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Liver transplantation (LT) from donors-with-HIV to recipients-with-HIV (HIV D+/R+) is permitted under the HOPE Act. There are only three international single-case reports of HIV D+/R+ LT, each with limited follow-up. We performed a prospective multicenter pilot study comparing HIV D+/R+ to donors-without-HIV to recipients-with-HIV (HIV D-/R+) LT. We quantified patient survival, graft survival, rejection, serious adverse events (SAEs), human immunodeficiency virus (HIV) breakthrough, infections, and malignancies, using Cox and negative binomial regression with inverse probability of treatment weighting. Between March 2016-July 2019, there were 45 LTs (8 simultaneous liver-kidney) at 9 centers: 24 HIV D+/R+, 21 HIV D-/R+ (10 D- were false-positive). The median follow-up time was 23 months. Median recipient CD4 was 287 cells/µL with 100% on antiretroviral therapy; 56% were hepatitis C virus (HCV)-seropositive, 13% HCV-viremic. Weighted 1-year survival was 83.3% versus 100.0% in D+ versus D- groups (p = .04). There were no differences in one-year graft survival (96.0% vs. 100.0%), rejection (10.8% vs. 18.2%), HIV breakthrough (8% vs. 10%), or SAEs (all p .05). HIV D+/R+ had more opportunistic infections, infectious hospitalizations, and cancer. In this multicenter pilot study of HIV D+/R+ LT, patient and graft survival were better than historical cohorts, however, a potential increase in infections and cancer merits further investigation.

While exogenous insulin administration remains the cornerstone of management for type I diabetes mellitus (T1DM), patients now have a variety of options that include whole organ pancreas transplant, islet cell transplant, extracorporeal mechanical (bihormonal artificial pancreas), and implanted bioartificial (encapsulated islet) delivery systems. The purpose of this review is to compare these options and consider future developments. Use of whole organ pancreas transplant has declined in the USA over the past several years. Pancreas transplant offers the most durable form of beta cell replacement, especially in the context of a simultaneous kidney-pancreas transplant or a pancreas after kidney transplant. However, pancreatic transplant is associated with significant perioperative morbidity including the risk of a leak of exocrine secretions. Despite a decline in popularity, pancreas transplant outcomes remain excellent. Pancreatic islet transplant offers the opportunity for beta cell replacement with less morbidity. Islet cell transplant outcomes have improved requiring fewer donor pancreata to achieve insulin independence. However, islet cell recipients continue to incur the risk of lifelong immunosuppression, and, to date, long-term islet cell transplant outcomes are not equal to whole organ transplant. Mechanical solutions have progressed significantly, as technology as enable continuous glucose monitoring and bihormonal (insulin and glucagon) pumps. This technology is limited by the sensitivity of the glucose monitor and the time to effective absorption and distribution of subcutaneous administration of hormones. Finally, bioartificial encapsulated islets are in early clinical trials. Encapsulation results in an immune privileged environment eliminating the need for immunosuppression. However, long-term survival of the islets in vivo has not been established, and other barriers (e.g., fibrin deposition occluding the pores of the encapsulated islet) remain to be overcome. The optimal therapeutic choice for patients with type 1 diabetes must be personalized for the patient and address their specific comorbid conditions (specifically concomitant renal failure), surgical risk, and medical literacy. Increase options promise the opportunity for better glucose control and further reduction in secondary diabetic complications.

BACKGROUND: One of the primary risks of HIV-positive to HIV-positive organ transplantation is loss of virological control because of donor-derived HIV superinfection, which occurs when an HIV-positive individual becomes infected with a new distinct HIV strain. In this study, as part of the larger HIV Organ Policy Equity pilot study, HIV-positive to HIV-positive kidney and liver transplant recipients in the USA were examined for evidence of sustained donor-derived HIV superinfection. METHODS: In this multicentre, prospective, observational study, HIV-positive to HIV-positive kidney and liver transplant recipients were followed in three hospitals in the USA. Candidates with well controlled HIV infection on ART, no active opportunistic infections, and minimum CD4 T-cell counts (>100 cells per μL for liver and >200 cells per μL for kidney per federal guidelines) were eligible to receive a kidney or liver from deceased HIV-positive donors without active infections or neoplasm. Peripheral blood mononuclear cells were collected from donor–recipient pairs at the time of transplantation, and from recipients at several timepoints up to 3 years after transplantation. Donor samples were assessed for HIV RNA viral load, CD4 cell count, and antiretroviral drug-resistant mutations. Donor and recipient HIV proviral DNA, and viral RNA from the viraemic timepoint were sequenced using a site-directed next-generation sequencing assay for the reverse transcriptase and gp41 genes. Neighbour-joining phylogenetic trees and direct sequence comparison were used to detect the presence of HIV superinfection. This study is registered with ClinicalTrials.gov, NCT02602262. FINDINGS: 14 HIV-positive to HIV-positive kidney and eight liver transplant recipients were followed from March, 2016, to July, 2019. 17 recipients had adequate viral sequences allowing for HIV superinfection assessment. Eight donors were suppressed (viral load

