Current status of liver transplantation in children

Pediatr Clin N Am 50 (2003) 1335 – 1374

Current status of liver transplantation in children S. V. McDiarmid, MD Division of Gastroenterology, Hepatology, and Nutrition, David Geffen School of Medicine, University of California, Los Angeles, Medical Center, 10833 Le Conte Avenue, Los Angeles, CA 90095-1752, USA

Liver transplantation for children with life-threatening acute or chronic liver disease has proven within two decades to have durable and high success rates [1– 3]. Thousands of children who are otherwise doomed to die currently live and are teaching the consequences of their rescue initiated by a radical, technically demanding surgical procedure and perpetuated by years of nonspecific immunosuppression. The euphoria of the late 1980s and early 1990s—when surgical techniques were refined, patient and graft survivals were escalating, waiting lists were shorter, and the long-term consequences of immunosuppression were less apparent—is currently countered by sobering concerns. In particular, two critical issues face the transplantation community: the crisis in donor supply [4,5], which is fueling the debate over how organs should be rationed, and the long-term complications of immunosuppressive therapy, including the risk of malignancy. Both of these domains of concern contain within their broader territories unique challenges for pediatric liver transplant patients. How are children to compete with the ever-increasing number of adults awaiting transplantation? Is it ethically correct to promote living donor transplantation as a solution? On the other end of the spectrum, assuming that a transplant occurs, what are the consequences of exposure to decades of immunosuppression, as is likely for children? What are the risks of de novo malignancy, renal failure, and long-term central nervous system toxicity for a 40-year-old person who received a transplant at the age of 1 year? This article focuses on current results of liver transplantation in children in the context of these two central themes and discusses new ideas that may enhance the future of children after liver transplantation.

E-mail address: [email protected] 0031-3955/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0031-3955(03)00150-0

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Donor supply The success of liver transplantation, proven convincingly in the 1990s, coincided with two other events in hepatology that have affected profoundly the number of patients currently considered eligible for liver transplantation. The first was the characterization of the hepatitis C virus [6] and with it the realization that increasing numbers of patients suffered from hepatitis C-related end-stage liver disease. The second was the success of liver transplantation as treatment for selected patients with hepatocellular carcinoma, who were previously managed either by resection or medical therapy [7]. Both conditions are linked, because many patients with hepatitis C also develop hepatocellular carcinoma, and both have high rates of recurrence after transplantation, which makes such candidates potential consumers of more than one liver graft. Although neither of these events in themselves seems relevant to pediatric liver transplant candidates, the increasingly disproportionate number of adults compared with children on the liver waiting list affects a pediatric candidate’s chance of being allocated an organ. In the United States, adults currently outnumber children by 15 to 1 on the United Network of Organ Sharing (UNOS) liver waiting list [5]. The essential issue for children is their access to transplantation. Paradoxically, although children younger than 5 years still have the highest mortality rate on the liver waiting list compared with other aged ranges and represent 46% of all children listed [8], they are the candidates considered to have two advantages for receiving a donor organ. They can be considered recipients of living donor grafts or cadaveric technical variants. That is, they can receive either a split graft, in which one liver is surgically divided to provide two transplantable segments, or a reduced segment (one liver for one recipient with discard of the remaining liver) [9]. Generally speaking, a pediatric recipient receives a left lobe or, more commonly, a left lateral segment from any of the partial liver graft techniques. Fig. 1 shows how the distribution of donor type (whole, living, or partial cadaveric) varies with recipient age for 1092 children who received a first liver transplant in the Studies of Pediatric Liver Transplant (SPLIT) registry [10]. The impetus for developing living donor liver transplantation [11] was the increasing number of children who were dying on the waiting list [9]. As a result, pediatric transplant programs with the option of performing living donor liver transplants have shown a decrease in the mortality rate of children who are awaiting liver transplant at their centers [2,12]. The success of pediatric living donor liver transplantation is well established worldwide. The Kyoto series, the largest in the world, is driven by virtually nonexistant cadaveric supply. Unlike results from North American and European pediatric liver transplant programs, which have the advantage of selecting recipients for living donor operations, the Kyoto results reflect all patients. The Kyoto series shows excellent and comparable patient and graft survival rates, 81% and 79% at 5 years, to the overall results of cadaveric pediatric liver transplantation [13]. In another large series, Reding et al [14] reported a 7-year experience with living donor transplants in children, which showed 1- and 5-year survival rates of 92% and 89% for patients

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Fig. 1. Donor type by recipient age at first transplant on registry. The donor graft type—whole, living, or partial cadaveric—is shown for recipient age ranges for 1092 children who received a first transplant in the SPLIT database. (From McDiarmid S, Anand R, SPLIT Research Group. Studies of pediatric liver transplantation: 2002 update. Pediatr Transplant, in press; with permission.)

and 90% and 86% for grafts, respectively. The same author also showed that 1-year patient and graft survival rates for cadaveric recipients, 87% and 75% respectively, were not significantly different compared with living donor recipients, 92% and 90%, respectively. From registry data, the outcome of whole cadaveric transplants compared with living donor transplants in children is comparable [10]. Although biliary complications may be more common than in living donor compared with whole organ transplants, these usually do not impact on patient or graft survival [15]. The success of the living donor procedure is not in question, and the ability to electively perform the operation before the patient deteriorates and have no impact on the cadaveric donor pool are compelling reasons to convince people that living donor liver transplantation is the solution to at least some of the pediatric donor shortage problem. The ethics of this procedure, which were enunciated carefully at the inception of living donor liver transplantation, still deserve careful scrutiny, particularly in countries in which cadaveric transplantation is an option [16,17]. The donor is most often a parent—a healthy young adult with responsibilities vital to the maintenance of the family. In one study, 41% of living donors experienced financial disadvantages [18]. Although the risk of morbidity and mortality from this procedure has been low to date, it is still measurable. The number of living donor deaths remains disputed; an editorial written in 2000 placed the number worldwide at six [19], with only one reported [20]. Although most of these deaths have been in adult-to-adult living donation,

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in which the donor provides a larger liver segment, the cause for alarm is not mitigated, because these donors are also believed to be highly selected, healthy, and usually young adults. Currently in countries with the option of using cadaveric donors, the role of pediatric living donor liver transplantation varies from center to center and is defined by an individual program’s philosophy. In some programs, living donation is reserved only for patients with chronic liver disease who are deteriorating rapidly despite exhaustive attempts to find a cadaveric organ or patients with fulminant liver failure. In other programs, parents are offered the choice of living donor liver transplantation at the evaluation visit, and subsequently a large proportion of children who receive transplants at such programs are recipients of living donor grafts. It remains unclear whether a more commonly accepted principle governing the practice of living donation in liver transplantation will emerge. In the interim, it is of paramount importance that databases are developed and rigorously maintained to register every living donor operation, all complications, and particularly the longterm outcome of the donor [21 – 23]. The use of technical variant cadaveric grafts poses fewer ethical dilemmas. Large pediatric programs spearheaded these techniques as the donor shortage problem became more acute in the early 1990s. de Ville de Goyet et al [24] were one of the first to report that mortality on their pediatric waiting list could be reduced substantially after implementing reduced liver transplantation. After this report, results using the split technique, which previously was associated with relatively poor outcome [25], improved [26,27], with many researchers advocating the advantages of in situ rather than ex situ splitting of the liver. Further understanding of variations in the biliary and vascular anatomy of the liver relevant to creating two transplantable segments also advanced the field [28]. By the mid 1990s, excellent results with split liver transplantation were being published [29]. At the University of California, Los Angeles (UCLA), researchers reported a 1-year actuarial graft survival rate of 80% for the left lateral segment and 93% for the right trisegmental graft regardless of urgency at the time of transplant. Subsequently, transplant surgeons urged the abandonment of the reduced size graft, in which the right lobe was discarded. Some reports also suggested that graft survival, both short and long term, was lower for reduced compared with other partial liver grafts [30,31]. Although the split technique, if performed in situ, increases the procurement operating time, no adverse effect on the outcome of other organs has been demonstrated [32]. Importantly, for the split technique to be accepted, outcome in terms of patient and graft survival for recipients of either segment had to be comparable to recipients of whole cadaveric organs. In single center reports, split transplantation has been shown to have equivalent outcomes to whole organ transplants. Recently the Kings College group [33] reported the outcome of a series of 80 consecutive pediatric split liver recipients. The Kaplan-Meier patient survival rates at 1 and 3 years were 93.5% and 88.1%, respectively, and graft survival rates were 89.7% and 86.1%, respectively. Vascular complications occurred in 7.5% and biliary complications in 8.7%. In some series, a higher rate of complications,

