Abstract
Objective
To describe the epidemiology and causes of graft loss after pediatric liver transplantation and to identify risk factors.
Summary Background Data
Graft failure after transplantation remains an important problem. It results in patient death or retransplantation, resulting in lower survival rates.
Methods
A series of 157 transplantations in 120 children was analyzed. Graft loss was categorized as early (within 1 month) and late (after 1 month). Risk factors were identified by analyzing recipient, donor, and transplantation variables.
Results
Kaplan-Meier 1-month and 1-, 3-, and 5-year patient survival rates were 85%, 82%, 77%, and 71%, respectively. Graft survival rates were 71%, 64%, 59%, and 53%, respectively. Seventy-one of 157 grafts (45%) were lost: 18 (25%) by death of patients with functioning grafts and 53 (75%) by graft-related complications. Forty-five grafts (63%) were lost early after transplantation. Main causes of early loss were vascular complications, primary nonfunction, and patient death. Main cause of late graft loss was fibrosis/cirrhosis, mainly as a result of biliary complications or unknown causes. Child-Pugh score, anhepatic phase, and urgent transplantation were risk factors for early loss. Donor age, donor/recipient weight ratio, blood loss, and technical-variant liver grafts were risk factors for late loss.
Conclusions
To prevent graft loss after pediatric liver transplantation, potential recipients should be referred early so they can be transplanted in an earlier phase of their disease. Technical-variant liver grafts are risk factors for graft survival. The logistics of the operation need to be optimized to minimize the length of the anhepatic phase.
In 1983, the National Institutes of Health in the United States concluded on the basis of then-available clinical results that orthotopic liver transplantation is an accepted treatment for end-stage liver disease. 1 In the following decades, results improved because of advances in surgical techniques, immunosuppressive regimens, and postoperative care. However, graft failure remains a problem, especially in pediatric liver transplantation. It has important consequences because patients will either die or receive a new liver graft. Death rates with or without a functioning graft vary from 17% and 30%, and retransplantation rates vary from 11% to 25%. 2–5 In addition, both patient and graft survival rates are lower after retransplantation than primary transplantation. 5,6 Finally, graft failure implies an additional claim on the already restricted donor pool.
Prevention of graft loss will improve the overall outcome after pediatric liver transplantation. Therefore, it is important to identify risk factors that may lead to graft loss. In the present study, the epidemiology of early and late graft loss after pediatric liver transplantation performed in a single center is described and risk factors are identified. Such an analysis provides insight into the causes of graft and patient loss and may help to decrease the number of retransplantations.
METHODS
Between 1982 and 1999, 157 orthotopic liver transplantations were performed in 120 children. Thirty-two children (27%) underwent 37 retransplantations. Twenty-nine children were retransplanted once, one child received two retransplants, and two children received three retransplants. Median age of the study population was 3.8 years (range 1 month to 16 years). Indications for transplantation were biliary atresia (n = 60 [50%]), metabolic disease (n = 24 [20%]), cirrhosis of various causes (n = 19 [16%]), fulminant hepatic failure (n = 14 [12%]), hepatoblastoma (n = 2 [2%]), and rupture of a giant liver hemangioma (n = 1 [1%]). The median Child-Pugh score was 10 (range 5–15). Sixteen children (14%) were class A, 38 (32%) were class B, and 65 (54%) were class C. Seventy-six children (63%) had previous upper abdominal operations before transplantation. The median follow-up of the study population was 3.6 years (range 0–16).
The selection of children was made as described earlier. 7 After referral, the diagnosis was confirmed and stage and progression of disease were determined. Serologic screening was done for cytomegalovirus, Epstein-Barr virus, and hepatitis B and C viruses. Complications of liver disease were treated if significant symptoms were present, and precautions were taken to prevent recurrence. Infectious foci were eradicated before children were listed for transplantation. Perioperative infection prevention was started before transplantation by selective bowel decontamination. 8 In addition, perioperative parenteral antibiotics were given and postoperative oral acyclovir prophylaxis was given to prevent herpesvirus infections. Immunosuppression in the first five children (4%) in this series consisted of azathioprine and prednisolone. Cyclophosphamide was given as well during the first 10 days after transplantation. Cyclosporine was added to this triple-immunosuppressive regimen in the remaining 115 children (96%). Clinically evident and histologically proven rejections in the first 4 weeks after transplantation were treated with intravenous methylprednisolone. After this period, rejections were treated with intravenous methylprednisolone or by increasing the prednisolone dose with tapering after treatment to a higher maintenance dose. Steroid-resistant rejections were treated with intravenous antithymocyte globulin.
