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Este mes en... American Journal of Transplantation

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Este mes en... American Journal of Transplantation:

  • 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.
  • Response to “Normothermic Machine Perfusion: a new world deserving careful exploration”
    We thank Pezzati and colleagues for endorsing our innovative endeavors in ex vivo liver normothermic perfusion (NMP)1, 2. We take issue however with the surmise that we implicitly assumed the notion that NMP provides superior outcomes in this small 10-liver pilot trial. Our trial was designed with safety not efficacy as the primary outcome determinant. 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 pre-transplant numbers of proinflammatory CD16+ monocytes can predict rejection. The study cohort consisted of 104 kidney transplant recipients (58 no-rejections and 46 biopsy-proven rejections), and 33 healthy individuals. Posttransplant median±IQR follow up time was 14.7 (0.3-34) months. 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 to no-rejections and healthy individuals (Hazard Ratio [HR], 1.60; 95% Confidential Interval [CI], 1.28 to 2.00; p<0,001 and HR, 1.47; CI, 1.18 to 1.82, p<0,001). In parallel, significantly less absolute numbers of CD16- monocytes were observed at pretransplant time point in rejectors vs non-rejectors (HR, 0.74; CI, 0.58 to 0.94; p<0,014). A higher pre-transplant number of CD16+ monocytes is significantly associated with a higher risk of acute rejection after kidney transplantation. 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.
  • 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 that participates in KPD receives priority for a repeat deceased donor transplant in the event their primary living donor KPD transplant fails, and 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 wait-listed patients is warranted. This article is protected by copyright. All rights reserved.
  • 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). 400 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. Pre-defined secondary analyses evaluated other outcomes such as liver enzyme levels, and sensitivity analyses compared adolescent to pre-adolescents. In the primary analysis sample of 379 participants, a higher pre-rejection MLVI predicted LAR [mean pre-rejection MLVI with LAR: 2.4 (3.6 SD) vs. without LAR, 1.6 (1.1); p=0.026]. 53% 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. 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.
  • Comment on the Article “OPTN/SRTR 2015 Annual Data Report: Pancreas”
    We read with great interest the most recent “OPTN/SRTR 2015 Annual Data Report: Pancreas” (1). We would like to bring to the attention of the editors and authors our serious concerns with respect to flaws in this SRTR report specifically related to pancreas transplantation alone (PTA). First, we noted substantial discrepancies in the number of PTAs (Table PA 1) presented in this article versus the number of PTAs that the International Pancreas Transplant Registry (IPTR) uses for its current analyses. This article is protected by copyright. All rights reserved.
  • 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 8/2012 and 2/2015 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 2 steps towards 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% C.I. [0.16 – 4.29], p = 0.03), and if network members themselves completed more steps (β = 2.84, 95% C.I. [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. This article is protected by copyright. All rights reserved.
  • Predicting Primary Nonfunction of Liver Transplants with Laboratory Values: Can it be done?
    Determination of primary nonfunction (PNF) of a liver transplant can be one of the most difficult assessments in transplantation. PNF can initially manifest in variety of ways both dramatic and subtle, and no one parameter is sufficient for diagnosis [1,2]. The determination of PNF informs the decision to relist for a second liver transplant. Once relisted, one or more additional confirmations are subsequently necessary in the context of deciding whether to retransplant as donors become available. In addition, a retransplant operation is not without risk, especially in the setting of the existing or impending multiorgan system failure that can be associated with PNF. This article is protected by copyright. All rights reserved.
  • 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, 9 adult patients (median age: 47 years) with hematological disorders who were treated with HSCT (N=7) or chemotherapy (N=2) in a single hematology department developed hemorrhagic cystitis due to BKPYV infection. The PCR products of BKPYV DNA obtained from each patient were sequenced. Of the 9 patients, 6 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. This article is protected by copyright. All rights reserved.
  • Novel application of localized nanodelivery of anti-IL6 protects organ transplant from ischemia reperfusion injuries
    Ischemia reperfusion injury (IRI) evokes intra-graft 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 (DC). While autophagy is a survival mechanism for ischemic DC, it also augments their production of IL6. Allograft derived dendritic cells (ADDC) lacking autophagy related gene 5 (Atg5) showed higher death rates post-transplantation. Transplanted ischemic hearts from CD11cCre/Atg5 conditional knockout mice showed marked reduction in intra-graft expression of IL6 as compared to controls. To antagonize the effect of IL6 locally in the heart, we synthesized novel anti-IL6 nanoparticles with capacity for controlled release of anti-IL6 over time. As compared to systemic delivery of anti-IL6, localized delivery of anti-IL6 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 IL6 in driving chronic rejection after IRI. These data carry potential clinical significance, by identifying an innovative, targeted strategy to manipulate organs prior to transplantation to diminish inflammation, leading to improved long term outcomes. This article is protected by copyright. All rights reserved.
  • “White-out” After Lung Transplantation: a multicentre cohort description of late acute graft failure
    Graft failure represents a leading cause of mortality following organ transplantation. Acute late-onset graft failure has not been widely reported. This paper describes the demographics, CT imaging pathology findings and treatment of patients presenting with the latter. A retrospective review of lung transplant recipients at 2 large-volume centres was performed. Acute late-onset graft failure was defined as sudden onset of bilateral infiltrates with an oxygenation index <200 without identifiable cause or concurrent extra-pulmonary organ failure. Laboratory data, bronchoalveolar lavage (BAL), radiology and histology 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. Trans-bronchial biopsies revealed acute fibrinoid organising pneumonia (AFOP), organising 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 dismal prognosis. This article is protected by copyright. All rights reserved.
  • Obituary of Thomas E. Starzl, M.D., Ph.D
    Thomas E. Starzl was born in LeMars, Iowa, where his father, Roman Starzl, owned and edited the town's newspaper. Young “Tommie” worked at every job on the paper, from printer's devil to reporter. His mother had been a nurse earlier in life. Her encouragement and her long fight with breast cancer inspired Starzl to pursue a medical career. After graduating from high school, he enlisted in the U.S. This article is protected by copyright. All rights reserved.
  • The First Transplant Surgeon: The Flawed Genius of Nobel Prize Winner, Alexis Carrel, by David Hamilton, World Scientific, London, 2017. 587 pages
    Most of us in organ transplantation know that Alexis Carrel was a pioneer in anastomosing blood vessels, essential if one is to transplant an organ. This was no mean feat in the first decade of the 20th century, when all he had available was straight needles threaded with silk. For these efforts he was awarded the Nobel Prize for Physiology or Medicine in 2012, becoming the youngest laureate of this category of the Prize to date and the first American-based winner. This article is protected by copyright. All rights reserved.
  • Breg dependent islet transplant tolerance is also NK-cell dependent
    Immunologic tolerance to solid organ and islet cell grafts has been achieved in various rodent models using antibodies directed at CD45RB and Tim-1. We have shown that this form of tolerance depends on regulatory B-cells. To elucidate further the mechanism by which Bregs induce tolerance we investigated the requirement of 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 following dual antibody treatment. In contrast, transplant tolerance induction was successful in CD1d-/- recipients (deficient in NK-T 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. This article is protected by copyright. All rights reserved.
  • 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). Herein, we report on a kidney-transplant recipient with SCD that was treated with everolimus, a mammalian target of rapamycin inhibitor. At 10 months after initiating therapy, HbF level was dramatically increased (from 4.8% to 15%) and there was excellent tolerance to treatment. This article is protected by copyright. All rights reserved.
  • 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 intra-graft 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 anti-graft 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 wondered 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 DCs 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. This article is protected by copyright. All rights reserved.
  • 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% vs. 1% for the early and late DCD groups, respectively (P=0.001). Patient survival was similar in all 3 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 of a protocol that includes a thrombolytic therapy, DCD LT yielded patient and graft survival rates comparable to DBD LT. This article is protected by copyright. All rights reserved.
  • 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 1988-2012 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 2006-2012 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 PKT recipients. This article is protected by copyright. All rights reserved.
  • 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 8 cases (5%) and in 6 cases the tissue sample was non-diagnostic (3.8%). The kidney tissue yield was 98.6%. There were four patients with intraoperative complications requiring laparotomy (2.5%) with 2 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. This article is protected by copyright. All rights reserved.
  • 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 non-transplant 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% non-white 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 vs. 60+ were 2.02 (95% 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. This article is protected by copyright. All rights reserved.
