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  • Epipericardial fat necrosis as cause of chest pain in patient after heart transplantation
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-24
    Caio Rebouças Fonseca Cafezeiro; Mariana Pezzute Lopes; Caio Tavares Silva; Mônica Samuel Ávila; Luis Fernando B. C. Seguro; Sandrigo Mangini; Iáscara Wozniak Campos; Fábio A. Gaiotto; Fabiana G. Marcondes‐Braga; Fernando Bacal

    Epipericardial fat necrosis is an uncommon clinical condition of unknown etiology. It typically presents as acute pleuritic chest pain and should be differentiated from acute pulmonary embolism and acute coronary syndrome. This condition is diagnosed by characteristic chest computed tomography findings of an ovoid mediastinal fatty lesion with intrinsic and surrounding soft‐tissue stranding. Treatment of epipericardial fat necrosis includes the administration of anti‐inflammatory agents, and symptoms usually resolve within a few days after treatment initiation. This disease entity has rarely been reported since it was first described in 1957. Most current knowledge of epipericardial fat necrosis is based on case reports that describe this condition in previously healthy individuals. We present the case of a 39‐year‐old woman with a history of heart transplant, who presented with chest pain secondary to epipericardial fat necrosis. Serial computed tomography revealed lesion resolution after appropriate treatment.

    更新日期:2020-01-24
  • Discrepancy analysis comparing molecular and histology diagnoses in kidney transplant biopsies
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-23
    Katelynn Madill‐Thomsen; Agnieszka Perkowska‐Ptasińska; Georg A. Böhmig; Farsad Eskandary; Gunilla Einecke; Gaurav Gupta; Philip F. Halloran;

    Discrepancy analysis comparing two diagnostic platforms offers potential insights into both without assuming either is always correct. Having optimized the Molecular Microscope Diagnostic System (MMDx) in renal transplant biopsies, we studied discrepancies within MMDx (reports and sign‐out comments) and between MMDx and histology. Interpathologist discrepancies have been documented previously and were not assessed. Discrepancy cases were classified as “clear” (eg, antibody‐mediated rejection [ABMR] vs T cell–mediated rejection [TCMR]), “boundary” (eg, ABMR vs possible ABMR), or “mixed” (eg, Mixed vs ABMR). MMDx report scores showed 99% correlations; sign‐out interpretations showed 7% variation between observers, all located around boundaries. Histology disagreed with MMDx in 37% of biopsies, including 315 clear discrepancies, all with implications for therapy. Discrepancies were distributed widely in all histology diagnoses but increased in some scenarios; for example, histology TCMR contained 14% MMDx ABMR and 20% MMDx no rejection. MMDx usually gave unambiguous diagnoses in cases with ambiguous histology, for example, borderline and transplant glomerulopathy. Histology lesions or features associated with more frequent discrepancies (eg, tubulitis, arteritis, and polyomavirus nephropathy) were not associated with increased MMDx uncertainty, indicating that MMDx can clarify biopsies with histologic ambiguity. The patterns of histology‐MMDx discrepancies highlight specific histology diagnoses in which MMDx assessment should be considered for guiding therapy.

    更新日期:2020-01-23
  • Successful simultaneous liver‐kidney transplantation for renal failure associated with hereditary complement C3 deficiency
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-23
    Jeremy S Nayagam; Samuel McGrath; Mahmoud Montasser; Michael Delaney; Tom D Cairns; Kevin J Marchbank; Steven H. Sacks; H Terry Cook; Sapna Shah; Nigel Heaton; Matthew C Pickering; Abid Suddle

    Hereditary complement C3 deficiency is associated with recurrent bacterial infections and proliferative glomerulonephritis. We describe a case of an adult with complete deficiency of complement C3 due to homozygous mutations in C3 gene: c.1811delT (Val604Glyfs*2), recurrent bacterial infections, crescentic glomerulonephritis and end‐stage renal failure. Following isolated kidney transplantation he would remain C3 deficient with a similar, or increased, risk of infections and glomerulonephritis. As C3 is predominantly synthesised in the liver, with a small proportion of C3 monocyte‐derived and kidney‐derived, he proceeded to simultaneous liver‐kidney transplantation. The procedure has been successful with restoration of his circulating C3 levels, normal liver and kidney function at 26 months of follow up. Simultaneous liver‐kidney transplant is a viable option to be considered in this rare setting.

    更新日期:2020-01-23
  • Idiopathic pulmonary fibrosis lung transplant recipients are at increased risk for EBV‐associated posttransplant lymphoproliferative disorder and worse survival
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-22
    Carlo J. Iasella; Spencer A. Winters; Abigail Kois; Jaehee Cho; Stefanie J. Hannan; Ritchie Koshy; Cody A. Moore; Christopher R. Ensor; Elizabeth A. Lendermon; Matthew R. Morrell; Joseph P. Pilewski; Pablo G. Sanchez; Daniel J. Kass; Jonathan K. Alder; S. Mehdi Nouraie; John F. McDyer

    Epstein‐Barr virus (EBV)–associated posttransplant lymphoproliferative disorder (EBV‐PTLD) is a serious complication in lung transplant recipients (LTRs) associated with significant mortality. We performed a single‐center retrospective study to evaluate the risks for PTLD in LTRs over a 7‐year period. Of 611 evaluable LTRs, we identified 28 cases of PTLD, with an incidence of 4.6%. Kaplan‐Meier analysis showed a decreased freedom from PTLD in idiopathic pulmonary fibrosis (IPF)‐LTRs (P < .02). Using a multivariable Cox proportional hazards model, we found IPF (hazard ratio [HR] 3.51, 95% confidence interval [CI] 1.33‐8.21, P = .01) and alemtuzumab induction therapy (HR 2.73, 95% CI 1.10‐6.74, P = .03) as risk factors for PTLD, compared to EBV mismatch (HR: 34.43, 95% CI 15.57‐76.09, P < .0001). Early PTLD (first year) was associated with alemtuzumab use (P = .04), whereas IPF was a predictor for late PTLD (after first year) (P = .002), after controlling for age and sex. Kaplan‐Meier analysis revealed a shorter time to death from PTLD in IPF LTRs compared to other patients (P = .04). The use of alemtuzumab in EBV mismatch was found to particularly increase PTLD risk. Together, our findings identify IPF LTRs as a susceptible population for PTLD. Further studies are required to understand the mechanisms driving PTLD in IPF LTRs and develop strategies to mitigate risk.

    更新日期:2020-01-23
  • Development and outcomes of de novo donor‐specific antibodies in low, moderate, and high immunological risk kidney transplant recipients
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-22
    Susan S. Wan; Steven J. Chadban; Narelle Watson; Kate Wyburn

    De novo donor‐specific antibodies (dnDSA) play an important role in antibody‐mediated rejection (ABMR) and graft failure, yet their development in kidney transplant recipients (KTx) of higher immunological risk has not been characterized. We prospectively determined the incidence of dnDSA at 3 and 12 months posttransplant and assessed their associations with outcomes in recipients stratified by low, moderate, and high immunological risk. Adult KTx were screened for DSA pretransplant, months 3 and 12 posttransplant, and when clinically indicated. Outcomes included incidence of dnDSA, death‐censored graft survival (DCGS), and ABMR. Of 371 recipients, 154 (42%) were transplanted across a pretransplant DSA that became undetectable by 12 months posttransplant in 78% of cases. dnDSA were detected in 16% (95% confidence interval [CI]: 12‐20%) by 3 months and 23% (95% CI: 18‐29%) by 12 months posttransplant. Incidence at 12 months was higher in the moderate (30%) and high‐risk groups (29%) compared to the low‐risk group (16%). dnDSA were associated with an increased risk of ABMR (hazard ratio [HR] 2.2; 95% CI: 1.1‐4.4; P = .04) but were not an independent risk factor for DCGS. In conclusion, dnDSA were more frequent in transplant recipients of higher immune risk and associated with an increased risk of ABMR.

    更新日期:2020-01-23
  • Expanding the Use of HCV Infected Organs and the Challenge of Third‐Party Payers
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-22
    Reem Daloul; Todd Pesavento; Anthony Michaels

    Since the publication of the first two novel reports demonstrating the feasibility of using Hepatitis C virus nucleic acid test positive (HCV NAT+) organs into negative recipients1,2, evidence regarding the safety of using HCV NAT+ organs have been mounting. However, the wide implementation of such a practice hinges on the ability to ensure timely delivery of direct acting antiviral (DAA) therapy after transplantation. To date, DAA coverage by third party payers for acute HCV infection cannot be guaranteed.

    更新日期:2020-01-23
  • Early reduction of regulatory T cells is associated with acute rejection in liver transplantation under tacrolimus‐based immunosuppression with basiliximab induction
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-22
    Ji Won Han; Dong Jin Joo; Jong Hoon Kim; Min‐Seok Rha; June Young Koh; Hye Jung Park; Jae Geun Lee; Myoung Soo Kim; Soon Il Kim; Eui‐Cheol Shin; Jun Yong Park; Su‐Hyung Park

    Treg cells are important in preventing acute rejection (AR) in solid organ transplantation, but the clinical relevance of the different kinetics early after liver transplantation (LT) in acute rejectors and non‐rejectors is unclear. We analyzed peripheral blood samples of 128 LT recipients receiving basiliximab induction plus tacrolimus immunosuppression. Samples were obtained at pre‐transplantation, D7, and D30 after LT. Frequency and phenotype of Tregs were analyzed by flow cytometry. The predictive value of Treg frequency at D7 was assessed for suspected acute rejection (SAR) and was validated for biopsy‐proven AR (BPAR). We found that the frequencies of total and activated Tregs at D7 were significantly lower in recipients with SAR and BPAR. Treg was more reduced in BPARs by in vitro tacrolimus treatment in the presence of basiliximab. Moreover, an early reduction of Treg frequency in rejectors was associated with a greater increase in Treg apoptosis and further attenuated IL‐2 signaling. D7 Treg frequency was an independent risk factor for SAR, which was also validated for BPAR. In conclusion, first‐week peripheral blood Treg frequency correlates with AR after LT under tacrolimus‐based immunosuppression, which needs to be proven in larger, geographically and clinically diverse populations.

    更新日期:2020-01-23
  • Ethical and logistical concerns for establishing NRP‐cDCD heart transplantation in the United States
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-21
    Brendan Parent; Nader Moazami; Stephen Wall; Julius Carillo; Zachary Kon; Deane Smith; B. Corbett Walsh; Arthur Caplan

    Controlled heart donation after circulatory determination of death (cDCD) is well established internationally with good outcomes and could be adopted in the United States to increase heart supply if ethical and logistical challenges are comprehensively addressed. The most effective and resource‐efficient method for mitigating warm ischemia after circulatory arrest is normothermic regional perfusion (NRP) in situ. This strategy requires restarting circulation after declaration of death according to circulatory criteria, which appears to challenge the legal circulatory death definition requiring irreversible cessation. Permanent cessation for life‐saving efforts must be achieved to assuage this concern and ligating principal vessels maintains no blood flow to the brain, which ensures natural progression to cessation of brain function. This practice—standard in some countries—raises unique concerns about prioritizing life‐saving efforts, informed authorization from decision‐makers, and the clinician's role in the patient's death. To preserve public trust, medical integrity, and respect for the donor, the donation conversation must not take place until after an un‐coerced decision to withdraw life‐sustaining treatment made in accordance with the patient's treatment goals. The decision‐maker(s) must understand cDCD procedure well enough to provide genuine authorization and the preservation/procurement teams must be kept separate from the clinical care team.

