Abstract

Key words : Center volume, Donation after circulatory death, Outcomes

Introduction

Demand for liver transplantation (LT) in the United States continues to exceed the supply of available deceased donor organs, resulting in longer wait times for transplant and greater likelihood of wait-list drop out.^1,2 This has prompted consideration of extended criteria donors, including donations after circulatory death (DCD).³ Utilization of DCD grafts in the United States has increased over the past 2 decades, with percentage of DCD grafts increasing from 0.5% in 1999 to 4.9% in 2007 and 6.1% in 2016.⁴ Use of DCD organs has, however, been reported to be associated with increased morbidity and inferior graft survival after LT, primarily due to a higher reported incidence of biliary complications (BCs).^3,5 Moreover, in the donor risk index, use of DCD allografts is among the strongest risk factors independently associated with likelihood of graft failure.⁶

Recent data have suggested that outcomes after DCD LT in the United States have improved over the past decade, likely as a result of improved donor and recipient selection for DCD LT.⁷ However, high-volume transplant centers account for the majority of DCD LT performed in the United States.⁸ Moreover, much of the published experience regarding DCD LT comes from high-volume centers, multicenter experiences, or database studies.⁹ Limited data exist on outcomes after DCD LT in low-volume centers. Consequently, the implications of expanded DCD use in this setting remain unclear.

Our hypothesis was that utilization of DCD LT could be expanded to lower-volume LT centers, as long as evidence- and protocol-based approaches were used. The primary aim of this retrospective analysis from a single low-volume LT center was to report our experience with DCD LT and identify variables that determine outcomes.

Materials and Methods

Recipients and donors
We conducted a retrospective review of all LTs performed at our transplant center from July 1, 2007 to February 28, 2014. Outcomes of LTs performed with allografts from DCD were compared with allografts from donors after brain death (DBD) during the study period. All donor and recipient variables were carefully reviewed and recorded.
We also included patients who underwent liver retransplant and simultaneous liver-kidney transplant in our study cohort.

Variables and outcomes analyzed
The following recipient variables were obtained: age, sex, etiology of liver disease, Model for End-Stage Liver Disease (MELD) score at the time of transplant, presence of hepatocellular carcinoma (HCC), hepatitis C virus (HCV) status, retransplant, death, cause of graft loss, and last follow-up date. Donor and organ procurement parameters analyzed included donor age, sex, cause of death, warm ischemic time (WIT), and cold ischemic time (CIT). Primary outcome measures evaluated were patient and allograft survival. Graft survival was estimated from transplant until graft loss (defined as date of retransplant or death) or date of last follow-up. Patient survival was estimated from transplant until death or date of last follow-up. Only primary solitary transplants were included in the patient and graft survival analyses. Univariate models and Kaplan-Meier modeling of graft survival included only solitary transplants with additional multivariable analysis performed on all transplant recipients. Secondary outcome measures evaluated were rate of BCs and impact of BCs on graft loss and death. In models examining the association between BCs and graft loss and death, BC was treated as a time-dependent variable within the Cox model.

Surgical techniques and immunosuppression
All donor and recipient operations were performed by 1 of 3 transplant surgeons from our center. University of Wisconsin solution was used for preservation of all liver allografts. After declaration of death, a 5-minute period of observation was followed before organ retrieval. Donor WIT was defined as the interval from withdrawal of ventilatory and circulatory support to aortic cross clamping and perfusion with cold preservation solution. Cold ischemia time was time from initiation of donor in vivo cold organ preservation to removal of the graft from 4 °C cold storage, and recipient WIT was time from removal from cold storage to establishment of reperfusion of the liver graft. Thrombolytic agents were not used during procurement over the study period.

All recipient transplant procedures were per­formed using standard piggyback technique without venovenous bypass. Duct-to-duct biliary reconst­ruction with transcystic biliary tube (5F ureteral stent, Bard polyurethane ureteral catheter; C. R. Bard, Inc.) was used except when deemed not feasible by the recipient’s surgeon. In recipients with indwelling biliary tubes, cholangiogram was perfor­med on posttransplant days 7 and 21 and as clinically indicated.

