Retransplantation

Early Retransplantation

The most common causes of early graft loss (within 7 to 30 days after primary transplant) requiring retransplantation are hepatic arterial thrombosis (HAT) and primary nonfunction (PNF). Both can be catastrophic events, as evidenced by the current United Network for Organ Sharing (UNOS) policy of awarding status 1A to patients with either diagnosis that meet defined criteria of liver failure ( Table 64-1 ) within the first 7 days of transplantation, thus placing them at the top of the waiting list for a deceased donor liver. The relative contribution of each to retransplantation varies by institution and may be related to how aggressive each institution is in accepting “marginal,” livers as well as how ill the recipients are at time of transplant.

PNF has been reported to serve as an indication for retransplant in up to 30% of cases. The cause is often multifactorial and includes donor and recipient factors. Significant donor factors include degree of steatosis in the donor allograft, increased cold ischemic time (>12 hours), reduced-size allograft, and older donor age (>50 years old). Significant recipient risk factors include worsening medical status, renal insufficiency, and retransplantation. In addition, prolonged warm ischemic time has been shown to be an important perioperative risk factor for PNF. The combination of these factors has the potential for additive effects that may yield particularly dismal outcomes, as was discovered when marginal livers were initially used in critically ill patients. In spite of poor posttransplant outcomes, these patients still have a better chance of survival accepting a marginal liver than waiting for a standard criteria donor liver. However, the elevated risk for graft failure and patient death has discouraged the use of marginal grafts in high-risk patients; they are now largely used in relatively healthier recipients with either tumors threatening to grow beyond transplantable criteria or non–critically ill recipients whose MELD score nevertheless underestimates their risk for death, placing them further down the list than their condition warrants.

In either case the practice of using marginal livers as a way to discard fewer donor organs and increase the functional organ pool has increased the rate of PNF. Although this might be associated with higher rates of retransplantation and the number of livers consumed per recipient, the provision that returns recipients with PNF to the top of the list likely increases the total number of livers available for transplantation, because the failed “marginal” grafts would otherwise have been discarded without an attempt at implantation.

Reported rates of early HAT range from 0% to 20%, with approximately 50% of events resulting in retransplantation. Generally a 3% to 5% rate is observed in recipients of whole organ allografts. HAT rates in children are nearly three times higher than those in adults, in part because of the use of living donors and split grafts from cadaveric donors, because 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 independently of HAT incidence, putting pediatric liver recipients of partial grafts at especially high risk for requiring retransplantation. Small vessel size also contributes to the increased risk for HAT in children, with early reports demonstrating that HAT incidence decreases as the arterial anastomosis moves proximally, using larger inflow vessels (hepatic artery 24%, celiac axis 11%, aorta 6%). Indeed, refinements in microsurgical techniques for arterial reconstruction have decreased the incidence of HAT in children. Furthermore, if HAT is detected early, catheter-directed thrombolysis, surgical thrombectomy, and immediate vascular reconstruction can often successfully treat HAT, avoiding the need for retransplantation. However, some centers still report that HAT constitutes nearly one third of retransplant indications.

Late Retransplantation

Recurrent disease and chronic rejection are the primary indications for late retransplantation. The vast majority of retransplants done for recurrent disease are in hepatitis C–positive patients, corresponding to the trend that end-stage liver disease secondary to hepatitis C virus (HCV) has become the most common indication for transplantation. Although HCV disease recurs almost universally after transplantation, retransplantation or death (from graft failure) occurs in only approximately 10% to 20% of patients, a number of which may not be the direct result of HCV activity. The latter includes cases of acute or chronic rejection related to HCV treatment, as well as technical issues completely unrelated to HCV. HCV protease inhibitors, such as telaprevir, which improve treatment efficacy against primary HCV, are now available and are also being used for recurrent HCV after transplant, offering the hope that HCV disease will contribute a decreasing number of both transplants and retransplants in the future. In addition, newer agents, including anti-HCV monoclonal antibodies, are currently being tested in the posttransplantation setting and may also serve to decrease the number of HCV-related retransplants.

Hepatitis B virus (HBV), on the other hand, has become an uncommon indication for retransplantation. As little as 15 years ago, recurrent disease resulted in such poor outcomes that HBV infection was on the verge of becoming a contraindication for liver transplantation. Although it remains a common infection, with more than 360 million people worldwide with chronic hepatitis B infection, the advent of hepatitis B immune globulin and nucleoside analogues lamivudine, tenofovir, and entecavir have completely changed the course of chronic HBV disease. The Centers for Disease Control and Prevention estimates that approximately 1 million persons in the United States are infected with HBV, but HBV cirrhosis accounts for only 6% (less than 400 a year) of primary transplants, and HBV recurrence requiring retransplantation is now almost never seen. Furthermore, since 2004, HBcAb-positive livers have accounted for 4.8% of liver transplants performed in HBV-negative patients because of the excellent disease control offered by current prophylaxis therapy.

Alcoholic liver disease (ALD) is the second most common cause of liver failure leading to transplantation, but retransplantation is rarely performed for recurrent ALD. Studies looking at recidivism rates suggest that ALD recipients use alcohol after transplantation at rates similar to those of non-ALD recipients, although those with ALD may consume more alcohol when drinking. Even when alcohol relapse occurs, the graft suffers only minor to moderate damage, with recurrent alcoholism accounting for barely 4% of graft failures. In addition, concerns that recidivism would lead to poor compliance with antirejection medication and premature graft loss have turned out to be unfounded. In fact, outcomes after transplantation for ALD are among the best of any primary diagnosis for liver transplantation in adults.

Autoimmune hepatitis (AIH) accounts for only 5% to 6% of all liver transplants and recurs in 15% to 40% of recipients. One study reported that in spite of a 20% recurrence of disease, 0 patients required retransplant, although mean follow-up was only 2 years. More compelling is the same center’s report that there was no statistically significant difference in 1- and 5-year graft or patient survival between patients who had recurrent disease and those who did not. Other centers report that one third of patients transplanted for chronic AIH have recurrence of disease, with a 50% need for retransplant among those that have recurrence. The risk for recurrence in those requiring retransplant was 78%, although there were only three such patients in that series. Such variability may be related to different posttransplant immunosuppression regimens, and some have even suggested that recurrent disease is associated with incomplete suppression of disease at the time of transplant. Although there are reports of recurrence-free survival in the setting of complete steroid withdrawal, most centers maintain AIH recipients on a higher degree of immunosuppression compared with other liver transplant recipients and continue maintenance steroids to minimize the risk for recurrence and need for retransplant.

Finally, HAT can also be an indication for late retransplantation, when the disruption in arterial blood supply is not severe enough to cause hepatocyte failure but does result in strictures and cholangiopathy of the bile ducts, which are much more sensitive to ischemic injury. Advances in endoscopic and percutaneous biliary intervention for management of ischemic cholangiopathy can now postpone or altogether avoid the need for retransplantation. However, there remains the subset of patients who develop secondary biliary cirrhosis or who experience repeated episodes of life-threatening biliary sepsis despite endoscopic or percutaneous intervention and thus progress to requiring retransplantation.