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ARTICLE
Single Center Long-Term Results of Pediatric Liver Transplantation

Objectives: Liver replacement continues to be the only definitive mode of therapy for children with end-stage liver disease. However, it remains challenging because of the rare donor organs, complex surgical demands, and the necessity to prevent long-term complications. Our objectives were to analyze 16 years of experience in the Shiraz University Organ Transplant Center.

Materials and Methods: We retrospectively analyzed the records of 752 patients (< 18 years old) who underwent orthotopic liver transplant at our center over a 16-year period. Mean age was 90 months, and male-to-female ratio was 1.25. Of the 752 transplants, 354 were whole organs, 311 were from living related donors, and 87 were in situ split liver allografts. Patient and graft survival rates were determined at 1, 3, and 5 years, and results between groups were compared.

Results: Overall mortality was 31.8%. The 1-, 3-, and 5-year patient survival rates were 77%, 69%, and 66%, respectively, whereas the respective graft survival rates were 75%, 68%, and 65%. We observed significant differences in survival according to graft type (log-rank test, P < .001). We also observed significant differences in survival probabilities according to age (log-rank test, P < .001). Cox regression was used to simultaneously analyze effects of age and graft type on survival.

Both graft type and age significantly affected survival (P < .001). The 1-, 3, and 5-year survival rates for patients having whole organ transplants were 88%, 81%, and 78%. Patients who received living donor grafts had respective survival rates of 66%, 60%, and 58%, with rates of 65%, 47%, and 47% for patients who received split grafts.

Conclusions: Our results were similar to those observed in the literature in terms of indication for transplant and posttransplant survival.


Key words : Children, Graft survival, Patient survival

Introduction

Children have distinct diseases, clinical suscep­tibilities, physiologic responses, and neurocognitive and neurodevelopmental features different from adults. In fact, even within the pediatric age group, differences can be found between newborns, infants, children, and adolescents.

Liver transplant provides a lifesaving treatment option for children with liver disease. Current challenges include identifying those ready for a liver transplant and the optimal timing for listing a patient for transplant. Within a span of 3 decades, pediatric liver transplant has matured as a clinical therapy that is practiced worldwide in numerous medical institutions. This transformation can be traced to a few critical developments, including improvements in immunosuppression, application of technical variant allografts, and selection of potential candidates and organ allocation.

In Iran, the first liver transplant in a child was performed in Namazi Hospital (Shiraz, Iran) in 1999.1 The number of liver transplant procedures has increased in our center to reach 113 pediatric transplants in 2015. Progress in the management of immunosuppressive therapy suitable for children has been of key importance in improving survival after transplant. The use of technical variant allografts has assisted in overcoming the shortage of suitable donors for children, permitted many more children to receive transplants, and reduced wait list mortality. Finally, our understanding of where, when, and how to use transplant therapy in children has improved. For example, for unresectable hepato­blastoma, when the tumor remains unresectable and a potential living donor is available, we now know that donor work-up and orthotopic liver transplant preparation should be initiated by the fourth or fifth cycle of chemotherapy.2 Comorbidities such as hepatopulmonary syndrome and impaired cardiac function, rather than size and age, are now the limiting factors to successful transplant procedures. With improved knowledge of candidate selection, 1-year graft survival after pediatric liver transplant exceeds 90% and the 5-year survival rate is 85%.3,4

Several factors about liver transplant must be considered if it is to be used in a manner that is consistent with the best medical interests of a pediatric patient. First, it must be remembered that it is a high-risk procedure, carrying a significant risk of mortality under the best circumstances. Second, there is potential for chronic disability and requirement for long-term drug administration. Although a long-term, high-quality life is possible, recent studies indicate that children who receive liver transplants have lower health-related quality of life levels than healthy individuals.5 Children who have received liver transplants have reported impairments across both physical and psychologic dimensions and have health-related quality of life levels comparable to children with other chronic health conditions such as cancer in remission or renal transplant.6,7 Liver transplant is indicated for all children with liver disease and progressive deterioration of health, before the appearance of complications that can make the procedure excessively risky. The following are indicators of need for transplant: cholestasis, pruritus, and/or ascites that are untreatable from a clinical point of view, portal hypertension with bleeding from varices that is unresponsive to treatment, multiple episodes of cholangitis or episodes of spontaneous bacterial peritonitis, progressively deficient hepatic synthesis, affected somatic growth, and hepatic encephalopathy.8,9

In general, indications for liver transplant in children include cholestatic diseases, metabolic disorders, acute liver failure resulting from viral infections or drug consumption, chronic hepatitis, cirrhosis, and malignancies.8 Nevertheless, biliary atresia is the most prevalent disease leading to liver transplant in children. The aim of this study was to analyze the 16-year liver transplant experience of a single center in Shiraz, Iran, which included 752 pediatric orthotopic liver transplants for end-stage liver disease and metabolic disorders and which focused on the effects of age and graft type on survival.

Materials and Methods

The study included all patients less than 18 years old who had undergone a first liver transplant at Namazi Hospital (Shiraz, Iran) between January 2000 and January 2016.

