One of the most important problems for patients

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1 Selection of Donors and Recipients for Living Donor Liver Transplantation Key Points 1. Living donor liver transplantation (LDLT) is increasingly used for adults with end-stage liver disease. 2. Standards for acceptable rates of donor morbidity, and even mortality, must be evaluated in the context of recipient risk of dying while on the waiting list and outcome after transplantation. 3. Use of our current criteria in Colorado for selection of donors and recipients indicated that 15% of recipients could undergo LDLT. (Liver Transpl 2000;6:S52-S58.) One of the most important problems for patients listed for liver transplantation is the lack of sufficient donor organs. Over the past 10 years, the number of patients listed for liver transplantation has increased more than 15-fold, with more than 15,000 patients currently listed in the United States. 1 However, the number of available donor livers has increased only 3-fold in the past 10 years. Because of the worsening shortage of donor livers, the median waiting time for US liver transplants has increased from 34 days in 1988 to 496 days in As a result, the number of patients dying while on the liver transplant list has increased from 196 in 1988 to 1,317 in With more patients dying awaiting a donor organ, there is a growing incentive to develop novel strategies to increase the availability of donor livers. One possible solution is the use of living donor orthotopic liver transplantation (LDLT). In this procedure, the native liver of the recipient is removed and replaced with a portion of the liver from a living donor. Although LDLT using the lateral segment of the left hepatic lobe is a common therapy for children in the United States, the small size of the graft has limited its use in adults. LDLT in adults using the right hepatic lobe provides a larger graft and overcomes concerns about small graft size. The current critical shortage of adult donor organs has stimulated several US From the Division of Gastroenterology and Hepatology, University of Colorado Health Sciences Center, Denver, CO. Address correspondence to, MD, Division of Gastroenterology and Hepatology, University of Colorado Health Sciences Center, 4200 E 9th Ave, B-158, Denver, CO Telephone: ; FAX: ; james.trotter@uchsc.edu Copyright 2000 by the American Association for the Study of Liver Diseases /00/ $3.00/0 doi: /jlts transplant centers to use the right hepatic lobe for LDLT in selected adult recipients. 2-5 The initial success of this surgery has led to an interest in LDLT at an increasing number of liver transplant centers in the United States. This article outlines our program s strategy toward the appropriate selection of donors and recipients for LDLT. Potential Advantages of LDLT The greatest of several potential benefits for the recipient with LDLT is the possible reduction in waiting time for transplantation. A shorter waiting time might mean that more patients could undergo transplantation before they die, thus reducing the number of deaths on the waiting list. In addition, a reduced waiting time may decrease the risk for clinical deterioration before transplantation, which could improve the success of the transplant. A recent analysis of adult living donor liver transplant recipients from the United Network for Organ Sharing (UNOS) showed a 40% reduction in waiting time for adult living donor liver transplant recipients between 1998 and 2000 compared with cadaveric transplant recipients over the same time. 1 Another potential advantage of LDLT is that surgery is often elective, usually not performed on an urgent or emergent basis. As a result, the evaluation for LDLT can be accomplished in a few days, after which surgery may be scheduled. Even more urgent evaluations have been performed within hours in the setting of fulminant hepatic failure. 6 Consequently, the medical conditions of the recipient and donor can be stabilized or improved before surgery, thus increasing the likelihood of a successful transplant. A third advantage is the quality of the donor organ. The liver from a living donor may be of better quality because it is harvested from a healthy person. The potential donor may also undergo extensive testing to rule out medical illness in the donor and abnormalities of the donor organ. Conversely, by definition, a cadaveric donor organ is harvested from a patient who has recently died. The donor frequently is maintained for days on mechanical ventilation and vasopressor therapy, with a critical illness that may compromise the function of the cadaveric liver. The next advantage is that the donor liver experi- S52 Liver Transplantation, Vol 6, No 6, Suppl 2 (November), 2000: pp S52-S58

