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Well-selected patients with kidney disease and diabetes mellitus who undergo simultaneous kidney-pancreas transplantation often experience dramatic improvements in quality of life and long-term survival compared to those who remain on medical therapy. Over the past several years the importance of frailty in the pancreas transplant candidate and recipient populations has grown. More patients with advanced age have entered the waitlist, and complications from prolonged diabetes, even in younger patients, have created increased evidence of risk for frailty. Given these concerns, and the broad challenges facing pancreas transplantation volumes overall, we generated this review to help establish the impact and implications. We summarize the interplay of immunological factors, aging, environmental factors, diabetes mellitus, and chronic kidney disease that put these patients at risk for frailty. We discuss its measurement and recommend a combination of two instruments (both well validated and one entirely objective). We describe the outcomes for patients before and after pancreas transplantation who may have frailty, and what interventions can be taken to mitigate its effects. Broader investigation into frailty in the pancreas transplant population is needed to better understand how to select patients for pancreas transplantation and to how manage its consequences thereafter. This article is protected by copyright. All rights reserved.

The construct of frailty was first developed in gerontology to help identify older adults with increased vulnerability when confronted with a health stressor. This article is a review of studies in which frailty has been applied to pre- and post-kidney transplantation (KT) populations. Although KT is the optimal treatment for end-stage kidney disease (ESKD), KT candidates often must overcome numerous health challenges associated with ESKD before receiving KT. After KT, the impacts of surgery and immunosuppression represent additional health stressors that disproportionately impact individuals with frailty. Frailty metrics could improve the ability to identify KT candidates and recipients at risk for adverse health outcomes and those who could potentially benefit from interventions to improve their frail status. The Physical Frailty Phenotype (PFP) is the most commonly used frailty metric in ESKD research, and KT recipients who are frail at KT (~20% of recipients) are twice as likely to die as nonfrail recipients. In addition to the PFP, many other metrics are currently used to assess pre- and post-KT vulnerability in research and clinical practice, underscoring the need for a disease-specific frailty metric that can be used to monitor KT candidates and recipients. Although frailty is an independent risk factor for post-transplant adverse outcomes, it is not factored into the current transplant program risk-adjustment equations. Future studies are needed to explore pre- and post-KT interventions to improve or prevent frailty.

Background Due to a substantial decline in pancreas transplantation (PT) across the United States over the past 15 years, we sought to understand the perceptions and practices of US PT programs. Methods Surveys were sent to members of the American Society of Transplantation Surgeons and the American Society of Transplantation by email and professional society postings between August 2019 and November 2019. Results One hundred twenty three responses were recorded from 56 unique programs. Program characteristics were obtained from the Scientific Registry of Transplant Recipients. Respondents were transplant surgeons (71%), transplant nephrologists (17%), trainees (9%), and allied professionals (3%). Programs were defined according to annual volume as: low ( 20). High-volume programs reported that these factors were most important for increased PT: expansion of recipient selection, more aggressive donor utilization, and hiring of PT program-specific personnel. At both the program and national level, the vast majority (82% and 79%, respectively) felt the number of PTs currently performed are not in balance with patients' needs. Conclusions Overall, programs reported that the option of PT is not offered adequately to diabetic patients and that strategies to maintain higher PT volume are most evident at intermediate, and especially, high-volume programs.

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.

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.

The current American Society of Transplantation (AST) accredited transplant fellowship programs in the United States provide no structured formal training in leadership and administration which is essential for successfully running a transplant program. We conducted a survey of medical directors of active adult kidney and kidney-pancreas transplant programs in the United States about their demographics, training pathways, and roles and responsibilities. The survey was emailed to 183 medical directors, and 123 (67.2%) completed the survey. A majority of respondents were older than 50 years (61%), males (80%), and holding that position for more than 10 years (47%). Only 51% of current medical directors had taken that position after completing a one-year transplant fellowship, and 58% took on the role with no prior administrative or leadership experience. The medical directors reported spending a median 50%-75% of time in clinical responsibilities, 25%-50% of time in administration, and 0%-25% time in research. The survey also captured various administrative roles of medical directors vis-a-vis other transplant leaders. The study, designed to be the starting point of an improvement initiative of the AST, provided important insight into the demographics, training pathways, roles and responsibilities, job satisfaction, education needs, and training gaps of current medical directors.

