Subsequent analysis was performed on the 218 recipients who had a retransplantation from 2001 to 2017. The graft survival for a second liver transplantation was 82% at 1 year, 76% at 5 years, and 65% at 10 years (Figure 3). The graft survival for a third transplantation was 96% at 1 year, 70% at 5 years, and 70% at 10 years. The 2 cases of a fourth transplantation have yet to meet an endpoint. Overall, graft survival from 2001 to 2017 for retransplantation was 85% at 1 year, 75% at 5 years, and 64% at 10 years. Patient survival for all retransplants from 2001 to 2017 was 89% at 1 year, 81% at 5 years, and 74% at 10 years (Figure 2).
Baseline characteristics were collected for both the overall cohort and eras from 1986 to 2000 and from 2001 to 2017. There are several notable differences between these 2 groups (Table 2). The mean time between transplant and retransplant has increased over time, from 1.9 to 4.2 years (P < 0.001). Patient age (P = 0.001) and weight (P < 0.001) have also increased significantly. There has been a reduction in air travel over time, with 55% of donor livers requiring air transport from 1986 to 2000 compared with 26% from 2001 to 2017 (P < 0.001). CIT has decreased from a mean of 9.3 to 7.6 hours (P = 0.018), to which the decrease in air travel may have contributed. The donor age (P < 0.001) has also increased. WIT has decreased from a mean of 111 to 44.6 minutes (P = 0.193); however, this was not found to be significant due to limited intraoperative data prior to 2000.
Univariate analysis found no significant difference in graft survival for the number of retransplants, use of whole or split donor livers, or pretransplant MELD score (Table 4). Increased patient age and low patient weight were found to be significantly associated with decreased graft survival from 1986 to 2000 (P = 0.001 and P = 0.019), while only low patient weight remained significant from 2001 to 2017 (P = 0.041). Similarly, increased donor age was significantly associated with decreased graft survival from 1986 to 2000 (P = 0.011), but this was not significant from 2001 to 2017 (P = 0.828). There was no significant difference in graft survival for other donor factors including sex, weight, CIT, and air travel. Similarly, there was no significant difference for recipient or operative factors including, WIT, or sex. There was no significant difference in graft or patient survival when comparing time with retransplant of <7 days, between 8 and 30 days, or >30 days (Figure 4). Multivariate Cox regression was performed using the data from 1986 to 2000 and only low patient weight (P = 0.042) and increased donor age (P = 0.025) were significantly associated with decreased graft survival (Table 5). Cox regression found that no variables were significantly associated with graft survival using data from 2001 to 2017 era.
This study shows that liver retransplantation is a valid and definitive treatment for both early hepatic graft failure and end-stage chronic liver disease occurring after primary liver transplantation. Importantly, it was demonstrated that graft survival for retransplantation in ASNZ has greatly improved over past 30 years. The most notable improvement occurred after 2000, where the 1-, 5-, and 10-year graft survival for retransplantation was 85%, 75%, and 64%, respectively, and the 1-, 5-, and 10-year patient survival for retransplantation was 89%, 81%, and 74%, respectively. This compares favorably with graft survival reported by the ANZLT liver transplantation registry from 2000 to 2017 for 4514 patients undergoing a first liver transplantation with a 1-, 5-, and 10-year graft survival of 88%, 79%, and 69%, respectively, and a 1-, 5-, and 10-year patient survival of 93%, 83%, and 74%, respectively.1 Similar trends of improved graft survival for retransplantation have been reported by other international studies5; however, graft survival for retransplantation remains worse than for a first transplant.2 Overall, graft and patient survival rates in ASNZ are excellent when compared with other countries around the world (Table 6).
Valuable lessons have been learned from the previous landmark studies of liver retransplantation. A number of models that predict survival following liver retransplantation have been developed; however, there is no consensus on which variables contribute to a worse outcome.16 Notable variables that have historically been shown to result in poorer outcomes include a time to retransplantation between 8 and 30 days, multiple liver transplants, a recipient MELD score >25, and advanced patient age.16 Donor characteristics, such as increased donor age and CIT, have been associated with poorer outcomes. The use of DCD donors has also been shown to have higher rates of graft failure17; however, only 3 of our retransplant recipients received a DCD organ. Of these 2 died, one at 10 days and the other at 255 days after retransplantation, but the limited number of cases precludes us from making any comment on the significance of this. This present study found no significant difference in survival when analyzing these key recipient and donor variables.
