History of pediatric liver transplantation in Latin America

According to data from the Transplant Society of Latin America and the Caribbean and national organizations and societies, by 2014, Latin American countries had performed more than 2,500 LT per year, representing 17% of the world’s transplant activity, thus resulting in a ratio of 4.4 LT pmp per year [18]. Of the top twenty countries with the highest rates of LT per million inhabitants, in Latin America, there are only Brazil and Argentina, even though they are countries with lower investment in health compared to those in North America and Europe. However, only eight of the twelve countries performing LT in Latin America do it on pediatric patients, and in 2016, a total of 4,593 pediatric LT were performed [19].

Specifically in Brazil, liver transplantation began in the 1960s with deceased donors, and in 1989, it was the first country in the world to perform the transplant procedure with a living donor. From 1989 to 2014, the LT procedure with deceased donors was performed 1,615 times, and from 1995 to 2014, 1,209 were performed with living donors. The implementation of living donor transplantation has mainly benefited the pediatric population, as this technique accounts for 53.4% of LT performed on children in Brazil [18, 19].

With the creation of the National Transplant System (SNT) in 1997, organ transplants in Brazil are regulated by a federal law that seeks to guarantee equal access to treatment on a national scale, and its control is carried out by the Health Departments of each state in the country, allowing for regional allocation [20]. It is recognized worldwide as one of the largest transplant systems in the world. Around 42.3% of LT are carried out in the South West region, due to the great economic disparity present in the country. With regard to pediatric LT, this difference is even greater, with 66% of them performed in the city of São Paulo [19].

Brazil is the second country in absolute numbers for LT. In the last two decades, there has been an increase in the donation rate: in 2006, it was 6.5 pmp, and in 2014 it was 13.1 pmp [19]. Although the annual donation rate has doubled in the past few years, it still cannot be compared to that seen in European countries (15 pmp) and the United States (26 pmp). This scenario can be explained by the lack of notification of potential brain-dead donors, family recurrence, and donors who are not viable due to the lack of adequate donor care in the region [18].

In general terms, Latin America started practicing LT early, but it has shown slow growth, mainly due to the prevalence of countries in a medium human development index zone, low government investment in health, and low health indices. Compared to more developed countries, Latin America invests around 10% to 15% of its gross domestic index in health, while countries in Europe, North America, and Oceania spend more than 20%. In addition, countries such as Japan, the United States, and Canada have better national registries of transplants performed, thus allowing an adequate assessment of pediatric LT activity. These evaluations allow the improvement of transplant centers’ quality, and thus have better results compared to Latin American countries. Although countries such as Brazil and Argentina have a volume of procedures comparable to European and North American countries, there is a great lack of information on pediatric transplants carried out throughout Latin America [19].

Etiopathogeny, clinical status, and diagnosis

PELD scores

The PELD score is a formula developed to assess the risk of death in pediatric patients waiting for a transplant and thus allocate the most severely ill patients as a priority on the waiting list. Until July 2006, the transplant waiting list in Brazil was organized in chronological order, i.e., the first person on the list was the one who was registered first, which was not an accurate representation of the degree of illness and of the patients’ risk of death [27]. Currently, the calculated PELD score is multiplied by three, and the result is used to include patients under twelve years of age on the waiting list. The parameters used for evaluation include serum albumin levels, INR, and bilirubin levels [28, 29]. Since then, pediatric transplants have increased from 6.5% to 9.3% [30]. Despite the establishment of priority on the waiting list according to the patient’s condition severity, data have shown that the reduction in time on the waiting list has not fallen significantly (from 23% to 15% in two years). In this scenario, living donor transplantation has become an alternative, especially for the pediatric population in Brazil [19].

Living and deceased donors

Liver transplantation has emerged for pediatric and adult patients as a therapeutic option for diseases that previously had no prospect of improvement. However, the waiting list for an organ remains a problem for transplants in general, especially in children, due to the lack of compatibility between the donor organ and the recipient patient’s body. In paediatric transplants, the volume of grafts has to be reduced, and in addition, the patients’ clinical conditions are usually severe and make the choice of deceased donors even more selective [28].

