Chronic Pancreas Allograft Rejection Followed by Successful HLA-Incompatible Islet Alloautotransplantation:A Novel Strategy?

The purpose of pancreas or islet transplantation is to restore glycemic control in order to mitigate diabetes-related complications and prevent severe hypoglycemia. Complications from chronic pancreas allograft rejection may lead to transplantectomy, even when the endocrine function remains preserved. We present first evidence of a successful HLA incompatible islet re-transplantation with islets isolated from a rejecting pancreas allograft after simultaneous kidney pancreas transplantation. The pancreas allograft was removed because of progressively painful pancreatic panniculitis from clinically uncontrolled chronic rejection. The endocrine function was preserved. Induction treatment for this “islet alloautotransplantation” consisted of plasmapheresis, IVIg and alemtuzumab. At 1 year, the patient retained islet graft function with good glycemic control and absence of severe hypoglycemia, despite persistent low-grade HLA donor-specific antibodies. His panniculitis had resolved completely. In our point of view, islet alloautotransplantation derived from a chronically rejecting pancreas allograft is a potential option to salvage (partial) islet function, despite preformed donor-specific antibodies, in order to maintain stable glycemic control. Thereby it protects against severe hypoglycemia, and it potentially mitigates kidney graft dysfunction and other diabetes-related complications in patients with continued need for immunosuppression and who are otherwise difficult to retransplant.</p

Chronic Pancreas Allograft Rejection Followed by Successful HLA-Incompatible Islet Alloautotransplantation:A Novel Strategy?

The purpose of pancreas or islet transplantation is to restore glycemic control in order to mitigate diabetes-related complications and prevent severe hypoglycemia. Complications from chronic pancreas allograft rejection may lead to transplantectomy, even when the endocrine function remains preserved. We present first evidence of a successful HLA incompatible islet re-transplantation with islets isolated from a rejecting pancreas allograft after simultaneous kidney pancreas transplantation. The pancreas allograft was removed because of progressively painful pancreatic panniculitis from clinically uncontrolled chronic rejection. The endocrine function was preserved. Induction treatment for this “islet alloautotransplantation” consisted of plasmapheresis, IVIg and alemtuzumab. At 1 year, the patient retained islet graft function with good glycemic control and absence of severe hypoglycemia, despite persistent low-grade HLA donor-specific antibodies. His panniculitis had resolved completely. In our point of view, islet alloautotransplantation derived from a chronically rejecting pancreas allograft is a potential option to salvage (partial) islet function, despite preformed donor-specific antibodies, in order to maintain stable glycemic control. Thereby it protects against severe hypoglycemia, and it potentially mitigates kidney graft dysfunction and other diabetes-related complications in patients with continued need for immunosuppression and who are otherwise difficult to retransplant.</p

Hypothermic Machine Perfusion in Liver Transplantation - A Randomized Trial

BACKGROUND Transplantation of livers obtained from donors after circulatory death is associated with an increased risk of nonanastomotic biliary strictures. Hypothermic oxygenated machine perfusion of livers may reduce the incidence of biliary complications, but data from prospective, controlled studies are limited. METHODS In this multicenter, controlled trial, we randomly assigned patients who were undergoing transplantation of a liver obtained from a donor after circulatory death to receive that liver either after hypothermic oxygenated machine perfusion (machine-perfusion group) or after conventional static cold storage alone (control group). The primary end point was the incidence of nonanastomotic biliary strictures within 6 months after transplantation. Secondary end points included other graft-related and general complications. RESULTS A total of 160 patients were enrolled, of whom 78 received a machine-perfused liver and 78 received a liver after static cold storage only (4 patients did not receive a liver in this trial). Nonanastomotic biliary strictures occurred in 6% of the patients in the machine-perfusion group and in 18% of those in the control group (risk ratio, 0.36; 95% confidence interval [CI], 0.14 to 0.94; P=0.03). Postreperfusion syndrome occurred in 12% of the recipients of a machine-perfused liver and in 27% of those in the control group (risk ratio, 0.43; 95% CI, 0.20 to 0.91). Early allograft dysfunction occurred in 26% of the machine-perfused livers, as compared with 40% of control livers (risk ratio, 0.61; 95% CI, 0.39 to 0.96). The cumulative number of treatments for nonanastomotic biliary strictures was lower by a factor of almost 4 after machine perfusion, as compared with control. The incidence of adverse events was similar in the two groups. CONCLUSIONS Hypothermic oxygenated machine perfusion led to a lower risk of nonanastomotic biliary strictures following the transplantation of livers obtained from donors after circulatory death than conventional static cold storage

