Objectives: Orthotopic liver transplant is the treatment of choice for patients with end-stage liver disease. Patients with first graft failure requiring liver retransplant are commonly seen at most liver transplant centers. However, patients with a second graft failure requiring a third graft are uncommon. Liver retransplant in this setting has only been pursued at a few large transplant centers.

Materials and Methods: This is a retrospective analysis of the long-term outcomes of recipients who underwent 3 or more orthotopic liver transplants. Between February 1998 and August 2009, 24 patients had 3 or more orthotopic liver transplants at the Mayo Clinic in Florida.

Results: Mean patient survival was 103.8 months for the study cohort. Actuarial patient survival after the last orthotopic liver transplant in -1, -5, and -10 years was 60%, 40%, 33%. Patients were transplanted with lower donor risk index score grafts in each subsequent orthotopic liver transplant. Patients who had a graft with a donor risk index score > 1.6 at the time of the third orthotopic liver transplant had significantly lower survival rate compared with those with grafts with a donor risk index
score ≤ 1.6.

Conclusions: Multiple liver retransplants offer acceptable patient survival. Each transplant program must decide whether to do multiple orthotopic liver transplants based on the program’s transplant volume and outcomes to help this subgroup of patients. The concerns of potentially decreasing access to first time orthotopic liver transplant candidates should also be weighed in the decision to move forward.

Key words : Liver retransplantation, Survival, Donor selection

Introduction

Orthotopic liver transplant (OLT) is the treatment of choice for patients with end-stage liver disease owing to a variety of causes. The combination of refined surgical technique, improved perioperative care of the recipient, and advances in immunosuppression in the last 2 decades have led to improved survival after OLT.¹ As a consequence of increased numbers of OLT, allograft failure owing to early and late complications and disease recurrence are more commonly encountered. The only life-saving treatment for patients with a failing liver allograft is liver retransplant. Liver retransplant requires extensive surgical expertise and experienced decision-making process before, during, and after the surgical procedure. Liver retransplant involves surgery of a previously operated on abdomen in an ill and immunosuppressed patient with an allograft failure. Liver retransplant has a higher rate of mortality owing to patient comorbidities and the technical demands of the procedure.^{2, 3} This increased mortality associated with liver retransplant, along with the limited availability of organs and increasing rate of death on the waiting list for the initial liver transplant increases the controversy of liver retransplant. Taking this issue 1 step further, outcomes of a third liver transplant have been anecdotally reported only from centers with high transplant volumes and may have even poorer outcomes if used in less-experienced centers.⁴

We aimed to retrospectively analyze the long-term outcomes of recipients who underwent 3 or more OLTs to better delineate recipient and donor criteria that are likely to increase survival after 3 or more OLTs.

Materials and Methods

Study cohort
This is a retrospective, cohort-based study that includes all patients who underwent 3 or more OLTs at the Mayo Clinic, Jacksonville, FL, USA, between March 1998 and July 2009. Clinical data obtained in the process of care were abstracted into a database for analysis. The study was approved by the Mayo Clinic Institutional Review Board and conforms with the ethical guidelines of the 1975 Helsinki Declaration.

We collected the clinical and laboratory data of relevant perioperative parameters at the time of initial OLT and the subsequent liver retransplant operations. The following recipient variables were studied separately for OLT and liver retransplant: age, sex, ethnicity, body mass index, total bilirubin, creatinine, international normalized ratio, length of hospital stay, reoperations for complications. Model for end-stage liver disease (MELD) scores were calculated retrospectively based on laboratory values at the time of OLT and each liver retransplant. In addition, the primary diagnosis of the disease that led to the first OLT, the reason for graft loss, and interval time (months) between transplants were recorded.

To compare the outcomes of patients with and without a liver retransplant, we also collected data of a cohort of 47 patients who presented to the transplant selection committee of the Mayo Clinic in Florida as a liver retransplant candidate but did not undergo liver retransplant. These were consecutive patients who underwent evaluation for liver retransplant candidacy between January 2003 and August 2009 for chronic graft failure.

