American Journal of Transplantation

Despite marked progress in clinical islet and pancreas transplantation, these approaches are restricted to patients with life-threatening hypoglycemic unawareness, due to the need for lifelong immunosuppression to prevent organ rejection and shortage of donor organ availability. In the case of islet transplantation, the need for multiple donors and suboptimal long-term outcomes are often due to the heterogeneity of islet preparations. For decades, intrahepatic infusion remains the only clinical route of islet delivery to routinely yield in posttransplant insulin independence. However, it is also important to recognize that while both auto- and allo-immune-mediated rejection clearly contribute to long-term islet graft failure, mounting evidence suggests that acute islet cell death, induced by inflammatory responses in the peri-transplant period, severely compromises engraftment. These considerations suggest that the liver may not be the optimal site for islet transplantation, highlighting the need to either improve the hepatic microenvironment to enhance islet cell engraftment and survival or identify a clinically relevant, extrahepatic site to further optimize islet cell engraftment, function, and retrievability.

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Calcineurin inhibitors nephrotoxicity revisited

Nicolas Pallet

doi : 10.1111/ajt.16590

Volume 21, Issue 9 p. 2929-2930

The journey of calcineurin inhibitors (CNIs) nephrotoxicity as an entity in the field of solid organ transplantation is a complicated story. The clinical use of CNIs has always been embedded with the idea that these molecules, especially at high doses, induce arterioles vasoconstriction, kill myocytes, and promote ischemia, ultimately leading to tubular atrophy, stripped fibrosis, and ischemic glomerulosclerosis. Indeed, the approval of cyclosporine in 1983 for clinical use is fairly concomitant with the publication of the description of the histological signature of CNIs renal impregnation, a feature long thought to be specific. Since then, a great effort has been made to minimize, or even avoid the use of CNIs in modern immunosuppression protocols with the aim to reduce the risk of nephrotoxicity. Tacrolimus, approved in 1994 for use in liver transplantation, has become the drug of choice versus cyclosporine owing to a more favorable tolerability profile and a better prevention of rejection and graft loss. Regarding nephrotoxicity, several studies supported tacrolimus as less nephrotoxic than cyclosporine, although long-term outcomes studies failed to demonstrate that tacrolimus is not nephrotoxic.1 The concept of CNIs nephrotoxicity as an entity has been seriously challenged in the beginning of the 2000s after the publication of studies supporting three critical notions: (i) CNIs toxicity alone represents <1% of the causes of kidney allograft loss;2 (ii) afferent arteriolar hyalinosis (ah), long felt to be a hallmark of CNIs nephrotoxicity, is observed in patients who have never seen CNIs,3 and (iii) signs of CNIs “nephrotoxicity” (ah) may indicate adequate CNIs exposure (and maybe better outcomes).4 This sequence of events may have steamed the clinical impression that the nephrotoxic potential of these drugs had been overestimated, and above all, it may have tempered the scientific interest required to better understand the mechanisms causing CNIs nephrotoxicity, an issue far from being solved.

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Clearing the hepatitis hurdle: Obstacles and opportunities in liver transplantation for people with HIV

William A. Werbel,Christine M. Durand,

doi : 10.1111/ajt.16608

Volume 21, Issue 9 p. 2931-2932

The early experience of liver transplantation for people with HIV (PWH) was plagued by three issues: hepatitis C virus (HCV), interactions with HIV antiretroviral therapy, and organ rejection. In the first multicenter trials in the United States and Spain, liver recipients with HIV-HCV coinfection had 3-year patient and graft survival around 60%, and acute rejection rates around 40%, significantly worse than in recipients with HCV mono-infection.1, 2 These findings generated concern. Without effective antivirals for HCV, some transplant programs stopped performing liver transplants in PWH. Thus, the hurdle of HCV coinfection was a major barrier to liver transplantation for PWH.

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Bold policy changes are needed to meet the need for organ transplantation in India

Sunil Shroff,John S. Gill,

doi : 10.1111/ajt.16537

Volume 21, Issue 9 p. 2933-2936

Twenty-five years after India passed legislation to legalize brain death, deceased donor transplantation remains underdeveloped while the country has established formidable capacity for living donor transplantation. Because of a large number of potential deceased donors, there is hope that deceased donation could help meet India's enormous need for organ transplantation. However, significant policy and practical barriers limit progress. The vast majority of potential deceased donors are poor motor vehicle accident victims who present for care in hospitals without the necessary infrastructure or expertise to support deceased donation. In contrast, transplant infrastructure and expertise are concentrated in private hospitals and are only accessible to those with the ability to pay. Given these realities, the potential of deceased donor transplantation can only be recognized if Indians who are likely to donate organs are also provided access to transplantation. In this viewpoint, we review the current status of organ transplantation in India and propose new policies to establish a national organization to oversee deceased donor services in all states, to fund resources needed to support deceased donation, to leverage the existing living donor infrastructure to advance deceased donor transplantation, and call for establishment of government policy on funding for posttransplant care and immunosuppression.

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The failing kidney allograft: A review and recommendations for the care and management of a complex group of patients

Michelle Lubetzky,Ekamol Tantisattamo,Miklos Z. Molnar,Krista L. Lentine,Arpita Basu,Ronald F. Parsons,Kenneth J. Woodside,Martha Pavlakis,Christopher D. Blosser,Neeraj Singh,Beatrice P. Concepcion,Deborah Adey,Gaurav Gupta,Arman Faravardeh,Edward Kraus,Song Ong,Leonardo V. Riella,John Friedewald,Alex Wiseman,Amtul Aala,Darshana M. Dadhania,Tarek Alhamad,

doi : 10.1111/ajt.16717

Volume 21, Issue 9 p. 2937-2949

The return to dialysis after allograft failure is associated with increased morbidity and mortality. This transition is made more complex by the rising numbers of patients who seek repeat transplantation and therefore may have indications for remaining on low levels of immunosuppression, despite the potential increased morbidity. Management strategies vary across providers, driven by limited data on how to transition off immunosuppression as the allograft fails and a paucity of randomized controlled trials to support one approach over another. In this review, we summarize the current data available for management and care of the failing allograft. Additionally, we discuss a suggested plan for immunosuppression weaning based upon the availability of re-transplantation and residual allograft function. We propose a shared-care model in which there is improved coordination between transplant providers and general nephrologists so that immunosuppression management and preparation for renal replacement therapy and/or repeat transplantation can be conducted with the goal of improved outcomes and decreased morbidity in this vulnerable patient group.