Cellular Islet Autoimmunity Associates with Clinical Outcome of Islet Cell Transplantation

Islet cell transplantation can cure type 1 diabetes (T1D), but only a minority of recipients remains insulin-independent in the following years. We tested the hypothesis that allograft rejection and recurrent autoimmunity contribute to this progressive loss of islet allograft function.Twenty-one T1D patients received cultured islet cell grafts prepared from multiple donors and transplanted under anti-thymocyte globulin (ATG) induction and tacrolimus plus mycophenolate mofetil (MMF) maintenance immunosuppression. Immunity against auto- and alloantigens was measured before and during one year after transplantation. Cellular auto- and alloreactivity was assessed by lymphocyte stimulation tests against autoantigens and cytotoxic T lymphocyte precursor assays, respectively. Humoral reactivity was measured by auto- and alloantibodies. Clinical outcome parameters--including time until insulin independence, insulin independence at one year, and C-peptide levels over one year--remained blinded until their correlation with immunological parameters. All patients showed significant improvement of metabolic control and 13 out of 21 became insulin-independent. Multivariate analyses showed that presence of cellular autoimmunity before and after transplantation is associated with delayed insulin-independence (p = 0.001 and p = 0.01, respectively) and lower circulating C-peptide levels during the first year after transplantation (p = 0.002 and p = 0.02, respectively). Seven out of eight patients without pre-existent T-cell autoreactivity became insulin-independent, versus none of the four patients reactive to both islet autoantigens GAD and IA-2 before transplantation. Autoantibody levels and cellular alloreactivity had no significant association with outcome.In this cohort study, cellular islet-specific autoimmunity associates with clinical outcome of islet cell transplantation under ATG-tacrolimus-MMF immunosuppression. Tailored immunotherapy targeting cellular islet autoreactivity may be required. Monitoring cellular immune reactivity can be useful to identify factors influencing graft survival and to assess efficacy of immunosuppression.Clinicaltrials.gov NCT00623610

Simultaneous Pancreas-Kidney Transplant After Bricker Loop Urinary Diversion: a case report

Simultaneous pancreas-kidney transplant is the ultimate therapy for patients who have uncontrolled and complicated type 1 diabetes mellitus with end-stage renal disease. The combined pancreas transplant provides a euglycemic milieu for the kidney and protects it from recurrence of diabetic complications. Our patient, a 41-year-old woman with end-stage diabetic nephropathy and history of multiple abdominal surgeries (ovarian cyst fenestration, adnexal extirpation, abdominal wall reconstruction), including urinary diversion (Bricker loop, above double J stent), underwent simultaneous pancreas-kidney transplant. After reperfusion, the kidney had immediate function and creatinine levels dropped to normal levels during the early postoperative period (creatinine of 102 mu mol/L, estimated glomerular filtration rate of 52 mL/min/1.73 m(2)) and remained stable during follow-up. Serum glucose levels dropped to within normal ranges postoperatively and remained so during follow-up. The postoperative course was complicated by hydronephrosis due to transient edema of the anastomosis of the ureter to the Bricker loop, after early incidental removal of the double J catheter. This was successfully treated with a temporary percutaneous nephrostomy. Multiple previous surgeries, including a Bricker deviation, may not be a definitive contraindication for simultaneous pancreas-kidney transplant. In selected cases, special considerations may lead to a successful procedure providing better quality of life and life expectancy, even for patients with multiple comorbidities.Transplant surger

A steady decline in pancreas transplantation rates.

