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Results from an International Survey of Donor and Recipient Eligibility for Solid Organ Pancreas Transplantation

Background Current solid organ pancreas transplantation protocols have differing donor criteria for donor pancreas acceptance and recipient eligibility criteria for transplant workup. We quantified this variation and compared current Australia and New Zealand (ANZ) solid pancreas transplant eligibility criteria with current international practice. Material/Methods A survey of donor and recipient eligibility criteria for solid pancreas transplantation was disseminated to 85 transplant units in 23 countries. Responses were grouped by regions (ANZ, North America, Eurotransplant, Europe, United Kingdom) and analyzed for significant differences between regions and for ANZ compared to all other regions. Results Responding UK pancreas transplant units reported the highest mean donor upper age limit (61 years old) and the highest mean donation after cardiac death donor (DCD) age limit (55 years old). All responding UK and USA units utilized DCD pancreas donors and accepted suitable type 2 diabetes (T2DM) recipients for pancreas transplantation; however, this was less common among responding European or Eurotransplant units. ANZ mean standard and DCD pancreas donor upper age limits (47 and 35 years old, respectively) were lower compared to all other regions (54 years old and 48 years old, respectively). Conclusions Pancreas donor age limits, DCD pancreas donor utilization, and transplanting T2DM recipients differ between responding pancreas transplant units. ANZ units have more conservative donor upper age limits compared to other responding units. Increased utilization of DCD pancreas donors and T2DM recipients while standardizing pancreas donor age limits might increase donor numbers and improve access to solid pancreas transplantation both locally and abroad.


Background
Solid organ pancreas transplantation, usually performed in combination with a kidney transplant when renal failure is present, is the definitive treatment for medically suitable patients with type 1 diabetes [1]. Pancreas transplant recipients have improved mortality and quality of life compared to patients on the waiting list or who cannot be transplanted [1][2][3]. In Australia and New Zealand, annual solid pancreas transplantation and pancreas donations have increased over the last decade [4][5][6][7][8], while in other regions such as the United States of America (USA) and the United Kingdom (UK), transplant numbers have decreased or plateaued during the same period [7,9]. However, the total number of solid pancreas transplants performed per capita annually in Australia/New Zealand is much lower than in the USA or the UK (2 per million population vs 2.8 in the UK and 3.1 in USA in 2018) [4,5,7,8].
National pancreas transplant protocols guide donor organ acceptance as well as recipient assessment for transplant eligibility [10][11][12][13][14]. However, differences exist in donor and recipient criteria determining organ acceptance and eligibility for entering transplant workup, respectively, between pancreas transplant protocols for different jurisdictions ( Table 1). Transplant volume can influence these differences, as demonstrated by a USA registry study reporting that low-volume pancreas transplant centers were accepting more 'favorable' pancreas donors with lower Pancreas Donor Risk Index (PDRI) [15] scores compared to high-volume centers [16]. Furthermore, varying eligibility criteria between regions might result in a pancreas transplant candidate or donor being considered high-risk in one jurisdiction but acceptable in another. We aimed to quantify these differences by region and to determine whether these differences were correlated with the transplant volume by region. We also compared Australia and New Zealand (ANZ) solid pancreas transplant criteria to those of similar units worldwide. We hypothesized that donor and recipient eligibility criteria for solid pancreas transplantation significantly differ between units as well as between countries and that local criteria are more conservative than those employed elsewhere.

Survey Development
A survey on donor and recipient eligibility criteria for pancreas transplantation was disseminated to pancreas transplant units worldwide. The survey format was chosen due to its ability to rapidly obtain information from a targeted population at a low cost [17]. With guidance from the existing literature [18][19][20], Microsoft Excel and Qualtrics were used to design the survey, consisting of 4 domains (Unit demographics, Recipient criteria, Donor criteria, and Other criteria) (Supplementary Table 1).
Unit demographics requested included the number of solid pancreas transplants performed between 1 January 2017 and 31 December 2017 stratified by transplant type: whether simultaneous pancreas-kidney (SPK) transplant, pancreas after kidney (PAK) transplant, or pancreas transplant alone (PTA). Recipient criteria questions included upper age limit, body mass index (BMI) limits, whether type 2 diabetic (T2DM) recipients were accepted, criteria regarding type 1 diabetes severity, smoking history, alcohol intake, recreational drug use, and any criteria regarding severity of peripheral vascular disease or cardiovascular disease. Donor criteria questions also included age and BMI limits, whether donation after cardiac death (DCD) donors were accepted, and whether specific criteria on age, BMI, and ischemic time existed for DCD donors, as well as any use of donor risk indices to guide donor pancreas acceptance. Other criteria questions included if any logistical factors would impede pancreas transplantation. Questions regarding immunological matching criteria were excluded, as their use depended on existing infrastructure and funding between various regions. Units could link national/regional protocols influencing unit-specific protocols. The survey (designed to be completed within 30 minutes) was piloted internally on  Table 2).