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Fig. 2. Kaplan-Meier survival curves show no difference in survival for patients who receive a split graft compared with a contemporary cohort of patients who received a whole organ. 5, whole liver graft; , split liver graft. (From Ghobrial R, Yersiz H, Farmer D, Amersi F, Goss J, Chen P, et al. Predictors of survival after in vivo split liver transplantation: analysis of 110 consecutive patients. Ann Surg 2000;232(3):312 – 23; with permission.)

especially biliary complications, which occur in up to 30%, has been reported [31,34,35]. In the UCLA series, patient survival for split grafts compared with a contemporary cohort of whole graft recipients was not different (Fig. 2), and similarly there was no difference in survival of recipients of the left lateral segment compared with right trisegmental grafts when matched for urgency (Fig. 3) [36]. In the same series of patients, a multivariate analysis showed that the only two factors of significance in predicting survival after split liver transplantation were the urgency status of the patient and the length of hospitalization of the donor. Although transaminases, protime, and bilirubin measurements were higher in the first week after split liver transplantation compared with living donor grafts, graft function after 7 days was not different between the two groups. These authors and others showing similar results [37] have used these good outcome data to support their position that split grafts should be used preferentially

Fig. 3. Kaplan-Meier patient survival curves show no difference in survival for patients who receive either a right or left segmental graft. 5, whole liver graft; , split liver graft. (From Ghobrial R, Yersiz H, Farmer D, Amersi F, Goss J, Chen P, et al. Predictors of survival after in vivo split liver transplantation: analysis of 110 consecutive patients. Ann Surg 2000;232(3):312 – 23; with permission.)

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over living grafts, thus avoiding the ethical issue of donor safety after living donation [38]. Researchers who advocate for increased use of the split technique also point out that this may be the only method available to immediately increase the cadaveric liver donor supply, and they have gone as far as to suggest that every good quality liver donor should be considered as two transplantable liver grafts [39,40]. By some estimates, between 15% and 43% of donors more than 70 kg would be suitable for splitting [41]. The European pediatric transplant database [42] and the UNOS database [43] suggest that patient and graft survival are not equivalent to whole cadaveric transplants for split and reduced organs, however. It seems that the discrepancy between single center reports and registry data is most likely explained by some centers developing a level of experience and excellence in the technique not shared by all pediatric programs attempting the procedure. Improvements in surgical training for transplant surgeons seem an obvious but perhaps difficult solution to achieve on a broad and uniform scale. Unfortunately, the database results have hampered attempts to develop mandatory splitting of every excellent quality liver donor, at least in the United States [44]. Currently, encouraging voluntarily collaboration between centers and surgeons who trust each other’s surgical expertise and donor selection seems to be the only way forward. The proof of this concept was exemplified recently by a report of international sharing of a split liver segment [45]. The split technique has its own ethical controversies. Does the organ ‘‘belong’’ to the patient to whom it was primarily allocated, and does that patient have the right to refuse for it to be split? Or does the organ belong to society, and physicians governed by allocation rules have the custodial responsibility of ensuring that the organ is used in the most beneficial way? A key factor that affects children’s access to transplantation is how they are ranked in relationship to adults on the liver waiting list. In February 2002, a major change was made in how patients in the United States are allocated cadaveric livers. In response to studies that showed that time waiting for transplant did not correlate with survival after liver transplantation [46,47], previous rules that preferentially allocated livers to persons who waited longest within four urgency categories were abandoned. Instead, scoring systems were developed for adults (medical end-stage liver disease score [MELD]) and children (pediatric end-stage liver disease score [PELD]) [48]. The MELD and PELD scores rank patients according to the severity of their disease as measured by their probability of death 3 months after listing. It was decided that only a few verifiable and objective parameters would be included in each score. Extensive multivariate analyses were performed to develop MELD and PELD, and models were designed to test their ability to predict the probability of death accurately 3 months after listing. PELD was developed from data provided by the Studies of Pediatric Liver Transplantation (SPLIT), a consortium of 38 centers in the United States and Canada that provide comprehensive data to the database before and after pediatric liver transplantation. Univariate analyses were performed on 18 factors that might affect death while awaiting transplantation. From factors significant at the univariate level, the non–

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event-based factors were examined in multivariate analyses. These factors were age younger than 1 year, height or weight less than two standard deviations below normal, total bilirubin, serum albumin, International Normalized Ratio (INR), and calculated glomerular filtration rate (GFR). Only the calculated GFR was found to not be significant at the multivariate level. The regression coefficients from the multivariate analyses were used as multiplicative factors in the final PELD equation [49]. For any PELD score, a probability of survival for 3 months after listing can be estimated (Fig. 4). This model showed a more than 80% chance of correctly ranking children with cadaveric liver disease awaiting transplantation by their probability of death 3 months after listing. The PELD score also has been validated in a separate database that shows a similar predictive accuracy [50]. The PELD score has been integrated with the MELD score for listing of all patients with end-stage liver disease who are awaiting liver transplantation in the United States. Several important and as yet unanswered questions remain, however, regarding how this new system will affect pediatric candidates on the liver waiting list. Will the same number of children actually receive organs under the new system? Will the large number of MELD scores compared with PELD scores overwhelm the pediatric patients’ chances of receiving a liver (remembering that if several patients

Fig. 4. The PELD score is shown as a predictor of survival 3 months after listing for liver transplantation. PELD = 0.436; age (<1 year): 0.687 Loge albumin + 0.480 Loge total bilirubin + 1.857 Loge INR + 0.667 growth failure (< 2SD). The computed score is multiplied by 10 to generate the final PELD score.

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have the same score, the one with the longest waiting time is allocated the liver)? Will the patients with hepatocellular carcinoma who can have their MELD score incrementally increased every 3 months become a disproportionately overrepresented population of patients with high scores (but who are not facing imminent death) who will divert pediatric donor livers away from pediatric candidates? Another aspect of liver donor allocation is whether children should have some preference to receive transplants from pediatric-aged donors. Although small pediatric cadaveric donors are only likely to be placed into small children, even a 10-year-old pediatric donor liver can be placed into a suitable adult recipient. In particular, most livers from pediatric donors from the age of 6 to younger than 18 years—often considered ideal donors—are currently most often transplanted into adults, as high as 76.3% in one study [51]. Many of these larger pediatric donor livers are also particularly suitable for the split liver transplant technique. To understand further the effect of exporting pediatric aged cadaveric liver grafts (defined as from donors younger than 18 years) to adult recipients, an analysis of UNOS data was performed [51]. For the years 1992 to 1997, 64% of pediatric aged cadaveric donors were transplanted into adults, which called into question whether children were being penalized. During the study period, researchers showed that the same percentage of children (7%) as adults was dying while on the waiting list, but more importantly, children younger than 1 year still had by far the highest rate of death of any other age group on the UNOS liver waiting list. These disadvantaged small children are ideal candidates for a split graft. One method to increase the practice of split liver transplantation would be to assign preferentially the larger pediatric aged donor livers to small children. Such a policy would detract nothing from the adult donor pool, because the right lobe graft would be used most often in an adult recipient. Further data analyses were performed to investigate the outcome of pediatric aged donors placed into pediatric aged recipients compared with adult recipients. In a multivariate analysis, the odds of graft failure were significantly reduced—0.66 (P < 0.01) if pediatric patients received livers (including split segments) from pediatric aged donors—but donor age had no effect on survival of adult recipients. Further support that pediatric donors should be directed to children came from other studies. One study showed that adult recipients had a worse outcome when they received a transplant from a donor aged younger than 12 years [52], and the European pediatric liver transplant registry showed a significant decrease in survival if children received a liver from a donor aged younger than 6 or older than 15 years [42]. As a result of these findings, some provision is made in the United States liver allocation policy for pediatric recipients to receive preferentially a pediatric donor liver [53]. An adult patient within a given region who is considered to have more urgent status still can override the rule. In Canada, pediatric donor policy is more advantageous to children. Pediatric donors are offered regionally and then nationally to any child on the list regardless of urgency unless there is a competing adult in renal failure or on life support. In Europe, pediatric donors are defined as less than 45 kg and less than 16 kg, and there is some priority in allocating pediatric donor livers to children.