Donor criteria evaluated included age, height, weight, race/ethnicity, cause of death, donation after brain-death, donation after cardiac death, cold ischemia time, and local, regional, or national organ allocation. Donor risk index (DRI) score was retrospectively calculated for each graft used for all transplants.⁵

Organ procurement was done with aortic and portal perfusion using University of Wisconsin solution. All OLTs and liver retransplants were performed using the piggyback technique, without venovenous bypass.

Statistical Analyses
Statistical analyses were performed with SPSS software for Windows (Statistical Product and Service Solutions, version 17.0, SSPS Inc, Chicago, IL, USA). Continuous data were reported as means ± standard deviation and compared using the t test. Categoric data were compared with the Mann-Whitney U test or the Fisher exact test. Long-term survival was estimated using Kaplan-Meier analysis by log rank testing. Values for P less than .05 were considered significant.

Results

Between February 1998 and August 2009, 1757 adult patients underwent 1955 consecutive OLTs at the Mayo Clinic in Florida. There were 180 patients who underwent 2 or more OLTs. Twenty-four patients underwent 3 or more OLTs (a total of 76 allografts): 21 patients received 3 OLTs, 2 patients had 4 OLTs, and 1 patient had 5 OLTs (a total of 52 liver retransplants). Four of these patients underwent their initial OLT at other centers.

Primary cause of liver disease was due to chronic hepatitis C in 13 patients (55%), primary sclerosing cholangitis in 5 patients (21%), hepatitis B in 3 patients (13%), alcohol in 1 patient (4%), hemangio­endothelioma in 1 patient (4%), and alpha-1 antitrypsin deficiency in 1 patient (4%). Three patients (13%) had hepatocellular carcinoma at the time of the initial OLT, and 1 patient developed de novo hepatocellular carcinoma during the second liver graft. All but 2 patients received a whole-size organ at first OLT: 1 patient had a partial right graft from a living donor, 1 patient had a partial left graft from a donation after brain-dead donor. Two patients had a donation after cardiac death grafts at the first OLT. For second and subsequent OLTs, whole-sized donation after brain-dead liver grafts were used.

Indications for 52 liver retransplants were vascular thrombosis (n=11, 21%), biliary complications (n=12, 23%), primary nonfunction (n=9, 17%), recurrence of disease (n=11, 21%), chronic rejection (n=5, 10%), and other (n=4, 8%).

Table 1 shows the patient characteristics and comparison of variables at the time of the first, second, and third OLT. The mean age at the time of the first OLT was 48.3 ± 10.2, at the second OLT it was 49.6 ± 10.0, and at the third OLT it was 51.2 ± 10.29 years (P = .6). There were 11 patients (46%) over age of 50 at the time of the third OLT.

Median wait time (listing-to-OLT) for the first OLT was 60 days (range, 1-532 days), for the second OLT it was 39 days (range, 0-300 days), and for third OLT it was 69 days (range, 0-886 days; P = .7). Mean interval between first to second and second to third OLTs were not different; 510.5 ± 1147.8 days versus 507.29 ± 1208.2 days (P = .9). Model for end-stage liver disease scores at listing were significantly different for the first, second, and third OLT, 14.8 ± 4.0, 21.6 ± 11.6, and 28.4 ± 10.6 (P = .039). Similarly, MELD scores at the time of transplant were significantly different between the first, second, and third OLTs, 18.6 ± 8.6, 24.3 ± 10.0, and 29.6 ± 9.5 (P = .04). Model for end-stage liver disease scores at the time of the third OLT were significantly higher compared with those of first (P = .006).

Mean DRI scores were significantly different between first, second, and third OLTs, 1.80 ± 0.43, 1.69 ± 0.37, and 1.41 ± 0.38 (P = .009). Mean donor ages were significantly different between first, second, and third OLTs, 51.1 ± 17.8, 42.9 ± 19.5, and 35.1 ± 16.5 years (P = .034).