We represent a group of investigators funded by the National Institutes of Health (R01AI120938, U01AI134591, U01AI138897) to conduct a prospective multicenter study of the landscape of HIV-infected (HIV+) donors and two prospective multicenter trials comparing outcomes between HIV+ recipients of HIV+ and non-HIV+ donor kidneys and livers. These clinical trials are ongoing (NCT02602262, NCT03500315, NCT03734393).

Belatacept, a T cell costimulation blocker, demonstrated superior renal function, lower cardiovascular risk, and improved graft and patient survival in renal transplant recipients. Despite the potential benefits, adoption of belatacept has been limited in part due to concerns regarding higher rates and grades of acute rejection in clinical trials. Since July 2011, we have utilized belatacept-based immunosuppression regimens in clinical practice. In this retrospective analysis of 745 patients undergoing renal transplantation at our center, we compared patients treated with belatacept (n = 535) with a historical cohort receiving a tacrolimus-based protocol (n = 205). Patient and graft survival were equivalent for all groups. An increased rate of acute rejection was observed in an initial cohort treated with a protocol similar to the low-intensity regimen from the BENEFIT trial versus the historical tacrolimus group (50.5% vs. 20.5%). The addition of a transient course of tacrolimus reduced rejection rates to acceptable levels (16%). Treatment with belatacept was associated with superior estimated GFR (belatacept 63.8 mL/min vs. tacrolimus 46.2 mL/min at 4 years, p < 0.0001). There were no differences in serious infections including rates of cytomegalovirus or BK viremia. We describe the development of a costimulatory blockade-based strategy that ultimately allows renal transplant recipients to achieve calcineurin inhibitor-free immunosuppression.

The current supply of deceased donor organs is insucient to meet the growing demand for transplantable organs. The median waiting time for a kidney from a deceased donor is over three years. Consequently, candidates for kidney transplantation are strongly encouraged to nd a living donor. However, many potential donors have low incomes and donation-related costs may discourage them from volunteering to be a donor. In 2008 the Department of Health and Human Services began to reimburse donor’s travel-related expenses via the National Living Donor Assistance Center (NLDAC). Using within transplant center variation in their applications for donor assistance, we use a dierence-in-dier ence model to estimate the impact of the NLDAC on the number of living donor kidney transplants. We nd that among participating transplant centers the program increased the number of living donor kidney transplants by approximately 14%. The NLDAC program provides an eective subsidy for donor’s altruism.

All 179 reports to the OPTN of potential renal cell carcinoma (RCC) transmission from 1/1/2008 through 12/31/2016 were reviewed. Cases were divided into those with donor tumor known or suspected at time of transplant (N = 147 donors), and those in which tumor was initially found after transplant (N = 32). We sought to understand the risk of transplanting either the affected kidney, the contralateral kidney or non-renal organs from donors with a suspected/confirmed unilateral RCC. In the case of RCC found prior to transplant, transplantation of 21 kidneys following excision of tumor, 47 contralateral kidneys and 198 non-renal organs was performed. No cases of RCC transmission were documented in this population. An additional six cases of live donor kidney transplantation involving resection of RCC were reported, also without transmission. Six of 9 other recipients in whom the diagnosis of RCC became available after implantation underwent allograft nephrectomy and 3 received tumor resection. No recurrent RCC was documented. Given the low rate of transmission and available treatment options, consideration should be given to judicious use of organs from donors with small solitary RCC.

