Objectives: Because of the shortage of available organs for transplants, graft allocation polices have been modified recently. This report deals with the effect of using organs after rescue allocation for pancreas transplant in a single center in the Eurotransplant Region to possibly expand the donor pool.

Materials and Methods: A retrospective analysis was performed. Between 2007 and 2010, 31 pancreas transplants were performed at the University Hospital of Leipzig, in Leipzig, Germany. Among these, 7 cases used rescue organs.
These organs had been officially offered to, but rejected by, at least 3 consecutive transplant centers. Donor/recipient and clinical/laboratory transplant/posttransplant outcomes from patients receiving rescue organs were collected and were compared with organs from conventional donors.

Results: Mean donor age was greater in the rescue organ group than in the conventional donor group (28.3 ± 10.7 y vs 23.0 ± 12.5 y). During follow-up (2.3 ± 0.6 y rescue organ group vs 3.9 ± 1.2 y conventional donor group), patient, kidney, and pancreas graft survival rates were 85% in all 3 categories in the rescue organ group, whereas outcomes for conventional donors were 88%, 85%, and 83%. Incidences of pancreatic graft thrombosis, delayed graft function, acute and late rejection episodes (eg, perioperative complications) were comparable between groups. No differences existed between mean serum urea levels and mean HbA1c levels between groups 2 years after transplant. Whereas 2 years after surgery, mean serum creatinine levels (rescue organ group, 78.8 ± 21.0 μmol/L vs 114.3 ± 28.4 μmol/L in the conventional donor group) showed significant differences between groups.

Conclusions: Results are promising. Further pro-spective studies are warranted to evaluate routine transplant of organs after rescue allocation.

Key words : Pancreas transplant, Pancreas donor, Extended donor criteria, Marginal donor

Introduction

Simultaneous pancreas-kidney transplant is the standard treatment for patients with type I diabetes mellitus and end-stage renal disease to achieve insulin independence.1 Because of improving outcomes of patients undergoing pancreas transplants, the demand for diabetic patients with a pancreas transplant has risen. However, the shortage of available pancreatic donor organs has led to an increase in patients on the wait lists.²

The present disparity between organ availability and the number of patients awaiting donation affects all transplants.³ Use of extended criteria donors has expanded the donor pool in liver, kidney, and heart transplant. Pancreas grafts are underused and today pancreata are recovered from only 25% to 35% of deceased donors in the United States and only 30.3% of all offered pancreatic grafts that were transplanted in 2011 in the Eurotransplant region.^4,5 This is partly because of strict criteria regarding the definition of an acceptable pancreatic donor in many transplant centers.^6-9 Use of pancreatic offers from nonstandard or extended criteria donors should be reconsidered.^9,10 Because of the possibility of using these organs for transplant, the so called “rescue allocation” strategy was introduced in the Eurotransplant region in the early 2000s.

When an organ is not used by regular allocation, Eurotransplant can invoke a rescue allocation procedure. The rescue allocation represents an internal mechanism in the Eurotransplant region that rescues potential grafts that are marginal/expanded, or grafts that could be lost owing to unfavorable grafting situation or logistical problems.^11,12

We present our experiences using organs from rescue allocation for pancreas transplant and compare them with conventional (CONV) donors regarding pre- and posttransplant outcomes.

Materials and Methods

Between 2007 und 2010, thirty-one pancreas transplants were performed at our institution. Twenty-six patients received a simultaneous pancreas/kidney transplant, 2 received a pancreas transplant alone, and 3 received a combined organ transplants (2 liver/pancreas transplants and 1 heart/pancreas and kidney transplant).

The pancreas was transplanted in standard technique with an intraperitoneal approach. The arterial anastomosis was sutured to the recipient’s common iliac artery. The venous anastomosis was done using the recipient’s caval vein. Enteric drainage was done with a duodenojejunostomy. The kidney transplant was performed using the same technique as a kidney transplant alone.

All patients received immunosuppression according to our internal center protocol. Therapy was induced with an anti-thymocyte globulin at a dose of 2 mg/kg. The maintenance immunosuppression consisted of a calcineurin inhibitor (usually tacrolimus) and an antimetabolite (mycophenolate mofetil). Steroids were withdrawn rapidly stepwise. The study was approved by the Ethical Review Committee of the institute. All protocols conformed with the ethical guidelines of the 1975 Helsinki Declaration. Informed consent was obtained from all subjects.