2 Donor and Recipient Selection for LDLT S53 ences minimal cold ischemic time because implantation occurs immediately after harvesting from the donor. From this standpoint, the liver from a living donor may be superior compared with the cadaveric donor. Finally, the use of a live donor adds another liver to the donor pool, allowing a cadaveric liver to go to another recipient. This could potentially shorten the waiting time and improve survival for recipients of cadaveric donor livers. Since the inception of the LDLT program at our center, the median waiting time for cadaveric UNOS status 2B recipients has decreased 27%, whereas the median waiting times for similar patients in the United States has increased 11% over the same period. 7 Potential Disadvantages of LDLT Even with the recent widespread application of LDLT in the past 2 years, only a fraction of all adult liver transplantations performed in the United States use living donors. Between January 1998 and June 2000, UNOS recorded only 213 adult living donor liver transplant recipients, whereas more than 10,000 cadaveric transplantations were performed during the same period. 1 Because a relatively small number of adult LDLTs have been performed, the full extent of the risks to the recipient and donor are not completely known. In addition, there are no long-term follow-up data for recipients or donors of this procedure because adult-to-adult right hepatic lobe LDLT has been performed for less than 5 years. The most important determinant in donor and recipient outcome is the experience and skill of the surgical team. Therefore, LDLT should only be performed in transplant centers in which the surgeons are vastly experienced in liver transplantation and major liver surgery. The ultimate impact of LDLT as an accepted treatment modality for patients with end-stage liver disease will depend largely on the morbidity and mortality rate of the donor right hepatectomy, as well as recipient outcome. Over the past year, several physicians have raised concerns regarding the safety and ethics of LDLT However, before a rational debate about LDLT can occur, there must be an accurate, comprehensive assessment of all complications for living liver transplant donors and recipients. Toward this end, the transplant community has recently launched an initiative through the American Society of Transplant Surgeons to generate a national database to record the outcomes for all donors and recipients of living donor liver transplants. For the recipient, the greatest risks are identical to those of conventional liver transplantation, i.e., surgical complications, infection, and rejection. To date, patient and graft survival for living donor liver transplant recipients has not been different from cadaveric recipients. In the survey of North American transplant centers by Renz and Busuttil, 12 survival for living donor liver transplant recipients was 180 of 208 patients (87%), similar to that of cadaveric transplantation. 12 LDLT patient and graft survival rates at the University of Colorado were 23 of 25 patients (92%) and 21 of 25 grafts (84%). 3,13 At the Medical College of Virginia, patient survival was 35 of 40 patients (88%), and graft survival was 34 of 40 grafts (85%). 3 Despite these favorable outcomes, several risks are inherent to LDLT. Although hepatic regeneration in the transplanted graft occurs very quickly, the living donor liver transplant recipient usually receives a smaller hepatic mass compared with a cadaveric transplant and therefore does not have as much hepatic function or reserve until the transplanted lobe regenerates to full size. However, rarely has this caused clinical problems. Marcos et al 14 reported the increase in mean liver mass in living donor liver transplant recipients 7, 14, 30, and 60 days posttransplantation. Recipients showed an increase in liver graft size of 87% at 7 days posttransplantation, from 862 ml at the time of donation to 1,614 ml at day 7. Remarkably, the graft reached 94% of its final regenerated volume by postoperative day 7. The transplant recipient may also incur a greater chance for biliary complications; the most common is a bile leak from the cut parenchymal surface of the graft. However, most are treatable with either a surgical or percutaneous approach. Biliary complications in LDLT have been recorded in a recent survey by Renz and Busuttil. 12 Of 208 reported LDLTs, 37 patients (18%) developed biliary complications, including 7 strictures, 4 anastomotic leaks, and 26 parenchymal leaks. The number of biliary complications at the University of Colorado 13 was 8 of 25 LDLTs (32%), and at the Medical College of Virginia, 7 of 40 LDLTs (18%). 3 Most donors undergo successful right hepatectomy without complications. In the survey by Renz and Busuttil, donor complications in 208 procedures (8%) were reported, including 6 biliary complications, 3 pressure ulcers, and 1 each of pulmonary embolus, incisional hernia, pneumonia, bowel obstruction, aborted donor, phlebitis, atelectasis, and death. Fan et al 15 published their experience with donor complications in 22 right hepatic lobe donor graft surgeries. Five patients (23%) developed complications, including wound infection, biliary stricture, cholestasis, peroneal nerve palsy, and small-bowel obstruction. All donors completely recovered and have returned to

