Pancreas transplantationBMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j1321 (Published 03 April 2017) Cite this as: BMJ 2017;357:j1321
All rapid responses
Title: Pancreas Transplantation: The untold origin of the story… the pancreas Donor
Authors: IM Shapey1,2 A Summers1,2, T Augustine1,2, MK Rutter1,3, D van Dellen1,2
1) Faculty of Medicine, Biology and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester UK.
2) Department of Renal and Pancreatic Transplantation, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
3) Manchester Diabetes Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
Article type: Rapid response/Letter
Word Count: 916
Keywords: Pancreas, Islet, Transplantation, Donor, Insulin
Acknowledgements: We would like to recognise the important and life changing gift provided by organ donors and their families which has facilitated the possibility of pancreas transplantation.
Funding: Medical Research Council (UK); Royal College of Surgeons of Edinburgh
We read with interest Dean et. al.’s State of the Art Review of Pancreas Transplantation. It is refreshing to have pancreas and islet transplantation receiving the international attention it urgently deserves. In patients with complex diabetes mellitus, pancreas and islet transplantation can offer life-changing and life-saving therapies. Improving knowledge and understanding amongst referring physicians regarding the potential benefits of pancreas transplantation is important because current referral rates to UK pancreas transplantation centres are low and do not reflect the number that may benefit from transplantation. For many decades, pancreas transplantation has been the forgotten sibling of liver, kidney and cardio-thoracic transplantation. The amelioration of both hyper- and hypo-glycaemia and alleviation of its associated macro- and micro-vascular complications stands to benefit numerous patients affected by diabetes with significant subsequent secondary benefits for healthcare resources.
Dean’s review focuses on the indications for, and outcomes following pancreas and islet transplantation. Unfortunately, this represents only the recipient’s half of the process, and does not acknowledge the major challenges facing pancreas and islet transplantation regarding the organ donor. Pancreas donation comes predominantly from deceased individuals following declaration of neurological (brain-stem) death or donation after circulatory death (formerly known as non-heart beating donation). Living pancreas donation occurs in small numbers in select centres, but, due to the associated morbidity for the donor (15-30%), has not become standard practice internationally.[1-2]
The main factors limiting the success of pancreas transplantation historically have been difficulties in optimising donor selection and achieving successful long-term function. Inappropriate donor organ selection, due to a lack of objective clarity for quality assessment, continues to impact adversely on patient outcomes in pancreas transplantation. Two-thirds of donor pancreata offered for transplantation are currently considered unsuitable. Outcomes remain far from ideal: in the UK, 6 out of 10 pancreas grafts have failed at 5 years when transplanted alone, and 3 out of 10 fail at 5 years when the pancreas is performed simultaneously with a kidney transplant, as occurs in over 80% of cases. The well-documented shortage of organs for transplantation creates an urgent need to improve objective methods for selection of high quality pancreata; and also to identify the ideal physiological environment to enable a transplanted pancreas to thrive in the longer term.
Contrary to other areas of organ transplantation such as the kidney, liver and heart, there is a paucity of research and knowledge in the field of donor organ assessment and viability testing in pancreas and islet transplantation to aid in critical decision making. Reliable and validated donor risk indices exist for both liver  and kidney transplantation , but the currently available pancreas donor risk index (PDRI)  is unreliable. Studies attempting to validate the PDRI as a predictive tool have provided mixed results [8-12], and this may account for its low utility when compared to its liver and kidney counterparts. Apart from cold ischaemic time, the PDRI relies entirely on donor characteristics, and the variable outcomes from validation studies [8-12] are therefore possibly a reflection of the absence of any quantifiable primary measures of the function and quality of the organ itself.
Current decision-making in donor selection is a qualitative process which is multifactorial and largely subjective with significant individual clinician and centre variability. The donor factors reported to have the greatest impact on future graft loss include body mass index,  age,  donor type  and cold ischaemic time . As the donor population grows older and larger, the negative impact of these factors on donor pancreas quality is likely to be an increasing problem. HbA1C and c-peptide are not routinely evaluated in organ donors in part due to limited local access in donor hospitals out-of-hours. Macroscopic features of the pancreas are also an important consideration; the degree of inter- and intra-lobular pancreatic steatosis, fibrosis and calcification are associated with the likelihood of reperfusion pancreatitis and poorer long-term function . Currently, visual assessment coupled with palpation is the best subjective evaluation of the quality of the solid organ pancreas.
In organ donors, the process of brain stem death causes high levels of systemic catecholamines and inflammation affecting all organs [16-18]. These changes, and the routine use of high-dose corticosteroids in intensive care units (ICU) , leads to hyperglycaemia in around 50% of donors which is managed with insulin. Traditional teaching suggests that donor hyperglycaemia is a transient phenomenon caused by reversible insulin resistance in the donor . Current and future work is identifying strategies to identify, quantify and correlate the effects of the catecholamine storm generated by brain stem death and the potential deleterious effects on beta-cell function both in the immediate and longer term.
If true progress is to be made in alleviating the devastating sequelae of diabetes, then a co-ordinated and concerted effort is required to improve the success of transplantation. This involves increasing our knowledge of the physiological behaviour of both donors and recipients along with technological advances. Doing so will allow us to identify which patient groups stand to benefit the most from transplantation and to determine which modalities of beta-cell replacement therapy (solid organ, cellular, or bio-artificial pancreas) are appropriate at a given time in a patient’s clinical journey with diabetes. Until we can achieve mass production of therapeutic grade beta-cells, which remains the holy grail of Beta cell replacement therapy, it is critical that we have strong objective criteria to assess the quality of donor pancreata which will maximise the number of patients with complex diabetes who can gain access to this state of the art therapy.
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Competing interests: Funding (IS): Medical Research Council (UK); Royal College of Surgeons of Edinburgh