Outcome measures
Donor/recipient and clinical/laboratory parameters such as transplant/posttransplant outcomes from patients receiving rescue organs were collected and compared at 2 years’ follow-up with conventional donors.

The Preprocurement Pancreas Allocation Suitability Score (P-PASS) score consists of following parameters of the Eurotransplant Pancreas Advisory Committee guidelines: age, body mass index, intensive care unit stay, cardiac arrest, serum sodium, serum amylase, lipase (eg, [nor]adrenaline), and use of dobutamine/dopamine. Conventional pancreatic donors were defined as nonextended donors between 10 and 44 years old and standard heart-beating multiple organ donors. Rescue organ donors were defined according to the definition given by Eurotransplant. In brief, it states that if organs are not arrangeable via regular allocation and are refused by at least 3 transplant centers, Eurotransplant is given the possibility to change from a patient-oriented to a center-oriented allocation procedure of the donor organ (rescue allocation).^11,12 This procedure was introduced for the rescue organs, which where not allocated because they were deemed marginal, had an unfavorable grafting situation, or had logistical problems. It is up to the accepting team to transplant patients with low-risk profile using a marginal graft, for example.^11,12 Complications were graded systematically according to the Clavien-Dindo classification.¹³

Pancreatic graft loss was defined as the need of daily insulin substitution, allograft pancreatectomy, or patient death. Kidney graft loss was defined as a return to dialysis or pretransplant serum creatinine level, transplant nephrectomy, or patient death. Delayed graft function was defined as the need for insulin substitution and/or dialysis at the time of the hospital care with no further need after discharge. Graft rejection was diagnosed by an increase of serum creatinine and/or pancreas enzyme (lipase). Kidney biopsy specimens were taken when rejection was suspected clinically. Treatment of rejection consisted of therapy with steroids and/or interleukin-2 antibodies or anti-thymocyte globulin.

Statistical analyses
We used the chi-square and Fisher exact tests for categoric variables and the Mann-Whitney U test for continuous variables. Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 18.0, IBM Corporation, Armonk, NY, USA), and P values < .05 were considered statistically significant.

Results

Between 2007 und 2010, thirty-one pancreas trans-plants were performed at the University Hospital of Leipzig, in Leipzig, Germany, including 7 patients (23%; 7 simultaneous pancreas/kidney transplants) receiving rescue organs and 24 patients (77%) receiving organs from CONV donors.

Baseline characteristics of the 7 patients receiving rescue organs are given in Table 1. Reasons for rescue allocation and refusal from other transplant centers were donor-related criteria (hemodynamic instability and/or cardiac arrest/resuscitation in 6 cases), elevated P-PASS scores (5 cases), prolonged intensive care unit stay (4 cases), history of substance abuse (7 cases), and logistic criteria (2 cases). A summary of pre- and posttransplant baseline characteristics of the entire study population is shown in Table 2.

In the rescue organ group, most of the donors were male (5 of 7), with a mean donor age of 28.3 ± 10.7 years versus 23.0 ± 12.5 years in the CONV donor group. These differences were not statistically significant. In rescue organ group, all 7 donors had nontraumatic causes of brain death, one of these had a history of hypertension. Two of the 7 donors had a history of alcohol abuse, another 3 of substance abuse. In 6 patients, cardiac reanimation was performed with a mean reanimation time of 19 ± 8.9 minutes. The P-PASS score (rescue organ group, 16.3 ± 2.5 points vs 13.2 ± 2.5 CONV donor group; P < .05) such as time spent in the intensive care unit (rescue organ group, 146.7 ± 74.4 h vs 71.1 ± 54.8 h in the CONV donor group; P < .05) was significantly higher in the rescue organ group.

Results after transplant
Results are shown in Table 3. Mean cold ischemia time of the pancreas (rescue organ group, 12.9 ± 2.1 vs 10.4 ± 2.6 h in the CONV donor group; P = NS) and mean kidney cold ischemia times (rescue organ group, 14.1 ± 2.7 vs 11.4 ± 3.5 h in the CONV donor group; P = NS) did not differ between groups. In the rescue organ group, patient, kidney, and pancreas survival rates at the end of follow-up were 85% across all groups. There was only 1 pancreas graft loss because of patient death with functioning organ in the rescue organ group. This patient received a combined heart/pancreas and kidney transplant. She died 6 months after transplant because of sepsis.

