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Living Related Liver Transplantation: The Ultimate Technique to Expand the Donor Pool?

Schemmer, Peter; Mehrabi, Arianeb; Friess, Helmut; Sauer, Peter; Schmidt, Jan; Büchler, Markus W.; Kraus, Thomas W.

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doi: 10.1097/01.tp.0000187132.49178.ec
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Abstract

More than 20,000 patients worldwide have undergone liver transplantation (LT) since 1963 and survival rates achieved by world standard units are greater than 85% at 1 year and 70% at 5 years (United Network Organ Sharing [UNOS]). The current situation of LT is marked by a dramatically increasing number of patients on the waiting list and the severe shortage of cadaveric livers. Since 1997 the number of LTs per year has reached a steady state, whereas the number of newly registered patients on the waiting list is still increasing (European Liver Transplant Registry [ELTR]). As a consequence the waiting time for LT has also increased steadily each year, rising from approximately 1 month in 1988 to more than a year in 1999. Currently, more than one-third of patients in the United States wait longer than 2 years for a liver graft (Organ Procurement and Transplant Network [OPTN]/ Scientific Registry of Transplant Recipients [SRTR]; http://www.ustransplant.org). This results in more patients being critically ill and hence becoming unsuitable for LT or them dying as a cause of deteriorated general conditions while being listed for LT. Today every sixth patient who needs a liver graft dies while waiting for LT. According to data of UNOS more than 17,000 patients have been listed for LT in early 2004. Each year about 9,000 new cases are added to the list, but only 5,000 cadaver livers are available for transplantation (UNOS). Cadaver donor organ availability appears to have reached a bottleneck state despite all the efforts to increase organ donation. Thus the gap between the number of patients in need of a liver graft and the number of organs donated has widened greatly. This impetus led to the development of living donor liver transplantation (LDLT) during the last few years, allowing an enhancement of the organ pool and consequently enabling the performance of a timely acceptable LT.

The feasibility of LDLT was first demonstrated in the United States in 1989 (1). The recipient was a child, who received the left lateral segments of its mother’s liver. Since this first operation, LDLT in children has been very successful. Survival/graft survival after pediatric LDLT is about 92%/90% and 89%/86% after 1 and 5 years, respectively. Live donors for pediatric LT have only very few complications (2,3). The experience gathered from pediatric LDLT and the increasing shortage of cadaveric livers for adults led surgeons to establish adult-to-adult LDLT, a procedure that began in 1994 and has been more widely applied over the past two years (4). Adult-to-adult LDLT is a very complex surgical procedure requiring careful surgical techniques protecting of the donor’s health and welfare (5). Either the full right side or the full left side of a liver from a healthy adult live donor is used as a graft for these recipients. Appropriate donor selection requires experience on the part of the entire transplant team, which is mainly comprised of transplant surgeons, hepatologists, psychiatrists, social workers, nursing staff, and transplant coordinators (6).

Until today, LDLT has had little impact on reducing mortality for the adult patients on the waiting list and most likely will not solve the problem of organ shortage in the future. Thus, despite all technically demanding surgical effort, the scarcity of cadaveric donors still remains an insurmountable problem limiting the application of LT.