Introduction The United Network for Organ Sharing (UNOS) implemented a new Kidney Allocation System (KAS) in December 2014 that is expected to substantially reduce racial disparities in kidney transplantation among waitlisted patients. However, not all dialysis facility clinical providers and end-stage renal disease (ESRD) patients are aware of how the policy change could improve access to transplantation. Methods We describe the ASCENT (Allocation System Changes for Equity in Kidney Transplantation) study, a randomized, controlled effectiveness-implementation study designed to test the effectiveness of a multicomponent intervention to improve access to the early steps of kidney transplantation among dialysis facilities across the United States. The multicomponent intervention consists of an educational webinar for dialysis medical directors, an educational video for patients and an educational video for dialysis staff, and a dialysis facility−specific transplantation performance feedback report. Materials will be developed by a multidisciplinary dissemination advisory board and will undergo formative testing in dialysis facilities across the United States. Results This study is estimated to enroll ∼600 US dialysis facilities with low waitlisting in all 18 ESRD networks. The co-primary outcomes include change in waitlisting and waitlist disparity at 1 year; secondary outcomes include changes in facility medical director knowledge about KAS, staff training regarding KAS, patient education regarding transplantation, and the intent of the medical director to refer patients for transplantation evaluation. Discussion The results from the ASCENT study will demonstrate the feasibility and effectiveness of a multicomponent intervention designed to increase access to the deceased donor kidney waitlist and to reduce racial disparities in waitlisting.

After over a decade of discussion, analysis, and consensus-building, a new kidney allocation system (KAS) was implemented on December 4, 2014. Key goals included improving longevity matching between donor kidneys and recipients and broadening access for historically disadvantaged subpopulations, in particular highly sensitized patients and those with an extended duration on dialysis but delayed referral for transplantation. To evaluate the early impact of KAS, we compared Organ Procurement and Transplantation Network data 1 year before versus after implementation. The distribution of transplants across many recipient characteristics has changed markedly and suggests that in many ways the new policy is achieving its goals. Transplants in which the donor and recipient age differed by more than 30 years declined by 23%. Initial, sharp increases in transplants were observed for Calculated Panel-Reactive Antibody 99-100% recipients and recipients with at least 10 years on dialysis, with a subsequent tapering of transplants to these groups suggesting bolus effects. Although KAS has arguably increased fairness in allocation, the potential costs of broadening access must be considered. Kidneys are more often being shipped over long distances, leading to increased cold ischemic times. Delayed graft function rates have increased, but 6-month graft survival rates have not changed significantly.

Costimulation blockade with the fusion protein belatacept provides a desirable side effect profile and improvement in renal function compared with calcineurin inhibition in renal transplantation. This comes at the cost of increased rates of early acute rejection. Blockade of the integrin molecule leukocyte function-associated antigen 1 (LFA-1) has been shown to be an effective adjuvant to costimulation blockade in a rigorous nonhuman primate (NHP) model of islet transplantation; therefore, we sought to test this combination in an NHP renal transplant model. Rhesus macaques received belatacept maintenance therapy with or without the addition of LFA-1 blockade, which was achieved using a murine-derived LFA-1-specific antibody TS1/22. Additional experiments were performed using chimeric rhesus IgG1 (TS1/22R1) or IgG4 (TS1/22R4) variants, each engineered to limit antibody clearance. Despite evidence of proper binding to the target molecule and impaired cellular egress from the intravascular space indicative of a therapeutic effect similar to prior islet studies, LFA-1 blockade failed to significantly prolong graft survival. Furthermore, evidence of impaired protective immunity against cytomegalovirus was observed. These data highlight the difficulties in translating treatment regimens between organ models and suggest that the primarily vascularized renal model is more robust with regard to belatacept-resistant rejection than the islet model.

OBJECTIVE Impaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in preventing SHEs in 50–80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment. RESEARCH DESIGN AND METHODS This multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA1c RESULTS The primary end point was successfully met by 87.5% of subjects at 1 year and by 71% at 2 years. The median HbA1c level was 5.6% (38 mmol/mol) at both 1 and 2 years. Hypoglycemia awareness was restored, with highly significant improvements in Clarke and HYPO scores (P > 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients. CONCLUSIONS Transplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs.

Pancreas transplantation offers a functional cure for many patients suffering from diabetes mellitus. Although the outcomes of pancreas transplants were originally plagued with high rates of acute cellular rejection, innovations in immunosuppression regimens over the last two decades have helped steadily improve the graft survival of pancreas transplants. This review surveys the latest trends in immunosuppressive management for pancreas transplant recipients, discussing the controversies and weighing the evidence supporting induction therapy, steroid avoidance/withdrawal, mTOR inhibitors, and new regimens based on costimulatory blockade agents.

