Incidence and Indications—Early and Late Liver Retransplantation
The incidence of graft failure after pediatric liver transplantation has been decreasing with surgical and medical progress, but still reaches 10% to 15% in the first year, about 20% within 5 years, and up to 30% within 10 years after transplantation. Retransplantations are usually differentiated into early retransplantations (within 30 days) and late retransplantations. The main indications for retransplantation, as well as the practical approaches, differ in these two phases.
Early retransplantation indications consist of primary nonfunction, early hepatic artery thrombosis (eHAT), or portal vein thrombosis. Primary nonfunction is defined as graft loss (retransplantation or recipient death) within 14 days after transplantation, usually associated with a progressive rise of transferase and bilirubin levels, with a decrease of prothrombin time, increase in lactate levels and hypoglycemia, not explained by vascular (hepatic artery thrombosis) or biliary complications, rejection, or recurrence of disease. It is reported to occur in 2% to 6% of patients after liver transplantation, with known risk factors, but no fully understood cause. Some publications report primary nonfunction as a retransplantation indication in 20% to 30% of cases.
Vascular complications such as early irreversible hepatic artery or portal vein thrombosis are the other common causes of acute transplantation failure, with reported rates of about 5% to 8% of eHAT and 2% of portal vein thrombosis cases after pediatric transplantation.
Late retransplantations, defined as occurring more than 30 days after transplantation, have other causes. Usually, end-stage liver disease based on progressing cirrhosis develops is owing to chronic rejection (37% of retransplantations) or biliary complications (9%), but also includes (late) HAT (11%) and acute rejection (11%). Some chronic rejections may be the result of humoral mechanisms, a long-underestimated process in the context of liver transplantation.
A feature specifically described after pediatric liver transplantation is progressive graft fibrosis in a long-term observation after 5 to 10 years. However, its role in potential later graft failure is unclear.
A more prolonged damage mechanism also occurs in chronic vascular and biliary complications, such as biliary strictures with cholestasis or ischemic-type biliary lesions, which can lead to progressive liver fibrosis or cirrhosis.
Recurrence of initial disease in the field of pediatric liver transplantation occurs in autoimmune hepatitis or primary sclerosing cholangitis, but only case reports have been presented for the recurrence of progressive familial intrahepatic cholestasis type 2 (PFIC2), mediated via antibodies against the previously absent bile salt export pump (BSEP) protein. Recurrence of malignancy or metastatic disease after primary liver tumors is the main cause of death after transplantation for hepatoblastoma or hepatocellular carcinoma, but not reported as an indication for retransplantation. For more details on recurrence, see Chapters 26 and 38 .
Overall, the most common indications for retransplantation are chronic rejection (15%-47% of retransplantations), primary graft nonfunction (~ 25%), vascular (9%-40%), and biliary complications (2%-11%).
Contraindications for Pediatric Liver Retransplantation
There is no general consensus regarding absolute and relative contraindications for retransplantation. One center reported medical reasons, including malignancy (e.g., post-transplantation lymphoproliferative disease), extrahepatic source of sepsis, or severe irreversible neurological injury as contraindications for retransplantation. One case report discussed the question of living donor retransplantation in an intellectually disabled girl. However, publications on the topic are scarce, and it can be assumed that these discussions are held individually for each patient in the respective transplant centers. The same goes for the previously cited contraindications, but also other comorbidities, technical difficulties (e.g., vascular restraints), and prognosis, including risk of recurrence, may be the reason of graft failure.
In difficult cases, most transplantation centers will have an ethics committee that also considers factors such as life expectancy and quality of life, with or without retransplantation, and advises clinicians and parents and guardians regarding the patient’s best interests. Depending on age and the clinical and neurological situation, the patient’s view also needs to be taken into consideration.
Recurrence of disease needs special considerations, depending on the specific disease and the risk for rerecurrence in the newly transplanted graft. Autoimmune disorders such as primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) have a reported recurrence rate of 18% to 40% in the graft, a risk that can be estimated to be repeated after retransplantation. The same applies to the development of antibodies against BSEP in liver transplantation for PFIC2. Despite attempts to reduce the antibody load via intravenous immunoglobulins (IVIGs), plasmapheresis, and rituximab before retransplantation, there have been descriptions of recurring BSEP disease after retransplantation in single cases, sometimes leading to repeated graft failure and decisions against retransplantation (see later).
As a rule of thumb, a minimum estimated chance of survival of 50% 5 years after transplantation has been clinically agreed on as a basis for the transplantation indication. The same requirement should also be consistently applied to the indication for retransplantation with a reported inferior outcome. However, even this seemingly fair concept raises ethical concerns—for example, with regard to disproportionately prioritizing younger (re)transplantation candidates.
Therefore the central issue is to investigate thoroughly the reasons for the retransplantation indication (e.g., vascular problems, infections, chronic rejection, recurrence of disease, chronic fibrosis or cirrhosis) and assess approaches to prevent recurrence after retransplantation. If the chances of improvement are low, and there is a reasonable risk of recurrence of the graft problem, this could be a contraindication for retransplantation.
Two cases may illustrate the difficulties in this decision-making process, as detailed in the following sections.
Case 1: Decision Against Further Transplantations Because of Antibody Formation
If a decision is made against further transplantations because of antibody formation, bone marrow transplantation may be considered as the ultimate treatment. For example, an 18-month-old boy was transplanted (living related donation) for PFIC2. He developed a recurrence of PFIC2 symptoms, with the detection of BSEP antibodies in plasma and liver histology a few months after transplantation. Immunosuppression was intensified from cyclosporin A (CSA) to tacrolimus (TAC), azathioprine was added, repeated steroid pulses and plasmaphereses were applied, and immunosuppression was changed to a combination therapy of TAC and everolimus.
