The rise and potential fall of pancreas transplantation.

BACKGROUND: The aim of this review is to bring pancreatic transplantation out of the specialist realm, informing practitioners about this important procedure, so that they feel better equipped to refer suitable patients for transplantation and manage, counsel and support when encountering them within their own speciality. SOURCES OF DATA: Narrative review conducted in May 2017. OVID interface searching EMBASE and MEDLINE databases, using Timeframe: Inception to June 1, 2017. Articles were assessed for clinical relevance and most up to date content with articles written in english as the only inclusion criteria. Other sources, used included conference proceedings/presentations, unpublished data from our institution (Oxford Transplant Centre). AREAS OF AGREEMENT: Pancreas transplantation has evolved from an experimental procedure to the gold standard of care for patients with type 1 diabetes and uraemia. Currently, it remains the most effective method of establishing and maintaining euglycemia over the longer term, halting and potentially reversing many of the secondary complications associated with diabetes. Significant improvements to quality of life and better life expectancy make it in the longer term, a lifesaving procedure compared to waiting candidates. AREAS OF CONTROVERSY: The future of solid organ pancreas transplantation remains uncertain, with extensive comorbidity and advances in alternative therapies makes the long-term growth of the procedure questionable. GROWING POINTS AND AREAS TIMELY FOR DEVELOPING RESEARCH: Therapies to alleviate problems associated with ischaemia reperfusion injury, graft pancreatitis and more effective monitoring methods for detecting and treating organ rejection are the key areas of growth.

Significance of steatosis in pancreatic transplantation.

The on-going success of whole organ pancreatic transplantation is dependent on overcoming the imbalance between demand and supply of optimal organs as well as tackling the vast comorbidity associated with the procedure. Pancreas steatosis is a common contributing factor to the problem and with obesity pandemics affecting the global population; the size and type of organs received from donors will only make steatosis more of an issue. The aim of this review is to highlight what is known about steatosis in the context of pancreas transplantation identifying potential methods to help its evaluation. Narrative review of literature from inception to June 2017, using OVID interface searching EMBASE and MEDLINE databases as well recent transplant conference data. All studies related to pancreas steatosis examined for clinical relevance with no exclusion criteria. Key ideas extracted and referenced. Pancreatic steatosis is not innocuous and is precariously regarded by transplant surgeons, however its associations with obesity, metabolic syndrome and long list of associated complications clearly show it needs more careful consideration. Radiologic and surgical advances now allow assessment of the fat content of organs, which could be used to quantify organs allowing better optimisation, but there is still much work to be done to refine the optimal method to achieve this.

The use of kinase inhibitors in solid organ transplantation.

INTRODUCTION: Despite the efficacy of current immunosuppression regimes used in solid organ transplantation, graft dysfunction, graft lost and antibody-mediated rejection continue to be problematic. As a result, clear attraction in exploiting key potential targets controlled by kinase phosphorylation has led to a number of studies exploring the use of these drugs in transplantation. Aim In this review, we consider the role of tyrosine kinase as a target in transplantation and summarize the relevant studies on kinase inhibitors that have been reported to date. METHODS: Narrative review of literature from inception to December 2016, using OVID interface searching EMBASE and MEDLINE databases. All studies related to kinase based immunosuppression were examined for clinical relevance with no exclusion criteria. Key ideas were extracted and referenced. CONCLUSION: The higher incidence of infections when using kinase inhibitors is an important consideration, however the number and range inhibitors and their clinical indications are likely to expand, but their exact role in transplantation is yet to be determined.

Preliminary Single-Center Canadian Experience of Human Normothermic Ex Vivo Liver Perfusion: Results of a Clinical Trial.

After extensive experimentation, outcomes of a first clinical normothermic machine perfusion (NMP) liver trial in the United Kingdom demonstrated feasibility and clear safety, with improved liver function compared with standard static cold storage (SCS). We present a preliminary single-center North American experience using identical NMP technology. Ten donor liver grafts were procured, four (40%) from donation after circulatory death (DCD), of which nine were transplanted. One liver did not proceed because of a technical failure with portal cannulation and was discarded. Transplanted NMP grafts were matched 1:3 with transplanted SCS livers. Median NMP was 11.5 h (range 3.3-22.5 h) with one DCD liver perfused for 22.5 h. All transplanted livers functioned, and serum transaminases, bilirubin, international normalized ratio, and lactate levels corrected in NMP recipients similarly to controls. Graft survival at 30 days (primary outcome) was not statistically different between groups on an intent-to-treat basis (p = 0.25). Intensive care and hospital stays were significantly more prolonged in the NMP group. This preliminary experience demonstrates feasibility as well as potential technical risks of NMP in a North American setting and highlights a need for larger, randomized studies.