Donor criteria were described in a previous report. 7 In six transplantations (4%), ABO-incompatible grafts were used because of an urgent indication for transplantation. Organ procurement was done according to standard techniques. 9,10 Euro-Collins preservation solution was used in 19 grafts (12%), University of Wisconsin solution in 134 grafts (85%), and histidine-tryptophan-ketoglutarate in 4 grafts (3%). Sixty-seven transplantations (43%) were full-size liver transplantations and 90 (57%) were technical-variant liver transplantations: 74 (47%) reduced-size liver grafts (39 left liver lobes, 10 right liver lobes, and 25 segmental liver grafts) and 16 (10%) split-liver grafts (6 left liver lobes, 1 right liver lobe, and 9 segmental liver grafts). Standard liver resection techniques were used for reduction or splitting of the graft. 11,12 Eighty transplantations (51%) were performed according to the conventional technique 13 and 77 (49%) with preservation of the recipient inferior vena cava (piggyback technique). 14
Outcome Parameters
Overall 1-month and 1-, 3-, and 5-year patient and graft survival rates were assessed. The outcome of 157 transplantations was analyzed and the incidence of graft loss was calculated. Patient survival was defined as the time period between transplantation and patient death. Graft survival was defined as the time period between transplantation and graft loss, either by patient death or by graft failure necessitating retransplantation. Survival times of patients and grafts alive at the end of follow-up were censored. The risk for graft loss during the course after transplantation was expressed as the percentage of grafts lost in relation to the number of grafts at risk during fixed periods. Early graft loss was defined as loss within 1 month after transplantation and late graft loss as loss after 1 month. Causes of graft loss were assessed by reviewing clinical information, histopathologic reports, and autopsy findings if available. Although causes of graft loss are often multifactorial, we tried to identify a main cause for graft loss.
Risk factors for graft loss were identified by comparing grafts that survived and grafts that were lost, based on variables related to the recipients, donors, and transplantation procedures. Recipient variables were age and weight, Child-Pugh score, diagnosis (biliary atresia vs. metabolic diseases and cirrhosis of various causes, and urgent vs. elective transplantations), and number of transplantations (primary transplantation vs. retransplantation). Donor variables were age, donor/recipient weight ratio, and length of the stay in the intensive care unit. Transplantation variables were cold ischemia time, duration of anhepatic phase, operation time, blood loss index, 7 and type of graft (full-size vs. technical-variant liver grafts). The anhepatic phase was defined as the period between closure of both the hepatic artery and portal vein and recirculation of the new liver graft. Urgent transplantations were defined as transplants performed after the child had received the code “high urgency” in Eurotransplant International, which is comparable with UNOS status I or IIa.
Statistical Analysis
Continuous data are presented as median with range and categorical data as number with percentage. The Kaplan-Meier method was used for assessing graft and patient survival rates, and the log-rank test was used to compare these rates between groups. The Mann-Whitney test was used to compare continuous variables between two groups, and the Pearson chi-square test or the Fisher exact test if numbers were sparse was used for comparison of categorical variables. Associations between variables were determined using the Spearman correlation coefficient. The level of significance was set at 0.05.
RESULTS
Overall 1-month and 1-, 3-, and 5-year patient survival rates were 85% (n = 102 patients at risk), 82% (n = 93), 77% (n = 69), and 71% (n = 48), respectively. Graft survival rates were 71% (n = 112 graft at risk), 64% (n = 94), 59% (n = 69), and 53% (n = 47), respectively. Eighty-six of 157 grafts (55%) were functioning at the end of the observation period and 71 grafts (45%) were lost. Eighteen of these 71 grafts (25%) were lost by death of patients with a well-functioning graft, 16 grafts (23%) were lost by patient death as a result of graft-related complications, and 37 grafts (52%) were lost by graft-related complications but patients were retransplanted. The latter indicates a retransplantation rate of 24%.
Forty-five of 71 lost grafts (63%) were lost early after transplantation and the remaining 26 (37%) were lost late after transplantation. One-, 3-, and 5-year survival rates of grafts that survived the first month after transplantation were 90% (n = 94), 83% (n = 69), and 75% (n = 47), respectively. The risk for graft loss in different time intervals after transplantation is shown in Figure 1. The median time interval between transplantation and graft loss was 10 days (range 1 day to 7.7 years).
