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.

Theatre within 36 h for patients with fracture of the proximal femur: can we deliver?

BACKGROUND: Proximal femur fractures carry significant levels of morbidity and mortality. Surgical delay is one factor that adversely affects outcome in these patients. In 2010, hospital-income from patients with proximal femur fractures was linked to the surgery being undertaken within 36 h of admission. Can we deliver this target? MATERIALS AND METHODS: Data from the 2009 National Hip Fracture Database was interrogated and appropriate patients were identified. Patient records were reviewed to identify the reasons for surgical delay. Mortality rates were compared within 36 h and after. RESULTS: Five-hundred and thirty-two patients were admitted in 2009, 118 (22 %) of them were delayed more than 36 h. Surgery was delayed for a variety of identified reasons. Median time to surgery was 24 h (1-273). Ninety-day mortality for patients treated within 36 h was 12.4 %, but 25 % (P = 0.047) in patients delayed for medical problems. CONCLUSIONS: Not all patients with a fracture of the proximal femur can have surgery within 36 h of their injury. However, we have identified and describe four specific areas that could increase the number of patients who meet this target.

Outcomes following potentially curative therapies for older patients with metastatic colorectal cancer.

Older age represents a major risk factor for developing colorectal cancer and the disease disproportionately affects patients older than 60 years of age. However, knowledge regarding the optimal management of older patients with metastatic colorectal cancer (mCRC) remains limited. The challenge of treating older patients arises in tailoring treatments to a heterogeneous cohort whilst adjusting for individuals with a wide variation of physiological reserve, a reduced tolerance to treatment side-effects and morbidity, and often different priorities as compared with younger patients. Data from the published literature supports the premise that older age alone is not an acceptable determinant of treatment options. In particular, patients aged 65-70 years with mCRC ought to be considered similarly to younger patients and patients aged 70-74 also stand to benefit from both hepatic resection and systemic therapy notwithstanding the higher rates of morbidity and mortality. Patients aged 75-79, and with sufficient physiological reserve ought to be considered for curative treatment options which are proportional to the extent of metastatic disease. Meanwhile, in patients aged ≥80 years, life-extending or life-enhancing benefit ought to be demonstrable prior to embarking upon major surgery as a curative treatment option. Older patients who meet the physiological eligibility criteria to enter clinical trials of systemic chemotherapy appear to gain similar benefit as younger patients and should not be excluded on the basis of age alone. Clinical trials that are specifically designed for older patients are feasible and could yield valuable information to guide clinical practice.

Data driven decision-making for older patients with hepatocellular carcinoma.

Older age is a risk factor for the development of HCC. However, the treatment options available for older patients with HCC, their safety, efficacy and utility, are poorly understood resulting in challenging decision-making. In this review, we aim to report the best available evidence to facilitate optimal decision making for older patients with HCC. We report that surgical resection for HCC is equally safe (90-day mortality ~3%) and effective (five-year disease free survival ~40%) for older patients as it is for younger patients. Five-year survival after ablation therapy for HCC is in excess of 50% in older patients, whilst morbidity rates are in the region of 3%. Survival rates of 30% after chemoembolisation reflects its role as a non-curative treatment. Transplantation is an option that may be helpful for a minority of patients, but the high risks of in-hospital mortality and lower likelihood of receiving a transplant should be duly considered before committing to this approach. We therefore advocate an individualised assessment for older patients based on these risk profiles and probabilities of optimal outcomes. In patients with a projected life-span ≥ 3 years, and who have sufficient physiological and functional reserve, surgical resection should be the treatment of choice. Patients with a projected life-span < 3 years are better served with loco-regional therapies, and tumour size, at a threshold of 3 cm, should guide the choice between ablation and chemoembolisation therapies.

Major Adverse Cardiovascular Events Following Simultaneous Pancreas and Kidney Transplantation in the United Kingdom.