  • 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 since there are not much 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 using microCT. Lungs from 28 donors were collected. Two lungs were unused, 6 were declined for non-allograft-related reasons (collectively denominated non-allograft declines, n=8), while 20 were declined because of allograft-related reasons. CT demonstrated normal lung parenchyma in only 4/8 non-allograft declines, while relatively normal parenchyma was found in 12/20 allograft-related declines. CT and microCT were able to confirm 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 to 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. This article is protected by copyright. All rights reserved.
  • 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 NK cells, which have similar functions 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 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. This article is protected by copyright. All rights reserved.
  • 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 classical 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, both in 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. This article is protected by copyright. All rights reserved.
  • 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 is 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 6,482 candidates listed in the Organ Procurement and Transplantation Network for pediatric heart transplantation between 2002 and 2014; 4,665 of the candidates (72%) were transplanted. Candidates were divided into groups according to the average annual transplant volume performed in the listing center during the study period: > 10, 6-10, 3-5, and <3. We used multivariate Cox regression analysis to identify independent risk factors for waitlist and post-transplant mortality. 24% of the candidates were listed in low volume centers (< 3 annual transplants). Of these listed candidates, only 36% received a transplant versus 89% in high volume centers (>10 annual transplants) (p <0.001). Listing at a low volume center (< 3 annual transplants) was the most significant risk factor for waitlist death (HR 4.5, CI 3.5-5.7 in multivariate Cox regression and HR 5.6, CI 4.4-7.3 in multivariate competing risk regression) and also significant for post-transplant death (HR 1.27, CI 1.0-1.6 in multivariate Cox regression). During the study period, a quarter of pediatric transplant candidates were listed in low volume transplant centers. These children had a limited transplant rate and a much greater risk of dying on the waitlist. This article is protected by copyright. All rights reserved.
  • 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 and bone marrow transplantation (CKBMT) that led to transient chimerism under a previously-published non-myeloablative conditioning regimen (Immune Tolerance Network study ITN036). Polychromatic flow cytometry (FCM) and high throughput sequencing of TCRβ hypervariable regions of DNA from peripheral blood T regulatory cells (Tregs) and CD4 non-Tregs revealed marked early enrichment of regulatory T cells (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 fraction of the T cell clones detected in post-transplant biopsy specimens by TCR 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 post-transplant period may contribute to tolerance following CKBMT. Furthermore, most conventional T cell clones detected in immunologically quiescent post-transplant biopsies appear to be circulating cells in the microvasculature rather than infiltrating T cells. This article is protected by copyright. All rights reserved.
  • Mortality Risk Factors Among Patients with Cirrhosis and a Low (≤15) MELD Sodium Score: An Analysis of Liver Transplant Allocation policy Using Aggregated Electronic Health Record Data
    Although the MELDNa 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 7,834 adult patients with cirrhosis, we determined whether the cause of cirrhosis/cirrhosis complications is associated with an increased risk of death among patients with a MELDNa ≤15 and whether patients with the greatest risk of death could benefit from liver transplantation (LT). Over a median follow-up of 2.3 years, 3,715 patients had a maximum MELDNa score ≤15. 3.4% were wait-listed for LT. Severe hypoalbuminemia, hepatorenal syndrome and hepatic hydrothorax conferred the greatest risk of death independent of MELDNa score with a 1 year predicted mortality >14%. Approximately 10% possessed these risk factors. Of these high risk patients, only 4% were wait-listed for liver transplantation despite no difference in non-liver comorbidities between patients wait-listed and those not listed. Also, risk factors for death among patients wait-listed were the same as those not wait-listed although the effect of malnutrition was significantly greater for wait-listed patients (HR 8.65 CI 2.57-29.11 versus HR 1.47 CI 1.08-1.98). Using the MELDNa score for allocation may continue to limit access to liver transplantation. This article is protected by copyright. All rights reserved.
  • 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 inter-individual 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 This article is protected by copyright. All rights reserved.
  • Improving the diagnostic criteria for primary liver graft non-function in adults utilizing standard and transportable laboratory parameters. An outcome based analysis
    Current diagnostic criteria for primary non-function (PNF) of liver grafts are based on clinical experience rather than statistical methods. A retrospective, single centre study was conducted of all adults (n=1,286) who underwent primary liver transplant 2000-2008 in our centre. Laboratory variable during the first post-liver transplant week were analysed. Forty two patients (3.7%) had 2-week graft failure. Transplant albumin, day-1 AST, day-1 lactate, day-3 bilirubin, day-3 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*D 3 INR)+(0.00153*D7 AST)-(0.0972*TxAlbumin)-4.5503. ROC analysis showed the model 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 EGD 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 non-marginal). This article is protected by copyright. All rights reserved.
  • Orthogonal Comparison of Molecular Signatures of Kidney Transplants with Subclinical and Clinical Acute Rejection – Equivalent Performance is Agnostic to either Technology or Platform
    We performed orthogonal technology comparisons of concurrent peripheral blood and biopsy tissue samples from 69 kidney transplant recipients, who underwent a comprehensive algorithm-driven clinical phenotyping. The sample cohort included patients with normal protocol biopsies and stable transplant function (TX, 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, demonstrating 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 allo-immune 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 TX, subAR and cAR in both blood and biopsy tissue, yielding equivalent predictive performance, that is agnostic to either technology or platform. Our data also provide strong biologic insights into the molecular mechanisms underlying these signatures, underscoring their logistical potential as molecular diagnostics to improve clinical outcomes following kidney transplantation. This article is protected by copyright. All rights reserved.
  • 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.
  • 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.
  • 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.
  • View From the American Society of Reconstructive Transplantation
  • 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.
  • Synthetic Fusion Protein CAR Technology to Redirect T Cell Antigen Specificity to Promote Organ Transplant Tolerance
  • 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.
  • Fc-Silent Anti-CD154 Domain Antibody Effectively Prevents Nonhuman Primate Renal Allograft Rejection
    The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti-CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004). The anti-CD154 dAb effectively blocked CD40-CD154 interactions but lacked crystallizable fragment (Fc) binding activity and resultant platelet activation. In a nonhuman primate kidney transplant model, anti-CD154 dAb was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (Median survival time 103 days). The combination of anti-CD154 dAb and conventional immunosuppression synergized to effectively control allograft rejection (Median survival time 397 days). Furthermore, anti-CD154 dAb treatment increased the frequency of CD4+CD25+Foxp3+ regulatory T cells. This study demonstrates that the use of a novel anti-CD154 dAb that lacks Fc binding activity is safe without evidence of thromboembolism and is equally as potent as previous anti-CD154 agents at prolonging renal allograft survival in a nonhuman primate preclinical model.
  • Comprehensive Analysis of Transcript Changes Associated With Allograft Rejection: Combining Universal and Selective Features
    We annotated the top transcripts associated with kidney transplant rejection by p-value, either universal for all rejection or selective for T cell–mediated rejection (TCMR) or antibody-mediated rejection (ABMR; ClinicalTrials.gov NCT01299168). We used eight class-comparison algorithms to interrogate microarray results from 703 biopsies, 205 with rejection. The positive comparators were all rejection, TCMR, or ABMR; the negative comparators varied from normal biopsies to all nonrejecting biopsies, including other diseases. The universal algorithm, rejection versus all nonrejection, identified transcripts mainly inducible by interferon γ. Selectivity for ABMR or TCMR required the other rejection class as well as nonrejection biopsies in the comparator to avoid selecting universal transcripts. Direct comparison of ABMR versus TCMR yielded only transcripts related to TCMR, the stronger signal. Transcripts highly associated with rejection were never completely specific for rejection: Many were increased in biopsies without rejection, reflecting sharing between rejection and injury-induced innate immunity. Union of the top 200 transcripts from universal and selective algorithms yielded 454 transcripts that permitted unsupervised analysis of biopsies in principal component analysis: PC1 was rejection, and PC2 was separation of TCMR from ABMR. Appreciating rejection-associated molecular changes requires a diverse case mix, accurate histologic classification (including C4d-negative ABMR), and both selective and universal algorithms.
  • Complement Polymorphisms in Kidney Transplantation: Critical in Graft Rejection?