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Patient and graft survival Patient and graft survival after pediatric liver transplantation has shown incremental improvements from the 1980s to the late 1990s. Several large pediatric programs have analyzed their results by era of transplantation [1,54,55]. Goss et al [1] analyzed the UCLA pediatric liver transplant experience and reported that 1- and 5-year actuarial patient survival rates for 256 children who received transplants between 1984 and 1992 were 78% and 75%, respectively, with corresponding graft survival rates of 62% and 56%, respectively. These rates were significantly worse compared with 184 children who received transplants between 1993 and 1997 and whose 1- and 5-year actuarial patient survival rates were 88% and 85%, respectively, and graft survival rates were 76% and 69%, respectively. On further analysis, children who received transplants at less than 1 year of age had the most improvement and in patient and graft survival in comparing the two transplant eras. In a multivariate analysis of this center’s experience, pretransplant patient age, the era of transplantation, and the number of allografts were significant in predicting patient survival rates, whereas allograft type and pretransplant diagnosis were not [1]. Similarly, the pediatric liver transplant program at the Universite´ Catholique de Louvain, Brussels [55] reported a 15% improvement in patient and graft survival between the 1984 to 1987 cohort and the 1995 to 1997 cohort. Five-year survival rate was significantly better in elective transplantation (82%) compared with highly urgent cases (63%). In their multivariate analysis, year of transplant also had a significant impact on survival. The SPLIT registry, which was initiated in 1995, gives an overview of the results of pediatric liver transplantation achievable in the last 7 years. Of 1092 first transplants, the KaplanMeier probability of patient survival at 1 and 3 years was 86.3% and 83.3%, respectively, with corresponding graft survival rates of 80.2% and 75.3%, respectively [10]. While death and graft loss occur less frequently than in the past, their early causes have remained similar over the years. Sepsis is still the most common final pathway to death, frequently predated by technical complications, such as hepatic artery thrombosis or bile perforation, both of which are associated with an increased risk of life-threatening infectious complications. From the SPLIT database of 1092 children undergoing a first liver transplantation, the most commonly reported causes of death were infection (28.3%) and cardiopulmonary complications (17%) [10]. Graft failure within 30 days was caused primarily by postoperative vascular complications (42.9%) and primary graft dysfunction (25.6%). Of the vascular complications, hepatic artery thrombosis is the most important. The consequences of hepatic artery thrombosis—urgent retransplantation, biliary leaks, peritonitis, relapsing septicemia, and biliary strictures—have an adverse effect on patient and graft survival in small children [56,57]. Not all children with hepatic artery thrombosis have a poor outcome, however. In a recent large series of 400 pediatric liver recipients [58], the incidence of hepatic artery thrombosis was 7.8%, and 83% of these children were alive 3.8 years after transplantation. Thirteen of 31 episodes were managed conservatively without retransplantation, and all

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these children are alive, although 5 required intervention for biliary strictures. Early surgical attempts at revascularization were attempted in 4 patients and were successful in 2 patients. Substantial progress has been made in reducing the incidence of hepatic artery thrombosis. The minute diameter of the hepatic artery in small children, which is often less than 3 mm, confronted surgeons with the problem of how to avoid what was predominantly a surgical complication. Microsurgical techniques [59], the operating microscope, and the avoidance of vascular grafts, combined with growing expertise, have been responsible for a drop in the hepatic artery thrombosis rate from 11% to 26% in the 1980s [56,60] to as low at 1.7% in the 1990s [59]. Although various methods of medical management after transplantation, such as anticoagulation, the use of antiplatelet agents, and avoidance of overtransfusion, are practiced commonly, none has proven to be important in the prevention of hepatic artery thrombosis [61 –64]. Cytomegalovirus (CMV) infection of the graft, clotting abnormalities, and immunologic factors have been implicated in the nonsurgical causes of hepatic artery thrombosis [65]. Bowel perforation is an especially feared complication after liver transplantation because of the high risk of overwhelming gram-negative sepsis. Previous abdominal surgery increases the risk of bowel perforation, which was associated in one study with a 50% mortality rate after one perforation; the rate increases to 78% after multiple perforations [66]. Because the most common indication for liver transplantation is biliary atresia with a failed Kasai, many children present for transplantation with a predisposing risk factor for bowel perforation. Biliary complications are relatively common after pediatric liver transplantation. In the SPLIT database, biliary complications occurred in 14% of children within the first 30 days after transplant and in 25% of children 1 to 24 months after transplant [67]. Leaks from the cut surface are generally benign but may form bilomas that can become infected. Biliary leaks and strictures at the anastomosis are potentially more serious. Biliary complications are particularly troublesome with technical variant cadaveric grafts. In one series, biliary complications in technical variant grafts were higher compared with whole cadaveric grafts (30% versus 17%) and carried an increased risk for septic complications [34]. Although portal vein thrombosis and hepatic vein thrombosis are also more commonly seen in patients with partial grafts, if recognized and treated early they seldom directly cause graft loss. Predicting long-term posttransplant outcome has taken on new urgency with the scarcity of donor organs. In a multivariate analysis of pretransplant variables, Cacciarelli et al [68] found that donor weight of less than 10 kg, cadaveric partial grafts, and highly urgent status were all independently associated with an increased risk of graft loss. Recently, the SPLIT research group undertook a multivariate analysis of various pre- and posttransplant factors that might be expected to influence early patient and graft survival [69]. In 861 children who received a first liver graft, pretransplant factors found to be significant at the univariate level that adversely affected patient and graft survival 6 months after transplant were diagnosis of fulminant liver

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failure, hospitalization at time of transplant, cadaveric partial graft, cyclosporinebased immunosuppression, severity of illness at transplant (PELD score), more than two reoperations, septicemia, hepatic artery thrombosis, portal vein thrombosis, retransplantation, long warm ischemia time, and days in the intensive care unit after transplant. Significant only for graft survival were donor age of less than 6 months and intraoperative blood loss. From these data, multivariate analyses were performed and only factors significant at the univariate level were included. In the multivariate analyses of pretransplant and baseline factors, only diagnosis, organ type, warm ischemia time, and intraoperative blood loss were significantly associated with patient survival at 6 months. When all pre- and posttransplant factors were included in the multivariate analyses, the significant influences on patient and graft survival at 6 months were factors related to technical complications: retransplantation, reoperation, septicemia, and vascular thrombosis. From these data it seems that potential risk factors that exist before transplantation have little impact on patient and graft survival at 6 months. The implications of this finding are that surviving to transplant becomes essential in determining the overall prognosis of children who are eligible for transplant. Whereas understanding of the causes of early patient and graft loss has not changed appreciably, understanding of late causes of death and graft loss is still evolving. Because substantial numbers of children have lived more than 10 years and some even more than 20 years after transplantation, causes of graft failure in long-term survivors are only just becoming apparent. Unlike their adult liver recipient counterparts, for whom recurrent disease and extrahepatic degenerative diseases have a powerful impact on late patient and graft loss [70], for children almost all late losses are related to immunosuppression— too little, or more often, too much. Causes of graft or patient loss from under-immunosuppression are often a result of noncompliance, whereas sepsis, posttransplant lymphoproliferative disease (PTLD), lymphomas, and other de novo malignancies are the result of too much immunosuppression. Several large pediatric liver transplant centers have reported strikingly similar results. Sudan et al [71] showed that sepsis, noncompliance, and graft failure were the most common causes of death 1 year after transplantation for pediatric liver recipients. Ryckman et al [72] also showed that after 3 months, sepsis was the most common cause of subsequent death. In Friedell et al’s study [73] of 279 children, sepsis was the most common cause of death in children who died after 1 year, followed by PTLD. In the experience of the pediatric liver transplant program at UCLA [74], of 285 children who survived more than 1 year with good follow-up, 2.4% (7 children) died at a mean of 5.2 years after liver transplantation. Five of the 7 deaths were attributed directly to immunosuppression: lymphoma (2 cases), sepsis (2 cases), and chronic rejection (1 case). In the same cohort of children, 7% required retransplantation more than a year after their first transplant. The most common indication was chronic rejection; almost all of these children received transplants before the routine use of tacrolimus. Recently the Brussels group [30] also analyzed late graft loss in more than 400 children. They also found complications and implications of long-term immunosuppressive therapy to be

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the most important factors influencing graft loss: infection (21.2%), PTLD (21%), and chronic rejection (17%). The consistent theme is that the effects of long-term immunosuppression are implicated in most of the causes of late patient death, and graft loss is having a disquieting effect on the transplant physicians who hold the stewardship of decades of life after transplant for their young patients. This realization is forcing a re-evaluation of approaches to immunosuppression from the time of transplant into the decades after the procedure.