A standard immunosuppression protocol was followed in all recipients, using steroid induction followed by tacrolimus, the dosage of which was adjusted based on trough levels. Rejection episodes were treated by increasing tacrolimus levels and steroid boluses, if necessary.

Biliary complications
Any cholangiographic abnormality noted on the routine posttransplant cholangiogram was followed up by performance of endoscopic retrograde cholangiopancreatography to confirm the abnormality and define its nature and severity, with performance of endoscopic therapy, as appropriate. Ischemic cholangiopathy was defined as the presence of diffuse, nonanastomotic, intrahepatic biliary strictures in the absence of hepatic artery thrombosis.

Statistical analyses
Categorical variables were analyzed using chi-square test and continuous variables using t test. Comparisons of patient and graft survival were performed using Kaplan-Meier method, and competing risks were used for comparison of BCs. Cox proportional hazards model was used for univariate models to predict graft loss and death, and forward stepwise selection was utilized for development of final multivariable models. Statistical analysis was performed using SAS version 9.4. The study protocol was approved by the institutional review board of Aurora St. Luke’s Medical Center.

Results

During the study period, 196 LTs were performed, of which 159 were primary single organ LTs, 33 were simultaneous liver-kidney transplants, and 4 were solitary liver retransplants. Almost one-third, that is, 61/196 (31%), of all LTs over the study period were performed using DCD grafts.

The average annual LT volume at our center over the study period was 28, with the percentage of DCD LT performed annually ranging from 14% to 35% (Figure 1). The median follow-up time after transplant was 36.4 months.

Donor and recipient variables
Recipient, transplant, and donor characteristics for the DCD and DBD groups are summarized in Table 1, Table 2, and Table 3, respectively. We found that DCD and DBD recipients were similar with respect to age, sex, HCV status, and presence of HCC (Table 1). We found that 25 DCD recipients (41%) were HCV positive and 19 (31%) had HCC. The mean MELD at LT was significantly higher in DBD recipients than in DCD recipients (28.0 ± 9.0 vs 22.4 ± 8.0; P < .01). Although no difference was observed in mean recipient WIT between the 2 groups, the DCD group had longer CIT (9.2 ± 2.7 vs 7.6 ± 2.7 hours; P < .01). (Table 2) Age, sex, and proportion of donors above 50 years of age were similar between groups (Table 3).

Patient and graft survival
Over the study period, 18 DCD grafts (29.5%) and 34 DBD grafts (25%) were lost. After a median follow-up of 36.4 months, patient and graft survival rates, according to Kaplan-Meier analyses, were not statistically different between DBD and DCD solitary LT recipients (P = .47 and P = .87, respectively) (Figure 2 and Figure 3). Estimates for patient and graft survival, respectively, were as follows: 88.4% versus 85.7% and 87.7% versus 86.3% at 1 year, 78.5% versus 74.2% and 76.5% versus 75.4% at 3 years, and 70.8% versus 62.0% and 65.1% versus 63.7% at 5 years.

Biliary complications
The spectrum and frequency of posttransplant BCs in the 2 study groups are outlined in Table 4. Although the DCD group had a greater frequency of BCs within the first year posttransplant, this did not reach statistical significance (35.3% vs 21.5%; P = .10). However, BCs that directly resulted in graft loss appeared more frequently in the DCD group than in the DBD group. The probability of BC leading to graft loss at 1 year among solitary liver recipients was 7.8% in the DCD group compared with 0.9% in the DBD group (P = .02) (Table 5). Modeling the differential impact of the various types of BC showed that ischemic cholangiopathy had the most significant association with graft loss (Table 6).