    The complement system, as part of the innate immune system, plays an important role in renal transplantation. Complement is involved in the protection against foreign organisms and clearance of apoptotic cells but can also cause injury to the renal allograft, for instance, via antibody binding or in ischemia–reperfusion injury. Numerous polymorphisms in complement factors have been identified thus far; some of them result in different functionalities or alter complement levels. In this review, we provide an overview of the literature on the role of complement polymorphisms in renal transplantation. Furthermore, we discuss functional complement polymorphisms that have not yet been investigated in kidney transplantation. By investigating multiple polymorphisms both in donor and recipient at the same time, a complotype can be constructed. Because the combination of multiple polymorphisms is likely to have a greater impact than a single one, this could provide valuable prognostic information.
  • Metrics and Data Analysis in Transplantation: Quality Improvement via Transparency
  • Adult Living Donor Liver Transplantation for Acute-on-Chronic Liver Failure in High–Model for End-Stage Liver Disease Score Patients
    The large volume of adult living donor liver transplantations (ALDLTs) at our center affords a unique opportunity to examine the impact of acute-on-chronic liver failure (ACLF) among high–Model for End-Stage Liver Disease MELD score patients. From February 1998 to March 2010, 1958 cirrhotic recipients were analyzed to study the relationship between MELD scores and ALDLT outcomes. A total of 327 high-MELD score recipients were categorized into ACLF and non-ACLF groups, and their outcomes were compared. The 5-year graft and patient survival in the high-MELD group were 75.2% and 76.4%, respectively, which were significantly worse than the low and intermediate MELD groups. The presence of ACLF associated with higher MELD scores appeared to be the dominant factor responsible for the inferior results of patients with MELD score of 30–34 points. The 5-year graft survivals in the ACLF group was 70.5% and in the non-ACLF group it was 81.0% (p = 0.035). Therefore, ALDLT should be performed as soon as possible in high-MELD score patients prior to ACLF development. Moreover, ACLF patients should be separately categorized when analyzing the outcomes of ALDLT. ALDLT for ACLF patients should not be discouraged because favorable outcomes can be expected through timely ALDLT and comprehensive management.
  • Transplant Infectious Diseases: A Review of the Scientific Registry of Transplant Recipients Published Data
    The Scientific Registry of Transplant Recipients (SRTR) serves to collect data on organ transplants performed in the United States. Although the infectious diseases data are limited and include mostly pretransplant serologies and other nonspecific infection-related outcomes, this multicenter data collection allows for insightful national data and the ability to monitor trends over time. We reviewed the published concise reports for each organ type in SRTR reports containing data from 2005 to 2014, and summarized our findings with respect to cytomegalovirus (CMV), Epstein-Barr virus, posttransplant lymphoproliferative disorder (PTLD), hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, general infection, and prophylaxis. Our review highlights a few developments. While rates of donor–recipient CMV serology combinations remain fairly constant over time, there are generally more seronegative donors and recipients among living donor transplants. There has been a reduction in PTLD for pediatric transplant recipients. There has also been a slight reduction in anti-HBV core antibody–positive donor organs and stable reporting of HCV-positive donor organs and HIV-positive recipients.
  • BK Polyomavirus Genomic Integration and Large T Antigen Expression: Evolving Paradigms in Human Oncogenesis
    Human polyomaviruses are ubiquitous, with primary infections that typically occur during childhood and subsequent latency that may last a lifetime. Polyomavirus-mediated disease has been described in immunocompromised patients; its relationship to oncogenesis is poorly understood. We present deep sequencing data from a high-grade BK virus–associated tumor expressing large T antigen. The carcinoma arose in a kidney allograft 6 years after transplantation. We identified a novel genotype 1a BK polyomavirus, called Chapel Hill BK polyomavirus 2 (CH-2), that was integrated into the BRE gene in chromosome 2 of tumor cells. At the chromosomal integration site, viral break points were found, disrupting late BK gene sequences encoding capsid proteins VP1 and VP2/3. Immunohistochemistry and in situ hybridization studies demonstrated that the integrated BK virus was replication incompetent. We propose that the BK virus CH-2 was integrated into the human genome as a concatemer, resulting in alterations of feedback loops and overexpression of large T antigen. Collectively, these findings support the emerging understanding that viral integration is a nearly ubiquitous feature in polyomavirus-associated malignancy and that unregulated large T antigen expression drives a proliferative state that is conducive to oncogenesis. Based on the current observations, we present an updated model of polyomavirus-mediated oncogenesis.
  • Disruption of Transplant Tolerance by an “Incognito” Form of CD8 T Cell–Dependent Memory
    Several approaches successfully achieve allograft tolerance in preclinical models but are challenging to translate into clinical practice. Many clinically relevant factors can attenuate allograft tolerance induction, including intrinsic genetic resistance, peritransplant infection, inflammation, and preexisting antidonor immunity. The prevailing view for immune memory as a tolerance barrier is that the host harbors memory cells that spontaneously cross-react to donor MHC antigens. Such preexisting “heterologous” memory cells have direct reactivity to donor cells and resist most tolerance regimens. In this study, we developed a model system to determine if an alternative form of immune memory could also block tolerance. We posited that host memory T cells could potentially respond to donor-derived non-MHC antigens, such as latent viral antigens or autoantigens, to which the host is immune. Results show that immunity to a model nonself antigen, ovalbumin (OVA), can dramatically disrupt tolerance despite undetectable initial reactivity to donor MHC antigens. Importantly, this blockade of tolerance was CD8+ T cell–dependent and required linked antigen presentation of alloantigens with the test OVA antigen. As such, this pathway represents an unapparent, or “incognito,” form of immunity that is sufficient to prevent tolerance and that can be an unforeseen additional immune barrier to clinical transplant tolerance.
  • Peripheral Blood Gene Expression Changes Associated With Primary Graft Dysfunction After Lung Transplantation
    Recipient responses to primary graft dysfunction (PGD) after lung transplantation may have important implications to the fate of the allograft. We therefore evaluated longitudinal differences in peripheral blood gene expression in subjects with PGD. RNA expression was measured throughout the first transplant year in 106 subjects enrolled in the Clinical Trials in Organ Transplantation-03 study using a panel of 100 hypothesis-driven genes. PGD was defined as grade 3 in the first 72 posttransplant hours. Eighteen genes were differentially expressed over the first year based on PGD development, with significant representation from innate and adaptive immunity genes, with most differences identified very early after transplant. Sixteen genes were overexpressed in the blood of patients with PGD compared to those without PGD within 7 days of allograft reperfusion, with most transcripts encoding innate immune/inflammasome-related proteins, including genes previously associated with PGD. Thirteen genes were underexpressed in patients with PGD compared to those without PGD within 7 days of transplant, highlighted by T cell and adaptive immune regulation genes. Differences in gene expression present within 2 h of reperfusion and persist for days after transplant. Future investigation will focus on the long-term implications of these gene expression differences on the outcome of the allograft.
  • Generating Antigen-Specific Regulatory T Cells in the Fast Lane
  • Prozone Effect Can Be Specific to Single Antigen Bead Kit Manufacturers
  • Representing Subnormothermic Machine Perfusion in Fatty Livers: The Complete Picture?
  • Defining the Tipping Point in Surgical Performance for Laparoscopic Donor Nephrectomy Among Transplant Surgery Fellows: A Risk-Adjusted Cumulative Summation Learning Curve Analysis
    The United Network for Organ Sharing recommends that fellowship-trained surgeons participate in 15 laparoscopic donor nephrectomy (LDN) procedures to be considered proficient. The American Society of Transplant Surgeons (ASTS) mandates 12 LDNs during an abdominal transplant surgery fellowship. We performed a retrospective intraoperative case analysis to create a risk-adjusted cumulative summation (RACUSUM) model to assess the learning curve of novice transplant surgery fellows (TSFs). Between January 2000 and December 2014, 30 novice TSFs participated in the organ procurement rotation of our ASTS-approved abdominal transplant surgery fellowship. Measures of surgical performance included intraoperative time, estimated blood loss, and incidence of intraoperative complications. The performance of senior TSFs was used to benchmark novice TSF performance. Scores were tabulated in a learning curve model, adjusting for case complexity and prior TSF case volume. Rates of adverse surgical events were significantly higher for novice TSFs than for senior TSFs. In univariable analysis, multiple renal arteries, high BMI, prior abdominal surgery, male donor, and nephrolithiasis were correlated with higher incidence of adverse surgical events. Based on the RACUSUM model, high intraoperative time is mitigated after 28 procedures, incidence of intraoperative complications tends to diminish after 24 procedures, and improvement in estimated blood loss did not remain consistent. TSFs exhibit a tipping point in LDN performance by 24–28 cases and proficiency by 35–38 cases.