Only 4 of 21 units used a risk index (Pre-procurement Pancreas
Suitability Score) to guide donor pancreas acceptance [23]. Finally, no association was observed between transplant volume by region and limits for donor age/BMI, or DCD donor age/WIT/CIT ( Table 3).  Table 2). Similarly, no association was observed between transplant volume by region with recipient age or BMI limits ( Table 3).
Acceptance of T2DM recipients for solid pancreas transplantation differed significantly between region (P=0.028) ( units reported that any history of peripheral vascular disease requiring revascularization would be an absolute contraindication for solid pancreas transplantation.

Other Criteria
Eight of 21 units (38%) stated that geographical factors would affect decisions to proceed with pancreas transplantation. Of these, 6 units (75%) stated associated concerns regarding CIT. One unit reported 'multiple factors' without further elaboration. Another unit specified an important factor was ensuring the surgeons explanting the donor organs were from the same transplant hospital. Fifteen of 21 units (71%) stated that logistical factors would not affect the decision to proceed with pancreas transplantation. Logistical factors affected transplantation decisions in 5 units (unavailability of vascular surgeons in 4 units and unavailability of intensive care beds post-operatively in 1 unit). One unit reported multiple factors (transport costs, donor team availability) would influence their decision to proceed with solid pancreas transplantation.

ANZ Against All Regions
The mean DCD donor upper age limit was lower in ANZ than in all other regions (35 years vs 47.5±7.2 years respectively, P=0.001) ( Table 4). The mean donor upper age limit was also lower in ANZ than in all other regions (46.7±2.9 years vs 53.9±5.8 years respectively, P=0.052). The difference between the mean recipient upper age limit also trended toward significance (58.3±4.1 for ANZ vs 52.5±3.5, P=0.075). Other donor and recipient characteristics were not significantly different between ANZ and all other regions.

Variation Between Units Within Regions
Responding UK, Eurotransplant and ANZ units reported recipient and donor pancreas age limits consistent with their national protocols [10,11,13,14]. Varying recipient and donor upper age limits were reported for the USA units (55-65 years and 45-65 years, respectively), consistent with the lack of formal recipient and donor age limits within the USA pancreas protocol [12]. Reported recipient and donor BMI limits were consistent between units (30-35 kg/m 2 ).

Variation Between National Pancreas Protocols
Transplant eligibility criteria for solid pancreas recipients and donor pancreas acceptance for the Eurotransplant [10], UK [13], and the USA [12] were compared with the Transplantation Society of Australia and New Zealand (TSANZ) criteria [14] ( Supplementary  Tables 2, 3). The Eurotransplant, UK, and USA do not have formal recipient upper age limits for solid pancreas transplantation. Eurotransplant and the USA do not have a recipient BMI upper limit, while this is 30 kg/m 2 for the UK. Regarding diabetes classification, the Eurotransplant and UK criteria stipulates autoantibody and C-peptide testing in selecting suitable pancreas transplant candidates, while USA criteria broadly define suitable recipients as those demonstrating pancreatic exocrine insufficiency. Only UK criteria contain relative and absolute contraindications for pancreas transplantation based on recipient comorbidities as well as addressing other risk-taking behavior such as drug or alcohol abuse. In comparison, the TSANZ pancreas recipient criteria state an upper age limit of 50 years, a BMI limit of under 35 kg/m 2 , and also suggests C-peptide testing to delineate the presence of low or absent insulin production. TSANZ criteria also comment on the risk of significant cardiovascular and peripheral vascular disease and risk-taking behavior in the form of smoking and illicit drug use.
Regarding donor criteria for solid pancreas acceptance, the upper donor age limit is 50 years old from Eurotransplant criteria (up to 60 years old in the Netherlands), while the UK criteria accept donation after brain death (DBD) donors under 66 years old and DCD donors under 56 years old for solid pancreas transplantation. Donor BMI criteria range from 25 kg/m 2 (UK) to 30 kg/m 2 (Eurotransplant). The USA does not have formal donor pancreas age or BMI limits but allocate donors above 50 years old and above 30 kg/m 2 differently to younger and lighter donors. In comparison, TSANZ donor pancreas criteria stipulate a 45-year age limit, a donor weight between 25 to 100 kg, and specific DCD donor pancreas criteria (Supplementary Table 2).

