Diabetes Mellitus (DM) is a growing pandemic [1–3] associated with increased risks of developing life-limiting systemic complications. Diabetic patients may experience reduced quality of life and incur high healthcare-associated costs, particularly in patients with poorly controlled disease. Pancreas transplantation significantly improves the quality of life of patients, and can limit the progression of serious medical comorbidities [4–7].

The number of patients on the UK waiting list for pancreas transplantation is at an all-time high, and waiting time has worsened following the COVID-19 pandemic [8]. As of March 2023, 265 patients are actively waiting for a pancreas graft in the United Kingdom, representing a 27% increase from before the pandemic [9]. Taken together, there is a need to optimise decision-making surrounding organ utilisation and expand the donor pool to match the current demands for pancreas transplantation. It is essential to understand factors that predict transplant outcomes. It is equally important to identify factors that do not lead to poor outcomes, preventing the unwarranted rejection of donor organs based on these factors.

Initial screening of donors includes various blood tests, such as serum amylase and liver blood tests. Hyperamylaseamia (defined as serum amylase levels greater than 110 UI/L) can be seen in up to 40% of donors, and a markedly elevated serum amylase (more than three times the upper limit of normal) is generally considered to represent pancreatitis [10]. However, this blood test has low specificity, and can be raised due to a variety of aetiologies [11, 12].

Serum liver blood tests (LBTs) are markers of acute hepatocellular or cholangiocyte injury. The embryological development of the pancreas is closely related to the formation of foregut and midgut structures. The pancreas shares the same vascular supply with other foregut/midgut structures (including liver), receiving blood from both coeliac trunk and superior mesenteric artery. Therefore, markers of acute hypoxic injury to the liver could be a surrogate for hypoxic injury to the pancreas [13, 14].

This study aims to ascertain whether donor amylase and LBTs predict pancreas graft survival in patients undergoing SPK transplantation.

Data on adult simultaneous pancreas and kidney (SPK) transplants was retrieved from the UK Transplant registry, maintained by the National Health Service Blood and Transplant (NHSBT). Adult recipients (>16 years) from all 8 UK pancreas transplant centres, transplanted between January 2016 and December 2021, were included. These dates were chosen because, before January 2016, serial donor amylase and serial LBTs were not recorded. Recipients of grafts donated following circulatory or brain stem death [donation following brain stem death (DBD)/donation following circulatory death (DCD)] were included.

Data were provided in an anonymized form (patient identifiable information and transplant unit not provided) as per NHSBT approvals, and individual ethical or institutional review board approval was not required for this project. This project was approved by the pancreas advisory board.

Data were extracted from NHSBT in August 2023. Data were cleaned, and values that were deemed impossible were removed. Our primary aim was to compare the impact of donor serum amylase on 3-year pancreas graft survival. Secondary analyses compared the impact of donor alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALT) and bilirubin, as well as renal blood tests and lactate, on 3-year pancreas graft survival.

Graft loss was defined as retransplantation, pancreatectomy or return to insulin therapy due to graft failure and was analysed as time-to-event, death censored, and measured until July 2023 (the common closure date of the study).

857 adult recipients of deceased donor pancreas (619 DBD and 238 DCDs) were included, with median follow up of 37.5 months. Median donor age was 34 (interquartile range 24–46). Cohort demographics are included in Table 1, with further details in Supplementary Table S1.

This large, statistically robust cohort study (619 DBD and 238 DCDs) has found no association between donor amylase and pancreas graft survival in SPK transplantation, on adjusted analyses. Although there was no evidence of an impact on outcome at any donor amylase level, relatively few pancreases were transplanted from donors with extreme increases in amylase (>1,000). Therefore, the impact of extreme elevations in amylase remain uncertain and such donor should be assessed on a case-by-case basis. It is reassuring that all four pancreases transplanted from donors with amylase >1,000 were functioning well at last follow up.

Additionally, our study has also found no association between donor LBTs and pancreas graft outcome. Hence, donor amylase and LBTs alone should not be a determining factor in organ utilisation in the modern era of pancreas transplantation.

