Living Donor Transplantation in Children

History and Significance of Pediatric Living Donor Liver Transplantation

The first living donor liver transplantation (LDLT) in the world was performed in Brazil by Raia in December 1988, but the recipient did not survive long. The first successful LDLT was reported by Strong et al in 1990. The recipient was a Japanese boy who received a left lateral segment from his mother. Unfortunately, chronic rejection developed a year later, and the patient underwent retransplantation with a liver from a deceased donor. He has been doing well since then. He has been doing well since then and is now working as a public servant. In 1989 Nagasue et al performed the first LDLT in Japan on a boy with biliary atresia. In the United States, Broelsch et al started an LDLT program in Chicago in 1989 and reported the cumulative result of 20 cases in 1990. Encouraged by these results, Ozawa in Kyoto and Makuuchi in Matsumoto started LDLT programs in Japan.

In the first experiences with LDLT the target subjects were pediatric patients. LDLT was developed as a technical innovation to overcome the shortage of size-matched deceased liver donors. Before the development of LDLT, reduction of an adult graft for use in a pediatric patient was attempted. In this procedure a large part of the graft was discarded and thus did not help adult patients, who accounted for the majority of patients on the waiting list. As the next step, an innovative technique of splitting an adult graft was developed and has become increasingly sophisticated. Even with the development of these techniques, there was still a shortage of organs. Subsequently LDLT was started. Pediatric recipients were preferred for two reasons: parents can be most easily selected as potential donors with the fewest ethical problems, and donor safety can be more easily preserved by leaving the larger right lobe of the donor intact after harvesting the left side of the liver. The left lobe is usually sufficient for the metabolic demands of a pediatric recipient.

Split-liver transplantation from deceased donors, if sufficiently available, can reduce the number of pediatric patients waiting for organ donation without decreasing the persistently inadequate donor pool for adult patients. So theoretically this procedure should be the first choice for pediatric liver transplantation in countries in which deceased donor livers can be retrieved easily, as reported by the Rogiers group. However, splitting of deceased donor livers is sometimes limited because of their marginal condition and the reluctance of centers or surgeons to establish split-liver programs, although such programs have started to expand. Alternatively, the development and clinical application of LDLT could successfully reduce mortality on the waiting list, as reported by both Essen and Brussels. Multimodal procedures, including the splitting technique and LDLT, should henceforth be considered as means of enlarging the overall donor pool for not only pediatric patients but also all recipients. At least in pediatric recipients, LDLT already has a solid foundation. In selected institutions an adult liver surgeon in one hospital and a pediatric transplant surgeon in a children’s hospital are both involved in LDLT for the pediatric recipient. Such combined participation is one means of respecting specialization on both sides. LDLT can be electively done, and this is suitable for the treatment of pediatric hepatic malignancies that need the multimodal planned strategy. With recent technical innovation, LDLT has been expanded to smaller or even newborn babies with congenital metabolic diseases or fulminant hepatic failure.

Ethical Issues and Informed Consent

Even in donation for pediatric recipients, living liver donors have a potential of mortality and morbidity. In general, the balance between donor safety and hope for the recipient’s survival should define the availability of LDLT. This balance is affected by the availability of deceased donors, so this situation should be different in each country. In the United States the annual number of LDLTs had a peak in 2001, more than 500, and has been decreasing since then. This might be related to the donor death in 2002 in an adult LDLT. In Japan the first and only mortality of a live liver donor occurred in 2002, also in a case for an adult recipient. In Japan the annual number of LDLTs had a peak of 566 in 2005 and has also decreased since then. However, the number for pediatric patients is quite stable, around 140 per year. At least in emergency cases or for pediatric patients, LDLT will remain significant from now on. In Asian countries LDLT has been well accepted and has developed into the main liver transplantation technique performed because the concept of brain death is not well established in this region. In recent years, even in Asian countries like Korea, the number of deceased donor liver transplantations (DDLTs) is increasing. In Japan, an innovative law for organ donation became effective in 2010, and the number of DDLTs is now increasing. This may change the balance of DDLT and LDLT in the near future. In Japan the relationship between the donor and the recipient is regulated by the principle of the Japanese Society of Transplantation that the donor and recipient should be relatives ( Table 48-1 ). Official documents identifying the donor and the donor’s relationship to the patient are mandatory. In pediatric LDLT the donor is usually one of the parents, a situation that affords the best matching of the donor and recipient with the least ethical conflict. Preserving the life of their child may be very gratifying for parents. However, in some instances, social pressure may oblige the parents to become donors. During the informed consent process, other means to avoid being a living donor should always be mentioned after all the risks and benefits of LDLT have been explained to the family in complete detail. In rare cases, siblings or parents younger than 18 years may be included as donor candidates for pediatric LDLT. In such cases, not only their emotional response to being a living donor but also their competence to understand the LDLT process and donor risk should be carefully evaluated during the initial stages of the LDLT process. Grandparents may be also included among the donor candidates, and in such cases extra risk to an elderly donor should be included in the informed consent discussion after meticulous evaluation of the health of the donor candidate. In repeat LDLT after initial failed LDLT, donor selection tends to be harder than in the initial one. When the donor is a more distant relative, such as an uncle or aunt, voluntary willingness should be carefully ascertained. In general, donor candidates should be interviewed independently in the absence of the recipient and other family members. If the parents are divorced, the parent living with the child is usually selected as the donor; however, the noncustodial parent may be included as a donor candidate if so desired.