Morbidity and Mortality After Live Liver Donation

Indeed LDLT is an option for transplant candidates who will die without a timely LT to obtain an optimal graft during an electively scheduled transplantation with (at least in theory) fewer complications, faster recovery, and better long-term outcome than cadaveric liver transplantation (CLT) (7). The safety of the donor is the first priority during the whole procedure of LDLT. Therefore, despite the acceptable results of LDLT, considerable debate persists concerning donor safety. Risks to the donor include those associated with invasive presurgical testing, surgical procedures, and postoperative care. It is very important that potential donors receive accurate and complete information on the risks of donor surgery (3,8–14). Reported complications in donors include pleural effusion, biliary problems, intraperitoneal abscess, bleeding, and infections (2,3,8–18). Most complications are minor and resolve on their own. In rare cases, the complications are serious enough to require another surgery, intervention, or medical treatment (3,8–16). Today, the risk of death from donor surgery performed in the United States and Europe is about 0.3% (19,20) and <1% (21,22), respectively. The death of a donor in New York in 2002 led to the scrutiny of the ethical and medical issues surrounding this procedure. As a result there was a 50% drop in the number of LDLT procedures and a decrease in the number of centers that perform this procedure (OPTN/SRTR). Lee et al. showed that the total complication rate in liver donors was 13.5%, which was relatively lower than that in previous reports (23). This wide range of complication rates undoubtedly results from the difference in the volume of donated liver tissue and the lack of consensus on the definition of a complication (18). Some investigators may have included every minor postoperative complication (3,9–11), while others reported only of severe or life-threatening complications (15,17,24,25). Beavers et al. documented that reported morbidity associated with right lobe donation for LDLT varied widely (0–67%), and they stressed the necessity for standardized definitions of morbidity and better methods for observing and measuring outcomes after liver donation in order to understand and potentially improve morbidity (18). There is strong evidence that the frequency of postoperative complications is significantly higher in right lobe donors compared with left lobe donors or left lateral segment donation (2,10,23). In addition, most complications occurred in the early postoperative period; oppositely, biliary obstructions on the other hand frequently occurred in the late postoperative period. Latter, being a result of injury caused to the left and common bile duct during hepatectomy, may increase the lifetime risk of the donor for developing secondary biliary cirrhosis. The significance of which may not be realized for several decades (26). Although adults do benefit from LDLT, it is not obvious that this fact goes beyond the risk carried by their live donors. In the absence of solid data on this issue, there is an immediate need for national or even international live donor registries. Until the required data are collected and analyzed in favor of LDLT, it can only be assumed that the indications existing for LDLT will be widened greatly and the ultimate potential benefit of LDLT be increased and the donor risks decreased. Thus, extensive discussion is still needed to make the right decision whether LDLT should be performed in each single case.

Based on data available today, the risks taken by live donors can only be justified if the society has done everything possible to provide as many cadaveric grafts as possible. Promising tools to further increase the pool of grafts from brain dead donors (i.e. cadaveric split liver transplantation) the use of nonheart-beating donors and assumed consent for cadaveric organ donation are not established in many centers or the latter two examples being prohibited by law. Further, people are still not sufficiently educated to fully understand that brain death is the end of a human being’s life. Especially lack of knowledge in the latter seems to be a hurdle for organ donation upon brain death.

Risk-Benefit Considerations for Recipients After LDLT

LDLT results in a decreased waiting time and high survival rate on the waiting list for CLT. The risks to which the recipient is exposed to after LDLT are in general comparable to those following CLT, with the exception that surgical complications especially biliary problems have a high likelihood (26–28). In addition, the recipient receives a smaller hepatic mass, but this proves to be a rare problem if a graft-to-recipient body weight ratio (GRBW) of >0.8% is applied (19,29,30). Many reports have focused on the posttransplant outcome and surgical complications for recipients of live donor liver grafts (2,9,31–35); however, the impact of LDLT on waiting-time mortality is not taken into account. Studies that analyzed the fate of patients on the waiting list failed to correlate waiting time with mortality because patients listed preemptively for transplant with early liver disease do not die while waiting (36). Nonetheless, for any given patient with decompensated cirrhosis, increased waiting time for LT is associated with increased mortality (37). A better measure of the overall impact of LDLT on survival may be obtained from the time of listing instead of from the time of transplant (38). Studies that examined posttransplant survival compared outcomes after LDLT and CLT (2,9,31–35), but benefits gained while awaiting LT may not have been considered if waiting time mortality is not analyzed. As waiting times increase for LT so does waiting time mortality. In the U.S., the average waiting time is 468 days with waiting time mortality as high as 20% (39). Thus, LDLT may offer more obvious survival benefits to subgroups of patients who have a long waiting time on the transplant list.

Complications and Small-for-Size Syndrome

Most complications after LDLT are similar to those observed after cadaveric transplantation (26). Several complications are more frequent with a living donor grafts as compared with grafts from deceased donors. In contrast to donor morbidity, recipient complications are abundant; however, up to 30% of recipients have at least one major complication (26). Major complications include hepatic artery thrombosis (HAT), portal venous thrombosis (PVT), hepatic vein obstruction, bile leak, bowel injury, intraabdominal abscess, sepsis, primary graft non-function (PNF), delayed graft function (DGF), major hemorrhage, and rejection. Minor complications on the other hand include incisional hernias and wound infections (11,26,28,30). Compared with adults, less pediatric recipients have complications. Major pediatric complications are bowel injuries during adhesiolysis (40). Graft size problems and biliary complications are usually associated with LDLT (41–43). Biliary complications are rarely a sole cause of graft loss but often lead to other infectious sequelae.