We obtained patient information from medical records, which included recipient characteristics (age, sex, and the initial diagnosis of liver disease) and donor characteristics (age, sex, and transplant features, including type of graft).

All protocols, experimental studies, and clinical trials involving human participants at our institution were approved by our ethics committee before the initiation of study and conformed to the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent was obtained from patients or their guardians before inclusion in the medical records database.

Criteria used to define complications of primary graft nonfunction included presence of persistent coagulopathy, acidosis, hyperkalemia, and pro­gressively elevated aminotransferases. Criteria used to define acute rejection included abnormal laboratory results (aminotransferase, alkaline phosphatase, bilirubin, gamma-glutamyltransferase levels) asso­ciated with hepatic histopathology. Criteria used to define chronic rejection included abnormal laboratory results (aminotransferase, alkaline phosphatase, bilirubin, gamma-glutamyltransferase levels) and confirmation with liver biopsy. Vascular and biliary complications were documented by imaging studies and laboratory findings.

Our cutoff date for data was January 1, 2016, with day of transplant considered day 0 in recipients.

Statistical analyses
Survival probabilities were estimated by the Kaplan-Meier method, with significance determined with the log-rank test. Cox regression analysis was used to consider variables on survival function simultaneously. P < .05 was considered statistically significant. Statistical analysis was performed with SPSS software (SPSS: An IBM Company, version 21, IBM Corporation, Armonk, NY, USA).

Results

Our study included 752 patients with mean age of 90 months (range, 2-204 mo) and male-to-female ratio of 1.25 (418 male and 334 female patients). There were 354 whole organ donors (47.1%), 311 living related donors (partial graft type; 41.4%), and 87 in situ split liver allografts (11.6%).

Patient groups included 128 patients (17%) below 2 years old, 409 patients (54.4%) between 2 and 12 years old, and 215 patients (28.6%) from 12 to 18 years old. The most common cause of end-stage liver disease was cholestatic disease (38.8%) followed by metabolic disorder (38%). Regarding the donors, 44.9% were female and 54.7% were male. The mean age (SD) of the donors was 22.04 (12.37) years (Table 1).

Mean patient survival was 117.67 months, and 1- and 5-year overall patient survival rates were 77% and 66%, respectively. We found mean patient survival to be 115.84 months and 1- and 5-year graft survival rates to be 75% and 65%, respectively (Table 2 and Figures 1 and 2).

We also determined patient survival according to the 3 age groups. For the 128 patients (17%) who were less than 2 years old, 1- and 5-year patient survival rates were 43% and 32%. One- and 5-year survival rates for the 409 patients (54.4%) who were between 2 and 12 years old were 82% and 71%, respectively. Finally, 1- and 5-year survival rates for the 215 patients (28.6%) who ranged from 12 to 18 years old were 86% and 78%, respectively (Table 3 and Figure 3). Survival rates were significantly different according to age (log-rank test, P < .001).

We also determined survival according to type of transplant. In the 354 patients (47.1%) who received whole organ donations, 1- and 5-year survival rates were 88% and 79%, respectively. One- and 5-year survival rates for the 311 patients (41.4%) who received living related-donor liver transplants (partial grafts) were 67% and 58%, respectively. Finally, 1- and 5-year survival rates for the 87 patients (11.6%) who received split graft liver transplants were 65% and 47%, respectively (Table 4 and Figure 4). Mean patient survival for each graft type was 11 years and 6 months for whole organ, 8 years and 10 months for living related donor graft, and 4 years and 9 months for split liver graft (Table 4). Survival results were significantly different among graft types (log-rank test, P < .001).

We also compared survival probabilities according to different ages and graft types. There were 19 patients and 9 events (47.4%) in the group who were less than 2 years old and had whole organ transplants, with 1- and 5-year survival rates of 68%, and 34% and mean survival of 39.33 months. There were 92 patients and 59 events (64.1%) who were less than 2 years old and had living donor-liver transplants; in these patients, 1- and 5-year survival rates were 41% and 33% and mean survival was 36.07 months. Finally, in the 17 patients (14 events; 82.3%) who were less than 2 years old and who received split liver grafts, 1- and 3-year survival rates were 23% and 16% and mean survival was 7.87 months.

We also compared the patients who were between 2 and 12 years old according to graft type. For recipients of whole organ grafts, there were 164 patients with 31 events (18.9%), and 1- and 5-year survival rates were 89% and 79%, with mean survival of 126.57 months. For recipients of living donations, there were 187 patients with 55 events (29.4%), and 1- and 5-year survival rates were 78% and 69%, with mean survival time of 125.81 months. For recipients of split liver grafts, there were 57 patients with 24 events (42.1%), and 1- and 5-year survival rates were 75% and 55%, with mean survival time of 66.98 months.

