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American Journal of Transplantation: Volume 21, Number 10, October 2021
doi : 10.1111/ajt.16050
Volume 21, Issue 10
Over the past decade, tremendous progress in basic science arenas, including cell biology and bioengineering, coupled with wide-ranging technological advances from gene editing to normothermic perfusion platforms have exploded the horizon of opportunity for cellular therapies. Parsons et al. (page 3225) paint the current landscape. They begin with familiar applications of islet and hepatocyte transplantation and progress to cellular infusions for immunomodulation and tolerance induction.
Sex Disparity in Transplant: A Problem Hiding in Plain Sight
Lara C. Pullen PHD
doi : 10.1111/ajt.16047
Volume 21, Issue 10 p. 3211-3212
This month's installment of “The AJT Report” explores the challenge of sex disparity in transplant and what might be done to address this ongoing problem. We also report on a recent amendment to the U.S. Food and Drug Administration’s COVID-19 vaccine emergency use authorizations that affects solid organ recipients.
B cells are going innate in human renal allografts
Xian C. Li MD, PHD
doi : 10.1111/ajt.16048
Volume 21, Issue 10 p. 3213-3213
B cells infiltrating kidney allografts express a transcriptional program of innate inflammatory cells and are not selected for allospecificity.
Time for increased awareness of sex as a biological variable in transplantation
Mandy L. Ford,Roslyn B. Mannon
doi : 10.1111/ajt.16733
Volume 21, Issue 10 p. 3215-3216
For the last several decades, it has been evident that sex affects the immune system and its responses. The high incidence of several autoimmune diseases in women of child-bearing age is particularly well appreciated,1 and emerging evidence demonstrates how biological sex impacts COVID-19 outcomes.2 As noted by Lepeytre et al, such studies grapple with our understanding of outcomes and immunological therapies as uniform in all recipients.3 In this issue of the AJT, Maenosono et al. provide compelling evidence demonstrating that recipient sex and estradiol levels impact transplant outcomes in an age-specific manner in both murine skin transplant and human renal transplant recipients.4 These data are timely in that they provide further evidence that sex is a relevant biological variable in transplantation and should compel the transplant research community to more rigorously address this variable in preclinical and clinical studies.
Correcting the sex disparity in access to liver transplantation: Lest perfect be the enemy of better
Allison J. Kwong,Jennifer C. Lai,W. Ray Kim
doi : 10.1111/ajt.16805
Volume 21, Issue 10 p. 3217-3218
The implementation of the model for end-stage liver disease (MELD) as the backbone of liver allocation policy in the United States in 2002 has overall improved waitlist outcomes and standardized access to liver transplantation for patients with end-stage liver disease. However, women experience higher waitlist mortality and lower transplant rates compared with men, attributed in part to underestimation of renal dysfunction by the use of serum creatinine in MELD and MELD-Na.1-3 Alternative models have been proposed to reduce this gap, including replacement of serum creatinine with estimated glomerular filtration rate or granting additional MELD points to women, but what has been lacking in the literature has been quantification and comparison of the potential impact of these models on the sex disparity itself.
Ecological factors and posttransplant outcomes: Causation or correlation?
Katherine Ross-Driscoll,Rachel E. Patzer,David A. Axelrod
doi : 10.1111/ajt.16716
Volume 21, Issue 10 p. 3219-3220
Social determinants of health (SDOH), defined by the World Health Organization as “the conditions in which people are born, work, live, and age, and the wider set of forces and systems shaping the conditions of daily life,” are widely acknowledged to contribute to variation in health outcomes.1 The Healthy People 2030 framework identifies an individual's neighborhood as one of the five key areas of SDOH.2 The neighborhoods where people live can influence health outcomes through a variety of pathways, including access to transportation, availability of healthy foods and physical activity spaces, rates of crime and violence, and prevalence of poor air and water quality. These forces continue to disproportionately impact racial and ethnic minority populations and low income persons who live and work in at-risk neighborhoods.3 In the transplant literature, place of residence has been previously correlated with patient outcomes including waitlist mortality4 and post-transplant outcomes.5
Perspectives of solid organ transplant recipients on taking medications: Valuable research, just the beginning
Eyal Shemesh,Dianne LaPointe Rudow
doi : 10.1111/ajt.16620
Volume 21, Issue 10 p. 3221-3222
In this volume, Tang et al.1 synthesize 119 qualitative studies that sought to describe patient-reported perceptions related to medication-taking in solid organ transplant recipients. This thoughtful review highlights an important body of research, which tries to incorporate patients' “voice” to inform care: a recognized goal in clinical medicine2 and transplant care.3 The Starzl Network of Excellence in Pediatric Transplantation (SNEPT), for example, recognizes the incorporation of patient's perspectives to inform clinical care as a top priority.4
Single-stage tracheal transplantation—From bench to bedside
Simran K. Randhawa,G Alexander Patterson
doi : 10.1111/ajt.16776
Volume 21, Issue 10 p. 3223-3224
We read with great interest and admiration the manuscript by Genden and colleagues titled "Single-Stage Long-Segment Tracheal Transplantation."1 In adult patients, the general limits of safe tracheal resection and direct end to end re-anastomosis has always been considered to be a maximum of 5–6 cm. Long-segment tracheal resection and replacement is a challenge and has led to a century-long search for a means of tracheal replacement. This search comprised a host of foreign materials, including stents, with many technical modifications. However, these were associated with inevitable replacement material or stent related complications; migration, granulation tissue, stenosis, hemorrhage, fistula, etc. Various creative combinations of tissue flaps and transfers as patches or tubes with or without scaffolding by autologous cartilage or foreign materials have also been performed without definitive success. Martinod and his group have nicely described a small clinical experience using cryopreserved tubular aortic homografts implanted as conduit generally with a supporting stent.2 Some of the problems associated with these methods are the lack of definitive respiratory epithelium or stable cartilaginous wall, which led to issues with secretion management, along with the added morbidities of prolonged stent use. Tissue engineered trachea grafts using stem cells have been implanted in a small number of patients.3 Of course this strategy received significant attention in major medical journals as well as the lay press a few years ago. However, this strategy, associated with extremely high morbidity and mortality rates, has been largely discredited.4
Challenges, highlights, and opportunities in cellular transplantation: A white paper of the current landscape
Ronald F. Parsons,Angeles Baquerizo,Varvara A. Kirchner,Sayeed Malek,Chirag S. Desai,Austin Schenk,Erik B. Finger,Todd V. Brennan,Kalpaj R. Parekh,Malcolm MacConmara,Kenneth Brayman,Jeffrey Fair,Jason A. Wertheim, on behalf of the ASTS Cellular Transplantation Committee
doi : 10.1111/ajt.16740
Volume 21, Issue 10 p. 3225-3238
Although cellular transplantation remains a relatively small field compared to solid organ transplantation, the prospects for advancement in basic science and clinical care remain bountiful. In this review, notable historical events and the current landscape of the field of cellular transplantation are reviewed with an emphasis on islets (allo- and xeno-), hepatocytes (including bioartificial liver), adoptive regulatory immunotherapy, and stem cells (SCs, specifically endogenous organ-specific and mesenchymal). Also, the nascent but rapidly evolving field of three-dimensional bioprinting is highlighted, including its major processing steps and latest achievements. To reach its full potential where cellular transplants are a more viable alternative than solid organ transplants, fundamental change in how the field is regulated and advanced is needed. Greater public and private investment in the development of cellular transplantation is required. Furthermore, consistent with the call of multiple national transplant societies for allo-islet transplants, the oversight of cellular transplants should mirror that of solid organ transplants and not be classified under the unsustainable, outdated model that requires licensing as a drug with the Food and Drug Administration. Cellular transplantation has the potential to bring profound benefit through progress in bioengineering and regenerative medicine, limiting immunosuppression-related toxicity, and providing markedly reduced surgical morbidity.