Immunosuppression: current practices and future directions The use of one of the calcineurin inhibitors (CNIs), cyclosporine or tacrolimus, still forms the basis of initial immunosuppression after pediatric liver transplantation. Tacrolimus is usually combined only with low-dose steroids, whereas cyclosporine-based protocols generally incorporate a third agent, such as azathioprine or mycophenolate mofetil. The SPLIT database provides some insight into current immunosuppressive practices in pediatric liver transplantation in the United States and Canada (Fig. 5) [10]. Of 1092 first liver transplant recipients, 33% were initiated on cyclosporine, compared with 55% initiated on tacrolimus. Twelve months after liver transplantation, 29% were receiving cyclosporine compared with

Fig. 5. Use of triple immunosuppression therapy over time. The combination of immunosuppressive drugs used is shown over the first transplant year for 1092 children who received a first liver transplant enrolled in the SPLIT registry. (From McDiarmid S, Anand R, SPLIT Research Group. Studies of pediatric liver transplantation: 2002 update. Pediatr Transplant, in press; with permission.)

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65.5% currently receiving tacrolimus. There seems to have been a change in immunosuppressive drugs used over the last several years. In 1996, 65% of transplant recipients received cyclosporine for initial immunosuppression compared with 18.6% in 2001. Only approximately one third of children (34.5%) received triple therapy initially. Induction therapy with either monoclonal or polyclonal antibodies was unusual; only 11% of children received this modality for initial induction. Although almost all children receive steroids at time of transplant, by 24 months this rate is down to 46.9%. Although in controlled trials neither cyclosporine- nor tacrolimus-based regimens have shown superiority over the other for either patient or graft survival, there is increasing evidence that tacrolimus-based therapy may decrease overall incidence of rejection and steroid-resistant rejection compared with children who receive cyclosporine. The first evidence of this was reported from the initial randomized multicenter trial of tacrolimus versus cyclosporine in 1995 [75]. A valid criticism of this study was that tacrolimus was compared with the older formulation of cyclosporine, however, rather than the newer microemulsion form (Neoral). In a recently presented large, multicenter European randomized trial of pediatric liver recipients who received either Neoral, azathioprine, and steroids or tacrolimus and steroids, freedom from rejection (55.5% versus 40.2%) or steroidresistant rejection (94% versus 70.4%) was significantly higher in the tacrolimustreated children [76]. In the extensive Pittsburgh experience that compared outcomes of tacrolimus- and cyclosporine-treated children over 20 years, patient and graft survival rates were improved under tacrolimus immunosuppression; however, this result may have been a reflection of other factors related to changes in clinical practice over time [77]. The same authors also reported less rejection, more freedom from steroids, and less hypertension in tacrolimus-treated children, a finding confirmed by others [78 – 80]. Steroid use after pediatric liver transplantation is also changing [81]. The wellknown adverse effects of steroids, particularly their association with poor growth after pediatric liver transplantation [82 – 85], have prompted most pediatric programs to practice some form of steroid withdrawal or minimization. Early studies, only one of which was randomized and controlled [86], reported that steroid withdrawal was safe and had a beneficial impact on growth [87 – 89]. Few recent studies have reported the success of various protocols of steroid withdrawal, however, and no further randomized trials have been conducted. Although some authors have suggested that steroid withdrawal is more often successful under tacrolimus therapy, in one of the only randomized trials that tested this claim, no difference was noted between successful steroid withdrawal at 3 months in adults treated with either tacrolimus or cyclosporine [90]. The current practice of steroid withdrawal varies. Some programs withdraw steroids as early as 3 months, whereas other programs start weaning at 3 months or delay weaning to 12 months or more. Little is known about whether ultra-short courses of steroids, such as 24 hours [91], 14 days [92], or steroid avoidance all together (as reported in adults) [93], are safe in children. Research also has not established which patients should not be weaned from steroids. The clearest

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contraindication seems to be children who received transplants for autoimmune hepatitis who have a high incidence of recurrence [94]. It is unclear if previous history of rejection, recent rejection episode, multiple episodes of rejection, and steroid-resistant rejection are important in deciding whether and when steroids should be weaned. Rejection An analysis of rejection from the SPLIT registry of 1902 first pediatric liver transplant recipients showed that rejection occurred most often in the first 3 months After transplant [10]. The cumulative rejection rates at 3 months were 0.45 increasing only modestly to 0 .59 at 24 months. The median time to first rejection was 16 days, the average rejection episodes/patient/year was 0.51, and more than one rejection occurred in 18.5% of children. Steroid-resistant rejection was relatively unusual and occurred in 11.2% of children. Antilymphocyte preparations, such as ATG or OKT3, were used as initial treatment for 8.3% of first rejection episodes and 3.8% of second rejection episodes but increased to 11.4% if patients experienced more than three rejection episodes. When Kaplan-Meier probabilities of rejection over time were examined for various factors, there was a trend to less rejection in children younger than 6 months and to recipients of living donor grafts—findings that were reported by other investigators [37,95,96]. In a univariate analysis, initiation of immunosuppression with tacrolimus compared with cyclosporine was the only factor that showed a significantly lower probability of rejection at 6 months: 51% versus 64% ( P = 0.01) [80]. At the time of last follow-up there was no difference in patient or graft survival between tacrolimus versus cyclosporine induction. Late acute rejection carries a different prognosis compared with early rejection [97,98]. It is frequently associated with low levels of immunosuppression, which are often related to noncompliance. The diagnosis may be delayed and the liver biopsy more difficult to interpret, with features of hepatitis and centrilobular venulitis and necrosis [99,100]. The response to steroids also can be suboptimal, and some authors have reported an increased risk of progression to chronic rejection [101]. Understanding the consequences of rejection may be a more important subject for study than the incidence of rejection. In contrast to kidney and heart allografts, the liver allograft is often described as an immunologically privileged organ [102]. Evidence continues to accumulate that rejection, particularly if steroid sensitive and occurring early after transplantation, seems to have no long-term adverse effects on either graft function or survival [69,103,104]. No prospective randomized trial that investigated a new immunosuppressive drug after liver transplantation has shown a significant improvement in patient or graft survival, despite significant improvements in rejection and even steroid-resistant rejection. A few adult studies and one pediatric study purported that rejection itself may have a beneficial effect on patient survival. Wiesner et al [104] showed that one episode of rejection resulted in a small but statistically significant improvement in patient