With the rising demand for pancreas transplantation due to the increasing global disease burden of diabetes mellitus [1–3] and longer waiting lists there is a need to widen access to pancreas transplantation through improved utilisation of grafts. Further knowledge and evidence-based organ assessment is crucial in quantifying extended-criteria and marginal donor organs [21]. At the time of organ selection, some serological markers such as amylase levels and liver blood tests can be useful taken together with other markers of increasing risk when deciding the suitability and quality of a pancreas allograft but it is important to note they are non-specific and that there are other donor variables that may affect these blood tests [10–12, 22]. Nonetheless, surgeons remain reluctant to accept pancreas grafts from donor with raised serum amylase due to concerns of inferior outcomes. This becomes more important during an era of DCD transplantation as these are more prone to ischaemic damage but represent an underused resource [23–25].

Vinkers et al established the Pre-procurement Pancreas Allocation Suitability Score (P-PASS) in 2008, where a total of nine clinical parameters were used to predict the odds of a donor allograft being accepted for transplantation. The P-PASS score includes donor body mass index, age, duration of intensive care stay, serum amylase, lipase, sodium, duration of donor cardiac arrest, and whether or not the donor was on vasopressor support. Liver function tests, cold ischaemia time and type of donor, i.e., DCDs vs. DBDs are excluded in P-PASS. A low P-PASS score of 17 and below were three times more likely to be accepted as pancreas donors than donor grafts that scored above 17 [20]. The P-PASS score has been utilised by Eurotransplant since 2009 [26]. Amylase levels were among the nine parameters in this scoring system, where raised Amylase of ≥130 iu/L contributes to a higher P-PASS score, which is associated with high odds of organ discard [20]. It is important to note that the P-PASS score was developed based on chance of organ decline, and not based on outcome in transplanted pancreases. It therefore reflects what clinicians perceive as high risk, rather than factors which actually predict pancreas quality.

Interestingly, two retrospective analyses by Schenker et al and Blok JJ et al [27] revealed that there is no significant difference in long-term patient and graft survivals between donors with low (≤17) and high (≥17) P-PASS scores [28]. This supports our findings and further reiterates that donor pancreas allografts should not be rejected based solely on high P-PASS scores and the parameters that deem a subgroup of donors as marginal donors.

In the US the Pancreas Donor Risk index was developed from data taken from the Scientific Registry of Transplant Recipients database and is linked to graft survival. It has also been validated in the UK cohort [29]. It may offer better predictions for more marginal pancreases and some studies have confirmed it is a better predictor of pancreas graft survival after SPK rather than after solitary pancreas transplantation [30]. It is also a better predictor than the P-PASS for pancreas graft survival [27]. Age, and cold ischaemia are included but amylase and lipase are excluded from the PDRI, as they were not associated with outcome. A recent systematic review conducted by Ling et al have shown that both P-PASS and PDRI are inadequate risk indices for use in solid pancreas transplantation due inadequate reporting of model performance metrics outside of current externally validated cohorts. P-PASS was derived for pancreas graft acceptance and not for prediction of graft survival. PDRI was validated for the outcomes of 1-year pancreas survival, and limited to graft survival for SPK transplants only [31]. These studies also did not focus on donor blood tests, and their impact on outcome, our study fills these gaps.

Liver function tests and amylase are both included in the North American Islet donor score which was developed to guide decision making as to whether to accept a particular pancreas to improve isolation outcomes [32, 33]. However, both amylase and transaminases were shown in the same Wang 2016 paper to have no impact on success of islet isolation from 1,056 donors. This mirrors our results in whole pancreas transplantation.

Additionally, it is worth noting that a previous smaller study by Hesse and Sutherland have demonstrated that an isolated elevation of amylase is not usually related to the functional status of the pancreas allograft, unless there was overt pancreatic trauma or pancreatitis. Graft function post-transplantation was found to be comparable in the recipients, regardless of whether the donor had normal or elevated amylase levels [34]. Krieger and others further echoes this, as they have shown that SPK graft survival rates in recipients of grafts from donors who had raised serum amylase compared favourably to outcomes in recipients of “ideal” donor grafts [35].

There are some limitations to the studies discussed above; both were performed in the early phases of pancreas transplantation, and only confined to the United States. Furthermore, the sample sizes in both studies were smaller than the present study. Both studies also reviewed graft outcomes based on arbitrary categories of normal and abnormal serum amylase, which reduces the power of the study [15–18]. Despite the limitations, these studies support our findings that hyperamylaseamia in donors is not a contraindication for pancreas organ donation. To our knowledge, our work is the largest cohort study to date, looking at the relationship between serum amylase and liver function tests upon pancreas graft survival in the modern era of pancreas transplantation. We have incorporated prospectively collected data from a large cohort, with robust statistical analysis as detailed above.