Recipient sex and estradiol levels affect transplant outcomes in an age-specific fashion
Ryoichi Maenosono,Yeqi Nian,Jasper Iske,Yang Liu,Koichiro Minami,Tabea Rommel,Friederike Martin,Reza Abdi,Haruhito Azuma,Bernhard A. Rosner,Hao Zhou,Edgar Milford,Abdallah Elkhal,Stefan G. Tullius
doi : 10.1111/ajt.16611
Volume 21, Issue 10 p. 3239-3255
Sex-specific influences have been shown for a variety of diseases. Whether donor or recipient sex and sex hormone levels impact alloimmune responses remains unclear. In unifactorial and multifactorial analyses of more than 400 000 SRTR listed kidney transplant patients, we found that younger female recipients had an inferior death-censored graft survival that was independent of donor sex. In contrast, graft survival was superior in older female recipients, suggesting the impact of recipient sex hormones over chromosomal sex mismatches. Those clinical changes were delineated in experimental skin and heart transplant models showing a prolongation of graft survival in ovariectomized young female recipients. In contrast, graft survival was comparable in ovariectomized and naïve old female recipients. Young ovariectomized mice showed reduced amounts and a compromised T cell proliferation. Deprivation of female hormones dampened the production of interferon (IFN)-? and interleukin (IL)-17+ by CD4+ T cells while augmenting systemic counts of Tregs. Increasing estradiol concentrations in vitro promoted the switch of naïve CD4+ T cells into Th1 cells; high physiological estradiol concentrations dampening Th1 responses, promoted Tregs, and prolonged graft survival. Thus, clinical observations demonstrate age-specific graft survival patterns in female recipients. Estrogen levels, in turn, impact the fate of T cell subsets, providing relevant and novel information on age- and sex-specific alloimmunity.
TIGIT regulates apoptosis of risky memory T cell subsets implicated in belatacept-resistant rejection
He Sun,Christina R. Hartigan,Ching-wen Chen,Yini Sun,Marvi Tariq,Jennifer M. Robertson,Scott M. Krummey,Aneesh K. Mehta,Mandy L. Ford
doi : 10.1111/ajt.16571
Volume 21, Issue 10 p. 3256-3267
Belatacept confers increased patient and graft survival in renal transplant recipients relative to calcineurin inhibitors, but is associated with an increased rate of acute rejection. Recent immunophenotypic studies comparing pretransplant T cell phenotypes of patients who reject versus those who remain stable on belatacept identified three potential “risky” memory T cell subsets that potentially underlie belatacept-resistant rejection: CD4+ CD28+ TEM, CD8+ CD28null, and CD4+ CD57+ PD1? subsets. Here, we compared key phenotypic and functional aspects of these human memory T cell subsets, with the goal of identifying additional potential targets to modulate them. Results demonstrate that TIGIT, an increasingly well-appreciated immune checkpoint receptor, was expressed on all three risky memory T cell subsets in vitro and in vivo in the presence of belatacept. Coculture of human memory CD4+ and CD8+ T cells with an agonistic anti-TIGIT mAb significantly increased apoptotic cell death of all three risky memory T cell subsets. Mechanistically, TIGIT-mediated apoptosis of risky memory T cells was dependent on FOXP3+ Treg, suggesting that agonism of the TIGIT pathway increases FOXP3+ Treg suppression of human memory T cell populations. Overall, these data suggest that TIGIT agonism could represent a new therapeutic target to inhibit belatacept-resistant rejection during transplantation.
Toll-like receptor 3 is an endogenous sensor of cell death and a potential target for induction of long-term cardiac transplant survival
Jiangqi Zhao,Xuyan Huang,Patrick Mcleod,Jifu Jiang,Winnie Liu,Aaron Haig,Anthony M. Jevnikar,Zhenyu Jiang,Zhu-Xu Zhang
doi : 10.1111/ajt.16584
Volume 21, Issue 10 p. 3268-3279
Inflammation posttransplant is directly linked to cell death programs including apoptosis and necrosis. Cell death leads to the release of cellular contents which can promote inflammation. Targeting of these pathways should be an effective strategy to prevent transplant rejection. Toll-like receptor 3 (TLR3) is emerging as a major endogenous sensor of inflammation. In this study, we assessed the role of TLR3 on cell death and transplant rejection. We showed that TLR3 is highly expressed on mouse microvascular endothelial cell (ECs) and the endothelium of cardiac grafts. We demonstrated that TLR3 interacting with dsRNA or self-RNA triggered apoptosis and necroptosis in ECs. Interestingly, TLR3-induced necroptosis led mitochondrial damage. Inhibition of the mitochondrial membrane permeability molecule Cyclophilin D prevented necroptosis in ECs. In vivo, endothelium damage and activities of caspase-3 and mixed lineage kinase domain-like protein were inhibited in TLR3?/? cardiac grafts compared with C57BL/6 grafts posttransplant (n = 5, p < .001). Importantly, TLR3?/? cardiac grafts had prolonged survival in allogeneic BALB/c mice (mean survival = 121 ± 67 vs. 31 ± 6 days of C57BL/6 grafts, n = 7, p = .002). In summary, our study suggests that TLR3 is an important cell death inducer in ECs and cardiac grafts and thus a potential therapeutic target in preventing cardiac transplant rejection.
