Preliminary assessment of the feasibility of autologous myeloid-derived suppressor cell infusion in non-human primate kidney transplantation.

Myeloid-derived suppressor cells (MDSC) are a heterogenous population of immunosuppressive myeloid cells now considered important immune regulatory cells in diverse clinical conditions, including cancer, chronic inflammatory disorders and transplantation. In rodents, MDSC administration can inhibit graft-versus-host disease lethality and enhance organ or pancreatic islet allograft survival. There is also evidence, however, that under systemic inflammatory conditions, adoptively-transferred MDSC can rapidly lose their suppressive function. To our knowledge, there are no reports of autologous MDSC administration to either human or clinically-relevant non-human primate (NHP) transplant recipients. Monocytic (m) MDSC have been shown to be more potent suppressors of T cell responses than other subsets of MDSC. Following their characterization in rhesus macaques, we have conducted a preliminary analysis of the feasibility and preliminary efficacy of purified mMDSC infusion into MHC-mismatched rhesus kidney allograft recipients. The graft recipients were treated with rapamycin and the high affinity variant of the T cell co-stimulation blocking agent cytotoxic T lymphocyte antigen 4 Ig (Belatacept) that targets the B7-CD28 pathway. Graft survival and histology were not affected by infusions of autologous, leukapheresis product-derived mMDSC on days 7 and 14 post-transplant (cumulative totals of 3.19 and 1.98 × 106 cells/kg in n = 2 recipients) compared with control monkeys that did not receive MDSC (n = 2). Sequential analyses of effector T cell populations revealed no differences between the groups. While these initial findings do not provide evidence of efficacy under the conditions adopted, further studies in NHP, designed to ascertain the appropriate mMDSC source and dose, timing and anti-inflammatory/immunosuppressive agent support are likely to prove instructive regarding the therapeutic potential of MDSC in organ transplantation.

Transplant advocacy in the era of the human immunodeficiency virus organ policy equity act.

In 2013, the Human Immunodeficiency Virus Organ Policy Equity (HOPE) Act was passed to permit the conduct of research on the transplantation of organs from donors infected with human immunodeficiency virus (HIV) into recipients who are HIV-positive. The HOPE Act workshop had many objectives including the discussion of the ethical issues involved in HIV-positive to HIV-positive transplantation, the informed consent process, and the role of independent advocates in the context of HIV to HIV transplantation. As of 2018, 22 transplant hospitals are approved, or undergoing approval, to perform HIV-positive to HIV-positive transplant surgeries, and this number is expected to grow. This study aims to: (i) briefly review the history and research of HIV+ transplantation prior to the HOPE Act, (ii) describe the ethical principles supporting the HOPE Act, (iii) characterize the informed consent process, and (iv) provide guidance regarding the role of independent advocates in the context of HIV-positive to HIV-positive transplantation.

Long-term Outcomes for Living Pancreas Donors in the Modern Era.

BACKGROUND: Living donor segmental pancreas transplants (LDSPTx) have been performed selectively to offer a preemptive transplant option for simultaneous pancreas-kidney recipients and to perform a single operation decreasing the cost of pancreas after kidney transplant. For solitary pancreas transplants, this option historically provided a better immunologic match. Although short-term donor outcomes have been documented, there are no long-term studies. METHODS: We studied postdonation outcomes in 46 segmental pancreas living donors. Surgical complications, risk factors (RF) for development of diabetes mellitus (DM) and quality of life were studied. A risk stratification model (RSM) for DM was created using predonation and postdonation RFs. Recipient outcomes were analyzed. RESULTS: Between January 1, 1994 and May 1, 2013, 46 LDSPTx were performed. Intraoperatively, 5 (11%) donors received transfusion. Overall, 9 (20%) donors underwent splenectomy. Postoperative complications included: 6 (13%) peripancreatic fluid collections and 2 (4%) pancreatitis episodes. Postdonation, DM requiring oral hypoglycemics was diagnosed in 7 (15%) donors and insulin-dependent DM in 5 (11%) donors. RSM with three predonation RFs (oral glucose tolerance test, basal insulin, fasting plasma glucose) and 1 postdonation RF, greater than 15% increase in body mass index from preoperative (Δ body mass index >15), predicted 12 (100%) donors that developed postdonation DM. Quality of life was not significantly affected by donation. Mean graft survival was 9.5 (±4.4) years from donors without and 9.6 (±5.4) years from donors with postdonation DM. CONCLUSIONS: LDSPTx can be performed with good recipient outcomes. The donation is associated with donor morbidity including impaired glucose control. Donor morbidity can be minimized by using RSM and predonation counseling on life style modifications postdonation.