With the increased use of DCD grafts, there is an increased vulnerability towards inevitable ischaemic-reperfusion injury during procurement [36, 37]. Due to the close anatomical relationship between the pancreas and its partially shared vascular supply with the foregut, raised donor LBTs may represent ischaemic injury to abdominal viscera [14, 38–42]. Raised liver blood tests (LBTs) in liver donors were frequently used to define extended-criteria donors, in the context of liver transplantation [43, 44]. Due to the partially shared vascular supply [14, 38–42] between liver and pancreas we hypothesised that elevations in LBTs, especially transaminases, reflect hypoxic injury to the liver and are therefore a surrogate for hypoxic injury to the pancreatic allograft. This is supported by work showing that donors dying from hypoxic brain injury have far higher transaminase levels [11, 12].

Parajuli and others have found that delayed kidney graft function represented a significant risk factor for early pancreas graft loss (<90 days post-transplant) in SPK transplant recipients [45]. In view of this, we have therefore separately assessed the impact of peak donor renal function tests in our study, as the function of the transplanted kidney can impact pancreas graft function [45, 46]. We have found that donor renal blood tests did not predict pancreas graft survival (Supplementary Table S3). However, transplanted kidney graft survival may be better assessed in a study dedicated to kidney grafts, with much larger cohorts of kidney transplants alone.

More recently, our group explored the significance of deranged LBTs in liver transplantation and found that raised donor transaminases do not predict post-liver transplant outcomes [13]. Our study mirrors these findings in pancreas transplant, as there were no associations between abnormal LBTs and pancreas graft survival. Since routine liver function tests are carried out as part of the work up for a potential transplant donor, our findings reinforces that rises in LBTs should not be considered as a limiting factor in pancreas allograft allocation.

Furthermore, whilst in intensive care units, some donors may be given insulin in response to donor hyperglycaemia of varying aetiologies [47, 48]. A recent, large cohort study by Shapey et al suggests that donor insulin use is associated with a higher risk of graft loss due to islet failure and a lower risk of graft loss due to thrombosis in pancreas transplant recipients [49]. This suggests that actual markers of organ function and pancreas physiology may be more predictive of pancreas transplant outcomes, rather than non-specific enzyme release, such as amylase.

This study is limited by the retrospective design. Specifically, we lack granularity of data regarding imaging and clinical features of acute pancreatitis, or details regarding pancreatic trauma. As we only included donated pancreas grafts which were accepted and used for transplantation, the vast majority will be from donors without clinical or radiological features of pancreatitis or pancreatic trauma. Therefore, we cannot comment on the suitability of pancreases from donors where these features are present. We also lack information on serum lipase. Though we acknowledge it is a more specific marker of pancreatic injury, it is not routinely performed in the UK setting. Further study into the effects of lipase and pancreas graft transplantation outcomes, in a healthcare system that routinely measures donor serum lipase, may be a point in future research.

There is also a degree of selection bias, as various clinicians have different thresholds for donor amylase when it comes to discarding grafts at the time of organ procurement. As described in our results section, there is a wide range of donor amylase values in the pancreas grafts that were transplanted in our study. Hence multivariable analysis was performed to adjust for key confounders.

Finally, the right skewed distribution of serum blood tests translates to smaller number of donors in the extremely elevated results. This is reflected in the marked increase in the confidence intervals of the cox regression model adjusted hazard ratios with restricted cubic splines (Figure 2). The low number of donor with high amylase may affect the power of our study, and the most powerful way of assessing this was by using restricted cubic splines (Figure 2). The confidence intervals around these splines reveal uncertainty as amylase level increases. These are confidence fairly narrow up to a peak amylase value of 500, and then sharply increase due to the lower numbers of pancreases transplanted from donors with amylase values greater than 500. Although pancreases from donors with severely increased peak amylase (>1,000) all performed well in this study, this is a small group. Therefore it remains uncertain whether large increases in amylase (>1,000) impact on graft survival, and such donors should be assessed, on a case-by-case basis.

In conclusion, our study has demonstrated that the use of pancreas grafts from donors with hyperamylasaemia and raised liver blood tests is not associated with inferior outcomes. Mild or moderately raised donor amylase and liver blood tests should therefore not be considered a barrier to transplantation and organ utilisation when other donor factors are considered acceptable. This knowledge should prevent unnecessary organ discard, and provides a simple method to expand the donor pool to meet current demands.