Small-for-size syndrome is observed in recipients after LDLT, which sometimes resolved spontaneously over time. It occurred in 22% of patients with left lobe grafts (44). It can be defined as the presence of persistent functional cholestasis, coagulopathy, intractable ascites, poor synthetic function, and reduced bacterial clearance. Finally, small-for-size grafts most of the time result in poor outcome after transplantation. Grafts with a GRBW of <0.8% show significantly poorer results in patient survival. Most grafts with a GRBW of >0.8–1.0% are associated with a good outcome (19,29,30). However, determining criteria are still unclear and may be affected by many factors such as pretransplant metabolic load, portal hypertension, and latent infection in the recipient. Some recipients of grafts with a standard live volume (SLV) of less than 30% of did not develop small-for-size syndrome, whereas others presented the syndrome even with grafts larger than 40% (19,29,30). Current studies show that the presence of cirrhosis or pretransplantation portal hypertension is an important predictor of developing small-for-size syndrome. The patients with cirrhosis might require a larger graft than those without cirrhosis. Soejima et al. reported that proposed minimum graft volume (GV) in adult-to-adult LDLT should have a GV/SLV ratio of more than 30% for recipients without cirrhosis and more than 45% for patients with cirrhosis (44).

Indications

The ideal candidate for LDLT seems to be a patient who is still in good general condition (UNOS status 2b, 3, and 4), allowing the chances for successful transplantation to be high. Thus, patients with a small hepatocellular carcinoma (HCC) or patients with an underlying liver disease that rarely reaches a high urgency priority on the waiting list would benefit the most from living donation (45,46).

Clinical experience has shown that as LDLT potentially amplifies the donor pool, extending the indication for this procedure is at present more often discussed, including cases of acute decompensation of chronic liver disease, advanced HCC and other primary liver tumors or nonresectable metastases of extrahepatic tumoral origin (47). LT at an early stage of primary liver cancer may result in long-term survival for some patients. It can be argued that patients with advanced HCC or even some patients with metastases may benefit from LDLT by offering them a better 3- and 5-year survival chance than other therapies (39). One should differentiate between marginal indications based on a rational fundament. There should be a substantial benefit to the recipient as opposed to those based on an emotional or heroic attempt to save the recipient’s life at extremes. Thus, extended indications for LDLT remain to be discussed further.

Heidelberg Center Approach to LDLT

We started LDLT at the Department of Surgery, Ruprecht-Karls-University Heidelberg in September 2002 (6,48). Potential candidates for LT according to Eurotransplant criteria were informed on all potential advantages and risks associated with LDLT, laying emphasis on the present risks of morbidity and mortality to the live donors. An extensive and thorough evaluation, as well as restrictive selection of these candidates was performed at our institution by an interdisciplinary team. Postoperative complications such as liver failure, bleeding and biliary complications as well as the risk of dying after live organ donation were extensively discussed with all potential live donors. Further they had to be informed on potential long-term consequences which are not well documented to date since both national and international donor registries are not yet established. Concerning potential long-term consequences following live organ donation a sufficient coverage through health insurance is important. Unfortunately, to date it remains unclear who will financially support these donors in the case of being handicapped with subsequent unemployment in our country. Further, the complex background as to why someone accepts to undergo major abdominal surgery for adult-to-adult LDLT was elucidated carefully. Our institutional evaluation algorithm has been published recently (48). After an evaluation of 100 candidates for LDLT according to our guidelines only 20 eligible candidates were identified for further assessment / check up for LDLT (48). As a consequence, in our unit less than 2% (3/184) of all LTs (domino transplantations excluded) performed in our unit from September 2003 to January 2005 have been living related while in Germany about 11% of all LTs are living related (47).

CONCLUSION

Whether LDLT is the ultimate technique to expand the donor pool remains more than questionable. This technique expands the donor pool today but it most likely will not solve alone the organ shortage in the future. In our opinion, it is a good tool to offer treatment of end-stage liver disease in selected patients; however, one has to be aware of the donor risks.

ACKNOWLEDGMENTS

We thank Genevieve Dei-Anane for helping us edit the manuscript.

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Keywords:

Living related liver transplantation; Organ shortage; Morbidity; Mortality; Controversies

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