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survival 36 months after liver transplantation. Dousset et al’s study [103], which investigated long-term graft function in adult liver recipients, showed that one episode of rejection had no influence on graft function 1 year after transplant. In children registered in the SPLIT database, rejection examined as either present or absent within 6 months after transplant indicated a significantly lower risk for death or graft loss. When rejection was analyzed as time variant variable, rejection, one or more than one episode versus no episodes lost its effect on patient or graft survival [105]. In a multivariate analysis of many factors that affect posttransplant survival, the predicted effect of one verus no episodes of rejection approached significance for patient survival (P = 0.06) [69]. The intriguing finding that some rejection may be protective of graft function and survival raises the question that a controlled amount of immune activation may be necessary to delete clones of recipientderived lymphocytes that are injurious to the graft [106]. Chronic rejection seems to be increasingly rare, and some investigators attribute this to the increasing use of tacrolimus in pediatric liver transplantation. Based on the extensive use of tacrolimus in Pittsburgh, Jain et al [107] reported that the incidence of chronic rejection—defined histologically as vanishing bile duct syndrome—occurred in 3.1% of 1048 tacrolimus-treated patients and was virtually absent in pediatric recipients [108]. A study of risk factors for chronic rejection in 385 pediatric liver recipients at the University of Chicago found that cadaveric donor recipients, African Americans, patients with two or more episodes of rejection, patients with PTLD and CMV disease, or patients with autoimmune hepatitis as the indication for transplant had a significantly higher risk of chronic rejection [109]. Changing ideas in immunosuppression therapy A better understanding of the consequences of rejection and the increasing awareness of the detriments of over-immunosuppression have instigated a change in thinking about new induction immunosuppression strategies in children and long-term maintenance therapy. New induction therapies no longer should strive to keep decreasing the incidence of rejection but rather to provide enough immunosuppression to control damaging rejection, therefore protecting graft function and survival without the added risks of unnecessary immunosuppression: infection, de novo malignancy, and long-term toxicities of CNIs, particularly nephrotoxicity. The ultimate but difficult-to-achieve goal of induction therapy will be to use methods that allow for the development of donor-specific tolerance, thereby allowing patients eventual freedom from all immunosuppression and its attendant toxicities. It remains unclear whether induction with antilymphocyte preparations is important to achieve long-term reduction of immunosuppression in children [110]. The monoclonal antibodies, basilixumab and daclizumab, which are directed against the interleukin- 2 receptor, have generated the most interest recently. The largest pediatric experience is from the Hanover group, which reported an 11.5% incidence of rejection using basilixumab induction, combined with low-

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dose cyclosporine, mycophenolate mofetil, and early weaning of steroids [111]. A decreased incidence of acute rejection also was reported in children who used a single dose of daclizumab, combined with mycophenolate mofetil, and prednisone for induction, with a delay in tacrolimus initiation until day 7 after transplant [112]. Because neither of these studies was randomized with a control group, it is difficult to foresee what the long-term benefits might be. One benefit of antibody induction therapy is to potentiate the recovery of renal function in children with renal impairment for whom a delay in starting a CNI has been demonstrated [113]. Minimizing long-term maintenance immunosuppression recently has become the focal point of new studies. Steroid withdrawal was the first step toward achieving this goal. Complete steroid avoidance is the extension of this concept. Steroid avoidance protocols rely on the use of either polyclonal or monoclonal antibody therapy because of high rejection rates for patients given monotherapy with either cyclosporine or tacrolimus [114]. In the only randomized controlled trial of steroid avoidance in liver transplant recipients (all adults) reported to date, thymoglobulin (a polyclonal, depleting antilymphocyte preparation), mycophenolate mofetil, and tacrolimus induction were compared with tacrolimus, mycophenolate mofetil, and steroids. The incidence of biopsy-proven rejection in the steroid-free thymoglobulin group was 20.5% compared with 32% in controls. Although success is not yet reported in pediatric liver transplantation, several centers are beginning the practice of complete steroid avoidance. Optimism that this approach may be successful has been fueled by studies in pediatric kidney recipients. Induction with a prolonged course of daclizumab [115] or with an antilymphocyte preparation [116] combined with mycophenolate mofetil and a CNI resulted in a low incidence of rejection, which challenged the long-held belief that long-term steroids are essential for kidney graft survival. Steroid withdrawal and even avoidance do not seem to depend on a fundamental change in the current reliance on CNIs for maintenance immunosuppression. As yet, no replacements for CNIs seem promising as primary therapy. Sirolimus (rapamycin) has a mechanism of action distinct from the CNIs, and although it may cause hyperlipidemia and thrombocytopenia, it is not nephrotoxic or neurotoxic [117], which makes it particularly attractive for use in children [118]. The first randomized trial of sirolimus after liver transplantation was in adults. The group that received sirolimus, cyclosporine, and prednisone had a lower incidence of rejection than the control group treated with tacrolimus and steroids [119]. Safety issues related to an observed increased incidence of vascular thromboses, particularly hepatic artery thrombosis, precluded further multicenter, randomized trials, however, particularly any including pediatric liver recipients, who already are at increased risk for hepatic artery thrombosis. Single center reports have been much more encouraging about the role of sirolimus in induction therapy after liver transplantation. In 56 adult liver transplant recipients, the incidence of rejection for patients who received sirolimus combined with low-dose tacrolimus was 14%, with only one episode of hepatic artery thrombosis [120]. Trotter et al [121] successfully used sirolimus as induction therapy combined with tacrolimus and only 3 days of steroids, with a reported 30% incidence of rejection. To date, no

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sirolimus study has reported successful early withdrawal of a CNI. The reported use of sirolimus in pediatric liver patients has been limited to mostly rescue therapy. Sirolimus has been used to replace CNIs in small numbers of children with unacceptable toxicity from the CNIs [122] or as primary therapy in a few selected patients [123]. Mycophenolate mofetil is usually combined with cyclosporine in induction regimens, less frequently with tacrolimus, although triple therapy with CNIs, steroids, and mycophenolate mofetil [124] or azathioprine has not been shown to be superior to dual therapy in randomized trials. One anticipated benefit of adding mycophenolate mofetil is to allow for the systematic lowering of tacrolimus or cyclosporine levels, with an attendant reduction in their toxicities. The proof of this concept, however, has not been well established. Small numbers of pediatric patients have used mycophenolate mofetil with low levels of CNIs, especially for cases involving severe CNI-induced nephrotoxicity or neurotoxicity [125,126]. The use of new immunosuppressive drugs in pediatric transplant recipients often has been limited by lack of pharmacokinetic data, especially in young children, who comprise the largest segment of the pediatric liver transplant population. Recently, useful pharmacokinetic studies in pediatric liver recipients have been published for basilixumab [127], tacrolimus oral suspension [128], sirolimus [129], and Neoral [130]. An interesting observation recently made, which is especially relevant to pediatric recipients of partial grafts, is that tacrolimus pharmacokinetic patterns retain the characteristics of the age of the donor, not the recipient. Tacrolimus doses may need to be two to five times higher in children compared with adults to achieve the same blood trough levels [128,131,132]. Lower doses of tacrolimus can be expected to be needed for the pediatric recipient of a partial graft from an adult compared with a pediatric graft [133]. To make further progress in substantially decreasing immunosuppression and its attendant long-term toxicities, one must find ways to minimize or even stop CNIs and, ultimately, all immunosuppression. Two transplant programs have reported considerable experience in weaning children from all immunosuppression after liver transplantation, despite the inability to predict for which children this strategy might be successful. The incidence of rejection during or after weaning—25% and 26%, respectively—was similar in both Mazariego’s and Takatsuki’s experience, although one program used cadaveric grafts [134] and the other used living related (usually a parent) donors [135]. Neither study reported graft loss as a result of weaning. Acute rejection could occur as long as 4 years after all immunosuppression was stopped, however, which implies that long-term, close surveillance of these patients is essential. As attractive as the concept of freedom from all immunosuppression is, the major factor that contributes to the reluctance of many transplant physicians to instigate complete withdrawal systematically in their patients is the inability to evaluate whether the host is truly nonresponsive to the allograft. Although studies are underway to develop the so-called ‘‘tolerance assay,’’ none has proved reliable in the clinical setting. In addition to attempts to withdraw ‘‘conventional’’ immunosuppression, there is increasing impetus to design innovative induction protocols that may promote