The coronavirus disease 2019 (COVID‐19) pandemic poses unprecedented challenges to the transplant community, including organ procurement organizations (OPOs), transplant centers, regulatory agencies, and recipient candidates. Access to timely, accurate information on the status of deceased donor viral infection is essential in determining organ acceptance. The Organ Procurement and Transplantation Network expeditiously added fields to collect these data; however, use of the data collection fields was not uniform nationally. Standardized, field‐defined data capture and reporting are vital to ensure optimal organ utilization during this pandemic, and to prepare the community for subsequent challenges.

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).

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.

PURPOSE OF REVIEW: Highlight developments in T and B cell biology that are helping elucidate the mechanisms underlying CD28 pathway blockade-mediated inhibition of alloantibodies in transplantation, and discuss recent clinical observations on the impact of belatacept on de novo and established HLA antibodies. RECENT FINDINGS: The identification of T follicular helper cells as the CD4+ T cell subset required for optimal humoral immunity, along with newly identified roles for CD28 and the B7 molecules on B cell lineage cells has begun to pave the way for improved understanding and discovery of the mechanisms of CD28 costimulation blockade-mediated antibody inhibition. There has been resurgent clinical interest in the ability of belatacept to attenuate alloantibody responses. New reports have continued to document its ability to prevent de novo antibody responses, and more recent studies have surfaced exploring its potential to control nascent or pre-existing HLA antibodies. SUMMARY: A growing understanding of the mechanisms of anti-CD28-mediated alloantibody inhibition and continued clinical successes will guide the clinical optimization of belatacept and next generation CD28 blockers to prevent and reduce alloantibodies over the long-term.

Background Given the potential utility of frailty, a clinical phenotype of decreased physiologic reserve and resistance to stressors, to predict postkidney transplant (KT) outcomes, we sought to understand the perceptions and practices regarding frailty measurement in US KT programs. Methods Surveys were emailed to American Society of Transplantation Kidney/Pancreas Community of Practice members and 202 US transplant programs (November 2017 to April 2018). Program characteristics were gleaned from Scientific Registry of Transplant Recipients. Results The 133 responding programs (response rate = 66%) represented 77% of adult KTs and 79% of adult KT candidates in the United States. Respondents considered frailty to be a useful concept in evaluating candidacy (99%) and endorsed a need to develop a frailty measurement specific to KT (92%). Frailty measurement was more common during candidacy evaluation (69%) than during KT admission (28%). Of the 202 programs, 38% performed frailty assessments in all candidates while 23% performed assessments only for older candidates. There was heterogeneity in the frailty assessment method; 18 different tools were utilized to measure frailty. The most common tool was a timed walk test (19%); 67% reported performing >1 tool. Among programs that measure frailty, 53% reported being less likely to list frail patients for KT. Conclusions Among US KT programs, frailty is recognized as a clinically relevant construct and is commonly measured at evaluation. However, there is considerable heterogeneity in the tools used to measure frailty. Efforts to identify optimal measurement of frailty using either an existing or a novel tool and subsequent standardization of its measurement and application across KT programs should be considered.

Recent evidence suggests that belatacept reduces the durability of preexisting antibodies to class I and class II human leukocyte antigens (HLAs). In this case series of 163 highly sensitized kidney transplant candidates whose calculated panel-reactive antibody (cPRA) activity was ≥98% to 100%, the impact of belatacept on preexisting HLA antibodies was assessed. Of the 163 candidates, 72 underwent transplantation between December 4, 2014 and April 15, 2017; 60 of these transplanted patients remained on belatacept consecutively for at least 6 months. We observed a decrease in the breadth and/or strength of HLA class I antibodies as assessed by FlowPRA in belatacept-treated patients compared to controls who did not receive belatacept. Specifically, significant HLA antibody reduction was evident for class I (P < .0009). Posttransplant belatacept-treated patients also had a clinically significant reduction in their cPRA compared to controls (P < .01). Collectively, these findings suggest belatacept can reduce HLA class I antibodies in a significant proportion of highly sensitized recipients and could be an option to improve pretransplant compatibility with organ donors.