Cold ischemia and warm ischemia times were similar between OLTs (P = .26 and P = .74).

Patient survival
The mean follow-up was 87.4 ± 40.3 months. The mean follow-up after the first OLT was 104.3 ± 45.0 months, after the second OLT it was 87.3 ± 32 months, and after the third OLT, it was 70.7 ± 37.3 months.

Kaplan-Meier survival analysis showed that overall estimated mean patient survival was 103.8 months (95% CI: 66.2-141.3 months) for the study cohort. Actuarial patient survival after the first OLT for 1, 5, and 10 years was 78%, 63%, and 36% (Figure 1). Actuarial patient survival after the last OLT in -1, -5, and -10 years was 60%, 40%, and 33%.

Patients denied or not retransplanted (n=47) had an estimated mean survival of 14.7 ± 2.3 months (95% CI: 10.2-19.2 months). Patients who had 2 OLTs (n=156) had an overall survival of 87.5 ± 5.1 months (95% CI: 77.5-97.5 months), and patients who had 3 or more OLTs had an overall survival of 60.7 ± 12.0 months (95% CI: 37.1-84.3 months). There was no difference in survival of patients after second and third OLT (P = .1). Survival of patients after the third OLT compared with that of patients who were denied or who were not retransplanted was significantly longer (P = .001).

Our analysis shows that patients were transplanted with lower DRI score grafts in each subsequent OLT. A cutoff donor risk index score of 1.6 showed that patients who had a graft with a donor risk index score > 1.6 at the time of the third OLT (5 patients, 20%) had significantly lower survival rates, with a mean of 11 months (95% CI: 0-28.0 months) versus 63.0 months in grafts with donor risk index scores ≤ 1.6 (95% CI: 36.5-89.4 months; P = .01) (Figure 2). Subgroup analysis of patients transplanted with a graft DRI score > 1.6 showed that recipient age was major contributor of inferior outcome: estimated mean survival rates were significantly lower for recipients ≥ 50 years of age who underwent a third OLT with a graft of a DRI score > 1.6 compared to the recipients with an age < 50: 2.3 months (95% CI: 0-4.6 months) versus 65.9 months (95% CI: 34.1-97.7 months; P = .04).

Model for end-stage liver disease scores increased with each subsequent OLT. To better define the effect of MELD score on outcome, we selected a cutoff value of ≥ 30, representing sicker patients at the time of the third OLT. There were 11 patients with MELD scores ≥ 30, and 13 patients with MELD scores < 30. There was a tendency for lower survival in recipients of a third OLT with MELD scores ≥ 30 compared to those with MELD scores < 30; however, this did not reach statistical significance (39 months, 95% CI: 13.5-64.4 vs 80.4 months, 95% CI: 48.5-112.3; P = .07) (Figure 3). Further analysis of the interplay between graft quality with recipient MELD scores revealed that in patients with MELD scores < 30, survival rates were lower in recipients who were transplanted with grafts of DRI scores > 1.6 versus grafts with DRI scores ≤ 1.6, (37.6 months, 95% CI: 0-76.1 vs 103.1 months, 95% CI: 72.2-133.9; P = .05). Similarly, in patients with MELD scores ≥ 30, survival rates were significantly lower for patients transplanted with graft DRI scores > 1.6 compared to DRI scores ≤ 1.6 (1.5 months, 95% CI: 0-4.4 vs 48.3 months, 95% CI: 20.1-76.6; P = .01).

Timing and urgency of the liver retransplant
Three patients (14.3%) underwent emergent transplant (United Network for Organ Sharing 1 status) for their first OLT. Seven patients (33.3%) underwent urgent liver retransplant for either the second or third OLT. Two of the 3 fourth OLTs were due to United Network for Organ Sharing 1 status.