    更新日期:2020-01-22
  • Rejection of xenogeneic porcine islets in humanized mice is characterized by graft‐infiltrating Th17 cells and activated B cells
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-21
    Frances T. Lee; Anil Dangi; Sahil Shah; Melanie Burnette; Yong‐Guang Yang; Allan D. Kirk; Bernhard J. Hering; Stephen D. Miller; Xunrong Luo

    Xenogeneic porcine islet transplantation is a promising potential therapy for type 1 diabetes (T1D). Understanding human immune responses against porcine islets is crucial for the design of optimal immunomodulatory regimens for effective control of xenogeneic rejection of porcine islets in humans. Humanized mice are a valuable tool for studying human immune responses and therefore present an attractive alternative to human subject research. Here, by using a pig‐to‐humanized mouse model of xenogeneic islet transplantation, we described the human immune response to transplanted porcine islets, a process characterized by dense islet xenograft infiltration of human CD45+ cells comprising activated human B cells, CD4+CD44+IL‐17+ Th17 cells, and CD68+ macrophages. In addition, we tested an experimental immunomodulatory regimen in promoting long‐term islet xenograft survival, a triple therapy consisting of donor splenocytes treated with ethylcarbodiimide (ECDI‐SP), and peri‐transplant rituximab and rapamycin. We observed that the triple therapy effectively inhibited graft infiltration of T and B cells as well as macrophages, promoted transitional B cells both in the periphery and in the islet xenografts, and provided a superior islet xenograft protection. Our study therefore indicates an advantage of donor ECDI‐SP treatment in controlling human immune cells in promoting long‐term islet xenograft survival.

    更新日期:2020-01-22
  • Impact of kidney transplantation on sleep apnea severity: A prospective polysomnographic study
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-21
    Valentina Forni Ogna; Adam Ogna; José Haba‐Rubio; Grzegorz Nowak; Jean‐Pierre Venetz; Délaviz Golshayan; Maurice Matter; Michel Burnier; Manuel Pascual; Raphaël Heinzer

    Fluid overload has been associated with a high prevalence of sleep apnea (SA) in patients with end‐stage kidney disease (ESKD). In this prospective study, we hypothesized that improvement in kidney function and hydration status after kidney transplantation (Tx) may result in an improvement in SA severity. A total of 196 patients on the kidney Tx waiting list were screened for SA using home nocturnal polysomnography (PSG) to measure the apnea‐hypopnea index (AHI) and underwent bioimpedance to assess body composition. Of 88 participants (44.9%) with SA (AHI ≥ 15/h), 42 were reassessed 6 months post‐Tx and were compared with 27 control patients. There was a significant, but small, post‐Tx improvement in AHI (from 44.2 ± 24.3 to 34.7 ± 20.9/h, P = .02) that significantly correlated with a reduction in fluid overload (from 1.8 ± 2.0 to 1.2 ± 1.2 L, P = .02) and body water (from 54.9% to 51.6%, P = .003). A post‐Tx increase in body fat mass (from 26% to 30%, P = .003) possibly blunted the beneficial impact of kidney Tx on SA. All parameters remained unchanged in the control group. In conclusion, SA is a frequent condition in ESKD patients and partially improved by kidney Tx. We suggest that SA should be systematically assessed before and after kidney Tx.

    更新日期:2020-01-22
  • Solid organ donation after death in the United States: Data‐driven messaging to encourage potential donors
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-21
    Kiran Bambha; Alexandra Shingina; Jennifer L. Dodge; Kevin O’Connor; Sue Dunn; Jennifer Prinz; Mark Pabst; Kathy Nilles; Lena Sibulesky; Scott W. Biggins

    US deceased donor solid organ transplantation (dd‐SOT) depends upon an individual's/family's altruistic willingness to donate organs after death; however, there is a shortage of deceased organ donors in the United States. Informing individuals of their own lifetime risk of needing dd‐SOT could reframe the decision‐making around organ donation after death. Using United Network for Organ Sharing (UNOS) data (2007‐2016), this cross‐sectional study identified (1) deceased organ donors, (2) individuals waitlisted for dd‐SOT (liver, kidney, pancreas, heart, lung, intestine), and (3) dd‐SOT recipients. Using US population projections, life tables, and mortality estimates, we quantified probabilities (Pr) of (1) becoming deceased organ donors, (2) needing dd‐SOT, and (3) receiving dd‐SOT. Lifetime Pr (per 100 000 US population) for males and females of becoming deceased organ donors were 212 and 146, respectively, and of needing dd‐SOT were 1323 and 803, respectively. Lifetime Pr of receiving dd‐SOT was 50% for males, 48% for females. Over a lifetime, males were 6.2 and females 5.5 times more likely to need dd‐SOT than to become deceased organ donors. Organ donation is traditionally contextualized in terms of charity toward others. Our analyses yield a new tool, in the form of quantifying an individual's own likelihood of needing dd‐SOT, which may assist with reframing motivations toward deceased donor organ donation.

    更新日期:2020-01-22
  • Obesity, Transplantation, and Bariatric Surgery: An Evolving Solution for a Growing Epidemic
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-21
    Tayyab S. Diwan; Tiffany C. Lee; Shunji Nagai; Enrico Benedetti; Andrew Posselt; Ginny Bumgardner; Sabrena Noria; Bryan A. Whitson; Lloyd Ratner; David Mason; Jon Friedman; Kenneth J. Woodside; Julie Heimbach;

    The increasing obesity epidemic has major implications in the realm of transplantation. Patients with obesity face barriers in access to transplantation as well as unique challenges in perioperative and postoperative outcomes. Due to comorbidities associated with obesity along with the underlying end‐stage organ disease leading to transplantation candidacy, these patients may not even be referred for transplant evaluation, much less be waitlisted or actually undergo transplantation. However, the utilization of bariatric surgery in this population can help optimize the transplant candidacy of patients with obesity and end‐stage organ disease as well as improve perioperative and postoperative outcomes. In this paper, we will review the impact of obesity on kidney, liver, and cardiothoracic transplant candidates and recipients, as well as explore potential interventions to address obesity in these populations.

    更新日期:2020-01-22
  • Combined GM‐CSF and G‐CSF administration mobilizes CD4+CD25hiFoxp3hi Treg in leukapheresis products of rhesus monkeys
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-20
    Kazuki Sasaki; Yu‐Chao Wang; Lien Lu; Julia Hughes; Veronica Vujevich; Angus W. Thomson; Mohamed B. Ezzelarab

    Early phase clinical trials are evaluating the feasibility, safety, and therapeutic potential of ex vivo expanded regulatory T cells (Treg) in transplantation. A limitation is the paucity of naturally occurring Treg numbers in peripheral blood. Hence, protracted ex vivo expansion is required to obtain sufficient Treg in order to meet target cell doses. Because cytokine administration has been used successfully to mobilize immune cells to the peripheral blood in experimental and clinical studies, we hypothesized that granulocyte macrophage–colony‐stimulating factor (GM‐CSF) and granulocyte‐CSF (G‐CSF) administration would enhance Treg percentages in leukapheresis products of rhesus monkeys. Following combined GM‐CSF and G‐CSF administration, the incidence of Treg in peripheral blood and leukapheresis products was elevated significantly, where approximately 3.7 × 106/kg CD4+CD25hiFoxp3hi or 6.8 × 106/kg CD4+CD25hiCD127lo Treg can be collected from individual products. Mobilized Treg expressed a comparable repertoire of surface markers, chemokine receptors, and transcription factors to naïve monkey peripheral blood Treg. Furthermore, when expanded ex vivo, mobilized leukapheresis product and peripheral blood Treg exhibited similar ability to suppress autologous CD4+ and CD8+ T cell proliferation. These observations indicate that leukapheresis products from combined GM‐CSF‐ and G‐CSF‐mobilized individuals are a comparatively rich source of Treg and may circumvent long‐term ex vivo expansion required for therapeutic application.

    更新日期:2020-01-21
  • Great variability in donor heart acceptance practices across the United States
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-20
    Kiran K. Khush; Robyn L. Ball

    Disparities in organ acceptance practices exacerbate donor heart nonuse and lead to increased waiting times and mortality for heart transplant candidates. We studied disparities in donor heart acceptance among US transplant centers and their relations to posttransplant outcomes. Candidate, potential transplant recipient match run, and deceased donor data were obtained from the United Network for Organ Sharing. We analyzed donor, candidate, and transplant center characteristics with respect to organ acceptance, offer acceptance, number of offers before acceptance (organ sequence number), and association with posttransplant mortality. A total of 693 420 donor heart offers made between April 2007 and December 2015 were included. We identified great variability in donor heart acceptance practices among US heart transplant centers. We identified donor and recipient characteristics that were strongly associated with heart organ and offer acceptance, and organ sequence number, and identified inconsistencies among centers with respect to how these characteristics influenced acceptance decisions. Finally, we identified characteristics that were highly predictive of donor heart nonuse and were not associated with increased recipient mortality, which may guide future efforts aimed at increasing use of available hearts for transplantation.

    更新日期:2020-01-21
  • Molecular diagnosis of kidney transplant failure based on urine
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-20
    Antje Wiesener; Karl X. Knaup; Maike Büttner‐Herold; Anne Dieterle; Johanna Stoeckert; Bernhard Riedl; Christian Morath; Alexandra Wald; Florian Vondran; Felix Braun; Johannes Schödel; Markus Schueler; Mario Schiffer; Kerstin Amann; André Reis; Cornelia Kraus; Michael S. Wiesener

    In light of the organ shortage, there is a great responsibility to assess postmortal organs for which procurement has been consented and to increase the life span of transplanted organs. The former responsibility has moved many centers to accept extended criteria organs. The latter responsibility requires an exact diagnosis and, if possible, omission of the harmful influence on the transplant. We report the course of a kidney transplant that showed a steady decline of function over a decade, displaying numerous cysts of different sizes. Clinical workup excluded the most frequent causes of chronic transplant failure. The filed allocation documents mentioned the donor’s disease of oral‐facial‐digital syndrome, a rare ciliopathy, which can also affect the kidney. Molecular diagnosis was performed by culturing donor tubular cells from the recipient´s urine more than 10 years after transplantation. Next‐generation panel sequencing with DNA from tubular urinary cells revealed a novel truncating mutation in OFD1, which sufficiently explains the features of the kidney transplants, also found in the second kidney allograft. Despite this severe donor disease, lifesaving transplantation with good long‐term outcome was enabled for 5 recipients.