  • Early Conversion From Calcineurin Inhibitor- to Everolimus-Based Therapy Following Kidney Transplantation: Results of the Randomized ELEVATE Trial
    In a 24-month, multicenter, open-label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10–14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus −1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy-proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus-treated patients (2.6%, p < 0.001) but similar to cyclosporine-treated patients (8.8%, p = 0.755). Reporting on de novo donor-specific antibodies (DSA) was limited but suggested more frequent anti-HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10–14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.
  • The Effect of MHC Antigen Matching Between Donors and Recipients on Skin Tolerance of Vascularized Composite Allografts
    The emergence of skin-containing vascularized composite allografts (VCAs) has provided impetus to understand factors affecting rejection and tolerance of skin. VCA tolerance can be established in miniature swine across haploidentical MHC barriers using mixed chimerism. Because the deceased donor pool for VCAs does not permit MHC antigen matching, clinical VCAs are transplanted across varying MHC disparities. We investigated whether sharing of MHC class I or II antigens between donors and recipients influences VCA skin tolerance. Miniature swine were conditioned nonmyeloablatively and received hematopoietic stem cell transplants and VCAs across MHC class I (n = 3) or class II (n = 3) barriers. In vitro immune responsiveness was assessed, and VCA skin-resident leukocytes were characterized by flow cytometry. Stable mixed chimerism was established in all animals. MHC class II–mismatched chimeras were tolerant of VCAs. MHC class I–mismatched animals, however, rejected VCA skin, characterized by infiltration of recipient-type CD8+ lymphocytes. Systemic donor-specific nonresponsiveness was maintained, including after VCA rejection. This study shows that MHC antigen matching influences VCA skin rejection and suggests that local regulation of immune tolerance is critical in long-term acceptance of all VCA components. These results help elucidate novel mechanisms underlying skin tolerance and identify clinically relevant VCA tolerance strategies.
  • 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.
  • A Soluble Form of P Selectin Glycoprotein Ligand 1 Requires Signaling by Nuclear Factor Erythroid 2–Related Factor 2 to Protect Liver Transplant Endothelial Cells Against Ischemia–Reperfusion Injury
    Liver endothelial cell (LEC) damage is essential in the pathogenesis of ischemia–reperfusion injury (IRI) in transplant recipients. We analyzed the mechanism of LEC resistance against IRI by using a novel recombinant soluble form of P selectin glycoprotein ligand 1, tandem P selectin glycoprotein ligand immunoglobulin (TSGL-Ig), in a mouse model of hepatic cold preservation (4°C in University of Wisconsin solution for 20 h) and syngeneic orthotopic liver transplantation (OLT). Unlike controls, TSGL-Ig protected orthotopic liver transplants against ischemia–reperfusion (IR) stress, shown by depressed serum alanine aminotransferase levels, well-preserved hepatic architecture, and improved survival (42% vs. 92%). TSGL-Ig suppressed neutrophil/macrophage sequestration and proinflammatory cytokine/chemokine programs in OLT. Treatment with TSGL-Ig mitigated LEC activation (P and E selectin, VCAM-1 and intercellular adhesion molecule 1 expression). In parallel in vitro studies, TSGL-Ig diminished cellular damage in H2O2-stressed LEC cultures (lactic acid dehydrogenase and alanine aminotransferase levels). Increased thioredoxin, glutamate-cysteine ligase, NAD(P)H quinone dehydrogenase 1, and hypoxia-inducible factor 1α expression, along with transcription factor nuclear factor erythroid 2–related factor 2 (Nrf2), implied that TSGL-Ig exerts antioxidant functions in IR-stressed OLT and H2O2-stressed LECs. Indeed, Nrf2-deficient livers suffered fulminant IRI compared with WT despite concomitant TSGL-Ig therapy. Thus, TSGL-Ig is not only acting as a competitive antagonist blocking leukocyte migration into IR-stressed liver, but it may also act directly as an agonist stimulating Nrf2-mediated cytoprotection in LECs. This study supports the role of P selectin signaling in hepatic homeostasis in OLT, with broad implications for tissue damage conditions.
  • Hiding in Plain Sight: A Case of Ornithine Transcarbamylase Deficiency Unmasked Post–Liver Transplantation
    Ornithine transcarbamylase deficiency represents the most common inherited defect of the urea cycle. This enzyme, predominantly found in the liver, plays a crucial role in recycling free ammonia, with deficiencies often leading to fatal complications. Here, we present the case of a 63-year-old man with alcoholic cirrhosis who underwent orthotopic liver transplantation, gradual worsening of his mental status, and progressive elevation of ammonia levels. Liver allograft function was deemed normal, raising concern for a donor-derived metabolic disorder of the urea cycle. Evaluation of the donor patient's blood revealed that the donor was heterozygous for the OTC gene. Posttransplantation changes in mental status should prompt a clinician to consider the most likely causes; however, once these have been ruled out, it is important to consider the less common causes of metabolic derangements. The rarity of these disorders makes expertise of diagnosis, standardization of evaluation, and treatment strategies challenging.
  • Preventive Strategies Against Cytomegalovirus and Incidence of α-Herpesvirus Infections in Solid Organ Transplant Recipients: A Nationwide Cohort Study
    We assessed the impact of antiviral preventive strategies on the incidence of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections in a nationwide cohort of transplant recipients. Risk factors for the development of HSV or VZV infection were assessed by Cox proportional hazards regression. We included 2781 patients (56% kidney, 20% liver, 10% lung, 7.3% heart, 6.7% others). Overall, 1264 (45%) patients received antiviral prophylaxis (ganciclovir or valganciclovir, n = 1145; acyclovir or valacyclovir, n = 138). Incidence of HSV and VZV infections was 28.9 and 12.1 cases, respectively, per 1000 person-years. Incidence of HSV and VZV infections at 1 year after transplant was 4.6% (95% confidence interval [CI] 3.5–5.8) in patients receiving antiviral prophylaxis versus 12.3% (95% CI 10.7–14) in patients without prophylaxis; this was observed particularly for HSV infections (3% [95% CI 2.2–4] versus 9.8% [95% CI 8.4–11.4], respectively). A lower rate of HSV and VZV infections was also seen in donor or recipient cytomegalovirus-positive patients receiving ganciclovir or valganciclovir prophylaxis compared with a preemptive approach. Female sex (hazard ratio [HR] 1.663, p = 0.001), HSV seropositivity (HR 5.198, p < 0.001), previous episodes of rejection (HR 1.95, p = 0.004), and use of a preemptive approach (HR 2.841, p = 0.017) were significantly associated with a higher risk of HSV infection. Although HSV and VZV infections were common after transplantation, antiviral prophylaxis significantly reduced symptomatic HSV infections.
  • Renal Allograft Survival in Nonhuman Primates Infused With Donor Antigen-Pulsed Autologous Regulatory Dendritic Cells
    Systemic administration of autologous regulatory dendritic cells (DCreg; unpulsed or pulsed with donor antigen [Ag]), prolongs allograft survival and promotes transplant tolerance in rodents. Here, we demonstrate that nonhuman primate (NHP) monocyte-derived DCreg preloaded with cell membrane vesicles from allogeneic peripheral blood mononuclear cells induce T cell hyporesponsiveness to donor alloantigen (alloAg) in vitro. These donor alloAg-pulsed autologous DCreg (1.4–3.6 × 106/kg) were administered intravenously, 1 day before MHC-mismatched renal transplantation to rhesus monkeys treated with costimulation blockade (cytotoxic T lymphocyte Ag 4 immunoglobulin [CTLA4] Ig) and tapered rapamycin. Prolongation of graft median survival time from 39.5 days (no DCreg infusion; n = 6 historical controls) and 29 days with control unpulsed DCreg (n = 2), to 56 days with donor Ag-pulsed DCreg (n = 5) was associated with evidence of modulated host CD4+ and CD8+ T cell responses to donor Ag and attenuation of systemic IL-17 production. Circulating anti-donor antibody (Ab) was not detected until CTLA4 Ig withdrawal. One monkey treated with donor Ag-pulsed DCreg rejected its graft in association with progressively elevated anti-donor Ab, 525 days posttransplant (160 days after withdrawal of immunosuppression). These findings indicate a modest but not statistically significant beneficial effect of donor Ag-pulsed autologous DCreg infusion on NHP graft survival when administered with a minimal immunosuppressive drug regimen.
