Key words : Outcomes research, Pancreas after kidney transplant, Pancreas transplant alone, Simultaneous pancreas and kidney transplants

Introduction

Pancreas transplant in combination with kidney transplant, either simultaneous (SPK) or pancreas after kidney (PAK), is an established treatment for patients with diabetes mellitus who develop renal failure, and pancreas transplant alone (PTA) is indicated for patients who develop hypoglycemic unawareness and associated unstable/labile diabetes (also known as brittle diabetes) despite optimal medical therapy.^1,2 Pancreas transplant can significantly improve patient survival and quality of life, prevent and/or improve some of the secondary diabetic complications, and provide independence from insulin therapy.³

Despite the increase in potential organ donors, there has been a decline in pancreas transplants during the 10-year period of 2004-2013.⁴ This trend has been reversed in the past 5 years, at least in United States. Many potential donor organs are not used for transplant, and pancreas discard rates are high.⁵ In the United Kingdom approximately 72% of all pancreases procured for transplant are discarded.⁶

A study by Mittal and colleagues⁷ has shown that graft failure rates among pancreas transplants approach 10% after 1 year. In the United States, the 90-day failure rate has steadily declined to 6.9% in 2019.⁸ The relatively high rate for early graft failure for pancreas transplant (eg, compared with kidney transplant) has incentivized the development of scoring systems to facilitate improved organ utilization and better outcomes. In 2008, the Eurotransplant Pancreas Advisory Committee introduced the Preprocurement Pancreas Suitability Score system (P-PASS).⁹ The P-PASS has a range of 9 to 27 and is calculated solely from 8 donor factors: donor age, sex, body mass index (BMI, calculated as weight in kilograms divided by height in meters squared), intensive care unit stay, cardiac arrest, serum sodium, serum amylase or lipase, and adrenaline or dobutamine. Preprocurement Pancreas Suitability Scores of 17 or less have been deemed ideal for prediction of graft function, and higher P-PASS scores are associated with higher rates of graft failure.^10-13 However, studies have not found any association between P-PASS score and long-term graft survival.^13-15

Another scoring system is the Pancreas Donor Risk Index (PDRI), which has been developed from the large national registry for donated organs in the United States.16 The PDRI comprises the 6 donor factors of age, sex, race, BMI, donor type (either donation after brainstem death or donation after circulatory death), and donor cause of death. There are also 2 transplant factors: cold ischemia time and type of transplant (SPK, PTA, or PAK). Although small studies in Spain¹⁷ and Brazil¹⁸ have concluded that PDRI cannot predict pancreatic graft outcomes, larger European Studies have validated the use of PDRI to estimate graft outcomes.^5,7,15

The objective of our study was to investigate the ability of the US PDRI and the European P-PASS systems to retrospectively predict outcomes for a population of pancreas recipients in Wales, UK.

Materials and Methods

Patient population
All patients who underwent a pancreas transplant (SPK, PTA, or PAK) from December 2004 to December 2017 in a single center were identified from a prospectively updated and maintained database. The Cardiff Transplant Unit is 1 of 8 transplant units in the United Kingdom that perform pancreas transplants, and it serves a population of over 2.3 million within a large geographic area.

Demographic data were collected from the donors (age, sex, BMI, cause of death, and warm and cold ischemia times) and recipients (age, sex, duration of diabetes, pretransplant glycated hemoglobin A1c level, associated renal failure, any previous transplants, human leukocyte antigen mismatch, and duration of follow-up). Additional data were collected from donors and recipients to calculate the P-PASS and PDRI. The primary outcomes were defined as presence of rejection episodes, 1-year and 5-year graft survival rates, duration of hospital stay, and patient survival.

In SPK patients, rejection was defined as the presence of biopsy-proven rejection in the kidney and/or pancreas grafts. In PTA patients, rejection was defined as biopsy-proven rejection of the pancreas graft. For PAK patients, any episodes of rejection in the kidney were excluded. Biopsies reported as “borderline changes” were excluded.

Calculation of Preprocurement Pancreas Suitability Scores and Pancreas Donor Risk Indexes
The P-PASS was calculated according to the model proposed by Vinkers and colleagues,⁹ and the US PDRI was calculated from the equation proposed by Axelrod and colleagues.¹⁶ We used an iOS-based software application (Pancreas Transplant DRI app, developed by Marc L. Melcher, from https://apps.apple.com/dk/app/pancreas-transplant-dri/id396068767). For patients with mixed ethnicity, the ethnicity selection option within this app was set to “Caucasian.”