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Fibroblast growth factor 7 releasing particles enhance islet engraftment and improve metabolic control following islet transplantation in mice with diabetes

Salamah M. Alwahsh,Omar Qutachi,Philip J. Starkey Lewis,Andrew Bond,June Noble,Paul Burgoyne,Nik Morton,Rod Carter,Janet Mann,Sofia Ferreira-Gonzalez,Marta Alvarez-Paino,Stuart J. Forbes,Kevin M. Shakesheff,Shareen Forbes

doi : 10.1111/ajt.16488

Volume 21, Issue 9 p. 2950-2963

Transplantation of islets in type 1 diabetes (T1D) is limited by poor islet engraftment into the liver, with two to three donor pancreases required per recipient. We aimed to condition the liver to enhance islet engraftment to improve long-term graft function. Diabetic mice received a non-curative islet transplant (n = 400 islets) via the hepatic portal vein (HPV) with fibroblast growth factor 7-loaded galactosylated poly(DL-lactide-co-glycolic acid) (FGF7-GAL-PLGA) particles; 26-µm diameter particles specifically targeted the liver, promoting hepatocyte proliferation in short-term experiments: in mice receiving 0.1-mg FGF7-GAL-PLGA particles (60-ng FGF7) vs vehicle, cell proliferation was induced specifically in the liver with greater efficacy and specificity than subcutaneous FGF7 (1.25 mg/kg ×2 doses; ~75-µg FGF7). Numbers of engrafted islets and vascularization were greater in liver sections of mice receiving islets and FGF7-GAL-PLGA particles vs mice receiving islets alone, 72 h posttransplant. More mice (six of eight) that received islets and FGF7-GAL-PLGA particles normalized blood glucose concentrations by 30-days posttransplant, versus zero of eight mice receiving islets alone with no evidence of increased proliferation of cells within the liver at this stage and normal liver function tests. This work shows that liver-targeted FGF7-GAL-PLGA particles achieve selective FGF7 delivery to the liver-promoting islet engraftment to help normalize blood glucose levels with a good safety profile.

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Bioenergetic maladaptation and release of HMGB1 in calcineurin inhibitor-mediated nephrotoxicity

Anna A. Zmijewska,Jaroslaw W. Zmijewski,Eugene J. Becker Jr.,Gloria A. Benavides,Victor Darley-Usmar,Roslyn B. Mannon,

doi : 10.1111/ajt.16561

Volume 21, Issue 9 p. 2964-2977

Calcineurin inhibitors (CNIs) are potent immunosuppressive agents, universally used following solid organ transplantation to prevent rejection. Although effective, the long-term use of CNIs is associated with nephrotoxicity. The etiology of this adverse effect is complex, and effective therapeutic interventions remain to be determined. Using a combination of in vitro techniques and a mouse model of CNI-mediated nephrotoxicity, we found that the CNIs, cyclosporine A (CsA), and tacrolimus (TAC) share a similar mechanism of tubular epithelial kidney cell injury, including mitochondrial dysfunction and release of High-Mobility Group Box I (HMGB1). CNIs promote bioenergetic reprogramming due to mitochondrial dysfunction and a shift toward glycolytic metabolism. These events were accompanied by diminished cell-to-cell adhesion, loss of the epithelial cell phenotype, and release of HMGB1. Notably, Erk1/2 inhibitors effectively diminished HMGB1 release, and similar inhibitor was observed on inclusion of pan-caspase inhibitor zVAD-FMK. In vivo, while CNIs activate tissue proremodeling signaling pathways, MAPK/Erk1/2 inhibitor prevented nephrotoxicity, including diminished HMGB1 release from kidney epithelial cells and accumulation in urine. In summary, HMGB1 is an early indicator and marker of progressive nephrotoxicity induced by CNIs. We suggest that proremodeling signaling pathway and loss of mitochondrial redox/bioenergetics homeostasis are crucial therapeutic targets to ameliorate CNI-mediated nephrotoxicity.

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Short-term therapy with anti-ICAM-1 monoclonal antibody induced long-term liver allograft survival in nonhuman primates

Suk Kyun Hong,Dongkyu Han,Sun-Kyung Lee,Jiyeon Kim,Eung-Soo Hwang,Haeryoung Kim,Jae-Il Lee,Kwangpyo Hong,Eui Soo Han,Jae-Hyung Cho,Jeong-Moo Lee,YoungRok Choi,Kwang-Woong Lee,Nam-Joon Yi,Jaeseok Yang,Kyung-Suk Suh

doi : 10.1111/ajt.16486

Volume 21, Issue 9 p. 2978-2991

Tolerance induction remains challenging following liver transplantation and the long-term use of immunosuppressants, especially calcineurin inhibitors, leads to serious complications. We aimed to test an alternative immunosuppressant, a chimeric anti-ICAM-1 monoclonal antibody, MD-3, for improving the outcomes of liver transplantation. We used a rhesus macaque liver transplantation model and monkeys were divided into three groups: no immunosuppression (n = 2), conventional immunosuppression (n = 4), and MD-3 (n = 5). Without immunosuppression, liver allografts failed within a week by acute rejection. Sixteen-week-long conventional immunosuppression that consisted of prednisolone, tacrolimus, and an mTOR inhibitor prolonged liver allograft survival; however, recipients died of acute T cell–mediated rejection (day 52), chronic rejection (days 62 and 66), or adverse effects of mTOR inhibitor (day 32). In contrast, 12-week-long MD-3 therapy with transient conventional immunosuppression in the MD-3 group significantly prolonged the survival of liver allograft recipients (5, 96, 216, 412, 730 days; p = .0483). MD-3 effectively suppressed intragraft inflammatory cell infiltration, anti-donor T cell responses, and donor-specific antibody with intact anti-cytomegalovirus antibody responses. However, this regimen ended in chronic rejection. In conclusion, short-term therapy with MD-3 markedly improved liver allograft survival to 2 years without maintenance of immunosuppressant. MD-3 is therefore a promising immune-modulating agent for liver transplantation.

