Outcomes of Pancreas Transplantation in the United States Using Cardiac-Death Donors

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1 American Journal of Transplantation 2006; 6: Blackwell Munksgaard C 2006 The Authors Journal compilation C 2006 The American Society of Transplantation and the American Society of Transplant Surgeons doi: /j x Outcomes of Pancreas Transplantation in the United States Using Cardiac-Death Donors P. R. Salvalaggio a,b, D. B. Davies c, L. A. Fernandez d and D. B. Kaufman b, a Department of Surgery, Saint Louis University School of Medicine, St Louis, MO b Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL c Division of Biostatistics, United Network for Organ Sharing, Richmond, VA d Department of Surgery, University of Wisconsin School of Medicine, Madison, WI Corresponding author: D. B. Kaufman, d-kaufman2@northwestern.edu Organs donated after cardiac death (DCD) are used to expand the donor pool. We analyzed the outcomes in the United States of pancreatic transplantation of organs from DCD donors performed between 1993 and We used the OPTN/UNOS Registry to compare outcomes of primary pancreas allografts from DCD donors and donors after brain death (DBD). The primary endpoints were graft failure and patient death. A national survey regarding the use of DCD donors in pancreas transplantation was conducted among the directors of pancreas transplant centers. Data were obtained on 47 simultaneous pancreaskidney transplants (SPK) and 10 solitary pancreas transplants from DCD donors and on 2431 SPK and 1607 solitary pancreas transplants from DBD donors. Recipients of a SPK transplants from DCD and DBD donors had equivalent patient and graft survival rates at 1, 3 and 5 years. For recipients of SPK transplants, the wait for organs from DCD donors was significantly shorter than that for organs from DBD donors. SPK recipients of organs from DCD donors had longer hospital stays than did recipients of organs from DBD donors. With renal allografts, the incidence of delayed graft function was almost four times higher with organs from DCD donors than with organs from DBD donors. Selective use of organs from DCD donors is safe for pancreas transplantation. Key words: Donation after cardiac death, marginal donors, pancreas transplantation Received 6 November 2005, revised 16 January 2006 and accepted for publication 1 February 2006 Introduction To overcome the gap between the numbers of patients waiting for transplantation and the limited supply of organs, transplant centers have to innovate to increase the donor pool. In pancreas transplantation, the use of marginal donors for transplantation is still uncommon, but has grown in the past few years (1 4). Marginal donors for pancreas transplantation often include individuals with advanced or very young age, obesity, hyperglycemia, hyperamylasemia or with vascular and congenital abnormalities (5 8). Since inferior survival rates have been associated with some of these variables, careful assessment on a case-by-case basis is required for safe utilization of pancreata from marginal donors (9 12). Other alternatives to expand the pancreatic donor pool include the use of living donors and the use of organs donated after cardiac death (DCD) (13,14). The use of organs from DCD donors is an old concept. Before publication of the brain-death law, most recovered organs were from DCD donors. However, as a result of the continued shortage of organs for transplantation, interest in the use of DCD donors has resurfaced. Controlled DCD donors (Maastricht category III) are hemodynamically stable individuals who, following a decision by their families to withdraw care and consent to organ donation, are extubated in the operating room or intensive care unit. This is a planned event in which the procurement team is present to recover the organs rapidly, therefore limiting warm ischemia. Uncontrolled DCD donors are individuals for whom the cessation of cardiopulmonary function is an unplanned event. This group consists of individuals found dead in the field of trauma (Maastricht category I) or who expire during attempted cardiopulmonary resuscitation (Maastricht category II). Brain-dead donors who die of cardiopulmonary arrest before organ donation are also considered uncontrolled DCD donors (Maastricht category IV) (15). The Institute of Medicine issued recommendations on the use of DCD donors (16,17). One important point is that a mandatory no touch period of 5 minutes after cardiac arrest has to be followed in order to declare a patient clinically dead before the initiation of organ recovery (16,17). 1059