Background The impact of functional status on survival among simultaneous pancreas-kidney transplant (SPKT) candidates and recipients is not well described. Methods We examined national Scientific Registry of Transplant Recipients (SRTR) data for patients listed for SPKT in the United States (2006-2019). Functional status was categorized by center-reported Karnofsky Performance Score (KPS). We used Cox regression to quantify associations of KPS at listing and transplant with subsequent patient survival, adjusted for baseline patient and transplant factors (adjusted hazard ratio, 95% LCLaHR95%UCL). We also explored time-dependent associations of SPKT with survival risk after listing compared with continued waiting in each functional status group. Results KPS distributions among candidates (N = 16 822) and recipients (N = 10 316), respectively, were normal (KPS 80-100), 62.0% and 57.8%; capable of self-care (KPS 70), 23.5% and 24.7%; requires assistance (KPS 50-60), 12.4% and 14.2%; and disabled (KPS 10-40), 2.1% and 3.3%. There was a graded increase in mortality after listing and after transplant with lower functional levels. Compared with normal functioning, mortality after SPKT rose progressively for patients capable of self-care (aHR, 1.001.181.41), requiring assistance (aHR, 1.061.311.60), and disabled (aHR, 1.101.552.19). In time-dependent regression, compared with waiting, SPKT was associated with 2-fold mortality risk within 30 days of transplant. However, beyond 30 days, SPKT was associated with reduced mortality, from 52% for disabled patients (aHR, 0.260.480.88) to 70% for patients with normal functioning (aHR, 0.260.300.34). Conclusions While lower functional status is associated with increased mortality risk among SPKT candidates and recipients, SPKT can provide long-term survival benefit across functional status levels in those selected for transplant.

Delayed gastric emptying is a significant postoperative complication of living donor hepatectomy for liver transplantation and may require endoscopic or surgical intervention in severe cases. Although the mechanism of posthepatectomy delayed gastric emptying remains unknown, vagal nerve injury during intraoperative dissection and adhesion formation postoperatively between the stomach and cut liver surface are possible explanations. Here, we present the first reported case of delayed gastric emptying following fully laparoscopic hepatectomy for living donor liver transplantation. Additionally, we also present a case in which symptoms developed after open right hepatectomy, but for which dissection for left hepatectomy was first performed. Through our experience and these two specific cases, we favor a neurovascular etiology for delayed gastric emptying after hepatectomy.

Deceased donor kidney allocation was reorganized in the United States to address several problems, including the highly sensitized patients disadvantaged with large, diverse repertoires of antibodies. Here, five transplant surgeons review their center's experience with the new allocation changes: highlighting areas of accomplishment, opportunities for improvement and, in some cases, stark differences in practice. Across these five centers the highly sensitized patients (CPRA ⩾98%) range from 5.5 to 9.2% of the 12,364 candidates on their collective waitlist. All centers reported greater rates of kidney transplantations in highly sensitized patients (12.4-27%). Three of the programs (Emory, UCSF, UW) relied upon the virtual crossmatch prior to organ acceptance in a majority of cases (70-86%)-the mere presence of antibody on HLA antibody screen was sufficient to exclude the donor in most cases at Emory and UCSF. Penn and UAB relied upon the physical flow crossmatch in almost all cases prior to proceeding with transplantation. Current or historical donor-specific antibody was occasionally crossed in certain cases at UW and UAB necessitating IVIG/plasmapheresis and/or B cell depletion perioperatively. Some authors raised concerns for cost efficiency given the increased need for organ/specimen transportation, and extensive use of hospital resources and ancillary services. In general, we found that the new allocation system has successfully achieved one of its primary goals-increased kidney transplantation in the disadvantaged, highly sensitized patients; the long-term outcomes in all patients and the cost ramifications of these changes will require continued reassessment and clarification.