Statistical analyses
All data analyses were performed with Prism software (version 9.0, GraphPad). Patients were divided into groups based on P-PASS (scores <17
and ≥17) and PDRI (indexes ≤1.57 and >1.57). The chi-square test for association was used to analyze the observed and expected frequencies. P < .05 was considered significant.

Graft survival times were censored for death, and graft failure dates were defined as the date for recommencement of antidiabetic/insulin therapy that continued for over 14 days. Cumulative survival was calculated with the Kaplan-Meier life table method, and differences in survival between groups of patients were analyzed by the log-rank method. Binary regression analysis was used to identify the effect of individual risk factors on acute rejection.

Results

Patient demographics
A total of 159 patients underwent pancreas transplant from December 2004 to December 2017, of which 108 (67.92%) were SPK, 18 (11.32%) were PTA, and 33 (20.75%) were PAK transplants. There were 114 patients (72%) who received transplants from donors after brainstem death, and 45 (28.30%) who received transplants from donors after cardiac death. Demographic details of donors and recipients are described Table 1. Median follow-up was 80 months (range, 2-178 months), and none of the patients was lost to follow-up.

Calculation of Pancreas Donor Risk Indexes and Preprocurement Pancreas Suitability Scores
The P-PASS and PDRI were retrospectively calculated. Of 159 patients, full data were available for 129 of the cohort (81.11%) to calculate P-PASS and 155 (97%) to calculate PDRI. Median P-PASS was 17 (range, 10-24) and median PDRI was 1.53 (range, 0.67-3.12).

The median P-PASS was 17 (range, 10-24) for SPK, 17 (range, 11-22) for PAK, and 16.5 (range, 10-22) for PTA patients (P = .24). The median PDRI was 1.59 (range, 0.67-3.12) for SPK, 1.24 (range, 0.73-2.47) for PAK, and 1.12 (range, 0.71-3.04) for PTA patients (P = .004). Compared individually, the PDRI values were significantly lower for PAK and PTA patients compared with SPK patients (P = .007 and P = .015, respectively).

There was a good correlation between P-PASS and PDRI (r2 = 0.539, P < .001) (Figure 1).

Rejection episodes
Forty-seven patients (30%) experienced at least 1 episode of biopsy-proven acute rejection during the follow-up period. Among the 129 patients for whom P-PASS was calculable, there were 12 (21%) and 27 patients (32%) with rejection in the <17 and ≥17 P-PASS groups, respectively (P = .202). Among the 155 patients for whom PDRI was calculable, there were 19 (23%) and 27 patients (38%) with rejection in the ≤1.57 and >1.57 PDRI groups, respectively (P = .047).

In a binary regression analysis for acute rejection, we observed that donor age and recipient sex were the main risk factors associated with more rejection episodes (P = .035 and P = .036, respectively) (Table 2), which explained the underlying possible association between PDRI and acute rejection.

Graft survival
The 1-year death-censored rates of graft survival were 95% and 80% for the <17 and ≥17 P-PASS groups, respectively. The rates of 5-year death-censored graft survival were 80% and 69% for the <17 and ≥17 P-PASS groups, respectively. Although there was a numerical difference in graft survival between the <17 P-PASS group and the ≥17 P-PASS group, this was not statistically significant (log-rank P = .132) (Figure 2).

The 1-year death-censored rates for graft survival were 95% and 81% for the ≤1.57 and >1.57 PDRI groups, respectively. The 5-year death-censored rates for graft survival were 78% and 67% for the ≤1.57 and >1.57 PDRI groups, respectively. Although there was a numerical difference in graft survival between the ≤1.57 and >1.57 PDRI groups, this was not statistically significant (log-rank P = .141) (Figure 3).

Patient survival
Overall actuarial patient survival rates were 98%, 92%, and 89% at 1 year, 3 years, and 5 years, respectively. The 1-year patient survival rates were 98% and 97% for the <17 and ≥17 P-PASS groups, respectively. The 5-year patient survival rates were 84% and 89% for the <17 and ≥17 P-PASS groups, respectively (log-rank P = .48) (Figure 4).

The 1-year patient survival rates were 99% and 97% for the ≤1.57 and >1.57 PDRI groups, respectively. The 5-year patient survival rates were 87% and 90% for the ≤1.57 and >1.57 PDRI groups, respectively (log-rank P = .82) (Figure 5).