miR-21 antagonism reprograms macrophage metabolism and abrogates chronic allograft vasculopathy
Vera Usuelli,Moufida Ben Nasr,Francesca D'Addio,Kaifeng Liu,Andrea Vergani,Basset El Essawy,Jun Yang,Emma Assi,Mayuko Uehara,Chiara Rossi,Anna Solini,Annalisa Capobianco,Elena Rigamonti,Luciano Potena,Massimo Venturini,Mario Sabatino,Lorena Bottarelli,Enrico Ammirati,Maria Frigerio,Eduardo Castillo-Leon,Anna Maestroni,Cinzia Azzoni,Cristian Loretelli,Andy Joe Seelam,Albert K. Tai,Ida Pastore,Gabriella Becchi,Domenico Corradi,Gary A. Visner,Gian V. Zuccotti,Nelson B. Chau,Reza Abdi,Marcus G. Pezzolesi,Paolo Fiorina
doi : 10.1111/ajt.16581
Volume 21, Issue 10 p. 3280-3295
Despite much progress in improving graft outcome during cardiac transplantation, chronic allograft vasculopathy (CAV) remains an impediment to long-term graft survival. MicroRNAs (miRNAs) emerged as regulators of the immune response. Here, we aimed to examine the miRNA network involved in CAV. miRNA profiling of heart samples obtained from a murine model of CAV and from cardiac-transplanted patients with CAV demonstrated that miR-21 was most significantly expressed and was primarily localized to macrophages. Interestingly, macrophage depletion with clodronate did not significantly prolong allograft survival in mice, while conditional deletion of miR-21 in macrophages or the use of a specific miR-21 antagomir resulted in indefinite cardiac allograft survival and abrogated CAV. The immunophenotype, secretome, ability to phagocytose, migration, and antigen presentation of macrophages were unaffected by miR-21 targeting, while macrophage metabolism was reprogrammed, with a shift toward oxidative phosphorylation in naïve macrophages and with an inhibition of glycolysis in pro-inflammatory macrophages. The aforementioned effects resulted in an increase in M2-like macrophages, which could be reverted by the addition of L-arginine. RNA-seq analysis confirmed alterations in arginase-associated pathways associated with miR-21 antagonism. In conclusion, miR-21 is overexpressed in murine and human CAV, and its targeting delays CAV onset by reprogramming macrophages metabolism.
Correcting the sex disparity in MELD-Na
Nicholas L. Wood,Douglas VanDerwerken,Dorry L. Segev,Sommer E. Gentry
doi : 10.1111/ajt.16731
Volume 21, Issue 10 p. 3296-3304
MELD-Na appears to disadvantage women awaiting liver transplant by underestimating their mortality rate. Fixing this problem involves: (1) estimating the magnitude of this disadvantage separately for each MELD-Na, (2) designing a correction for each MELD-Na, and (3) evaluating corrections to MELD-Na using simulated allocation. Using Kaplan-Meier modeling, we calculated 90-day without-transplant survival for men and women, separately at each MELD-Na. For most scores between 15 and 35, without-transplant survival was higher for men by 0–5 percentage points. We tested two proposed corrections to MELD-Na (MELD-Na-MDRD and MELD-GRAIL-Na), and one correction we developed (MELD-Na-Shift) to target the differences we quantified in survival across the MELD-Na spectrum. In terms of without-transplant survival, MELD-Na-MDRD overcorrected sex differences while MELD-GRAIL-Na and MELD-Na-Shift eliminated them. Estimating the impact of implementing these corrections with the liver simulated allocation model, we found that MELD-Na-Shift alone eliminated sex disparity in transplant rates (p = 0.4044) and mortality rates (p = 0.7070); transplant rates and mortality rates were overcorrected by MELD-Na-MDRD (p = 0.0025, p = 0.0006) and MELD-GRAIL-Na (p = 0.0079, p = 0.0005). We designed a corrected MELD-Na that eliminates sex disparities in without-transplant survival, but allocation changes directing smaller livers to shorter candidates may also be needed to equalize women's access to liver transplant.
MELD is MELD is MELD? Transplant center–level variation in waitlist mortality for candidates with the same biological MELD
Tanveen Ishaque,Amber B. Kernodle,Jennifer D. Motter,Kyle R. Jackson,Teresa P. Chiang,Samantha Getsin,Brian J. Boyarsky,Jacqueline Garonzik-Wang,Sommer E. Gentry,Dorry L. Segev,Allan B. Massie
doi : 10.1111/ajt.16603
Volume 21, Issue 10 p. 3305-3311
Recently, model for end-stage liver disease (MELD)-based liver allocation in the United States has been questioned based on concerns that waitlist mortality for a given biologic MELD (bMELD), calculated using laboratory values alone, might be higher at certain centers in certain locations across the country. Therefore, we aimed to quantify the center-level variation in bMELD-predicted mortality risk. Using Scientific Registry of Transplant Recipients (SRTR) data from January 2015 to December 2019, we modeled mortality risk in 33 260 adult, first-time waitlisted candidates from 120 centers using multilevel Poisson regression, adjusting for sex, and time-varying age and bMELD. We calculated a "MELD correction factor" using each center's random intercept and bMELD coefficient. A MELD correction factor of +1 means that center's candidates have a higher-than-average bMELD-predicted mortality risk equivalent to 1 bMELD point. We found that the “MELD correction factor” median (IQR) was 0.03 (?0.47, 0.52), indicating almost no center-level variation. The number of centers with “MELD correction factors” within ±0.5 points, and between ±0.5–± 1, ±1.0–±1.5, and ±1.5–±2.0 points was 62, 41, 13, and 4, respectively. No centers had waitlisted candidates with a higher-than-average bMELD-predicted mortality risk beyond ±2 bMELD points. Given that bMELD similarly predicts waitlist mortality at centers across the country, our results support continued MELD-based prioritization of waitlisted candidates irrespective of center.