Redfield RR, Parsons RF, Rodriguez E, Mustafa M, Cassuto J, Vivek K, Noorchashm H, Naji A, Levine MH, Abt PL. Underutilization of A2 ABO incompatible kidney transplantation. Clin Transplant 2011 DOI: 10.1111/j.1399-0012.2011.01543.x. © 2011 John Wiley & Sons A/S. Abstract: Background: ABO compatibility creates a disadvantage for O and B renal allograft candidates. A2 ABO incompatible transplant may decrease waiting times and generate equivalent graft survival to an ABO compatible transplant. Methods: Death-censored graft survival was compared between A recipients and O, B, and AB recipients of an A2 allograft with multivariate Cox regression models utilizing data from the United Network of Organ Sharing (UNOS) between 1997 and 2007. Results: Eighty-five percent of A2 kidneys were transplanted into ABO compatible recipients vs. 15% into ABO incompatible recipients. Rates of A2 incompatible kidney transplants did not increase over the study period (14.8% to 14.6%). Mean wait time for A2→O kidneys was 337 vs. 684 d for O→O and for A2→B kidneys, 542 vs. 734 d for B→B. Adjusted relative risk of graft loss at five-yr was similar between O, B, and AB recipients compared to A recipients of an A2 allograft, corresponding to a five-yr graft survival of 84%, 86.2%, 86.1%, and 86.1%, respectively. Conclusion: A2 incompatible kidney transplantation is underutilized. Graft outcomes are similar among A2 compatible and incompatible recipients. Shorter waiting time and improved access might be achieved if A2 kidneys are considered in all blood groups.

A major obstacle to transplantation tolerance is humoral immunity. In this paper, we demonstrate that the intrinsic developmental propensity of the B lymphocyte compartment for acquisition of self-tolerance can be harnessed to induce humoral unresponsiveness to transplanted alloantigens. In the current study, when transitional B cells developed in the presence of donor lymphoid cells, the mature B lymphocyte compartment failed to mount a donor-specific alloantibody response to an organ transplant—despite unrestrained acute T cell-mediated allograft rejection. Specifically, we generated an experimental system wherein a B6 strain B cell compartment developed de novo in the presence of F1 (B6xBALB/c) lymphoid cells and in a T cell-deficient setting. Following establishment of a steady-state B cell compartment, these B6 mice were transplanted with heterotopic cardiac allografts from allogeneic BALB/c donors. The mice were then inoculated with purified syngeneic B6 T cells. As expected, all cardiac allografts were acutely rejected. However, the B lymphocyte compartment of these mice was completely inert in its capacity to form a BALB/c-specific alloantibody response. Using an alloantigen-specific Ig transgenic system, we demonstrated that this profound degree of humoral tolerance was caused by clonal deletion of alloreactive specificities from the primary B cell repertoire. Thus, de novo B cell compartment development at the time of transplantation is of critical importance in recipient repertoire “remodeling” to a humoral tolerant state.

Aim Since the new KAS, candidates with cPRA = 100% were prioritized for deceased donor (DD) kidneys, their transplant rates increased from 2.7% to as high as 19.1%. A recent simulation (CJSAN 11:505-511, 2016), predicted that not all cPRA=100% are equally advantaged. While ∼ 75% cPRA =100% candidates were compatible with an average of 17 donors (total donors = 6141), ∼ 25% were incompatible with every donor and related to cPRA values of 99.45–>99.99% being ”rounded up” to 100%. Indeed, 91% of candidates without a compatible donor had cPRA values >99.9%. Subsequent data with actual transplants (AJT 16:1834-1847, 2016) supported those predictions. In our program, 61 cPRA = 100% candidates were transplanted from 12/04/14-01/12/18. Surprisingly, 15 recipients had cPRA values ⩾99.95%. In this study, we identified their characteristics. Methods HLA profiles and demographic information from 15 cPRA ⩾99.95% recipients were compared to 30 non-transplanted case controls with cPRA ⩾99.95%. The HLA typing data of each subject was entered into Haplostats (haplostat.org) and the top ranked phased haplotypes for each were recorded. Results Among cPRA⩾99.95% recipients, 11/15 (73%) had one or both of their HLA haplotypes ranked among the top 125 CAU haplotypes. CAU haplotypes were the focus as CAU represent ∼ 67% of kidney donors. Notably, 7/15 recipients had one or both of their HLA haplotypes among the top four ranked CAU haplotypes and 6/15 received transplants from homozygous donors. Among recipients, eight were AA (53%), six were CAU and one was HIS. In contrast, among 30 case controls, 4 (13.3%) had one haplotype ranked in the top 125 and 17 had one haplotype ranked in the top 8000. For 9 candidates, neither HLA haplotype was ranked among the top 10,000 CAU haplotypes. Importantly, 25/30 (83.3%) controls were African American. Conclusions Kidney transplant candidates with cPRA⩾99.95% were more likely to be transplanted when at least one of their HLA haplotypes was frequent (rank ⩽ 125). This novel observation offers an opportunity to medically optimize a subset of highly sensitized candidates before deceased donor transplantation. It also suggests amendments may be necessary to minimize racial disparity in the KAS. Additionally, alternative approaches should be considered for candidates not likely to receive a DD offer. H.M. Gebel: 2. Consultant; Company/Organization; Astellas, Thermofisher.