Challenges in pancreas transplantation.

Whole-organ pancreas transplantation, either alone or combined with a kidney transplant, is the only definitive treatment for many patients with type 1 diabetes that restores normal glucose homoeostasis and insulin independence. Pancreas transplantation delays, or potentially prevents, secondary diabetes complications and is associated with improvement in patient survival when compared with either patients remaining on the waiting list or those receiving kidney transplant alone. Pancreas transplantation is safe and effective, with 1-year patient survival >97 % and graft survival rates of 85 % at 1 year and 76 % at 5 years in recent UK data. This review focuses on some current areas of interest in pancreas transplantation.

Machine Perfusion of Donor Livers for Transplantation: A Proposal for Standardized Nomenclature and Reporting Guidelines.

With increasing demand for donor organs for transplantation, machine perfusion (MP) promises to be a beneficial alternative preservation method for donor livers, particularly those considered to be of suboptimal quality, also known as extended criteria donor livers. Over the last decade, numerous studies researching MP of donor livers have been published and incredible advances have been made in both experimental and clinical research in this area. With numerous research groups working on MP, various techniques are being explored, often applying different nomenclature. The objective of this review is to catalog the differences observed in the nomenclature used in the current literature to denote various MP techniques and the manner in which methodology is reported. From this analysis, we propose a standardization of nomenclature on liver MP to maximize consistency and to enable reliable comparison and meta-analyses of studies. In addition, we propose a standardized set of guidelines for reporting the methodology of future studies on liver MP that will facilitate comparison as well as clinical implementation of liver MP procedures.

Liver Transplantation After Ex Vivo Normothermic Machine Preservation: A Phase 1 (First-in-Man) Clinical Trial.

The number of donor organs suitable for liver transplantation is restricted by cold preservation and ischemia-reperfusion injury. We present the first patients transplanted using a normothermic machine perfusion (NMP) device that transports and stores an organ in a fully functioning state at 37°C. In this Phase 1 trial, organs were retrieved using standard techniques, attached to the perfusion device at the donor hospital, and transported to the implanting center in a functioning state. NMP livers were matched 1:2 to cold-stored livers. Twenty patients underwent liver transplantation after NMP. Median NMP time was 9.3 (3.5-18.5) h versus median cold ischaemia time of 8.9 (4.2-11.4) h. Thirty-day graft survival was similar (100% NMP vs. 97.5% control, p = 1.00). Median peak aspartate aminotransferase in the first 7 days was significantly lower in the NMP group (417 IU [84-4681]) versus (902 IU [218-8786], p = 0.03). This first report of liver transplantation using NMP-preserved livers demonstrates the safety and feasibility of using this technology from retrieval to transplantation, including transportation. NMP may be valuable in increasing the number of donor livers and improving the function of transplantable organs.

Abdominal Wall Transplantation: Skin as a Sentinel Marker for Rejection.

Abdominal wall transplantation (AWTX) has revolutionized difficult abdominal closure after intestinal transplantation (ITX). More important, the skin of the transplanted abdominal wall (AW) may serve as an immunological tool for differential diagnosis of bowel dysfunction after transplant. Between August 2008 and October 2014, 29 small bowel transplantations were performed in 28 patients (16 male, 12 female; aged 41 ± 13 years). Two groups were identified: the solid organ transplant (SOT) group (n = 15; 12 ITX and 3 modified multivisceral transplantation [MMVTX]) and the SOT-AWTX group (n = 14; 12 ITX and 2 MMVTX), with the latter including one ITX-AWTX retransplantation. Two doses of alemtuzumab were used for induction (30 mg, 6 and 24 h after reperfusion), and tacrolimus (trough levels 8-12 ng/mL) was used for maintenance immunosuppression. Patient survival was similar in both groups (67% vs. 61%); however, the SOT-AWTX group showed faster posttransplant recovery, better intestinal graft survival (79% vs. 60%), a lower intestinal rejection rate (7% vs. 27%) and a lower rate of misdiagnoses in which viral infection was mistaken and treated as rejection (14% vs. 33%). The skin component of the AW may serve as an immune modulator and sentinel marker for immunological activity in the host. This can be a vital tool for timely prevention of intestinal graft rejection and, more important, avoidance of overimmunosuppression in cases of bowel dysfunction not related to graft rejection.

