Pediatric organ transplantation has greatly improved survival and management of pathological conditions resistant to therapeutic interventions in pediatric populations with end-stage organ failure, and is regarded as a treatment of choice. Organs and tissues that are usually transplanted include heart, kidney, liver, lung, intestine, pancreas, and bone marrow. Transplantation is one of the most challenging and complex areas of existing therapies particularly in children because of their size, immune system, off-label use of immunosuppressive drugs, and significant adverse effects of these therapeutic interventions on growth, skeletal development, and quality of life (QOL). Advances in immunosuppressive strategies have significantly enhanced the care of patients and graft survival rates but the long-term risks of these therapeutic interventions are not well recognized. Mainly due to the lack of randomized clinical trials (RCTs) in the pediatric population, mainly because of issues related to conducting clinical trials in children and small number of pediatric transplantation cases per year. The main aim of this review is to highlight the current advances, significant challenges associated with pediatric organ transplantation, and to explore future perspectives.
Lung transplantation is a therapeutic option for children and infants with incurable and end-stage diseases of the lungs or pulmonary vascular system. Sweet et al. reported that 125 pediatric lung transplantations were performed annually worldwide, with an average of 2–3 transplants per center per year . The first reported pediatric lung transplantation was performed at the University of Toronto in 1987 in a 16-year-old boy with familial pulmonary fibrosis . Pediatric lung transplant procedures currently performed are bilateral sequential lung transplant and single lung transplant (Table 1) [3–8]; the most common is bilateral sequential lung transplant . The primary diagnoses leading to lung transplantation in the pediatric age group are: cystic fibrosis making up more than 50% of candidates , idiopathic pulmonary arterial hypertension, bronchiolitis obliterans, and idiopathic pulmonary fibrosis  (Table 2) [4,10–14]. There are quite a few important factors that are exceptional to pediatric lung transplantation like size, immune response, viral infections, nutrition, gastroesophageal reflux, and risk of aspiration [15–18]. The size of both pediatric lung donor and recipient may present extraordinary surgical encounters with regards to size matching and bronchial and vascular anastomoses. Unlike adults, pediatric immune system is immature and particularly developing in infants. Ibrahim et al. reported that young children may have less risk of acute and chronic allograft rejection and hence have more tolerance of transplantation . Moreover, respiratory tract viral infections are also of prime importance in pediatric transplantation . Median survival of 4.9 years from the time of transplantation has been reported by the International Society for Heart and Lung Transplantation registry . Graft failure is considered to be the most common cause of death in the first 30 days following pediatric lung transplantation and accounts for about 30% of early mortality. In addition to graft failure, noncytomegalovirus infections and bronchiolitis obliterans syndrome are also main causes of death from one-month to one-year posttransplantation [10,21] (Table 2).
Liver transplantation has been very successful in treating children with end-stage liver disease, and offers the opportunity for a long patient survival. The first successful liver transplant was performed by Starzl et al. on a 19-month-old girl with hepatocellular carcinoma in 1967. Current pediatric liver transplant procedures consist of whole-liver transplantation, split-liver transplantation, and reduced-size-liver transplantation that is performed in case of living-related donor liver transplantation [23–27] (Table 1). The main indications for liver transplantation in the pediatric population includes acute liver failure, liver tumors, biliary atresia, sclerosing cholangitis, Alagille's syndrome, nonsyndromic paucity of intrahepatic bile ducts, progressive familial intrahepatic cholestasis, and inherited inborn errors of metabolism  (Table 2). Survival after transplantation for acute liver failure has been reported to be improved from 70% at 1 year to 87%, with 5-year survival rates of 67 to 80% [28–30]. The most common causes of death worldwide include infections (accounting for roughly 30% of deaths), followed by rejection, cardiopulmonary causes, central nervous system complications, malignancies, and surgical complications [31–33].
Intestinal transplantation is a therapeutic option in the management of pediatric patients with irreversible intestinal failure. Three types of transplant procedures are performed in children: isolated intestinal transplantation, combined liver and intestinal transplantation, and multivisceral transplantion  (Table 1). Intestinal transplantation is mainly performed in patients with short-bowel syndrome, with multivisceral transplantation reserved to those who develop cholestatic liver disease from prolonged total parenteral nutrition. Indications for intestinal transplantation include depletion of central venous access sites, multiple episodes of catheter-related sepsis, intractable electrolyte disturbances, chronic dehydration, and progressive cholestatic liver failure  (Table 2). The long-term survival rates after pediatric intestinal transplant according to underlying disease are unknown . In children younger than 18 months, risk factors affecting survival include small body size and advanced liver disease .
Heart transplantation is an accepted treatment option for infants and children with end-stage heart failure or complex or inoperable congenital cardiac defects. The first pediatric heart transplant was carried out by Kantrowitz et al. who, in 1967, transplanted the heart of an anencephalic infant into a 3-week-old with tricuspid atresia. Based on the most recent data, there are now, approximately, 100 centers performing over 500 pediatric heart transplants yearly worldwide . Pediatric heart transplant procedures currently performed are orthotopic and heterotopic heart transplantation [6,7] (Table 1). The main indication for heart transplantation in children includes cardiomyopathy, uncorrectable congenital heart defects, and correctable conditions associated with high operative risk and cardiac tumors  (Table 2). Half-life of patients with pediatric heart transplantation has been reported to be 19.7, 16.8, and 14.5 years for infants; recipients aged 1–5 and 6–10 years, respectively . The causes of death following heart transplantation in children include rejection, infection, cardiac allograft vasculopathy, technical issues, acute graft dysfunction, neoplasm, and chronic graft dysfunction .
