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.

Examining the Role of the Health Belief Model Framework in Achieving Diversity and Equity in Organ Donation Among South Asians in the United Kingdom.

Organ donation continues to be low among ethnic minorities in the United Kingdom (UK), especially within the South Asian community, with a disproportionate number of patients of South Asian ethnicity awaiting organ transplants. In 2020/21, Minority Ethnic (ME) patients comprised almost a third of the national transplant waiting list, highlighting the continued imbalance between the need for transplants in South Asian communities and the availability of suitable organs. Median waiting times for transplants show that, generally, white patients wait less time than ME patients; Only 39.5% of ME families consented to proceed with deceased organ donation when approached compared to 69% of white families. How to increase awareness among the South Asian community on the scarcity of organ donors continues to be a growing challenge facing the healthcare system in the UK and globally. This article reflects on the education strategy implemented using the Health Belief Model. It provides a detailed framework with which to consider the rationale that led to a specific behaviour, in this case organ donation among the three major ethnicities (i.e., Indian, Pakistani, Bangladeshi) within the South Asian community as part of a single study.

Kidney Transplantation From Hepatitis-C Viraemic Donors:Considerations for Practice in the United Kingdom.

Background: Donor hepatitis-C (HCV) infection has historically represented a barrier to kidney transplantation (KT). However, direct-acting antiviral (DAA) medications have revolutionised treatment of chronic HCV infection. Recent American studies have demonstrated that DAA regimes can be used safely peri-operatively in KT to mitigate HCV transmission risk. Methods: To formulate this narrative review, a comprehensive literature search was performed to analyse results of existing clinical trials examining KT from HCV-positive donors to HCV-negative recipients with peri-operative DAA regimes. Results: 13 studies were reviewed (11 single centre, four retrospective). Outcomes for 315 recipients were available across these studies. A sustained virological response at 12 weeks (SVR12) of 100% was achieved in 11 studies. One study employed an ultra-short DAA regime and achieved an SVR12 of 98%, while another achieved SVR12 of 96% due to treatment of a missed mixed genotype. Conclusion: HCV+ KT is safe and may allow increased utilisation of organs for transplantation from HCV+ donors, who often have other favourable characteristics for successful donation. Findings from US clinical trials can be applied to the United Kingdom transplant framework to improve organ utilisation as suggested by the NHSBT vision strategy "Organ Donation and Transplantation 2030: meeting the need".

Surgical management of Encapsulating Peritoneal Sclerosis (EPS) in children: international case series and literature review.

BACKGROUND: Encapsulating Peritoneal Sclerosis (EPS) is a rare phenomenon in paediatric patients with kidney failure treated with peritoneal dialysis (PD). This study highlights clinical challenges in the management of EPS, with particular emphasis on peri-operative considerations and surgical technique. METHODS: Retrospective analysis of all paediatric patients with EPS treated at the Manchester Centre for Transplantation. RESULTS: Four patients were included with a median duration of 78 months on PD. All patients had recurrent peritonitis (> 3 episodes), and all had symptoms within three months of a change of dialysis modality from PD to haemodialysis or transplant. In Manchester, care was delivered by a multi-disciplinary team, including surgeons delivering the adult EPS surgical service with a particular focus on nutritional optimisation, sepsis control, and wound management. The surgery involved laparotomy, lavage, and enterolysis of the small bowel + / - stoma formation, depending on intra-abdominal contamination. Two patients had a formal stoma, which were reversed at three and six months, respectively. Two patients underwent primary closure of the abdomen, whereas two patients had re-look procedures at 48 h with secondary closure. One patient had a post-operative wound infection, which was managed medically. One patient's stoma became detached, leading to an intra-abdominal collection requiring re-laparotomy. The median length of stay was 25 days, and patients were discharged once enteral feeding was established. All patients remained free of recurrence with normal gut function and currently two out of four have functioning transplants. CONCLUSIONS: This series demonstrates 100% survival and parenteral feed independence following EPS surgery. Post-operative morbidity was common; however, with individualised experience-based decision-making and relevant additional interventions, patients made full recoveries. Health and development post-surgery continued, allowing the potential for transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.