Figure 1. Number of grafts lost and risk of graft loss after transplantation. Between 5 and 6 years, no grafts were lost. *Percentage graft loss according to the number of grafts at risk during that period.
Causes of Graft Loss
Death with Functioning Graft
Median time between transplantation and death was 22 days (range 1 day to 6.2 years). Nine children died within 1 month after transplantation. Causes of death in these children were brain death (n = 5), sepsis (n = 2), hyperkalemia (n = 1), and rupture of a splenic artery aneurysm (n = 1). Nine children died more than 1 month after transplantation. Causes were sepsis (n = 4; 2 months and 2, 3, and 8 years after transplantation), posttransplant lymphoproliferative disease (n = 2; 3.5 and 4 years), epileptic seizures (n = 1; 6 months), metastases of a hepatoblastoma (n = 1; 7 months), and de novo malignancy (leukemia, n = 1; 6 years).
Vascular Complications
Median time between transplantation and graft loss resulting from a vascular complication was 6 days (range 1–13). Twelve grafts (8%) were lost because of hepatic artery thrombosis, four (2%) because of portal vein thrombosis, and one (1%) because of combined thrombosis of the hepatic artery and portal vein. Three grafts (2%) were lost as a result of hepatic outflow obstruction caused by torsion of the inferior caval vein, compression of the inferior vena cava by the graft, and thrombosis of the hepatic veins. Fifteen children were retransplanted; of these, seven are currently alive and five died of graft failure before any reintervention could be performed.
Primary Nonfunction
Median time between transplantation and graft loss resulting from primary nonfunction (PNF) was 3 days (range 2–11). Three children died because no new liver became available in time, and six underwent retransplantation. Of the latter, three died, including one who died of PNF of the new graft. Three children (33%) who had PNF were alive at the end of the observation period.
Fibrosis or Cirrhosis
Graft loss resulting from fibrosis or cirrhosis was caused by secondary biliary cirrhosis (5/157 [3%]), ischemic-type biliary strictures (3/157 [2%]), de novo hepatitis C (1/157 [1%]), or portal fibrosis 15 of unknown cause (5/157 [3%]). Median time between transplantation and graft loss resulting from fibrosis or cirrhosis was 2.2 years (range 2 months to 7.7 years). Causes of secondary biliary cirrhosis were diverse: bile duct strictures, a leaking gallbladder conduit with a necrotic extrahepatic bile duct, bile leakage from the cut surface of a segmental graft with a stricture proximal to the hepaticojejunostomy, stricture of the choledochocholedochostomy, and stenosis of a Roux-en-Y hepaticojejunostomy. One of these children died of sepsis after a surgical intervention, and four children were retransplanted between 3 months and 4.5 years after transplantation, after which one died of sepsis. Children with ischemic-type biliary strictures underwent successful retransplantation 8, 12, and 22 months, respectively, after transplantation. De novo hepatitis C of unknown source was diagnosed in one child with poor liver function test results who died of sepsis 4 years after transplantation. Of the five children in whom the cause of portal fibrosis remained unknown, three underwent successful retransplantation and two died before retransplantation could be performed.
Rejection
Two grafts (1%) were lost because of acute rejection that did not respond to methylprednisolone or antithymocyte globulin therapy. In both patients, who initially received immunosuppressive therapy with cyclosporine, graft failure developed, and they underwent retransplantation after 8 days. One child died of brain stem herniation shortly after retransplantation and the other recovered completely. Four grafts (3%) were lost as a result of chronic rejection. One child was considered unfit for retransplantation and died 11 months after primary transplantation. Three remaining children underwent successful retransplantation 10, 13, and 16 months after initial transplantation.
Multisystem Organ Failure
One patient died of multisystem organ failure after a third retransplantation and another died after graft failure from portal vein thrombosis.
Graft Necrosis
A left liver lobe graft was lost after a second retransplantation in a 1-year-old child. The retransplantation procedure was complicated by extensive blood loss from the resection surface of the graft and necrosis of a part of the graft without vascular thrombosis. Because the graft was considered compromised, a third retransplantation was performed after 10 days, and recovery was complete.