OBJECTIVE: People with type 1 diabetes and kidney failure have an increased risk for major adverse cardiovascular events (MACE). Simultaneous pancreas and kidney transplantation (SPKT) improves survival, but the long-term risk for MACE is uncertain. RESEARCH DESIGN AND METHODS: We assessed the frequency and risk factors for MACE (defined as fatal cardiovascular disease and nonfatal myocardial infarction or stroke) and related nonfatal MACE to allograft failure in SPKT recipients with type 1 diabetes who underwent transplantation between 2001 and 2015 in the U.K. In a subgroup, we related a pretransplant cardiovascular risk score to MACE. RESULTS: During 5 years of follow-up, 133 of 1,699 SPKT recipients (7.8%) experienced a MACE. In covariate-adjusted models, age (hazard ratio 1.04 per year [95% CI 1.01-1.07]), prior myocardial infarction (2.6 [1.3-5.0]), stroke (2.3 [1.2-4.7]), amputation (2.0 [1.02-3.7]), donor history of hypertension (1.8 [1.05-3.2]), and waiting time (1.02 per month [1.0-1.04]) were significant predictors. Nonfatal MACE predicted subsequent allograft failure (renal 1.6 [1.06-2.6]; pancreas 1.7 [1.09-2.6]). In the subgroup, the pretransplant cardiovascular risk score predicted MACE (1.04 per 1% increment [1.02-1.06]). CONCLUSIONS: We report a high rate of MACE in SPKT recipients. There are a number of variables that predict MACE, while nonfatal MACE increase the risk of subsequent allograft failure. It may be beneficial that organs from hypertensive donors are matched to recipients with lower cardiovascular risk. Pretransplant cardiovascular risk scoring may help to identify patients who would benefit from risk factor optimization or alternative transplant therapies and warrants validation nationally.

Should End-of-Life Preferences Be Discussed Routinely before High-Risk Surgery?

Encapsulating peritoneal sclerosis (EPS) is a rare but devastating complication of peritoneal dialysis. It is characterized by peritoneal neovascularization, fibrosis, and calcification ultimately leading to intestinal obstruction and eventual failure. Surgery for EPS has a mortality approaching 50% and most patients require some form of postoperative life-sustaining therapy (LST) during their admission. A 43-year-old gentleman with progressive EPS and significant comorbidities was assessed for enterolysis after a failed first attempt at another center. Because of his comorbidities, postoperative mortality was quoted above 50%. The patient favored surgery to improve his survival and quality of life, but was reluctant to receive prolonged LST in the event of failure of surgical therapy. The surgical team, in conjunction with a palliative care physician, therefore held extensive discussions with the patient and his partner regarding LST and its limitations. Clinical parameters to trigger a transition to palliative care were identified and agreed. Limitations on LST that are directly expressed by patients can represent a contraindication to surgery for many surgeons. Surgical Buy-In is a concept described as a perceived contract, or covenant, between the patient and clinician regarding implied consent for postoperative LST. Currently, preoperative discussions regarding limitations of LST are infrequent, and there can be reticence among patients and surgeons to have these conversations, leading to dissatisfaction on behalf of the patient and their family. After the Montgomery legal ruling, the provision and perception of informed consent are particularly pertinent. The palliative care physician is uniquely placed to contribute to such discussions as part of the surgical multidisciplinary team.

Biliary tract imaging for retained calculi after laparoscopic cholecystectomy: is risk stratification useful?

The aim of this study was to determine the incidence of common bile duct (CBD) calculi patients undergoing laparoscopic cholecystectomy (LC) without routine intraoperative cholangiography (IOC) and the usefulness of risk stratification in guiding appropriate biliary tract imaging. Five hundred forty consecutive LCs were performed during the 12-month study period. Four hundred fifty-eight (84.8%) patients with low risk of CBD stones proceeded immediately to LC. Forty-four (8.1%) high-risk patients underwent endoscopic retrograde cholangiopancreatography (ERCP). Thirty-four (6.3%) moderate risk patients underwent magnetic resonance cholangiopancreatography. Four (0.7%) patients had an equivocal risk with 2 undergoing IOC. The preoperative incidence of CBD stones was 29/540 (5.4%), while 11 patients (2.04%) were readmitted with retained CBD calculi and underwent successful stone extraction with ERCP. The incidence of retained CBD calculi after LC without IOC is low. Risk stratification helps to accurately predict CBD stones and facilitates appropriate and cost-effective use of ERCP and magnetic resonance cholangiopancreatography.