Duration of hospital stay
The overall median hospital stay was 15 days (range, 6-346 days). For the factor of transplant type, the median duration of hospital stay was 18 days (range, 8-346 days) for SPK, 11 days (range, 7-32 days) for PTA, and 12 days (range, 6-98 days) for PAK transplant. Median hospital stay was 15 days (range, 7-346 days) for the <17 P-PASS group and 18 days (range, 7-103 days) for the ≥17 P-PASS group (P = .97). Median hospital stay was 14 days (range, 6-65 days) for the <17 P-PASS group and 18 days (range, 6-346 days) for the ≥17 P-PASS group (P = .10).

Discussion

This study showed that overall higher PDRI and
P-PASS were associated with a numerically higher number of rejection episodes and lower rates of graft survival. For graft survival, these numerical differences were not statistically significant. For rejection, a higher PDRI was associated with significantly higher number of acute rejection episodes. We observed no effect of PDRI or P-PASS on patient survival or duration of hospital stay. The data we present here suggest that the use of these 2 systems to evaluate pancreases for transplant is questionable.

The demand for pancreas transplants continues to grow, and rigorous selection and optimal utilization of organs are important factors for successful outcomes. The European P-PASS and the US PDRI systems are designed to facilitate effective and objective evaluation of data from pancreas transplant donors. We performed this study to investigate the ability of these models to retrospectively predict outcomes. The calculated values for P-PASS and PDRI showed good correlation, and neither system appeared superior for prediction of pancreas transplant outcomes. However, this correlation may represent a form of selection bias by the pancreas surgeon during selection of potential grafts, whose independent decision may consider factors identical to most (if not all) of the components/factors of both systems.

Vinkers and colleagues9 have previously stated that ideal donors should have a P-PASS of <17. Some studies^11,19 have reported an association between higher graft survival and lower P-PASS scores. However, more recent studies,^10,13-15 including those from the Eurotransplant pancreas transplant centers, have shown that P-PASS scores were not associated with pancreas graft survival. Our results are in line with other published studies,^10,13-15 and we observed no statistical significance in graft survival between the 2 P-PASS groups. The numerical difference between graft survival in P-PASS <17 and ≥17 reduced with the time posttransplant. Thus, utilization of grafts with P-PASS ≥17 can be considered safe as a  to expand the donor pool with the usual caveats.

The PDRI system was designed by Axelrod and colleagues¹⁶ to identify donor factors that increase the risk of graft failure. Results from the use of the PDRI to predict graft survival are controversial. Kopp and colleagues⁵ and Ayami and colleagues10 have reported a significant association between PDRI score and graft survival, and PDRI appears to be a better predictor of graft survival compared with P-PASS. However, several other studies^17,18 have shown that the PDRI was not able to predict graft survival. Interestingly, in a UK study, Mittal and colleagues⁷ found no significant association between PDRI score and graft survival in PTA and PAK groups but a significant association in the SPK group. We did not show the same findings in this study; however, in our population the PDRI scores were significantly lower in the pancreases accepted for PAK and PTA transplants. This is likely secondary to a more stringent selection bias for such patients. The lack of difference in graft survival between PDRI groups signifies that the score alone is not a useful predictor of pancreas transplant outcome.

This present study also showed that rates of biopsy-proven acute rejection after pancreas transplant are associated with high PDRI scores. To our knowledge, no other study has reported this association. A regression analysis was performed to identify the predictive factors for pancreas rejection. We found that donor age was highly predictive of rejection rates. This is supported by studies on the effect of immunosenescence on transplant outcomes. Older donors might elicit a more potent immune response within the recipient, and this response may lead to more episodes of acute graft rejection.^20-22 In addition, female sex within recipients was significantly associated with more episodes of rejection, and this has also been supported in previous studies and may be the result of greater likelihood of pregnancy-associated preexisting antibodies against anti- human leukocyte antigen²³ despite negative crossmatch.

This study has several limitations. This is not a randomized controlled trial and has inherent problems associated with retrospective data analysis. However, a randomized controlled trial in this area would not be ethically appropriate, and although data analysis was performed retrospectively, the data were collected and maintained prospectively. The second limitation is the sample size. Although the overall number of patients included in our study was reasonable, we were compelled to divide the patients into relatively small groups, which increased the possibility of a type 2 statistical error. We assumed that all cases of acute rejection were referred to our transplant center for follow-up treatment. Also, we excluded rejections that were diagnosed without a biopsy; however, given that untreated rejection can lead to graft failure, this is unlikely to be a significant factor.

Conclusions

The P-PASS and PDRI systems were not helpful to predict graft survival and patient survival after pancreas transplant in our population. Use of these models as basis for organ selection remains questionable. Our study showed a significant association between PDRI scores and acute graft rejection, and our hypothesis provides an explanation for this finding; however, future studies with larger cohorts are required to verify or refute our findings.

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