  • Reactivation of Latent HPV Infections After Renal Transplantation
    Female renal transplant recipients (RTRs) have an increased risk for developing human papillomavirus (HPV)–related (pre)malignant lesions of the genital tract. This study aims to assess the genital prevalence of HPV before and after renal transplantation (RT). In female patients who were counseled for RT at the Radboud University Medical Center Nijmegen, the Netherlands, gynecological examination was performed at first visit, and 1 and 2 years later. HPV self-sampling and questionnaires on sexual behavior were performed every 3 months. In 65 patients who underwent RT, the high-risk human papillomavirus (hrHPV) prevalence as assessed with the highly sensitive SPF10 -LiPA25 test increased significantly from 19% before to 31% after RT (p = 0.045). Based upon the clinically validated Cobas 4800 HPV test, the hrHPV prevalence increased from 10% before to 14% after RT (p = 0.31). During follow-up, no changes in sexual behavior were reported. Thirty-three patients who did not undergo RT showed a hrHPV prevalence of 21% at study entry and of 27% after 12 months with the sensitive test, and a stable prevalence of 16% with the clinically validated test. The results of this study indicate that activation of latent HPV infections may contribute to the increased risk of HPV-related (pre)malignant lesions in female RTRs.
  • 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.
  • Testing the Efficacy of Contrast-Enhanced Ultrasound in Detecting Transplant Rejection Using a Murine Model of Heart Transplantation
    One of the key unmet needs to improve long-term outcomes of heart transplantation is to develop accurate, noninvasive, and practical diagnostic tools to detect transplant rejection. Early intragraft inflammation and endothelial cell injuries occur prior to advanced transplant rejection. We developed a novel diagnostic imaging platform to detect early declines in microvascular perfusion (MP) of cardiac transplants using contrast-enhanced ultrasonography (CEUS). The efficacy of CEUS in detecting transplant rejection was tested in a murine model of heart transplants, a standard preclinical model of solid organ transplant. As compared to the syngeneic groups, a progressive decline in MP was demonstrated in the allografts undergoing acute transplant rejection (40%, 64%, and 92% on days 4, 6, and 8 posttransplantation, respectively) and chronic rejection (33%, 33%, and 92% on days 5, 14, and 30 posttransplantation, respectively). Our perfusion studies showed restoration of MP following antirejection therapy, highlighting its potential to help monitor efficacy of antirejection therapy. Our data suggest that early endothelial cell injury and platelet aggregation contributed to the early MP decline observed in the allografts. High-resolution MP mapping may allow for noninvasive detection of heart transplant rejection. The data presented have the potential to help in the development of next-generation imaging approaches to diagnose transplant rejection.
  • Relationship Among Viremia/Viral Infection, Alloimmunity, and Nutritional Parameters in the First Year After Pediatric Kidney Transplantation
    The Immune Development in Pediatric Transplantation (IMPACT) study was conducted to evaluate relationships among alloimmunity, protective immunity, immune development, physical parameters, and clinical outcome in children undergoing kidney transplantation. We prospectively evaluated biopsy-proven acute rejection (BPAR), de novo donor-specific antibody (dnDSA) formation, viremia, viral infection, T cell immunophenotyping, and body mass index (BMI)/weight Z scores in the first year posttransplantation in 106 pediatric kidney transplant recipients. Outcomes were excellent with no deaths and 98% graft survival. Rejection and dnDSAs occurred in 24% and 22%, respectively. Pretransplant cytomegalovirus (CMV) and Epstein–Barr virus (EBV) serologies and subsequent viremia were unrelated to BPAR or dnDSA. Viremia occurred in 73% of children (EBV, 34%; CMV, 23%; BMK viremia, 23%; and JC virus, 21%). Memory lymphocyte phenotype at baseline was not predictive of alloimmune complications. Patients who developed viral infection had lower weight (−2.1) (p = 0.028) and BMI (−1.2) (p = 0.048) Z scores at transplantation. The weight difference persisted to 12 months compared with patients without infection (p = 0.038). These data indicate that there is a high prevalence of viral disease after pediatric kidney transplantation, and underweight status at transplantation appears to be a risk factor for subsequent viral infection. The occurrence of viremia/viral infection is not associated with alloimmune events.
  • Soluble Adhesion Molecules During Ex Vivo Lung Perfusion Are Associated With Posttransplant Primary Graft Dysfunction
    Ex vivo lung perfusion (EVLP) enables assessment of marginal donor lungs for transplantation. We aimed to discover biomarkers in EVLP perfusate that could predict development of primary graft dysfunction (PGD). From September 2008 to August 2013, 100 clinical EVLPs were performed. Eleven patients developed PGD grade 3 within 72 h after transplant. The non-PGD group consisted of 34 patients without PGD grade 3. Nonbilateral lung transplants or transplant after extracorporeal life support were excluded from analyses. Soluble intercellular adhesion molecule 1 (sICAM-1), soluble VCAM-1 (sVCAM-1), and soluble E selectin (sE-selectin) levels, as markers of endothelial activation, were measured in the perfusate of EVLP by enzyme-linked immunosorbent assay and were correlated with clinical outcome. Levels of sICAM-1 at 1 h and sVCAM-1 at 1 and 4 h were significantly higher in the PGD group compared with the non-PGD group. The sE selectin levels were not statistically different between the study groups. Higher levels of sVCAM-1 at 1 and 4 h were statistically significantly associated with PGD either alone or after adjustment for other PGD risk factors. These adhesion molecules may help identify donor lungs at higher risk of PGD during EVLP.
  • 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.
  • Left-Sided Living Kidney Donation Leads to Transiently Reduced Adrenocortical Responsiveness
    Living kidney donation is safe and established, but can lead to long-term complications such as chronic fatigue. Since the adrenal vein is usually transected during left-sided donor nephrectomy—which is not necessary on the right—we hypothesized that venous congestion might lead to an impairment of adrenal function, offering a possible explanation. In this prospective open label, monocentric cohort study, adrenal function was compared in left- and right-sided living kidney donors. The primary endpoint was plasma cortisol response to low-dose adrenocorticotropic hormone (ACTH) stimulation. Secondary endpoints included plasma renin and ACTH concentration as well as adrenal volume in response to donor nephrectomy. A total of 30 healthy donors—20 left- and 10 right-sided donations—were included. On postoperative day 1, response to low-dose ACTH stimulation was intact, but significantly lower after left-sided donor nephrectomy. After 28 days, adrenal responsiveness to ACTH stimulation did not differ any longer. Magnetic resonance imaging volumetry showed no significant adrenal volume change over 4 weeks, neither after left- nor after right-sided nephrectomy. In conclusion, left-sided living kidney donation entails a transiently reduced adrenocortical responsiveness, which returns to baseline after 28 days.
  • American Journal of Transplantation: Volume 17, Number 3, March 2017
    On the cover this month: Transplantation's considerable benefit is tempered by a continued requirement for nonspecific T cell–directed immunosuppression, and with it, impaired protective immunity, particularly against viral pathogens. This month we highlight articles covering the breadth of viral disease in transplantation, including well-known pathogens such as Epstein–Barr virus (Dharnidharka, page 611; AlDabbagh et al, page 770), cytomegalovirus (Zheng et al, page 657), and BK virus (Kuppachi et al, page 813), as well as less common pathogens such as West Nile virus (Wilson et al, page 803) and parainfluenza virus (Helanterä et al, page 809). We also feature a recent commentary on an emerging threat, Zika virus (Nogueira et al, page 791, and Blumberg and Fishman's editorial on page 599). These articles continue to underscore the immune consequences of organ transplantation, and impel continued work toward more precise immune management strategies. Cover design by Scott Behm and Deanna Hoskins, Duke University Department of Surgery.
  • MACRA Is Here to Stay
    This month “The AJT Report” explores how the Medicare Access and CHIP Reauthorization Act (MACRA) may impact transplantation. Also this issue, we review France's new opt-out policy for organ transplantation.
  • Dendritic Cell Identification for Dummies
    Guilliams et al's unsupervised computational analysis of flow cytometry or mass cytometry data outperforms manual analysis using antibody panels that could distinguish DC subsets from macrophages across tissues and species, whether at steady state or following inflammation.