Risk Factors for Early and Late Graft Loss
The Child-Pugh score, duration of the anhepatic phase, and urgent transplantations proved to be risk factors for early graft loss (Table 1). Because of multicolinearity between these factors, as shown in the lower half of Table 1, a multivariate analysis could not be performed to assess the independent contribution of each variable on the incidence of graft loss. 16 One-month and 1-, 3-, and 5-year graft survival rates after urgent transplantation were 54%, 46%, 46%, and 42%, respectively, compared with 77%, 70%, 63%, and 57%, respectively, after elective transplantation (P < .01). In six patients, hepatectomy was performed before transplantation because of a toxic liver syndrome resulting from liver failure. This resulted in a median anhepatic phase of 18.5 hours (range 8–36) in these instances. Five of these patients died shortly after transplantation of brain death (n = 4) and graft failure (n = 1). When excluding these patients from analysis, the duration of the anhepatic phase still proved to be a risk factor for early graft loss and was associated with the urgency of the transplantation as well as with the Child-Pugh score (data not shown).
Table 1. RISK FACTORS FOR EARLY GRAFT LOSS AND ASSOCIATIONS BETWEEN THESE RISK FACTORS
Continuous variables are presented as median (range) and categorical variables as number (percentage).
*r, Spearman correlation coefficient.
The donor age, donor/recipient weight ratio, blood loss index, and technical-variant liver grafts proved to be risk factors for late graft loss (Table 2). Because of multicolinearity, a multivariate analysis was not meaningful in this situation as well. Survival rates of the different graft types are listed in Table 3. Survival of technical-variant liver grafts was significantly lower than full-size liver grafts (P = .05). This was mainly caused by low survival of segmental grafts (P = .03 vs. full-size grafts). Causes of graft loss based on graft types are listed in Table 4. Hepatic artery thrombosis was significantly more often a cause of loss after transplantation of full-size grafts compared with technical-variant liver grafts (P < .04).
Table 2. RISK FACTORS FOR LATE GRAFT LOSS AND ASSOCIATIONS BETWEEN THESE RISK FACTORS
Continuous variables are presented as median (range) and categorical variables as number (percentage).
D/R, donor/recipient.
*r, Spearman correlation coefficient.
Table 3. GRAFT SURVIVAL BASED ON TYPE OF GRAFT
Number of grafts at risk is given in parentheses.
*P value vs. full-size grafts.
Table 4. CAUSES OF GRAFT LOSS
* Including one graft lost to combined hepatic artery and portal vein thrombosis.
†P < .04 vs. technical-variant.
DISCUSSION
Despite good 1- and 5-year patient survival rates of 82% and 71%, respectively, graft loss after pediatric liver transplantation remains a significant problem. During a 16-year experience, 45% of all grafts were lost. The issue of graft loss is more pronounced against the background of the existing shortage of donor livers. A retransplantation rate of 24% underlines the important problem of graft loss in this context. Graft survival rates as well as the retransplantation rate are comparable with other reports on pediatric liver transplantation. 2,5,17 However, these rates are inferior compared with adult transplantation. 18 It appears that more grafts are needed to save one pediatric patient, causing more pressure on the already restricted donor pool. These findings emphasize the importance of a better understanding of graft loss after pediatric liver transplantation. Most lost grafts (63%) were lost within 1 month after transplantation. Long-term survival rates of grafts that survived the first month after transplantation were excellent. Grafts were lost due to death of children with a well-functioning graft (25%) or graft-related complications (75%).
Risk factors for early graft loss were urgent transplantations, poor clinical condition of the child before transplantation (as expressed by a high Child-Pugh score), and duration of the anhepatic phase. Because of multicolinearity, a multivariate analysis could not be performed to assess the independent contribution of each variable on the incidence of graft loss. 16 The impact of the risk factors urgency and a high Child-Pugh score can be reduced by timely referral of potential recipients. The length of the anhepatic phase should be minimized. An important measure in this respect is to prepare the new (partial) graft either before the start of the recipient operation or preferably by a separate team during the recipient hepatectomy.