    更新日期:2020-01-21
  • Outcomes of patients with detectable CMV DNA at randomization in the phase III trial of letermovir for the prevention of CMV infection in allogeneic hematopoietic cell transplantation
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-18
    Francisco M. Marty; Per T. Ljungman; Roy F. Chemaly; Hong Wan; Valerie L. Teal; Joan R. Butterton; Wendy W. Yeh; Randi Y. Leavitt; Cyrus S. Badshah

    Letermovir, a cytomegalovirus (CMV) terminase‐complex inhibitor, is indicated for prophylaxis of CMV infection and disease in adult CMV‐seropositive recipients of allogeneic hematopoietic cell transplantation (HCT). In a phase III, double‐blind, randomized trial, letermovir significantly reduced the risk of clinically significant CMV infection (CS‐CMVi) vs placebo through Week 24 post‐HCT. This analysis investigated outcomes in participants with detectable CMV DNA at randomization, who were excluded from the primary efficacy analysis. In total, 70 of 565 randomized participants had detectable CMV DNA at randomization (letermovir 48; placebo 22). Study treatment completion rates were greater in letermovir‐treated participants compared with placebo (52.1% vs 9.1%). The incidence of CS‐CMVi or imputed primary endpoint events through Week 24 were 64.6% and 90.9% in the letermovir and placebo groups, respectively (treatment difference −26.1%; P = .010). Kaplan‐Meier event rates for CS‐CMVi onset through Week 14 (end‐of‐treatment period) were 33.1% for letermovir and 86.6% for placebo (P < .001). Median viral loads at the CS‐CMVi events was similar in both treatment arms. All‐cause mortality through Week 24 posttransplant was 15.0% for letermovir and 18.2% for placebo; through Week 48, mortality rates were 26.5% and 40.9%, respectively (P = .268). Overall, clinical outcomes were similar to those reported for participants with undetectable CMV DNA at randomization.

    更新日期:2020-01-21
  • Access to transplantation for persons with intellectual disability: Strategies for nondiscrimination
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-18
    Ashton Chen; Mahwish Ahmad; Andrew Flescher; William L. Freeman; Stephanie Little; Paulo N. Martins; Robert M. Veatch; Aaron Wightman; Keren Ladin

    Disqualifying patients with intellectual disabilities (ID) from transplantation has received growing attention from the media, state legislatures, the Office of Civil Rights, and recently the National Council on Disability, as well as internationally. Compared with evidence‐based criteria used to determine transplant eligibility, the ID criterion remains controversial because of its potential to be discriminatory, subjective, and because its relationship to outcomes is uncertain. Use of ID in determining transplant candidacy may stem partly from perceived worse adherence and outcomes for patients with ID, fear of penalties to transplant centers for poor outcomes, and stigma surrounding the quality of life for people with ID. However, using ID as a contraindication to solid organ transplantation is not evidence‐based and reduces equitable access to transplantation, disadvantaging an already vulnerable population. Variability and lack of transparency in referral and evaluation allows for gatekeeping, threatens patient autonomy, limits access to lifesaving treatment, and may be seen as unfair. We examine the benefits and harms of using ID as a transplant eligibility criterion, review current clinical evidence and ethical considerations, and make recommendations for transplant teams and regulatory agencies to ensure fair access to transplant for individuals with ID.

    更新日期:2020-01-21
  • Reassessment of the clinical impact of preformed donor‐specific anti‐HLA‐Cw antibodies in kidney transplantation
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-18
    Jonathan Visentin; Thomas Bachelet; Olivier Aubert; Arnaud Del Bello; Charlie Martinez; Frédéric Jambon; Gwendaline Guidicelli; Mamy Ralazamahaleo; Charlène Bouthemy; Marine Cargou; Nicolas Congy‐Jolivet; Thoa Nong; Jar‐How Lee; Rebecca Sberro‐Soussan; Lionel Couzi; Nassim Kamar; Christophe Legendre; Pierre Merville; Jean‐Luc Taupin

    Anti‐denatured HLA‐Cw antibodies are highly prevalent, whereas anti‐native HLA‐Cw antibodies seem to lead to random flow cytometry crossmatch results. We aimed to reassess crossmatch prediction for anti‐HLA‐Cw using 2 types of single antigen flow beads (classical beads and beads with diminished expression of denatured HLA), and to compare the pathogenicity of preformed anti‐denatured and anti‐native HLA‐Cw antibodies in kidney transplantation. We performed 135 crossmatches with sera reacting against donor HLA‐Cw (classical beads fluorescence ≥500); only 20.6% were positive. Forty‐three (31.6%) were anti‐denatured HLA antibodies (beads with diminished expression of denatured HLA fluorescence <300); all were crossmatch negative. The correlation between classical beads fluorescence and the crossmatch ratio was low (ρ = 0.178), and slightly higher with beads with diminished expression of denatured HLA (ρ = 0.289). We studied 52 kidney recipients with preformed anti‐HLA‐Cw donor‐specific antibodies. Those with anti‐native HLA antibodies experienced more acute and chronic antibody‐mediated rejections (P = .006 and .03, respectively), and displayed a lower graft survival (P = .04). Patients with anti‐native HLA‐Cw antibodies more frequently had previous sensitizing events (P < .000001) or plausibility of their antibody profile according to known anti‐native HLA‐Cw eplets (P = .0001). Anti‐native but not anti‐denatured HLA‐Cw antibodies are deleterious, which underscores the need for reagents with diminished expression of denatured HLA.

    更新日期:2020-01-21
  • Neighborhood socioeconomic deprivation is associated with worse patient and graft survival following pediatric liver transplantation
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-20
    Sharad I. Wadhwani; Andrew F. Beck; John Bucuvalas; Laura Gottlieb; Uma Kotagal; Jennifer C. Lai

    Long‐term outcomes remain suboptimal following pediatric liver transplantation; only one‐third of children have normal biochemical liver function without immunosuppressant comorbidities 10 years post‐transplant. We examined the association between an index of neighborhood socioeconomic deprivation with graft and patient survival using the Scientific Registry of Transplant Recipients. We included children <19 years who underwent liver transplantation between 1/1/2008‐12/31/2013 (n=2868). Primary exposure was a neighborhood socioeconomic deprivation index—linked via patient home ZIP code—with a range of 0‐1 (values nearing 1 indicate neighborhoods with greater socioeconomic deprivation). Primary outcome measures were graft failure and death, censored at 10 years post‐transplant. We modeled survival using Cox proportional hazards. In univariable analysis, each 0.1 increase in the deprivation index was associated with a 14.3% (95%CI: 3.8%‐25.8%) increased hazard of graft failure and a 12.5% (95%CI: 2.5%‐23.6%) increased hazard of death. In multivariable analysis adjusted for race, each 0.1 increase in the deprivation index was associated with a 11.5% (95%CI: 1.6%‐23.9%) increased hazard of graft failure and a 9.6% (95%CI: ‐0.04%‐20.7%) increased hazard of death. Children from high deprivation neighborhoods have diminished graft and patient survival following liver transplantation. Greater attention to neighborhood context may result in improved outcomes for children following liver transplantation.

    更新日期:2020-01-21
  • Donor‐specific chimeric antigen receptor Tregs limit rejection in naive but not sensitized allograft recipients
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-19
    Antoine Sicard; Caroline Lamarche; Madeleine Speck; May Wong; Isaac Rosado‐Sánchez; Mathilde Blois; Nicolas Glaichenhaus; Majid Mojibian; Megan K. Levings

    Cell therapy with autologous donor‐specific regulatory T cells (Tregs) is a promising strategy to minimize immunosuppression in transplant recipients. Chimeric antigen receptor (CAR) technology has recently been used successfully to generate donor‐specific Tregs and overcome the limitations of enrichment protocols based on repetitive stimulations with alloantigens. However, the ability of CAR‐Treg therapy to control alloreactivity in immunocompetent recipients is unknown. We first analyzed the effect of donor‐specific CAR Tregs on alloreactivity in naive, immunocompetent mice receiving skin allografts. Tregs expressing an irrelevant or anti‐HLA‐A2‐specific CAR were administered to Bl/6 mice at the time of transplanting an HLA‐A2+ Bl/6 skin graft. Donor‐specific CAR‐Tregs, but not irrelevant‐CAR Tregs, significantly delayed skin rejection, and diminished donor‐specific antibodies (DSAs) and frequencies of DSA‐secreting B cells. Donor‐specific CAR Treg‐treated mice also had a weaker recall DSA response, but normal responses to an irrelevant antigen, demonstrating antigen‐specific suppression. When donor‐specific CAR Tregs were tested in HLA‐A2 sensitized mice, they were unable to delay allograft rejection or diminish DSAs. The finding that donor‐specific CAR‐Tregs restrain de novo but not memory alloreactivity has important implications for their use as an adoptive cell therapy in transplantation.

    更新日期:2020-01-21
  • Response to "Reply to: 'The decreasing predictive power of MELD in an era of changing etiology of liver disease'"
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-14
    Elizabeth L. Godfrey; Tahir H. Malik; Jennifer C. Lai; Ayse L. Mindikoglu; N. Thao N. Galván; Ronald T. Cotton; Christine A. O'Mahony; John A. Goss; Abbas Rana

    We appreciate Kwong et al.'s utilization of Harrell's c‐statistic and its ability to incorporate follow‐up time as a valuable contribution to the discussion about our group's findings.1 We acknowledge that the conventional area under receiver‐operating‐characteristic curve concordance statistic has limitations; however, we selected the conventional c‐statistic to remain methodologically consistent with the manner in which the Model for End‐Stage Liver Disease (MELD) was originally designed and validated, first to predict post‐TIPS survival, then when applied to ESLD generally, and finally when integrated into allocation.

    更新日期:2020-01-14
  • Trajectories of health‐related quality of life among renal transplant patients associated with graft failure and symptom distress: Analysis of the BENEFIT and BENEFIT‐EXT trials
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-11
    Intan Purnajo; Jennifer L. Beaumont; Martin Polinsky; Evo Alemao; Matthew J. Everly

    Understanding the correlation between transplant symptoms, health‐related quality of life (HRQoL), and graft outcomes is needed to support patient‐focused drug development and posttransplant management. A post‐hoc analysis of patient‐reported outcomes from the Phase III belatacept trials was conducted in order to investigate the interrelationship between trajectories of HRQoL, symptom experience, and allograft outcomes. HRQoL and symptom experience were evaluated using Short‐Form 36 Survey (SF‐36) and Modified Transplant Symptom Occurrence and Distress Scale (MTSOSD‐59R), respectively. HRQoL was captured in 831 eligible renal transplant patients at baseline, 12, 24, and 36 months posttransplant. Following transplantation, patients reported improvements in all SF‐36 subscales compared to baseline. Latent class analysis revealed four trajectories in perceived general health, which were associated with graft failure after adjustment. Compared to patients with good perceived health, patients with fair and poor perceived health had 4.7 (95% confidence interval [CI] 1.5‐14.8, P < .01) and 19.8 (95% CI 5.9‐66.0, P < .01) times the risk of graft failure, respectively. Using multinomial logistic regression, different sets of symptoms were associated with perceived general health at baseline and 12 months posttransplant. The study supports monitoring HRQoL and symptom experience to capture each patient's health perspective, improve drug development, and optimize posttransplant management.