  • Elementary, My Dear Watson—The Era of Natural Language Processing in Transplantation
    A novel pilot study by Srinivas et al (page 671) demonstrates the feasibility of automated data extraction from unstructured data within electronic health records, which may enhance available data for model building to predict graft loss following kidney transplantation.
  • Financial Incompatibility and Paired Kidney Exchange: Walking a Tightrope or Blazing a Trail?
    Engaging compatible kidney donor–recipient pairs from other countries for participation in a paired kidney exchange program in the United States poses a number of ethical challenges that deserve close scrutiny. Rees et al's article is on page 782.
  • Zika Virus in Transplantation: Emerging Infection and Opportunities
    Assay development for organ donor screening and clinical diagnosis should be accelerated with research to define the behavior of Zika in transplantable organs. See the article from Nogueira et al (page 791).
  • Treg-Centric View of Immunosuppressive Drugs in Transplantation: A Balancing Act
    Regulatory CD4+ Foxp3+ T cells (Tregs) are critical in controlling immunity and tolerance. Thus, preserving Treg numbers and function in transplanted patients is essential for the successful minimization of maintenance immunosuppression. Multiple cellular signals control the development, differentiation, and function of Tregs. Many of these signals are shared with conventional Foxp3− T cells (Tconv) and are targeted by immunosuppressive drugs, negatively affecting both Tregs and Tconv. Because intracellular signals vary in optimal intensity in different T cell subsets, improved specificity in immunosuppressive regimens must occur to benefit long-term transplant outcomes. In this regard, recent advances are gradually uncovering differences in the signals required in Tregs and Tconv biology, opening the door to new potential therapeutic approaches to either enhance or spare Tregs. In this review, we will explain the prominent cell signaling pathways critical for Treg maintenance and function, while reporting the effects of immunosuppressive drugs targeting these signaling pathways in clinical transplantation settings.
  • Peripheral Blood Epstein–Barr Viral Nucleic Acid Surveillance as a Marker for Posttransplant Cancer Risk
    Several viruses, such as Epstein–Barr virus, are now known to be associated with several human cancers, but not all patients with these viral infections develop cancer. In transplantation, such viruses often have a prolonged time gap from infection to cancer development, and many are preceded by a period of circulating and detectable nucleic acids in the peripheral blood compartment. The interpretation of a viral load as a measure of posttransplant risk of developing cancer depends on the virus, the cancer and associated pathogenic factors. This review describes the current state of knowledge regarding the utility and limitations of peripheral blood nucleic acid testing for Epstein–Barr virus in surveillance and risk prediction for posttransplant lymphoproliferative disorders.
  • Utility of Ecological Risk Factors for Evaluation of Transplant Center Performance
    There is substantial evidence across different healthcare contexts that social determinants of health are strongly associated with morbidity and mortality in the United States. These factors, including socioeconomic status, behavior and environmental risks, education, social support, healthy food, and access to healthcare also vary widely by region and individual communities. One of the implications of heterogeneity in these risks is the potential impact on measured quality of healthcare providers. In particular, there is concern that providers treating disproportionally vulnerable communities may be disadvantaged by lack of risk adjustment for these factors that affect health but not indicators of quality of care. Recently, the National Quality Forum has endorsed risk adjustment for sociodemographic characteristics based on these concerns. These issues are salient to transplant programs since social determinants of health impact transplant patient outcomes and vary by region. In this viewpoint, we argue that integration of ecological (area-level) factors in risk adjustment models used to assess transplant center quality should be strongly considered. We believe this reform could be accomplished rapidly, would attenuate disparities in access to care by reducing disincentives to treat patients from vulnerable communities, and improve risk adjustment and calibration of models used for center evaluations.
  • A Novel Rodent Orthotopic Forelimb Transplantation Model That Allows for Reliable Assessment of Functional Recovery Resulting From Nerve Regeneration
    Improved nerve regeneration and functional outcomes would greatly enhance the utility of vascularized composite allotransplantation (VCA) such as hand and upper extremity transplantation. However, research aimed at achieving this goal has been limited by the lack of a functional VCA animal model. We have developed a novel rat midhumeral forelimb transplant model that allows for the characterization of upper extremity functional recovery following transplantation. At the final end point of 12 weeks, we found that animals with forelimb transplantation including median, ulnar and radial nerve coaptation demonstrated significantly improved grip strength and forelimb function as compared to forelimb transplantation without nerve approximation (grip strength: 1.71N ± 0.57 vs. no appreciable recovery; IBB scale: 2.6 ± 0.7? vs. 0.8 ± 0.40; p = 0.0005), and similar recovery to nerve transection-and-repair only (grip strength: 1.71N ± 0.57 vs. 2.03 ± 0.42.6; IBB scale: 2.6 ± 0.7 vs. 2.8 ± 0.8; p = ns). Moreover, all forelimb transplant animals with nerve coaptation displayed robust axonal regeneration with myelination and reduced flexor muscle atrophy when compared to forelimb transplant animals without nerve coaptation. In conclusion, this is the first VCA small-animal model that allows for reliable and reproducible measurement of behavioral functional recovery in addition to histologic evaluation of nerve regeneration and graft reinnervation.
  • ASP2409, A Next-Generation CTLA4-Ig, Versus Belatacept in Renal Allograft Survival in Cynomolgus Monkeys
    Belatacept is the first costimulatory blockade agent approved for maintenance immunosuppression in kidney transplant recipients. Clinical results have indicated that belatacept is associated with superior renal function and improved metabolic profile; however, higher incidence of acute rejection and posttransplant lymphoproliferative disorder are the shortcomings of this agent. In this study, ASP2409, a new cytotoxic T-lymphocyte associated protein 4-immunoglobulin possessing 14-fold higher in vitro CD86 binding affinity than belatacept, was tested for renal allograft survival in cynomolgus monkeys. ASP2409 monotherapy dose-dependently prolonged renal allograft survival. Low-dose ASP2409 in combination with a subtherapeutic dose of tacrolimus showed much longer median survival time than monotherapy. Similar allograft survival results were observed in regimens based on high-dose ASP2409, belatacept, and therapeutic-dose tacrolimus. The results of renal allograft histopathology with high-dose ASP2409-based regimens were not inferior to the belatacept-based regimen. Moreover, higher frequencies of FoxP3-positive regulatory T cells in renal allografts were observed in ASP2409- and belatacept-based regimens compared with tacrolimus-based regimens. No serious side effects related to ASP2409 administration were found during the study. These data suggest that ASP2409 is a promising candidate for calcineurin inhibitor-sparing or -avoidance regimens.
  • Immunosuppression With CD40 Costimulatory Blockade Plus Rapamycin for Simultaneous Islet–Kidney Transplantation in Nonhuman Primates
    The lack of a reliable immunosuppressive regimen that effectively suppresses both renal and islet allograft rejection without islet toxicity hampers a wider clinical application of simultaneous islet–kidney transplantation (SIK). Seven MHC-mismatched SIKs were performed in diabetic cynomolgus monkeys. Two recipients received rabbit antithymocyte globulin (ATG) induction followed by daily tacrolimus and rapamycin (ATG/Tac/Rapa), and five recipients were treated with anti-CD40 monoclonal antibody (mAb) and rapamycin (aCD40/Rapa). Anti-inflammatory therapy, including anti–interleukin-6 receptor mAb and anti–tumor necrosis factor-α mAb, was given in both groups. The ATG/Tac/Rapa recipients failed to achieve long-term islet allograft survival (19 and 26 days) due to poor islet engraftment and cytomegalovirus pneumonia. In contrast, the aCD40/Rapa regimen provided long-term islet and kidney allograft survival (90, 94, >120, >120, and >120 days), with only one recipient developing evidence of allograft rejection. The aCD40/Rapa regimen was also tested in four kidney-alone transplant recipients. All four recipients achieved long-term renal allograft survival (100% at day 120), which was superior to renal allograft survival (62.9% at day 120) with triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and steroids). The combination of anti-CD40 mAb and rapamycin is an effective and nontoxic immunosuppressive regimen that uses only clinically available agents for kidney and islet recipients.