Brain stem herniation and sepsis were important causes of death of children with well-functioning grafts. An important question is whether these deaths could have been avoided. Most children who died early after transplantation with a well-functioning graft were urgently transplanted for fulminant hepatic failure, a diagnosis with a high rate of patient loss. 19 Death in these children is related to the advanced stage of their disease and the extent of cerebral edema, which ultimately will result in irreversible brain injury, multisystem organ failure, or sepsis. 20,21 This might be avoidable by early referral to a transplant center, early diagnostics (including intracranial pressure monitoring), 22 and transplantation of these children as soon as possible after the diagnosis has been made and spontaneous recovery is excluded. Premature hepatectomy before transplantation for toxic liver syndrome seemed not to contribute to an improved outcome in these patients. Support of an extracorporeal bioartificial liver, of which early results are promising, might be useful in such instances. 23
Sepsis early after transplantation has been associated with surgical interventions, blood loss, and immunosuppressive therapy. 24,25 Knowledge of patterns of infection after pediatric liver transplantation should lead to preventive measures to reduce the death rate. 25 Sepsis proved to be the main cause of death more than 1 month after transplantation; this has also been reported by others. 4,26 Sepsis in this situation occurs suddenly but can be rapidly progressive and fatal. 4 It is a misunderstanding that children who receive low-dose immunosuppression have the same risk for infections as the general pediatric population. 26
Risk factors for late graft loss were technical-variant liver grafts, high donor age, high donor/recipient weight ratio, and high blood loss index. Because of multicolinearity, a multivariate analysis was not performed. However, technical-variant liver graft seems to be the most important variable responsible for late graft loss. Survival of technical-variant liver grafts was lower compared with full-size grafts. In an earlier report on technical-variant liver grafts only used in elective transplantations, we could not show a statistically significant difference in graft survival between both types of grafts. 27 Apparently, technical-variant grafts are more often used in urgent situations, thereby leading to lower survival rates compared with full-size liver grafts. This is also stressed by others, who have found that the proportion of grafts lost because of death of the recipient after urgent transplantation was higher with partial grafts. 28 Further, it was recently shown that reduced-size and split-liver grafts are independent predictors of graft loss. 29
Graft-related complications leading to graft loss included mainly vascular complications, PNF, and fibrosis or cirrhosis of the graft. The risk for hepatic artery thrombosis is increased in case of transplantation of full-size grafts in small children because of the relatively small arteries. 11 However, a technical-variant graft proved to be an important risk factor for portal vein thrombosis and obstruction of the hepatic outflow tract. 30 Primary nonfunction has important implications for graft survival as well as for patient survival because it always results in graft loss, and only 33% of the children who had PNF survived. We still lack understanding of the etiology of PNF. 31 Reduced-size liver grafts proved to be an independent risk factor for PNF after multivariate analysis. 32 Explanations for the higher incidence of PNF in these partial grafts might be the influence of older donors with fatty changes in their biopsies, 32,33 prolonged cold ischemia times, 32 or improper cooling of such grafts during the back-table procedure. Also, insufficient liver mass with consequently insufficient capacity or too much liver mass resulting in hypoperfusion of the graft may contribute to such losses. Currently, required graft size is often estimated by using the donor/recipient age or weight ratio. 11,34 However, the liver volume/body weight ratio is not constant during a child’s growth. 35 To provide adequate liver volume and thereby reduce the chance for PNF, calculation of the standard liver volume for the individual recipient, as done in living-donor liver transplantation, 36,37 may also be necessary in transplantation of technical-variant grafts. However, this hypothesis has to be confirmed by prospective studies.
Main causes of late graft loss proved to be fibrosis or cirrhosis, including secondary biliary cirrhosis, ischemic-type biliary lesions, hepatitis C, and fibrosis or cirrhosis of unknown origin. The incidences of these complications were higher after using technical-variant grafts compared with full-size liver grafts and were in most instances associated with biliary complications. Recently, we found more biliary complications after transplantation of technical-variant grafts compared with full-size grafts, as expressed by a higher incidence of bile leakage and cholangitis. 27 In addition, the occurrence of biliary complications is an independent risk factor for portal fibrosis 1 year after transplantation. 38 These findings emphasize the importance of preventing biliary complications by securing vascularization of the bile ducts and checking the transection surface of technical-variant grafts for bile leakage.
This study showed that graft loss after pediatric liver transplantation is a substantial problem. From the analysis, it is clear that adaptation of several factors can reduce the incidence of graft loss. Potential recipients should be referred early so they can undergo transplantation in an earlier phase of their disease, with consequently lower Child-Pugh scores and in a less urgent situation. Donor selection is important, especially in transplantation of technical-variant liver grafts. Fatty grafts or overly large age and weight discrepancies with the recipient should be avoided. Factors related to the recipient operation remain important. The logistics of the operation need to be optimized to minimize the cold ischemia time and anhepatic phase. Technical-variant liver grafts should be prepared with the utmost care to prevent biliary complications.
