Ethics in Living Donor Transplantation

Living Donors in Pediatric Liver Transplantation

In contrast to end-stage renal disease, for which individuals have the options of dialysis and transplantation, end-stage liver disease has no alternative therapy. In the 1980s this was particularly acute for children. The most frequent cause of end-stage liver disease in children is biliary atresia, and the majority of children with this disease require liver transplantation before 2 years of age. Because very few babies or small children die from head trauma or brain death, circumstances in which they could be a source of a donor liver, there is a large gap between pediatric patients in need of liver transplantation and the availability of pediatric donors. In the 1980s this situation resulted in reported mortality rates of 20% to 30% among infants and children awaiting transplantation at the leading transplantation centers. In many parts of the world, especially Asia, where organ transplantation from brain-dead donors was severely restricted, most children with biliary atresia died.

By the mid 1980s innovative surgical techniques such as reduced-size and split-liver deceased donor grafts lowered but did not eliminate waiting list mortality for infants and children. Although these innovative approaches benefited children, such approaches were criticized on two points: (1) reduced-size grafts may have exacerbated adult waiting list mortality by “stealing” a graft from potential adult recipients and (2) the split-liver procedure resulted in lower graft survival for the adult candidate than that achieved with a full-size graft.

However, the development of techniques to divide deceased donor livers (known as split-liver transplantation ) also led to the possibility of living partial-liver donation. Although several failed attempts occurred in the late 1980s in Brazil and a successful case was reported in Australia in 1989, more widespread adoption would not occur until a team from the University of Chicago published a paper that discussed both the clinical need for LDLT and the ethical justification for performing a prospective protocol study of 20 pediatric LDLTs that underwent ethical review by an institutional review board (IRB) that approved the study and required written informed consent. The excellent results of the first 20 donor-recipient pairs published in 1991 served as the basis for expansion of the technique to many of the leading liver surgery programs in the United States, Europe, and Asia. There was still a lack of standard technique defining the extent of resection required to obtain an appropriate graft and how much residual liver must be left in the donor to assume a safe recovery.

The pediatric operative procedure has undergone substantial modification since the first cases. During Chicago’s protocol series, the left lobectomy was abandoned after the first three cases in favor of the left lateral segmentectomy as a graft source for infants and children because of the high incidence of surgical complications experienced with the former procedure. Further technical modifications have included avoiding vascular conduits and using microscopic arterial anastomotic techniques. Overall 1-year survival for pediatric recipients of living donor grafts is greater than 80%. In addition, pediatric recipients of living donor grafts have a significantly improved survival when compared to recipients of deceased donor full-size, reduced-size, or split grafts. Although at least two living donor deaths from left lateral donations have been reported, the relatively low complication rate and lack of long-term sequelae among the donors continues to make this procedure a clinically and ethically acceptable source of organs for transplantation in selected recipients Currently the adult-to-child LDLT has become a standard of care in many developed countries, including the United States, Japan, South Korea, Germany, Belgium, and France.

In summary, the development and maturation of PLDLT has addressed two broad issues of surgical innovation: (1) it meets a demonstrated need by saving lives with a safe and predictable operation, and (2) it was introduced to the surgical community after intensive scrutiny of its clinical and ethical justification.

Living Donors in Adult Liver Transplantation

In contrast to the measured way PLDLT was introduced by the transplant community, after a reported protocol series proved its efficacy and safety, adult-to-adult living donor liver transplantation (ALDLT) was disseminated rapidly without a comparable protocol study. The first successful ALDLT was performed in Japan in 1993 using the donor’s left lobe. The increasing awareness of the importance of graft volume and graft-to-recipient weight ratios led to the introduction of right lobe LDLT. The Kyoto group published the first successful case using a living donor right lobe graft (for transplantation into a 9-year-old recipient because of abnormal arterial anatomy supplying the left lobe), but in general this was used for adults who needed more liver donor mass. In 1997 Lo et al reported the first seven cases of high-urgency ALDLT using an extended right lobe graft (segments IV to VIII and the middle hepatic vein) between May and November 1996. Two of the donors had complications requiring reoperation after discharge (one incisional hernia and one bile duct stricture), and one recipient died 16 days after transplantation. The first reported successful ALDLT in the United States using the right lobe was reported by the Colorado group in 1998. Following the initial case reports, a number of centers on three continents began performing ALDLT. Although some originally used the left lobe, its smaller size and less favorable anatomical positioning was believed to increase the risk for graft failure. As a result, most centers began using the right lobe and extended right lobe.