Mechanism, assessment and management of pain in chronic pancreatitis: Recommendations of a multidisciplinary study group.

DESCRIPTION: Pain in patients with chronic pancreatitis (CP) remains the primary clinical complaint and source of poor quality of life. However, clear guidance on evaluation and treatment is lacking. METHODS: Pancreatic Pain working groups reviewed information on pain mechanisms, clinical pain assessment and pain treatment in CP. Levels of evidence were assigned using the Oxford system, and consensus was based on GRADE. A consensus meeting was held during PancreasFest 2012 with substantial post-meeting discussion, debate, and manuscript refinement. RESULTS: Twelve discussion questions and proposed guidance statements were presented. Conference participates concluded: Disease Mechanism: Pain etiology is multifactorial, but data are lacking to effectively link symptoms with pathologic feature and molecular subtypes. Assessment of Pain: Pain should be assessed at each clinical visit, but evidence to support an optimal approach to assessing pain character, frequency and severity is lacking. MANAGEMENT: There was general agreement on the roles for endoscopic and surgical therapies, but less agreement on optimal patient selection for medical, psychological, endoscopic, surgical and other therapies. CONCLUSIONS: Progress is occurring in pain biology and treatment options, but pain in patients with CP remains a major problem that is inadequately understood, measured and managed. The growing body of information needs to be translated into more effective clinical care.

Total pancreatectomy with islet autotransplantation: summary of a National Institute of Diabetes and Digestive and Kidney diseases workshop.

A workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases focused on research gaps and opportunities in total pancreatectomy with islet autotransplantation (TPIAT) for the management of chronic pancreatitis (CP). The session was held on July 23, 2014, and structured into 5 sessions: (1) patient selection, indications, and timing; (2) technical aspects of TPIAT; (3) improving success of islet autotransplantation; (4) improving outcomes after total pancreatectomy; and (5) registry considerations for TPIAT. The current state of knowledge was reviewed; knowledge gaps and research needs were specifically highlighted. Common themes included the need to identify which patients best benefit from and when to intervene with TPIAT, current limitations of the surgical procedure, diabetes remission and the potential for improvement, opportunities to better address pain remission, gastrointestinal complications in this population, and unique features of children with CP considered for TPIAT. The need for a multicenter patient registry that specifically addresses the complexities of CP and total pancreatectomy outcomes as well as postsurgical diabetes outcomes was repeatedly emphasized.

A validated model for predicting outcome after liver transplantation: implications on transplanting the extremely sick.

Given the organ shortage, there is a need to optimize outcome after liver transplantation (LT). We defined posttransplant hospital length of stay > 60 days (LOS > 60) as a surrogate of suboptimal outcome. In the first phase of the study, a 'Study cohort' (SC) of 643 patients was used to identify risk factors and construct a mathematical model to identify recipients with anticipated inferior results. In the second phase, a cohort of 417 patients was used for validation of the model ['Validation Cohort' (VC)]. In the SC, 65 patients (10.1%) had LOS > 60 days. One- and 3-year patient/graft survival rates were 81.9%/76.1% and 73.4%/67.4%, respectively. Patient and graft survival rates of those with LOS > 60 days were inferior (P < 0.0001), while transplant cost was greater [3.42 relative units (RU) vs. 1 RU, P < 0.0001]. In a multivariable analysis, pretransplant dialysis (P < 0.001), mechanical ventilation (P < 0.015), MELD (P < 0.003), and age (P < 0.009) were predictors of LOS > 60 days [ROC curve - 0.75 (95% CI 0.70, 0.81)]. In the VC, 53 patients (12.7%) were expected to have adverse outcome by the model. These patients had longer LOS (P < 0.0001), higher cost (<0.0001), and inferior patient and graft survival (P < 0.007).

The development of practice guidelines for independent living donor advocates.

The practice recommendations discussed here are based on the findings of the national survey as well as the opinions of the authors. The recommendations that are proposed here are not exhaustive and are aspirational in intent and are likely to evolve with time. Practice guidelines are recommended for legal and regulatory issues (e.g., state or federal laws), consumer or public benefit (e.g., improving service delivery, avoiding harm to the patient, decreasing disparities in underserved or vulnerable populations), and for professional guidance (e.g., new role, professional risk management issues, advances in practice). Without such practice guidelines, donors, and indirectly the candidates, may be at increased risk for possible bias or undue harm.