    更新日期:2020-01-13
  • Targeted Donor Complement Blockade After Brain‐Death Prevents Delayed Graft Function In A Non‐Human Primate Model Of Kidney Transplantation
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-10
    Juan S. Danobeitia; Tiffany J. Zens; Peter J. Chlebeck; Laura J. Zitur; Jose A. Reyes; Michael J. Eerhart; Jennifer Coonen; Saverio Capuano; Anthony M. D’Alessandro; Jose R. Torrealba; Daniel Burguete; Kevin Brunner; Edwin Van; Amersfoort; Yolanda Ponstein‐Simarro Doorten; Cees Van Kooten; Ewa Jankowska‐Gan; William Burlingham; Jeremy Sullivan; Arjang Djamali; Myron Pozniak; Yucel Yankol; Luis A. Fernandez

    Delayed graft function (DGF) in renal transplantation is associated with reduced graft survival and increased immunogenicity. The complement‐driven inflammatory response after brain death (BD) and post‐transplant reperfusion injury play significant roles in the pathogenesis of DGF. In a non‐human primate model, we tested complement‐blockade in BD donors to prevent DGF and improve graft survival. BD donors were maintained 20‐hours, kidneys were procured and stored at 4°C for a 43–48 hours prior to implantation into ABO‐compatible, non‐sensitized, MHC‐mismatched recipients. Animals were divided into three different donor‐treatment groups: G1‐Vehicle, G2‐rhC1INH+heparin, and G3‐heparin only. G2 donors showed significant reduction in classical complement pathway activation and decreased levels of TNFα and MCP‐1. DGF was diagnosed in 4/6 (67%) G1‐recipients, 3/3 (100%) of G3‐recipients, and 0/6 (0%) of G2‐recipients (p=0.008). In addition, G2‐recipients showed superior renal function, reduced sC5b‐9, and reduced urinary NGAL in the first week post‐transplant. We observed no differences in incidence or severity of graft rejection between groups. Collectively, the data indicate that donor‐management targeting complement activation prevents the development of DGF. Our results suggest a pivotal role for complement activation in BD‐induced renal injury and postulate complement‐blockade as a promising strategy for the prevention of DGF after transplantation.

    更新日期:2020-01-11
  • Maintaining the permanence principle for death during in situ normothermic regional perfusion for donation after circulatory death organ recovery: A United Kingdom and Canadian proposal
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-10
    Alex Manara; Sam D. Shemie; Stephen Large; Andrew Healey; Andrew Baker; Mitesh Badiwala; Marius Berman; Andrew J. Butler; Prosanto Chaudhury; John Dark; John Forsythe; Darren H. Freed; Dale Gardiner; Dan Harvey; Laura Hornby; Janet MacLean; Simon Messer; Gabriel C. Oniscu; Christy Simpson; Jeanne Teitelbaum; Sylvia Torrance; Lindsay C. Wilson; Christopher J.E. Watson

    There is international variability in the determination of death. Death in donation after circulatory death (DCD) can be defined by the permanent cessation of brain circulation. Post‐mortem interventions that restore brain perfusion should be prohibited as they invalidate the diagnosis of death. Retrieval teams should develop protocols that ensure the continued absence of brain perfusion during DCD organ recovery. In situ normothermic regional perfusion (NRP) or restarting the heart in the donor's body may interrupt the permanent cessation of brain perfusion since, theoretically, collateral circulations may restore it. We propose refinements to current protocols to monitor and exclude brain reperfusion during in situ NRP. In abdominal NRP, complete occlusion of the descending aorta prevents brain perfusion in most cases. Inserting a cannula in the ascending aorta identifies inadequate occlusion of the descending aorta or any collateral flow and diverts flow away from the brain. In thoraco‐abdominal NRP opening the aortic arch vessels to atmosphere allows collateral flow to be diverted away from the brain, maintaining the permanence standard for death and respecting the dead donor rule. We propose that these hypotheses are correct when using techniques that simultaneously occlude the descending aorta and open the aortic arch vessels to atmosphere.

    更新日期:2020-01-11
  • Early Graft Losses in Paired Kidney Exchange: Experience from 10 Years of the National Kidney Registry
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-10
    Jennifer Verbesey; Alvin G. Thomas; Matt Ronin; Jennifer Beaumont; Amy Waterman; Dorry L. Segev; Stuart M. Flechner; Matthew Cooper

    Cooperative kidney paired donation (KPD) networks account for an increasing proportion of all living donor kidney transplants in the United States. There is sparse data on the rate of primary non‐function (PNF) losses and their consequences within KPD networks. We studied National Kidney Registry (NKR) transplants (2/14/2009‐12/31/2017) and quantified PNF, graft loss within 30 days of transplantation, and graft losses in the first year post‐transplant and assessed potential risk factors. Of 2364 transplants, there were 38 (1.6%) grafts lost within the first year, 13 (0.5%) with PNF. When compared to functioning grafts, there were no clinically significant differences in blood type compatibility, degree of HLA mismatch, number of veins/arteries, cold ischemia, and travel times. Of 13 PNF cases, 2 were due to early venous thrombosis, 2 to arterial thrombosis, and 2 to failure of desensitization and development of AMR. Given the low rate of PNF, the NKR created a policy to allocate chain‐end kidneys to recipients with PNF following event review and attributable to surgical issues of donor nephrectomy. It is expected that demonstration of low incidence of poor early graft outcomes and the presence of a ‘safety net’ would further encourage program participation in national KPD.

    更新日期:2020-01-11
  • Does Foxp3+ T cell‐mediated lung transplant tolerance depend on BALT formation?
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-09
    Ankit Bharat

    Lung transplantation, while increasingly being offered to an expanding list of end‐stage lung diseases, still suffers from poor long‐term outcomes due to the development of allograft rejection. Regulatory Foxp3+ T cells have emerged as important modulators of lung transplant tolerance (1). Bronchus‐associated lymphoid tissue (BALT), enriched in Foxp3+ T cells as well as B cells, develops following lung transplantation. While some studies have implicated BALT in the pro‐inflammatory host response and allograft rejection, others have shown that BALT promotes tolerance, predominantly through the accumulation of Foxp3+ T cells (2, 3).

    更新日期:2020-01-11
  • Evidence for a rebalanced hemostatic system in pediatric liver transplantation: A prospective cohort study
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-08
    Maureen J. M. Werner; Vincent E. de Meijer; Jelle Adelmeijer; Ruben H. J. de Kleine; René Scheenstra; Sander T. H. Bontemps; Koen M. E. M. Reyntjens; Jan B. F. Hulscher; Ton Lisman; Robert J. Porte

    In adults with end‐stage liver disease concurrent changes in pro‐ and antihemostatic pathways result in a rebalanced hemostasis. Children though, have a developing hemostatic system, different disease etiologies, and increased risk of thrombosis. This study aimed to assess the hemostatic state of children during and after liver transplantation. Serial blood samples were obtained from 20 children (≤16 years) undergoing primary liver transplantation (September 2017‐October 2018). Routine hemostasis tests, thrombomodulin‐modified thrombin generation, clot lysis times, and hemostatic proteins were measured. Reference values were established using an age‐matched control group of 30 children. Thrombocytopenia was present in study patients. Von Willebrand factors were doubled and ADAMTS13 levels decreased during and after transplantation up until day 30, when platelet count had normalized. Whereas prothrombin time and activated partial thromboplastin time were prolonged during transplantation, thrombin generation was within normal ranges, except during perioperative heparin administration. Fibrinogen, factor VIII levels, and clot lysis time were elevated up until day 30. In conclusion, children with end‐stage liver disease are in tight hemostatic balance. During transplantation a temporary heparin‐dependent hypocoagulable state is present, which rapidly converts to a hemostatic balance with distinct hypercoagulable features that persist until at least day 30. This hypercoagulable state may contribute to the risk of posttransplant thrombosis.

    更新日期:2020-01-09
  • Iron Overload as a Risk Factor for Hepatic Ischemia‐Reperfusion Injury in Liver Transplantation: Potential role of ferroptosis
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-07
    Naoya Yamada; Tadayoshi Karasawa; Taiichi Wakiya; Ai Sadatomo; Homare Ito; Ryo Kamata; Sachiko Watanabe; Takanori Komada; Hiroaki Kimura; Yukihiro Sanada; Yasunaru Sakuma; Koichi Mizuta; Nobuhiko Ohno; Naohiro Sata; Masafumi Takahashi

    Hepatic ischemia‐reperfusion (I/R) injury is a major problem in liver transplantation (LT). Although hepatocyte cell death is the initial event in hepatic I/R injury, the underlying mechanism remains unclear. In the present study, we retrospectively analyzed the clinical data of 202 pediatric living donor LT and found that a high serum ferritin level, a marker of iron overload, of the donor is an independent risk factor for liver damage after LT. Since ferroptosis has been recently discovered as an iron‐dependent cell death that is triggered by a loss of cellular redox homeostasis, we investigated the role of ferroptosis in a murine model of hepatic I/R injury, and found that liver damage, lipid peroxidation, and upregulation of the ferroptosis marker Ptgs2 were induced by I/R, and all of these manifestations were markedly prevented by the ferroptosis‐specific inhibitor ferrostatin‐1 (Fer‐1) or α‐tocopherol. Fer‐1 also inhibited hepatic I/R‐induced inflammatory responses. Furthermore, hepatic I/R injury was attenuated by iron chelation by deferoxamine and exacerbated by iron overload with a high iron diet. These findings demonstrate that iron overload is a novel risk factor for hepatic I/R injury in LT, and ferroptosis contributes to the pathogenesis of hepatic I/R injury.

    更新日期:2020-01-07
  • Pancreatic islets engineered with a FasL protein induce systemic tolerance at the induction phase that evolves into long‐term graft‐localized immune privilege
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-05
    Kyle B. Woodward; Hong Zhao; Pradeep Shrestha; Lalit Batra; Min Tan; Orlando Grimany‐Nuno; Laura Bandura‐Morgan; Nadir Askenasy; Haval Shirwan; Esma S. Yolcu

    We have previously shown that pancreatic islets engineered to transiently display a modified form of FasL protein (SA‐FasL) on their surface survive indefinitely in allogeneic recipients without a need for chronic immunosuppression. Mechanisms that confer long‐term protection to allograft are yet to be elucidated. We herein demonstrated that immune protection evolves in two distinct phases; induction and maintenance. SA‐FasL‐engineered allogeneic islets survived indefinitely and conferred protection to a second set of donor‐matched, but not third‐party, unmanipulated islet grafts simultaneously transplanted under the contralateral kidney capsule. Protection at the induction phase involved a reduction in the frequency of proliferating alloreactive T cells in the graft‐draining lymph nodes, and required phagocytes and TGF‐β. At the maintenance phase, immune protection evolved into graft site‐restricted immune privilege as the destruction of long‐surviving SA‐FasL‐islet grafts by streptozotocin followed by the transplantation of a second set of unmanipulated islet grafts into the same site from the donor, but not third party, resulted in indefinite survival. The induced immune privilege required both CD4+CD25+Foxp3+ Treg cells and persistent presence of donor antigens. Engineering cell and tissue surfaces with SA‐FasL protein provides a practical, efficient, and safe means of localized immunomodulation with important implications for autoimmunity and transplantation.