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Circular RNA Foxo3 in cardiac ischemia-reperfusion injury in heart transplantation: A new regulator and target

Yale Su,Cuilin Zhu,Bowen Wang,Hao Zheng,Vivian McAlister,James C. Lacefield,Douglas Quan,Tina Mele,Adam Greasley,Kexiang Liu,Xiufen Zheng,

doi : 10.1111/ajt.16475

Volume 21, Issue 9 p. 2992-3004

Ischemia-reperfusion (I/R) injury occurring in heart transplantation (HT) remains as a leading cause of transplant heart graft failure. Circular RNAs (circRNAs) play important roles in gene regulation and diseases. However, the impact of circRNAs on I/R injury during HT remains unknown. This study aims to investigate the role of circular RNA Foxo3 (circFoxo3) in I/R injury in HT. Using an in vivo mouse HT model and an in vitro cardiomyocyte culture model, we demonstrated that circFoxo3 is significantly upregulated in I/R-injured hearts and hypoxia/reoxygenation (H/R)-damaged cardiomyocytes. Knockdown of circFoxo3 using siRNA not only reduces cell apoptosis and death, mitochondrial damage, and expression of apoptosis/death-related genes in vitro, but also protects heart grafts from prolonged cold I/R injury in HT. We also show that circFoxo3 interacts with Foxo3 proteins and inhibits the phosphorylation of Foxo3 and that it indirectly affects the expression of miR-433 and miR-136. In conclusion, circRNA is involved in I/R injury in HT and knockdown of circFoxo3 with siRNA can reduce I/R injury and improve heart graft function through interaction with Foxo3. This study highlights that circRNA is a new type of molecular regulator and a potential target for preventing I/R injury in HT.

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Risk factors and outcomes for delayed kidney graft function in simultaneous heart and kidney transplant recipients: A UNOS/OPTN database analysis

Sandesh Parajuli,Aos. S. Karim,Brenda L. Muth,Glen.E. Leverson,Qiuyu Yang,Ravi Dhingra,Jason W. Smith,David P. Foley,Didier A. Mandelbrot,

doi : 10.1111/ajt.16535

Volume 21, Issue 9 p. 3005-3013

There are no prior studies assessing the risk factors and outcomes for kidney delayed graft function (K-DGF) in simultaneous heart and kidney (SHK) transplant recipients. Using the OPTN/UNOS database, we sought to identify risk factors associated with the development of K-DGF in this unique population, as well as outcomes associated with K-DGF. A total of 1161 SHK transplanted between 1998 and 2018 were included in the analysis, of which 311 (27%) were in the K-DGF (+) group and 850 in the K-DGF (?) group. In the multivariable analysis, history of pretransplant dialysis (OR: 3.95; 95% CI: 2.94 to 5.29; p < .001) was significantly associated with the development of K-DGF, as was donor death from cerebrovascular accident and longer cold ischemia time of either organ. SHK recipients with K-DGF had increased mortality (HR: 1.99; 95% CI: 1.52 to 2.60; p < .001) and death censored kidney graft failure (HR: 3.51; 95% CI: 2.29 to 5.36; p < .001) in the multivariable analysis. Similar outcomes were obtained when limiting our study to 2008–2018. Similar to kidney-only recipients, K-DGF in SHK recipients is associated with worse outcomes. Careful matching of recipients and donors, as well as peri-operative management, may help reduce the risk of K-DGF and the associated detrimental effects.

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A world-wide survey on kidney transplantation practices in breast cancer survivors: The need for new management guidelines

Keith S. Hansen,Hila Ghersin,Merisa Piper,Mehdi Tavakol,Brian Lee,Laura J. Esserman,John P. Roberts,Chris Freise,Nancy L. Ascher,Rita A. Mukhtar,

doi : 10.1111/ajt.16483

Volume 21, Issue 9 p. 3014-3020

Kidney transplantation reduces mortality in patients with end stage renal disease (ESRD). Decisions about performing kidney transplantation in the setting of a prior cancer are challenging, as cancer recurrence in the setting of immunosuppression can result in poor outcomes. For cancer of the breast, rapid advances in molecular characterization have allowed improved prognostication, which is not reflected in current guidelines. We developed a 19-question survey to determine transplant surgeons’ knowledge, practice, and attitudes regarding guidelines for kidney transplantation in women with breast cancer. Of the 129 respondents from 32 states and 14 countries, 74.8% felt that current guidelines are inadequate. Surgeons outside the United States (US) were more likely to consider transplantation in a breast cancer patient without a waiting period (p = .017). Within the US, 29.2% of surgeons in the Western region would consider transplantation without a waiting period, versus 3.6% of surgeons in the East (p = .004). Encouragingly, 90.4% of providers surveyed would consider eliminating wait-times for women with a low risk of cancer recurrence based on the accurate prediction of molecular assays. These findings support the need for new guidelines incorporating individualized recurrence risk to improve care of ESRD patients with breast cancer.