The altruistic elderly, a valuable but unrecognised kidney donor group. A case report of an 85-year-old unspecified kidney donor.

BACKGROUND: Kidney transplantation is the definitive treatment for end stage renal disease (ESRD), offering improved quality of life and survival benefit over remaining on dialysis. There is, however, a prevailing significant mismatch between patients awaiting transplantation and available donor kidneys. Over time, initial stringent donor criteria have broadened and organs from extended criteria donors (ECDs) and older donors are now being accepted for transplantation. The spectrum of living donors has also undergone a change from close family members to an increasingly non-related, non-directed altruistic donors, newly classified as 'unspecified' donors. Unspecified elderly donors could be a potential untapped resource to expanding the kidney donor pool globally. CASE PRESENTATION: We present a case of an 85 year and 8 months old individual, who donated to an unrelated non-directed matched recipient in the national deceased donor transplant waiting list with excellent donor and recipient outcomes at 7 years. CONCLUSION: To our knowledge she is one of the oldest reported unspecified living kidney donors in the world to date. This case illustrates that elderly donors in good health can come forward to donate, knowing that it is safe and valuable. Once the immediate perioperative challenges after kidney donation are managed, elderly donors rarely encounter long term sequelae. We therefore report this case to increase awareness and refocus attention of transplant teams on elderly donors as a potential untapped group to help address the organ shortage problem in renal transplantation.

Modeling Data Journeys to Inform the Digital Transformation of Kidney Transplant Services: Observational Study.

BACKGROUND: Data journey modeling is a methodology used to establish a high-level overview of information technology (IT) infrastructure in health care systems. It allows a better understanding of sociotechnical barriers and thus informs meaningful digital transformation. Kidney transplantation is a complex clinical service involving multiple specialists and providers. The referral pathway for a transplant requires the centralization of patient data across multiple IT solutions and health care organizations. At present, there is a poor understanding of the role of IT in this process, specifically regarding the management of patient data, clinical communication, and workflow support. OBJECTIVE: To apply data journey modeling to better understand interoperability, data access, and workflow requirements of a regional multicenter kidney transplant service. METHODS: An incremental methodology was used to develop the data journey model. This included review of service documents, domain expert interviews, and iterative modeling sessions. Results were analyzed based on the LOAD (landscape, organizations, actors, and data) framework to provide a meaningful assessment of current data management challenges and inform ways for IT to overcome these challenges. RESULTS: Results were presented as a diagram of the organizations (n=4), IT systems (n>9), actors (n>4), and data journeys (n=0) involved in the transplant referral pathway. The diagram revealed that all movement of data was dependent on actor interaction with IT systems and manual transcription of data into Microsoft Word (Microsoft, Inc) documents. Each actor had between 2 and 5 interactions with IT systems to capture all relevant data, a process that was reported to be time consuming and error prone. There was no interoperability within or across organizations, which led to delays as clinical teams manually transferred data, such as medical history and test results, via post or email. CONCLUSIONS: Overall, data journey modeling demonstrated that human actors, rather than IT systems, formed the central focus of data movement. The IT landscape did not complement this workflow and exerted a significant administrative burden on clinical teams. Based on this study, future solutions must consider regional interoperability and specialty-specific views of data to support multi-organizational clinical services such as transplantation.

Laterality in laparoscopic hand assisted donor nephrectomy - Does it matter anymore? Outcomes of a large retrospective series.