Current strategies for immunotherapy after transplantation are primarily T-lymphocyte directed and effectively abrogate acute rejection. However, the reality of chronic allograft rejection attests to the fact that transplantation tolerance remains an elusive goal. Donor-specific antibodies are considered the primary cause of chronic rejection. When naive, alloreactive B-cells encounter alloantigen and are activated, a resilient "sensitized" state, characterized by the presence of high-affinity antibody, is established. Here, we will delineate findings that support transient B-lymphocyte depletion therapy at the time of transplantation to preempt sensitization by eliminating alloreactive specificities from the recipient B-cell pool (ie, "repertoire remodeling"). Recent advances in our understanding of B-lymphocyte homeostasis provide novel targets for immunomodulation in transplantation. Specifically, the tumor necrosis factor-related cytokine BLyS is the dominant survival factor for "tolerance-susceptible" transitional and "preimmune" mature follicular B-cells. The transitional phenotype is the intermediate through which all newly formed B-cells pass before maturing into the follicular subset, which is responsible for mounting an alloantigen-specific antibody response. Systemic BLyS levels dictate the stringency of negative selection during peripheral B-cell repertoire development. Thus, targeting BLyS will likely provide an opportunity for repertoire-directed therapy to eliminate alloreactive B-cell specificities in transplant recipients, a requirement for the achievement of humoral tolerance and prevention of chronic rejection. In this review, the fundamentals of preimmune B-cell selection, homeostasis, and activation will be described. Furthermore, new and current B-lymphocyte-directed therapy for antibody-mediated rejection and the highly sensitized state will be discussed. Overall, our objective is to propose a rational approach for induction of humoral transplantation tolerance by remodeling the primary B-cell repertoire of the allograft recipient.

B lymphocytes are required for the pathogenesis of autoimmune diabetes in NOD mice. Previous studies established that a lymphopenic transitional (TR) B cell compartment reduces the competitive constraint on the entry of newly emerging TR B cells into the splenic follicle (FO), thereby disrupting a peripheral negative selection checkpoint in NOD mice. Thus, development of clinically feasible immunotherapeutic approaches for restoration of appropriate negative selection is essential for the prevention of anti-islet autoimmunity. In this study we hypothesized that in vivo neutralization of the B lymphocyte stimulator (BLyS/BAFF) may enhance the stringency of TR→FO selection by increasing TR B cell competition for follicular entry in NOD mice. This study demonstrated that in vivo BLyS neutralization therapy leads to the depletion of follicular and marginal zone B lymphocytes. Long-term in vivo BLyS neutralization caused an increased TR:FO B cell ratio in the periphery indicating a relative resistance to follicular entry. Moreover, in vivo BLyS neutralization: 1) restored negative selection at the TR→FO checkpoint, 2) abrogated serum insulin autoantibodies, 3) reduced the severity of islet inflammation, 4) significantly reduced the incidence of spontaneous diabetes, 5) arrested the terminal stages of islet cell destruction, and 6) disrupted CD4 T cell activation in NOD mice. Overall, this study demonstrates the efficacy of B lymphocyte-directed therapy via in vivo BLyS neutralization for the prevention of autoimmune diabetes.