Discussion
This is the first study to report differences in donor and recipient criteria for solid pancreas transplant eligibility between units from various countries with comparisons to current criteria in Australia and New Zealand. The main differences between regions were pancreas donor and DCD donor upper age limits and the acceptance of DCD pancreas donors and T2DM recipients for solid pancreas transplantation. There are a few reasons for these differences.
Firstly, differences between local pancreas allocation protocols contribute to the differences in unit responses observed (Supplementary Tables 2, 3). For instance, Eurotransplant guidelines defines pancreas donors >50 years old and with BMI ³30 kg/m 2 as so-called extended-criteria donors [10], with the Netherlands extending the DBD donor upper age limit to 60 years old. UK criteria also have a donor upper age limit of up to 60 years for DBD donors. However, ANZ guidelines would not accept pancreas donors >45 years old [14]. Also, the presence of unique mechanisms such as donor-recipient age-matching, which is built into the UK pancreas allocation scheme [11], may have contributed to the high mean donor (and DCD donor) age limit reported by responding UK units, allowing selected older recipients to receive older donor pancreata.
Secondly, individual pancreas units are likely to assess transplant candidates on a case-by-case basis, using existing guidelines as relative rather than absolute contraindications for transplantation. Units reported slightly higher recipient and donor upper age limits and upper BMI limits than their corresponding national pancreas transplant guidelines (Supplementary  Tables 2, 3). For instance, Eurotransplant units reported a donor upper age limit of 45 to 55 years old despite the Eurotransplant guidelines recommending a donor upper age limit of 50 years old (with donors over 50 considered as meeting extended criteria) [10]. Our unit has previously transplanted patients up to 55 years old, although solid pancreas transplants in patients above 50 years of age are relatively rare. Transplant caseload in individual centers and available expertise may also influence these differences [16], although no significant associations between transplant volume by region and donor/recipient age and BMI were noted in our results.
The varying acceptance of T2DM patients for solid pancreas transplantation is due to the difficulty in classifying diabetes type (and assessing transplant benefit) [24,28,29]. Solid pancreas transplantation has been avoided in the setting of insulin resistance, leading to the use of C-peptide testing as a surrogate for insulin synthesis [25]. High C-peptide levels are not usually be observed in type 1 diabetic patients (with little to no insulin production) [25]. However, retrospective reviews of solid pancreas recipients with diabetes classified by C-peptide levels showed no significant difference in graft survival by diabetes type at 5-10 years, although sample sizes were generally small [26][27][28]. Furthermore, when diabetes classification was based on a combination of autoantibodies, C-peptide measurements, and absence of ketoacidosis, some type 1 diabetic patients still had detectable C-peptide levels, while some T2DM patients had low C-peptide levels <0.8 ng/ml [29], which was used in other studies to classify type 1 diabetic patients [27,28]. Therefore, C-peptide should be used in combination with clinical and biochemical criteria, as C-peptide alone may not correctly classify diabetes type [30] or predict transplant outcomes [26,27]. This correlates with our findings, in which the top reported criteria for assessing T2DM recipients for solid pancreas transplantation included C-peptide levels, insulin dependence, and recipient BMI.
Despite previous findings [24,31], there is evidence that including older donors and recipients results in non-inferior solid pancreas transplant outcomes [32,33]. A retrospective study showed non-inferior outcomes at 5 years after transplant between solid pancreas recipients from different age groups (from <30 to ³60 years old) [34]. Similarly, a Canadian study found no difference in pancreas/kidney or patient survival between recipients ³55 years and recipients <55 years old [35]. The Extended Pancreas Donor Program study showed similar 1-year pancreas survival between a cohort transplanted with extended criteria organs (donors aged 50-60 years) and a standard criteria donor cohort [36]. This implies that carefully selected older recipients (³55 years old) and donors (>50 years old) have non-inferior solid pancreas transplant outcomes compared to standard criteria donors and recipients. Also, a recent systematic review reported non-inferior outcomes up to 10 years with DCD donors (compared to DBD) for solid pancreas transplantation [37].
Despite the differences in the criteria presented above, some similarities exist among pancreas transplanting units. Recipient and donor BMI limits were uniform within most responding pancreas transplant units. C-peptide and autoantibody testing were commonly used measures for identifying suitable type 1 diabetic candidates for transplantation throughout responding units. Smoking, excessive alcohol intake, and illicit drug use were relative contraindications for pancreas transplantation; however, most units did not require total abstinence from such risk-taking behavior to determine eligibility for solid pancreas transplantation (with the exception of illicit drug use). Most units did not use donor risk indices to guide donor pancreas acceptance.
A limitation of the present study was the relatively low response rate. Anticipating this, we contacted department heads directly via telephone and email to introduce the survey prior to sending the initial survey invitation, followed by a reminder 1 month later. The survey response rate, while low, is similar to that of other survey-based organ transplant research [38,39]. Another limitation was that data consisted of pre-specified and free-text responses, which varied in details. For example, responses to cardiac and vascular criteria such as 'stable coronary artery disease' or 'absence of clinically relevant peripheral vasculopathy' limited our analysis. Also, responses pertaining to extended donor criteria were also excluded from the analysis, as the definition of an extended criteria donor differs between units, making comparison difficult. These limitations are due to the survey format; however, this was a low-cost method to contact a large cross-section of the international pancreas transplant community relatively quickly. We also acknowledge that the variability in pancreas transplant eligibility criteria worldwide involves more factors than those included in this survey, such as human leukocyte antigen (HLA) matching, which is included in USA and UK pancreas allocation protocols [11][12][13], as well as institutional factors such as availability of donor retrieval services. However, capturing such data was beyond the scope of our project.
Given the response rate, we acknowledge the results may not be fully representative of worldwide practice. However, the existing variation demonstrated warrants further research into determining optimal pancreas donor and recipient eligibility criteria for solid pancreas transplantation. Certainly, despite the differences in eligibility criteria, pancreas transplant outcomes are fairly similar between jurisdictions. UK data from 2018/2019 reported 1-and 5-year pancreas graft survival at 90% and 81%, respectively, similar to ANZ data from 2018 showing 1-and 5-year pancreas graft survival of 90% and 85%, respectively [9,40]. One-year and 5-year patient survival was 98% and 89%, respectively, from UK data and 96% and 92%, respectively, from ANZ data during the same period [9,40]. Similarly, 1-and 5-year patient survival for SPK transplants was 97.6% and 91.9%, respectively from USA data [7]. Standardizing eligibility criteria would potentially reduce nonutilization of donor organs as well as increasing wait-listing of recipients previously felt to be too high-risk for transplantation. Indeed, in ANZ, donor age is currently the second most common reason for donor pancreas non-retrieval (21% of non-retrieved pancreata in 2018), following the donor being 'not medically suitable' [4]. However, such changes in donor/recipient eligibility criteria need to consider other factors, such as the current waiting time and mortality on the solid pancreas waiting list (as an alternative to transplanting with older donors), and ensuring that other donor factors are accounted for such that the overall pancreas donor quality remains acceptable. In what year did your unit start performing solid organ pancreas transplants?