The liver retransplant interval < 3 months between the second and third OLT or the third and fourth OLT was associated with a shorter mean overall survival: 61.5 months (95% CI: 39.4-83.7 months) versus 173 months (95% CI: 113.9-232.0 months), which did not reach statistical significance (P = .08).

Current status of recipients and mortality
Table 2 shows the characteristics of 13 recipients (54%) who were not alive at the end of the study. Seven of these were in-hospital deaths. Five of 13 deaths (38% of the deaths) were due to graft failure; the remaining 8 deaths (62%) were from nonhepatic complications with a functioning graft.

The surviving 11 patients had a complicated course after their final OLT: 4 of them (44%) required a reoperation within 1 month after their final transplant, 2 patients (22%) have been on long-term hemodialysis, 5 patients (55%) have required rehospitalization for infection, and 3 patients (33%) required treatment of acute rejection in the hospital (Table 3).

Discussion

Patients with the first graft failure requiring liver retransplant are commonly seen at most liver transplant centers. However, patients with a second graft failure requiring a third graft are uncommon, and liver retransplant in this setting has only been pursued in a few large transplant centers.

This study retrospectively evaluated the long-term outcomes of adult liver transplant recipients who underwent 3 or more OLTs. The main finding of this study was an overall 1-, 5-, and 10-year survival of 78%, 63%, and 36%, in a selected group of sick and complicated patients. In addition, we showed that patients with graft failure who were not offered a liver retransplant had a significantly shorter survival.

Liver retransplant causes controversy in the medical, economic, and ethical fields as overall graft and patient survival is less than those undergoing initial OLT. The combination of the limited donor organ pool, the increased number of patients dying while waiting on the waiting list, and the financial constraints with a failing graft challenges the current organ allocation system of providing efficient distribution of a limited resource. The discrepancy between the number of available organs and increasing number of potential recipients will worsen until significant future advances are made in providing alternative management for chronic liver disease. Allocation of scarce liver grafts, especially for liver retransplants, requires balancing of ethical principles: beneficence, fairness, and utility.⁶ Liver retransplant can be regarded as unfair because some patients get multiple liver grafts, whereas other patients die awaiting their first OLT. Patients who have long-term relations with the transplant program may have an advantage as opposed to equally sick patients listed for their first OLT. Another major concern is that the results of liver retransplant are not equivalent to the first OLT.

Liver retransplant is commonly denied based on historical poorer outcomes compared to the first OLT.^{2, 7-8} It has been reported that the liver retransplant rate in the 18- to 49-year age range demonstrated a decline by half from 1996 to 2005. During the same time, new registrations for liver retransplant dropped from 4.6% to 2.7%, potentially because of better posttransplant patient care but also by representing a possible policy shift toward denying liver retransplant.⁹ However, with an increasing life span after OLT, and thus, an increased chance of recurrent primary disease in the allograft, the transplant community will likely face an increased number of OLT recipients with graft failure.

Liver retransplant candidates represent a complicated group and have a more-rapid rate of decompensation with a higher rate of postoperative morbidity and mortality than primary OLT candidates. In a previous report from UCLA, patient survival was significantly lower with multiple liver retransplant patients compared to first time OLT recipients and therefore, they adopted a policy allowing only 1 liver retransplant for the adult population.⁴ Our analysis showed that these patients have higher morbidity as the number of transplants increased. At the time of third OLT, mean MELD scores were significantly higher, and length of postoperative hospital stay was significantly longer compared to their first OLT (data not shown).

Donor risk index has facilitated the analysis of graft use and practices by objectively assessing the grafts and providing a quantitative measure.¹⁰ As such, any interaction of DRI with recipient factors is important in short- and long-term complications as well as in overall survival of recipients. Since its publication, DRI has become an accepted scoring system of donor graft quality in the United States, which helps in objective comparison of liver transplant results between institutions. Although, there are various models predicting outcome after liver retransplant, few publications address the effect of donor quality on the outcome of liver retransplant.^11-12 Our study adds to the growing body of evidence that the survival after liver retransplant increases not only with better patient selection but also with better organ selection. Our policy of using better grafts for more-complicated liver retransplant recipients resulted with a statistically significant negative correlation of DRI score with the number of grafts. A cutoff value of selecting grafts with a donor risk index < 1.6 at the time of third OLT revealed an estimated mean 5-year survival rate of 54%, representing a significantly improved outcome that might be a valuable parameter in the decision making.