Lymphocyte homeostasis poses a multi-faceted biological puzzle, because steady pre-immune populations must be maintained at an acceptable steady state to yield effective protection, despite stringent selective events during their generation. In addition, activated, memory and both short- and long-term effectors must be governed by independent homeostatic mechanisms. Finally, advancing age is accompanied by substantial changes that impact the dynamics and behavior of these pools, leading to cumulative homeostatic perturbations and compensation. Our laboratory has focused on the over-arching role of BLyS family ligands and receptors in these processes. These studies have led to a conceptual framework within which distinct homeostatic niches are specified by BLyS receptor signatures, which define the BLyS family ligands that can afford survival. The cues for establishing these receptor signatures, as well as the downstream survival mechanisms involved, are integrated with cell extrinsic inputs via cross talk among downstream mediators. A refined understanding of these relationships should yield insight into the selection and maintenance of B cell subsets, as well as an appreciation of how homeostatic mechanisms may contribute to immunosenescence.

Priority is given to patients with hepatocellular carcinoma (HCC) to receive liver transplants, potentially causing significant regional disparities in organ access and possibly outcomes in this population. Our aim was to assess these disparities by comparing outcomes in long waiting time regions (LWTR, regions 5 and 9) and short waiting time regions (SWTR regions 3 and 10) by analyzing the United Network for Organ Sharing (UNOS) database. We analyzed 6,160 HCC patients who received exception points in regions 3, 5, 9, and 10 from 2002 to 2012. Data from regions 5 and 9 were combined and compared to data from regions 3 and 10. Survival was studied in three patient cohorts: an intent-to-treat cohort, a posttransplant cohort, and a cohort examining overall survival in transplanted patients only (survival from listing to last posttransplant follow-up). Multivariate analysis and log-rank testing were used to analyze the data. Median time on the list in the LWTR was 7.6 months compared to 1.6 months for SWTR, with a significantly higher incidence of death on the waiting list in LWTR than in SWTR (8.4% versus 1.6%, P

To update the reader on the recent literature in liver, kidney, pancreas, and intestine static cold preservation, and to identify which solutions are most advantageous for each organ.The comparison of randomized trials of histidine-tryptophan-ketoglutarate (HTK), Celsior, and University of Wisconsin solutions has shown equivalent risk of delayed graft function after kidney transplantation. Similar outcomes have been observed after pancreas preservation with University of Wisconsin, HTK, and Celsior solution. In live-donor liver transplantation, University of Wisconsin and HTK solution have shown equivalent results, whereas in the recent trials of deceased-donor liver transplantation, University of Wisconsin, HTK, and Celsior solutions have shown equivalence. Contrary to the most clinical trials, national registry data in kidney, pancreas, and liver transplantation demonstrate more detrimental effects and earlier graft loss after preservation with HTK versus University of Wisconsin solution. Early outcomes after intestinal transplantation with University of Wisconsin or HTK solution have shown no significant difference and animal studies indicate intraluminal preservation may be beneficial.The University of Wisconsin solution is the standard criterion static cold preservation for the procurement of liver, kidney, pancreas, and intestine. University of Wisconsin, HTK, and Celsior solutions all provide similar allograft outcomes in most clinical trials, but subtle differences have become more apparent in the recent studies and registry reports.

Background Long-lived plasma cells (PCs) that form after alloantigen sensitization produce donor-specific alloantibodies that generate a positive serum crossmatch and preclude transplantation. New approaches for desensitization, including PC depletion with proteasome inhibition, show promise but carry considerable toxicity. Recently, eosinophils have been shown to govern PC persistence. Interleukin 5 (IL-5) depletion is known to reduce eosinophils in human asthmatics. We hypothesized that treatment with an anti-IL-5 antibody can deplete alloreactive PCs, reduce donor-specific alloantibodies, and serve as a less toxic alternative to proteasome inhibition. Methods BALB/c mice were sensitized with B6 skin allografts. Starting at 8 wk after sensitization, control mice received injections of phosphate-buffered saline, whereas experimental mice received weekly injections of an anti-IL-5 antibody. PCs were enumerated by enzyme-linked immunosorbent spot after 8 wk. Results All control and experimental recipients of skin allografts developed positive crossmatches when screened at 8 wk after sensitization. All experimental mice treated with anti-IL-5 showed a reduction in their total PC numbers. Also, in contrast to the known adverse effects of proteasome inhibition, experimental mice treated with anti-IL-5 exhibited negligible weight loss or lymphopenia. Conclusions Treatment with anti-IL-5 is sufficient to reduce, but not eliminate, alloreactive PCs in the bone marrow. This is because of the targeted reduction of eosinophils leading to a reduction in the PC survival factors a proliferation-inducing ligand and IL-6. Generalized toxicity was not observed in experimental mice. Overall, IL-5 directed immunotherapy can eliminate PC's but is unlikely to be a clinically significant desensitization strategy given the persistence of DSA