Conclusions
How many solid organ pancreas transplants were performed in your unit from 1 Jan 2017 to 31 Dec 2017?

Recipient Eligibility
Does your unit have a recipient age limit for acceptance to solid pancreas transplant workup? If so, please specify the age limit.
Does your unit have a recipient body mass index (BMI) limit for acceptance to solid pancreas transplant workup? If so, please specify the BMI limit.
Regarding SPK transplants, does your unit transplant both Type 1 and Type 2 diabetic recipients?
Does your unit have any eligibility criteria for Type 2 diabetes recipients to receive an SPK?
What range of C-peptide levels would be acceptable?
List any specific criteria pertaining to insulin dependence (i.e. <1 unit/kg/day) Please specify any specific endocrine criteria utilised in your unit for Type 2 diabetic patients (i.e. C-peptide levels, insulin dependence) In Type 1 diabetic patients, are there specific endocrine criteria for acceptance for pancreas transplant workup in your unit?
For pancreas-only transplantation (PTA/PAK), are similar endocrine criteria used as above to determine eligibility for transplantation?
Is current smoking in potential recipients an absolute contraindication to entering the waiting list for solid organ pancreas transplantation in your unit?
Is excessive alcohol intake in potential recipients an absolute contraindication to entering the waiting list for solid organ pancreas transplantation in your unit?
Is illicit substance use in potential recipients an absolute contraindication to entering the waiting list for solid organ pancreas transplantation in your unit? If so, what is the donor age limit for DCD pancreas donors in your unit?
If so, what is the donor BMI limit for DCD pancreas donors in your unit?
If so what is the warm ischaemic time limit for DCD pancreas donors in your unit?
If so what is the cold ischaemic time limit for DCD pancreas donors in your unit?
Would the acceptance of other organs (liver, heart, kidney) for transplantation affect the acceptance of a DCD pancreas donor in your unit?

Other Criteria
Do geographical factors affect the decision to proceed with solid organ pancreas transplantation in your unit?
Do logistical factors affect the decision to proceed with solid organ pancreas transplantation in your unit?
Do other factors not mentioned above affect the decision to proceed with solid organ pancreas transplantation in your unit? ABO -ABO blood group; BMI -body mass index; DBD -donation after brain death donor; DCD -donation after cardiac death donor; HLA -human leucocyte antigen.