-sized graft in two small children (9.8 and 14 kg) who had end-stage renal disease and a completely thrombosed IVC. After mobilizing the right lobe of the liver and obtaining total vascular occlusion of the liver, we used a Fogarty catheter to dilate the retrohepatic IVC. In the right hepatic vein, we made a venotomy and extended it inferiorly onto the retrohepatic IVC. To that venotomy, we anastomosed the donor left renal vein, using continuous 7-0 Prolene sutures. Both patients attained excellent renal allograft function: One had a serum creatinine level of 0.30 mg/dL at 6 mo after transplant, and the other had a level of 0.29 mg/dL at 1 year. In these two small children with completely thrombosed IVC, our technique for transplanting an adult-sized kidney provided adequate venous outflow.
  • American Journal of Transplantation: Volume 17, Number 4, April 2017
    On the cover this month: Despite increasingly focused immunosuppressive strategies, transplant patients remain at increased risk for myriad infections. This month, we present a Comprehensive Review from Jay Fishman (page 856) on the current state of transplant infectious disease management, including an updated rubric on the diagnosis and treatment of opportunistic infections. Also, we present two articles (Noyan et al, page 917, and Boardman et al, page 931) showing the effect of engineered T regulatory cells as an experimental approach toward donor-specific control of alloimmunity. Cover design by Deanna Hoskins, Duke University Department of Surgery.
  • New Rule Requires Some Physicians to Report on Postoperative Visits
    Later this year, nine states will require surgeons to report information on the number of postoperative visits they provide their patients. In this issue of “The AJT Report,” we take a look at how this change in reporting may impact transplantation. Also this issue, we review the results of liver transplantation in recipients with the hepatitis C virus.
  • The Tpm Subset of the CD8+ T Cell Memory Family
    Expression levels of CX3CR1 subdivide CD8+ T cell memory subsets with different functions and reveal a new member, the CX3CR1int subset, that patrols peripheral tissues and returns to the blood via the lymph.
  • Generating Antigen-Specific Regulatory T Cells in the Fast Lane
    Human regulatory T cells engineered to express a chimeric antigen receptor targeting HLA-A2 efficiently suppress alloimmune responses in humanized mouse models of transplantation. See Noyan et al's article on page 917.
  • Synthetic Fusion Protein CAR Technology to Redirect T Cell Antigen Specificity to Promote Organ Transplant Tolerance
    In response to the article by Boardman et al (page 931), the authors provide a brief update on chimeric antigen receptor technology, particularly regarding regulatory T cells in the context of transplantation.
  • Infection in Organ Transplantation
    The prevention, diagnosis, and management of infectious disease in transplantation are major contributors to improved outcomes in organ transplantation. The risk of serious infections in organ recipients is determined by interactions between the patient's epidemiological exposures and net state of immune suppression. In organ recipients, there is a significant incidence of drug toxicity and a propensity for drug interactions with immunosuppressive agents used to maintain graft function. Thus, every effort must be made to establish specific microbiologic diagnoses to optimize therapy. A timeline can be created to develop a differential diagnosis of infection in transplantation based on common patterns of infectious exposures, immunosuppressive management, and antimicrobial prophylaxis. Application of quantitative molecular microbial assays and advanced antimicrobial therapies have advanced care. Pathogen-specific immunity, genetic polymorphisms in immune responses, and dynamic interactions between the microbiome and the risk of infection are beginning to be explored. The role of infection in the stimulation of alloimmune responses awaits further definition. Major hurdles include the shifting worldwide epidemiology of infections, increasing antimicrobial resistance, suboptimal assays for the microbiologic screening of organ donors, and virus-associated malignancies. Transplant infectious disease remains a key to the clinical and scientific investigation of organ transplantation.