The early advances in LDLT occurred in Asia, where there are very few deceased donors, but the techniques were not quickly adopted by the international community because there was skepticism about the completeness and transparency of the programs due to lack of reports of morbidity and mortality. In December 2000 the National Institutes of Health (NIH) and the American Association for the Study of Liver Diseases cosponsored a 2-day workshop titled “Living Donor Liver Transplantation” to review the scientific, medical, and nonmedical issues associated with LDLT. They created a table of complications based on 10 large series, which found bile duct strictures to be the most severe complication, occurring in 3% to 8% of all donors. Other complications were found in 2% or less of all donors. Liver function declines were found to be temporary, with bilirubin level and prothrombin time returning to normal within 3 to 5 days. The conference reported a significant incidence of complications based on 11 large series in the recipients. These included postoperative bleeding in 46%, biliary track complications in 15% to 30%, hepatic artery thrombosis in 3% to 10%, hepatic venous outflow obstruction in 5%, and intrahepatic hemorrhage in 5%. However, there was no consensus on when LDLT should be performed. As the NIH report stated, some groups believed that this procedure should be limited to only those patients who were critically ill, whereas others thought it should be used only in those who were more clinically stable. In fact, some programs viewed the living donor option as a way to help those who were excluded from receiving a deceased donor organ because of a contraindication (e.g., large hepatocellular carcinoma [HCC]). The lack of consensus on who were the appropriate recipients, what the appropriate donor work-up should entail, and the appropriate surgical technique to be used led Cronin et al to ask whether the expansion was “too much too soon.”

The NIH report was published in February 2002, weeks after the publicized death of Mike Hurwitz, a reporter who was donating to his brother Adam, a physician. At the time of the conference it was noted that there had been two reports of living donor deaths, and at the conference two additional deaths were acknowledged. Hurwitz’s death led to much soul-searching within the U.S. transplant community, as well as in the public at large. The number of LDLTs fell from its peak of 524 in 2001 to 363 in 2002, and in 2012 only 246 LDLTs were performed in the United States (of which 52 were pediatric recipients). Although there is still no living liver donor registry, several researchers have attempted to determine the total number of deaths worldwide, with one study reporting 14 deaths by March 2005, another reporting 19 deaths between 1989 and 2006, and another study reporting 23 deaths as of October 2012.

A major conclusion of the consensus conference was the need for a prospective study of LDLT focusing on the relative risks and benefits of the use of living versus cadaveric livers and on the short- and long-term complications of the donor operation. In 2003 the National Institute of Diabetes and Digestive and Kidney Diseases established a multicenter clinical study, the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL), which consists of nine U.S. high-volume transplant centers and a data coordinating center responsible for maintaining a clinical database. The A2ALL cohort has now published reports on recipient morbidity, recipient outcomes, comparative outcomes between deceased donor and living donor transplants for HCC, donor evaluation, and donor morbidity, all of which will be discussed later. The study is providing critical information about safety and efficacy, but national registries for all donors and all recipients are needed.

Although ALDLT remains the primary source of LDLT in Asia, the number of centers performing ALDLT in the United States has been decreasing. In 2011 only 25% (27 of 110) adult liver programs performed an LDLT, a significant decrease from several years before. A few programs have high volume, but many perform only a handful of these procedures annually, which places donors and recipients at risk and is discussed further later.

Recipient Selection

Not every patient with end-stage liver disease is an appropriate candidate for, or will benefit from, liver transplantation. To assist in the rational allocation of this scare resource, the United Network for Organ Sharing (UNOS) has established indications and contraindications for potential recipients of a deceased donor liver transplant. In addition, in 2002 UNOS introduced the MELD score for allocation of grafts to adult patients with chronic liver disease awaiting transplantation in the United States. MELD scoring uses a clinical algorithm to rank those who are sick enough to benefit from liver transplant, thereby reducing deaths on the waiting list, but not so sick that they are likely to have a high posttransplant mortality. In contrast to the formal rules that guide allocation of deceased donor livers, allocation of a living donor liver is left to the surgeon or program to make decisions on appropriate recipient selection, often with little oversight. Although this discretionary process is not inherently wrong, it does leave room for poor decision making that may place the donor and recipient at significant risk for little potential benefit.

There are, however, situations in which the living donor option may be preferentially sought. In the current system of regional distribution of deceased donor livers, a wide disparity in waiting times exists between regions and centers. In situations where the waiting time is disproportionately long, because of blood type or geographical location, or because of urgency due to the nature of the patient’s disease (e.g., those with small HCCs and an expected prolonged waiting time for transplant), use of a living donor may be justifiable. In addition, there are some circumstances in which use of a living donor can be immediately lifesaving (e.g., the controversial practice of transplantation of the patient with acute liver failure [ALF] using a living donor graft).

Overall, selection of the recipient for LDLT must optimize the expected recipient benefit. The graft-to-recipient weight ratio should be sufficiently large to provide enough hepatic mass and avoid the small-for-size syndrome. LDLT should not be used as a salvage operation in those situations that have a low 1-year patient survival.