The long-lived plasma cells, which develop after alloantigen sensitization, produce donor specific alloantibodies (DSAs) that generate a positive serum cross-match and preclude transplantation. Bortezomib, a proteasome inhibitor, is being investigated in clinical desensitization protocols, however preclinical studies in a transplant model are nonexistent. We hypothesized that sustained treatment with only a proteasome inhibitor would eliminate plasma cells and reduce DSA over time. Cardiac allografts were transplanted into murine recipients. Eight weeks after allograft rejection the proteasome inhibitor, bortezomib, was injected intravenously twice weekly for 60 days. Serum alloantibody responses were assayed using flow cross-match. Total and alloreactive plasma cell numbers were enumerated using flow cytometry and ELISPOT. All recipients of cardiac allografts rejected their graft promptly within 16 days and demonstrated alloantibody by flow cross-match. DSA was sustained in the control mice while mice treated with bortezomib had sustained elimination of DSA and a marked reduction in plasma cell population. Also, bortezomib was associated with an increased level of BLyS. Within a murine model, proteasome inhibition can eliminate alloantibody secreting plasma cells, and reduce alloantibody. Cessation of bortezomib is not associated with return of DSA.

Background. Immunologic rejection is a major barrier to successful long-term outcomes in clinical transplantation. The importance of B lymphocytes—and their secretory products, alloantibodies—in the pathogenesis of allograft rejection is accepted. Furthermore, it is now clear that the dominant regulator of peripheral B-cell homeostasis and tolerance is the B-Lymphocyte Stimulator (BLyS), also referred to as the B-cell activating factor (BAFF). Recently, a novel class of clinical immunotherapeutic agents specific for BLyS, and its family of cytokines, has emerged for the treatment of B-cell-mediated diseases. In this study, we demonstrate the potential utility of BLyS-directed immunotherapy in preventing allograft rejection using a murine islet transplantation model. Methods. A transient period of mature peripheral B-cell depletion was induced by means of in vivo BLyS neutralization using a murine analog of the monoclonal antibody, Benlysta. Subsequently, fully major histocompatibility complex-mismatched islets were transplanted into naive diabetic mice followed by a short course of rapamycin. Results. After BLyS neutralization, indefinite islet allograft survival was achieved. Induction therapy with rapamycin was necessary, but not sufficient, for the achievement of this long-term graft survival. The tolerant state was associated with (1) abrogation of the donor-specific antibody response, (2) transient preponderance of immature/transitional B cells in all lymphoid organs, (3) impaired CD4 T-cell activation during the period of B-cell depletion, and (4) presence of a “regulatory” cytokine milieu. Conclusions. In vivo BLyS neutralization effectively induces humoral tolerance and promotes long-term islet allograft survival in mice. Therefore, B-lymphocyte-directed immunotherapy targeting the homeostatic regulator, BLyS, may be effective in promoting transplantation tolerance.

Transplantation tolerance remains an elusive goal as B-cell-initiated chronic humoral rejection evades current immunosuppression. B-cell-directed therapy is thus emerging as a key component in achieving transplantation tolerance and long-term graft survival. Here, we propose strategies of B-cell repertoire remodeling to achieve humoral unresponsiveness to donor antigens with implementation of fundamental B-cell immunobiology and use of newly developed B-cell-directed agents.

