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.

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 Other sources, used included conference proceedings/presentations, unpublished data from our institution (Oxford Transplant Centre).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.

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.

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.

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.

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.

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.

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.

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.

Systematic review of outcome of downstaging hepatocellular cancer before liver transplantation in patients outside the Milan criteria.

BACKGROUND: The aim of this systematic review was to assess the evidence on tumour downstaging before liver transplantation in patients with hepatocellular carcinoma (HCC) initially staged beyond the Milan criteria. METHODS: MEDLINE (from 1952), Embase (from 1980) and the Cochrane Library were searched. The review included cohort studies that reported the outcomes of patients with HCC outside the Milan criteria who underwent downstaging before transplantation. RESULTS: Eight studies met the inclusion criteria and included a total of 720 patients who underwent transplantation following downstaging after initial presentation with disease outside the Milan criteria. The rate of successful downstaging varied from 24 to 69 per cent of patients. Reported survival rates ranged from 82 to 100 per cent, 79 to 100 per cent and 54·6 to 94 per cent at 1, 3 and 5 years respectively. These were comparable with results for patients presenting within the Milan criteria. CONCLUSION: Successful downstaging of HCC to within the Milan criteria is feasible in a proportion of patients. Absolute and disease-free survival rates in patients transplanted following downstaging are comparable to those in patients within the Milan criteria.

Cold machine perfusion versus static cold storage of kidneys donated after cardiac death: a UK multicenter randomized controlled trial.

One third of deceased donor kidneys for transplantation in the UK are donated following cardiac death (DCD). Such kidneys have a high rate of delayed graft function (DGF) following transplantation. We conducted a multicenter, randomized controlled trial to determine whether kidney preservation using cold, pulsatile machine perfusion (MP) was superior to simple cold storage (CS) for DCD kidneys. One kidney from each DCD donor was randomly allocated to CS, the other to MP. A sequential trial design was used with the primary endpoint being DGF, defined as the necessity for dialysis within the first 7 days following transplant. The trial was stopped when data were available for 45 pairs of kidneys. There was no difference in the incidence of DGF between kidneys assigned to MP or CS (58% vs. 56%, respectively), in the context of an asystolic period of 15 min and median cold ischemic times of 13.9 h for MP and 14.3 h for CS kidneys. Renal function at 3 and 12 months was similar between groups, as was graft and patient survival. For kidneys from controlled DCD donors (with mean cold ischemic times around 14 h), MP offers no advantage over CS, which is cheaper and more straightforward.

Pancreas allograft thrombosis following intravenous immunoglobulin administration to treat parvovirus B19 infection.

Pancreas graft thrombosis is one of the commonest non-immunological causes for early graft loss after transplantation. This case report describes a patient who developed graft thrombosis after intravenous immunoglobulin administration to treat acute parvovirus B19 infection. The potential role of hypercoagulability in graft thrombosis and the implications for immunoglobulin therapy in transplant patients with hypercoagulable states is discussed.

Polyoma virus infection and urothelial carcinoma of the bladder following renal transplantation.

Renal transplant recipients are at increased risk of bladder carcinoma. The aetiology is unknown but a polyoma virus (PV), BK virus (BKV), may play a role; urinary reactivation of this virus is common post-renal transplantation and PV large T-antigen (T-Ag) has transforming activity. In this study, we investigate the potential role of BKV in post-transplant urothelial carcinoma by immunostaining tumour tissue for PV T-Ag. There was no positivity for PV T-Ag in urothelial carcinomas from 20 non-transplant patients. Since 1990, 10 transplant recipients in our unit have developed urothelial carcinoma, and tumour tissue was available in eight recipients. Two patients were transplanted since the first case of PV nephropathy (PVN) was diagnosed in our unit in 2000 and both showed PV reactivation post-transplantation. In one of these patients, there was strong nuclear staining for PV T-Ag in tumour cells, with no staining of non-neoplastic urothelium. We conclude that PV infection is not associated with urothelial carcinoma in non-transplant patients, and is uncommon in transplant-associated tumours. Its presence in all tumour cells in one patient transplanted in the PVN era might suggest a possible role in tumorigenesis in that case.