  • Long-Term Medical and Psychosocial Outcomes in Living Liver Donors
    Due to the enduring organ shortage, living donor liver transplantation has been a valuable treatment strategy for advanced liver disease patients for over 20 years. A variety of reviews have summarized the extensive data now available on medical and psychosocial risks to living donors in the aftermath of donation. However, evidence on donor medical and psychosocial outcomes beyond the first year postdonation has not been synthesized in any previous review. The evidence base on such “long-term” outcomes has been growing in recent years. A review of this evidence would therefore be timely and could serve as an important resource to assist transplant centers in their efforts to fully educate prospective donors and gain informed consent, as well as develop appropriate postdonation clinical care and surveillance plans. We reviewed recent literature on long-term donor outcomes, considering (a) medical outcomes, including mortality risk, rates of complications, abnormalities detected in laboratory testing, and the progress of liver regeneration; and (b) donor-reported psychosocial outcomes reflecting physical, emotional, and interpersonal/socioeconomic well-being, as well as overall health-related quality of life. We summarize limitations and gaps in available evidence, and we provide recommendations for future research and clinical care activities focused on long-term outcomes in liver donors.
  • Long-Term Non–End-Stage Renal Disease Risks After Living Kidney Donation
    Despite generally positive outcomes and high rates of satisfaction, living kidney donors are at risk for both medical and psychosocial problems. In this review, the authors summarize non–end-stage renal disease (ESRD) risks for donors and describe limitations to the data. We review the evidence of medical risks (e.g. increased cardiovascular disease and mortality, preeclampsia) and psychosocial risks (e.g. mood disturbance, financial burden). We then discuss the evidence of differential risks among subsets and the impact of postdonation events (e.g. development of diabetes). Collectively, available evidence indicates the following. (1) Recognizing the importance of non-ESRD risks has been overshadowed by analyses of the reported risk of ESRD. This imbalance should be remedied. (2) There is little quantification of the true contribution of donation to medical and psychosocial outcomes. (3) Most studies, to date, have been retrospective, with limited sample sizes and diversity and with less-than-ideal controls for comparison of outcomes. (4) Many postdonation events (diabetes and hypertension) can now be reasonably predicted, and their association with adverse outcomes can be quantified. (5) Mechanisms and systems need to be implemented to evaluate and care for donors who develop medical and/or psychosocial problems. (6) Costs to donors are a significant burden, and making donation financially neutral should be a priority.
  • Integrating APOL1 Gene Variants Into Renal Transplantation: Considerations Arising From the American Society of Transplantation Expert Conference
    Thirteen percent of individuals of African ancestry express two variant copies of the gene encoding apolipoprotein 1 (APOL1) that has been associated with an increased risk of end-stage renal disease (ESRD) in the general population. Limited studies suggest that the survival of transplanted kidneys from donors expressing two APOL1 risk alleles is inferior to that of kidneys from donors with zero or one risk allele. In living kidney donation, two case reports describe donors expressing two APOL1 risk alleles who developed ESRD. Given the potential impact of APOL1 variants on the utility and safety of kidney transplantation and living kidney donation, the American Society of Transplantation convened a meeting with the goals of summarizing the current state of knowledge with respect to transplantation and APOL1, identifying knowledge gaps and studies to address these gaps, and considering approaches to integrating APOL1 into clinical practice. The authors recognize that current data are not sufficient to support traditional evidence-based guidelines but also recognize that it may require several years to generate the necessary data. Thus, approaches as to how APOL1 might currently be integrated into the clinical decision-making process were considered. This report summarizes the group's deliberations.
  • Living Donor Uterus Transplant and Surrogacy: Ethical Analysis According to the Principle of Equipoise
    The uterus is the most recent addition to the list of organs that can be successfully transplanted in humans. This article analyzes living donor uterus transplantation according to the ethical principle of equipoise. A comparison is made between living donor uterus transplantation and gestational surrogate motherhood. Both are solutions to absolute uterine infertility that allow the transfer of genetic material from intended parents to a child. The analysis concludes that living donor uterus transplantation does not violate the ethical principle of equipoise and should be considered an ethically acceptable solution to absolute uterine infertility.