    更新日期:2020-01-06
  • Is interleukin‐6 receptor blockade (tocilizumab) beneficial or detrimental to pig‐to‐baboon organ xenotransplantation?
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-03
    Guoqiang Zhang; Hayato Iwase; Liaoran Wang; Takayuki Yamamoto; Abhijit Jagdale; David Ayares; Yong Li; David K. C. Cooper; Hidetaka Hara

    The interleukin (IL)‐6/IL‐6 receptor‐α (IL‐6Rα)/signal transduction and activation of the transcription 3 (STAT3) pathway plays an important role in inflammation. Anti‐human IL‐6Rα blockade by tocilizumab (TCZ) has been used in pig‐to‐baboon organ xenotransplant models, but whether it is beneficial remains uncertain. After xenotransplant, there were significant increases in both baboon and pig IL‐6 in the baboon serum, especially in baboons that received TCZ before xenotransplant. In vitro observations demonstrated that human, baboon, and pig IL‐6 can activate the IL‐6/IL‐6Rα/STAT3 pathway in human, baboon, and pig cells, respectively. Activation of the IL‐6/IL‐6Rα/STAT3 pathway was blocked by TCZ in human and baboon cells but not in pig cells (ie, pig IL‐6R). Siltuximab (human IL‐6 inhibitor) bound to both human and baboon, but not pig, IL‐6 and suppressed activation of the IL‐6/IL‐6Rα/STAT3 pathway. These results indicate that TCZ and siltuximab do not cross‐react with pig IL‐6R and pig IL‐6, respectively. Rapamycin partially inhibited human, baboon, and pig IL‐6/IL‐6Rα/STAT3 pathways and suppressed inflammatory gene expression. TCZ treatment increased serum IL‐6 because it could no longer bind to baboon IL‐6Rα. We suggest that increased serum IL‐6 may be detrimental to the pig xenograft because it is likely to bind to pig IL‐6R, resulting in activation of pig cells.

    更新日期:2020-01-04
  • Diagnostic yield of 18F‐FDG PET/CT imaging and urinary CXCL9/creatinine levels in kidney allograft subclinical rejection
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-03
    Oriane Hanssen; Laurent Weekers; Pierre Lovinfosse; Alexandre Jadoul; Catherine Bonvoisin; Antoine Bouquegneau; Stéphanie Grosch; Alexandre Huynen; Dany Anglicheau; Roland Hustinx; Francois Jouret

    Subclinical kidney allograft acute rejection (SCR) corresponds to “the unexpected histological evidence of acute rejection in a stable patient.” SCR detection relies on surveillance biopsy. Noninvasive approaches may help avoid biopsy‐associated complications. From November 2015 to January 2018, we prospectively performed positron emission tomography/computed tomography (PET/CT) after injection of F18‐fluorodeoxyglucose (18F‐FDG) in adult kidney transplant recipients with surveillance biopsy at ~3 months posttransplantation. The Banff‐2017 classification was used. The ratio of the mean standard uptake value (mSUVR) between kidney cortex and psoas muscle was measured. Urinary levels of CXCL‐9 were concomitantly quantified. Our 92‐patient cohort was categorized upon histology: normal (n = 70), borderline (n = 16), and SCR (n = 6). No clinical or biological difference was observed between groups. The mSUVR reached 1.87 ± 0.55, 1.94 ± 0.35, and 2.41 ± 0.54 in normal, borderline, and SCR groups, respectively. A significant difference in mSUVR was found among groups. Furthermore, mSUVR was significantly higher in the SCR vs normal group. The area under the receiver operating characteristic curve (AUC) was 0.79, with 83% sensitivity using an mSUVR threshold of 2.4. The AUC of urinary CXCL‐9/creatinine ratios comparatively reached 0.79. The mSUVR positively correlated with ti and acute composite Banff scores. 18F‐FDG‐PET/CT helps noninvasively exclude SCR, with a negative predictive value of 98%. External validations are required.

    更新日期:2020-01-04
  • Protective role of Nrf2 against ischemia reperfusion injury and cardiac allograft vasculopathy
    Am. J. Transplant. (IF 7.163) Pub Date : 2020-01-03
    Naoto Fukunaga; Hiroyuki Kawajiri; Mitesh V. Badiwala; Jagdish Butany; Ren‐ke Li; Filio Billia; Vivek Rao

    Ischemia‐reperfusion injury (IRI) and cardiac allograft vasculopathy (CAV) remain unsolved complications post–heart transplant (Tx). The antioxidant transcription factor Nuclear factor erythroid 2‐related factor 2 (Nrf2) has been suggested to inhibit reactive oxygen species‐mediated NF‐κB activation. We hypothesized that Nrf2 inhibits NF‐κB activation post–Tx and suppresses IRI and the subsequent development of CAV. IRI and CAV were investigated in murine heterotopic Tx models, respectively. Nrf2 wild‐type (WT) and KO mice were used as donors. Sulforaphane was used as an Nrf2 agonist. In saline‐treated animals following 24 hours of reperfusion in isogenic grafts, Nrf2‐KO showed significantly less SOD1/2 activity compared with WT. Nrf2‐KO displayed significantly high total and phosphorylated p65 expressions and percentage of cells with nuclear p65. mRNA levels of NF‐κB‐mediated proinflammatory genes were also high. Graft dysfunction, apoptosis, and caspase‐3 activity were significantly higher in Nrf2‐KO. In the allograft studies, graft beating score was significantly weaker in Nrf2‐KO compared with WT. Nrf2‐KO also demonstrated significantly more coronary luminal narrowing. In WT animals, sulforaphane successfully augmented all the protective effects of Nrf2 with increase of SOD2 activity. Nrf2 inhibits NF‐κB activation and protects against IRI via its antioxidant properties and suppresses the subsequent development of CAV.

    更新日期:2020-01-04
  • Predictors of mortality in solid‐organ transplant recipients with bloodstream infections due to carbapenemase‐producing Enterobacterales: the impact of cytomegalovirus disease and lymphopenia
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-31
    Elena Pérez‐Nadales; Belén Gutiérrez‐Gutiérrez; Alejandra M. Natera; Edson Abdala; Maira Reina Magalhães; Alessandra Mularoni; Francesco Monaco; Ligia Camera Pierrotti; Maristela Pinheiro Freire; Ranganathan N. Iyer; Seema Metha; Elisa Grazia Calvi; Mario Tumbarello; Marco Falcone; Mario Fernández‐Ruiz; José María Costa‐Mateo; Meenakshi M. Rana; Tania Mara Varejão Strabelli; Mical Paul; María Carmen Fariñas; Wanessa Trindade Clemente; Emmanuel Roilides; Patricia Muñoz García; Laurent Dewispelaere; Belén Loeches; Warren Lowman; Ban Hock Tan; Rosa Escudero‐Sánchez; Marta Bodro Marimont; Paolo Antonio Grossi; Fabio Soldani; Filiz Gunseren; Nina Nestorova; Álvaro Pascual; Luis Martínez‐Martínez; José María Aguado; Jesús Rodríguez‐Baño; Julián Torre‐Cisneros;

    Treatment of carbapenemase‐producing Enterobacterales bloodstream infections (CPE‐BSI) in solid‐organ transplant recipients (SOT) is challenging. The objective of this study was to develop a specific score to predict mortality in SOT recipients with CPE‐BSI. A multinational, retrospective (2004‐2016) cohort study (INCREMENT‐SOT, ClinicalTrials.gov NCT02852902) was performed. The main outcome variable was 30‐day all‐cause mortality. The INCREMENT‐SOT‐CPE score was developed using logistic regression. The global cohort included 216 patients. The final logistic regression model included the following variables: INCREMENT‐CPE mortality score ≥8 (8 points), no source control (3 points), inappropriate empirical therapy (2 points), cytomegalovirus disease (7 points), lymphopenia (4 points), and the interaction between INCREMENT‐CPE score ≥8 and CMV disease (minus 7 points). This score showed an area under the receiver operating characteristic curve of 0.82 (95% CI 0.76‐0.88) and classified patients into three strata: 0–7 (low mortality), 8‐11 (high mortality) and 12‐17 (very‐high mortality). We performed a stratified analysis of the effect of monotherapy versus combination therapy among 165 patients who received appropriate therapy. Monotherapy was associated with higher mortality only in the very‐high (adjusted HR 2.82, 95% CI 1.13‐7.06, P=0.03) and high (HR 9.93, 95% CI 2.08‐47.40, P=0.004) mortality risk strata. A score‐based algorithm is provided for therapy guidance.

    更新日期:2019-12-31
  • Novel cell‐permeable p38‐MAPK inhibitor efficiently prevents porcine islet apoptosis and improves islet graft function
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-30
    Hirofumi Noguchi; Chika Miyagi‐Shiohira; Yoshiki Nakashima; Issei Saitoh; Masami Watanabe

    During islet transplantation, mitogen‐activated protein kinase (MAPK) p38 is preferentially activated in response to the isolation of islets and the associated inflammation. Although therapeutic effects of p38 inhibitors are expected, the clinical application of small‐molecule inhibitors of p38 is not recommended because of their serious adverse effects on the liver and central nervous system. Here we designed peptides to inhibit p38, which were derived from the sites on p38 that mediate binding to proteins such as MAPK kinases. Peptide 11R‐p38I110 significantly inhibited the activation of p38. To evaluate the effects of 11R‐p38I110, porcine islets were incubated with 10 µmol/L 11R‐p38I110 or a mutant form designated 11R‐mp38I110. After islet transplantation, blood glucose levels reached the normoglycemic range in 58.3% and 0% of diabetic mice treated with 11R‐p38I110 or 11R‐mp38I110, respectively. These data suggest that 11R‐p38I110 inhibited islet apoptosis and improved islet function. Peptide p38I110 is a noncompetitive inhibitor of ATP and targets a unique docking site. Therefore, 11R‐p38I110 specifically inhibits p38 activation, which may avoid the adverse effects that have discouraged the clinical use of small‐molecule inhibitors of p38. Moreover, our methodology to design “peptide inhibitors” could be used to design other inhibitors derived from the binding sites of proteins.