  • The Knife's Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism but With a Significant Risk of CMV Reactivation and Disease in Rhesus Macaques
    Although stable mixed-hematopoietic chimerism induces robust immune tolerance to solid organ allografts in mice, the translation of this strategy to large animal models and to patients has been challenging. We have previously shown that in MHC-matched nonhuman primates (NHPs), a busulfan plus combined belatacept and anti-CD154-based regimen could induce long-lived myeloid chimerism, but without T cell chimerism. In that setting, donor chimerism was eventually rejected, and tolerance to skin allografts was not achieved. Here, we describe an adaptation of this strategy, with the addition of low-dose total body irradiation to our conditioning regimen. This strategy has successfully induced multilineage hematopoietic chimerism in MHC-matched transplants that was stable for as long as 24 months posttransplant, the entire length of analysis. High-level T cell chimerism was achieved and associated with significant donor-specific prolongation of skin graft acceptance. However, we also observed significant infectious toxicities, prominently including cytomegalovirus (CMV) reactivation and end-organ disease in the setting of functional defects in anti-CMV T cell immunity. These results underscore the significant benefits that multilineage chimerism-induction approaches may represent to transplant patients as well as the inherent risks, and they emphasize the precision with which a clinically successful regimen will need to be formulated and then validated in NHP models.
  • Big Data, Predictive Analytics, and Quality Improvement in Kidney Transplantation: A Proof of Concept
    We sought proof of concept of a Big Data Solution incorporating longitudinal structured and unstructured patient-level data from electronic health records (EHR) to predict graft loss (GL) and mortality. For a quality improvement initiative, GL and mortality prediction models were constructed using baseline and follow-up data (0–90 days posttransplant; structured and unstructured for 1-year models; data up to 1 year for 3-year models) on adult solitary kidney transplant recipients transplanted during 2007–2015 as follows: Model 1: United Network for Organ Sharing (UNOS) data; Model 2: UNOS & Transplant Database (Tx Database) data; Model 3: UNOS, Tx Database & EHR comorbidity data; and Model 4: UNOS, Tx Database, EHR data, Posttransplant trajectory data, and unstructured data. A 10% 3-year GL rate was observed among 891 patients (2007–2015). Layering of data sources improved model performance; Model 1: area under the curve (AUC), 0.66; (95% confidence interval [CI]: 0.60, 0.72); Model 2: AUC, 0.68; (95% CI: 0.61–0.74); Model 3: AUC, 0.72; (95% CI: 0.66–077); Model 4: AUC, 0.84, (95 % CI: 0.79–0.89). One-year GL (AUC, 0.87; Model 4) and 3-year mortality (AUC, 0.84; Model 4) models performed similarly. A Big Data approach significantly adds efficacy to GL and mortality prediction models and is EHR deployable to optimize outcomes.
  • Eculizumab Therapy for Chronic Antibody-Mediated Injury in Kidney Transplant Recipients: A Pilot Randomized Controlled Trial
    We hypothesized that de novo donor-specific antibody (DSA) causes complement-dependent endothelial cell injury in kidney transplants, as assessed by expression of endothelial cell–associated transcripts (ENDATs), that may be attenuated through complement inhibition. In total, 15 participants (five control, 10 treatment) with DSA and deteriorating renal function were enrolled. The treatment group received 6 mo of eculizumab followed by 6 mo of observation, whereas controls were observed. The primary end point was percentage change in estimated GFR (eGFR) trajectory over the treatment period. The treatment group had an improved eGFR trajectory versus control, based on our predetermined two-sided 0.10 significance level (p = 0.09). Within-subject analysis of treated participants at 6-mo intervals did not show significant change (p = 0.60). Modeling C1q status showed that C1q-positive patients had significantly higher mean eGFR than patients with negative C1q (p = 0.04). Biopsies revealed elevated renal ENDATs in most participants, but ENDATs were not reduced with complement inhibition. Our data suggest that eculizumab treatment may stabilize kidney function in patients with chronic persistent DSA based on our pilot a priori significance threshold. ENDAT expression predicative of acute humoral injury is not reduced with complement inhibition in this chronic setting. Further studies will be necessary to determine which patients may benefit from eculizumab.
  • Kidney Intragraft Homing of De Novo Donor-Specific HLA Antibodies Is an Essential Step of Antibody-Mediated Damage but Not Per Se Predictive of Graft Loss
    Donor-specific HLA antibody (DSA)-mediated graft injury is the major cause of kidney loss. Among DSA characteristics, graft homing has been suggested as an indicator of severe tissue damage. We analyzed the role of de novo DSA (dnDSA) graft homing on kidney transplantation outcome. Graft biopsy specimens and parallel sera from 48 nonsensitized pediatric kidney recipients were analyzed. Serum samples and eluates from graft biopsy specimens were tested for the presence of dnDSAs with flow bead technology. Intragraft dnDSAs (gDSAs) were never detected in the absence of serum dnDSAs (sDSAs), whereas in the presence of sDSAs, gDSAs were demonstrated in 72% of biopsy specimens. A significantly higher homing capability was expressed by class II sDSAs endowed with high mean fluorescence intensity and C3d- and/or C1q-fixing properties. In patients with available sequential biopsy specimens, we detected gDSAs before the appearance of antibody-mediated rejection. In sDSA-positive patients, gDSA positivity did not allow stratification for antibody-mediated graft lesions and graft loss. However, a consistent detection of skewed unique DSA specificities was observed over time within the graft, likely responsible for the damage. Our results indicate that gDSAs could represent an instrumental tool to identify, among sDSAs, clinically relevant antibody specificities requiring monitoring and possibly guiding patient management.
  • Evaluation of C1q Status and Titer of De Novo Donor-Specific Antibodies as Predictors of Allograft Survival
    De novo donor-specific antibodies (dnDSAs) that develop after renal transplantation are independent predictors of allograft loss. However, it is unknown if dnDSA C1q status or titer at the time of first detection can independently predict allograft loss. In a consecutive cohort of 508 renal transplant recipients, 70 developed dnDSAs. Histologic and clinical outcomes were correlated with the C1q assay or dnDSA titer. C1q positivity correlated with dnDSA titer (p < 0.01) and mean fluorescence intensity (p < 0.01) and was more common in class II versus class I dnDSAs (p < 0.01). C1q status correlated with tubulitis (p = 0.02) and C4d status (p = 0.03) in biopsies at the time of dnDSA development, but not T cell–mediated rejection (TCMR) or antibody-mediated rejection (ABMR). De novo DSA titer correlated with Banff g, i, t, ptc, C4d scores, TCMR (p < 0.01) and ABMR (p < 0.01). Post-dnDSA graft loss was observed more frequently in recipients with C1q-positve dnDSA (p < 0.01) or dnDSA titer ≥ 1:1024 (p ≤ 0.01). However, after adjustment for clinical phenotype and nonadherence in multivariate models, neither C1q status nor dnDSA titer were independently associated with allograft loss, questioning the utility of these assays at the time of dnDSA development.
  • Changes in Urinary Microbiome Populations Correlate in Kidney Transplants With Interstitial Fibrosis and Tubular Atrophy Documented in Early Surveillance Biopsies
    An unbalanced microbiome may lead to disease by creating aberrant immune responses. A recent association of cellular rejection with the development of interstitial fibrosis and tubular atrophy (IFTA) suggests the role of immune-mediated tissue injury. We hypothesized that developing IFTA correlates with altered urinary tract microbiomes (UMBs). UMBs at two serial time points, 1 and 6–8 months posttransplant, were assessed by 16S microbial ribosomal gene sequencing in 25 patients developing biopsy-proven IFTA compared to 23 transplant patients with normal biopsies and excellent function (TX) and 20 healthy nontransplant controls (HC). Streptococcus, the dominant genera in HC males, was lower in IFTA and TX males at 1 month compared to HCs. At 6–8 months, Streptococcus was further decreased in IFTA males, but normalized in TX. IFTA males and females had increases in number of genera per sample at 6–8 months. UMB composition varied substantially between individuals in all groups. Despite the wide variation in UMBs between individuals, IFTA was associated with a loss in dominant resident urinary microbes in males, and a parallel increase in nonresident, pathogenic bacteria in males and females. UMB changes may contribute to IFTA development by alteration of the host immune response.