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tolerance to the allograft. As knowledge evolves regarding the complexities of the initial and ongoing recipient response to the allograft [136] and the role of donorderived hematopoietic cells, it is apparent that some current immunosuppressive strategies maybe antitolerogenic. Some immune activation is necessary for tolerance induction and may be mediated by the interleukin-2 and tumor necrosis factor [137]. What role do cyclosporine and tacrolimus, both of which decrease interleukin-2 production, and interleukin-2 Receptor blocking monoclonal antibodies have in abrogating tolerizing mechanisms [138]? Clonal depletion and clonal exhaustion of alloreactive T cells seem to be central to the induction and maintenance of tolerance [139]. The role of the large number of donor-derived passenger lymphocytes in the liver graft, which quickly migrate to peripheral lymphoid tissue, may be important in initiating a graft-versus-host response, which aids in the containment of the host’s response to the graft [140]. Likewise, methods to achieve early depletion of host T cells could be important; hence, the recent upsurge in interest in using depleting antibodies or other conditioning regimens in induction regimens [141]. The amount and timing of depleting strategies are crucial. If the balance between the host-versus-graft reaction and the graft-versus-host reaction is lost, then either rejection or clinical graft-versus-host disease is the consequence [106]. Early clinical trials are underway to investigate another immune pathway important to tolerance induction. Blockade of the costimulatory pathway of T-cell activation has been shown in animal models to be an effective inducer of tolerance. One promising biologic agent that is entering clinical trials is CTLA4 Ig, which blocks the costimulatory interaction between CD28 and B7 [142,143]. Short-term complications Problems that stem from the technical challenges posed by pediatric liver transplantation still remain the most important category of complications in the first 6 months after liver transplantation. In the SPLIT database, complications within the first 30 days after transplant were most often vascular in nature, followed by biliary tract complications (15.6% and 14%, respectively) [10]. Of the nontechnical complications, respiratory complications, including diaphragmatic paresis and ventilator dependence, occurred in 18% of patients. Infection was also another early complication, with 39.1% of patients having culture-positive bacterial infections and 9.8% having fungal infections. Intra-abdominal and line infections were the most common source of bacterial infection in the early posttransplant period. Frequently, bacterial and fungal infections are secondary consequences of technical complications, such as vascular thrombosis, biliary leaks, and strictures, which then contribute to a prolonged intensive care unit stay—a risk factor for infection. Fungal sepsis, particularly invasive aspergillosis [144], is associated with a high mortality rate and is often seen in the context of other risk factors, particularly reoperation, bowel perforation, and extensive intensive care unit stays [145]. Prophylaxis for high-risk adult liver recipients with antifungal drugs, such as

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itraconazole and fluconazole, has been shown to be effective in lowering mortality rates [146]. Improvements in the technical complication rate after liver transplantation have been associated with a decrease in invasive candidiasis [147]. New classes of antifungal agents, such as the caspofungins [148,149], and the availability of lipid complex formulations of amphotericin, which are less nephrotoxic, provide new treatment strategies that hopefully will improve outcome after fungal infection [150]. Viral diseases are a frequent problem in young children, who often sustain a primary infection after liver transplantation. Generally their greatest impact is in the first months after transplant, when immunosuppression is at its peak [151]. CMV and Epstein-Barr virus (EBV) infection and disease have been reduced substantially by the use of prophylactic strategies using variable courses of ganciclovir (either orally or intravenously), acyclovir, and CMV hyperimmunoglobulin [152 –156]. For CMV prophylaxis in adults, oral ganciclovir is more effective than oral acyclovir [156]. In children, however, oral ganciclovir has poor and highly variable rates of absorption [157]. Successful treatment of CMV disease depends on early recognition, and serial measurements of CMV viral load can be useful in guiding treatment [155]. Common respiratory viruses may still prove devastating if they become disseminated and invasive in children with new transplants. Adenovirus, parainfluenza virus, and influenza virus are the biggest threats because they may induce a lethal necrotizing pneumonitis [158,159]. To date, antiviral therapies against these viruses have had only limited efficacy. Recently there has been an increasing awareness of the clinical illnesses caused by herpesvirus 6 and 7, either as primary or reactivated infections. Infection with herpesvirus 6, the virus responsible for roseola, is the best characterized in transplant recipients and may cause fever, rash, hepatitis, and encephalopathy [160]. These findings are particularly important for young children undergoing transplantation who are likely to have had no prior exposure to these viruses. Coinfection with CMV and herpesviruses 6 and 7 has been demonstrated [161 – 163]. Long-term complications Late complications after pediatric liver transplantation fall into two general categories: (1) complications related to the allograft itself and (2) extrahepatic complications, most of which are secondary to long-term exposure to immunosuppressive drugs. It is unclear which complications have the greatest long-term morbidity and will contribute to eventual mortality in years to come. The Birmingham Group [164] has performed protocol biopsies on pediatric recipients at 1, 5, and 10 years after transplantation, and their results are sobering in considering what may lay ahead. At 1 year after transplantation, 59% of children had a normal liver biopsy, at 5 years the rate was 28%, and by 10 years the rate was only 19%. Hepatitis was the most common histologic abnormality, rejection was rare, and over time, fibrosis increased. In another study, Peeters et al [165] described fibrosis in 31% of protocol biopsies at 1 year after transplant and correlated this

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finding with warm and cold ischemia time, biliary complications, and CMV status. In contrast, Rosenthal et al [166] found that although protocol biopsies at 1 year in healthy children with normal liver tests frequently showed portal or parenchymal infiltrates, they were clinically insignificant. Causes of late graft dysfunction Understanding the causes of late graft dysfunction that occurs years after transplantation can offer insight into what one might project graft survival to be beyond 10 years. Most 10-year graft survival curves for pediatric liver transplant recipients are relatively flat after the first months after transplant, unlike graft survivals for pediatric recipients of kidney and heart allografts, which show continued attrition over time. It remains to be seen if this relative stability in long-term liver graft survival will persist after two or three decades. Unlike adults, in whom death with a functioning graft occurs in as many as 61% of patients [70], graft dysfunction in children that leads to graft loss and even death is more common. In 1995, the author analyzed causes of graft dysfunction that occurred 1 year after liver transplantation in 285 children routinely followed at UCLA [167]. This was in the era of predominately cyclosporine use, and the author noted acute rejection in 30% and chronic rejection in 18% of children. Noncompliance was implicated in 32% of acute and 27% of chronic rejection episodes. The author noted that 28% of liver biopsies showed evidence of nonviral hepatitis, however. Shortly thereafter, the author and others reported that several children who received transplants for non-autoimmune liver diseases spontaneously developed autoantibodies [168,169]. This late appearing, nonviral hepatitis was sometimes severe and caused bridging fibrosis or cirrhosis that led to graft failure. Over the past 5 years, this entity— posttransplant immune hepatitis—has been described increasingly as an important cause of late graft dysfunction in children after liver transplantation [170 –172]. The characteristic features, which usually occur in patients more than 1 year after liver transplantation, are biopsy evidence of chronic hepatitis, hypergammaglobulinemia, and positive autoantibodies. The lesion responds to increasing steroid doses, usually in conjunction with azathioprine or mycophenolate mofetil, but not to increasing levels of CNIs [173,174]. If recognized and treated early, the biochemical abnormality is usually reversible, although the author has seen children with late presentations and established cirrhosis that have required retransplantation. The explanation for the appearance of destructive autoantibodies in patients whose liver disease initially was non-autoimmune is not well understood. It may be a consequence of immune dysregulation in the presence of long-term immunosuppression or may be a manifestation of atypical rejection. What is also unknown is the long-term prognosis for the graft or the attendant adverse consequences of the increased immunosuppression, which seems to be necessary to stabilize graft function. Of the known causes of new-onset hepatitis late after liver transplantation, de novo hepatitis C is the most difficult to treat. In children who received transplants