Predictors of graft failure and death
Forward stepwise selection was performed to develop a final multivariable model predicting graft and patient survival by evaluating all donor, procurement, transplant, and recipient variables. On univariable analysis, we found that HCV recipients who received an organ from donors >50 years old was predictive of graft survival (hazard ratio [HR] = 5.37; 95% CI, 1.59-18.18; P < .01) and patient survival (HR = 5.08; 95% CI, 1.5-17.19; P < .01) in DCD recipients. (Table 7) Of note, donor age alone was not predictive of graft or patient survival. Non-White ethnicity of the recipient was also associated with patient survival.

Multivariable analysis also identified that the presence of HCV in recipients receiving organs from donors >50 years of age was a significant predictor of graft and patient survival following solitary LT (HR = 2.59; 95% CI, 1.24-5.44; P = .01 and HR = 2.79; 95% CI, 1.31-5.92; P < .01, respectively). Among solitary LT recipients, BC had an adverse impact on graft survival in both groups (HR = 3.02; 95% CI, 1.23-7.43; P = .02 in the DCD group; HR = 2.60; 95% CI, 1.10-6.15; P = .03 in the DBD group) (Table 8). However, when all transplants were included in modeling of graft loss, presence of BC was only significantly associated with graft loss in DCD recipients (HR = 3.28; 95% CI, 1.57-6.85; P < .01 in the DCD group; HR = 1.69; 95% CI, 0.79-3.63; P = .18 in the DBD group) (Table 8). Development of BC following solitary LT was only observed to have an adverse impact on patient survival in the DCD cohort (HR = 3.25; 95% CI, 1.30-8.13; P = .01).

Discussion

Strategies to increase the available donor pool for LT include optimal utilization of extended criteria donors, including DCD. Utilization of DCD allografts in LT has, however, been limited by concerns regarding decreased allograft survival, primarily due to an increased incidence of BCs.^3,5 However, this has to be weighed against the survival benefit conferred by DCD grafts, especially in those with more advanced liver disease, which has been shown to outweigh the reported inferior outcomes.¹⁰

The effects of center volume on outcomes in LT have been previously demonstrated.^11,12 Additionally, high-volume LT centers have also been observed to use high-risk grafts more often and with improved outcomes.¹³ More recent single-center publications from high-volume DCD programs have demonstrated equivalent outcomes between DCD and DBD LT.^14,15 The use of DCD and consequently the reported published experience in the United States are driven by high-volume centers, although DCD LTs constitute a very small proportion of overall LT in these centers.^8,9 However, in 2014, only 16 centers in the United States performed more than 100 LTs (https://optn.transplant.hrsa.gov/data/view-data-reports/national-data). Presently, a paucity of data and, consequently, unanswered questions remain regarding the applicability of DCD LT to low-volume centers.

Lower-volume programs may be reluctant to use DCD allografts, given their potential impact on outcomes and reported survival rates. Challenges related to deceased donor organ availability in our organ procurement organization have resulted in a disproportionately higher utilization of DCD grafts at our center, with 31% of all LTs over the study period, even though our average annual LT volume was less than 30. This also likely explains the higher mean MELD scores at transplant in our cohort. Our observed graft survival rates in the DCD group of 86.3% and 78.6% at 1 and 3 years, respectively, however, compare favorably with prior reports from high-volume LT centers and those analyzing the scientific registry of transplant recipients.^3,5,9 Our results, therefore, may have broader applicability and implications for most LT centers in the United States, regardless of center volume.