The current mainstay of immunotherapy in clinical transplantation is T lymphocyte directed. However, it has long been appreciated that the emergence of an alloimmune response mounted by the B lymphocyte compartment and detectable as donor-specific antibodies is a critical challenge to long-term graft survival. Thus, achieving robust transplantation tolerance will require induction of tolerance in both the T- and B-cell compartments. Here we propose that the natural developmental propensity of the B-lymphocyte compartment acquisition of tolerance to self-antigens can be recapitulated to achieve humoral transplantation tolerance. It is our contention B-lymphocyte directed induction immunotherapy would be an important component of emerging strategies for induction of Transplantation tolerance.

T lymphocytes are the primary targets of immunotherapy in clinical transplantation. However, B lymphocytes are detrimental to graft survival by virtue of their capacity to present antigen to T cells via the indirect pathway of allorecognition and the generation of donor specific alloantibody. Furthermore, the long-term survival of organ allografts remains challenged by chronic rejection, a process in which activated B cells have been found to play a significant role. Therefore, the achievement of transplantation tolerance will likely require induction of both T and B cell tolerance to alloantigens. Moreover, human and animal investigations have shown that subsets of B cells, Transitional and Regulatory, are inherently tolerogenic. Developing therapeutic strategies that exploit these populations may be key to achieving transplantation tolerance. In this review we describe the current evidence for the essential role of B cells in transplant tolerance and discuss emerging B cell directed strategies to achieve allograft tolerance.

T lymphocytes are the primary targets of immunotherapy in clinical transplantation; however, B lymphocytes and their secreted alloantibodies are also highly detrimental to the allograft. Therefore, the achievement of sustained organ transplant survival will likely require the induction of B-lymphocyte tolerance. During development, acquisition of B-cell tolerance to self-antigens relies on clonal deletion in the early stages of B-cell compartment ontogeny. We contend that this mechanism should be recapitulated in the setting of alloantigens and organ transplantation to eliminate the alloreactive B-cell subset from the recipient. Clinically feasible targets of B-cell-directed immunotherapy, such as CD20 and B-lymphocyte stimulator (BLyS), should drive upcoming clinical trials aimed at remodeling the recipient B-cell repertoire.

Aim On 12/4/2014, the OPTN implemented a new KAS for deceased donor (DD) transplantation. Among the many changes was increased priority for highly sensitized (HS) candidates (cPRA≥99%). Such candidates now have the highest priority for national (100%) and regional (99%) sharing. Initial OPTN data indicate that these candidates receive ∼15% of all DD transplants. While the new KAS has introduced broader sharing, it has also presented new logistical and time-sensitive challenges. Therefore, we sought to assess the utility of the virtual crossmatch (vXM) in the new KAS. Methods Between 12/04/2014 and 3/27/2015, we performed 64 DD transplants. Among transplanted patients with cPRA ≥99%, we assessed whether the transplant was performed based on a prospective, physical crossmatch (pXM) or vXM. The vXM was defined as the absence of donor specific antibody. For all vXM-based transplants, we reviewed results of the retrospective pXM, graft function and episodes of early rejection. Results During this time period, 24/64 (37.5%) of the DD transplants were performed in HS candidates. Among this group, 23/24 (96%) kidneys were imported and 16 (66.6%) were transplanted solely on a prospective vXM to minimize cold ischemia time. For all vXM-based transplants, a pXM was performed concurrently with the transplant. In no instance was the pXM unexpectedly positive due to HLA antibody. Most importantly, there were no instances of hyperacute or accelerated graft rejection among any of the HS candidates transplanted based on a vXM. Conclusions Due to the new KAS, centers are now receiving more organ offers for HS patients. Frequently, offers come from centers at great distances and often there is insufficient time to ship material for a prospective pXM. Rather, centers must accept or decline what may be a patient’s only opportunity for a compatible organ, solely on a vXM. Additionally, vXM-based transplantation minimizes cold ischemia time. Our data demonstrate that a vXM can identify HS candidates who can proceed safely to transplant without a prospective pXM. Limitations to performing a vXM include; incomplete/incorrect donor HLA type, lack of current patient serum or equivocal donor specific antibodies. Nonetheless, the vXM can prove beneficial for allocating organs to the most disadvantaged candidates.