    更新日期:2019-12-30
  • Harnessing the microbiota for therapeutic purposes
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-30
    Timur Liwinski; Eran Elinav

    The myriads of microorganisms colonizing the human host (microbiome) affect virtually every aspect of its physiology in health and disease. The past decade witnessed unprecedented advances in microbiome research. The field rapidly transitioned from descriptive studies to deep mechanistic insights into host‐microbiome interactions. This offers the opportunity for microbiome‐targeted therapeutic manipulation. Currently, several strategies of microbiome‐targeted interventions are intensively explored. Best evidence from human randomized clinical trials is available for fecal microbiota transplantation (FMT). However, patient eligibility as well as long‐term efficacy and safety are not sufficiently defined. Therefore, there is currently no officially approved indication for FMT. Probiotics (live microorganisms) have long been discussed as a means to aid human health but have yielded varying results. Emerging techniques utilizing microbiota‐targeted diets, small microbial molecules, recombinant bacteriophages, and precise control of strain abundance recently yielded promising results but require further investigation. The rapid technological progress of “omics” tools spurs advances in personalized medicine. Understanding and integration of interindividual microbiome variability holds potential to promote personalized preventive and therapeutic approaches. Emerging evidence points towards the microbiome as an important player having an impact on transplantation outcomes. Microbiome‐targeted interventions have potential to aid against the many challenges faced by transplant recipients.

    更新日期:2019-12-30
  • Multiplex tissue imaging: an introduction to the scope and challenges
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-30
    Christopher O.C. Bellamy; Sandrine Prost

    That allograft biopsies are still needed reflects that histopathology outperforms other modalities in difficult settings, because the underlying truth in a tissue sample cannot be recapitulated with other approaches. The unique advantage of tissue sections is the retention of spatial relationships to molecular level.

    更新日期:2019-12-30
  • Operationalizing mucosal biopsies using machine learning to determine lung allograft dysfunction
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-30
    Ankit Bharat

    Lung allografts suffer from a high incidence of acute as well as chronic rejection. Due to exposure to the external milieu, lung allografts are also uniquely susceptible to damage from noxious stimuli. The diagnosis of allograft injury and differentiation from rejection requires transbronchial biopsy which is associated with severe complications, such as pneumothorax and bleeding, and is frequently inaccurate due to the heterogeneity observed in histopathology. The study by Halloran et al (1) attempts to operationalize machine learning based microarray analysis of pre‐validated rejection‐associated transcripts within mucosal biopsies, in lieu of transbronchial biopsies, to improve diagnostic accuracy and safety.

    更新日期:2019-12-30
  • Immediate Administration of Antiviral Therapy after Transplantation of Hepatitis C‐infected Livers into Uninfected Recipients: Implications for Therapeutic Planning
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-30
    Emily Bethea; Ashwini Arvind; Jenna Gustafson; Karin Andersson; Daniel Pratt; Irun Bhan; Michael Thiim; Kathleen Corey; Patricia Bloom; Jim Markmann; Heidi Yeh; Nahel Elias; Shoko Kimura; Leigh Anne Dageforde; Alex Cuenca; Tatsuo Kawai; Kassem Safa; Winfred Williams; Hannah Gilligan; Meghan Sise; Jay Fishman; Camille Kotton; Arthur Kim; Christin Marks; Sarah Shao; Mariesa Cote; Linda Irwin; Paul Myoung; Raymond T. Chung

    The practice of transplanting hepatitis C (HCV)‐infected livers into HCV‐uninfected recipients has not previously been recommended in transplant guidelines, in part because of concerns over uncontrolled HCV infection of the allograft. Direct‐acting antivirals (DAAs) provide an opportunity to treat donor derived HCV‐infection, and should be administered early in the post‐transplant period. However, evidence on the safety and efficacy of an immediate DAA treatment approach, including how to manage logistical barriers surrounding timely DAA procurement, are required prior to broader use of HCV‐positive donor organs. We report the results of a trial in which fourteen HCV‐negative patients underwent successful liver transplantation from HCV‐positive donors. Nine patients received viremic (nucleic acid testing (NAT)‐positive) livers, and started a 12‐week course of oral glecaprevir‐pibrentasvir (GP) within 5 days of transplant. Five patients received livers from HCV antibody‐positive non‐viremic donors and were followed using a reactive approach. Survival in NAT‐positive recipients is 100% at a median follow‐up of 46 weeks. An immediate treatment approach for HCV NAT‐positive liver transplantation into uninfected recipients is safe and efficacious. Securing payer approval for DAAs early in the post‐transplant course could enable need‐based allocation of HCV‐positive donor organs irrespective of candidate HCV status, while averting chronic HCV allograft infection.

    更新日期:2019-12-30
  • Triple (GGTA1, CMAH, B2M) modified pigs expressing an SLA class Ilow phenotype—Effects on immune status and susceptibility to human immune responses
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-28
    Rabea Hein; Hendrik J. Sake; Claudia Pokoyski; Joachim Hundrieser; Antje Brinkmann; Wiebke Baars; Monika Nowak‐Imialek; Andrea Lucas‐Hahn; Constanca Figueiredo; Hans‐Joachim Schuberth; Heiner Niemann; Björn Petersen; Reinhard Schwinzer

    Porcine xenografts lacking swine leukocyte antigen (SLA) class I are thought to be protected from human T cell responses. We have previously shown that SLA class I deficiency can be achieved in pigs by CRISPR/Cas9‐mediated deletion of β2‐microglobulin (B2M). Here, we characterized another line of genetically modified pigs in which targeting of the B2M locus did not result in complete absence of B2M and SLA class I but rather in significantly reduced expression levels of both molecules. Residual SLA class I was functionally inert, because no proper differentiation of the CD8+ T cell subset was observed in B2Mlow pigs. Cells from B2Mlow pigs were less capable in triggering proliferation of human peripheral blood mononuclear cells in vitro, which was mainly due to the nonresponsiveness of CD8+ T cells. Nevertheless, cytotoxic effector cells developing from unaffected cell populations (eg, CD4+ T cells, natural killer cells) lysed targets from both SLA class I+ wildtype and SLA class Ilow pigs with similar efficiency. These data indicate that the absence of SLA class I is an effective approach to prevent the activation of human CD8+ T cells during the induction phase of an anti‐xenograft response. However, cytotoxic activity of cells during the effector phase cannot be controlled by this approach.

    更新日期:2019-12-29
  • B cell clonal expansion within immune infiltrates in human cardiac allograft vasculopathy
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-27
    Carolina Moore; Baoshan Gao; Krishna M. Roskin; Elena‐Rodica M. Vasilescu; Linda Addonizio; Michael M. Givertz; Joren C. Madsen; Emmanuel Zorn

    Cardiac allograft vasculopathy (CAV) is associated with intragraft B cell infiltrates. Here, we studied the clonal composition of B cell infiltrates using 4 graft specimens with CAV. Using deep sequencing, we analyzed the immunoglobulin heavy chain variable region repertoire in both graft and blood. Results showed robust B cell clonal expansion in the graft but not in the blood for all cases. Several expanded B cell clones, characterized by their uniquely rearranged complementarity‐determining region 3, were detected in different locations in the graft. Sequences from intragraft B cells also showed elevated levels of mutated rearrangements in the graft compared to blood B cells. The number of somatic mutations per rearrangement was also higher in the graft than in the blood, suggesting that B cells continued maturing in situ. Overall, our studies demonstrated B cell clonal expansion in human cardiac allografts with CAV. This local B cell response may contribute to the pathophysiology of CAV through a mechanism that needs to be identified.

    更新日期:2019-12-29
  • Regulatory B cells require antigen recognition for effective allograft tolerance induction
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-27
    Shoko Kimura; Charles G. Rickert; Lisa Kojima; Mohamed Aburawi; Naoki Tanimine; Fermin Fontan; Kevin Deng; Haley Tector; Kang Mi Lee; Heidi Yeh; James F. Markmann

    Through multiple mechanisms, regulatory B cells (Breg) have been shown to play an important role in the development of allograft tolerance. However, a careful understanding of the role of antigen‐specificity in Breg‐mediated allograft tolerance has remained elusive. In experimental models of islet and cardiac transplantation, it has been established that Bregs can be induced in vivo by anti‐CD45RB ± anti‐TIM1antibody treatment, resulting in prolonged, Breg‐dependent allograft tolerance. The importance of Breg antigen recognition has been suggested but not confirmed through adoptive transfer experiments, using tolerant WT C57BL/6 animals challenged with either BALB/c or C3H grafts. However, the importance of receptor‐specificity has not been formally tested. Here, we utilize the novel ovalbumin‐specific B cell receptor transnuclear (OBI) mice in multiple primary tolerance and adoptive transfer experiments to establish that Breg‐dependent allograft tolerance relies on antigen recognition by B cells. Additionally, we identify that this Breg‐dependent tolerance relies on the function of transforming growth factor‐β. Together, these experiments mark important progress toward understanding how best to improve Breg‐mediated allograft tolerance.

    更新日期:2019-12-29
  • Living‐donor single‐lobe lung transplantation for pulmonary hypertension due to alveolar capillary dysplasia with misalignment of pulmonary veins
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-28
    Daisuke Nakajima; Hiromi Oda; Katsutaka Mineura; Tatsuya Goto; Itaru Kato; Shiro Baba; Tadashi Ikeda; Toyofumi F. Chen‐Yoshikawa; Hiroshi Date

    This is a case report of successful single‐lobe lung transplantation for pulmonary hypertension secondary to alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV). A 6‐year‐old boy underwent living‐donor single‐lobe transplantation with the right lower lobe from his 31‐year‐old mother. The pre‐transplant graft size matching was acceptable: the estimated graft forced vital capacity (FVC) was 96.5% of the recipient’s predicted FVC, and the graft size measured by computed tomography (CT) volumetry was 166% of the recipient’s chest cavity volume. Right pneumonectomy followed by implantation was performed under cardiopulmonary bypass (CPB). The pulmonary arterial pressure was significantly decreased to 31/12 mmHg immediately after transplantation, and the first PaO2/FiO2 in the intensive‐care unit (ICU) was 422 mmHg. Lung perfusion scintigraphy showed 97.5% perfusion to the right implanted lung three months after transplantation. Chest CT showed a mass rapidly growing in the native left upper lobe six months after transplantation, which was diagnosed as post‐transplant lymphoproliferative disorder (PTLD) by a CT‐guided biopsy. After immunosuppressant reduction and six courses of chemotherapy with rituximab, he underwent native left upper lobectomy for salvage lung resection 13 months after transplantation. Seven months after lobectomy, he has returned to normal school life without any sign of tumor recurrence.

    更新日期:2019-12-29
  • Now is the time for the Organ Procurement and Transplantation Network (OPTN) to change regulatory policy to effectively increase transplantation in the United States; Carpe Diem
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-27
    Kenneth A. Andreoni

    With the Centers for Medicare and Medicaid Services (CMS) proposing to remove outcome measures from the transplant centers’ renewal for Conditions of Participation an exciting opportunity surfaces for the Organ Procurement and Transplantation Network (OPTN) to make an equally bold change and allow for increased transplantation options for patients in the United States.