In December of 2014, the Organ Procurement and Transplant Network (OPTN) implemented the first major change to kidney allocation policy in several decades. Now, with 2 years of follow-up, we can reflect on the kidney allocation system (KAS) and determine both the magnitude and effect of the policy

Our research utilizes the experimental economics laboratory to investigate the impact that reducing disincentives has on organ donation. The experiment consists of four treatments across different levels of donation related costs, which reflect the disincentives associated with being an organ donor. Our experimental results indicate that sizable increases in the organ donation rate are achievable if we reduce the level of disincentives present. The largest observed donation rates arise when a financial return is offered for being an organ donor, which is prohibited under the National Organ Transplant Act (NOTA), but nearly 80% of the gains observed under the positive financial incentives can be achieved if all of the disincentives are eliminated.

Solid organ pancreas transplantation is a durable treatment for establishing normal blood glucose levels in patients with diabetes. Historically, younger patients with type 1 diabetes have been the primary recipients of pancreas transplants. As surgical techniques and post-operative immunosuppression regimens have continued to improve, indications have expanded such that non-traditional recipients are being evaluated for pancreas transplantation. These recipients include patients with type 2 diabetes, patients older than 50 years of age, and patients with chronic infectious diseases, including HIV and HCV. Despite limited literature in these patient populations, pancreas transplantation is a viable treatment for endocrine pancreas failure in appropriately selected patients, regardless of disease etiology or age. This review summarizes the current literature on pancreas transplantation in non-traditional recipients.

Patients with end-stage renal disease (ESRD) demonstrate a greater risk for renal cell carcinoma (RCC) than the general population. This study compared pathological and clinical outcomes in patients with RCC with and without ESRD. Patients with ESRD who underwent nephrectomy and were found to have RCC at our institution since 1999 were identified. The control group was composed of patients from the general population with RCC. The primary outcome was risk of cancer recurrence. The study included 338 RCC patients: 84 with ESRD and 243 without ESRD. In the ESRD group, mean tumor size was smaller, there was decreased prevalence of advanced T category (>3) , and the average Karakiewicz nomogram score was lower. ESRD was associated with decreased tumor recurrence and clear cell pathology. No patients with ESRD had metastatic disease. There was no difference in overall or cancer-specific mortality between the ESRD and control groups. Patients with ESRD who develop RCC have a better prognosis compared to RCC in patients without ESRD, which is likely secondary to favorable histopathologic phenotype as well as the likelihood of early diagnosis. Thus, the delay between nephrectomy and renal transplantation may not be necessary, especially in patients with asymptomatic, low grade tumors.

PURPOSE OF REVIEW Advances in surgical technique and immunosuppression have significantly improved outcomes after pancreas transplantation, and as a result pancreas transplants increasingly are being performed for indications other than type 1 diabetes mellitus. This review summarizes the current literature on pancreas transplantation in unconventional recipient populations. RECENT FINDINGS An increasing body of work suggests that pancreas transplantation can be performed with good outcomes in patients with type 2 diabetes mellitus and those 50 years of age and older. Obesity appears detrimental to patient and pancreas graft survival, and bariatric surgery prior to transplantation may be of increasing interest and relevance. There are limited data yielding mixed outcomes on pancreas transplantation in patients with HIV or hepatitis C virus. However, rapidly improving antiviral therapies are prolonging survival in patients with HIV and chronic hepatitis C virus infections and may increase the number of candidates available for pancreas transplantation in these populations in the future. SUMMARY Despite limited literature in these patient populations, pancreas transplantation may be a viable treatment option for endocrine pancreas failure in appropriately selected patients regardless of disease cause or age.

The effect of CKD on the risks of bariatric surgery is not well understood. Using the American College of Surgeons National Surgical Quality Improvement Program Participant Use File, we analyzed 27,736 patients who underwent bariatric surgery from 2006 through 2008. Before surgery, 34 (0.12%) patients were undergoing long-term dialysis. Among those not undergoing dialysis, 20,806 patients (75.0%) had a normal estimated GFR or stage 1 CKD, 5011 (18.07%) had stage 2 CKD, 1734 (6.25%) had stage 3 CKD, 94 (0.34%) had stage 4 CKD, and 91 (0.33%) had stage 5 CKD. In an unadjusted analysis, CKD stage was directly associated with complication rate, ranging from 4.6% for those with stage 1 CKD or normal estimated GFR to 9.9% for those with stage 5 CKD (test for trend, P

Transplantation tolerance is a state of immune unresponsiveness (or benign responsiveness) to the presence of specific, nonself antigens in the absence of chronic immunosuppressive therapy. Renal transplant tolerance remains a desired yet generally unattained goal that would enable transplantation to be performed without the risk of graft rejection or the need for broadly immunosuppressive drugs, which can have toxic effects. Studies published in the past few years have provided evidence that B cells have an important role in both graft rejection and transplantation tolerance. Indeed, antibody-dependent and antibody-independent functions of B cells account for both tolerogenic and rejection-promoting immune responses in transplant recipients. This Review comprises a discussion of the mechanisms involved in the induction of B-cell tolerance and a survey of current and emerging therapies that target the effects of B cells in transplant recipients.

