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ARTICLE
Retransplant of the Liver: 12-Year Experience of the Shiraz Organs Transplantation Center

Objectives: Liver transplant is the most effective treatment modality for patients with end-stage liver disease, metabolic disorders, hepatic malignancy, and acute liver failure. When a graft fails after primary liver transplant, retransplant of the liver remains the only option. Here, we report the past 12-year experience of the Shiraz Transplant Center regarding liver retransplant.

Materials and Methods: This is a retrospective cohort study of a 12-year period (2004-2015) of the Shiraz Center in Iran.

Results: Of the 3107 patients who had a liver transplant during the study period, 58 retransplants were performed (1.86%) in 57 patients. The leading cause of retransplant was primary nonfunction in 24 patients (41.4% of retransplant cases and 0.77% of all liver transplant cases). The second leading cause of retrans­plant was vascular complications in 25 patients (23 with hepatic artery thrombosis and 2 with portal vein thrombosis), accounting for 43.1% of retransplant cases and 0.80% of all liver transplant cases. In addition, 5 patients (8.6%) had retransplant for rejection, which accounted for 0.16% of all liver transplant cases. Four patients with retransplant (6.9%) had recurrence of primary disease, which accounted for 0.12% of all liver transplant cases. Most liver retransplants occurred early (≤ 30 days after primary transplant) at the Shiraz Transplant Center. Five-year survival rate after retransplant was 35%, and retransplant for hepatic artery thrombosis was more common in children.

Conclusions: Because most patients required retrans­plants in the early period after primary transplant, the decision for retransplant must be considered carefully with full multidisciplinary evaluation and only in skilled hands. Retransplant in subgroups of patients with little chance of a successful outcome should be avoided.


Key words : Hepatic artery thrombosis, Primary graft failure, Vascular complication

Introduction

Liver transplant is an effective treatment modality for patients with end-stage liver diseases, such as metabolic disorders and hepatic malignancies, and for patients with acute liver failure. Unfortunately, the graft often fails after the primary transplant, with liver retransplant remaining the only choice for patients. Retransplants presently account for 8% to 17% of all liver transplants according to previous studies.1-5

Indications for retransplant can be divided into 2 groups: retransplant during the first 30 days after transplant (early retransplant) and retransplant greater than 1 month after transplant (late retransplant). For early retransplant, the most common causes of early graft loss (within 7 to 30 days after primary transplant) are hepatic artery thrombosis (HAT) and primary nonfunction (PNF).3,6

Primary nonfunction is an indication for retransplant in up to 30% of cases.1,3 Causes can be due to both donor and recipient factors. Donor factors include the degree of steatosis in the donor allograft, increased cold ischemic time (> 12 h), reduced-size allograft, and older donor age (> 50 years old).7,8 Recipient factors include worsened medical condition, renal insufficiency, and retransplant. In addition, prolonged warm ischemic time has been shown to be an important risk factor for PNF.9,10

Rates of early HAT range from 0% to 20%, with approximately 50% of events resulting in retransplant.11 Generally, HAT rates of 3% to 5% have been observed in recipients of whole organ allografts.11-13 In children, HAT rates are nearly 3 times higher than those of adults,11 in part because of the use of living donors and split grafts from deceased donors. Indeed, higher rates of HAT are also seen in adult recipients of partial grafts. Split and living donor grafts are also associated with increased risk for graft failure independent of HAT incidence,14,15 putting pediatric liver recipients of partial grafts at especially high risk for requiring retransplant. Small vessel size can also contribute to increased risk of HAT in children.

Patients with PNF and HAT who meet the defined criteria of liver failure within the first 7 days of transplant are placed at the top of wait lists for a deceased donor liver. Primary nonfunction of a liver within 7 days after transplant can be defined in 2 ways. First, when aspartate aminotransferase levels are ≥ 3000 U/L and when 1 or both of the following occur: (1) an international normalized ratio ≥ 2.5 and (2) acidosis, defined as having an arterial pH ≤ 7.3 or venous pH of 7.25 and/or lactate ≥ 4 mmol/L. Second, in a hepatic candidate, PNF can be defined as HAT in a transplanted liver within 7 days after transplant, with evidence of severe liver injury as defined in the first scenario above.16 On the other hand, recurrence of primary disease and chronic rejection are primary indications for late retransplant.