Clinical parameters and biomarkers predicting spontaneous operational tolerance after liver transplantation: A scoping review
Christian Appenzeller-Herzog,Steffen Hartleif,Julien Vionnet
doi : 10.1111/ajt.16585
Volume 21, Issue 10 p. 3312-3323
Indefinite allograft acceptance after immunosuppression withdrawal (ISW), also known as operational tolerance (OT), can occur spontaneously after liver transplantation (LT), but reliable and reproducible prognosis of OT versus non-OT outcomes remains elusive. To prime this, systematic extraction of OT-predictive factors from the literature is crucial. We provide the first comprehensive identification and synthesis of clinical parameters and biomarkers predicting spontaneous OT in non-autoimmune/non-replicative viral LT recipients selected for ISW. We searched Embase, Medline, the Cochrane Central Register of Controlled Trials, clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform for articles, conference abstracts, and ongoing trials. We contacted principal investigators of stand-alone abstracts and ongoing trials for unpublished data and screened citations and references of eligible articles. Twenty-three articles reporting on 11 completed ISW studies, 13 abstracts, and five trial registry entries were included. Longer time between LT and ISW was the only clinical parameter that may increase the incidence of OT. Prognostic biomarkers conspicuously differed between pediatric and adult ISW candidates. These included allograft gene expression patterns and peripheral blood immune exhaustion markers for adults, and histological allograft scores for children. Our results will foster cross-validation efforts to facilitate safe and harmonized candidate selection for successful ISW.
Sleeve gastrectomy prior to liver transplantation is superior to medical weight loss in reducing posttransplant metabolic complications
Suzanne R. Sharpton,Norah A. Terrault,Mehdi M. Tavakol,Andrew M. Posselt
doi : 10.1111/ajt.16583
Volume 21, Issue 10 p. 3324-3332
Strategies to optimize the management of obesity-related metabolic complications after liver transplantation (LT) are needed. We examined the effect of pre-LT sleeve gastrectomy (SG), as compared to medical weight loss (MWL), on post-LT outcomes. This is a cohort study of adults (?18 years) with medically complicated obesity who were eligible for pre-LT SG and underwent LT from January 1, 2006 to June 1, 2016. Logistic regression models evaluated the association of SG on post-LT diabetes and hypertension, defined as new-onset or progressive disease post-LT. Cox regression models evaluated the association of SG on recurrent and de novo nonalcoholic fatty liver disease (NAFLD). Among 70 LT recipients who were eligible for pre-LT SG, 14 (20%) underwent SG and 56 (80%) underwent MWL only. Mean follow-up was 5.2 years post-LT. The SG cohort sustained higher % total body weight loss at 3 years post-LT (28.9% vs. 5.4%, p < .001). In multivariable analyses, SG was associated with significantly lower risk of post-LT diabetes (OR 0.04, 95% CI 0.00–0.41, p = .01), hypertension (OR 0.15, 95% CI 0.04–0.67, p = .01), and recurrent and de novo NAFLD (HR 0.19, 95% CI 0.04–0.91, p = .04). When compared to MWL, SG resulted in sustained weight loss and significantly lower risk of diabetes, hypertension, and recurrent and de novo NAFLD post-LT.
Ambient air pollution and posttransplant outcomes among kidney transplant recipients
Yijing Feng,Miranda R. Jones,JiYoon B. Ahn,Jacqueline M. Garonzik-Wang,Dorry L. Segev,Mara McAdams-DeMarco
doi : 10.1111/ajt.16605
Volume 21, Issue 10 p. 3333-3345
Fine particulate matter (PM2.5), a common form of air pollution which can induce systemic inflammatory response, is a risk factor for adverse health outcomes. Kidney transplant (KT) recipients are likely vulnerable to PM2.5 due to comorbidity and chronic immunosuppression. We sought to quantify the association between PM2.5 and post-KT outcomes. For adult KT recipients (1/1/2010–12/31/2016) in the Scientific Registry of Transplant Recipients, we estimated annual zip-code level PM2.5 concentrations at the time of KT using NASA's SEDAC Global PM2.5 Grids. We determined the associations between PM2.5 and delayed graft function (DGF) and 1-year acute rejection using logistic regression and death-censored graft failure (DCGF) and mortality using Cox proportional hazard models. All models were adjusted for sociodemographics, recipient, transplant, and ZIP code level confounders. Among 87 233 KT recipients, PM2.5 was associated with increased odds of DGF (OR = 1.59; 95% CI: 1.48–1.71) and 1-year acute rejection (OR = 1.31; 95% CI: 1.17–1.46) and increased risk of all-cause mortality (HR = 1.15; 95% CI: 1.07–1.23) but not DCGF (HR = 1.05; 95% CI: 0.97–1.51). In conclusion, PM2.5 was associated with higher odds of DGF and 1-year acute rejection and elevated risk of mortality among KT recipients. Our study highlights the importance of considering environmental exposure as risk factors for post-KT outcomes.
Effect of delayed graft function on longer-term outcomes after kidney transplantation from donation after circulatory death donors in the United Kingdom: A national cohort study
Benedict L. Phillips,Maria Ibrahim,George H. B. Greenhall,Lisa Mumford,Anthony Dorling,Chris J. Callaghan
doi : 10.1111/ajt.16574
Volume 21, Issue 10 p. 3346-3355
Kidneys from donation after circulatory death (DCD) donors are utilized variably worldwide, in part due to high rates of delayed graft function (DGF) and putative associations with adverse longer-term outcomes. We aimed to determine whether the presence of DGF and its duration were associated with poor longer-term outcomes after kidney transplantation from DCD donors. Using the UK transplant registry, we identified 4714 kidney-only transplants from controlled DCD donors to adult recipients between 2006 and 2016; 2832 recipients (60·1%) had immediate graft function and 1882 (39·9%) had DGF. Of the 1847 recipients with DGF duration recorded, 926 (50·1%) had DGF < 7 days, 576 (31·2%) had DGF 7–14 days, and 345 (18·7%) had DGF >14 days. After risk adjustment, the presence of DGF was not associated with inferior long-term graft or patient survivals. However, DGF duration of >14 days was associated with an increased risk of death-censored graft failure (hazard ratio 1·7, p = ·001) and recipient death (hazard ratio 1·8, p < ·001) compared to grafts with immediate function. This study suggests that shorter periods of DGF have no adverse influence on graft or patient survival after DCD donor kidney transplantation and that DGF >14 days is a novel early biomarker for significantly worse longer-term outcomes.