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Rituximab for recurrence of primary focal segmental glomerulosclerosis after kidney transplantation: Results of a nationwide study

Camille Lanaret,Dany Anglicheau,Vincent Audard,Mathias Büchler,Sophie Caillard,Lionel Couzi,Paolo Malvezzi,Laurent Mesnard,Dominique Bertrand,Franck Martinez,Vincent Pernin,Didier Ducloux,Coralie Poulain,Antoine Thierry,Arnaud Del Bello,Jean P. Rerolle,Clarisse Greze,Charlotte Uro-Coste,Julien Aniort,Céline Lambert,Nicolas Bouvier,Betoul Schvartz,Nicolas Maillard,Johnny Sayegh,Julie Oniszczuk,Marie-Pascale Morin,Christophe Legendre,Nassim Kamar,Anne E. Heng,Cyril Garrouste,

doi : 10.1111/ajt.16504

Volume 21, Issue 9 p. 3021-3033

Rituximab (RTX) therapy for primary focal segmental glomerulosclerosis recurrence after kidney transplantation (KT) has been extensively debated. We aimed to assess the benefit of adding RTX to plasmapheresis (PP), corticosteroids, and calcineurin inhibitors (standard of care, SOC). We identified 148 adult patients who received KT in 12/2004–12/2018 at 21 French centers: 109 received SOC (Group 1, G1), and 39 received immediate RTX along with SOC (Group 2, G2). In G1, RTX was introduced after 28 days of SOC in the event of failure (G1a, n = 19) or PP withdrawal (G1b, n = 12). Complete remission (CR) was achieved in 46.6% of patients, and partial remission (PR) was achieved in 33.1%. The 10-year graft survival rates were 64.7% and 17.9% in responders and nonresponders, respectively. Propensity score analysis showed no difference in CR+PR rates between G1 (82.6%) and G2 (71.8%) (p = .08). Following the addition of RTX (G1a), 26.3% of patients had CR, and 31.6% had PR. The incidence of severe infections was similar between patients treated with and without RTX. In multivariable analysis, infection episodes were associated with hypogammaglobulinemia <5 g/L. RTX could be used in cases of SOC failure or remission for early discontinuation of PP without increasing the risk of infection.

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Kidney recipients with allograft failure, transition of kidney care (KRAFT): A survey of contemporary practices of transplant providers

Tarek Alhamad,Michelle Lubetzky,Krista L. Lentine,Emmanuel Edusei,Ronald Parsons,Martha Pavlakis,Kenneth J. Woodside,Deborah Adey,Christopher D. Blosser,Beatrice P. Concepcion,John Friedewald,Alexander Wiseman,Neeraj Singh,Su-Hsin Chang,Gaurav Gupta,Miklos Z. Molnar,Arpita Basu,Edward Kraus,Song Ong,Arman Faravardeh,Ekamol Tantisattamo,Leonardo Riella,Jim Rice,Darshana M. Dadhania

doi : 10.1111/ajt.16523

Volume 21, Issue 9 p. 3034-3042

Kidney allograft failure and return to dialysis carry a high risk of morbidity. A practice survey was developed by the AST Kidney Pancreas Community of Practice workgroup and distributed electronically to the AST members. There were 104 respondents who represented 92 kidney transplant centers. Most survey respondents were transplant nephrologists at academic centers. The most common approach to immunosuppression management was to withdraw the antimetabolite first (73%), while only 12% responded they would withdraw calcineurin inhibitor (CNI) first. More than 60% reported that the availability of a living donor is the most important factor in their decision to taper immunosuppression, followed by risk of infection, risk of sensitization, frailty, and side effects of medications. More than half of respondents reported that embolization was either not available or offered to less than 10% as an option for surgical intervention. Majority reported that ?50% of failed allograft patients were re-listed before dialysis, and less than a quarter of transplant nephrologists performed frequent visits with their patients with failed kidney allograft after they return to dialysis. This survey demonstrates heterogeneity in the care of patients with a failing allograft and the need for more evidence to guide improvements in clinical practice related to transition of care.

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The effect of cholecalciferol supplementation on allograft function in incident kidney transplant recipients: A randomized controlled study

Yohei Doi,Makoto Tsujita,Takayuki Hamano,Yoshitsugu Obi,Tomoko Namba-Hamano,Toshihide Tomosugi,Kenta Futamura,Manabu Okada,Takahisa Hiramitsu,Norihiko Goto,Akira Nishiyama,Asami Takeda,Shunji Narumi,Yoshihiko Watarai,Yoshitaka Isaka

doi : 10.1111/ajt.16530

Volume 21, Issue 9 p. 3043-3054

It is unknown whether cholecalciferol supplementation improves allograft outcomes in kidney transplant recipients (KTRs). We conducted a single-center randomized, double-blind, placebo-controlled trial of daily 4000 IU cholecalciferol supplementation in KTRs at 1-month posttransplant. The primary endpoint was the change in eGFR from baseline to 12-month posttransplant. Secondary endpoints included severity of interstitial fibrosis and tubular atrophy (IFTA) at 12-month posttransplant and changes in urinary biomarkers. Of 193 randomized patients, 180 participants completed the study. Changes in eGFR were 1.2 mL/min/1.73 m2 (95% CI; ?0.7 to 3.1) in the cholecalciferol group and 1.8 mL/min/1.73 m2 (95% CI, ?0.02 to 3.7) in the placebo group, with no significant between-group difference (?0.7 mL/min/1.73 m2 [95% CI; ?3.3 to 2.0], p = 0.63). Subgroup analyses showed detrimental effects of cholecalciferol in patients with eGFR <45 mL/min/1.73 m2 (Pinteraction <0.05, between-group difference; ?4.3 mL/min/1.73 m2 [95% CI; ?7.3 to ?1.3]). The degree of IFTA, changes in urine albumin-to-creatinine ratio, or adverse events including hypercalcemia and infections requiring hospitalization did not differ between groups. In conclusion, cholecalciferol supplementation did not affect eGFR change compared to placebo among incident KTRs. These findings do not support cholecalciferol supplementation for improving allograft function in incident KTRs.