Screening recommendations for prostate cancer remain controversial, and no specific guidelines exist for screening in renal transplant candidates. To examine whether the use of prostate-specific antigen (PSA)–based screening in patients with ESRD affects time to transplantation and transplant outcomes, we retrospectively analyzed 3782 male patients ≥18 years of age undergoing primary renal transplant evaluation during a 10-year period. Patients were grouped by age per American Urological Association screening guidelines: group 1, patients 69 years. A positive screening test result was defined as a PSA level >4 ng/ml. We used univariate analysis and Cox proportional hazards models to identify the independent effect of screening on transplant waiting times, patient survival, and graft survival. Screening was performed in 63.6% of candidates, and 1198 candidates (31.7%) received kidney transplants. PSA screening was not associated with improved patient survival after transplantation (P=0.24). However, it did increase the time to listing and transplantation for candidates in groups 1 and 2 who had a positive screening result (P

The shortage of cadaveric donors for simultaneous pancreas-kidney transplantation has prompted the use of cadaveric organs from pediatric donors. The long-term outcome and its impact on overall long-term survival are unknown. A total of 680 recipients receiving cadaver Simultaneous pancreas-kidney (SPK) transplantation from pediatric and adult donors between July 1986 and September 2001 were analyzed and compared. Ten-year kidney and pancreas graft survival for SPK transplantation from donors aged18 years (n = 142) were 80% and 72%, respectively, compared to 61% pancreas and kidney graft survival from donorsor =18 years of age (n = 538; p = 0.03 and 0.05, respectively). Five years post-transplant, blood glucose, HbA1c and creatinine clearance were significantly better in recipients from pediatric donors (85.3 +/- 13 mg/dL, 5.5 +/- 3.5% and 65.6 +/- 16 mL/min, respectively), compared to recipients from adult donors (95.1 +/- 29 mg/dL, 5.9 +/- 3.5% and 58.3 +/- 17 mL/min; p = 0.001, 0.01 and 0.002, respectively). Causes of graft failure for kidney and pancreas transplants were similar between the two groups. No statistically significant difference was observed in patient survival between recipients from pediatric donors compared to adult donors (85% vs. 76%, p = 0.29). When recipients of SPK from pediatric donors were stratified according to age (3-11 years and 12-17 years) and compared, no difference in kidney or pancreas graft survival was observed (kidney 76.4% vs. 81.3%, p = 0.15; pancreas 75% vs. 76%, p = 0.10, respectively). Pediatric donors represent a valuable source of organs, providing excellent short- and long-term outcomes. Wide utilization of pediatric organs will substantially increase the donor pool.

Small animal models with the capacity to support engraftment of a functional human immune system are needed to facilitate studies of human alloimmunity. In the present investigation, non-obese diabetic (NOD) severe combined immunodeficient ( scid) β2-microglobulin-null ( B2mnull) mice engrafted with human peripheral blood lymphocytes (hu-PBL-NOD-sc/d B2mnull mice) were used as in vivo models for studying human skin allograft rejection. Hu-PBL-NOD- scid B2mnull mice were established by injection of human spleen cells or PBLs and transplanted with full-thickness allogeneic human skin. Human cell engraftment was enhanced by injection of anti-mouse CD122 antibody. The respective contributions of human CD4+ and CD8+ cells in allograft rejection were determined using depleting antibodies. Human skin grafts on unmanipulated NOD- scid B2mnull mice uniformly survived but on chimeric hu-PBL-NOD- scid B2mnull mice exhibited severe immune-mediated injury that often progressed to complete rejection. The alloaggressive hu-PBLs did not require prior in vitro sensitization to elicit targeted effector cell activity. Extensive mononuclear cell infiltration directed towards human-origin endothelium was associated with thrombosis and fibrin necrosis. No evidence of graft-versushost disease was detected. Either CD4+ or CD8+ T cells may mediate injury and alloimmune rejection of human skin grafts on hu-PBL-NOD-sc/d B2mnull mice. It is proposed that Hu-PBL-NOD-sc/d B2mnull mice engrafted with human skin will provide a useful model for analysis of interventions designed to modulate human allograft rejection.