  • Prevention of Allograft Rejection by Use of Regulatory T Cells With an MHC-Specific Chimeric Antigen Receptor
    CD4+CD25highFOXP3+ regulatory T cells (Tregs) are involved in graft-specific tolerance after solid organ transplantation. However, adoptive transfer of polyspecific Tregs alone is insufficient to prevent graft rejection even in rodent models, indicating that graft-specific Tregs are required. We developed a highly specific chimeric antigen receptor that recognizes the HLA molecule A*02 (referred to as A2-CAR). Transduction into natural regulatory T cells (nTregs) changes the specificity of the nTregs without alteration of their regulatory phenotype and epigenetic stability. Activation of nTregs via the A2-CAR induced proliferation and enhanced the suppressor function of modified nTregs. Compared with nTregs, A2-CAR Tregs exhibited superior control of strong allospecific immune responses in vitro and in humanized mouse models. A2-CAR Tregs completely prevented rejection of allogeneic target cells and tissues in immune reconstituted humanized mice in the absence of any immunosuppression. Therefore, these modified cells have great potential for incorporation into clinical trials of Treg-supported weaning after allogeneic transplantation.
  • Expression of a Chimeric Antigen Receptor Specific for Donor HLA Class I Enhances the Potency of Human Regulatory T Cells in Preventing Human Skin Transplant Rejection
    Regulatory T cell (Treg) therapy using recipient-derived Tregs expanded ex vivo is currently being investigated clinically by us and others as a means of reducing allograft rejection following organ transplantation. Data from animal models has demonstrated that adoptive transfer of allospecific Tregs offers greater protection from graft rejection compared to polyclonal Tregs. Chimeric antigen receptors (CAR) are clinically translatable synthetic fusion proteins that can redirect the specificity of T cells toward designated antigens. We used CAR technology to redirect human polyclonal Tregs toward donor-MHC class I molecules, which are ubiquitously expressed in allografts. Two novel HLA-A2-specific CARs were engineered: one comprising a CD28-CD3ζ signaling domain (CAR) and one lacking an intracellular signaling domain (ΔCAR). CAR Tregs were specifically activated and significantly more suppressive than polyclonal or ΔCAR Tregs in the presence of HLA-A2, without eliciting cytotoxic activity. Furthermore, CAR and ΔCAR Tregs preferentially transmigrated across HLA-A2-expressing endothelial cell monolayers. In a human skin xenograft transplant model, adoptive transfer of CAR Tregs alleviated the alloimmune-mediated skin injury caused by transferring allogeneic peripheral blood mononuclear cells more effectively than polyclonal Tregs. Our results demonstrated that the use of CAR technology is a clinically applicable refinement of Treg therapy for organ transplantation.
  • Th17 Responses to Collagen Type V, kα1-Tubulin, and Vimentin Are Present Early in Human Development and Persist Throughout Life
    T helper 17 (Th17)–dependent autoimmune responses can develop after heart or lung transplantation and are associated with fibro-obliterative forms of chronic rejection; however, the specific self-antigens involved are typically different from those associated with autoimmune disease. To investigate the basis of these responses, we investigated whether removal of regulatory T cells or blockade of function reveals a similar autoantigen bias. We found that Th17 cells specific for collagen type V (Col V), kα1-tubulin, and vimentin were present in healthy adult peripheral blood mononuclear cells, cord blood, and fetal thymus. Using synthetic peptides and recombinant fragments of the Col V triple helical region (α1[V]), we compared Th17 cells from healthy donors with Th17 cells from Col V–reactive heart and lung patients. Although the latter responded well to α1(V) fragments and peptides in an HLA-DR–restricted fashion, Th17 cells from healthy persons responded in an HLA-DR–restricted fashion to fragments but not to peptides. Col V, kα1-tubulin, and vimentin are preferred targets of a highly conserved, hitherto unknown, preexisting Th17 response that is MHC class II restricted. These data suggest that autoimmunity after heart and lung transplantation may result from dysregulation of an intrinsic mechanism controlling airway and vascular homeostasis.