Footnotes
Correspondence: Prof. Dr. M. J. H. Slooff, University Hospital Groningen, Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.
E-mail: m.j.h.Slooff@chir.azg.nl
Accepted for publication May 3, 2001.
References
- 1.National Institutes of Health Consensus Development Conference Statement. Liver transplantation. Hepatology 1984; 4: 107S–110S. [PubMed] [Google Scholar]
- 2.Eckhoff DE, D’Alessandro AM, Knechtle SJ, et al. 100 consecutive liver transplants in infants and children: an 8-year experience. J Pediatr Surg 1994; 29: 1135–1139. [DOI] [PubMed] [Google Scholar]
- 3.Andrews W, Sommerauer J, Roden J, et al. 10 years of pediatric liver transplantation. J Pediatr Surg 1996; 31: 619–624. [DOI] [PubMed] [Google Scholar]
- 4.Ryckman FC, Alonso MH, Bucuvalas JC, et al. Long-term survival after liver transplantation. J Pediatr Surg 1999; 34: 845–849. [DOI] [PubMed] [Google Scholar]
- 5.Goss JA, Shackleton CR, McDiarmid SV, et al. Long-term results of pediatric liver transplantation: an analysis of 569 transplants. Ann Surg 1998; 228: 411–420. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Achilleos OA, Mirza DF, Talbot D, et al. Outcome of liver retransplantation in children. Liver Transplant Surg 1999; 5: 401–406. [DOI] [PubMed] [Google Scholar]
- 7.Peeters PM, TenVergert EM, Bijleveld CM, et al. The influence of intraoperative blood loss on graft survival and morbidity after orthotopic liver transplantation in children. Pediatr Surg Int 1995; 10: 120–125. [Google Scholar]
- 8.Rosman C, Klompmaker IJ, Bonsel GJ, et al. The efficacy of selective bowel decontamination as infection prevention after liver transplantation. Transplant Proc 1990; 22: 1554–1555. [PubMed] [Google Scholar]
- 9.Starzl TE, Hakala TR, Shaw BW Jr, et al. A flexible procedure for multiple cadaveric organ procurement. Surg Gynecol Obstet 1984; 158: 223–230. [PMC free article] [PubMed] [Google Scholar]
- 10.Starzl TE, Miller C, Broznick B, et al. An improved technique for multiple organ harvesting. Surg Gynecol Obstet 1987; 165: 343–348. [PMC free article] [PubMed] [Google Scholar]
- 11.Otte JB, Ville-de-Goyet J, Sokal E, et al. Size reduction of the donor liver is a safe way to alleviate the shortage of size-matched organs in pediatric liver transplantation. Ann Surg 1990; 211: 146–157. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Broelsch CE, Emond JC, Whitington PF, et al. Application of reduced-size liver transplants as split grafts, auxiliary orthotopic grafts, and living related segmental transplants. Ann Surg 1990; 212: 368–375. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Starzl TE, Groth CG, Brettschneider L, et al. Orthotopic homotransplantation of the human liver. Ann Surg 1968; 168: 392–415. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Ringe B, Pichlmayr R, Burdelski M. A new technique of hepatic vein reconstruction in partial liver transplantation. Transplant Int 1988; 1: 30–35. [DOI] [PubMed] [Google Scholar]
- 15.Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol 1995; 19: 1409–1417. [DOI] [PubMed] [Google Scholar]
- 16.Hosmer D Jr, Lemeshow S. Applied logistic regression. New York: John Wiley; 1989.
- 17.Salt A, Noble JG, Barnes ND, et al. Liver transplantation in 100 children: Cambridge and King’s College Hospital series. Br Med J 1992; 304: 416–421. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Wiesner RH. A long-term comparison of tacrolimus (FK506) versus cyclosporine in liver transplantation: a report of the United States FK506 Study Group. Transplantation 1998; 66: 493–499. [DOI] [PubMed] [Google Scholar]
- 19.Adam R, Bismuth H, Castaing D, et al. Registry of the European Liver Transplant Association, Data Analysis 05/1968–12/1997. European Liver Transplant Registry (ELTR); 1999.