  • The Impact of Anastomosis Time During Kidney Transplantation on Graft Loss: A Eurotransplant Cohort Study
    Recent studies raised the concern that warm ischemia during completion of vascular anastomoses in kidney implantation harms the transplant, but its precise impact on outcome and its interaction with other risk factors remain to be established. We investigated the relationship between anastomosis time and graft survival at 5 years after transplantation in 13 964 recipients of deceased donor solitary kidney transplants in the Eurotransplant region. Anastomosis time was independently associated with graft loss after adjusting for other risk factors (adjusted hazard ratio [HR] 1.10 for every 10-min increase, 95% confidence interval [CI] 1.06–1.14; p < 0.0001), whereas it did not influence recipient survival (HR 1.00, 95% CI 0.97–1.02). Kidneys from donation after circulatory death (DCD) were less tolerant of prolonged anastomosis time than kidneys from donation after brain death (p = 0.02 for interaction). The additive effect of anastomosis time with donor warm ischemia time (WIT) explains this observation because DCD status was no longer associated with graft survival when adjusted for this summed WIT, and there was no interaction between DCD status and summed WIT. Time to create the vascular anastomoses in kidney transplantation is associated with inferior transplant outcome, especially in recipients of DCD kidneys.
  • Early Macrophage Infiltration and Sustained Inflammation in Kidneys From Deceased Donors Are Associated With Long-Term Renal Function
    Kidney transplants from living donors (LDs) have a better outcome than those from deceased donors (DDs). Different factors have been suggested to justify the different outcome. In this study, we analyzed the infiltration and phenotype of monocytes/macrophages and the expression of inflammatory and fibrotic markers in renal biopsy specimens from 94 kidney recipients (60 DDs and 34 LDs) at baseline and 4 months after transplantation. We evaluated their association with medium- and long-term renal function. At baseline, inflammatory gene expression was higher in DDs than in LDs. These results were confirmed by the high number of CD68-positive cells in DD kidneys, which correlated negatively with long-term renal function. Expression of the fibrotic markers vimentin, fibronectin, and α–smooth muscle actin was more elevated in biopsy specimens from DDs at 4 months than in those from LDs. Gene expression of inflammatory and fibrotic markers at 4 months and difference between 4 months and baseline correlated negatively with medium- and long-term renal function in DDs. Multivariate analysis point to transforming growth factor-β1 as the best predictor of long-term renal function in DDs. We conclude that early macrophage infiltration, sustained inflammation, and transforming growth factor-β1 expression, at least for the first 4 months, contribute significantly to the difference in DD and LD transplant outcome.
  • Predonation Prescription Opioid Use: A Novel Risk Factor for Readmission After Living Kidney Donation
    Implications of opioid use in living kidney donors for key outcomes, including readmission rates after nephrectomy, are unknown. We integrated Scientific Registry of Transplant Recipients data with records from a nationwide pharmacy claims warehouse and administrative records from an academic hospital consortium to quantify predonation prescription opioid use and postdonation readmission events. Associations of predonation opioid use (adjusted odds ratio [aOR]) in the year before donation and other baseline clinical, procedural, and center factors with readmission within 90 days postdonation were examined by using multivariate logistic regression. Among 14 959 living donors, 11.3% filled one or more opioid prescriptions in the year before donation. Donors with the highest level of predonation opioid use (>305 mg/year) were more than twice as likely as nonusers to be readmitted (6.8% vs. 2.6%; aOR 2.49, 95% confidence interval 1.74–3.58). Adjusted readmission risk was also significantly (p < 0.05) higher for women (aOR = 1.25), African Americans (aOR = 1.45), spouses (aOR = 1.42), exchange participants (aOR = 1.46), uninsured donors (aOR = 1.40), donors with predonation estimated glomerular filtration rate <60 mL/min/1.73 m2 (aOR = 2.68), donors with predonation pulmonary conditions (aOR = 1.54), and after robotic nephrectomy (aOR = 1.68). Predonation opioid use is independently associated with readmission after donor nephrectomy. Future research should examine underlying mechanisms and approaches to reducing risks of postdonation complications.
  • Donor BMI >30 Is Not a Contraindication for Live Liver Donation
    The increased prevalence of obesity worldwide threatens the pool of living liver donors. Although the negative effects of graft steatosis on liver donation and transplantation are well known, the impact of obesity in the absence of hepatic steatosis on outcome of living donor liver transplantation (LDLT) is unknown. Consequently, we compared the outcome of LDLT using donors with BMI <30 versus donors with BMI ≥30. Between April 2000 and May 2014, 105 patients received a right-lobe liver graft from donors with BMI ≥30, whereas 364 recipients were transplanted with grafts from donors with BMI <30. Liver steatosis >10% was excluded in all donors with BMI >30 by imaging and liver biopsies. None of the donors had any other comorbidity. Donors with BMI <30 versus ≥30 had similar postoperative complication rates (Dindo-Clavien ≥3b: 2% vs. 3%; p = 0.71) and lengths of hospital stay (6 vs. 6 days; p = 0.13). Recipient graft function, assessed by posttransplant peak serum bilirubin and international normalized ratio was identical. Furthermore, no difference was observed in recipient complication rates (Dindo-Clavien ≥3b: 25% vs. 20%; p = 0.3) or lengths of hospital stay between groups. We concluded that donors with BMI ≥30, in the absence of graft steatosis, are not contraindicated for LDLT.
  • Portrayal of Brain Death in Film and Television
    We sought to evaluate whether television and cinematic coverage of brain death is educational or misleading. We identified 24 accessible productions that addressed brain death using the archives of the Paley Center for Media (160 000 titles) and the Internet Movie Database (3.7 million titles). Productions were reviewed by two board-certified neurologists. Although 19 characters were pronounced brain dead, no productions demonstrated a complete examination to assess for brain death (6 included an assessment for coma, 9 included an evaluation of at least 1 brainstem reflex, but none included an assessment of every brainstem reflex, and 2 included an apnea test). Subjectively, both authors believed only a small fraction of productions (13% A.L., 13% J.W.) provided the public a complete and accurate understanding of brain death. Organ donation was addressed in 17 productions (71%), but both reviewers felt that the discussions about organ donation were professional in a paucity of productions (9% for A.L., 27% for J.W.). Because television and movies serve as a key source for public education, the quality of productions that feature brain death must be improved.
  • The Role of Antiviral Prophylaxis for the Prevention of Epstein–Barr Virus–Associated Posttransplant Lymphoproliferative Disease in Solid Organ Transplant Recipients: A Systematic Review
    The role of antiviral prophylaxis for the prevention of posttransplant lymphoproliferative disease (PTLD) remains controversial for solid organ transplantation (SOT) recipients who are seronegative for Epstein–Barr virus (EBV) but who received organs from seropositive donors. We performed a systematic review and meta-analysis to address this issue. Two independent assessors extracted data from studies after determining patient eligibility and completing quality assessments. Overall, 31 studies were identified and included in the quantitative synthesis. Nine studies were included in the direct comparisons (total 2366 participants), and 22 were included in the indirect analysis. There was no significant difference in the rate of EBV-associated PTLD in SOT recipients among those who received prophylaxis (acyclovir, valacyclovir, ganciclovir, valganciclovir) compared with those who did not receive prophylaxis (nine studies; risk ratio 0.95, 95% confidence interval 0.58–1.54). No significant differences were noted across all types of organ transplants, age groups, or antiviral use as prophylaxis or preemptive therapy. There was no significant heterogeneity in the effect of antiviral prophylaxis on the incidence of PTLD. In conclusion, the use of antiviral prophylaxis in high-risk EBV-naive patients has no effect on the incidence of PTLD in SOT recipients.
  • Kidney Exchange to Overcome Financial Barriers to Kidney Transplantation
    Organ shortage is the major limitation to kidney transplantation in the developed world. Conversely, millions of patients in the developing world with end-stage renal disease die because they cannot afford renal replacement therapy—even when willing living kidney donors exist. This juxtaposition between countries with funds but no available kidneys and those with available kidneys but no funds prompts us to propose an exchange program using each nation's unique assets. Our proposal leverages the cost savings achieved through earlier transplantation over dialysis to fund the cost of kidney exchange between developed-world patient–donor pairs with immunological barriers and developing-world patient–donor pairs with financial barriers. By making developed-world health care available to impoverished patients in the developing world, we replace unethical transplant tourism with global kidney exchange—a modality equally benefitting rich and poor. We report the 1-year experience of an initial Filipino pair, whose recipient was transplanted in the United states with an American donor's kidney at no cost to him. The Filipino donor donated to an American in the United States through a kidney exchange chain. Follow-up care and medications in the Philippines were supported by funds from the United States. We show that the logistical obstacles in this approach, although considerable, are surmountable.


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Actualizada el: 08-Abr-2013