Alemtuzumab induction and steroid-free maintenance immunosuppression in pancreas transplantation.

Alemtuzumab is a humanized anti-CD52 antibody that depletes lymphocytes and has been increasingly used as induction agent in transplantation. The impact of alemtuzumab induction immunosuppression in pancreas transplantation was evaluated, with particular reference to steroid avoidance in maintenance. A total of 100 patients who received 102 pancreas transplants (83 simultaneous kidney-pancreas [SPK], 15 pancreas after kidney transplantation [PAK] and 4 pancreas transplant alone [PTA]) were included. All patients received two doses of 30-mg alemtuzumab i.v. with tacrolimus (trough level 8-12 ng/mL) and mycophenolate mofetil (MMF,1g/day) with no maintenance steroids. This analysis included 62 male and 38 female recipients, with mean (+/-SD) age of 42 (+/-7.6) years. Median follow-up was 17 months (range 8-41 months). One-year patient, pancreas and kidney graft survival (actuarial) was 97%, 89% and 94%, respectively. Overall incidence of rejection was 25%. Side effects of alemtuzumab administration included thrombocytopenia (14%), pulmonary edema (2%) and rash (1%). Twenty-five percent required reoperations (12% for bleeding). Infectious complications included Cytomegalovirus (CMV,6.8%) BK viruria (3.8%), fungal infections (4%), primary varicella (1%) and posttransplant lymphoproliferative disorders (PTLD,1%). Eighty-three percent did not require any steroids posttransplant. These results indicate that alemtuzumab is safe and enables pancreas transplantation to be carried out without maintenance steroids in 83% of cases and acceptable rejection rate.

Role of transplantation in the management of hepatic malignancy.

BACKGROUND: The acceptance of liver transplantation in the management of hepatic malignancy declined after early poor outcomes. Despite recent developments, including stricter selection criteria and improved adjuvant therapies, the role of liver transplantation in the management of cancer remains controversial. This review explores the evidence for the current role of liver transplantation in the management of hepatic malignancy in the context of recent advances in surgical resection and non-surgical treatments. METHODS: A literature search was conducted using the Cochrane Library and Ovid MEDLINE and EMBASE, using terms for hepatic malignancy and interventions that included liver transplantation, percutaneous interventions, chemotherapy and surgical resection. RESULTS AND CONCLUSION: In patients with primary hepatocellular carcinoma, improved selection has led to outcomes equivalent to those from surgical resection and comparable to those in patients transplanted for non-malignant indications. Recent studies suggest that selection criteria may be refined further. Surgical resection or percutaneous therapies may reduce the risk of progression while waiting for a transplant. Recent improvements have occurred in neoadjuvant therapies for cholangiocarcinoma. Nevertheless, a number of questions regarding the role of liver transplantation for hepatic malignancy remain.

The influence of pulsatile preservation in kidney transplantation from non-heart-beating donors.

Continuous hypothermic pulsatile perfusion (CHPP) may offer improved early function compared with cold static perfusion (CSP) for heart-beating cadaveric donors. With an expanding pool of donors, ie, non-heart-beating donors (NHBD), we present our preliminary results with the use of CHPP compared with CSP to preserve kidney grafts retrieved from NHBD. Eighteen consecutive locally procured cadaveric kidneys from NHBD were preserved using CHPP using UW machine perfusion solution in the Life Port kidney transporter. Perfusion parameters were measured serially during pulsatile perfusion. This group was compared with 18 NHBD cadaveric kidneys preserved with CSP. No organs were lost due to faulty technique of preparation or preparation of pulsatile perfusion. Immediate renal function was observed in 13 cases (72.2%). In CSP in NHBD, we had 16 cases with delayed graft function (88.8%). These early results show that the use of pulsatile perfusion to preserve kidneys from NHBD may be associated with improved early outcomes. Longer follow-up is required to answer the more important question as to whether it offers long-term improvements that justify the extra cost and complexity.