- 20.Goss JA, Shackleton CR, Maggard M, et al. Liver transplantation for fulminant hepatic failure in the pediatric patient. Arch Surg 1998; 133: 839–846. [DOI] [PubMed] [Google Scholar]
- 21.Nicolette L, Billmire D, Faulkenstein K, et al. Transplantation for acute hepatic failure in children. J Pediatr Surg 1998; 33: 998–1002. [DOI] [PubMed] [Google Scholar]
- 22.Alper G, Jarjour IT, Reyes JD, et al. Outcome of children with cerebral edema caused by fulminant hepatic failure. Pediatr Neurol 1998; 18: 299–304. [DOI] [PubMed] [Google Scholar]
- 23.Detry O, Arkadopoulos N, Ting P, et al. Clinical use of a bioartificial liver in the treatment of acetaminophen-induced fulminant hepatic failure. Am Surg 1999; 65: 934–938. [PubMed] [Google Scholar]
- 24.Cacciarelli TV, Esquivel CO, Moore DH, et al. Factors affecting survival after orthotopic liver transplantation in infants. Transplantation 1997; 64: 242–248. [DOI] [PubMed] [Google Scholar]
- 25.George DL, Arnow PM, Fox A, et al. Patterns of infection after pediatric liver transplantation. Am J Dis Child 1992; 146: 924–929. [DOI] [PubMed] [Google Scholar]
- 26.Sudan DL, Shaw-BW J, Langnas AN. Causes of late mortality in pediatric liver transplant recipients. Ann Surg 1998; 227: 289–295. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Sieders E, Peeters PM, TenVergert EM, et al. Analysis of survival and morbidity after pediatric liver transplantation with full-size and technical-variant grafts. Transplantation 1999; 68: 540–545. [DOI] [PubMed] [Google Scholar]
- 28.Ville-de-Goyet J, Hausleithner V, Reding R, et al. Impact of innovative techniques on the waiting list and results in pediatric liver transplantation. Transplantation 1993; 56: 1130–1136. [DOI] [PubMed] [Google Scholar]
- 29.Cacciarelli TV, Dvorchik I, Mazariegos GV, et al. An analysis of pretransplantation variables associated with long-term allograft outcome in pediatric liver transplant recipients receiving primary tacrolimus (FK506) therapy. Transplantation 1999; 68: 650–655. [DOI] [PubMed] [Google Scholar]
- 30.Sieders E, Peeters PMJG, TenVergert EM, et al. Early vascular complications after pediatric liver transplantation. Liver Transplant 2000; 6: 326–332. [DOI] [PubMed] [Google Scholar]
- 31.Strasberg SM, Howard TK, Molmenti EP, et al. Selecting the donor liver: risk factors for poor function after orthotopic liver transplantation. Hepatology 1994; 20: 829–838. [DOI] [PubMed] [Google Scholar]
- 32.Ploeg RJ, D’Alessandro AM, Knechtle SJ, et al. Risk factors for primary dysfunction after liver transplantation: a multivariate analysis. Transplantation 1993; 55: 807–813. [DOI] [PubMed] [Google Scholar]
- 33.Pruim J, van Woerden WF, Knol E, et al. Donor data in liver grafts with primary non-function—a preliminary analysis by the European Liver Registry. Transplant Proc 1989; 21: 2383–2384. [PubMed] [Google Scholar]
- 34.Broelsch CE, Emond JC, Thistlethwaite JR, et al. Liver transplantation, including the concept of reduced-size liver transplants in children. Ann Surg 1988; 208: 410–420. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Balistreri WF. Liver and biliary system: the development of heptic and biliary structures and function. In: Behrman RE, Kliegman RM, eds. Nelson textbook of pediatrics. Philadelphia: Saunders; 1992: 1001–1004.
- 36.Urata K, Kawasaki S, Matsunami H, et al. Calculation of child and adult standard liver volume for liver transplantation. Hepatology 1995; 21: 1317–1321. [PubMed] [Google Scholar]
- 37.Heinemann A, Wischhusen F, Puschel K, et al. Standard liver vol-ume in the Caucasian population. Liver Transplant Surg 1999; 5: 366–368. [DOI] [PubMed] [Google Scholar]
- 38.Peeters PM, Sieders E, van den Heuvel M, et al. Predictive factors for portal fibrosis in pediatric liver transplant recipients. Transplantation 2000; 70: 1581–1587. [DOI] [PubMed] [Google Scholar]