The ViKTORIES trial: A randomized, double-blind, placebo-controlled trial of vitamin K supplementation to improve vascular health in kidney transplant recipients
Jennifer S. Lees,Alastair J. Rankin,Keith A. Gillis,Luke Y. Zhu,Kenneth Mangion,Elaine Rutherford,Giles H. Roditi,Miles D. Witham,Donna Chantler,Maurizio Panarelli,Alan G. Jardine,Patrick B. Mark
doi : 10.1111/ajt.16566
Volume 21, Issue 10 p. 3356-3368
Premature cardiovascular disease and death with a functioning graft are leading causes of death and graft loss, respectively, in kidney transplant recipients (KTRs). Vascular stiffness and calcification are markers of cardiovascular disease that are prevalent in KTR and associated with subclinical vitamin K deficiency. We performed a single-center, phase II, parallel-group, randomized, double-blind, placebo-controlled trial (ISRCTN22012044) to test whether vitamin K supplementation reduced vascular stiffness (MRI-based aortic distensibility) or calcification (coronary artery calcium score on computed tomography) in KTR over 1 year of treatment. The primary outcome was between-group difference in vascular stiffness (ascending aortic distensibility). KTRs were recruited between September 2017 and June 2018, and randomized 1:1 to vitamin K (menadiol diphosphate 5 mg; n = 45) or placebo (n = 45) thrice weekly. Baseline demographics, clinical history, and immunosuppression regimens were similar between groups. There was no impact of vitamin K on vascular stiffness (treatment effect ?0.23 [95% CI ?0.75 to 0.29] × 10?3 mmHg?1; p = .377), vascular calcification (treatment effect ?141 [95% CI ? 320 to 38] units; p = .124), nor any other outcome measure. In this heterogeneous cohort of prevalent KTR, vitamin K supplementation did not reduce vascular stiffness or calcification over 1 year. Improving vascular health in KTR is likely to require a multifaceted approach.
Perspectives of solid organ transplant recipients on medicine-taking: Systematic review of qualitative studies
James Tang,Jasmijn Kerklaan,Germaine Wong,Martin Howell,Nicole Scholes-Robertson,Chandana Guha,Ayano Kelly,Allison Tong
doi : 10.1111/ajt.16613
Volume 21, Issue 10 p. 3369-3387
Medicine-taking among transplant recipients is a complex and ubiquitous task with significant impacts on outcomes. This study aimed to describe the perspectives and experiences of medicine-taking in adult solid organ transplant recipients. Electronic databases were searched to July 2020, and thematic synthesis was used to analyze the data. From 119 studies (n = 2901), we identified six themes: threats to identity and ambitions (impaired self-image, restricting goals and roles, loss of financial independence); navigating through uncertainty and distrust (lacking tangible/perceptible benefits, unprepared for side effects, isolation in decision-making); alleviating treatment burdens (establishing and mastering routines, counteracting side effects, preparing for the unexpected); gaining and seeking confidence (clarity with knowledge, reassurance through collective experiences, focusing on the future outlook); recalibrating to a new normal posttransplant (adjusting to ongoing dependence on medications, in both states of illness and health, unfulfilled expectations); and preserving graft survival (maintaining the ability to participate in life, avoiding rejection, enacting a social responsibility of giving back). Transplant recipients take medications to preserve graft function, but dependence on medications jeopardizes their sense of normality. Interventions supporting the adaptation to medicine-taking and addressing treatment burdens may improve patient satisfaction and capacities to take medications for improved outcomes.
Transplantation for pulmonary arterial hypertension with congenital heart disease: Impact on outcomes of the current therapeutic approach including a high-priority allocation program
Sébastien Hascoët,Margaux Pontailler,Jérôme Le Pavec,Laurent Savale,Olaf Mercier,Dominique Fabre,Sacha Mussot,Gérald Simonneau,Xavier Jais,Séverine Feuillet,Francois Stephan,Sarah Cohen,Damien Bonnet,Marc Humbert,Philippe Dartevelle,Elie Fadel
doi : 10.1111/ajt.16600
Volume 21, Issue 10 p. 3388-3400
Patients with end-stage pulmonary arterial hypertension due to congenital heart disease have limited access to heart-lung transplantation or double-lung transplantation. We aimed to assess the effects of a high-priority allocation program established in France in 2007. We conducted a retrospective study to compare waitlist and posttransplantation outcomes before versus after implementation of the high-priority allocation program. We included 67 consecutive patients (mean age at listing, 33.2 ± 10.5 years) with pulmonary arterial hypertension due to congenital heart disease listed for heart-lung transplantation or double-lung transplantation from 1997 to 2016. At one month, the incidences of transplantation and death before transplantation were 3.5% and 24.6% in 1997–2006, 4.8% and 4.9% for patients on the regular list in 2007–2016, and 41.2% and 7.4% for patients listed under the high-priority allocation program (p < .001 and p = .0001, respectively). Overall survival was higher in patients listed in 2007–2016 (84.2% and 61.2% at 1 and 10 years vs. 36.8% and 22.1%, p = .0001). Increased incidence of transplantation, decreased waiting list mortality, and improved early and long-term outcomes were observed in patients with pulmonary arterial hypertension due to congenital heart disease listed for transplantation in the recent era, characterized by implementation of a high-priority allocation program.