There are notable differences in the donor and recipient characteristics in this study when compared with other reports. From 2001 to 2017, the average age of ASNZ retransplantation recipients was 46 years, similar to the United States; however, the average donor age was 42.5 years compared with 34 years in the United States.18 ASNZ data also show a mean retransplant interval of well over 1 year compared with an average interval between 1 and 6 months in the United States. ASNZ donor livers had a mean CIT of 7.6 hours compared with 8.45 hours from a major US center.3 This same US study showed that a CIT of >12 hours was of borderline significance in predicting survival.
The indications for retransplantation in this study are different compared with previous studies, and this may have contributed to the difference in outcomes. In 1 major US study, from 1999 to 2003 the majority of retransplants were due to graft nonfunction (37.5%), hepatic artery thrombosis (20%), disease recurrence (17.5%), and graft rejection (12.5%).5 The data from this ASNZ study show that from 2001 to 2017 retransplantation commonly resulted from hepatic artery or portal vein thrombosis (27%) and disease recurrence (24%) and graft nonfunction only accounted for 16% of retransplantations. The notable decrease in graft nonfunction in ASNZ may be contributing to improved survival, as less grafts are failing in the short term following retransplantation.
The difference in graft survival comparing ASNZ data and other regions may also be related to other factors. Transplantation services around the world are different, and each has its own method of patient and donor selection. We hypothesize that graft survival following retransplantation may be associated with local factors, such as quality of the surgical and theater team, physician experience, hospital services including Intensive Care Unit access, interventional radiology, medication availability, pathology services, other support staff, and efficient donor services. These unreported factors clearly may influence which variables are significantly related to graft survival across different centers.
This study has shown that changes in recipient and donor characteristics have occurred over time while graft survival has also increased. Advanced donor age was shown previously to predict poor outcome; however, this ASNZ registry study found that this was no longer the case. This was despite the fact that older recipients were transplanted and older donor livers were used. Only 8% of liver donors were older than 60 years in the 1986–2000 era, and this increased to 13% in the 2001–2017 era. Previous studies found that recipient’s weight of <50 kg was associated with poor survival and likely reflected poor outcomes due to frailty. This relationship was not found in the present study and is likely due to a change in recipient selection and earlier waitlisting over time. In the early era, 15% of recipients had a weight <50 kg compared with only 3.5% in the 2001–2017 era. The cause of graft failure has also changed over time, with a large decrease in frequency of acute or chronic rejection and a comparative increase in liver disease recurrence. These changes in recipient and donor selection are likely due to improvements in surgical and medical treatment. Moreover, liver transplantation recipients are living longer after the first transplant, and the resulting longer retransplantation interval likely accounts for the increased number of retransplants for liver disease recurrence. While we have no data on patients who were denied retransplantation due to increased risk of mortality, this data suggest that the selection criteria being used is contributing towards the improved outcomes we have found.
As this is a multicenter registry study, the data for some variables was incomplete. Only those variables which were collected consistently in each center were used for the final analysis. A detailed analysis of additional variables of interest was not able to be computed due to insufficient data. There is scope for further analysis of variables associated with graft survival that have not been included in this study. These include some specific variables previously shown to be significant, including renal function, requirements of ventilator support, and the use of marginal donor livers.19
In addition to graft and patient survival, other ethical and financial factors must be considered when allocating donor livers. The question remains: will patients, donor families, and society accept repeated use of scarce donor livers in one individual? Existing ethical guidelines recommended that the previous use of a resource, such as a liver allograft, should not impact current patient needs.8 The reality is not as clear, however, as society preferences for fairness in accessing indivisible healthcare resources must also be considered.20 There needs to be further consideration going forward on how to allocate organs when outcomes are comparable for retransplantation.
In summary, this study has confirmed a notable improvement in graft survival for liver retransplantation from 2001 to 2017 when compared with 1986 to 2000. ASNZ has excellent survival rates when compared with other countries. Survival after retransplantation is comparable to a first transplant and should not be a barrier for organ allocation. Several key variables that were previously associated with poorer outcomes are not shown to impact outcomes in ASNZ. These contemporary results should be utilized by liver transplant waitlist prioritization methods to avoid discrimination against those who need a life-saving retransplant.
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© 2019 The Authors. Published by Wolters Kluwer Health, Inc.
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