Several published reports have identified donor and recipient variables associated with outcomes following DCD LT.^3,5 Recipient MELD score at transplant has been shown to be inversely associated with outcomes following DCD LT.^16,17 Our mean MELD score at transplant in DCD recipients was lower than in the DBD cohort, which may have contributed to our observed outcomes. In an analysis of the scientific registry of transplant recipients, Mathur and colleagues identified age, male sex, African American ethnicity, HCV positivity, and MELD at LT as recipient factors associated with graft failure.¹⁶ Non-White ethnicity was also associated with decreased patient survival in our DCD cohort. In line with our observation that donor age impacts outcome, multiple previous studies have identified advanced donor age as an independent predictor of outcome in DCD LT.^16,18 However, other reports have shown that the impact of donor age on graft survival in DCD LT could be ameliorated by strict donor selection criteria.^17,19,20 However, in our study, the impact of donor age was only adversely associated with outcomes among recipients with HCV infection, an effect that may be less significant in the post-direct acting antiviral (DAA) era. Prior published reports have shown the impact of CIT on outcomes in DCD LT, with recent data underscoring the need to minimize CIT to improve outcomes.^7,16,21 However, we did not find a significant impact of CIT on graft or patient survival, although CIT was significantly higher in the DCD group. The reasons for this are not entirely clear.

As with previous studies of DCD LT, we found a higher incidence of BCs in DCD LT, although this did not reach statistical significance. Our observed BC rate in the DCD cohort was similar to other previous single-center and database studies.^5,22 When we analyzed the entire cohort, including recipients of both solitary liver and simultaneous liver-kidney transplants, we found that BCs impacted graft survival only in DCD recipients. This is likely due to the nature of the BC in DCD recipients, with a predominance of ischemic cholangiopathy, and is in line with a recent report from the multicenter DCD consortium that reported a 3-fold higher risk of graft failure at 6 months in DCD recipients with ischemic cholangiopathy.²³ The differential impact of ischemic cholangiopathy on graft loss among the various types of BCs highlights the need to develop strategies to prevent ischemic cholangiopathy in DCD LT. The pathogenesis of ischemic cholangiopathy in DCD LT remains unclear and may be due to ischemia-reperfusion-related injury of peribiliary vascular structures, resulting in the formation of microthrombi and consequent development of ischemic injury of the bile ducts.²⁴ Injection of tissue plasminogen activator into the donor hepatic artery has been shown to decrease the incidence of ischemic cholangiopathy.^25,26 Emerging data with use of hypothermic oxygenated perfusion in DCD LT have also shown good 5-year outcomes comparable to DBD and superior to untreated DCD LT despite higher risk features, such as extended donor WIT, higher median donor age, and functional WIT.²⁷

As with DBD LT, the utilization of older donors for HCV-positive recipients appears to produce inferior outcomes in DCD LT.¹⁶ However, some database studies have shown comparable outcomes after DCD LT in recipients with HCV.²⁸ Admittedly, our study was performed prior to the widespread availability of highly effective DAAs for HCV. Patients with HCV were, however, distributed equally among both groups, and, arguably, our outcomes would have been even better in the DAA era. Our chosen study period represented the time period with maximal DCD utilization in our program. We plan to report our more recent experience with DCD LT in the future.

One of the limitations of our study was its retrospective study design. Although single-center studies such as ours have smaller numbers of recipients, sometimes resulting in inadequate power to detect differences, the proportion of DCD donors in our study sample was much higher than most other single-center studies of DCD LT. In addition, unlike database or multicenter studies, our experience eliminates the impact of variation in practice patterns among transplant centers. The approach to donor selection and surgical techniques remained the same throughout the study period, suggesting that the observed lack of differences in graft and patient survival between DCD and DBD LT is unlikely to be explained by these factors. In addition to the composite end points of graft and patient survival, we also evaluated a key secondary outcome measure the event rate of BCs and its impact on outcome. Database studies are also inherently limited by the level of detail regarding individual LT recipients, including causes of graft loss. Although our study population also included patients undergoing liver retransplant and simultaneous liver-kidney transplant, their numbers were relatively small and distributed evenly among the 2 study groups.

Conclusions

We report comparable outcomes after DCD LT versus after DBD LT from a low-volume center, where almost one-third of all LTs over the study period were performed using DCD grafts. Our experience highlights the applicability of DCD LT in low-volume transplant centers. Strategies to minimize ischemic cholangiopathy, including consideration of newer evolving modalities such as normothermic regional perfusion, could further expand the use of DCD LTs.

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