3 S54 work. At our institution, 6 of 25 donors (24%) developed the following complications: bile leak (2 donors), incisional hernia (1 donor), transient neuropraxia (1 donor), reoperation for drainage tube retrieval (1 donor), and transient encephalopathy (1 donor). 16 All donors have fully recovered and returned to their predonation occupations and activities. At the Medical College of Virginia, 7 of 40 donors (18%) experienced reported complications, including intraoperative pressure ulcers (3 donors), phlebitis (1 donor), prolonged ileus (1 donor), and atelectasis (2 donors). 3 The donor is left with approximately half or less of their hepatic mass immediately after hepatectomy; however, rarely is there clinical evidence of hepatic insufficiency other than a prolonged prothrombin time, elevated serum aminotransferase levels, and increased bilirubin level, which normalize after 1 week. 4 The greatest concern for donor safety is the risk for donor death. As noted, 1 death was recorded in 208 donor surgeries (0.5%) in the survey by Renz and Busuttil. 12 Selection of Recipients The initial evaluation for living donor liver transplant recipients is identical to that for conventional liver transplantation. All recipients considered for LDLT must qualify for conventional transplantation because retransplantation immediately after LDLT would require the use of a cadaveric donor. The selection of appropriate recipients for living donor liver transplants is an evolving process and differs among centers. LDLT has been performed in patients with UNOS status 1, 2A, 2B, and 3. In patients with acute liver failure (UNOS status 1), progression to death occurs over the course of a few days or weeks. In this setting, the evaluation of potential donors must be performed within a few hours or days, depending on the condition of the recipient. LDLT has been performed successfully in this setting. However, less than 5% of all liver transplantations are performed for patients with fulminant hepatic failure. Although the use of LDLT in this setting is dramatic, the relative impact of LDLT is limited because of the small fraction of liver transplantations performed for fulminant hepatic failure. As experience has grown, some transplant centers performing LDLT have found an increased incidence of complications and mortality for status 2A recipients compared with status 2B or 3 patients. 3 As a result, these critically ill patients may be better suited for expedited cadaveric transplantation instead of LDLT. There is currently no consensus about the selection of status 2B and 3 patients for LDLT. At our center, we believe LDLT should be offered primarily to status 2B patients. These patients are at the greatest risk for dying before a cadaveric donor organ becomes available. Consequently, the risk undertaken by the donor is balanced by the risk for recipient death without LDLT. In addition, 1-year survival for status 3 patients is not improved by transplantation. Other centers believe that the selection criteria for LDLT should be routinely extended to include status 3 patients. 3 They argue that less sick patients have the best chance for survival after transplantation. Furthermore, transplantation of status 3 patients may prevent future clinical deterioration and cadaveric transplantation. Patients with hepatocellular carcinoma (HCC), the most common malignancy in liver transplant recipients, pose a special problem. Once HCC is diagnosed in a potential liver transplant recipient, the patient may develop progressive malignant disease to the point that liver transplantation is contraindicated (tumor size 5 cm, 3 hepatic tumors, or metastatic disease). Although UNOS has recently changed its guidelines to increase the priority of patients with HCC, many patients still do not survive long enough to undergo transplantation. The advantage of LDLT in the setting of HCC is that the transplantation could be performed before the malignancy spreads. Therefore, patients with HCC with limited tumor burden (tumor size 5 cm, 3 tumors, and no evidence of malignant disease) may be considered for LDLT. LDLT may be the best treatment option for an increasing number of patients with cirrhosis with small hepatomas. The current relative contraindications for living donor liver transplant recipients vary among centers. At our center, we have excluded some patients for consideration for LDLT. Although all these patients were deemed suitable for a cadaveric transplant, they were rejected for LDLT because of a comorbid condition(s) that could jeopardize the success of the LDLT. These included advanced age, significant medical comorbid conditions, obesity, or patients with marginal psychosocial function. Of 100 potential living donor liver transplant recipients evaluated at our center between 1997 and 1999 (Fig. 1), 33 patients (33%) were rejected for the following recipient issues: medical comorbidity (15 patients), high-risk psychosocial (8 patients), obesity (7 patients), and retransplantation (3 patients). 17 Eighteen more patients (18%) were not considered for LDLT for the following reasons: unable to gain financial approval for LDLT (6 patients), refused LDLT evaluation (4 patients), and imminent cadaveric transplantation (8 patients).