In the CONV donor group, patient, kidney, and pancreas survival rates were 88%, 85%, and 83%. There were 2 pancreatic graft losses because of thromboses and consecutive allograft pancrea-tectomies, and 2 because of graft necrosis/sepsis with allograft pancreatectomy. Overall complications (Table 4) were similar in both groups. After Clavien-Dindo classification, subgroup analyses showed no significant differences between the groups over the single grades. Incidences of pancreatic graft thrombosis, delayed graft function, acute and late rejection episodes, and infections were comparable between groups (Table 3).

At 2 years’ follow-up, no differences existed between mean serum urea levels (rescue organ group, 6.5 ± 1.3 mmol/L vs 7.3 ± 2.6 mmol/L in the CONV donor group) or between mean HbA1c levels (rescue organ group, 5.3% ± 0.2% vs 5.9% ± 0.9% in the CONV donor group). Mean serum creatinine levels 2 years after transplant (rescue organ group, 78.8 ± 21.0 μmol/L vs 114.3 ± 28.4 μmol/L in the CONV donor group; P < .05) showed significant differences favoring the rescue organ group. Parameters indicative of ischemia/reperfusion injury (eg, mean C-reactive protein) (rescue organ group, 145.7 ± 52.3 nmol/L vs 134.2 ± 58.1 nmol/L in CONV donor group), mean lipase (rescue organ group, 0.81 ± 0.5 μmol/L vs 0.88 ± 0.75 μmol/L in the CONV donor group) and insulin substitution was shown to be similar on analysis (Table 3).

Discussion

Increasing incidence of type 1 diabetes (eg, improved outcomes for patients receiving a pancreas transplant) increases the demand for pancreas transplant.¹⁴ Because of the high rate of surgical complications and technical difficulties, surgeons remain reluctant to accept pancreatic organs from unstable or older donors.^15-19 Ideal pancreatic donors are usually between the ages of 10 and 45 years, have a body weight of between 30 and 80 kg, have sustained brain death due to head trauma, are hemodynamically stable, and have been hospitalized for < 48 hours.^17,20-23 Therefore, grafts from donors are underused. Loss and associates published a study on the avoidable loss of some pancreata in the allocation process after analyzing allocation protocols of all Eurotransplant-registered German whole pancreas donors between 2005 and 2009.²⁴ Only 37% (n = 1758) of the offered pancreata were transplanted. Seventy-five percent of grafts were lost owing to donor-related reasons. The median number of offers required to place a pancreas was 4 (range, 1-24). The unused pancreata were withdrawn after a median of 8 offers (range, 1-33 offers) to 5 centers (range, 1-14 centers). It seems reasonable to expand the donor pool by including organs from marginal donors.²⁴

To the best of our knowledge, this is the first study reporting the use of rescue organs for pancreas transplant within the Eurotransplant region area and the results at 2 years’ follow-up after transplant. The results showed no differences in the rate of surgical- and organ-related long-term complications (eg, graft and patient survival) compared with CONV donors. The HbA1c value was 5.3% ± 0.2% in the rescue organ group, which was similar to 5.9% ± 0.9% in the CONV donor group (P = NS). The rate of graft thrombosis and delayed graft function for marginal organs also were comparable between groups.

In our study, pancreatic organs were accepted and transplanted at our center after a median of 3.5 refusals by other centers because of donor-related criteria (eg, hemodynamic instability, prolonged intensive care unit stay, medical history) or logistic criteria.

There are many studies reporting recipient risk factors that affect graft survival and complications after pancreas transplants.^25,26 Conversely, donor factors that have a bearing on transplant outcomes have not been well described and are restrictive among all performed organ transplants.^2,27-28

We contend that the most important determinant of pancreas suitability is inspection of the organ by an experienced pancreas transplant surgeon. Pancreas grafts from older donors without calcification, extensive fibrosis, or fatty infiltration could expand the donor pool for transplant. However, these parameters are not objective.

