Liver Retransplantation

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.