  • Continuous Normothermic Ex Vivo Kidney Perfusion Is Superior to Brief Normothermic Perfusion Following Static Cold Storage in Donation After Circulatory Death Pig Kidney Transplantation
    Hypothermic preservation is known to cause renal graft injury, especially in donation after circulatory death (DCD) kidney transplantation. We investigated the impact of cold storage (SCS) versus short periods of normothermic ex vivo kidney perfusion (NEVKP) after SCS versus prolonged, continuous NEVKP with near avoidance of SCS on kidney function after transplantation. Following 30 min of warm ischemia, kidneys were removed from 30-kg Yorkshire pigs and preserved for 16 h with (A) 16 h SCS, (B) 15 h SCS + 1 h NEVKP, (C) 8 h SCS + 8 h NEVKP, and (D) 16 h NEVKP. After contralateral kidney resection, grafts were autotransplanted and pigs followed up for 8 days. Perfusate injury markers such as aspartate aminotransferase and lactate dehydrogenase remained low; lactate decreased significantly until end of perfusion in groups C and D (p < 0.001 and p = 0.002). Grafts in group D demonstrated significantly lower serum creatinine peak when compared to all other groups (p < 0.001) and 24-h creatinine clearance at day 3 after surgery was significantly higher (63.4 ± 19.0 mL/min) versus all other groups (p < 0.001). Histological assessment on day 8 demonstrated fewer apoptotic cells in group D (p = 0.008). In conclusion, prolonged, continuous NEVKP provides superior short-term outcomes following DCD kidney transplantation versus SCS or short additional NEVKP following SCS.
  • Inducing Hepatitis C Virus Resistance After Pig Liver Transplantation—A Proof of Concept of Liver Graft Modification Using Warm Ex Vivo Perfusion
    Normothermic ex vivo liver perfusion (NEVLP) offers the potential to optimize graft function prior to liver transplantation (LT). Hepatitis C virus (HCV) is dependent on the presence of miRNA(microRNA)-122. Miravirsen, a locked-nucleic acid oligonucleotide, sequesters miR-122 and inhibits HCV replication. The aim of this study was to assess the efficacy of delivering miravirsen during NEVLP to inhibit miR-122 function in a pig LT model. Pig livers were treated with miravirsen during NEVLP or cold storage (CS). Miravirsen absorption, miR-122 sequestration, and miR-122 target gene derepression were determined before and after LT. The effect of miravirsen treatment on HCV infection of hepatoma cells was also assessed. NEVLP improved miravirsen uptake versus CS. Significant miR-122 sequestration and miR-122 target gene derepression were seen with NEVLP but not with CS. In vitro data confirmed miravirsen suppression of HCV replication after established infection and prevented HCV infection with pretreatment of cells, analogous to the pretreatment of grafts in the transplant setting. In conclusion, miravirsen delivery during NEVLP is a potential strategy to prevent HCV reinfection after LT. This is the first large-animal study to provide “proof of concept” for using NEVLP to modify and optimize liver grafts for transplantation.
  • Graft-Versus-Host Disease Following Liver Transplantation: Development of a High-Incidence Rat Model and a Selective Prevention Method
    Graft-versus-host disease (GvHD) following liver transplantation (LT) is a rare but serious complication with no presently available animal model and no preventive measures. To develop a rat model of GvHD after LT (LT-GvHD), we preconditioned hosts with sublethal irradiation plus reduction of natural killer (NK) cells with anti-CD8α mAb treatment, which invariably resulted in acute LT-GvHD. Compared with those in the peripheral counterpart, graft CD4+CD25− passenger T cells showed lower alloreactivities in mixed leukocyte culture. Immunohistology revealed that donor CD4+ T cells migrated and formed clusters with host dendritic cells in secondary lymphoid organs, with early expansion and subsequent accumulation in target organs. For selectively preventing GvHD, donor livers were perfused ex vivo with organ preservation media containing anti-TCRαβ mAb. T cell–depleted livers almost completely suppressed clinical GvHD such that host rats survived for >100 days. Our results showed that passenger T cells could develop typical LT-GvHD if resistant cells such as host radiosensitive cells and host radioresistant NK cells were suppressed. Selective ex vivo T cell depletion prevented LT-GvHD without affecting host immunity or graft function. This method might be applicable to clinical LT in prediagnosed high-risk donor–recipient combinations and for analyzing immunoregulatory mechanisms of the liver.