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Autologous bone marrow-derived mesenchymal stromal cell therapy with early tacrolimus withdrawal: The randomized prospective, single-center, open-label TRITON study

Marlies E. J. Reinders,Koen E. Groeneweg,Sanne H. Hendriks,Jonna R. Bank,Geertje J. Dreyer,Aiko P. J. de Vries,Melissa van Pel,Helene Roelofs,Volkert A. L. Huurman,Paula Meij,Dirk J. A. R. Moes,Willem E. Fibbe,Frans H. J. Claas,Dave L. Roelen,Cees van Kooten,Jesper Kers,Sebastiaan Heidt,Ton J. Rabelink,Johan W. de Fijter

doi : 10.1111/ajt.16528

Volume 21, Issue 9 p. 3055-3065

After renal transplantation, there is a need for immunosuppressive regimens which effectively prevent allograft rejection, while preserving renal function and minimizing side effects. From this perspective, mesenchymal stromal cell (MSC) therapy is of interest. In this randomized prospective, single-center, open-label trial, we compared MSCs infused 6 and 7 weeks after renal transplantation and early tacrolimus withdrawal with a control tacrolimus group. Primary end point was quantitative evaluation of interstitial fibrosis in protocol biopsies at 4 and 24 weeks posttransplant. Secondary end points included acute rejection, graft loss, death, renal function, adverse events, and immunological responses. Seventy patients were randomly assigned of which 57 patients were included in the final analysis (29 MSC; 28 controls). Quantitative progression of fibrosis failed to show benefit in the MSC group and GFR remained stable in both groups. One acute rejection was documented (MSC group), while subclinical rejection in week 24 protocol biopsies occurred in seven patients (four MSC; three controls). In the MSC group, regulatory T cell numbers were significantly higher compared to controls (p = .014, week 24). In conclusion, early tacrolimus withdrawal with MSC therapy was safe and feasible without increased rejection and with preserved renal function. MSC therapy is a potentially useful approach after renal transplantation.

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Every 2-month belatacept maintenance therapy in kidney transplant recipients greater than 1-year posttransplant: A randomized, noninferiority trial

Idelberto R. Badell,Ronald F. Parsons,Geeta Karadkhele,Octav Cristea,Sue Mead,Shine Thomas,Jennifer M. Robertson,Grace S. Kim,John J. Hanfelt,Stephen O. Pastan,Christian P. Larsen

doi : 10.1111/ajt.16538

Volume 21, Issue 9 p. 3066-3076

Belatacept results in improved kidney transplant outcomes, but utilization has been limited by logistical barriers related to monthly (q1m) intravenous infusions. Every 2-month (q2m) belatacept has potential to increase utilization, therefore we conducted a randomized noninferiority trial in low immunologic risk renal transplant recipients greater than 1-year posttransplant. Patients on belatacept were randomly assigned to q1m or q2m therapy. The primary objective was a noninferiority comparison of renal function (eGFR) at 12 months with a noninferiority margin (NIM) of 6.0 ml/min/1.73 m2. One hundred and sixty-six participants were randomized to q1m (n = 82) or q2m (n = 84) belatacept, 163 patients received treatment, and 76 q1m and 77 q2m subjects completed the 12-month study period. Every 2-month belatacept was noninferior to q1m, as the difference in mean eGFR adjusted for baseline renal function did not exceed the NIM. Two-month dosing was safe and well tolerated, with no patient deaths or graft losses. Four rejection episodes and three cases of donor-specific antibodies (DSAs) occurred among q2m subjects; however, only one rejection and one instance of DSA were observed in subjects adherent to the study protocol. Every 2-month belatacept therapy may facilitate long-term utilization of costimulation blockade, but future multicenter studies with long-term follow-up will further elucidate immunologic risk. (ClinicalTrials.gov NCT02560558).

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Clinical use of donation after circulatory death pancreas for islet transplantation

Jason B. Doppenberg,Michiel F. Nijhoff,Marten A. Engelse,Eelco J. P. de Koning,

doi : 10.1111/ajt.16533

Volume 21, Issue 9 p. 3077-3087

Due to a shortage of donation after brain death (DBD) organs, donation after circulatory death (DCD) is increasingly performed. In the field of islet transplantation, there is uncertainty regarding the suitability of DCD pancreas in terms of islet yield and function after islet isolation. The aim of this study was to investigate the potential use of DCD pancreas for islet transplantation. Islet isolation procedures from 126 category 3 DCD and 258 DBD pancreas were performed in a 9-year period. Islet yield after isolation was significantly lower for DCD compared to DBD pancreas (395 515 islet equivalents [IEQ] and 480 017 IEQ, respectively; p = .003). The decrease in IEQ during 2 days of culture was not different between the two groups. Warm ischemia time was not related to DCD islet yield. In vitro insulin secretion after a glucose challenge was similar between DCD and DBD islets. After islet transplantation, DCD islet graft recipients had similar graft function (AUC C-peptide) during mixed meal tolerance tests and Igls score compared to DBD graft recipients. In conclusion, DCD islets can be considered for clinical islet transplantation.

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Face transplantation: A longitudinal histological study focusing on chronic active and mucosal rejection in a series with long-term follow-up

Anissa Moktefi,Mikael Hivelin,Philippe Grimbert,Maryvonnick Carmagnat,Emilie Sbidian,Barbara Papouin,Caroline Suberbielle,Pierre Wolkenstein,Romain Bosc,Jean-Paul Meningaud,Laurent Lantieri,Nicolas Ortonne,

doi : 10.1111/ajt.16489

Volume 21, Issue 9 p. 3088-3100

The 2007 Banff working classification of skin-containing Tissue Allograft Pathology addressed only acute T cell–mediated rejection in skin. We report the longitudinal long-term histological follow-up of six face transplant recipients, focusing on chronic and mucosal rejection. We identified three patterns suggestive of chronic rejection (lichen planus-like, vitiligo-like and scleroderma-like). Four patients presented lichen planus-like and vitiligo-like chronic rejection at 52 ± 17 months posttransplant with severe concomitant acute T cell–mediated rejection. After lichen planus-like rejection, two patients developed scleroderma-like alterations. Graft vasculopathy with C4d deposits and de novo DSA led to subsequent graft loss in one patient. Chronic active rejection was frequent and similar patterns were noted in mucosae. Concordance between 124 paired skin and mucosal biopsies acute rejection grades was low (? = 0.2, p = .005) but most grade 0/I mucosal rejections were associated with grade 0/I skin rejections. We defined discordant (grade?II mucosal rejection and grade 0/I skin rejection) (n = 55 [70%]) and concordant (grade?II rejection in both biopsies) groups. Mucosal biopsies of the discordant group displayed lower intra-epithelial GranzymeB/FoxP3 ratios suggesting a less aggressive phenotype (p = .08). The grading system for acute rejection in mucosa may require phenotyping. Whether discordant infiltrates reflect a latent allo-immune reaction leading to chronic rejection remains an open question.