During the informed consent process, it is essential that the possibility of donor mortality be included. In a survey of 3565 LDLTs in Japan, the incidence of complications after donor surgery was 8.4% overall, 9.4% for right lobe donation, 8.7% for left lobe donation, and 3.5% for left lateral segment donation. According to the report of Lo in a review of Asian LDLTs in 2003, the incidence of complications for donors was 9.3% for left lateral segmentectomy and 7.5% for left lobectomy ( Table 48-2 ). From the recent report from Kyoto University, the incidence of biliary complications in left-sided graft donors was significantly lower than that of right-sided graft donors ( Table 48-3 ). Unlike adult LDLT, in pediatric LDLT, postdonation liver failure is considered unlikely in the donor, but events such as pulmonary embolism or serious infectious episode may nevertheless result in death of the donor. Bile leakage is commonly cared for conservatively or with simple drainage, but some may need relaparotomy. Adhesion of the gastric wall to the cut surface of the liver also occurs more frequently after left-sided hepatectomy than after right lobectomy. Such adhesion causes gastric stasis ( Fig. 48-1 ). With accumulation of LDLTs, various complications have been experienced, such as pleural effusion, peptic ulcers, temporary numbness of extremities, palsy of vocal cord, ugly scar of the wound, and so on. Donor candidates should be informed in advance about all the possible donor risks.

Even though the recipients are children, they have the right to select the treatment option according to their age and ability. Family members or physicians and coordinators must explain the treatment before the procedure. During puberty or adolescence, LDLT is sometimes difficult for patients to accept. They may be distressed to live with the sacrifice being made by their parent or relative. They may experience considerable anxiety about the operation and the future if not completely informed. Their anxiety should be relieved after a patient, thorough explanation. The goal that all family members can enjoy and participate in the happy, healthy life of the patient should be presented as the motivation for LDLT.

Indications

Indications for LDLT are basically not different from those for deceased donor transplantation ( Fig. 48-2 ). However, in LDLT the organ is donated to a specified recipient and not shared by other candidates. Therefore the indication is not affected by the problem of organ allocation as it is in deceased donor transplantation. Contraindications to deceased donor transplantation are not necessarily the same for LDLT. For example, cases with malignant disease such as hepatoblastoma, which is large and invasive, may be considered to have low priority or be excluded from listing in deceased donor transplantation. However, in LDLT the operation might be done with full understanding of the potential donor, recipient, and other relatives about the potential risk for recurrence of the original disease and risk of the surgery itself. The advantage of LDLT is that total hepatectomy and transplantation can be done on an elective basis. Chemotherapy followed by LDLT and the following posttransplant chemotherapy can be organized as one treatment strategy for advanced hepatoblastoma.

Donor Evaluation

Donor evaluation in LDLT is necessary both for the safety of the donor and recipient ( Table 48-4 ). Suitable donors can be selected on the basis of two perspectives: (1) donors with normal liver function and normal anatomy with adequate size of the liver and (2) donors without any systemic diseases, abnormalities, and high possibility of postoperative risks. In Japan, criteria for donor selection are determined in each institution with approval of the institution’s review board ( Table 48-5 ). As the initial phase, preliminary conditions such as age, relationship to the recipient, ABO blood matching, and history of any diseases can be identified. After full consent has been given, the medical tests start. If multiple candidates are available, conventional studies may be performed at the initial screening for each if requested. Such studies include a blood count; coagulation profile; blood chemistry studies for hepatic and renal function; serological tests for hepatitis C and B virus, syphilis, and human immunodeficiency virus; electrocardiography; chest radiography; and ultrasonography of the liver. After preliminary examination the results are presented as a tool for selecting the final candidate.

The age of the donor should ideally be between 20 and 60 years, although we include 60 to 70 years if no younger donor is available. Younger candidates should be evaluated for their competence in making a voluntary decision. Candidates older than 60 years are judged on an individual basis in terms of cardiopulmonary and neurological function in addition to the routine workup.

Postoperative pulmonary embolism is a genuine threat to the donor. Smoking, routine use of birth control pills, or serious obesity should be considered a possible risk factor for this complication. The possibility of diet and correction of the habit is one of the advantages of living donor transplantation. A body mass index greater than 30 should be corrected, or an alternative donor should be selected out of concern for the donor’s safety.