This retrospective study was performed to analyse if laterality of the retrieved living donor kidney had any effect on donor and recipient outcomes after hand assisted laparoscopic donor nephrectomy (HALDN). 739 donors who underwent HALDN between January 2006 and January 2018 at a large tertiary transplant centre in the United Kingdom were included. Donor outcomes in individuals undergoing right versus left HALDN were compared with respect to conversion rates, morbidity, warm and cold ischaemia times and recipient failure rates, vascular and ureteric complications. 604 (81.7%) underwent left HALDN and 135 (18.3%) underwent right HALDN, mean age was 47.1 years and 46.8 years respectively with comparable gender distribution. The operative time was shorter for the left side (p = 0.003) and improved during the study for the left but not the right side. In recipients who received left kidneys there were more early technical failures observed (8 versus 1) though not statistically significant. Most centres prefer performing a left nephrectomy and recipient surgeons prefer a left kidney for transplantation primarily because of having a longer vein. This large study provides reassurance that right HALDN nephrectomy is a safe procedure with similar outcomes to left HALDN.

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.

Transplant Options for Patients With Diabetes and Advanced Kidney Disease: A Review.

Optimal glycemic control in kidney transplant recipients with diabetes is associated with improved morbidity and better patient and allograft survival. Transplant options for patients with diabetes requiring insulin therapy and chronic kidney disease who are suitable candidates for kidney transplantation should include consideration of ß-cell replacement therapy: pancreas or islet transplantation. International variation related to national regulatory policies exists in offering one or both options to suitable candidates and is further affected by pancreas/islet allocation policies and transplant waiting list dynamics. The selection of appropriate candidates depends on patient age, coexistent morbidities, the timing of referral to the transplant center (predialysis versus on dialysis) and availability of living kidney donors. Therefore, early referral (estimated glomerular filtration rate < 30 mL/min/1.73 m2) is of the utmost importance to ensure adequate time for informed decision making and thorough pretransplant evaluation. Obesity, cardiovascular disease, peripheral vascular disease, smoking, and frailty are some of the conditions that need to be addressed before acceptance on the transplant list, and ideally before dialysis becoming imminent. This review offers insights into selection of pancreas/islet transplant candidates by transplant centers and an update on posttransplant outcomes, which may have practice implications for referring nephrologists.

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.

No evidence of improvement in neuropathy after renal transplantation in patients with end stage kidney disease.

To assess the impact of renal transplantation on peripheral nerve damage in patients with chronic kidney disease (CKD). Fifteen patients with CKD (eGFR <15 mL/min/1.73 m2 ) underwent longitudinal assessment after renal transplantation (age: 56.88 ± 2.53 years, eGFR: 46.82 ± 4.86) and were compared with 15 age-matched controls (age: 58.25 ± 2.18 years, eGFR: 86.0 ± 2.0). The neuropathy symptom profile (NSP), neuropathy disability score (NDS), vibration perception threshold (VPT), cold and warm sensation threshold (CST and WST), cold and heat induced pain (CIP and HIP), deep breathing heart rate variability (DB-HRV), nerve conduction studies and corneal confocal microscopy (CCM) to quantify small nerve fibre pathology, were undertaken within 1-month of renal transplantation (baseline) and at 6, 12 and 24 months of follow up. There was no significant difference in NSP (P = .1), NDS (P = .3), VPT (P = .6), CST (P = .2), CIP (P = .08), HIP (P = .1), DB-HRV (P = .9) and sural (P = .4) and peroneal (P = .1) nerve amplitude between patients with CKD and controls at baseline. However, sural (P = .04), peroneal (P = .002) and tibial (P = .007) nerve conduction velocity and tibial nerve amplitude (P = .03) were significantly lower, WST (P = .02) was significantly higher and corneal nerve fibre density (P = .004) was significantly lower in patients with CKD compared with controls. There was no significant change in NSP, NDS, quantitative sensory testing, DB-HRV, nerve conduction or CCM parameters 24 months after renal transplantation. There is evidence of small and large fibre neuropathy in patients with CKD, but no change up to 24 months after successful renal transplantation.

Talaromycosis in a renal transplant recipient returning from South China.