Despite these therapeutic attempts, cholestasis and increasing fibrosis were not preventable, so a liver retransplantation was performed at 2 years and 4 months, with preceding plasmapheresis. This retransplantation again developed severe cholestasis with cholangitis, leading to repeated fibrosis and with additional perfusion injury and graft failure. A second retransplantation was performed at 2 years, 6 months, accompanied by repeated plasmaphereses and increased immunosuppression (basiliximab, CsA, mycophenolate mofetil [MMF], steroids).
The patient again developed cholestasis and fibrosis related to BSEP antibodies after 6 weeks. Several increases of immunosuppression were initiated that resulted in quadruple therapy with TAC, everolimus, MMF, and steroids. This controlled the histological rejection component, but cholestasis and pericholangitis, as well as progressing fibrosis, persisted.
In the transplantation conference, it was agreed that another liver retransplantation would not improve the results and was decided against. In this case, a bone marrow transplantation 9 months after the last retransplantation then prevented further BSEP antibody formation, and the last retransplantation recovered to stable graft function.
Case 2: Several Retransplantations After Repeated Early Hepatic Artery Thrombosis
A 12-month-old boy was transplanted for biliary atresia with a modified split organ, with intraoperatively repeated thromboses of the portal vein and one HAT, corrected directly. Five days after the first transplantation, early uncorrectable HAT was detected, and the patient was relisted and retransplanted at day 12 after the first transplantation, with a complete organ. Intensive coagulation tests only showed possible protein S deficiency. This retransplantation again showed eHAT after 3 days, so a third transplantation was performed 2 days later, with increased anticoagulation.
After an uneventful 6 months, the patient developed hepatosplenomegaly, with liver vein thrombosis detected after another 3 months despite therapeutic anticoagulation. The repeated coagulation testing now showed minimally elevated cardiolipin antibody levels. Interventional radiology allowed for a partial thrombectomy, but the graft damage was such that after more discussion, the patient was relisted for transplantation.
Because of the detection of human leukocyte antigen (HLA) antibodies, plasmaphereses and rituximab were applied before the fourth transplantation. Despite all anticoagulatory efforts, another eHAT occurred, so the procedures had to be discussed in view of repeated thromboses and the very difficult question of their prevention.
Finally, the patient was listed for what was decided to be the last attempt. This transplantation was accompanied by intensive anticoagulation (aspirin and heparin; intermittent phenprocoumon [Marcumar] later) and immunosuppression (basiliximab, steroids, TAC, MMF). Despite this, cellular rejection was repeatedly detected by histology; donor-specific antibodies (DSAs) were measured. Combined cellular and humoral rejection were diagnosed and seen as a severe risk factor for thrombophilia.
Antithymocyte globulin (ATG) was given 13 times, and histology then showed only humoral rejection, which was treated with plasmaphereses, bortezomib, rituximab, and repeated IVIG. Finally, basic immunosuppression was changed from TAC to sirolimus, with the aim of obtaining additional immunomodulatory effects and maximizing immunosuppression to prevent thrombophilia.
This fifth and last transplantation proved successful. The patient was generally doing fine 6 years later, despite immunological consequences such as permanent immunoglobulin deficiency requiring supplementation.
The questions around retransplantation become still more relevant in cases of reretransplantation. Not only medical aspects, such as surgical feasibility (abdominal condition, adhesions, possibilities for vascular and biliary connections), but more urgent questions of prevention of disease recurrence in the retransplantation arise. Also, the allocation of more organs from a limited donor pool to one recipient and deciding whether it is reasonable to put the patient through the reretransplantation procedure need to be taken into consideration.
Timing for Relisting Patients With Graft Failure
Relisting and retransplantation are urgent in cases of primary nonfunction owing to the high risk of acute liver necrosis with acute liver failure, high lactate levels, hemodynamic instability, and the associated infection risks. Permanent eHAT or portal vein thromboses are also generally considered as an urgent indication for retransplantation because of possible liver abscess formation and biliary sequelae for the graft.
Studies investigating urgent revascularisation surgery in eHAT have reported the possibility of restoring arterial perfusion in 61%of patients, leading to 30% to 38% long-term graft survival. In contrast, long-term graft survival in failed or not attempted revascularization was reported in only 3 of 26 cases (12%).
Other authors have reported the formation of arterial collaterals in eHAT after unsuccessful surgical vascularization, but also inevitable biliary damage requiring retransplantation in most cases after early uncorrectable HAT, in a variable time frame. A different approach is interventional radiology intervention with reasonable results in case of revascularization.
In cases of uncorrectable eHAT, complications ranging from biliary complications to liver necrosis, sepsis, and liver failure are likely, so immediate retransplantation preparations may be discussed, depending on the possibilities.
Primary nonfunction and uncorrectable hepatic artery or portal vein thrombosis are recognized as an indication for exceptional or high-urgency relisting in several allocation systems. These include the model for end-stage liver disease (MELD) system used by Eurotransplant and United Network for Organ Sharing (UNOS).
The flow chart in Figure 40.1 summarizes the practical approaches to early graft complications.
In chronic graft failure or recurrence of disease, the timing decision for relisting has to be considered individually based on the progression of indicators of liver failure and fibrosis and also considering the risks and advantages of retransplantation. Certainly, the primary approach to chronic graft failure will be to try everything to save the graft by addressing possible causes (e.g., chronic rejection, drug toxicity, cholestasis). On the other hand, in advanced liver fibrosis and cirrhosis, and in conditions with progressive graft failure, the possible waiting time after listing also needs to be considered.
The practical approaches in cases of (imminent) graft failure regarding pre-transplantation, peritransplantation, and post-transplantation management for different causes are summarized in Tables 40.1 and 40.2 .