Beta-cell death and dysfunction drives hyperglycaemia in organ donors.

BACKGROUND: Donor hyperglycaemia following brain death has been attributed to reversible insulin resistance. However, our islet and pancreas transplant data suggest that other mechanisms may be predominant. We aimed to determine the relationships between donor insulin use and markers of beta-cell death and beta-cell function in pancreas donors after brain death. METHODS: In pancreas donors after brain death, we compared clinical and biochemical data in 'insulin-treated' and 'not insulin-treated donors' (IT vs. not-IT). We measured plasma glucose, C-peptide and levels of circulating unmethylated insulin gene promoter cell-free DNA (INS-cfDNA) and microRNA-375 (miR-375), as measures of beta-cell death. Relationships between markers of beta-cell death and islet isolation outcomes and post-transplant function were also evaluated. RESULTS: Of 92 pancreas donors, 40 (43%) required insulin. Glycaemic control and beta-cell function were significantly poorer in IT donors versus not-IT donors [median (IQR) peak glucose: 8 (7-11) vs. 6 (6-8) mmol/L, p = .016; C-peptide: 3280 (3159-3386) vs. 3195 (2868-3386) pmol/L, p = .046]. IT donors had significantly higher levels of INS-cfDNA [35 (18-52) vs. 30 (8-51) copies/ml, p = .035] and miR-375 [1.050 (0.19-1.95) vs. 0.73 (0.32-1.10) copies/nl, p = .05]. Circulating donor miR-375 was highly predictive of recipient islet graft failure at 3 months [adjusted receiver operator curve (SE) = 0.813 (0.149)]. CONCLUSIONS: In pancreas donors, hyperglycaemia requiring IT is strongly associated with beta-cell death. This provides an explanation for the relationship of donor IT with post-transplant beta-cell dysfunction in transplant recipients.

Donor insulin therapy in intensive care predicts early outcomes after pancreas transplantation.

AIMS/HYPOTHESIS: Approximately 50% of organ donors develop hyperglycaemia in intensive care, which is managed with insulin therapy. We aimed to determine the relationships between donor insulin use (DIU) and graft failure in pancreas transplantation. METHODS: UK Transplant Registry organ donor data were linked with national data from the UK solid pancreas transplant programme. All pancreas transplants performed between 2004 and 2016 with complete follow-up data were included. Logistic regression models determined associations between DIU and causes of graft failure within 3 months. Area under the receiver operating characteristic curve (aROC) and net reclassification improvement (NRI) assessed the added value of DIU as a predictor of graft failure. RESULTS: In 2168 pancreas transplant recipients, 1112 (51%) donors were insulin-treated. DIU was associated with a higher risk of graft loss from isolated islet failure: OR (95% CI), 1.79 (1.05, 3.07), p = 0.03, and this relationship was duration/dose dependent. DIU was also associated with a higher risk of graft loss from anastomotic leak (2.72 [1.07, 6.92], p = 0.04) and a lower risk of graft loss from thrombosis (0.62 [0.39, 0.96], p = 0.03), although duration/dose-dependent relationships were only identified in pancreas transplant alone/pancreas after kidney transplant recipients with grafts failing due to thrombosis (0.86 [0.74, 0.99], p = 0.03). The relationships between donor insulin characteristics and isolated islet failure remained significant after adjusting for potential confounders: DIU 1.75 (1.02, 2.99), p = 0.04; duration 1.08 (1.01, 1.16), p = 0.03. In multivariable analyses, donor insulin characteristics remained significant predictors of lower risk of graft thrombosis in pancreas transplant alone/pancreas after kidney transplant recipients: DIU, 0.34 (0.13, 0.90), p = 0.03; insulin duration/dose, 0.02 (0.001, 0.85), p = 0.04. When data on insulin were added to models predicting isolated islet failure, a significant improvement in discrimination and risk reclassification was observed in all models: no DIU aROC 0.56; DIU aROC 0.57, p = 0.86; NRI 0.28, p < 0.00001; insulin duration aROC 0.60, p = 0.47; NRI 0.35, p < 0.00001. CONCLUSIONS/INTERPRETATION: DIU predicts graft survival in pancreas transplant recipients. This assessment could help improve donor selection and thereby improve patient and graft outcomes.

Peri-transplant glycaemic control as a predictor of pancreas transplant survival.

AIMS: The relationship between peri-transplant glycaemic control and outcomes following pancreas transplantation is unknown. We aimed to relate peri-transplant glycaemic control to pancreas graft survival and to develop a framework for defining early graft dysfunction. METHODS: Peri-transplant glycaemic control profiles over the first 5 days postoperatively were determined by an area under the curve [AUC; average daily glucose level (mmol/L) × time (days)] and the coefficient of variation of mean daily glucose levels. Peri-transplant hyperglycaemia was defined as an AUC ≥35 mmol/day/L (daily mean blood glucose ≥7 mmol/L). Risks of graft failure associated with glycaemic control and variability and peri-transplant hyperglycaemia were determined using covariate-adjusted Cox regression. RESULTS: We collected 7606 glucose readings over 5 days postoperatively from 123 pancreas transplant recipients. Glucose AUC was a significant predictor of graft failure during 3.6 years of follow-up (unadjusted HR [95% confidence interval] 1.17 [1.06-1.30], P = .002). Death censored non-technical graft failure occurred in eight (10%) recipients with peri-transplant normoglycaemia, and eight (25%) recipients with peri-transplant hyperglycaemia such that hyperglycaemia predicted a 3-fold higher risk of graft failure [HR (95% confidence interval): 3.0 (1.1-8.0); P = .028]. CONCLUSION: Peri-transplant hyperglycaemia is strongly associated with graft loss and could be a valuable tool guiding individualized graft monitoring and treatment. The 5-day peri-transplant glucose AUC provides a robust and responsive framework for comparing graft function.