The UK Pancreas Allocation Scheme for Whole Organ and Islet Transplantation.

In order to develop a national allocation scheme for donor pancreases, factors affecting waiting time and transplant outcomes in the United States (US) and United Kingdom (UK) were analyzed and compared. Blood group, sensitization, dialysis requirement, and whether the patient was waiting for a kidney and pancreas or pancreas alone affected waiting time in both countries; ethnicity and body mass index (BMI) also affected waiting time in the US. Ninety-day pancreas survival was similar in the UK and US, and was poorer for patients receiving a pancreas alone, with older donors, higher BMI and longer duration of ischemia in both countries. Factors affecting outcome, together with published data on factors affecting islet transplantation, informed the development of a points based allocation scheme for deceased donor pancreases in the UK providing equitable access for both whole organ and islet recipients through a single waiting list. Analysis of the allocation scheme 3 years after its introduction in December 2010 showed that the results were broadly as simulated, with a significant reduction in the number of long waiting patients and an increase in the number of islet transplants. There remains a surplus of highly sensitized patients in the waiting list, which the scheme should address in time.

De novo donor-specific HLA antibodies: biomarkers of pancreas transplant failure.

This study assesses the role of posttransplant HLA antibody monitoring in the surveillance of pancreas transplant recipients. Four hundred thirty-three pancreas transplants were performed at the Oxford Transplant Centre 2006-2011 (317 simultaneous pancreas kidney [SPK] and 116 isolated pancreas [IP]). HLA antibody monitoring was performed at 0, 6 and 12 months and annually and during clinical events. There was no association between pancreas graft failure and recipient or donor characteristics. Posttransplant antibody status, available for 354 (81.8%) of recipients, demonstrated that 141 (39.8%) developed de novo HLA antibodies, of which 52 (36.9%) were de novo donor-specific HLA antibodies (DSA) (34 SPK, 18 IP). The development of antibodies to donor HLA, but not to nondonor HLA, was significantly associated with poorer graft outcomes, with 1- and 3-year graft survival inferior in SPK recipients (85.2% vs. 93.5%; 71.8% vs. 90.3%, respectively; log-rank p = 0.002), and particularly in IP recipients (50.0% vs. 82.9%; 16.7 vs. 79.4%, respectively; log-rank p = 0.001). In a multivariate analysis, development of de novo DSA emerged as a strong independent predictor of pancreas graft failure (hazard ratio 4.66, p < 0.001). This is the largest study to examine de novo HLA antibodies following pancreas transplantation and clearly defines a high-risk group in need of specific intervention.

Alemtuzumab and sirolimus in renal transplantation: six-year results of a single-arm prospective pilot study.

mTOR inhibitors avoid calcineurin nephrotoxicity, but sirolimus de novo is associated with unacceptable side effects and higher rejection rates. We have investigated a modified strategy: alemtuzumab induction with tacrolimus and mycophenolate maintenance, switching from tacrolimus to sirolimus at 6 months and stopping mycophenolate at 12 months. Here, we report the 6-year follow-up of 30 patients prospectively recruited to this single-arm pilot study and compare outcomes to a matched contemporaneous control group of 30 patients who received standard induction and calcineurin-inhibitor-based immunosuppression.Six-year patient and graft survival were 83% and 80%(alemtuzumab) versus 77% and 70% (control). Rejection rates in the first 6 months were similar in alemtuzumab (6.6%) and control groups (10%). A higher than expected incidence of rejection in the alemtuzumab group following cessation of mycophenolate at 1 year (17%) was mitigated in later patients by retaining low dose mycophenolate. Mean eGFR was higher in the alemtuzumab group at all time points but not significantly (p»0.16). Tacrolimus levels in the first 6 months were significantly higher in the contemporaneous control group (p<0.001). Alemtuzumab induction with initial treatment with tacrolimus enables conversion to sirolimus without the side effects and incidence of acute rejection seen in earlier protocols.

Novel approaches to preventing ischemia-reperfusion injury during liver transplantation.