Talaromycosis is a fungal infection endemic in Southeast Asia. We report a case of a renal transplant recipient who developed infection after a trip to South China. She presented with constitutional symptoms and was found to have an FDG-avid lung mass. Histopathology demonstrated small yeast cells and culture grew Talaromyces marneffei. The patient was treated with 2 weeks of liposomal amphotericin B followed by itraconazole. The dose of tacrolimus was significantly reduced because of the interaction with itraconazole. Mycophenolate mofetil was discontinued. After 12 months of treatment, the mass had completely resolved. Talaromycosis has mainly been reported in patients with AIDS and is uncommon among solid organ transplant recipients. The immune response against T. marneffei infection is mediated predominantly by T cells and macrophages. The diagnosis may not be suspected outside of endemic areas. We propose a therapeutic approach in transplant patients by extrapolating the evidence from the HIV literature and following practices applied to other endemic mycoses.

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.

A Successful Treatment of Encapsulating Peritoneal Sclerosis in an Adolescent Boy on Long-term Peritoneal Dialysis: A Case Report.

Encapsulating peritoneal sclerosis (EPS) is a rare life-threatening complication associated with peritoneal dialysis (PD). EPS is characterized by progressive fibrosis and sclerosis of the peritoneum, with the formation of a membrane and tethering of loops of the small intestine resulting in intestinal obstruction. It is very rare in children. We present a case of a 16-year-old adolescent boy who developed EPS seven years after being placed on continuous ambulatory peritoneal dialysis (CAPD) complicated by several episodes of bacterial peritonitis. The diagnosis was based on clinical, radiological, intraoperative and histopathological findings. The patient was successfully treated with surgical enterolysis. During a 7-year follow-up, there have been no further episodes of small bowel obstruction documented. He still continues to be on regular hemodialysis and is awaiting a deceased donor kidney transplant. EPS is a long-term complication of peritoneal dialysis and is typically seen in adults. Rare cases may be seen in the pediatric population and require an appropriate surgical approach that is effective and lifesaving for these patients.

Early nerve fibre regeneration in individuals with type 1 diabetes after simultaneous pancreas and kidney transplantation.

AIMS/HYPOTHESIS: The study aimed to assess the impact on neuropathy of simultaneous pancreas and kidney transplantation (SPK) in individuals with type 1 diabetes. METHODS: This longitudinal observational study examined neuropathic symptoms, deficits, quantitative sensory testing, neurophysiology, corneal confocal microscopy and skin biopsy results in 32 healthy (non-diabetic) control participants, 29 individuals with type 1 diabetes and severe diabetic peripheral neuropathy [DPN] and 36 individuals with type 1 diabetes after SPK. RESULTS: Following SPK, HbA1c, eGFR, triacylglycerols and HDL improved significantly (all p < 0.05). Compared with the DPN group, which remained unchanged over the 36 month study period, corneal confocal microscopy assessments improved over 36 months following SPK, with increasing corneal nerve fibre density of 5/mm2 (95% CI 1.8, 8.2; p = 0.003) and corneal nerve fibre length of 3.2 mm/mm2 (95% CI 0.9, 5.5; p = 0.006). The Neuropathy Symptom Profile and peroneal nerve conduction velocity also improved significantly by 36 months compared with DPN (2.5; 95% CI 0.7, 4.3; p = 0.008 and 4.7 m/s; 95% CI 2.2, 7.4; p = 0.0004, respectively), but with a temporal delay compared with the corneal confocal microscopy assessments. Intraepidermal nerve fibre density did not change following SPK; however, mean dendritic length improved significantly at 12 (p = 0.020) and 36 (p = 0.019) months. In contrast, there were no changes in the Neuropathy Disability Score, quantitative sensory testing or cardiac autonomic function assessments. Except for a small decrease in corneal nerve fibre density in the healthy control group, there were no changes in any other neuropathy measure in the healthy control or DPN groups over 36 months. CONCLUSIONS/INTERPRETATION: SPK is associated with early and maintained small nerve fibre regeneration in the cornea and skin, followed by an improvement in neuropathic symptoms and peroneal nerve conduction velocity.

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.

Laparoscopic hand-assisted adrenalectomy for tumours larger than 5 cm.