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before 1990, studies reported a 10.2% incidence of de novo hepatitis C [175]. The author’s experience in managing these children has been discouraging. Only 1 of 12 had a sustained response to antiviral therapy, 4 developed rapidly progressive liver failure while on therapy and required urgent retransplantation, and only 1 survived. The author’s experience differs from that of others, who have described a relatively indolent course for de novo hepatitis C children infected after transplant [176,177] and a lower incidence (6.2%) in children who received transplants before 1990 [178]. Posttransplant management to contain the universal reinfection of the graft by hepatitis C is still largely ineffective and is associated with a high incidence of side effects [179]. Unlike adult liver recipients, for whom recurrence of hepatitis C is a major problem [180], recurrent disease after pediatric liver transplantation is relatively unusual. Recurrence of autoimmune-mediated liver diseases, such as autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis, has been documented in adults [181]. The topic most relevant to children is the aggressive nature of recurrence of autoimmune hepatitis. In one small study [94], recurrence occurred in five of six grafts, which led to graft loss in three. In a larger series of 28 children who received transplants for autoimmune hepatitis, 39.2% had recurrence after liver transplantation [35]. In comparison, rates of recurrence in adults are 25% to 28% [182,183]. Crypotogenic cirrhosis also has been reported to recur in adult liver recipients [184] and children, in whom a 17% recurrence rate was described [185]. Recurrence after liver transplantation for primary liver tumors in children is also less common than for adults, and although it is seldom a cause of graft dysfunction, it is still a significant cause of late patient death. Hepatoblastoma, the most common primary liver tumor for which liver transplantation is indicated in children, has a good prognosis. Reyes et al [186] reported an 83% 5-year actuarial survival rate, which was similar to other series [187 – 189]. Selection of patients with hepatoblastoma for resection or transplant is important, as is the role of chemotherapy before and after transplant. Some evidence exists that large tumors that involve both lobes at presentation—even if tumor shrinkage is achieved after chemotherapy and resection is possible—have a better recurrence-free survival rate if transplanted before any attempts at resection are made [190]. This is borne out by several studies that show excellent results for unresectable hepatoblastoma after liver transplantation when combined with pre- and posttransplant chemotherapy [187,191,192]. Extrahepatic metastases, and large vessel invasion seem to be risk factors for recurrence, as are prior attempts at resection of large tumors. Liver transplantation for hepatocellular carcinoma has several different features compared with adults. Most importantly, the recurrence rate after transplantation for hepatocellular carcinoma is higher for children than for adults. This may relate to the overall poor prognosis of children who present with hepatocellular carcinoma. Overall disease-free survival rate was only 17% at 5 years in one series [193]. These children frequently present with large tumors in noncirrhotic livers, and both factors are associated with a particularly poor prognosis with or without transplant [194].

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Long-term toxicities of immunosuppression: nephrotoxicity Renal impairment remains the most serious complication of continued reliance on long-term CNI use [195]. In the 1990s, reports appeared that renal impairment after pediatric liver transplantation was common, more serious than expected, and not significantly different between cyclosporine- and tacrolimus-treated patients [196 – 199]. Clinicians also increasingly realized that relying only on serum creatinine as a serial measure of renal function underestimated the severity of the problem [200,201] and that glomerular filtration rate (GFR) was the most valid measurement [202]. Even calculated GFR, most often using the Schwartz formula, was shown to overestimate true GFR [203 –205]. The use of timed isotope plasma clearance methods for the measurement of GFR made GFR studies much more practical for children, because the difficulties of performing timed, prolonged urine collections were eliminated [206]. Few studies of true GFR in children after liver transplantation have been performed, however, and most have not been performed serially over years of CNI exposure. The author [207] reported that 73% of cyclosporine-treated children had a true GFR of less than 70 mL/min/m2 after liver transplantation. For children treated for 12 to 24 months, the mean GFR was 79 mL/min/m2, which fell significantly to 52 mL/min/m2 for children treated for longer than 24 months. A progressive fall in GFR also was reported by Berg et al [204], who found that children had lower GFRs after liver transplantation when compared with normal children. Children who required antihypertensive drugs and children who received transplants for metabolic disease had the lowest GFRs. Taking the available evidence together, in the first year after transplant the fall in GFR seems to vary somewhat and depends on pretransplant renal function. There seems to be a general consensus that early renal impairment induced by CNI use is often reversible, and dose reduction can be beneficial [208,209]. Although less well documented, at some point renal impairment seems to become irreversible. What is unknown is when that transition occurs, if it is predictable, and whether it is avoidable. Recent data from more than 10 years of exposure to CNIs in adult liver transplant recipients are concerning. Gonwa et al [210] showed that 13 years after transplantation, 9.5% of 834 adults liver recipients were on dialysis or required a kidney transplant. Although pediatric recipients may start off with better renal function and have a greater functioning nephron mass compared with their adult counterparts, even if by 20 years after transplantation children show similar degrees of renal impairment as the adults in Gonwa’s study, then the chances become worrisome that substantial numbers of children who receive a liver transplant before their fifth birthday will develop renal failure in early adulthood. Several observations lend credence to the idea that long-term renal impairment is not being overstated. Children who undergo retransplantation after several years of CNI exposure often develop unexpected degrees of renal failure when exposed to higher CNI levels after retransplantation. Years after transplantation, children who develop even mild dehydration as part of an acute intercurrent illness may present with unusually high creatinine levels. also Considerable numbers of children also develop hypertension after liver transplantation. Studies in pediatric

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liver recipients have reported a 17% to 33% incidence of hypertension that requires therapy [199,204,211]. Hypertension in the early posttransplant period is relatively common and may be compounded by steroid use. Earlier steroid withdrawal may well improve this early-onset hypertension. In the SPLIT database [67], although approximately one third of children are receiving antihypertensive medications 1 year after transplant, this number falls to 16% at 24 months after transplant. Hypertension that requires medication beyond 1 year after transplant or occurs as a new onset problem several years after transplant may carry an entirely different prognosis than early hypertension. The extent of this problem in children a decade or more after liver transplantation is not known. There is a notable lack of studies investigating renal function in children more than 10 years after transplant. This effort likely require collaboration among several centers whose pediatric liver transplant programs began in the 1980s. Some currently available alternatives to CNIs have been used in pediatric liver transplantation to try to ameliorate long-term CNI-induced nephrotoxicity. The strategy most often used is to reduce doses of CNIs markedly or eliminate them altogether and add either mycophenolate mofetil or sirolimus. Although improvement in renal function after such changes has been shown [123,212], it is unclear whether such strategies can improve long established renal impairment secondary to many years of CNI exposure. Until we are able to minimize CNI exposure safely or develop strategies to avoid CNI use altogether, if not initially after transplant, then after the first year or two, renal impairment with the long-term threat of renal failure will continue to cast a shadow over the long-term prognosis of pediatric liver transplantation. De novo malignancies PTLD, including true lymphomas such as Burkitt’s, Hodgkin’s, and nonHodgkin’s lymphoma, are still the most important neoplasms that occur after pediatric liver transplantation in children and are associated with a substantial mortality. As the potency of immunosuppressive strategies has increased, so has the incidence of PTLD, ranging from 2% to 27%,[213 – 217], and the time to its appearance has shortened [218]. PTLD in children is almost always an EBV-driven B-cell proliferation that causes a spectrum of disease that ranges from relatively benign lymphohyperplasias to true lymphomas. Presenting symptoms and signs are protean, and PTLD can involve almost any organ, including the graft itself [219]. Risk factors for PTLD are primary EBV infection after transplant, young age, an EBV-negative recipient receiving a transplant from an EBV-positive donor, and CMV infection [220 – 222]. Many clinicians draw a distinct difference between true lymphomas, such as Burkitt’s, Hodgkin’s, and non-Hodgkin’s, and PTLD. PTLD is almost always a B-cell driven proliferation seen more often within the first 2 years after transplant, is highly associated with a primary EBV infection, and usually is treated successfully by withdrawal of immunosuppression [223]. In contrast, the true lymphomas generally occur years after transplant, often in patients maintained on low-dose