Previous studies have shown that patient survival rates at 1 and 5 years after liver retransplant are 73% and 63%, respectively.17 In this study, we report the experience of the Shiraz Center Transplant regarding liver retransplant over the past 12 years.

Materials and Methods

Patients
Fifty-seven patients (29 males and 28 females) who had undergone liver retransplant were included in this study at Shiraz Center, which is affiliated with Shiraz University for Medical Sciences in Iran. The age of the patients was categorized into 2 groups: adults (77%) and children (23%). One of these patients received 2 livers, resulting in 58 cases.

Study design
Patient data from 2004 to 2015 were retrieved from the Center’s database. This retrospective study was approved by the institutional ethics committee of Shiraz University for Medical Sciences.

The first liver transplant at the Shiraz Center was performed in 1993 by Seyyed Ali Malek Hosseini, and the number of liver transplants has increased gradually since 2004, reaching 534 liver transplants in 2015 (Figure 1). As shown in Figure 2, the first liver retransplant in Shiraz Center was performed in 2004.

Statistical analyses
The Kaplan-Meier method was used to estimate survival probabilities, with log-rank test used to analyze significance. P < .05 was considered statis­tically significant. Collected data were analyzed with SPSS software (SPSS: An IBM Company, version 21.0, IBM Corporation, Armonk, NY, USA).

Results

Of 3107 patients who had liver transplant surgery at the Shiraz Transplant Center from 2004 to 2015, 57 patients required a retransplant. One of these patients received 2 livers and was excluded to estimate the survival probabilities; however, some calculations were based on 58 retransplant cases. Table 1 shows characteristics of adult and pediatric patients who underwent retransplant at our center during the study period and shows their primary diseases.

We found that the leading cause of retransplant was PNF. Specifically, 24 of 58 retransplant cases (41.4%; 0.77% of all liver transplant cases) had PNF as the leading cause for retransplant. However, vascular complications were seen in 25 patients (23 patients had HAT and 2 patients had portal vein thrombosis), accounting for 43.1% of retransplant cases and 41.5% of total liver transplant cases. Rejection was the cause of retransplant in 5 cases (8.6%), accounting for 0.16% of our total liver transplant cases. In addition, 4 patients had recurrence of primary disease, acco­unting for 6.9% of retransplant cases and 0.12% of our total whole liver transplant cases. Table 2 shows the liver retransplant cases concerning the time of retransplant.

Most retransplants occurred on day 3 after the first transplant. Figure 3 illustrates the time between the first and second transplant. As shown in Figure 4, 32 of 57 patients died and most deaths occurred during the first year after liver retransplant (27 patients). Patient survival at 3 months and 3 years (57% and 35%, respectively) after retransplant is shown in Table 3 and Figure 5. Survival results at 3 months and 3 years for patients less than 18 years old (75% and 55%, respectively) compared with adults (52% and 24%, respectively) are shown in Table 4. We found no significant differences in survival between pediatric and adult patients (P = .151; Table 4 and Figure 6).

Discussion

Liver retransplant is the only effective therapy for graft failure after primary transplant. Retransplant rates range from 8% to over 17%.1-5 In our study, our rate of retransplant was only 1.77%. This lower rate was due to the small number of liver retransplant cases in the early years of this study and also due to high mortality rates of patients on wait lists (our wait list exceeded 1000 patients). The policy of the Shiraz Center gives priority to patients on wait lists. These factors led to a reduced number of liver retran­splants, especially those requiring late liver retransplant. For these reasons, early retransplant has become the main indication for liver retransplant at our center.