In order to reduce the waiting time for an organ, the PELD score was implemented, which prioritizes LT. However, there was still the problem of compatibility between donors and recipients, which is why the technique of living donor liver transplantation (LDLT) was introduced, especially favoring the pediatric population [18, 19]. This technique benefits from good graft quality, early treatment of children, extensively evaluated grafts with optimal function, shorter cold ischemia time, and elective scheduling of the operation. These advantages outweigh the difficulties related to some possible complications, such as biliary reconstruction, organ size incompatibility, and the smaller caliber of vascular anastomoses [27–30].

Besides the option between deceased and living donors, there are also reduced, partial, double, or domino LT techniques. Split liver transplantation (SLT) increases the supply of organs for liver transplantation, as it divides the donated liver into two grafts that are normally transplanted into an adult and a child. Both the orthotopic transplant technique and SLT have equivalent patient survival and complication rates [18, 31].

The Brazilian policy aimed at encouraging the acceptance of split grafts by adult transplant centers ensures that all potentially divisible livers are offered first to pediatric patients with higher PELD scores and then the remaining grafts are offered secondarily to adult candidates [32].

Influence of nutritional aspects

The nutritional aspects of patients who are candidates for liver transplantation are directly influenced by their residual liver function, which causes metabolic changes that lead to a state of protein-energy malnutrition. This condition is characterized by an increase in glycolysis, lipid oxidation and protein catabolism, resulting in a loss of adipose tissue, with a depletion of essential fatty acids (linoleic and alpha-linolenic) and long-chain polyunsaturated fatty acids, as well as muscle tissue [33].

The high incidence of malnutrition in children who are candidates for transplantation, in addition to liver dysfunction, can also be attributed to the delay in their referral and the long time they remain on waiting lists [27]. The degree of nutrition before and after liver transplantation is an important predictor of the success of this therapy, both in the pediatric and adult population, since episodes of acute graft rejection are more associated with a lower percentage of total body fat [33]. According to a cohort study that analyzed variables related to the survival of paediatric patients and the post-transplant graft, children with low body weight or with pre-transplant malnutrition had a higher rate of late post-transplant mortality, as well as growth retardation, delayed neuropsychomotor development, and increased hospital admissions, consequently generating higher costs related to their treatment [21, 27]. Thus, malnutrition should be considered as important a parameter for predicting the success of transplant therapy as the other clinical manifestations usually analyzed for this. In addition to the organ failure resulting from the progression of the liver disease, there are other factors contributing to the persistence of the pediatric patient’s catabolic state in the post-transplant period, including the stress of the surgical intervention, the use of immunosuppressive therapy, the occurrence of new liver dysfunction, or the appearance of other concomitant conditions, such as sepsis, renal failure and, in pediatric patients, the worsening of the catabolic state due to physiological growth. Therefore, providing aggressive nutritional support in the post-operative period is essential for a better recovery and acceptance of the transplant [33].

Surgical techniques

Currently, the main therapeutic option for children with EHBA is hepatoportoenterostomy (HPE) surgery [34]. The Kasai technique and its variations consist of an anastomosis performed in an intestinal conduit to the surface of the hepatic hilum, of the Y-de-Roux type, to enable biliary drainage [21]. Despite the technical options for the LT procedure, there are currently two types of transplant: whole-liver and split deceased-donor and living-donor transplant, which correspond, respectively, to whole organ transplant and transplant of only part of the liver, which can come from a living or a deceased donor [26].

Several factors have a direct impact on the success of this surgical procedure, including the age of the patient. The outcome of liver transplantation in children is better when performed as early as possible after diagnosis. According to a review study on biliary atresia, the process of draining the bile ducts via portoenterostomy is satisfactory in up to 80% of children when performed in children under two months of age, a rate which drops to 10% to 20% in infants operated on at four months of age [21].