Overall outcomes were poorer for patients with higher MELD scores in our cohort. While mortality was increased in all groups with a concomitant rise in MELD score, patients with a score ≥ 30 had a 21% five-year survival rate. In our cohort, none of the patients with MELD score ≥ 30 survived when grafts with DRI score > 1.6 were used.

In the first OLT population, traditionally marginal livers have been directed to candidates with relatively low MELD scores according to the rationale that healthier and/or younger patients can better withstand the posttransplant period. This has indeed been the practice in many centers (as in our center), evidenced by the strong negative correlation of DRI scores with MELD scores. High DRI graft recipients consistently had poorer outcomes. One explanation might be that the multiple, previous OLTs causing a cumulative detrimental effect on organ systems resulting in multiple morbidities and complications. At a given MELD score, especially with higher scores, biological reserves of the liver retransplant recipients might be more impaired compared to first-time OLT recipients. In an outcome-based approach, the practice of using better grafts for third-time liver retransplant patients will undoubtedly cause ethical questions. Our patients received better grafts with each subsequent OLT, which increases the ethical dilemma of using better grafts for potentially poor outcome associated recipients. Model for end-stage liver disease allocation system is blind to previous transplant status. Surgeons accepting the organs are not blind to previous transplant status of these patients and may shift the balance toward using better organs for liver retransplant. However, designing an allocation scheme based on strict outcome criteria would result in a discriminatory process whereby liver retransplant candidates may be disadvantaged. Our limited experience shows that multiple liver retransplant patients do not survive with marginal grafts. As first-time OLT and multiple OLT recipients are different patient populations, different approaches for graft selection and perhaps distribution are needed to optimize outcomes. Previous studies also found recipient age an independent predictor of survival after liver retransplant, with older patients demonstrating poorer outcomes.^{2, 13} When grafts with lower DRIs were used for older patients, we noticed significantly improved outcomes.

Quality of life is an additional concern in multiple liver retransplant recipients. These patients had a longer postoperative hospital stay, and required reoperation at a higher rate in the early postoperative period. Analysis of the current status of the surviving recipients showed that rehospitalization rate after the first 3 months was low with satisfactory graft function despite a relatively higher rate of kidney dysfunction and new-onset insulin requirement.

This is a single-center analysis of multiple retransplanted recipients managed with a uniform surgical technique and medical protocols throughout the study with complete long-term follow-up and a comparison with patients rejected for liver retransplant. As such, it is a unique contribution to the literature. This study was limited by the relatively small sample size and heterogenous group of liver retransplant patients who underwent 3 or more OLTs and reveals the pressing need for similar analyses from other large liver transplant programs. Small sample size does not permit a multivariable analysis to determine overlapping factors. Another limitation is its retrospective design that spanned over a decade. It is possible that other variables (such as significant advances in perioperative critical care in the last decade) could have influenced outcome differences between liver retransplant during the study.

Our study showed that multiple liver retransplant offers acceptable patient survival. Improved outcomes can be obtained by careful patient and graft selection. Each transplant program must decide whether to do multiple OLTs based on the program’s transplant volume and outcomes to help this subgroup of patients. The concerns of potentially decreasing access to first-time OLT candidates should also be weighed in the decision to move forward. The discrepancy between the number of available organs and increasing number of potential liver retransplant recipients will worsen until significant advances are made in providing alternative medical therapies or in increasing the donor pool. Ideally, designing an alternative allocation system that balances use, fairness, and outcomes for liver retransplant candidates would represent the best balance between the needs of these complex patients and the needs of other patients awaiting liver transplant.

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