4 Donor and Recipient Selection for LDLT S55 Figure 1. Outcome of 100 potential recipients evaluated for LDLT. Only 25 of the remaining 49 patients (50%) were able to identify a suitable donor for evaluation. The reasons patients did not have donors were often multifactorial, including no children, spouse, family member, or friend aged between 18 and 60 years; estrangement from family and/or friends; incompatible blood type; and obvious contraindication in the potential donor (active drug abuse, known severe medical problem, or massive obesity). With greater experience, the recipient selection criteria for LDLT may be broadened to include patients with medical comorbidities. However, in our experience, the majority of potential living donor liver transplant recipients listed for cadaveric transplants are unable to undergo LDLT because of medical comorbidities or the inability to identify a donor for evaluation. These factors may limit the widespread application of LDLT. Selection of Donors The potential living liver transplant donor must be in excellent medical and psychological condition. The specific tests and sequence of testing vary among centers. At our institution, we have 3 phases of donor evaluation (Table 1). First, potential recipients are identified, and financial clearance is obtained from the recipient s insurance carrier. The recipient may then accept volunteer potential donors with an identical or compatible blood type. The way in which potential donors are recruited for evaluation is important. The donor s decision to donate should be entirely voluntary and without direct or implied coercion of the donor by the recipient or transplant team. However, potential donors need to be aware that LDLT is a viable procedure for selected patients listed for liver transplantation. At our program as part of the evaluation for conventional transplantation, we make all potential conventional liver transplant recipients aware of the possibility of LDLT. This issue is discussed with them, and they are given appropriate literature regarding this procedure. If a potential donor is interested in pursuing LDLT, he or she must then voluntarily contact the transplant center. Potential donors are initially screened by an experienced hepatology nurse to determine obvious contraindications for donation. The following information is obtained from the potential donor: blood type; age; height; weight; brief medical, surgical, and psychiatric history; current medications; current smoking status; and nature of the relationship with the recipient. Screening laboratory tests are obtained (serum electrolyte levels, complete cell count, liver function tests, hepatitis C antibody, hepatitis B surface antigen, and hepatitis B core antibody). The results of the initial screening tests are then reviewed by the transplant team to determine whether further evaluation is warranted. Potential donors who pass this initial screening process are then offered complete donor evaluation. The second phase of evaluation determines whether the potential donor is medically, surgically, and psychologically fit to donate. The initial medical evaluation of the potential donor is performed after the potential donor has called to schedule an appointment. This evaluation should be performed by a transplant hepatologist so that the risks and benefits of donation and transplantation may be fully explained to the donor. During this evaluation, a complete medical history and physical examination are performed, as well as an electrocardiogram, chest radiograph, and the blood tests listed in Table 1. If potential donor is found suitable after this phase of evaluation, the patient is scheduled for surgical, anesthesia, psychosocial, and psychiatric evaluations and abdominal magnetic resonance imaging. Some potential donors require a third phase of evaluation, which includes tests to follow up potential abnormalities discovered during routine evaluation: endoscopic retrograde cholangiopancreatography, angiogram, liver biopsy, etc. At our center, we perform a liver biopsy only if there is concern about the donor s liver. The potential recipient and donor are then presented to the Transplant Selection Committee to determine ultimate suitability for LDLT. If both donor and recipient