    更新日期:2019-12-29
  • Thrombotic microangiopathy involving kidney allograft and peripheral nerves
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-27
    Elie Naddaf; P. James B. Dyck; Samar Said; Hatem Amer

    While thrombotic microangiopathy (TMA) can commonly affect the kidney, peripheral nerve involvement has not been reported to date. A 56‐year‐old man, recipient of a kidney allograft, reported severe headaches, tremors, and diarrhea followed by sudden‐onset right foot drop after increasing his dose of tacrolimus. He then developed acute right hand pain, numbness, and weakness. At presentation, neurological examination and electroneuromyography confirmed the presence of right worse than left, sciatic and ulnar mononeuropathies. Kidney biopsy showed evidence of a thrombotic microangiopathy. Similarly, nerve biopsy showed thrombosis of epineurial blood vessels with minimal inflammation. Herein, we demonstrated that thrombotic microangiopathy can involve the peripheral nerves, resulting in major morbidity. Distinguishing TMA from vasculitis is important because it has major treatment implications.

    更新日期:2019-12-27
  • Robotic kidney transplantation in the obese patient: 10‐year experience from a single center
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-24
    Ivo G. Tzvetanov; Mario Spaggiari; Kiara A. Tulla; Caterina Di Bella; Obi Okoye; Pierpaolo Di Cocco; Hoonbae Jeon; Jose Oberholzer; Pier Cristoforo Giulianotti; Enrico Benedetti

    Despite increasing obesity rates in the dialysis population, obese kidney transplant candidates are still denied transplantation by many centers. We performed a single‐center retrospective analysis of a robotic‐assisted kidney transplant (RAKT) cohort from January 2009 to December 2018. A total of 239 patients were included in this analysis. The median BMI was 41.4 kg/m2, with the majority (53.1%) of patients being African American and 69.4% of organs sourced from living donors. The median surgery duration and warm ischemia times were 4.8 hours and 45 minutes respectively. Wound complications (mostly seromas and hematomas) occurred in 3.8% of patients, with 1 patient developing a surgical site infection (SSI). Seventeen (7.1%) graft failures, mostly due to acute rejection, were reported during follow‐up. Patient survival was 98% and 95%, whereas graft survival was 98% and 93%, at 1 and 3 years respectively. Similar survival statistics were obtained from patients undergoing open transplant over the same time period from the UNOS database. In conclusion, RAKT can be safely performed in obese patients with minimal SSI risk, excellent graft function, and patient outcomes comparable to national data. RAKT could improve access to kidney transplantation in obese patients due to the low surgical complication rate.

    更新日期:2019-12-25
  • Pseudomonas aeruginosa and acute rejection independently increase the risk of donor‐specific antibodies after lung transplantation
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-24
    Hrishikesh S. Kulkarni; Kevin Tsui; Suraj Sunder; Alex Ganninger; Laneshia K. Tague; Chad A. Witt; Derek E. Byers; Elbert P. Trulock; Ruben Nava; Varun Puri; Daniel Kreisel; Thalachallour Mohanakumar; Andrew E. Gelman; Ramsey R. Hachem

    Factors contributing to donor‐specific HLA antibody (DSA) development after lung transplantation have not been systematically evaluated. We hypothesized that the isolation of Pseudomonas aeruginosa in respiratory specimens would increase the risk of DSA development. Our objective was to determine the risk of DSA development associated with the isolation of Pseudomonas aeruginosa after lung transplantation. We conducted a single‐center retrospective cohort study of primary lung transplant recipients and examined risk factors for DSA development using Cox regression models. Of 460 recipients, 205 (45%) developed DSA; the majority developed Class II DSA (n = 175, 85%), and 145 of 205 (71%) developed DSA to HLA‐DQ alleles. Univariate time‐dependent analyses revealed that isolation of Pseudomonas from respiratory specimens, acute cellular rejection, and lymphocytic bronchiolitis are associated with an increased risk of DSA development. In multivariable analyses, Pseudomonas isolation, acute cellular rejection, and lymphocytic bronchiolitis remained independent risk factors for DSA development. Additionally, there was a direct association between the number of positive Pseudomonas cultures and the risk of DSA development. Our findings suggest that pro‐inflammatory events including acute cellular rejection, lymphocytic bronchiolitis, and Pseudomonas isolation after transplantation are associated with an increased risk of DSA development.

    更新日期:2019-12-25
  • Outcomes of kidney retransplantation after graft loss as a result of BK virus nephropathy in the era of newer immunosuppressant agents
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-24
    Napat Leeaphorn; Charat Thongprayoon; Woojin J. Chon; Lee S. Cummings; Michael A. Mao; Wisit Cheungpasitporn

    We conducted this study using the updated 2005‐2016 Organ Procurement and Transplantation Network database to assess clinical outcomes of retransplant after allograft loss as a result of BK virus–associated nephropathy (BKVAN). Three hundred forty‐one patients had first graft failure as a result of BKVAN, whereas 13 260 had first graft failure as a result of other causes. At median follow‐up time of 4.70 years after the second kidney transplant, death‐censored graft survival at 5 years for the second renal allograft was 90.6% for the BK group and 83.9% for the non‐BK group. In adjusted analysis, there was no difference in death‐censored graft survival (P = .11), acute rejection (P = .49), and patient survival (P = .13) between the 2 groups. When we further compared death‐censored graft survival among the specific causes for first graft failure, the BK group had better graft survival than patients who had prior allograft failure as a result of acute rejection (P < .001) or disease recurrence (P = .003), but survival was similar to those with chronic allograft nephropathy (P = .06) and other causes (P = .05). The better allograft survival in the BK group over acute rejection and disease recurrence remained after adjusting for potential confounders. History of allograft loss as a result of BKVAN should not be a contraindication to retransplant among candidates who are otherwise acceptable.

    更新日期:2019-12-25
  • Organ donor intervention research informed consent – Timing and risk
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-24
    Elisa J. Gordon; Robert M. Veatch; Peter Abt; Peter P. Reese

    Developing patient‐centered informed consent processes for deciding whether to accept intervention organs and participating in organ donor intervention research is essential for protecting transplant candidates’ autonomy.1 Richard Freeman’s letter is highly encouraging given his appreciation for the value patients placed on informed consent for intervention organs, and for recognizing the feasibility of implementing research and clinical informed consent into clinical practice, even in urgent contexts.2

    更新日期:2019-12-25
  • Hand transplantation in the United States: A review of the Organ Procurement and Transplantation Network/United Network for Organ Sharing Database
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-21
    Rachel E. Hein; David S. Ruch; Christopher S. Klifto; Fraser J. Leversedge; Suhail K. Mithani; Tyler S. Pidgeon; Marc J. Richard; Linda C. Cendales

    Hand transplantation is the most common application of vascularized composite allotransplantation (VCA). Since July 3, 2014, VCAs were added to the definition of organs covered by federal regulation (the Organ Procurement and Transplantation Network (OPTN) Final Rule) and legislation (the National Organ Transplant Act). As such, VCA is subject to requirements including data submission. We performed an analysis of recipients reported to the OPTN to have received hand transplantation between 1999 and 2018. Forty‐three patients were identified as having been listed for upper extremity transplantation in the United States. Of these, 22 received transplantation prior to July 3, 2014 and 10 from then to December 31, 2018. Of patients transplanted after 2014, posttransplant functional scores included a decrease in Disabilities of the Arm, Shoulder and Hand questionnaire in 3 of 10 patients, Carroll test scores ranging from 9 to 60 of 99, and monofilament testing with protective sensation achieved in 4 of 6 patients. Complications included rejection in nine recipients with Banff scores from II‐IV. One patient experienced graft failure 5 days after transplantation. Of the remaining patients, two were reported as receiving monotherapy and seven receiving dual or triple immunosuppression therapy. The inclusion of VCA in the OPTN Final Rule standardized parameters for safe implementation and data collection.

    更新日期:2019-12-22
  • Coronary computed tomography–angiography quantitative plaque analysis improves detection of early cardiac allograft vasculopathy: A pilot study
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-21
    Robert J. H. Miller; Jacek Kwiecinski; Kevin S. Shah; Evann Eisenberg; Jignesh Patel; Jon A. Kobashigawa; Babak Azarbal; Balaji Tamarappoo; Daniel S. Berman; Piotr J. Slomka; Evan Kransdorf; Damini Dey

    Cardiac allograft vasculopathy (CAV) is an increasingly important complication after cardiac transplant. We assessed the additive diagnostic benefit of quantitative plaque analysis in patients undergoing coronary computed tomography–angiography (CCTA). Consecutive patients undergoing CCTA for CAV surveillance were identified. Scans were visually interpreted for coronary stenosis. Semiautomated software was used to quantify noncalcified plaque (NCP), as well as its components. Optimal diagnostic cut‐offs for CAV, with coronary angiography as gold standard, were defined using receiver operating characteristic curves. In total, 36 scans were identified in 17 patients. CAV was present in 17 (46.0%) reference coronary angiograms, at a median of 1.9 years before CCTA. Median NCP (147 vs 58, P < .001), low‐density NCP (median 4.5 vs 0.9, P = .003), fibrous plaque (median 76.1 vs 31.1, P = .003), and fibrofatty plaque (median 63.6 vs 27.6, P < .001) volumes were higher in patients with CAV, whereas calcified plaque was not (median 0.0 vs 0.0, P = .510). Visual assessment of CCTA alone was 70.6% sensitive and 100% specific for CAV. The addition of total NCP volume increased sensitivity to 82.4% while maintaining 100% specificity. NCP volume is significantly higher in patients with CAV. The addition of quantitative analysis to visual interpretation improves the sensitivity for detecting CAV without reducing specificity.

    更新日期:2019-12-22
  • Adipose‐derived stromal cell therapy combined with a short course nonmyeloablative conditioning promotes long‐term graft tolerance in vascularized composite allotransplantation
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-21
    Riccardo Schweizer; Adriano Taddeo; Matthias Waldner; Holger J. Klein; Nina Fuchs; Pranitha Kamat; Stefan Targosinski; André A. Barth; Mathias C. Drach; Vijay S. Gorantla; Paolo Cinelli; Jan A. Plock

    The risks of chronic immunosuppression limit the utility of vascularized composite allotransplantation (VCA) as a reconstructive option in complex tissue defects. We evaluated a novel, clinically translatable, radiation‐free conditioning protocol that combines anti‐lymphocyte serum (ALS), tacrolimus, and cytotoxic T‐lymphocyte‐associated protein 4 immunoglobulin (CTLA4‐Ig) with adipose‐derived stromal cells (ASCs) to allow VCA survival without long‐term systemic immunosuppression. Full‐mismatched rat hind‐limb‐transplant recipients received tacrolimus (0.5 mg/kg) for 14 days and were assigned to 4 groups: controls (CTRL) received no conditioning; ASC‐group received CTLA4‐Ig (10 mg/kg body weight i.p. postoperative day [POD] 2, 4, 7) and donor ASCs (1 × 106 iv, POD 2, 4, 7, 15, 28); the ASC‐cyclophosphamide (CYP)‐group received CTLA4‐Ig, ASC plus cyclophosphamide (50 mg/kg ip, POD 3); the ASC‐ALS‐group received CTLA4‐Ig, ASCs plus ALS (500 µL ip, POD 1, 5). Banff grade III or 120 days were endpoints. ASCs suppressed alloresponse in vitro. Median rejection‐free VCA survival was 28 days in CTRL (n = 7), 34 in ASC (n = 6), and 27.5 in ASC‐CYP (n = 4). In contrast, ASC‐ALS achieved significantly longer, rejection‐free VCA survival in 6/7 animals (86%), with persistent mixed donor‐cell chimerism, and elevated systemic and allograft skin Tregs, with no signs of acute cellular rejection. Taken together, a regimen comprised of short‐course tacrolimus, repeated CTLA4‐Ig and ASC administration, combined with ALS, promotes long‐term VCA survival without chronic immunosuppression.