With regard to the risk factors influencing the success of the surgical intervention, the discrepancy between the arterial and portal diameters of the donor and recipient, the recipient’s low weight, and the smaller diameter of the portal vein, in addition to the surgical skills and experience of the transplant team, are important variables to be considered in the pediatric population. This is because liver transplantation in children poses a challenge in terms of size discrepancies between the portal vein and the hepatic artery between donor and recipient, due to the small size of the vasculature and biliary tree in children [23].

Thus, there are three possible outcomes for pediatric patients undergoing surgical treatment for EHBA: satisfactory response, partial response, or therapeutic failure. A satisfactory response is a patient with a good clinical evolution, while a partial response is a patient who has good bile duct drainage but progresses to liver fibrosis. Finally, therapeutic failure is a clinical evolution that is the same or even worse than that of untreated patients [21].

Post-surgery complications

Although liver transplantation is one of the safest solid organ transplant procedures, with satisfactory success rates, it is considered a complex procedure and has high morbidity and mortality rates, with several consequences for the transplant patients’ quality of life.

Hepatic artery thrombosis, which compromises the blood supply to the bile ducts, is one of the most serious complications. In a specialized center, 19% of 99 patients had vascular complications, with arterial events being predominant and often associated with graft loss and mortality. Biliary complications affected 15.7% of 134 children, with a higher risk in patients aged > 2 years, with arterial thrombosis, or previous Kasai surgery. In general, arterial complications are more common, occur early in the postoperative period, and are associated with high rates of graft loss and patient mortality. In contrast, venous complications are less frequent, occur late in the postoperative period, and have no significant effect on graft loss or mortality rates [23].

Acute cellular rejection occurs in approximately 50% of patients within the first 3 months and, although often asymptomatic initially, can progress to chronic rejection and require retransplantation if left untreated. Early retransplantation, usually due to vascular or graft failure, has significantly reduced survival rates: 42.4% at 1 year and 33.9% at 5 years [35].

Infectious complications are common, with 21% of patients presenting with severe sepsis and requiring intensive care, mainly due to bloodstream bacterial infections. Acute kidney injury (AKI) is also common, with an estimated incidence of up to 40.8% in adults and 7% requiring replacement therapy; in children, it is associated with multiple factors such as prolonged surgery, bleeding, use of nephrotoxic drugs, and hemodynamic instability. These complications usually occur three months after transplantation and are classified as biliary stricture, bile leakage, obstruction, stones, and Oddi sphincter dysfunction.They were more prevalent in LT with small grafts, with risk factors including ischemia time, hepatic artery thrombosis or stenosis, cytomegalovirus (CMV) infection, and chronic rejection. Knowledge of this complication is necessary to differentiate it from rejection, infection, or recurrence of the primary disease, since the initial phases of these conditions can be confusing [26, 36].

Massive postoperative bleeding occurred in 43% of 68 children in a United States hospital, defined by hemoglobin < 8.5 g/dL, INR > 1.5, thrombocytopenia, and surgical duration > 10 h. Most bleeding episodes require reoperation or transfusions, especially in patients with an arterial duct or previous abdominal surgery [35].

Malnutrition in pre-transplant patients also influences the success of the procedure. Several studies also report functional consequences of liver transplantation, such as patients’ intolerance to physical exercise. It has been observed that the recipient’s exercise capacity is significantly impaired in the postoperative period, regardless of the type of organ transplant. Another decisive factor in the prognosis of transplant patients is the timing of referral to transplant centers. The LDLT technique has enabled transplant teams to recommend liver transplantation as a therapeutic option early in the disease, but late referral is still a problem and can compromise the success of the procedure [27]. In a study conducted at a transplant center in Brazil, vascular complications were more frequent in patients who underwent LDLT than in deceased donor transplants. However, one of the advantages of the LDLT technique is that it has a markedly reduced ischemia time [36–38].