ABO blood typing should be identical or compatible in general, but in pediatric recipients younger than 2 years, ABO combination does not affect the outcome even under the conventional immunosuppression (see later). The second line of screening is endoscopy of the upper and lower gastrointestinal tract, blood tests to check for tumor markers (α-fetoprotein, carcinoembryonic antigen), respiratory function tests, echocardiography, and an imaging study of the liver. The imaging study of the donor liver is important to ensure safe surgical procedures in both the donor and recipient. For this purpose, three-dimensional (3-D) computed tomography (CT) angiography is a suitable modality because it is less invasive and provides considerable information. Conventional catheter angiography is not necessary because it is invasive for the donor. Magnetic resonance imaging may present the same information as enhanced CT does without serious risk for the allergy to the contrast dye, but sometimes the images are not as clear as those obtained with CT. It is important to assess the potential volume of the graft in adult transplantation because the graft is sometimes critically small. When the right lobe is necessary for bigger recipients from relatively smaller donors, residual volume after the graft harvesting should also be estimated. Thirty percent of the whole liver is commonly used as the smallest limit of the residual volume. Segmental volume can be calculated using commercially available simulation software. In pediatric cases the graft is usually selected among the whole left lobe and the whole or a part of the left lateral segment. Small-for-size problems are rare, but in small infants, large-for-size problems are more important. In addition to the volume of the graft, the size of the potential graft estimated on CT scan should be compared with the diameter of the peritoneal cavity of the recipient.

Preoperative 3-D bile duct imaging of the donor liver is also informative for both adult and pediatric cases, although there is a concern about hypersensitivity for the contrast medium.

Fatty liver is a common contraindication to donation, with fatty infiltration of more than 25% to 35% being a criterion for exclusion. In LDLT the use of a fatty liver graft up to the moderate level can be justified, even though ischemia-reperfusion injury tends to be severe in such grafts. In our institution the averaged plain CT value of the liver measured at multiple spots is compared with that of the spleen. If the ratio is lower than 1, which means that the liver has less density than the spleen does, fatty infiltration is more than 30%. However, an exact diagnosis of the degree of fatty infiltration depends on preoperative liver biopsy. Accurate diagnosis of nonalcoholic steatohepatitis, which may be suspected from hepatic profile and imaging studies, also depends on the pathological findings by needle biopsy.

Size Matching and Anatomy of the Donor Liver

In most pediatric LDLT, graft options consist of the full left lobe, including the middle hepatic vein (segments II, III, and IV); the left lateral segment with a part of segment IV, but without the middle hepatic vein; the left lateral segment (segments II and III); and the partial or reduced left lateral segment (segment II or segment III, or reduced both). Selection of the graft is based on the potential volume of the graft in relation to the recipient’s body size. The relative size of the standard liver volume is used as one of indices. We use the ratio of graft weight to recipient body weight: graft weight (g)/recipient’s body weight (g) × 100 (%). If this ratio is within 1% to 3%, the graft size is considered adequate. Generally the left lobe is used in a recipient with a body weight between 20 and 40 kg, whereas the left lateral segment or the left lateral segment plus a portion of segment IV is used for smaller recipients. When a slightly larger graft than the left lobe is necessary, the left half of the caudate lobe can be added. By preoperative volumetry, the volume of the potential graft can be estimated in cubic centimeters. The specific gravity of the hepatic graft is considered to be 1. Therefore volume is calculated in the same manner as weight. If the potential graft is 200 g and the recipient’s body weight is 10 kg, the ratio is 2%. The smallest unit in conventional LDLT is the left lateral segment. If the ratio of graft weight to recipient body weight is more than 4%, poor perfusion of the graft may cause unsatisfactory primary function. In general the mother may be more suitable than the father in infantile cases because of her possibly smaller liver. Of course, after information is provided about the risks of the large-for-size problem, the final decision should be made in the family. If only a large donor liver is available, reduction of the left lateral segment is necessary. Monosegment transplantation using segment II or III or a part of both, as discussed later in this chapter, is a solution in such a case. Regarding size matching, the size of the graft should be compared with the size of the recipient’s peritoneal cavity on CT images. If the anteroposterior diameter of the potential graft is greater than the anteroposterior diameter of the recipient’s peritoneal cavity by 2 cm or more, primary closure is expected to be difficult. In such a case, skin closure or prosthesis closure can be used, but this technique may cause more trouble than simple closure.

Because the left lobe is more commonly used than the right lobe, the anatomy of the left lobe of the donor is an important factor in LDLT in pediatric recipients. In left lateral segmentectomy the hepatic vein from segments II and III may become separated on entry into the inferior vena cava (IVC). In left lobectomy the left and middle hepatic veins may also separately drain into the IVC. Consideration of such possibilities is necessary before LDLT. Regarding the anatomy of the portal vein, P2 and P3 may branch separately from the main portal trunk and form a trifurcation with the right portal trunk ( Fig. 48-3 ). A left-sided gallbladder is frequently associated with this variation of the portal vein. If available, an alternative donor should be chosen. On evaluation of the donor artery, an aberrant left hepatic artery arising from the left gastric artery is not very rare. This artery is in the lesser omentum, and attention should be paid to preserving as long a vessel as possible because a longer vessel can be more easily used as the reconstruction vessel ( Fig. 48-4 ). When left lobectomy is being considered, the size and distribution of the middle hepatic artery should be assessed. For evaluation of bile duct anatomy, 3-D reconstruction CT is very useful. Preoperative assessment by such imaging facilitates better understanding of the intraoperative cholangiogram ( Fig. 48-5 ).

Technical Considerations