  • Identification and Characterization of microRNAs Associated With Human β-Cell Loss in a Mouse Model
    Currently there is no effective approach for monitoring early β-cell loss during islet graft rejection following human islet transplantation (HIT). Due to ethical and technical constraints, it is difficult to directly study biomarkers of islet destruction in humans. Here, we established a humanized mouse model with induced human β-cell death using adoptive lymphocyte transfer (ALT). Human islet grafts of ALT-treated mice had perigraft lymphocyte infiltration, fewer insulin+ β cells, and increased β-cell apoptosis. Islet-specific miR-375 was used to validate our model, and expression of miR-375 was significantly decreased in the grafts and increased in the circulation of ALT-treated mice before hyperglycemia. A NanoString expression assay was further used to profile 800 human miRNAs in the human islet grafts, and the results were validated using quantitative real-time polymerase chain reaction. We found that miR-4454 and miR-199a-5p were decreased in the human islet grafts following ALT and increased in the circulation prior to hyperglycemia. These data demonstrate that our in vivo model of induced human β-cell destruction is a robust method for identifying and characterizing circulating biomarkers, and suggest that miR-4454 and miR-199a-5p can serve as novel biomarkers associated with early human β-cell loss following HIT.
  • Predictive Modeling of Tacrolimus Dose Requirement Based on High-Throughput Genetic Screening
    Any biochemical reaction underlying drug metabolism depends on individual gene–drug interactions and on groups of genes interacting together. Based on a high-throughput genetic approach, we sought to identify a set of covariant single-nucleotide polymorphisms predictive of interindividual tacrolimus (Tac) dose requirement variability. Tac blood concentrations (Tac C0) of 229 kidney transplant recipients were repeatedly monitored after transplantation over 3 mo. Given the high dimension of the genomic data in comparison to the low number of observations and the high multicolinearity among the variables (gene variants), we developed an original predictive approach that integrates an ensemble variable-selection strategy to reinforce the stability of the variable-selection process and multivariate modeling. Our predictive models explained up to 70% of total variability in Tac C0 per dose with a maximum of 44 gene variants (p-value <0.001 with a permutation test). These models included molecular networks of drug metabolism with oxidoreductase activities and the multidrug-resistant ABCC8 transporter, which was found in the most stringent model. Finally, we identified an intronic variant of the gene encoding SLC28A3, a drug transporter, as a key gene involved in Tac metabolism, and we confirmed it in an independent validation cohort.
  • Early Conversion to Prednisolone/Everolimus as an Alternative Weaning Regimen Associates With Beneficial Renal Transplant Histology and Function: The Randomized-Controlled MECANO Trial
    In renal transplantation, use of calcineurin inhibitors (CNIs) is associated with nephrotoxicity and immunosuppression with malignancies and infections. This trial aimed to minimize CNI exposure and total immunosuppression while maintaining efficacy. We performed a randomized controlled, open-label multicenter trial with early cyclosporine A (CsA) elimination. Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS), and CsA. At 6 months, immunosuppression was tapered to P/CsA, P/MPS, or P/everolimus (EVL). Primary outcomes were renal fibrosis and inflammation. Secondary outcomes were estimated glomerular filtration rate (eGFR) and incidence of rejection at 24 months. The P/MPS arm was prematurely halted. The trial continued with P/CsA (N = 89) and P/EVL (N = 96). Interstitial fibrosis and inflammation were significantly decreased and the eGFR was significantly higher in the P/EVL arm. Cumulative rejection rates were 13% (P/EVL) and 19% (P/CsA), (p = 0.08). A post hoc analysis of HLA and donor-specific antibodies at 1 year after transplantation revealed no differences. An individualized immunosuppressive strategy of early CNI elimination to dual therapy with everolimus was associated with decreased allograft fibrosis, preserved allograft function, and good efficacy, but also with more serious adverse events and discontinuation. This can be a valuable alternative regimen in patients suffering from CNI toxicity.
  • First-Year Waitlist Hospitalization and Subsequent Waitlist and Transplant Outcome
    Frailty is associated with inferior survival and increased resource requirements among kidney transplant candidates, but assessments are time-intensive and costly and require direct patient interaction. Waitlist hospitalization may be a proxy for patient fitness and could help those at risk of poor outcomes. We examined United States Renal Data System data from 51 111 adult end-stage renal disease patients with continuous Medicare coverage who were waitlisted for transplant from January 2000 to December 2011. Heavily admitted patients had higher subsequent resource requirements, increased waitlist mortality and decreased likelihood of transplant (death after listing: 1–7 days: hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.20–1.28; 8–14 days: HR 1.49, 95% CI 1.42–1.56; ≥15 days: HR 2.07, 95% CI 1.99–2.15; vs. 0 days). Graft and recipient survival was inferior, with higher admissions, although survival benefit was preserved. A model including waitlist admissions alone performed better (C statistic 0.76, 95% CI 0.74–0.80) in predicting postlisting mortality than estimated posttransplant survival (C statistic 0.69, 95% CI 0.67–0.73). Although those with a heavy burden of admissions may still benefit from kidney transplant, less utility is derived from allografts placed in this population. Current kidney allocation policy, which is based in part on longevity matching, could be significantly improved by consideration of hospitalization records of transplant candidates.