Post-transplant mortality is mainly linked to sepsis, multiple organ failure, recurrent neoplasms, respiratory failure, and arterial thrombosis, highlighting management complexity and the importance of intensive monitoring in the first weeks after transplantation. Pediatric liver transplantation is challenging due to the small size of the vasculature and biliary tree, and the incidence of vascular complications reported in the literature varies widely, but is always higher than in samples analyzing LT in adults [35, 36].

Survival and prognosis

Since the first pediatric LT was performed in 1963, survival rates have improved due to advances in surgical techniques, organ preservation, pediatric intensive care, and immunosuppressive therapy. Currently, liver transplantation is considered a long-lasting procedure that gives patients a good long-term survival rate [26, 29].

In a 2013 study, the survival rates at 1, 5, and 10 years in patients who received a cadaveric donor transplant were 89.3%, 78.1%, and 68.5%. In the case of living donors, it was 93.1%, 85.7%, and 67.5% [26]. It is known that multiple factors are associated with the survival rates of pediatric patients after transplantation. In the 2012 cohort study, which analyzed 430 pediatric transplant procedures with living donors, it was concluded that factors such as low body weight (≤ 10 kg) and hepatic artery thrombosis were determinants of worse patient and graft survival [27].

In a 2018 study, in which 84 children and adolescents were evaluated, 40 of whom were transplanted, the probability of survival at 180 days was 70%, and 67.2% at the end of 5 years after transplantation. In addition, in the evaluation of the group transplanted for chronic liver diseases, survival after 5 years was within the results obtained by the main transplant centers, with a rate that can reach 90% in the first year after transplantation and 64.3% to 83.3% in 5 years [24].

The variables related to the worst outcome were: late referral for treatment, decreased albumin and sodium, increased serum bilirubin, increased INR (higher PELD score), extent of liver fibrosis, degree of destruction of intrahepatic bile ducts, previous episodes of cholangitis, site of bile duct obliteration (distal obliteration, type I, has a better prognosis), the form of atresia (perinatal form has a better prognosis compared to embryonic form) and presence of cirrhosis [21].

The presence or absence of ascites, according to a study conducted in 2020, plays an important role in the prognosis of pediatric patients with indications for liver transplantation. According to the study, which assessed 106 children with cirrhosis secondary to biliary atresia, the presence of ascites was associated with a one-year decrease in the survival rate of these patients. Furthermore, the one-year survival rate for patients without ascites was 97.1%, compared to only 56.9% in the presence of ascites. This is attributable to the fact that pediatric patients who develop ascites have a more exacerbated state of systemic inflammation and, consequently, are more likely to develop organ dysfunction [34].

Improvements in surgical techniques have resulted in a significant improvement in the survival rate of patients with biliary atresia, corresponding to values between 80% and 90% [21]. Despite data showing improvements in the survival of pediatric patients, liver transplantation remains a complex surgery with considerable morbidity and mortality rates. Approximately 40% of pediatric patients can present post-surgical complications, and early diagnosis of these complications is a crucial factor for survival rates, considering that the 5-year survival rate for patients who underwent their first transplant is 76.4% compared to a rate of 64.5% for patients who required re-transplantation after complications [26].

Pediatric liver transplantation in a COVID-19 scenario

The COVID-19 pandemic is one of the main challenges currently faced by the LT program in Brazil and around the world. Meanwhile, indications for liver transplantation in children have been restricted, due to the risk of contamination of these patients and donors by the SARS-COV-2 virus. In addition, other limitations, such as the significant increase in intensive care unit (ICU) bed occupancy and the reorganization of health services to meet the demand from COVID-positive patients, have also affected the organ transplant service. Furthermore, there was a significant reduction in the number of allograft donors in Brazil during this period [39, 40].