Donor insulin use predicts beta-cell function after islet transplantation.

Insulin is routinely used to manage hyperglycaemia in organ donors and during the peri-transplant period in islet transplant recipients. However, it is unknown whether donor insulin use (DIU) predicts beta-cell dysfunction after islet transplantation. We reviewed data from the UK Transplant Registry and the UK Islet Transplant Consortium; all first-time transplants during 2008-2016 were included. Linear regression models determined associations between DIU, median and coefficient of variation (CV) peri-transplant glucose levels and 3-month islet graft function. In 91 islet cell transplant recipients, DIU was associated with lower islet function assessed by BETA-2 scores (ß [SE] -3.5 [1.5], P = .02), higher 3-month post-transplant HbA1c levels (5.4 [2.6] mmol/mol, P = .04) and lower fasting C-peptide levels (-107.9 [46.1] pmol/l, P = .02). Glucose at 10 512 time points was recorded during the first 5 days peri-transplant: the median (IQR) daily glucose level was 7.9 (7.0-8.9) mmol/L and glucose CV was 28% (21%-35%). Neither median glucose levels nor glucose CV predicted outcomes post-transplantation. Data on DIU predicts beta-cell dysfunction 3 months after islet transplantation and could help improve donor selection and transplant outcomes.

Simultaneous en-bloc pancreas and kidney transplantation from a small pediatric donor after circulatory death.

Simultaneous pancreas and kidney transplantation (SPKT) is an effective treatment option for patients with type 1 diabetes and end stage renal disease. Increasing demands for organs for transplantation coupled with a rise in age and size of adult donors has led to greater utilization of pediatric donors, and with good outcomes. Nonetheless, there remains reticence among transplant surgeons to transplant pancreases from small pediatric donors despite the optimal characteristics and macroscopic features of the younger pancreas. We report a successful case of SPKT from a small pediatric donor and explore the aspects of potential concern that might have led some clinicians to decline these organs. We also discuss the measures taken to overcome potential obstacles to successful transplantation from this donor source, and the rationale behind them.

Insulin therapy in organ donation and transplantation.

Hyperglycaemia is common in hospitalized individuals, and is often caused by physiological stress associated with critical illness or major surgery. Insulin therapy is an established treatment for hyperglycaemia and acute hyperkalaemia, and has also been used for myocardial dysfunction resistant to inotropic support. Insulin is commonly used in both organ donors and transplant recipients for hyperglycaemia, but the underlying knowledge base supporting its use remains limited. Insulin therapy plays an important yet poorly understood role in both organ donation and transplantation. Tight glycaemic control has been extensively studied in critical care over the past 15 years; however, this has not yet translated into the field of transplantation, where patients are more unwell and where improved outcomes remain an ongoing challenge. Insulin therapy and optimization of glycaemic control represent important areas for future hypothesis-driven research into organ donation and transplantation, such as amelioration of ischaemia-reperfusion injury, rejection and infection.

When politics meets science: What impact might Brexit have on organ donation and transplantation in the United Kingdom?

Brexit may lead to major political, societal, and financial changes-this has significant implications for a tax revenue funded healthcare system such as the United Kingdom's (UK) National Health Service. The complex relationship between European Union (EU) legislation and clinical practice of organ donation and transplantation is poorly understood. However, it is unclear what impact Brexit may have on organ donation and transplantation in the UK and EU. This work aims to describe the current legislative interactions affecting organ donation and transplantation regulation and governance within the UK and EU. We consider the potential impact of Brexit on the practical aspects of transplantation such organ-sharing networks, logistics, and the provision of health care for transplant patients when traveling to the EU from the UK and vice versa, as well as personnel, and research. Successful organ donation and transplantation practices rely on close collaboration and co-operation across Europe and throughout the United Kingdom. The continuation of such relationships, despite the proposed legislative change, will remain a vital and necessary component for the ongoing success of transplantation programs.

Regional perfusion by extracorporeal membrane oxygenation of abdominal organs from donors after circulatory death: a systematic review.

Organs from donors after circulatory death (DCDs) are particularly susceptible to the effects of warm ischemia injury. Regional perfusion (RP) by extracorporeal membrane oxygenation (ECMO) is increasingly being advocated as a useful remedy to the effects of ischemia/reperfusion injury, and it has been reported to enable the transplantation of organs from donors previously deemed unsuitable. The MEDLINE, Embase, and Cochrane databases were searched, and articles published between 1997 and 2013 were obtained. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two hundred ten articles were identified, and 11 were eligible for inclusion. Four hundred eighty-two kidneys and 79 livers were transplanted from regional perfusion-supported donor after circulatory death (RP-DCD) sources. One-year graft survival was lower with uncontrolled RP-DCD liver transplantation, whereas 1-year patient survival was similar. Primary nonfunction and ischemic cholangiopathy were significantly more frequent with RP-DCDs versus donors after brain death (DBDs), but there was no difference in postoperative mortality between the 2 groups. The 1-year patient and graft survival rates for RP-DCD kidney transplantation were better than the rates with standard DCDs and were comparable to, if not better than, the rates with DBDs. At experienced centers, delayed graft function (DGF) for kidney transplantation from RP-DCDs was much less frequent in comparison with all other donor types. In conclusion, RP aids the recovery of DCD organs from ischemic injury and enables transplantation with acceptable survival. RP may help to increase the donor pool, but its benefits must still be balanced with the recognition of significantly higher rates of complications in liver transplantation. In kidney transplantation, significant reductions in DGF can be obtained with RP, and there are potentially important implications for long-term outcomes. Significant ethicolegal issues exist, and they are preventing a worldwide consensus on optimum RP protocols and an accurate appreciation of outcomes.