BACKGROUND: Achieving immunological tolerance to transplanted myoblasts would reduce the adverse effects associated with the sustained immunosuppression required for this experimental therapeutic approach in Duchenne muscular dystrophic patients. METHODS: Mdx mice were transplanted with fully allogeneic BALB/c myoblasts in the tibialis anterior muscles. Seven days before transplantation (-7), host mice received 107 total donor spleen cells i.v. (donor-specific transfusion, DST) with 500 microg of anti-CD154 mAb i.p. on days -7, -4, 0, +4. RESULTS: Results showed a high level of dystrophin expression in 83, 60, and 20% of the mice 1, 3, and 6 months, respectively, after transplantation of myoblasts. No antibodies against the donor cells were produced up to 3 months after transplantation. However, abundant activated cytotoxic cells were present in muscles still expressing high percentage of dystrophin positive fibers. CONCLUSIONS: In conclusion, the DST + anti-CD154 mAb treatments effectively prolonged myoblast survival, but this treatment could not develop tolerance to complete allogeneic myoblast transplantation.

Eight manufacturing facilities participating in the National Institutes of Health-sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed.

Type I diabetes remains a significant clinical problem in need of a reliable, generally applicable solution. Both whole organ pancreas and islet allotransplantation have been shown to grant patients insulin independence, but organ availability has restricted these procedures to an exceptionally small subset of the diabetic population. Porcine islet xenotransplantation has been pursued as a potential means of overcoming the limits of allotransplantation, and several preclinical studies have achieved near-physiologic function and yearlong survival in clinically relevant pig to primate model systems. These proof-of-concept studies have suggested that xenogeneic islets may be poised for use in clinical trials. In this commentary, we examine recent progress in islet xenotransplantation, with a critical eye towards the gaps between the current state of the art and the state required for appropriate clinical investigation.

Background. Treatment with a single donor-specific transfusion (DST) plus a brief course of anti-CD154 monoclonal antibody (mAb) prolongs skin allograft survival in mice. It is known that prolongation of allograft survival by this method depends in part on deletion of alloreactive CD8+ T cells at the time of tolerance induction. Recent data suggest that infection with lymphocytic choriomeningitis virus (LCMV) abrogates the ability of this protocol to prolong graft survival. Methods. To study the mechanism by which viral infection abrogates allograft survival, we determined (1) the fate of tracer populations of alloreactive transgenic CD8+ T cells and (2) the duration of skin allograft survival following treatment with DST and anti-CD154 mAb in the presence or absence of LCMV infection. Results. We confirmed that treatment of uninfected mice with DST and anti-CD154 mAb leads to the deletion of alloreactive CD8+ T cells and is associated with prolongation of skin allograft survival. In contrast, treatment with DST and anti-CD154 mAb in the presence of intercurrent LCMV infection was associated with the failure to delete alloreactive CD8+ T cells and with the rapid rejection of skin allografts. The number of alloreactive CD8+ cells actually increased significantly, and the cells acquired an activated phenotype. Conclusions. Interference with the deletion of alloreactive CD8+ T cells mediated by DST and anti-CD154 mAb may in part be the mechanism by which viral infection abrogates transplantation tolerance induction.

Many transplantation programs utilize noninvasive abdominal and pelvic imaging in the pre-operative evaluation of recipient candidates. Practice patterns vary, and consensus guidelines addressing the risks and benefits of computed tomography (CT) and magnetic resonance imaging (MRI) in the pre-transplant evaluation process do not currently exist. In this single-center study, we examined the frequency, clinical significance, and associated costs of CT and MRI findings during the pre-transplant evaluation of renal transplant recipients. A retrospective chart review of 3041 adult patients who underwent a CT/CTA or MRI/MRA of the abdomen and pelvis for pre-transplant evaluation between 2005 and 2010 was performed. Pre-transplant imaging with MRI offered a more sensitive evaluation in comparison with CT, with the notable exception of abnormalities in which calcium was detected. Patients imaged with CT had a significantly greater proportion of subsequent clinical actions arising from imaging findings. The total financial cost of MRI was greater than that of CT. No cases of nephrogenic systemic fibrosis (NSF) in patients who received MultiHance gadolinium contrast were reported. In conclusion, the risks, benefits, and costs of CT/CTA and MRI/MRA must be carefully considered to optimize the pre-operative evaluation of renal transplant recipients.