2 Salvalaggio et al. DCD donors are a potential source for a variety of solid organs for transplantation, including pancreases (14,18 22). The use of DCD donors is increasing, constituting a greater number of deceased organ donation in the United States (23,24). Conservative estimation suggests that the use of DCD donors can add about 1000 donors per year to the number of standard deceased donors, increasing the total number by 20% to 25% (23,25,26). The aim of this study was to analyze the national results of pancreas transplantation from DCD donors. We also sought to provide a basis of information to guide transplant centers in using this source of donor organs. Methods Study design This is a retrospective study of pancreas transplantation outcomes in the United States. We analyzed information from the OPTN/UNOS (United Network for Organ Sharing) database on all pancreas transplants performed between 1993 and 2003 from programs that had performed at least 1 DCD pancreas transplant. The first year that DCD status was recorded in the OPTN/UNOS database was Follow-up of patients was conducted through November We reviewed the available information regarding all recipients of primary whole pancreatic allografts who were 18 years of age or older. Included were 2431 simultaneous pancreas-kidney transplantation (SPK) recipients of organs donated after brain death (DBD), 47 SPK recipients of DCD donors, 1607 recipients of solitary pancreases from DBD donors and 10 recipients of solitary pancreases from DCD donors. Donor and recipient demographics are described in Tables 1 and 2, respectively. Endpoints Actuarial 1-, 3- and 5-year patient and graft survival rates were determined for the recipients of pancreas transplants from the time of transplantation. Kidney graft failure was defined as removal, loss of function requiring return to dialysis or death with a functioning graft. Pancreas graft failure was defined as removal of the graft, loss of endocrine function requiring return Table 1: Characteristics of donors of pancreatic allografts Donor type DBD DCD DBD DCD Recipient category SPK SPK Solitary Solitary Age (years) Gender (% males) Race Caucasian 78% 94% 79% 80% African American 12% 0% 9% 20% Hispanic 8% 4% 10% 0% Other races 2% 2% 2% 0% Pressors (%) BMI Kidney total ischemia (h) Pancreas total ischemia (h) DBD = donors in which donation after brain death was used; DCD = donors in which donation after cardiac death was used; SPK = simultaneous pancreas-kidney transplant; BMI = body mass index. p < 0.01 vs. DCDs. Table 2: Characteristics of recipients of pancreatic allografts Donor type DBD DCD DBD DCD Recipient category SPK SPK Solitary Solitary Age (years) Gender (% of males) Race Caucasian 85% 89% 92% 90% African American 9% 2% 5% 0% Hispanic 5% 4% 2% 10% Other races 1% 5% 1% 0% HLA (% mismatch) PRA (>20%) 10% 4% 15% 20% On dialysis at 80% 74% transplant Creatinine at time at transplant (mg/dl) Waiting list time (days) Length of stay in hospital (days) DBD = donors in which donation after brain death was used; DCD = donors in which donation after cardiac death was used; SPK = simultaneous pancreas kidney transplant; Solitary = solitary pancreas transplant; BMI = body mass index. to exogenous insulin therapy, or death with a functioning graft. We also examined potential confounding donor and recipient variables. Donor factors included age, gender, race, HLA mismatch, presensitization, as indicated by the presence of high panel-reactive antibody (PRA) levels, body mass index (BMI), use of pressors before organ procurement and time of warm and cold ischemia. Recipient characteristics at the time of transplantation included age, gender, race, dialysis dependence and year of transplant. Delayed graft function (DGF) was defined as a need for any dialysis treatment during the first post-transplant week. Survey A national survey was performed among the directors of pancreas transplant programs who have had experience with the use of DCD organs in pancreas transplantation. A formal letter was mailed to the pancreas transplant program directors and individuals that did not reply were subsequently interviewed by phone. We asked the directors about specific aspects of their experience in the use of DCD organs for transplantation, including the criteria applied in the selection of donors and recipients, the time of warm ischemia, the technique used during organ procurement, the specific care of donors and recipients, the results of the transplants and post-operative complications. The results of the survey were analyzed separately from that obtained from the UNOS database. Statistical analysis We used chi-square, Fisher, Wilcoxon-Z (two-sample, two-sided) and Student t-tests to compare proportions and means between the DCD and DBD groups. We used Kaplan-Meier survival estimates with log-rank comparisons for a univariate comparison of death-censored graft survival and patient survival in the DCD and DBD groups. A probability of type 1 error (p = 0.05) was considered to be the threshold of statistical significance. Statistical analysis was performed using SAS software (version 9.1, SAS Institute Inc., Cary, NC) American Journal of Transplantation 2006; 6:

3 Pancreas Transplantation and Donation after Cardiac Death SPK Solitary* Figure 1. Number of pancreas transplants from DCD performed per year Results Use of pancreas allografts from DCD donors The UNOS database identified 57 pancreas allografts from DCD donors between 1993 and The use of DCD pancreas allografts increased steadily during the study period (Figure 1). At the same time the UNOS database registered 1802 kidneys and 404 liver transplants from DCD donors that were performed during this study period. In 1993, 61 kidneys, 9 livers and 5 pancreases for SPK transplant allografts from DCD donors constituted, respectively, 0.08% of the deceased kidney pool, 0.03% of the liver pool and 0.07% of the pancreas pool. In 2003 by the end of the study period, the use of DCD donors grew 0.4% of the kidney and 0.2% of the liver pool. However, pancreases from DCD donors accounted for only 0.1% of all pancreas transplants. Donor and recipient demographics The most common donor was Caucasian, male, younger than 30 years old, with a BMI of less than 25. There were no DCD African American donors of organs for SPK transplantation, whereas 9% of the DBD pancreas donors were African American. The mean age and BMI of donors were similar in the DCD and DBD groups. Three-quarters of DBD donors had required pressors for hemodynamic support as compared to only 34% of the DCD donors (Table 1). Interestingly, among pancreases used for SPK transplantation the average preservation time of the pancreas allograft was similar for organs from DCD donors (15.7 h) and DBD donors (15.4 h). There were no major differences between the two groups of transplant recipients in terms of gender, age, race, PRA and donor-recipient HLA mismatch (Table 2). Based on the variables analyzed, we could find no selection bias for or against any recipient group receiving organs from DCD donors. For recipients of SPK transplants, the wait for organs from DCD donors (185 days) was significantly shorter than the wait for organs from DBD donors (284 days) (p = 0.03). Survey Organs from DCD donors have been used for pancreas transplantation in only 13 (from 142 nationwide) pancreas transplant centers. Written or telephone surveys about the practice of pancreas transplantation using organs from DCD donors were completed by nine directors of transplant centers. It is important to note that the overall experience of these centers represented 89.5% of these procedures performed in the United States during the study period. Program directors believed that DCD are an acceptable and underused source of organs for pancreas transplantation. Directors stated that in terms of surgical complications, as well as both patient and graft survival, the results obtained with organs from DCD donors are comparable to those achieved with organs from DBD donors. There was a split among the program directors as to the optimal pancreas transplant recipient. Fifty percent of them stated that pancreases from DCD donors should be used for either SPK or solitary pancreas transplantation, 30% believed that these pancreases should be used only for SPK transplantation and 20% said that these organs should be directed only to recipients of solitary pancreas transplants. Transplant centers are selective in identifying DCD donors for pancreas transplantation. The donors tended to be relatively young with low BMI and hemodynamically stable. There was consensus that organ procurement should be performed under controlled conditions with extubation in the operating room. Few directors would accept a planned extubation in the ICU or pre-operative area. Similarly, few of them would accept organs from donors who had experienced cardiac arrest after the diagnosis of brain death. There was general agreement regarding the limits of warm ischemia, the most common response being a limit of a maximum between 20 and 45 min. Eighty percent of the program directors considered the time of warm ischemia to begin from the start of hemodynamic instability (systolic blood pressure <50, peripheral oxygen saturation <70%, no pulse). Eighty percent of the centers follow the Institute of Medicine recommendation of 5 min of American Journal of Transplantation 2006; 6:

4 Salvalaggio et al. obligatory no-touch time after cardiac arrest. Only two centers followed the Pittsburgh Protocol (2 minutes of notouch ) or the original Maastricht Protocol (10 minutes notouch ) (16,17,27,28). Other factors mentioned as part of the process of deciding whether or not to accept organs from DCD donors were the use of local donors, the importance of minimizing cold ischemia time, procurement by the same transplant team involved with the recipient operation, the quality of the cold preservation flush, the macroscopic appearance of the pancreas and the possible use of pulsatile perfusion of kidneys recovered for SPK transplants. Opinions were divided with respect to whether the liver and pancreas have to be removed en bloc or separated in situ during removal from the donor. Program directors