A survival comparison according to graft type was also made for patients who ranged from 12 to 18 years old. For recipients of whole organ grafts, there were 170 patients with 30 events (17.6%), and 1- and 5-year survival rates were 90% and 82%, with mean survival of 144.61 months. For recipients of living donations, there were 32 patients with 11 events (34.4%), and 1- and 5-year survival rates were 72% and 64%, with mean survival of 72.19 months. For recipients of split liver grafts, there were 13 patients with 5 events (38.5%), and 1- and 5-year survival rates were 77% and 55%, with mean survival of 62.74 months (Table 5).

Cox regression analysis was used to consider simultaneously the effects of age, diagnosis, and graft type on survival function. We found that all factors (graft type, diagnosis, and age) significantly affected survival (P ≤ .001, P = .004, and P < .001). In a hazard ratio (HR) calculation comparing patients who received whole organ grafts versus patients who received split grafts, graft type was significant (P ≤ .001); hazard ratio was also significant for living donor grafts versus split grafts (P = .006). Regarding original diagnosis, hazard ratio was significant when we compared the metabolic diagnosis versus other diagnosis (P = .009); however, no significance in hazard ratio was shown when we compared diagnosis of cholestasis and hepatitis versus other diagnosis. In addition, hazard ratio regarding age showed significant difference in those less than 2 years old versus those who ranged from 12 to 18 years (P ≤ .001), whereas hazard ratio was not significant when we compared the 2-year to 12-year age group versus the 12-year to 18-year age group (Table 6).

Discussion

Liver transplant started in Iran in 1994, and the most common indication for liver transplant in children at our center is biliary atresia. This primary indication is the same as in other pediatric series.10-14 Similar to other published studies, age and weight had the greatest effects on patient survival and survival rates were lowest in patients who were less than 2 years old. In our center, most of the patients who received living donor and split liver grafts were those who were less than 2 years old, and this age group also had the lowest survival rate.

The overall 5-year survival rate in our study was 66%, which is less than that reported by most international groups. Migliazza and associates conducted a study in Spain and reported patient survival to be 80% at 1 year, 74% at 5 years, and 74% at 10 years.15 Moray and associates reported 5- and 10-year survival rates of 82.3% and 78.9%.16 At the Children’s Hospital of Pittsburgh, Jain and associates17 reported 5-year survival rate of 72%; however, the same study reported that survival rates for children greater than 2 years of age were 79.5% at 1 year, 75.7% at 5 years, and 71.6% at 10 years, results that are similar to our results. We found 1-year survival to be 82% in those between 2 and 12 years and 86% for those from 12 to 18 years old. The 5-year survival rates in these same age groups in our study were 71% and 78%, which were somewhat better. However, 1- and 5-year survival rates were better in Jain and associates17 who reported rates of 72.6% and 66.9%, respectively, for those who were less than 2 years old, whereas our results were 43% and 32% at 1 and 5 years, respectively.

We found that survival in pediatric patients who received whole organ grafts was better than survival in patients who received other graft types. In addition, most patients received whole organ grafts at our center, and the number of whole organ graft transplants has increased yearly, suggesting that the donation system has improved in Iran. Therefore, increasing whole organ transplants will probably lead to improved survival in patients treated at the Shiraz Organ Transplant Center. Our percentage of whole organ liver transplants is better than that reported in other pediatric series. In Chile, Buckel and associates reported that 47% of pediatric patients (N = 132) received whole organ grafts18; in Brazil, Tannuri and associates reported that, in 206 patients, 39.8% received whole organ grafts.19

Compared with a study by Haseli and associates of 392 pediatric patients under 18 years old who had undergone a first liver transplant1 at Namazi Hospital between April 2000 and March 2011, we can conclude that the number of pediatric transplant procedures and the survival rate have improved between 2009 to 2016. In addition, Haseli and associates also reported that 50 deaths (46.3%) occurred in the first month posttransplant and 78 deaths (63%) occurred in the first trimester posttransplant, a rate similar to that also reported by Jain and associates, who reported a death rate of 55.4% within the first 3 months posttransplant.17

Conclusions

Results in our patient sample are similar to those reported in the literature in terms of indications for transplant and posttransplant survival. Nevertheless, we need to improve our results in terms of reducing the number of complications unrelated to the graft.


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DOI : 10.6002/ect.2017.0110


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From the 1Shiraz Organ Transplant Center and the 2Department of Pediatric Gastroenterology, Organ Transplantation Center, Namazi Teaching Hospital, Shiraz University of Medical Sciences, Shiraz, I. R. Iran; the 3Organ Procurement Unit, Namazi Teaching Hospital, and the 4Statistics Advisor, Namazi Teaching Hospital, Shiraz, I. R. Iran
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare. This article was extracted from Mohammad Hussein Al Sayyed’s fellowship of organ transplant surgery thesis. The authors thank Shiraz University of Medical Sciences, Shiraz, Iran, and also the Center for Development of Clinical Research of Namazi Teaching Hospital.
Corresponding author: Alireza Shamsaeefar, Department of Organ Transplantation, Namazi Hospital, Shiraz, I. R. Iran
Phone: +989177111566
E-mail: shamsaeefar@yahoo.com