Renal transplantation in children with chronic kidney disease and end-stage renal disease appears to be the ideal form of renal replacement therapy. The first successful pediatric kidney transplantation was reported in 1966 . There are three main sources for kidney donors: living-related donors; deceased donors; and living unrelated donors  (Table 1). The most common indications for transplantation in children are congenital abnormalities of the kidney and urinary tract, and focal segmental glomerulosclerosis  (Table 2). The leading cause of death among pediatric kidney transplant recipients is infection, followed by cardiovascular diseases, malignancies, and dialysis-related complications .
BONE MARROW TRANSPLANTATION
Bone marrow transplantation also called as hematopoietic stem cell transplant, is the treatment of choice for numerous childhood diseases. A bone marrow transplant involves taking cells that are normally found in the bone marrow (stem cells); filtering those cells, and giving them back either to the patient they were taken from or to another person. The main aim of bone marrow transplantation is to transfuse healthy bone marrow cells into a person after his/her own unhealthy bone marrow has been eliminated. The different types of bone marrow transplants performed includes autologous bone marrow transplant, allogeneic bone marrow transplant, and umbilical cord blood transplant  (Table 1). Indications for hematopoietic stem cell transplant recommended by the European Blood and Marrow Transplantation group based on current clinical practices in Europe are acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, lymphoma, myelodysplastic syndrome, hemophagocytic lymphohistiocytosis, primary immune deficiencies, acquired severe aplastic anemia, hereditary bone marrow failure syndromes, amegakaryocytic thrombocytopenia, congenital neutropenia, hemoglobinopathies, metabolic diseases, and tumors  (Table 2). The complications following bone marrow transplantation in pediatric population include bacterial infection, thrombocytopenia, fluid overload, liver damage, arterial hypertension, respiratory distress, multiorgan failure, graft rejection, and graft-versus-host disease, which is a severe and life-threatening complication [42,43].
Advances in immunosuppressive therapies have significantly enhanced the care of patients and have dramatically decreased the rate of acute rejection in children. Despite the advances in immunosuppressive therapy, the control of adverse effects associated with immunosuppression remains elusive. This is mainly due to the lack of clinical studies with robust data to rationalize the use of these agents and has led to off-license usage and thereby adverse effects of these medications in children [44,45] (Table 3). In children, these adverse effects can disrupt normal growth and development and have a significant impact on overall QOL that may jeopardize adherence to treatment. Some immunosuppressant adverse effects can be fatal so that drug adverse effects are actually the leading cause of mortality following transplant . Furthermore, the long-term risk of these therapeutic interventions is not well recognized and promotes numerous challenges specific to this age group population [44,47▪].
RANDOMIZED CONTROLLED TRIALS
Despite the progresses in the field of pediatric transplantation, the clinical development of this therapeutic approach remains an important challenge, mainly because of barriers in conducting clinical transplantation research in children [48▪▪]. Obtaining informed consent either from children themselves or from both parents/legal guardians is a foremost barrier for conducting RCTs in pediatric populations [49,50]. Well designed observational studies involving potential confounding factors might be a solution for overcoming ethical concerns related to RCTs in pediatric population. Another shortcoming of RCTs, both in surgical and clinical settings of pediatric transplantation, are related to the inability to translate the results obtained from adult studies and from pediatric studies examining similar diseases and procedures. For researchers to overcome these barriers, it is necessary to have a clearer understanding of the mechanisms that determine success or failure of transplantation in children and how they differ from those in adults and in other diseases [48▪▪]. The small number of pediatric transplantation cases per year is another reason for lack of RCTs in pediatric patients with transplantation; therefore, it is important to generate a registries of pediatric patients with organ transplantation [48▪▪]. The appropriate design of RCTs for new immunosuppressive agents and study end points including growth, pubertal development, QOL outcome criteria, and compliance should be well defined in children. The most essential consideration for future RCTs is to build in a provision for the long-term follow-up of all patients recruited. These will be essential data unfortunately lacking in the existing literature.
CLINICAL CONCERNS FOLLOWING ORGAN TRANSPLANTATION IN CHILDREN
The clinical concerns of solid-organ transplantation are related to the transplanted organ (acute or chronic allograft rejection, native disease within the allograft, surgical complications), posttransplant therapy (infection, malignancy, cardiovascular diseases, nephrotoxic, kidney disease, and growth retardation), or the original disease, or they may be multifactorial . The success of solid-organ transplant can be measured not only in terms of allograft and patient survival, but also by the ability of transplantation to restore an optimal QOL. Longitudinal growth provides a major contribution to patient QOL, as it is known that growth failure, pubertal delay, and short stature have considerable effects on self-esteem and psychosocial development [52,53]. Chronic kidney disease of multifactorial cause may occur after all pediatric solid-organ transplantation [54,55]. Infectious disease is a major source of morbidity and mortality in all forms of pediatric solid-organ transplantation [56,57]. Malignancy is a significant problem faced by pediatric recipients of solid-organ transplants . Cognitive development in children is adversely affected by chronic disease, with infants being particularly vulnerable because of their rapid neurological growth. Various pretransplant factors may contribute to developmental outcomes in transplant recipients, including disease onset and severity, longer duration of disease, and pretransplant morbidity . Future research should focus on overcoming the clinical consequences following organ transplantation in children.
The appropriate design of RCTs for novel drugs and study end points including growth, pubertal development, QOL outcome criteria and compliance should be well defined in children. Future RCTs should consider long-term follow-up of pediatric patients following organ transplantation for determining long-term predictors of response.
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Conflicts of interest
The authors declare that they have no competing interests.
Author's contributions: All the authors were involved in writing and critically revising the manuscript for important intellectual content and have approved this final version.
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