    更新日期:2019-12-21
  • An international comparison of deceased donor kidney utilization: What can the United States and the United Kingdom learn from each other?
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-21
    Maria Ibrahim; Gabe Vece; Jenny Mehew; Rachel Johnson; John Forsythe; David Klassen; Chris Callaghan; Darren Stewart

    In transplant, meaningful international comparisons in organ utilization are needed. This collaborative study between the United Kingdom (UK) and the United States (US) aimed to develop a kidney utilization metric allowing for legitimate intercountry comparisons. Data from the UK and US transplant registries, including all deceased donor kidneys recovered from 2006 to 2017, were analyzed. To identify a potentially comparable kidney utilization rate (UR), several denominators were assessed. We discovered that the proportion of transplanted kidneys from elderly donors in the UK (10.7%) was 18 times greater than that in the US (0.6%). Conversely, en bloc pediatric kidney transplant was more common in the US. Donation after circulatory death utilization has risen in both countries but is twice as prevalent in the UK (39% of transplants) vs the US (20%). In addition, US and UK URs are not directly comparable due to fundamental system differences. However, using a suite of URs revealed practice areas likely to yield the most benefit if improved, such as efforts to increase kidney offer acceptance in the US and to reduce postacceptance discard in the UK. Methods used in this study, including novel intracountry risk‐adjusted UR trend logistic regression analyses, can be translated to other international transplant registries in pursuit of further global learning opportunities.

    更新日期:2019-12-21
  • Role of Donor Macrophages after Heart and Lung Transplantation
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-18
    BJ Kopecky; C Frye; Y Terada; KR Balsara; D Kreisel; KJ Lavine

    Since the 1960s, heart and lung transplantation remain the optimal therapy for patients suffering from end‐stage disease, extending and improving quality of life for thousands of individuals annually. Expanding donor organ availability and immunologic compatibility are priorities to help meet the clinical demand for organ transplantation. While effective, current immunosuppression is imperfect as it lacks specificity and imposes unintended adverse effects such as opportunistic infections and malignancy that limit the health and longevity of transplant recipients. In this review, we focus on donor macrophages as a new target to achieve allograft tolerance. Donor organ‐directed therapies have the potential to improve allograft survival while minimizing patient harm related to global suppression of recipient immune responses. Topics highlighted will include the role of ontogenically distinct donor macrophage populations in ischemia‐reperfusion injury and rejection including their interaction with allograft infiltrating recipient immune cells and potential therapeutic approaches. Ultimately, a better understanding of how donor intrinsic immunity influences allograft acceptance and survival will provide new opportunities to improve the outcomes of transplant recipients.

    更新日期:2019-12-19
  • Liver transplantation and chronic disease management: Moving beyond patient and graft survival
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-17
    Marina Serper; Sumeet K Asrani

    With advances in surgical techniques, multidisciplinary care and immunosuppression, patient and graft survival continue to improve in liver transplantation (LT). Excellent patient and graft survival have translated into an aging liver transplant recipient (LTRs) cohort that resembles a general chronic disease population. (1) LTRs are becoming more medically complex related to LT indication (e.g. non‐alcoholic fatty liver disease) and with increased prevalence of relevant chronic conditions such as chronic kidney disease (CKD) (1, 2)

    更新日期:2019-12-19
  • Neutrophils cause a “NET” increase in skin allograft allogenicity
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-17
    Sophie Brouard; Nuala Mooney

    While current immunosuppressive treatments efficiently prevent early rejection of organ transplants such as kidney, they have little or no effect in skin transplantation.

    更新日期:2019-12-18
  • Real‐life food‐safety behavior and incidence of foodborne infections in solid organ transplant recipients
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-16
    Matti Lindup; Lorena van den Bogaart; Déla Golshayan; John‐David Aubert; Julien Vionnet; Julien Regamey; Manuel Pascual; Oriol Manuel; Matteo Mombelli

    Food‐safety measures are recommended in solid organ transplant (SOT) recipients. However, the actual adherence of patients in a real‐life setting and the impact on the incidence of foodborne infections remain largely unexplored. We performed a survey among SOT recipients followed at our institution, aiming to evaluate their food‐safety behavior. We assessed the incidence of microbiologically proven foodborne infections by chart review. One hundred ninety‐seven SOT recipients (kidney = 117, lung = 35, liver = 29, and heart = 16) participated in the survey. Overall, 17.7% of the participants observed all food‐safety recommendations (22.0% avoided food at risk of contamination while 67.9% applied hygiene recommendations). Patients within the first year after transplantation (odds ratio [OR] 5.42; P = .001) and females (OR 4.67; P = .001) followed food‐safety recommendations more closely. Although the majority of SOT recipients felt concerned and actively sought information on food safety (68%‐70%), only 27% were able to recognize all risks of foodborne infection in hypothetical scenarios. Incidence of proven foodborne infections was 17.9% (95% confidence interval 9.9%‐30.9%) 5 years after transplantation. Importantly, foodborne infections occurred exclusively among patients not following food‐safety recommendations. In summary, most SOT recipients eat foods that make them at risk of foodborne infections. Our results indicate that there is room for improvement in patient education, particularly later after transplantation, and reinforce current food‐safety recommendations.

    更新日期:2019-12-17
  • Hypertension, but not body mass index, is predictive of increased pancreatic lipid content and islet dysfunction
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-16
    Daniel M. Tremmel; Austin K. Feeney; Samantha A. Mitchell; Peter J. Chlebeck; Sierra A. Raglin; Luis A. Fernandez; Jon S. Odorico; Sara D. Sackett

    Pancreatic steatosis is thought to be a negative risk factor for pancreas transplant outcomes. Despite considering donor body mass index (BMI) and the visualization of intercalated fat as indicators of donor pancreas lipid content, transplant surgeons do not use a quantitative method to directly measure steatosis when deciding to transplant a pancreas. In this study, we used nondiabetic human pancreata donated for research to measure the pancreatic and islet‐specific lipid content to determine which clinical markers correlate best with lipid content. Interestingly, we found that BMI and age correlate with increased pancreatic lipid content (Panc‐LC) in men, but not women. Our findings further suggest that total Panc‐LC correlates with an increase in islet lipid content for both men and women. We noted that pancreata donated from individuals with a history of hypertension have increased Panc‐LC independent of donor BMI or sex. Moreover, we identify hypertension as a risk factor for reduced islet function after islet isolation. Together, our findings emphasize differences in pancreas graft quality related to pancreatic and islet lipid content, which may not be predicted by assessing BMI alone but may be influenced by a donor history of hypertension.

    更新日期:2019-12-17
  • Risk prediction models for survival after heart transplantation: A systematic review
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-16
    Natasha Aleksova; Ana C. Alba; Victoria M. Molinero; Katherine Connolly; Ani Orchanian‐Cheff; Mitesh Badiwala; Heather J. Ross; Juan G. Duero Posada

    Risk prediction scores have been developed to predict survival following heart transplantation (HT). Our objective was to systematically review the model characteristics and performance for all available scores that predict survival after HT. Ovid Medline and Epub Ahead of Print and In‐Process & Other Non‐Indexed Citations, Ovid Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Clinical Trials were searched to December 2018. Eligible articles reported a score to predict mortality following HT. Of the 5392 studies screened, 21 studies were included that derived and/or validated 16 scores. Seven (44%) scores were validated in external cohorts and 8 (50%) assessed model performance. Overall model discrimination ranged from poor to moderate (C‐statistic/area under the receiver operating characteristics 0.54‐0.77). The IMPACT score was the most widely validated, was well calibrated in two large registries, and was best at discriminating 3‐month survival (C‐statistic 0.76). Most scores did not perform particularly well in any cohort in which they were assessed. This review shows that there are insufficient data to recommend the use of one model over the others for prediction of post‐HT outcomes.

    更新日期:2019-12-17
  • Extracellular vesicles derived from injured vascular tissue promote the formation of tertiary lymphoid structures in vascular allografts
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-16
    Mélanie Dieudé; Julie Turgeon; Annie Karakeussian Rimbaud; Déborah Beillevaire; Shijie Qi; Nathalie Patey; Louis A. Gaboury; Éric Boilard; Marie‐Josée Hébert

    Tertiary lymphoid structures (TLS) accumulate at sites of chronic injury where they function as an ectopic germinal center, fostering local autoimmune responses. Vascular injury leads to the release of endothelial‐derived apoptotic exosome‐like vesicles (ApoExo) that contribute to rejection in transplanted organs. The purpose of the study was to evaluate the impact of ApoExo on TLS formation in a model of vascular allograft rejection. Mice transplanted with an allogeneic aortic transplant were injected with ApoExo. The formation of TLS was significantly increased by ApoExo injection along with vascular remodeling and increased levels of antinuclear antibodies and anti‐perlecan/LG3 autoantibodies. ApoExo also enhanced allograft infiltration by γδT17 cells. Recipients deficient in γδT cells showed reduced TLS formation and lower autoantibodies levels following ApoExo injection. ApoExo are characterized by proteasome activity, which can be blocked by bortezomib. Bortezomib treated ApoExo reduced the recruitment of γδT17 cells to the allograft, lowered TLS formation, and reduced autoantibody production. This study identifies vascular injury‐derived extracellular vesicles (ApoExo), as initiators of TLS formation and demonstrates the pivotal role of γδT17 in coordinating TLS formation and autoantibody production. Finally, our results suggest proteasome inhibition with bortezomib as a potential option for controlling TLS formation in rejected allografts.

    更新日期:2019-12-17
  • Expanding the use of hepatitis C positive donors and keeping recipient safety at the forefront
    Am. J. Transplant. (IF 7.163) Pub Date : 2019-12-15
    Norah A. Terrault; Linda Sher

    The opioid crisis, the need for more organs for all transplant candidates and the availability of effective direct acting antivirals (DAAs) for hepatitis C virus (HCV) have converged to bring transplants from HCV‐viremic donors to the forefront. While use of such organs in recipients with preexisting chronic HCV is well‐established, use in HCV negative patients is a newer phenomenon and requires delineation of the risks and benefits to wait‐listed patients and examination of programmatic and financial requirements to ultimately inform best practices for the transplant community.

    更新日期:2019-12-17
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