The most frequent causes of liver retransplant are vascular complications, PNF, chronic rejection, and recurrence of primary disease.18 The most frequent causes of late retransplant are chronic rejection and primary disease recurrence.18 In our center, the most common indication for liver retransplant was PNF (24 patients) and HAT (23 patients). Together, PNF and HAT accounted for more than 81% of indications for retransplant. In previous studies, PNF was the cause of retransplant in up to 30% of cases,1,3 whereas our rate was 41.4%.

Previous rates of early HAT range from 0% to 20%, with approximately 50% of events resulting in retransplant.11 As previously reported, a 3% to 5% rate is generally observed in recipients of whole organ allografts.11-13 However, HAT rates in children are nearly 3 times higher than those of adults.11 In our study, HAT resulted in 40% of retransplants, with a rate of 81% when we observed only recipients of whole organ allografts. In addition, HAT was the leading cause of retransplant in 6 of 13 pediatric patients, that is, approximately 46% of all pediatric cases (Table 1).

During the first month after primary transplant, our center performed 48 retransplants during the study period, with 83% of these done for emergency situations. However, during our study period, there were only 9 retransplants performed after the first month of the primary transplant (that is, late liver retransplant) (Table 2). The distribution of these late cases was as follows: 5 cases of chronic rejection, 4 cases of recurrence of primary disease, and 1 case of chronic HAT. As a result of the Shiraz Transplant Center policy that gives priority to patients on wait lists, the number of retransplant procedures for patients with recurrent disease is low.

Anatomically, a second liver transplant can be complex and can require extensive preoperative planning for the identification of suitable vascular inflow, which may involve the use of vascular grafts. Furthermore, retransplant patients tend to be more critically ill than recipients of primary grafts at the same Model for End-Stage Liver Disease score, adding to the challenge of what is already a lengthy retransplant operation. In such circumstances, critical patients, those requiring nonelective operations (81% of retransplants were due to PNF and HAT), and the use of marginal livers will result in increased mortality. In our study population, 27 patients died within the first year after retransplant (23 adult and 4 pediatric patients; Figure 4). According to cause of retransplant, mortality in the first year after retransplant was distributed as 17 PNF, 8 HAT, and 2 recurrence cases. Mortality mostly occurred in the first month after retransplant, with 10 PNF patients dying 2 days after retransplant. This high rate of mortality in such groups leads to the question of the efficacy of retransplant for those patients, especially when we take into account the death rate on the wait lists.

Patient and graft survival rates are lower after liver retransplant than after primary liver transplant, with survival being better with late versus with early liver retransplant.19 As shown previously, overall 1-, 3-, 5-, and 10-year survival rates after first retransplant were 66%, 61%, 57%, and 47%, respectively.17,20,21 In our center, 5-year survival after retransplant was 35% (Table 3). Therefore, the decision for retransplant must be considered carefully with full multi­disciplinary evaluation and only in skilled hands. Retransplant in subgroups of patients with little chance of a successful outcome should be avoided. Various models have been developed to identify the factors that influence the survival, including the model from Markmann and associates1 (which considered age, time interval to transplant, number of grafts, and United Network for Organ Sharing status) and the model from Rosen and colleagues22 (which considered age, bilirubin and creatinine levels, United Network for Organ Sharing status, and cause of graft failure). It would be useful to identify high-risk patients who could have poor outcomes after retransplant. These models might be helpful in the selection of appropriate candidates for retransplant.


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DOI : 10.6002/ect.2017.0246


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From the 1Shiraz Organ Transplant Center, Namazi Teaching Hospital, Shiraz University of Medical Sciences; the 2Organ Procurement Unit, Namazi Teaching Hospital; and the 3Biostatistics Department, Namazi Teaching Hospital, Shiraz, IR Iran
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare. This article was extracted from the organ transplant surgery fellowship thesis of Taiser Saleh. The authors thank Shiraz University of Medical Sciences, Shiraz, Iran, and the Center for Development of Clinical Research of Nemazee Hospital and Dr. Nasrin Shokrpour for editorial assistance.
Corresponding author: Taiser Saleh, Namazi Hospital, Shiraz, IR Iran
Phone: +989107520938
E-mail: dteser@hotmail.com