5 S56 Table 1. Evaluation Phases for LDLT Phase 1 Recipient 1. UNOS status 1, 2A, 2B, or, at some centers, 3 2. Financial clearance for LDLT 3. Absence of significant contraindication (morbid obesity [recipient weight 130% of ideal body weight]; severe medical problem compromising outcome [pulmonary hypertension, previous CABG, etc]) 4. Psychosocially stable 5. Age 65 yr Donor 1. Age 18 and 60 yr 2. Identical or compatible blood type with recipient 3. Absence of previous significant abdominal surgery 4. Absence of major medical problems (diabetes; severe or uncontrolled hypertension; hepatic, cardiac, renal, or pulmonary disease; or active infection) 5. Demonstrable, significant, long-term relationship with recipient 6. Blood type; normal liver function test results; serum electrolyte levels; complete blood count with differential cell count; negative hepatitis B surface antigen, hepatitis B core antibody, and hepatitis C antibody 7. Absence of alcohol or illicit substance abuse Phase 2 1. Complete medical history and physical examination of potential donor 2. Laboratory tests (serum ferritin, iron, transferrin, ceruloplasmin, alpha 1 -antitrypsin level and phenotype; rapid plasma reagin, thyroid-stimulating hormone, cytomegalovirus antibody [IgG], Epstein-Barr virus antibody [IgG, IgM], antinuclear antibody, human immunodeficiency antibody), toxicology/substance abuse screen, urinalysis, blood oxygen saturation 3. Chest radiograph 4. Electrocardiogram 5. Formal surgical evaluation of donor 6. Anesthesia preoperative evaluation 7. Magnetic resonance imaging of the liver, biliary system, and hepatic vasculature Phase 3 Other tests or consultations to clarify potential problems uncovered during evaluation (endoscopic retrograde cholangiopancreatography, hepatic angiogram, liver biopsy, echocardiogram, stress echocardiogram, etc) Abbreviations: CABG, coronary artery bypass grafting; IgG, immunoglobulin G. are considered appropriate for LDLT after this evaluation, the transplantation is scheduled, usually within a few weeks of the evaluation. At our center, 15 of 25 identified donors (60%) who were evaluated ultimately were approved for donation. 17 The psychological and social issues related to LDLT donation are particularly relevant. The most important consideration is that the decision to donate must be entirely voluntary. At our institution, all potential donors are evaluated by a social worker and psychiatrist, whose primary goal is to ensure that the donation is voluntary. In addition, it is important to discover psychiatric and/or social problems in the potential donor that could influence their decision to donate or their postoperative course. The social worker and psychiatrist who perform this evaluation should be members of the transplant team and must be experienced in the assessment of liver transplant recipients so they can assess the patient in the context of the particular psychosocial demands of liver transplantation. Although most donors are first-degree relatives of the recipient, this is not a requirement. The potential donor must have a demonstrable, long-term, significant relationship with the recipient. Potential donors include spouses, first-degree relatives (parents or children), second-degree relatives (e.g., cousins, grandchildren, or grandparents), long-term friends, or steprelatives. Becoming a living organ donor may have both positive and negative psychosocial effects on the donor. Although the donor may gain psychological benefit from helping the recipient, potential negative psychosocial aspects of donation must be considered during donor evaluation. These include indirect costs of dona-

6 Donor and Recipient Selection for LDLT S57 tion (transportation to the transplant center for medical evaluation and care, lodging, and lost wages), stress on the donor and donor family, change in body image, and inability to work for at least 4 to 8 weeks after donation. The recipient s insurance carrier pays for all medical expenses related to the donor surgery for the donor. Currently, almost all third-party payers approve LDLT. However, in most cases, the process to gain approval for LDLT is separate from conventional transplantation. Insurance carriers often require data justifying the efficacy of this new procedure before approving the transplantation. This often requires significant time and effort on the part of the financial coordinator of the liver transplant team. The time to obtain financial approval for LDLT can take up to several months and may add to the waiting time on the list for the recipient. However, if LDLT becomes a more routine procedure, the financial approval process will likely occur more quickly. Many insurers already have a policy of comprehensive approval for conventional transplantation or LDLT, whichever surgery is indicated for the recipient. The cost of LDLT compared with conventional transplantation is unknown. However, preliminary data from our center and the Medical College of Virginia have shown that the cost of organ acquisition and LDLT is similar to cadaveric transplantation. 