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immunosuppression. Whereas tumor cells show EBV expression, viremia as measured by polymerase chain reaction (PCR) in the peripheral blood for EBV virus is often not demonstrable. Although lymphomas tend to occur late, rapid evolution of a polymorphous proliferation into a typical monoclonal Burkitt’s lymphoma has been described [224]. The true lymphomas carry a much worse prognosis than early PTLD [221], do not respond to antiviral drugs or the withholding of immunosuppression, and require chemotherapy for treatment [224]. No good surveillance strategies, other than routine physical examinations and the rapid evaluation of suspicious lesions or changes in overall clinical status, seem effective. The incidence and mortality of PTLD that occurs in the early posttransplantation period has decreased over the past several years [225,226], falling from 40% to 70% [220,227,228] to 10% to 20% [229,230]. This decrease seems to be directly attributable to the increasing use of surveillance for EBV viremia using serial EBV PCR determinations in the peripheral blood, particularly when it became clear that following EBV serologies was not useful [231]. Several investigators have reported that a rising EBV PCR copy number is an indictor of increasing viral load and is an important monitoring tool for the detection of primary EBV infection or reactivation [232 – 234], which can be pre-emptively treated. Researchers also agree that although a rising EBV PCR is not specific for PTLD, it is sensitive [232 –234]. Allen et al [235] demonstrated that virus load had 69% sensitivity and 76% specificity for PTLD, whereas McDiarmid et al. showed 100% sensitivity and 27% specificity. Various prophylaxis regimens against EBV infection using ganciclovir, acyclovir, or CMV hyperimmunoglobulin (also shown to have high levels of EBV antibodies), alone or in combination are commonly used, particularly in high-risk recipients (ie, EBV-naı¨ve recipients of EBV-positive grafts). If prophylaxis fails, then pre-emptive treatment of a rising EBV PCR before clinical disease has occurred seems to be important for preventing progression to PTLD. Lowering immunosuppression, with or without the use of antiviral drugs or CMV hyperimmunoglobulin, is the key to pre-emptive management [236]. In the UCLA experience, a combination of prevention and pre-emptive therapy using ganciclovir for prophylaxis and pre-emptive treatment, along with lowering of immunosuppression, has reduced the incidence of PTLD from 10% to 5% and more recently to less than 1% [225]. The role of antiviral therapy in the management of a rising viral load or once PTLD has been diagnosed is disputed. It is generally believed that the lytic phase of the virus, against which antiviral drugs are effective, occurs early and is short lived. Increasing evidence suggests that the lytic replication can occur sporadically in up to 45% of patients with PTLD [237]. Further advances in the management of PTLD have focused on when it is appropriate to reintroduce immunosuppression and thus avoid rejection. The basic tenant behind stopping immunosuppression is to allow the host’s natural EBVspecific T-cell response to reappear and limit the disease. Simultaneously, antidonor T-cell responses are also likely to be reactivated. Using an enzyme-linked immunospot (Elispot) methodology, which allows a determination of T-cell

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function by the production of interferon from cytotoxic T cells [238,239], investigators have shown when T-cell specificity reappears and becomes of sufficient strength to potentially cause rejection [240]. At this point immunosuppression can be restarted. New therapies for PTLD that is unresponsive to lowering of immunosuppression or for EBV-related lymphomas include anti-CD20 (a receptor found on most B cells) monoclonal antibodies and the injection of in vitro expanded autologous EBV-specific cytotoxic T cells [241]. Although the role of the most commonly used anti-CD 20 monoclonal antibody in use, rituximab, has proved successful in treating lymphomas [242], its use in PTLD is less clear [243]. Profound and prolonged B-cell depletion occurs after rituximab use, which exposes the patient to additional risks of other infections [244]. The drawback of autologous injection of EBV-specific cytotoxic T cells is that they are most efficiently grown up from patients who already have EBV infection, but even then, up to 30 days may be necessary before enough cells can be cultured. Ways to expand EBV-specific T cells in EBV-naı¨ve recipients are being explored [245]. PTLD and lymphomas are not the only EBV-driven tumors seen after pediatric liver transplantation. EBV-associated spindle cell smooth muscle tumors [246] and leiomyosarcomas [247] also have been described. As yet, other de novo malignancies in children after liver transplantation have not been reported extensively. Kaposi’s sarcoma [248] and fibrosarcomas have been described [249]. There is concern that with more years of immunosuppressive exposure the risk of skin cancer and other solid organ tumors already reported to be increased in adult liver recipients [250,251] in comparison to the normal population also will occur in young adults who received transplants as children. Several areas in long-term pediatric liver transplantation follow-up still remain poorly understood. The ‘‘natural history’’ of children after liver transplantation still may be too short for researchers to know how their futures will evolve. Instead, they try to project from what they already know and are beginning to observe. The early neurotoxic effects of CNIs are well known [252,253]. The risk of developing neurotoxicity may be related to polymorphisms in the multidrug-resistant gene [254]. What is not yet understood is the effect of decades of exposure to such neurotoxins. How might development, cognitive function, and personality be affected? Cardiovascular risk is of increasing concern in adult recipients [255]. The triad of hypertension, hyperlipidemia, and de novo diabetes, which are associated with immunosuppression use, substantially increases the risks for cardiovascular complications. Some evidence exists that at least with cyclosporine therapy, lipid profiles in children may be abnormal. In one study, 50% of children had serum cholesterols more than the seventy-fifth percentile [256]. How might this change with time? Studies of quality of life, development, and cognitive function after pediatric liver transplantation have been producing troubling results. In an early study, children who underwent liver transplantation had significantly lower nonverbal intelligence, lower academic achievement, and poorer scores for learning and memory compared with children with cystic fibrosis [257]. Other investigators found

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learning problems in 26% of children [258], and 50% of children were functioning at least one grade level lower than expected [259]. In a study of children with biliary atresia who received transplants before 2 years of age, 35% demonstrated developmental delays [258]. Conversely, neurodevelopmental outcome at more than 4 years of follow-up seemed to be within normal limits in 25 children who received transplants before 1 year of age [260]. Preteens and teenagers also seem to be at risk. De Bolt et al [261] reported that children between 6 and 11 years of age had lower scores for social, scholastic, and physical function compared with healthy children. In a large study of psychosocial adjustment in 146 patients followed at a single center, Tornqvist et al [262] found that older children, particularly boys, had more psychosocial adjustment problems than healthy children. Girls perceived themselves to be less scholastically competent than their peers, whereas boys had significantly lower perceptions of their self-worth and athletic competency. The same center also reported that earlier age at transplant was associated with higher scores for aggressive behavior and lower scores for activities and competence. The longer after transplantation, the more problems mothers reported for somatic complaints, anxiety, depression, and issues with competence and social activities [263]. These findings shed light on the increasingly recognized problem of noncompliance in teenagers, which in this author’s experience has become a heart-breaking cause of patient death. To date, quality-of-life studies after pediatric liver transplantation have been hampered by lack of an instrument designed specifically for this population. It is hoped that upcoming studies will seek to address this important deficit. Current information suggests that some children are functioning less well than might be expected. One study of health-related quality of life in children after liver transplantation found that 71% of children had mild disability and 29% had moderate disability [264]. Bucuvalas et al [265] showed that quality of life was lower for pediatric transplant patients compared with normal children but was similar to children with chronic disease. In the Japanese living donor experience, 82% of children were said to lead a ‘‘normal life’’ judging from their activities, whereas 14% remained at home or in hospital secondary to complications [266].

Summary There are two critical issues on opposite ends of the timeline for patients who are eligible for liver transplantation. On the one hand, the crisis in the cadaveric organ supply makes surviving to transplant ever more risky. On the other hand, patients who receive successful transplants face the consequences of long-term immunosuppression and its potentially life-threatening complications. The donor shortage is forcing difficult decisions that affect all patients who await liver transplantation. It is important to scrutinize carefully the results of all policies that govern allocation and the ethics of the solutions we advocate to ensure that no patient subgroup is being at a disadvantage.

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Current immunosuppression practices are being challenged by an increasing understanding of the immunologic events triggered by the allograft and the goal to free patients from consequences of a lifetime of immunosuppression. Clinicians can expect, and perhaps require, that new immunosuppressive protocols will address how the planned intervention might be expected to advance the understanding of tolerance mechanisms. As knowledge increases, clinicians can anticipate innovative new immunosuppressive proposals. Calcineurin and steroid-free induction, the use of donor-derived bone marrow infusion, recipient pretreatment, costimulatory blockade, and new antibody induction approaches are all being proposed—often in combination—for clinical trials. Researchers face additional challenges in defining endpoints if the goal is not just the short-term reduction in rejection but the minimization, and eventual discontinuation, of immunosuppressive drugs while maintaining excellent long-term graft function. How much ‘‘failure’’ will be accepted and how will it be defined? How will clinicians interpret liver biopsies if they begin to accept that some lymphocytic infiltrates may be beneficial mediators of the ongoing immune activation necessary for the maintenance of tolerance? How will they adjust immunosuppression practices to the dynamic processes in the immune response that maintain tolerance? Remarkable short-term successes in providing transplants for thousands of children with liver failure have brought these challenges into sharp focus. Clinicians must seek to move the life-giving science of transplantation toward a new goal: providing long lifetimes of excellent graft function with minimal toxicity from immunosuppressive drugs and the hope of freedom from immunosuppression altogether. Pediatric liver recipients, whose grafts have inherent tolerogenic potential and for whom we can anticipate decades of life after transplant, may prove to be an ideal study population to further these goals.

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