The integrin αvβ6 activates latent transforming growth factor-β (TGF-β) within the kidney and may be a target for the prevention of chronic allograft fibrosis after kidney transplantation. However, TGF-β also has known immunosuppressive properties that are exploited by calcineurin inhibitors (CNIs); thus, the net benefit of αvβ6 inhibition remains undetermined. To assess the acute impact of interference with αvβ6 on acute rejection, we tested a humanized αvβ6-specific monoclonal antibody (STX-100) in a randomized, double-blinded, placebo-controlled nonhuman primate renal transplantation study to evaluate whether αvβ6 blockade alters the risk of acute rejection during CNI-based immunosuppression. Rhesus monkeys underwent renal allotransplantation under standard CNI-based maintenance immunosuppression; 10 biopsy-confirmed rejection-free animals were randomized to receive weekly STX-100 or placebo. Animals treated with STX-100 experienced significantly decreased rejection-free survival compared to placebo animals (p = 0.049). Immunohistochemical analysis confirmed αvβ6 ligand presence, and αvβ6 staining intensity was lower in STX-100-treated animals (p = 0.055), indicating an apparent blockade effect of STX-100. LAP, LTBP-1 and TGF-β were all decreased in animals that rejected on STX-100 compared to those that rejected on standard immunosuppression alone, suggesting a relevant effect of αvβ6 blockade on local TGF-β. These data caution against the use of αvβ6 blockade to achieve TGF-β inhibition in kidney transplantation.

The rapid expansion of the kidney transplant waiting list has heightened the awareness of the transplant and medical community tooptimize the use of donor organs. Despitethis, donors at increased risk of infectious transmission organs, organs that may be suitable for transplantation, are being discarded at significant rates (1‐4). Donors at increased risk of infectious transmission organs are those organs deemed by the OPTN to result in an increased risk of infectious transmission. Increasing the utilization of such organs may increase the number of patients who are able to receive a timely transplant. However, the use of infectious risk donor (IRD) organs, a new term coined by the authors, has appropriately come under additional scrutiny since the transmission of HIV and HCV to four transplant recipients in 2007 (5). The use of these high risk organs brings with it a rare, but potentially devastating risk. Transplant physicians as wellaspatientsmustmakeaconsidereddecisionontherisk/ benefit of accepting such an organ despite the fact that the trade off of risk and benefit is not fully known. In addition, the transplant community must also be mindful of the impact of infectious transmission on the public perception of the organ supply which may ultimately affect organ donation. In this issue Chow et al. (6) present a Markov decision process model designed to aid physicians (and patients) in the decision to accept or decline donors at increased risk of infectious transmission kidneys based on the estimated survival after accepting versus declining the offer. The ultimate goal of the model is to increase the utilization of donors at increased risk of infectious transmission kidneys. The authors are to be commended for the development of thismodelandforacknowledgingthelimitations.However, there are several aspects that require further study and consideration that may complement the model developed. Further it is important to acknowledge that any model predicatedonestimatedriskofaseverebutrareevent,may easily under or over estimate the risk depending on the accuracy of the assumptions made and changes in prevalence or by pure bad luck. Although the empirical model does illustrate the efficacy of utilizing donors at increased risk of infectious transmission organs (given the assumptions made), the model does not account for behaviors associated with accepting and rejectingdonors at increasedrisk of infectioustransmission organs at the physician and patient level. Specifically it assumesthatphysiciansoperateasperfectdecisionagents on behalf of their patients and that they understand the relevantprobabilitiesandutilizethemoptimally.Inessence

The transplant surgeon's decision to accept and utilize an organ typically is made within a constrained time window, explicitly cognizant of numerous health-related risks and under the potential influence of considerable regulatory and institutional pressures. This decision affects the health of two distinct populations, those patients receiving organ transplants and those waiting to receive a transplant; it also influences the physician's life and their institute's productivity. The numerous, at times nonaligned, incentives established by the complex clinical and regulatory environment, have been derived specifically to influence physicians' behaviors, and though well intended, may lead to responses that are nonoptimal when considering the myriad stakeholders being influenced. This may compromise the quality of care provided to the population at risk, and has potential to influence the physician-patient relationship. A synergistic collaboration between transplant physicians and economists that is focused on this decision environment may help to alleviate these strains. This viewpoint discusses behavioral economic principles and how they might be applied to transplantation. Specifically, the previous medical decision-making literature on transplantation will be reviewed and a discussion on how a behavioral model of physician decision making can be utilized will be explored. To date this approach has not been integrated into transplantation decision making.