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Different-team procurements: A potential solution for the unintended consequences of change in lung allocation policy

Zhizhou Yang,William D. Gerull,Hailey M. Shepherd,Gary F. Marklin,Tsuyoshi Takahashi,Bryan F. Meyers,Benjamin D. Kozower,G. Alexander Patterson,Ruben G. Nava,Ramsey R. Hachem,Chad A. Witt,Derek E. Byers,Rodrigo Vazquez Guillamet,Michael K. Pasque,Yan Yan,Daniel Kreisel,Varun Puri

doi : 10.1111/ajt.16553

Volume 21, Issue 9 p. 3101-3111

The new lung allocation policy has led to an increase in distant donors and consequently enhanced logistical burden of procuring organs. Though early single-center studies noted similar outcomes between same-team transplantation (ST, procuring team from transplanting center) and different-team transplantation (DT, procuring team from different center), the efficacy of DT in the contemporary era remains unclear. In this study, we evaluated the trend of DT, rate of transplanting both donor lungs, 1-year graft survival, and risk of Grade 3 primary graft dysfunction (PGD) using the Scientific Registry of Transplant Recipient (SRTR) database from 2006 to 2018. A total of 21619 patients (DT 2085, 9.7%) with 19837 donors were included. Utilization of DT decreased from 15.9% in 2006 to 8.5% in 2018. Proportions of two-lung donors were similar between the groups, and DT had similar 1-year graft survival as ST for both double (DT, HR 1.108, 95% CI 0.894–1.374) and single lung transplants (DT, HR 1.094, 95% CI 0.931–1.286). Risk of Grade 3 PGD was also similar between ST and DT. Given our results, expanding DT may be a feasible option for improving lung procurement efficiency in the current era, particularly in light of the COVID-19 pandemic.

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Remote intervention engagement and outcomes in the Clinical Trials in Organ Transplantation in Children consortium multisite trial

Sarah Duncan-Park,Claire Dunphy,Jacqueline Becker,Christine D’Urso,Rachel Annunziato,Joshua Blatter,Carol Conrad,Samuel B. Goldfarb,Don Hayes Jr.,Ernestina Melicoff,Marc Schecter,Gary Visner,Brian Armstrong,Hyunsook Chin,Karen Kesler,Nikki M. Williams,Jonah N. Odim,Stuart C. Sweet,Lara Danziger-Isakov,Eyal Shemesh

doi : 10.1111/ajt.16567

Volume 21, Issue 9 p. 3112-3122

Remote interventions are increasingly used in transplant medicine but have rarely been rigorously evaluated. We investigated a remote intervention targeting immunosuppressant management in pediatric lung transplant recipients. Patients were recruited from a larger multisite trial if they had a Medication Level Variability Index (MLVI) ?2.0, indicating worrisome tacrolimus level fluctuation. The manualized intervention included three weekly phone calls and regular follow-up calls. A comparison group included patients who met enrollment criteria after the subprotocol ended. Outcomes were defined before the intent-to-treat analysis. Feasibility was defined as ?50% of participants completing the weekly calls. MLVI was compared pre- and 180 days postenrollment and between intervention and comparison groups. Of 18 eligible patients, 15 enrolled. Seven additional patients served as the comparison. Seventy-five percent of participants completed ?3 weekly calls; average time on protocol was 257.7 days. Average intervention group MLVI was significantly lower (indicating improved blood level stability) at 180 days postenrollment (2.9 ± 1.29) compared with pre-enrollment (4.6 ± 2.10), p = .02. At 180 days, MLVI decreased by 1.6 points in the intervention group but increased by 0.6 in the comparison group (p = .054). Participants successfully engaged in a long-term remote intervention, and their medication blood levels stabilized. NCT02266888.

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Center variation in long-term outcomes for socioeconomically deprived children

Sharad I. Wadhwani,Chiung-Yu Huang,Laura Gottlieb,Andrew F. Beck,John Bucuvalas,Uma Kotagal,Courtney Lyles,Jennifer C. Lai,

doi : 10.1111/ajt.16529

Volume 21, Issue 9 p. 3123-3132

Neighborhood socioeconomic deprivation is associated with adverse outcomes after pediatric liver transplant. We sought to determine if this relationship varies by transplant center. Using SRTR, we included patients <18 years transplanted 2008–2013 (N = 2804). We matched patient ZIP codes to a deprivation index (range [0,1]; higher values indicate increased socioeconomic deprivation). A center-level patient-mix deprivation index was defined by the distribution of patient-level deprivation. Centers (n = 66) were classified as high or low deprivation if their patient-mix deprivation index was above or below the median across centers. Center quality was classified as low or high graft failure if graft survival rates were better or worse than the overall 10-year graft survival rate. Primary outcome was patient-level graft survival. We used random-effect Cox models to evaluate center-level covariates on graft failure. We modeled center quality using stratified Cox models. In multivariate analysis, each 0.1 increase in the patient-mix deprivation index was associated with increased hazard of graft failure (HR 1.32; 95%CI: 1.05, 1.66). When stratified by center quality, patient-mix deprivation was no longer significant (HR 1.07, 95%CI: 0.89, 1.28). Some transplant centers care for predominantly high deprivation children and maintain excellent outcomes. Revealing and replicating these centers’ practice patterns should enable more equitable outcomes.