OBJECTIVE: Adrenal surgery remains a distinct surgical challenge. Technical challenges associated with laparoscopic adrenalectomy are tumour size, haemorrhage control and oncological compromise. Hand-assisted laparoscopic (HAL) adrenalectomy, utilizing a hand-port device, offers minimally invasive surgery with the advantages and safety of tactile feedback. We aimed to assess the efficacy of HAL for patients requiring adrenalectomy for tumours over 5 cm in size. CONTEXT: Hand-assisted laparoscopic surgery is used in several surgical specialities over totally laparoscopic surgery to manage sizeable pathology, reduce operating time and conversion rates. HAL adrenalectomy is demonstrated in this series as a safe alternative to laparoscopic adrenalectomy for large adrenal tumours. DESIGN: A retrospective analysis of all HAL adrenalectomies performed over 8 years (October 2006-May 2015) by a single surgeon was performed. This case series is the largest study of this technique. PATIENTS: All patients who were fit for surgery with adrenal tumours (over 5 cm) were included. ANALYSIS: Primary endpoints were overall mortality, operating time, hospital stay, complications and conversion to open surgery. RESULTS: A total of 56 patients underwent the procedure. A total of 43 had unilateral and 13 bilateral lesions. Most lesions (45) were histologically benign. These included functioning and non-functioning tumours. Median tumour size was 8 cm (range 5-19 cm). There was one (1.8%) intra-operative conversion and no peri-operative mortality. Postoperative complications occurred in 8 (14%) patients, all self-limiting. The median length of stay was 6 days (range 2-21). There was one recurrence of pathology with repeat surgery. CONCLUSION: Hand-assisted laparoscopic surgery offers a safe reproducible approach to adrenal surgery combining minimally invasive surgery with tactile integration. Although previously described in small numbers, this represents the largest case series to date. HAL is a safe minimally invasive surgical option for larger tumours, including malignancies. The HAL technique may additionally offer a shorter learning curve for trainee adrenal surgeons.

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.

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study.

Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.

Links between a biomarker profile, cold ischaemic time and clinical outcome following simultaneous pancreas and kidney transplantation.

In sepsis, trauma and major surgery, where an explicit physiological insult leads to a significant systemic inflammatory response, the acute evolution of biomarkers have been delineated. In these settings, Interleukin (IL) -6 and TNF-α are often the first pro-inflammatory markers to rise, stimulating production of acute phase proteins followed by peaks in anti-inflammatory markers. Patients undergoing SPKT as a result of diabetic complications already have an inflammatory phenotype as a result of uraemia and glycaemia. How this inflammatory response is affected further by the trauma of major transplant surgery and how this may impact on graft survival is unknown, despite the recognised pro-inflammatory cytokines' detrimental effects on islet cell function. The aim of the study was to determine the evolution of biomarkers in omentum and serum in the peri-operative period following SPKT. The biochemical findings were correlated to clinical outcomes. Two omental biopsies were taken (at the beginning and end of surgery) and measured for CD68+ and CD206+ antibodies (M1 and M2 macrophages respectively). Serum was measured within the first 72 h post-SPKT for pro- and anti-inflammatory cytokines (IL -6, -10 and TNF-α), inflammatory markers (WCC and CRP) and endocrine markers (insulin, C-peptide, glucagon and resistin). 46 patients were recruited to the study. Levels of M1 (CD68+) and M2 (CD206+) macrophages were significantly raised at the end of surgery compared to the beginning (p = 0.003 and p < 0.001 respectively). Levels of C-peptide, insulin and glucagon were significantly raised 30 min post pancreas perfusion compared to baseline and were also significantly negatively related to prolonged cold ischaemic time (CIT) (p < 0.05). CRP levels correlated significantly with the Post-Operative Morbidity Survey (p < 0.05). The temporal inflammatory marker signature after SPKT is comparable to the pattern observed following other physiological insults. Unique to this study, we find that CIT is significantly related to early pancreatic endocrine function. In addition, this study suggests a predictive value of CRP in peri-operative morbidity following SPKT.