Correlation between BAL CXCR3 chemokines and lung allograft histopathologies: A multicenter study
Michael Y. Shino,Ning Li,Jamie L. Todd,Megan L. Neely,Jerry Kirchner,Heather Kopetskie,Michelle L. Sever,Courtney W. Frankel,Laurie D. Snyder,Elizabeth N. Pavlisko,Tereza Martinu,Lianne G. Singer,Wayne Tsuang,Marie Budev,Pali D. Shah,John M. Reynolds,Nikki Williams,Mark A. Robien,Scott M. Palmer,Stephen Sam Weigt,John A. Belperio
doi : 10.1111/ajt.16601
Volume 21, Issue 10 p. 3401-3410
The histopathologic diagnosis of acute allograft injury is prognostically important in lung transplantation with evidence demonstrating a strong and consistent association between acute rejection (AR), acute lung injury (ALI), and the subsequent development of chronic lung allograft dysfunction (CLAD). The pathogenesis of these allograft injuries, however, remains poorly understood. CXCL9 and CXCL10 are CXC chemokines induced by interferon-? and act as potent chemoattractants of mononuclear cells. We hypothesized that these chemokines are involved in the mononuclear cell recruitment associated with AR and ALI. We further hypothesized that the increased activity of these chemokines could be quantified as increased levels in the bronchoalveolar lavage fluid. In this prospective multicenter study, we evaluate the incidence of histopathologic allograft injury development during the first-year post-transplant and measure bronchoalveolar CXCL9 and CXCL10 levels at the time of the biopsy. In multivariable models, CXCL9 levels were 1.7-fold and 2.1-fold higher during AR and ALI compared with “normal” biopsies without histopathology. Similarly, CXCL10 levels were 1.6-fold and 2.2-fold higher during these histopathologies, respectively. These findings support the association of CXCL9 and CXCL10 with episodes of AR and ALI and provide potential insight into the pathogenesis of these deleterious events.
Metabolic measures before surgery and long-term diabetes outcomes in recipients of total pancreatectomy and islet autotransplantation
Yoshihide Nanno,Solvejg Wastvedt,Martin L. Freeman,Guru Trikudanathan,Sarah J. Schwarzenberg,Elissa M. Downs,Varvara A. Kirchner,Timothy L. Pruett,Gregory J. Beilman,Srinath Chinnakotla,Bernhard J. Hering,Melena D. Bellin
doi : 10.1111/ajt.16573
Volume 21, Issue 10 p. 3411-3420
In this single-center, retrospective cohort study, we aimed to elucidate simple metabolic markers or surrogate indices of ?-cell function that best predict long-term insulin independence and goal glycemic HbA1c control (HbA1c ? 6.5%) after total pancreatectomy with islet autotransplantation (TP-IAT). Patients who underwent TP-IAT (n = 371) were reviewed for metabolic measures before TP-IAT and for insulin independence and glycemic control at 1, 3, and 5 years after TP-IAT. Insulin independence and goal glycemic control were achieved in 33% and 68% at 1 year, respectively. Although the groups who were insulin independent and dependent overlap substantially on baseline measures, an individual who has abnormal glycemia (prediabetes HbA1c or fasting glucose) or estimated IEQs/kg < 2500 has a very high likelihood of remaining insulin dependent after surgery. In multivariate logistic regression modelling, metabolic measures correctly predicted insulin independence in about 70% of patients at 1, 3, and 5 years after TP-IAT. In conclusion, metabolic testing measures before surgery are highly associated with diabetes outcomes after TP-IAT at a population level and correctly predict outcomes in approximately two out of three patients. These findings may aid in prognostic counseling for chronic pancreatitis patients who are likely to eventually need TP-IAT.
Single-stage long-segment tracheal transplantation
Eric M. Genden,Brett A. Miles,Timothy J. Harkin,Samuel DeMaria,Andrew J. Kaufman,Erica Mayland,Vivian F. Kaul,Sander S. Florman
doi : 10.1111/ajt.16752
Volume 21, Issue 10 p. 3421-3427
Tracheal transplantation has been envisioned as a viable option for reconstruction of long-segment tracheal defects. We report the first human single-stage long-segment tracheal transplantation. Narrow-band imaging and bronchoscopic biopsies demonstrate allograft vascularization and viable epithelial lining. The recipient was immunosuppressed with Tacrolimus, Mycophenolate mofetil, and corticosteroids. Six months after transplantation, the trachea is both functional and the patient is breathing without the need of a tracheostomy or stent.
Significant hospitalization cost savings to the payer with a pharmacist-led mobile health intervention to improve medication safety in kidney transplant recipients
David J. Taber,James N. Fleming,Zemin Su,Patrick Mauldin,John W McGillicuddy,Aurora Posadas,Mulugeta Gebregziabher
doi : 10.1111/ajt.16737
Volume 21, Issue 10 p. 3428-3435
This was an economic analysis of a 12-month, parallel arm, randomized controlled trial in adult kidney recipients 6 to 36 months posttransplant (NCT03247322). All participants received usual posttransplant care, while the intervention arm received supplemental clinical pharmacist-led medication therapy monitoring and management, via a smartphone-enabled mHealth app, integrated with risk-based televisits. Hospitalization charges were captured from the study institution accounts payable and non-study institution hospitalization charges were estimated using multiple imputation. Multivariable modeling was used to assess the impact of the intervention on charges. The intervention significantly reduced rates of hospitalization (1.08 per patient-year in the control arm vs 0.65 per patient-year in the intervention arm, p = .007). The control arm had estimated hospitalization costs of $870,468 vs $390,489 in the intervention arm. Modeling demonstrated a 49% lower hospitalization charge risk in the intervention arm (RR 0.51, 95% CI 0.28-0.91; p = .022). From a payer or societal perspective, the net estimated cost savings, after accounting for intervention delivery costs, was $368,839, with a return on investment (ROI) of $4.30 for every $1 spent. These results demonstrate that a mHealth-enabled, pharmacist-led intervention significantly reduced hospitalization costs for payers over a 12-month period and has a positive ROI.
Febrile neutropenia after kidney transplantation
Geoffrey K. Dube,Heather K. Morris,Russell J. Crew,Marcus R. Pereira,David J. Cohen,Sumit Mohan,Syed A. Husain
doi : 10.1111/ajt.16714
Volume 21, Issue 10 p. 3436-3443
Neutropenia is common after kidney transplant. There are few data on febrile neutropenia episodes (FNE) after kidney transplant. We studied FNE in a single-center retrospective cohort of 1682 kidney transplant recipients. Neutropenia (absolute neutrophil count [ANC] <1000) occurred in 32% and FNE in 3%. There were 56 FNE. Median time to FNE was 143 days, and median time from onset of neutropenia to onset of FNE was 5.5 days. The most common sources of infection were urine, blood, and lungs, and in 20% of FNE no source was identified. No infectious organism was identified in 46% of FNE, and opportunistic infections were uncommon. Patient survival was similar among those with and without FNE, but FNE was associated with increased death-censored graft failure (DCGF). Following FNE, acute rejection occurred in 31% and DCGF in 15%, often in the setting of persistent reduced immunosuppression. In conclusion, FNE are common after kidney transplant and are associated with inferior long-term outcomes.