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Donor genetic variants as risk factors for thrombosis after liver transplantation: A genome-wide association study

Yanni Li,Lianne M. Nieuwenhuis,Michiel D. Voskuil,Ranko Gacesa,Shixian Hu,Bernadien H. Jansen,Werna T. U. Venema,Bouke G. Hepkema,Hans Blokzijl,Henkjan J. Verkade,Ton Lisman,Rinse K. Weersma,Robert J. Porte,Eleonora A. M. Festen,Vincent E. de Meijer

doi : 10.1111/ajt.16490

Volume 21, Issue 9 p. 3133-3147

Thrombosis after liver transplantation substantially impairs graft- and patient survival. Inevitably, heritable disorders of coagulation originating in the donor liver are transmitted by transplantation. We hypothesized that genetic variants in donor thrombophilia genes are associated with increased risk of posttransplant thrombosis. We genotyped 775 donors for adult recipients and 310 donors for pediatric recipients transplanted between 1993 and 2018. We determined the association between known donor thrombophilia gene variants and recipient posttransplant thrombosis. In addition, we performed a genome-wide association study (GWAS) and meta-analyzed 1085 liver transplantations. In our donor cohort, known thrombosis risk loci were not associated with posttransplant thrombosis, suggesting that it is unnecessary to exclude liver donors based on thrombosis-susceptible polymorphisms. By performing a meta-GWAS from children and adults, we identified 280 variants in 55 loci at suggestive genetic significance threshold. Downstream prioritization strategies identified biologically plausible candidate genes, among which were AK4 (rs11208611-T, p = 4.22 × 10?05) which encodes a protein that regulates cellular ATP levels and concurrent activation of AMPK and mTOR, and RGS5 (rs10917696-C, p = 2.62 × 10?05) which is involved in vascular development. We provide evidence that common genetic variants in the donor, but not previously known thrombophilia-related variants, are associated with increased risk of thrombosis after liver transplantation.

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Nonviral liver disease is the leading indication for liver transplant in the United States in persons living with human immunodeficiency virus

Isabel Campos-Varela,Jennifer L. Dodge,Norah A. Terrault,Danielle Brandman,Jennifer C. Price,

doi : 10.1111/ajt.16569

Volume 21, Issue 9 p. 3148-3156

We evaluated whether indications for liver transplantation (LT) have changed among people with/without human immunodeficiency virus (HIV) infection and compared LT outcomes and trends by HIV serostatus. LT recipients (2008–2018) from the United Network for Organ Sharing and Organ Procurement and Transplantation Network (UNOS/OPTN) were identifed. Among 62 195 LT recipients, 352 (0.6%) were HIV-infected. The proportion of HIV-infected patients increased over time (P trend = .001), as did the number of transplant centers performing LT for HIV-infected recipients; average annual percentage change of 9.2% (p < .001). Nonviral causes became the leading indication in 2015 for HIV-uninfected and in 2018 for HIV-infected (P trend < .001). Three-year cumulative patient survival rates were 77.5%, for HIV-infected and 84.6%, for HIV-uninfected (p = .15). Over time, graft and patient survival rates improved for both HIV-infected and uninfected (p < .001). Among HCV-infected LT recipients, 3-year patient survival rates were 72.5% for HIV-infected and 81.8% for HIV-uninfected (p = .02). However, in a subanalysis restricted to 2014–2018, differences in graft and patient survival by HIV serostatus were no longer observed (3-year patient survival rates were 81.2% for HIV-infected and 86.4% for HIV-uninfected, p = .34). In conclusion, in the United States, nonviral liver disease is now the leading indication for LT in HIV-infected patients, and posttransplant outcomes have improved over time.

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Liver simulated allocation model does not effectively predict organ offer decisions for pediatric liver transplant candidates

Nicholas L. Wood,Douglas B. Mogul,Emily R. Perito,Douglas VanDerwerken,George V. Mazariegos, … See all authors

doi : 10.1111/ajt.16621

Volume 21, Issue 9 p. 3157-3162

The SRTR maintains the liver-simulated allocation model (LSAM), a tool for estimating the impact of changes to liver allocation policy. Integral to LSAM is a model that predicts the decision to accept or decline a liver for transplant. LSAM implicitly assumes these decisions are made identically for adult and pediatric liver transplant (LT) candidates, which has not been previously validated. We applied LSAM's decision-making models to SRTR offer data from 2013 to 2016 to determine its efficacy for adult (?18) and pediatric (<18) LT candidates, and pediatric subpopulations—teenagers (?12 to <18), children (?2 to <12), and infants (<2)—using the area under the receiver operating characteristic (ROC) curve (AUC). For nonstatus 1A candidates, all pediatric subgroups had higher rates of offer acceptance than adults. For non-1A candidates, LSAM's model performed substantially worse for pediatric candidates than adults (AUC 0.815 vs. 0.922); model performance decreased with age (AUC 0.898, 0.806, 0.783 for teenagers, children, and infants, respectively). For status 1A candidates, LSAM also performed worse for pediatric than adult candidates (AUC 0.711 vs. 0.779), especially for infants (AUC 0.618). To ensure pediatric candidates are not unpredictably or negatively impacted by allocation policy changes, we must explicitly account for pediatric-specific decision making in LSAM.

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Age-related effects on thymic output and homeostatic T cell expansion following depletional induction in renal transplant recipients

He Xu,Hui-Jie Lee,Robin Schmitz,Brian I. Shaw,Shu Li,Allan D. Kirk,

doi : 10.1111/ajt.16625

Volume 21, Issue 9 p. 3163-3174

Thymic output and homeostatic mature cell proliferation both influence T cell repopulation following depletional induction, though the relative contribution of each and their association with recipient age have not been well studied. We investigated the repopulating T cell kinetics in kidney transplant recipients who underwent alemtuzumab induction followed by belatacept/rapamycin-based immunosuppression over 36-month posttransplantation. We focused specifically on the correlation between repopulating T cell subsets and the age of patients. Substantial homeostatic Ki67-expressing T cell proliferation was seen posttransplantation. A repertoire enriched for naïve T (TNaïve) cells emerged posttransplantation. Analysis by generalized estimating equation linear models revealed a strong negative linear association between reconstituting TNaïve cells and advancing age. A relationship between age and persistence of effector memory cells was shown. We assessed thymic output and found an increase in the frequency of recent thymic emigrants (RTEs, CD4+CD31+) at 12-month posttransplantation. Patients under 30 years of age showed significantly higher levels of CD4+CD31+ cells than patients over 55 years of age pre- and posttransplantation. IL-7 and autologous mature dendritic cells (mDCs) induced CD57? cell proliferation. In contrast, mDCs, but not IL-7, induced CD57+ cell proliferation. This study establishes the relationship between age and thymic output during T cell homeostatic repopulation after alemtuzumab induction.