OBJECTIVE To describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010. RESEARCH DESIGN AND METHODS A total of 677 islet transplant-alone or islet-after-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999–2002), mid (2003–2006), or recent (2007–2010) transplant era based on annual follow-up to 5 years. RESULTS Insulin independence at 3 years after transplant improved from 27% in the early era (1999–2002, n = 214) to 37% in the mid (2003–2006, n = 255) and to 44% in the most recent era (2007–2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001). Reduction of HbA1c and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting blood glucose stabilization also showed improvements in the most recent era. There were also modest reductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 year in 2007–2010 vs. 60–65% in 1999–2006 (P < 0.01). Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001). CONCLUSIONS The CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007–2010 compared with those in 1999–2006, with fewer islet infusions and adverse events per recipient.

Alloantigen exposure typically provokes an adaptive immune response that can foster rejection of transplanted organs, and these responses present the most formidable biological barrier to kidney transplantation. Although most cellular alloimmune responses can be therapeutically controlled with T-cell-specific immunosuppressants, humoral alloimmune responses remain relatively untamed. Importantly, humoral immunity, typically manifesting as allospecific antibody production, is increasingly recognized for its variable appearance after kidney transplantation. Indeed, the appearance of alloantibody can herald the onset of rapid and destructive antibody-mediated rejection or have no demonstrable acute effects. The factors determining the end result of alloantibody formation remain poorly understood. This review will discuss the breadth of alloantibody responses seen in clinical kidney transplantation and provide an overview of potential factors explaining the phenotypic variability associated with humoral alloimmunity. We propose several avenues ripe for future investigation including the influence of innate immune components and the potential influence of heterologous immune responses in determining the ultimate clinical import of an alloantibody response.

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.

The objective of this analysis was to compare the results of transplantation of livers, pancreases, kidneys, and lungs from donation after cardiac death (DCD) donors to organs transplanted from donation after brain death (DBD) donors.From January 1984 through July 2000, outcomes of 382 DCD kidneys were compared to 1,089 kidneys (SPK) transplants and 36 liver transplants from DCD donors were compared to 455 SPK and 510 liver transplants from DBD donors. Likewise, 31 simultaneous pancreas-kidneys transplants from DBD donors.The rate of delayed graft function (DGF) was higher in kidneys transplanted from DCD donors (27.5% versus 21.3%, p=0.01). Likewise, discharge creatinines were higher in recipients of DCD kidneys (1.9 mg/dL versus 1.7 mg/dL, p=0.001). There was no difference in 10-year graft survival between DCD and DBD recipients (45.0% versus 48.0%, p=0.054). No difference in 5-year pancreatic and renal allograft survival was seen after SPK from DCD or DBD donors. After liver transplantation, biliary strictures were higher in recipients of DCD livers (13.9% versus 8.0%, p=0.03). Likewise, 3-year patient and graft survivals were lower for recipients of DCD livers (65.8% versus 84.9%, p=0.01; and 58.6% versus 76.9%, p=0.006).This large experience with transplantation from DCD donors demonstrates that similar patient and graft survivals can be expected when compared to recipients of organs from DBD donors.

Achieving immunological tolerance to transplanted myoblasts would reduce the adverse effects associated with the sustained immunosuppression required for this experimental therapeutic approach in Duchenne muscular dystrophic patients.Mdx mice were transplanted with fully allogeneic BALB/c myoblasts in the tibialis anterior muscles. Seven days before transplantation (-7), host mice received 107 total donor spleen cells i.v. (donor-specific transfusion, DST) with 500 microg of anti-CD154 mAb i.p. on days -7, -4, 0, +4.Results showed a high level of dystrophin expression in 83, 60, and 20% of the mice 1, 3, and 6 months, respectively, after transplantation of myoblasts. No antibodies against the donor cells were produced up to 3 months after transplantation. However, abundant activated cytotoxic cells were present in muscles still expressing high percentage of dystrophin positive fibers.In conclusion, the DST + anti-CD154 mAb treatments effectively prolonged myoblast survival, but this treatment could not develop tolerance to complete allogeneic myoblast transplantation.

Completion of the First FDA Phase 3 Multicenter Trial of Islet Transplantation in Type 1 Diabetes by the NIH CIT Consortium