According to data provided by a retrospective cohort study carried out at a pediatric LT center in Brazil, 97 LT were carried out in 2019 before the arrival of the SARS-COV-2 virus in Brazil, compared to 77 in the same time interval after the start of the pandemic, which represented a 20.6% reduction in the activity of this service [40]. This scenario had a negative impact on the mortality rate on the waiting list who were candidates for transplant therapy, which went from 8.4% to 11.9% before and after the pandemic, respectively. In addition to changes in the number of pediatric LT performed during the pandemic, there were also changes in the epidemiological profile of the children transplanted. A study conducted in 2022 showed that patients referred for transplantation during the pandemic period had higher PELD/MELD scores, a higher prevalence of complications such as ascites, and a higher frequency of pre-transplant hospitalizations, all of which combined with a younger age when compared to the same profile of pre-pandemic patients [41, 42].

Also, in the study in question, 66.2% of transplanted children who acquired the SARS-COV-2 virus were symptomatic, with respiratory symptoms (runny nose and cough) being the most prevalent. With regard to the management of these patients, 87.8% were treated on an outpatient basis, 8.4% needed to be hospitalized, and only 5.4% of the total number of infected patients developed a serious condition and required monitoring in the ICU. Among the children who required hospitalization, 33% also needed to have their immunosuppressive therapy adjusted due to COVID-19 infection. Thus, based on an analysis of the epidemiological profile of these patients with major complications, it was concluded that an interval of less than six months between the transplant and COVID-19 infection is a predictor of severity in pediatric patients [41, 42].

Therefore, various preventive measures have been employed to reduce the possibility of infection in pediatric patients before and after transplantation. These include the implementation of epidemiological and clinical screening, RT-PCR testing, and intensified quarantine measures for donors and recipients. In addition, some transplant programs have restricted pre-, intra-, and post-operative care to the same medical team [40].

Challenges and improvements

In Latin America, liver transplantation has experienced slow growth due to a lack of financial and educational support, limiting its reach and the availability of donors [4]. However, recent advances in the field of pediatric liver transplantation have improved outcomes. A 2022 study in Brazil developed a new prognostic model for children on the transplant waiting list, based on INR and ALT values, aimed at supporting clinical decision-making for children with pediatric acute liver failure (PALF). This new prognostic model is considered to be the first formulated in Latin America [25].

Although Brazil is the second country in absolute number of LT worldwide and the largest pediatric transplant center in Latin America, the outcomes of pediatric liver transplantation in the country still reveal significant challenges when compared with other middle-income countries. In terms of transplants per million population, Brazil still lags behind many developed countries and even some upper-middle-income nations. While Brazil doubled its donation rate from 6.5 pmp in 2006 to 13.1 pmp in 2014, this figure remains lower than that seen in European countries (15 pmp) and far below the United States (26 pmp) [19].

Moreover, there is a marked geographic concentration: 66% of pediatric LT are performed solely in the city of São Paulo. This indicates unequal access, with less developed regions facing logistical barriers, a shortage of trained teams, and lower notification rates of potential donors. Compared with other middle-income countries (such as Argentina or Mexico), Brazil has a comparable or even greater transplant volume, but important gaps remain in the systematic national registry and outcome evaluation. In other countries, more robust national databases allow real-time analyses of survival, complications, and regional flows, supporting fairer and more effective policies [4, 19].

Technically, Brazil has made significant advances with the use of LDLT, accounting for 53.4% of pediatric transplants [19]. This strategy partially offsets the shortage of deceased pediatric donors but also brings specific challenges, such as a higher incidence of vascular complications in LDLT compared with deceased donor transplants [37].

Regarding survival, Brazilian data are comparable to international centers: 1-, 5-, and 10-year survival of 89.3%, 78.1%, and 68.5% for deceased donors, and 93.1%, 85.7%, and 67.5% for living donors [26]. However, there is a strong influence from factors such as delayed diagnosis, poor nutritional status, and the complexity of postoperative care, all of which directly impact outcomes, especially among more vulnerable populations [21, 24, 27, 32].