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Posttransplant nephrotic syndrome resulting from NELL1-positive membranous nephropathy

Johannes Münch,Bastian M. Krüger,Antje Weimann,Thorsten Wiech,Linda Reinhard,Elion Hoxha,Frederick Pfister,Jan Halbritter,

doi : 10.1111/ajt.16610

Volume 21, Issue 9 p. 3175-3179

Membranous nephropathy (MN) constitutes a major cause of nephrotic syndrome (NS) in adults. After kidney transplantation (KTx), both recurrent and de novo MN has been reported. In addition to PLA2R and THSD7A, recent identification of neural EGFL-like-1 protein, NELL1, as a potential disease antigen has enriched our understanding of MN pathogenesis. To date, NELL1-positive MN has only been described in native kidneys, but never been diagnosed in renal allografts. We here report on a 56-year-old male kidney transplant recipient suffering from amyotrophic lateral sclerosis (ALS), who developed NS 25 years after KTx. Allograft biopsy revealed NELL1-positive MN. Using specifically established immunoblotting techniques, we detected new-onset NELL1-IgG1, IgG3, and IgG4 antibodies in the patient´s serum correlating with the course of proteinuria. While primary renal disease was undetermined, MN recurrence seemed unlikely given the long-time span since KTx. By clinical investigation of de novo etiologies, we did not detect an underlying malignancy. However, previous self-medication with dimercaptopropane sulfonate (DMPS) and alpha lipoic acid (ALA) represented a potential trigger and cessation associated with partial remission of proteinuria. This report illustrates the first case of posttransplant NS due to NELL1-positive MN. Monitoring NELL1 antibodies in the serum promise to be a non-invasive diagnostic tool guiding disease management.

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Simultaneous pancreas and kidney transplant after bilateral lung transplant for a recipient with cystic fibrosis

Jonathan A. Fridell,Andrew J. Lutz,John A. Powelson,

doi : 10.1111/ajt.16597

Volume 21, Issue 9 p. 3180-3183

Cystic fibrosis (CF) is an inherited autosomal recessive disorder. Despite optimized therapy, the majority of affected individuals ultimately die of respiratory failure. Lung transplantation is the only available therapy that deals definitively with the end-stage pulmonary disease and has become the treatment of choice for some of these patients. As patients with CF are living longer, extrapulmonary manifestations may develop including pancreatic failure, which manifests as exocrine insufficiency and CF-related diabetes (CFRD). Both of these can be managed through pancreas transplantation. We have previously reported our series of three simultaneous lung and pancreas transplants in patients with CF, which were complicated by surgical issues for both the thoracic and abdominal portions, rejection and resistant infections with disappointing long-term survival. Based on these results, a sequential approach was adopted: first, the thoracic transplant; and second, once the patient has recovered, the abdominal transplants. This is the first reported case of pancreas and kidney transplantation performed after a lung transplant in a patient with CF. It demonstrates a successful approach to treating CF with a lung transplant, and in an effort to improve the patient's long-term outcome, treating CFRD and pancreatic enzyme insufficiency, with a subsequent pancreas transplant.

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Successful living donor liver transplantation for liver failure due to maternal T cell engraftment following cord blood transplantation in X-linked severe combined immunodeficiency disease: Case report

Noriki Okada,Yuta Kawahara,Yukihiro Sanada,Yuta Hirata,Shinya Otomo,Hitomi Niijima,Akira Tanaka,Akira Morimoto,Alan K. Lefor,Taizen Urahashi,Yoshikazu Yasuda,Koichi Mizuta,Yasunaru Sakuma,Naohiro Sata

doi : 10.1111/ajt.16588

Volume 21, Issue 9 p. 3184-3189

Maternal T cells from perinatal transplacental passage have been identified in up to 40% of patients with severe combined immunodeficiency (SCID). Although engrafted maternal T cells sometimes injure newborn tissue, liver failure due to maternal T cells has not been reported. We rescued a boy with X-linked SCID who developed liver failure due to engrafted maternal T cell invasion following living donor liver transplantation (LDLT) following unrelated umbilical cord blood transplantation (UCBT). After developing respiratory failure 3 weeks postpartum, he was diagnosed with X-linked SCID. Pathological findings showed maternal T cells engrafted in his liver and hepatic fibrosis gradually progressed. He underwent UCBT at 6 months, but hepatic function did not recover and liver failure progressed. Therefore, he underwent LDLT using an S2 monosegment graft at age 1.3 years. The patient had a leak at the Roux-en-Y anastomosis, which was repaired. Despite occasional episodes of pneumonia and otitis media, he is generally doing well 6 years after LDLT with continued immunosuppression agents. In conclusion, the combination of hematopoietic stem cell transplantation (HSCT) and liver transplantation may be efficacious, and HSCT should precede liver transplantation for children with X-linked SCID and liver failure.

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Unexpected hepatitis B virus infection after liver transplantation — United States, 2014–2019

Danae Bixler,Pallavi Annambhotla,Martha P. Montgomery,Tonya Mixon-Hayden,Ben Kupronis,Marian G. Michaels,Ricardo M. La Hoz,Sridhar V. Basavaraju,Saleem Kamili,Anne Moorman,

doi : 10.1111/ajt.16045

Volume 21, Issue 9 p. 3190-3195

This article describes 14 cases of donor-derived hepatitis B virus infection in liver transplant recipients despite the donors having had negative testing for hepatitis B prior to organ procurement. The majority of the involved donors were also seropositive for hepatitis C and had a history of injection drug use. This report underscores the need for serial posttransplant hepatitis B testing of recipients, even when initial donor and recipient testing is negative, and the importance of pretransplant hepatitis B vaccination in transplant candidates.

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