18,19 A comprehensive cost comparison between these 2 procedures will be reported when more LDLTs have been performed. Potential Impact of LDLT on Liver Transplantation Based on the successful preliminary results of adult LDLT at a few centers, there has been rapid acceptance and great excitement about the potential widespread application of this procedure. The impact of adult LDLT on liver transplantation will depend largely on the success and safety of donor and recipient surgery, as well as the proportion of cadaveric recipients deemed suitable for LDLT. For widespread acceptance of adult LDLT, graft and patient survival must be similar to those of cadaveric transplantation. In addition, the morbidity and mortality of right hepatic lobe donors must be minimized. It is our opinion that the most appropriate recipients for adult living donor liver transplants are patients with decompensated advanced liver disease (Child-Turcotte-Pugh score 10) or acute hepatic failure. Recipients should be without significant comorbidities that could compromise patient and graft survival. Using our current selection criteria, only approximately 5% of the patients listed for cadaveric transplants are ultimately able to undergo LDLT (Fig. Figure 2. Potential impact of LDLT on liver transplantation. 2). However, with greater experience, the indications for living donor liver transplant recipient selection may broaden to include a greater proportion of patients currently listed for cadaveric transplantation. There are many areas for future investigation in LDLT. The most important issue is a comprehensive analysis of the complications of living liver transplant donors and recipients. In addition, the impact of LDLT on waiting list mortality needs to be measured. A consensus regarding the selection of recipients based on severity of illness (UNOS status 2a v 2B v 3) needs to be developed based on outcome data for these patients. A comprehensive comparison of the expense of LDLT versus cadaveric transplantation should be performed. Such an analysis should compare the sum of pretransplantation, transplantation, and posttransplantation care. LDLT may reduce the expense of pretransplantation care by shortening the waiting time before transplantation. LDLT has rapidly emerged as a viable treatment option for selected patients listed for cadaveric

7 S58 transplantation. The continued careful application of LDLT in adults could help partially alleviate the current organ shortage and reduce the number of patients dying while awaiting cadaveric liver transplantation. References 1. United Network for Organ Sharing, Scientific Data Registry, Data, Marcos A. Right lobe living donor liver transplantation: A review. Liver Transpl 2000;6: Marcos A, Ham JM, Fisher RA, Olzinski AT, Posner MP. Single-center analysis of the first 40 adult-to-adult living donor liver transplants using the right lobe. Liver Transpl 2000;6: Marcos A, Fisher RA, Ham JM, et al. Right lobe living donor liver transplantation. Transplantation 1999;68: Wachs ME, Bak TE, Karrer FM, et al. Adult living donor liver transplantation using a right hepatic lobe. Transplantation 1998; 66: Bak T, Everson G, Wachs M, et al. Living-donor liver transplantation for adults with fulminant hepatic failure (FHF): An underutilized resource [abstract]? Liver Transpl Surg 1999;5:C Trotter JF, Wachs M, Bak T, Trouillot T, Everson GT, Kam I. The effect of living donor liver transplantation on the waiting time of cadaveric UNOS status 2B patients at one center [abstract]. Hepatology 2000 (in press). 8. Lee KH, Tan KC. Whither living donor liver transplantation? Liver Transpl 2000;6: Strong RW. Whither living donor liver transplantation? Liver Transpl Surg 1999;5: Fan ST. Donor safety in living donor liver transplantation. Liver Transpl 2000;6: Hirano I, Blei AT. Deaths after living related liver transplantation. Liver Transpl 2000;6: Renz J, Busuttil RW. Results of living donor liver transplantation: Survey of North American liver transplant centers. New Engl J Med 2000 (submitted). 13. Wachs M, Bak T, Trotter JF, et al. Right hepatic lobe living donor liver transplantation: Results of 25 cases [abstract]. Hepatology 2000 (submitted). 14. Marcos A, Fisher RA, Ham JM, et al. Liver regeneration and function in donor and recipient after right lobe adult to adult living donor liver transplantation. Transplantation 2000;69: Fan ST, Lo CM, Liu CL, Yong BH, Chan JK, Ng IO. Safety of donors in live donor liver transplantation using right lobe grafts. Arch Surg 2000;135: Bak T, Wachs M, Trotter J, et al. Adult donors of right hepatic lobes for living donor liver transplantation: Results of first 16 patients [abstract]. Transplantation 2000;69:S175A. 17. Trotter JF, Wachs M, Trouillot T, Steinberg T, Bak T, Everson GT, Kam I. Evaluation of 100 patients for living donor liver transplantation. Liver Transpl 2000;6: Ham JM, Marcos A, Fisher RA, et al. Is living donor liver transplant cost-effective [abstract]? Transplantation 2000;69:S175A. 19. Trotter JF, Wachs M, Trouillot T, et al. A comparison of charges for organ acquisition: Cadaveric vs adult living donor liver transplantation [abstract]. Transplantation 2000;69:S175A.