One important objective clinical parameter is the P-PASS score. Several studies have demonstrated that this score has predictive value for evaluating suitability of a pancreas during different stages of the allocation.¹⁴ Pancreas donors with P-PASS scores below 17 were 3 times more likely to be accepted as pancreas donors with P-PASS scores equal to or above 17 points.¹⁴ In our study, the mean P-PASS score of our 7 patients receiving rescue organs was 16.3 ± 1.7. Even though the score for the rescue organ group in this study was under 17, these organs had a significantly higher risk profile (Table 1).

With the ongoing shortage of available organs, transplant centers are interested in expanding the donor pool by accepting pancreata from donors who have less than ideal allografts. Some studies have shown excellent short- and long-term results using organs from marginal/extended criteria donors outside the Eurotransplant region.

A series of 100 pancreas transplants (48 from nonmarginal donors and 52 from marginal donors), in which marginal donors were defined as patients older than 45 years and/or with hemodynamic instability at the time of procurement, showed similar results. Delayed pancreas endocrine function was 6.2% for nonmarginal donors compared with 0% for marginal donors. Surgical complications (eg, infections and relaparotomy) were 12.5% for nonmarginal donors and 9.6% for marginal donors. The 1-year graft survival and patient survival rates were 91.7% and 97.9% for nonmarginal donors and 94.2% and 98.1% for marginal donors.¹⁹

In another study, 2 cohorts of simultaneous kidney/pancreas transplants (simultaneous pan-creas/kidney transplant) were examined: the first from extended donors, which were defined younger than 10 years of age or older than 45 years, or donation after cardiac death and the second was from CONV donors. Among 79 simultaneous pancreas/kidney transplant, 19 (24%) were from extended donors (12 organs from donors older than 45 years, three < 10 years, and 4 from donation after cardiac death donors), and the remaining 60 from CONV donors. After a median follow-up of 29 months, the results of patient, kidney, and pancreatic graft survival rates were not significantly different between both cohorts. The incidences were similar for delayed kidney graft function (5% in each group), early pancreatic loss because of thromboses (5% extended vs 8% CONV donors), acute rejection (16% extended vs 18% CONV donors), surgical complications, and infections. There were no significant differences in 1-year mean serum creatinine (123 μmol/L [1.4 mg/dL] in each group) or HbA1c levels (5.2% vs 5.5%) between extended and CONV donor groups.⁹

Schenker and associates²⁹ reported their long-term results using donors aged 45 years and older (n = 69 patients) compared with standard donors (n = 271 patients). Recipient characteristics and some donor characteristics (eg, body mass index, sex, intensive care unit stay, cardiac arrest, serum sodium and amylase, use of vasopressor agents, cold ischemia time) were comparable between both groups. The age and cause of death (brain death cerebro-cardiovascular) were significantly higher in the > 45-year-old donor group. Cumulative patient survival was 96% versus 98% after one, 82% versus 91% after five, and 82% versus 88% after ten years, with 1-, 5-, and 10-year kidney graft survival rates of 82%, 72%, and 57%, versus 93%, 83%, and 73%. Pancreas transplant survival after 1, 5, and 10 years were 69%, 60%, and 45% in older donors (> 45 years) and 88%, 76%, and 72% in younger donors (< 45 years). There were 14 cases (20%) of venous thrombosis in the older group and 25 (9%) in the younger group (P = .012).²⁹

A limitation of this study is its retrospective design, which did not allow for randomization and prospectively defined measurements. A German prospective multicenter study is currently being conducted. The Extended Pancreas Donor Study (EXPAND) aims to evaluate the use of expanded criteria pancreas grafts. Results of this study are eagerly awaited.¹⁰ Until then, retrospective analyses such as this study are the best estimation of results obtained after transplant of rescue organs as defined by the Eurotransplant region. An additional limitation may be the small sample size, which is not suited to allow conclusions for all patients, especially not outside the Eurotransplant region. However, a systematic review of the literature, which focuses on the results obtained outside the Eurotransplant region, confirms our results.

In conclusion, pancreata allocated through the Eurotransplant region rescue allocation procedure might, after careful consideration of recipient safety and donor risk profile, be a good option for expanding the donor pool, even in small volume centers. However, determining long-term feasibility and reasonability using large, multicentric, prospective studies (ie, the EXPAND study) are warranted. The process of allocation could benefit from a more standardized approach to donor criteria and cutoffs.

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