Long-term outcomes of sensitized lung transplant recipients after peri-operative desensitization
Meghan Aversa,Tereza Martinu,Christopher Patriquin,Marcelo Cypel,David Barth,Rasheed Ghany,Jin Ma,Shaf Keshavjee,Lianne G. Singer,Kathryn Tinckam
doi : 10.1111/ajt.16707
Volume 21, Issue 10 p. 3444-3448
The Toronto Lung Transplant Program has been using a peri-operative desensitization regimen of plasma exchange, intravenous immune globulin, and antithymocyte globulin in order to accept donor-specific antibody (DSA)-positive lung transplants safely since 2008. There are no long-term data on the impact of this practice on allograft survival or the development of chronic lung allograft dysfunction (CLAD). We extended our prior study to include long-term follow-up of 340 patients who received lung transplants between January 1, 2008 and December 31, 2011. We compared allograft survival and CLAD-free survival among patients in three cohorts: DSA-positive, panel reactive antibody (PRA)-positive/DSA-negative, and unsensitized at the time of transplant. The median follow-up time in this extension study was 6.7 years. Among DSA-positive, PRA-positive/DSA-negative, and unsensitized patients, the median allograft survival was 8.4, 7.9, and 5.8 years, respectively (p = .5908), and the median CLAD-free survival was 6.8, 7.3, and 5.7 years, respectively (p = .5448). This follow-up study confirms that long-term allograft survival and CLAD-free survival of patients who undergo DSA-positive lung transplants with the use of our protocol do not differ from other lung transplant recipients. Use of protocols such as ours, therefore, may improve access to transplant for sensitized candidates.
Letermovir in lung transplant recipients with cytomegalovirus infection: A retrospective observational study
Tobias Veit,Dieter Munker,Jürgen Barton,Katrin Milger,Teresa Kauke,Bruno Meiser,Sebastian Michel,Michael Zoller,Hans Nitschko,Oliver T. Keppler,Jürgen Behr,Nikolaus Kneidinger
doi : 10.1111/ajt.16718
Volume 21, Issue 10 p. 3449-3455
Letermovir is a new antiviral drug approved for the prophylaxis of CMV infection in allogeneic stem cell transplants. The aim of the study was to assess the therapeutic efficacy of letermovir in difficult to treat CMV infections in lung transplant recipients. All lung transplant recipients between March 2018 and August 2020, who have been treated with letermovir for ganciclovir-resistant or refractory CMV infection were included in the study and analysed retrospectively. In total, 28 patients were identified. CMV disease was present in 15 patients (53.6%). In 23 patients (82.1%), rapid response was noticed, and CMV-viral load could be significantly decreased (>1 log10) after a median of 17 [14–27] days and cleared subsequently in all of these patients. Five patients (17.9%) were classified as non-responder. Thereof, development of a mutation of the CMV UL56 terminase (UL-56-Gen: C325Y) conferring letermovir resistance could be observed in three patients (60%). Common side effects were mild and mostly of gastrointestinal nature. Mild adjustments of the immunosuppressive drugs were mandatory upon treatment initiation with letermovir. In addition to other interventions, letermovir was effective in difficult to treat CMV infections in lung transplant recipients. However, in patients with treatment failure mutation conferring letermovir, resistance should be taken into account.
Bilateral lung transplantation during pregnancy after ECMO for influenza-A caused ARDS
Philipp Foessleitner,Konrad Hoetzenecker,Alberto Benazzo,Katrin Klebermass-Schrehof,Anke Scharrer,Herbert Kiss,Alex Farr
doi : 10.1111/ajt.16781
Volume 21, Issue 10 p. 3456-3460
Pregnant women with influenza-A have an increased risk of developing acute respiratory distress syndrome (ARDS). Extracorporeal membrane oxygenation (ECMO) can be used as salvage therapy, with lung transplantation as a therapeutic option. However, successful bilateral lung transplantation during pregnancy has never been reported before. We herein report the case of a 34-year-old primipara, who was diagnosed with ARDS caused by influenza-A-induced pneumonia at early gestation. After considering all possible therapeutic options and being fully dependent on VV-ECMO support, she underwent bilateral lung transplantation. The transplantation with intraoperative central VA-ECMO support was successfully performed with good recovery after an initial primary graft dysfunction. The pregnancy was prolonged until 29+5 gestational weeks. The newborn exhibited growth retardation and was initially stabilized, but later died due to severe, hypoxic respiratory failure and pulmonary hypertension. In conclusion, lung transplantation is a possible salvage therapy for patients with severe lung failure following ARDS during pregnancy. However, it places the mother and unborn child at risk. A multi-professional approach is warranted to diagnose and treat complications at an early stage.
Pediatric living-donor lobar lung transplantation in postpneumonectomy-like anatomy caused by pulmonary hypoplasia with congenital diaphragmatic hernia
Nobuyuki Yoshiyasu,Masaaki Sato,Chihiro Konoeda,Jun Nakajima
doi : 10.1111/ajt.16626
Volume 21, Issue 10 p. 3461-3464
When performing living-donor lobar lung transplantation on small children of height 100 cm or under, accommodation of an oversized adult lobar graft is problematic, sometimes necessitating single lobar transplantation in combination with contralateral pneumonectomy. We here report a unique case of living-donor lobar lung transplantation in a 9-year-old boy with congenital pulmonary hypoplasia. Although he was 104 cm tall, and the available adult lower lobe graft appeared to be oversized, his right lung was hypoplastic, resulting in his mediastinum being shifted to the right and thus already showing “postpneumonectomy-like” anatomy. His father's left lower lobe was successfully transplanted into the left thorax without performing a contralateral pneumonectomy. Three-dimensional reconstruction of computed tomography images and computed tomography volumetry were extremely helpful in matching the size of the graft and planning this unique surgery.