  • Remote Ischemic Conditioning on Recipients of Deceased Renal Transplants Does Not Improve Early Graft Function: A Multicenter Randomized, Controlled Clinical Trial
    Delayed graft function is a frequent complication following deceased donor renal transplantation, and is closely related to ischemia–reperfusion injury. Experimental and clinical studies have shown protection by remote ischemic conditioning (RIC). We hypothesized that recipient RIC before kidney graft reperfusion reduces the time to graft recovery. This multicenter, blinded, randomized, controlled clinical trial included 225 adult recipients of renal transplants from deceased donors at four transplantation centers in Denmark, Sweden, and the Netherlands. Participants were randomized 1:1 to RIC or sham-RIC. RIC consisted of 4 × 5-min thigh occlusion by an inflatable tourniquet each followed by 5-min deflation, performed during surgery prior to graft reperfusion. The tourniquet remained deflated for sham-RIC. The primary endpoint was the estimated time to a 50% decrease in baseline plasma creatinine (tCr50) calculated from plasma creatinine measurements 30 days posttransplant or 30 days after the last, posttransplant dialysis. No significant differences were observed between RIC and sham-RIC-treated patients in the primary outcome median tCr50 (122 h [95% confidence interval [CI] 98–151] vs. 112 h [95% CI 91–139], p = 0.58), or the number of patients receiving dialysis in the first posttransplant week (33% vs. 35%, p = 0.71). Recipient RIC does not reduce the time to graft recovery in kidney transplantation from deceased donors. ClinicalTrials.gov: NCT01395719.
  • Risk Assessment in High- and Low-MELD Liver Transplantation
    Allocation of liver grafts triggers emotional debates, as those patients, not receiving an organ, are prone to death. We analyzed a high–Model of End-stage Liver Disease (MELD) cohort (laboratory MELD score ≥30, n = 100, median laboratory MELD score of 35; interquartile range 31–37) of liver transplant recipients at our center during the past 10 years and compared results with a low-MELD group, matched by propensity scoring for donor age, recipient age, and cold ischemia time. End points of our study were cumulative posttransplantation morbidity, cost, and survival. Six different prediction models, including donor age x recipient MELD (D-MELD), Difference between listing MELD and MELD at transplant (Delta MELD), donor-risk index (DRI), Survival Outcomes Following Liver Transplant (SOFT), balance-of-risk (BAR), and University of California Los Angeles–Futility Risk Score (UCLA-FRS), were applied in both cohorts to identify risk for poor outcome and high cost. All score models were compared with a clinical-oriented decision, based on the combination of hemofiltration plus ventilation. Median intensive care unit and hospital stays were 8 and 26 days, respectively, after liver transplantation of high-MELD patients, with a significantly increased morbidity compared with low-MELD patients (median comprehensive complication index 56 vs. 36 points [maximum points 100] and double cost [median US$179 631 vs. US$80 229]). Five-year survival, however, was only 8% less than that of low-MELD patients (70% vs. 78%). Most prediction scores showed disappointing low positive predictive values for posttransplantation mortality, such as mortality above thresholds, despite good specificity. The clinical observation of hemofiltration plus ventilation in high-MELD patients was even superior in this respect compared with D-MELD, DRI, Delta MELD, and UCLA-FRS but inferior to SOFT and BAR models. Of all models tested, only the BAR score was linearly associated with complications. In conclusion, the BAR score was most useful for risk classification in liver transplantation, based on expected posttransplantation mortality and morbidity. Difficult decisions to accept liver grafts in high-risk recipients may thus be guided by additional BAR score calculation, to increase the safe use of scarce organs.


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Carlos Tello Royloa


Actualizada el: 08-Abr-2013