have not emphasized the use of experimental strategies to minimize injury to organs from DCD donors as a crucial step toward optimizing outcomes. Survival after transplantation of pancreases from DCD versus DBD donors Kaplan-Meier analysis demonstrated similar patient and graft survival with the use of DCD or DBD organs for SPK and solitary pancreas transplantation (Figure 2). In SPK recipients, the survival rates of kidney grafts from DBD donors were at 92% at 1 year, 82% at 3 years and 74% at 5 years, while the corresponding rates for kidneys from DCD donors were 96% at 1 year, 83% at 3 years and 79% at 5 years (p = 0.64). The survival rates of pancreas grafts from DBD donors at 1, 3 and 5 years were, respectively, 86%, 77% and 70%, while those for pancreas grafts from DCD donors were, respectively, 85%, 80% and 74% (p = 0.51). Patient survival rates among recipients of organs from DBD donors at the same time points were 96%, 89% and 84%, respectively; those among recipients of organs from DCD donors were 98%, 93% and 89%, respectively (p = 0.63). For recipients of solitary pancreas transplants from DCD organs, patient survival rates at 1 and 3 years were 95% and 88%, respectively, while the rates for recipients from DBD donors were 100% and 72%, respectively. At the same intervals after transplantation, pancreas graft survival rates were, respectively, 81% and 62% for those from DBD donors and 90% and 45% for those from DCD donors. During the follow-up of SPK recipients it was found that 10% of patients on the DBD donors group and 17% on the DCD donors group had their insulin and/or oral hypoglycemic medication resumed (p = 0.12). For recipients of a pancreas transplant alone, 18% on the DBD donors group and 30% on the DCD donors group had their insulin and/or oral hypoglycemic medication resumed (p = 0.33). Thrombosis, delayed graft function, length of hospital stay Vascular thrombosis was the most common cause of pancreas failure in all groups. In SPK transplant recipients, A. Survival Rate (%) B. Survival Rate (%) C. Survival Rate (%) DBD DCD Time (months) DBD DCD Time (months) DBD DCD Time (months) Figure 2. Kaplan-Meier analysis for patient survival (A); kidney (B) and pancreas (C) graft survival of SPK transplant recipients from DCD and DBD donors American Journal of Transplantation 2006; 6:

5 Pancreas Transplantation and Donation after Cardiac Death the incidence of thrombosis in organs from DCD donors (12.8%) was higher than in those from DBD organs (6.1%), p = For SPK recipients whose pancreas failed, acute cellular rejection (9%), bleeding (18%) and chronic rejection (9%) were common causes in the DCD group contrasting with chronic allograft rejection (14%) and infection (6%) in the DBD group. The incidence of DGF of the kidney in SPK transplant recipients of organs from DCD donors was almost four times higher than that with DBD allografts, 28.2% versus 7.6% respectively (p < 0.01). Patients who received grafts from DCD donors had a similar hospital length of stays (LOS) than did those who received organs from DBD donors (Table 2). Discussion Previous single-center studies (14,29) and the present study support the viewpoint that pancreata from DCD donors should be considered in select circumstances to expand the donor pool. The major finding of this study was that patient and graft survival rates for recipients of SPK transplantation from DCD and DBD donors were nearly identical. It is important to highlight that the national results mirror prior findings reported by the University of Wisconsin group in SPK recipients (22,29). We are now extending their pioneer report showing the national experience with the use of DCD donors in pancreas transplantation (SPK and solitary pancreas transplants). We have also surveyed transplant program directors in order to set basic guidelines for the use of DCD donors in pancreas transplantation. Other studies have also endorsed the use of DCD donors for kidney and liver transplantation in multicenter studies (23,25). Organs from DCD donors might be also useful for islet, heart and lung transplantation (24,30 32). Our data showed that the typical characteristics of DCD donors for pancreas transplantation (e.g. age, BMI) were not very different from DBD donors for pancreas transplantation, reflecting the generally conservative nature of donor selection for pancreas transplantation. An important consideration for pancreas use from a DCD donor was hemodynamic stability. Another important finding of our study was the clear reduction of the time that SPK transplant recipients had to wait for organs from DCD donors as compared to organs from DBD donors. We might speculate that centers that are using DCD donors have an opportunity to expand the pancreas organ pool, which can allow recipients to have a shorter waiting time on the transplant list. Some European kidney transplant programs have reported that up to 40% of kidneys come from DCD donors (26). Nonetheless, the total number of pancreases from such donors is still very limited and has grown at a slow pace (15). There undoubtedly are multiple reasons for this lack of popularity of organs from DCD donors. One obvious issue is the simple inertia described by Rudich et al. (23). Organ procurement organizations have found no need to implement DCD programs until relatively recently. Thus, it is still unknown exactly how much the DCD donor pool could contribute to expand pancreatic transplantation. Our survey of transplant directors showed some differences among transplant centers in terms of how donors are managed. We asked these directors how procurement is performed at their centers, how death and warm ischemia should be defined and which DCD donors and recipients of their pancreases should be selected. Our findings from this survey might be used as initial guidelines for organ procurement organizations and transplant centers willing to pursue pancreas transplantation from DCD donors. We recommend the use of controlled, young, lean, hemodynamically stable donors procured by an experienced pancreas transplant team that will look for the characteristics of the organ, account correctly for the warm ischemia period and follow the norms of The Institute of Medicine (16,17). The recipient operation should be coordinated to minimize cold ischemia time. It is generally recognized that recipients of kidneys from DCD donors develop renal allograft DGF more often than do recipients of kidneys from DBD donors (33,34). The etiology of DGF is probably multifactorial, but the mechanisms of donor injury, donor hemodynamics and procurement technique must also be considered. Total organ preservation, as well as warm and cold ischemic times, may also be pivotal in the causation of DGF. Moreover, several OPOs have reported that the use of pulsatile perfusion of the kidneys leads to a significantly lower risk of DGF than occurs in kidneys that have not undergone pulsatile perfusion (23,35). The present study, unlike previous ones, found that the greater rate of renal allograft DGF does not lead to a correspondingly greater incidence of acute allograft rejection nor appear to compromise either graft or patient survival (21,23,35,36). It is also of interest that our study found no impact on pancreatic allograft survival even in SPK recipients who had post-operative DGF. However, there is also a similar number of patients who had to resume insulin use after transplantation of pancreases from DCD and DBD donors (data not shown). Therefore, it seems that the initial injury that strikes renal allografts does not have a functional impact on pancreatic grafts at least for the initial 5 years after transplant. We also found that recipients of SPK transplants from DCD donors experienced similar hospital stays and vascular thrombosis rates as did those who received transplants from DBD donors. Future studies using a larger cohort of patients and multivariate analysis will be needed to confirm these conclusions. American Journal of Transplantation 2006; 6:

6 Salvalaggio et al. The limitations of this study include a lack of detail about recipient-selection criteria that might distinguish recipients of organs from DCD and DBD donors. It was assumed that all patients listed for transplantation were subjected to a rigorous pre-operative workup and were therefore comparable with respect to the severity of co-morbid medical issues. Moreover, the cohort of solitary pancreas recipients from DCD donors was extremely small. The number of SPK transplant recipients from DCD donors was also limited in size and dominated by procedures done at a single transplant center. In summary, patient and graft outcomes support the use of selected DCD donors for pancreas transplantation. Recipients of SPK transplants from DCD donors had a shorter waiting time than did recipients of SPK transplants from DBD donors. The highest incidence of DGF occurred in kidney allografts from DCD donors transplanted into SPK recipients. These recipients also had longer hospital stays, albeit with no higher rate of surgical complications. The use of pancreases from DCD donors can therefore be recommended with some caveats. DCD donors should be controlled, young, lean and hemodynamically stable. Organ procurement should be done by a well-trained pancreas transplant team. The recipient operation should be coordinated to minimize cold ischemia time. Justification for the use of allografts from DCD donors may be defended by long-term patient and graft survival rates and complication rates similar to those in recipients of pancreases from DBD donors. Acknowledgments We thank the Department of Biostatistics at UNOS, in particular Maureen Mac Bride and Ann Harper for important suggestions and help in the acquisition of the data. The data reported here have been supplied by UNOS as the contractor for the OPTN. 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