Successful treatment of Epstein–Barr virus–associated primary central nervous system lymphoma due to post-transplantation lymphoproliferative disorder, with ibrutinib and third-party Epstein–Barr virus–specific T cells
Soi C. Law,Thanh Hoang,Kacey O'Rourke,Joshua W. D. Tobin,Jay Gunawardana,Dorothy Loo-Oey,Karolina Bednarska,Lilia Merida de Long,Muhammed B. Sabdia,Greg Hapgood,Emily Blyth,Leighton Clancy,Stefanie Hennig,Colm Keane,Maher K. Gandhi
doi : 10.1111/ajt.16628
Volume 21, Issue 10 p. 3465-3471
Primary central nervous system lymphoma (PCNSL) occurring following organ transplantation (post-transplantation lymphoproliferative disorder [PTLD]) is a highly aggressive non-Hodgkin lymphoma. It is typically treated with high-dose methotrexate-based regimens. Outcomes are dismal and clinical trials are lacking. It is almost always Epstein–Barr virus (EBV) associated. Two patients (CA1-2) presented with EBV-associated PCNSL after renal transplant. CA1 was on hemodialysis and had prior disseminated cryptococcus and pseudomonas bronchiectasis, precluding treatment with methotrexate. CA2 was refractory to methotrexate. Both were treated off-label with the first-generation Bruton's tyrosine kinase inhibitor ibrutinib for 12 months. Cerebrospinal fluid penetration at therapeutic levels was confirmed in CA1 despite hemodialysis. Both patients entered remission by 2 months. Sequencing confirmed absence of genetic aberrations in human leukocyte antigen (HLA) class I/II and antigen-presentation/processing genes, indicating retention of the ability to present EBV-antigens. Between Weeks 10 and 13, they received third-party EBV-specific T cells for consolidation with no adverse effects. They remain in remission ?34 months since therapy began. The strength of these findings led to an ongoing phase I study (ACTRN12618001541291).
Full facial retransplantation in a female patient—Technical, immunologic, and clinical considerations
Martin Kauke,Adriana C. Panayi,Ali-Farid Safi,Valentin Haug,Bridget Perry,Branislav Kollar,Marie-Christine Nizzi,Justin Broyles,Donald J. Annino,Francisco M. Marty,Indranil Sinha,Christine G. Lian,George F. Murphy,Anil Chandraker,Bohdan Pomahac
doi : 10.1111/ajt.16696
Volume 21, Issue 10 p. 3472-3480
There is limited experience with facial retransplantation (fRT). We report on the management of facial retransplantation in a facial vascularized composite allotransplant recipient following irreversible allograft loss 88 months after the first transplant. Chronic antibody-mediated rejection and recurrent cellular rejection resulted in a deteriorated first allograft and the patient underwent retransplantation. We summarize the events between the two transplantations, focusing on the final rejection episode. We describe the surgical technique of facial retransplantation, the immunological and psychosocial management, and the 6-month postoperative outcomes. Removal of the old allograft and inset of the new transplant were done in one operation. The donor and recipient were a good immunological match. The procedure was technically complex, requiring more proximal arterial anastomoses and an interposition vein graft. During the first and second transplantation, the facial nerve was coapted at the level of the branches. There was no hyperacute rejection in the immediate postoperative phase. Outcomes 6 months postoperatively are promising. We provide proof-of-concept that facial retransplantation is a viable option for patients who suffer irreversible facial vascularized composite allograft loss.
Changes in influenza and other respiratory virus activity during the COVID-19 pandemic—United States, 2020–2021
Sonja J. Olsen,Amber K. Winn,Alicia P. Budd,Mila M. Prill,John Steel,Claire M. Midgley,Krista Kniss,Erin Burns,Thomas Rowe,Angela Foust,Gabriela Jasso,Angiezel Merced-Morales,C. Todd Davis,Yunho Jang,Joyce Jones,Peter Daly,Larisa Gubareva,John Barnes,Rebecca Kondor,Wendy Sessions,Catherine Smith,David E. Wentworth,Shikha Garg,Fiona P. Havers,Alicia M. Fry,Aron J. Hall,Lynnette Brammer,Benjamin J. Silk
doi : 10.1111/ajt.16049
Volume 21, Issue 10 p. 3481-3486
Clinical xenotransplantation: Pathways and progress in the transplantation of organs and tissues between species , Cooper David, K.C., Byrne, Guerard, Basel, Switzerland: Springer International Publishing, 2020, 306 pages
Peter J. Cowan
doi : 10.1111/ajt.16630
Volume 21, Issue 10 p. 3487-3487
Tongue ulcer in a pediatric heart transplant recipient
Elizabeth H. Ristagno,Jonathan N. Johnson,Shelagh A. Cofer
doi : 10.1111/ajt.16698
Volume 21, Issue 10 p. 3488-3490
Racial and sex representation in clinical trials: Where are we in abdominal organ transplantation?
Aaron Zaldana,Sarah Barhouma,Brittany Rocque,Arianna Barbetta,Cameron Goldbeck,Linda Sher,Juliet Emamaullee
doi : 10.1111/ajt.16619
Volume 21, Issue 10 p. 3491-3493
In with the new and, mostly better: Considering the OPTN blood-borne virus policy updates
James B. Hendele,Ajit P. Limaye,Lena Sibulesky
doi : 10.1111/ajt.16688
Volume 21, Issue 10 p. 3494-3495
COVID-19 infection in solid organ transplant recipients after SARS-CoV-2 vaccination
Hani M. Wadei,Thomas A. Gonwa,Juan C. Leoni,Sadia Z. Shah,Nabeel Aslam,Leigh L. Speicher
doi : 10.1111/ajt.16618
Volume 21, Issue 10 p. 3496-3499
Eplet mismatch imputation studies should include immunologic risk assessment
Scott M. Krummey,Robert A. Bray,Howard M. Gebel,Harold C. Sullivan
doi : 10.1111/ajt.16562
Volume 21, Issue 10 p. 3500-3501
Second field high-resolution HLA typing for immunologic risk stratification in kidney transplantation
Aleksandar Senev,Marie-Paule Emonds,Maarten Naesens
doi : 10.1111/ajt.16606
Volume 21, Issue 10 p. 3502-3503
Accurate eplet identification is necessary for accurate risk assessment
Rachel M. Engen,Anat R. Tambur
doi : 10.1111/ajt.16612
Volume 21, Issue 10 p. 3504-3504