Ischemia-reperfusion injury (IRI) results in profound allograft damage during liver transplantation. The process of IRI results in adenosine triphosphatase (ATP) depletion, the production of reactive oxygen species, and progressive tissue destruction. This injury process is accelerated on reperfusion in the recipient. Over the last decade an increasing body of literature has identified a complex interplay of molecular and cellular pathways responsible for causing IRI. This article summarizes recent developments, drawing on preclinical and clinical studies, focusing on how the detrimental effects of IRI can be prevented in liver transplantation. We present a balanced overview on how machine preservation technologies, the coagulation system, antioxidants, cytoprotective agents, cytokines, preservation solutions, and the innate and adaptive immune system can be targeted to prevent IRI in liver transplantation.

Pancreas transplantation from donors after circulatory death from the United Kingdom.

This study reports the comparative short-term results of pancreas transplantation from donors after circulatory death (DCD) (Maastricht III & IV), and pancreases from brainstem deceased donors (DBD). Between January 2006 and December 2010, 1009 pancreas transplants were performed in the United Kingdom, with 134 grafts from DCD and 875 from DBD. DCD grafts had no premortem pharmacological interventions performed. One-year pancreas and patient survival was similar between DCD and DBD, with pancreas graft survival significantly better in the DCD cohort if performed as an SPK. Early graft loss due to thrombosis (8% vs. 4%) was mainly responsible for early graft loss in the DCD cohort. These results from donors with broader acceptance criteria in age, body mass index, premortem interventions, etc. suggest that DCD pancreas grafts may have a larger application potential than previously recognized.

B cell repopulation after alemtuzumab induction-transient increase in transitional B cells and long-term dominance of naïve B cells.

In organ transplantation, the composition of the B-cell compartment is increasingly identified as an important determinant for graft outcome. Whereas naïve and transitional B cells have been associated with long-term allograft survival and operational tolerance, memory B cells have been linked to decreased allograft survival. Alemtuzumab induction therapy effectively depletes B cells, but is followed by rapid repopulation up to levels exceeding base line. The characteristics of the repopulating B cells are currently unknown. We studied the phenotypic and functional characteristics of B cells longitudinally in 19 kidney transplant recipients, before and at 6, 9 and 12 months after alemtuzumab induction therapy. A transient increase in transitional B cells and cells with phenotypic characteristics of regulatory B cells, as well as a long-term dominance in naïve B cells was found in alemtuzumab-treated kidney transplant recipients, which was not influenced by conversion from tacrolimus to sirolimus. At all time-points after treatment, B cells showed unaltered proliferative and IgM-producing capacity as compared to pretransplant samples, whereas the ability to produce IgG was inhibited long-term. In conclusion, induction therapy with alemtuzumab results in a long-term shift toward naïve B cells with altered phenotypic and functional characteristics.

Systematic review of total pancreatectomy and islet autotransplantation for chronic pancreatitis.

BACKGROUND: Total pancreatectomy and islet autotransplantation (TP/IAT) is a treatment option in a subset of patients with chronic pancreatitis. A systematic review of the literature was performed to evaluate the outcome of this procedure, with an attempt to ascertain when it is indicated. METHODS: MEDLINE (1950 to present), Embase (1980 to present) and the Cochrane Library were searched to identify studies of outcomes in patients undergoing TP/IAT. Cohort studies that reported the outcomes following the procedure were included. The MOOSE guidelines were used as a basis for this review. RESULTS: Five studies met the inclusion criteria. The techniques reported for pancreatectomy and islet cell isolation varied between studies. TP/IAT was successful in reducing pain in patients with chronic pancreatitis. Comparing morphine requirements before and after the procedure, two studies recorded significant reductions. Concurrent IAT reduced the insulin requirement after TP; the rate of insulin independence ranged from 46 per cent of patients at 5 years' mean follow-up to 10 per cent at 8 years. The impact on quality of life was poorly reported. The studies reviewed did not provide evidence for optimal timing of TP/IAT in relation to the evolution of chronic pancreatitis. CONCLUSION: This systematic review showed that TP/IAT had favourable outcomes with regard to pain reduction. Concurrent IAT enabled a significant proportion of patients to remain independent of insulin supplementation.

Simultaneous pancreas kidney transplantation in the HIV-positive patient.

HIV is no longer an absolute contraindication to solid organ transplantation. However, few reports have been published with regards to pancreas or simultaneous pancreas kidney transplantation in the HIV-positive recipient. We report, to our knowledge, the first simultaneous pancreas kidney transplantation (SPK) performed in an HIV-positive patient in the United Kingdom. We reflect on the article recently published by Miro et al in Transplantation Proceedings and highlight strategies used by our department to prevent drug interactions in these complex patients.