BACKGROUND/OBJECTIVES: After years of growth in many pancreas transplant programs, UNOS has reported declining transplant numbers in the USA. This precipitating trend urges for an evaluation of the transplant numbers and scientific productivity in the Eurotransplant region and the UK. METHODS: We performed a trend analysis of pancreas transplantation rates, between 1997 and 2016, adjusting for changes in population size, and an analysis of scientific publications in this field. We used information from the UNOS, Eurotransplant, and UK transplant registry and bibliometric information from the Web of Science database. RESULTS: Between 2004 and 2016 there was an average annual decline in pancreas transplantation rates per million inhabitants of 3.3% in the USA and 2.5% in the Eurotransplant region. In the UK, transplant numbers showed an average annual decline of 1.0% from 2009 to 2016. Publications in Q1 journals showed an annual change of -2.1% and +20.1%, before 2004, and a change of -3.8% and -5.5%, between 2004 and 2016, for USA and Eurotransplant publications, respectively. CONCLUSIONS: Adjusting pancreas transplantation rates for changes in population size showed a clear decline in transplant numbers in both the USA and Eurotransplant region, with first signs of decline in the UK. Following this trend, the number of scientific publications in this field have declined worldwide

The role of flavin mononucleotide (FMN) as a potentially clinically relevant biomarker to predict the quality of kidney grafts during hypothermic (oxygenated) machine perfusion

Hypothermic machine perfusion (HMP) provides preservation superior to cold storage and may allow for organ assessment prior to transplantation. Since flavin mononucleotide (FMN) in perfusate has been proposed as a biomarker of organ quality during HMP of donor livers, the aim of this study was to validate FMN as a biomarker for organ quality in the context of HMP preserved kidneys. Perfusate samples (n = 422) from the paired randomised controlled COPE-COMPARE-trial, comparing HMP with oxygenation (HMPO2) versus standard HMP in kidneys, were used. Fluorescence intensity (FI) was assessed using fluorescence spectroscopy (excitation 450nm; emission 500-600nm) and validated by fluorospectrophotometer and targeted liquid chromatography mass spectrometry (LC-MS/MS). Fluorescence intensity (FI)(ex450;em500-600) increased over time during machine perfusion in both groups (p<0.0001). This increase was similar for both groups (p = 0.83). No correlation, however, was found between FI(ex450;em500-600) and post-transplant outcomes, including day 5 or 7 serum creatinine (p = 0.11; p = 0.16), immediate graft function (p = 0.91), creatinine clearance and biopsy-proven rejection at one year (p = 0.14; p = 0.59). LC-MS/MS validation experiments of samples detected FMN in only one perfusate sample, whilst the majority of samples with the highest fluorescence (n = 37/38, 97.4%) remained negative. In the context of clinical kidney HMP, fluorescence spectroscopy unfortunately appears to be not specific and probably unsuitable for FMN. This study shows that FMN does not classify as a clinically relevant predictive biomarker of kidney graft function after transplantation

Thirty Years of Pancreas Transplantation at Leiden University Medical Center: Long-Term Follow-Up in a Large Eurotransplant Center

BACKGROUND: An overview of 30 years of pancreas transplantation at a high volume center. Analysis of patient survival- and graft survival-associated risk factors. METHODS: All pancreas transplantations performed in our center from January 1, 1984, till December 31, 2012, were evaluated. Covariates influencing pancreas graft survival were analyzed using both univariate and multivariate analysis and Kaplan-Meier analysis. RESULTS: In the study period, 349 pancreas transplantations were performed. With the introduction of modern induction therapy in 1999, 5-year patient survival improved to 92.0% (P = 0.003). Five-year pancreas graft survival improved to 80.3% (P = 0.026). Pancreas graft survival was influenced by left or right donor kidney, transplant type, local origin of procurement team, pancreas cold ischemia time, recipient cerebrovascular disease. Pancreas donor risk index increased to 1.39 over the years and pancreas donor risk index 1.24 or higher is a risk factor for graft survival (P = 0.007). CONCLUSIONS: This study has shown excellent results in patient and pancreas graft survivals after 30 years of pancreas transplantation in a high volume center. Different donor, transplant, and recipient related risk factors influence pancreas graft survival. Even with higher risk pancreas donors, good results can be achieved