Solid-organ transplantation in childhood: transitioning to adult health care

Pediatric solid-organ transplantation is an increasingly successful treatment for solid-organ failure. With dramatic improvements in patient survival rates over the last several decades, there has been a corresponding emergence of complications attributable to pretransplant factors, transplantation itself, and the management of transplantation with effective immunosuppression. The predominant solid-organ transplantation sequelae are medical and psychosocial. These sequelae have a substantial effect on transition to adult care; as such, hurdles to successful transition of care arise from the patients, their families, and pediatric and adult health care providers. Crucial to successful transitioning is the ongoing development of a sense of autonomy and responsibility for one's own care. In this article we address the barriers to transitioning that occur with long-term survival in pediatric solid-organ transplantation. Although a particular transitioning model is not promoted, practical tools and strategies that contribute to successful transitioning of pediatric patients who have received a transplant are suggested.     

Growth following solid-organ transplantation

One of the ultimate goals of successful transplantation (Tx) in pediatric solid-organ transplant recipients is the attainment of optimal final adult height. Except for kidney Tx there are limited data to address this issue. Remarkably similar factors impact on growth in pediatric kidney, liver, and heart recipients. Age is a primary factor, with younger recipients exhibiting the greatest immediate catch-up growth. Graft function is a significant contributory factor: a reduction in glomerular filtration rate (GFR) correlates with poor growth in kidney recipients, and the need for re-Tx is associated with impaired growth in liver recipients. The known adverse impact of corticosteroids on growth has led transplant physicians/surgeons to either modify the dose or attempt steroid withdrawal. In kidney and liver recipients this is associated with the development of acute rejection episodes. In infant heart transplant recipients the avoidance of maintenance corticosteroid immunosuppression is associated with normal growth velocity in the majority of recipients. With the marked improvement in patient and graft survival rates in pediatric solid-organ graft recipients, it is timely that the quality-of-life issues receive paramount attention. In children, normal growth following solid-organ Tx should be an achievable goal that results in normal final adult height.     

Challenges in pediatric transplantation: the impact of chronic kidney disease and cardiovascular risk factors on long-term outcomes and recommended management strategies

Barriers to successful outcomes following pediatric transplantation have shifted from ischemic reperfusion injury and rejection to more long-term complications. Of particular concern is the high prevalence of CKD owing to preexisting damage and nephrotoxicity, as well as other CV complications such as hypertension and cardiomyopathy. All of these contribute to graft loss and shortened life expectancy, thereby limiting the success story of solid-organ transplantation. Managing CKD and related CV morbidity should be integral to the care of pediatric transplant patients, and timely detection of any irregularities would increase the chances of restoring lost kidney function. GFR is still the widely accepted indicator of renal function, and nuclear medicine techniques are the gold standard measurement methods. These methods are limited by costs, radiation exposure and substrate injection, and current practice still uses the Schwartz estimate, despite its well-documented limitations. Newer endogenous markers of GFR, such as cystatin C clearance, give a more accurate measure of true GFR but have not been embraced in the management of pediatric transplant recipients. Furthermore, indirect markers (e.g., microalbuminuria and hypertension) could also aid early detection of renal damage. The effects of mainstay immunosuppressants on kidney and heart function are varied, with available data indicating favorable outcomes with tacrolimus compared with ciclosporin. There is a need for appropriately designed and powered randomized controlled trials to validate innovative concepts for tailored immunosuppression in the pediatric population. To date, very few studies have generated long-term data in pediatric renal transplant patients - results of 1-4-yr study favored tacrolimus over ciclosporin, but other immunosuppressive agents also need to be evaluated.     

Vaccinations and solid-organ transplantation: review and recommendations

Pediatric solid-organ transplant recipients are at high risk for various infectious diseases. Many children are not fully vaccinated before transplantation. To reduce the risk of morbidity and mortality from vaccine-preventable disease, physicians treating pediatric solid-organ transplant recipients should monitor the immunization status of these patients. Consensus on the most appropriate immunization schedule for solid-organ transplant recipients is lacking. Therefore, we provide a review of the currently available data on immunization safety and efficacy and describe strategies to avoid vaccine-preventable diseases in pediatric solid-organ transplant recipients.     

Pediatric liver transplantation

Considerable strides have been made over the last several decades toward improving outcomes in pediatric liver transplantation. Refinements in surgical technique has allowed for the use of living donor and deceased donor split-liver grafts, thus expanding the pool of available organs and reducing waitlist mortality. The use of a multidisciplinary team continues to be paramount in the care of the transplant recipient. With improvements in overall graft and survival, indications for liver transplantation have also broadened. Currently, pediatric transplant patients have a 5-year survival of over 85%. Long-term morbidity is mainly associated with complications from immunosuppression and chronic rejection. Here we review indications for liver transplantation in children, surgical considerations, post-operative complications, and long-term outcomes.     

Outcomes in pediatric solid-organ transplantation

LaR Pediatric solid-organ transplantation is an increasingly successful treatment for organ failure. Five- and 10-yr patient survival rates have dramatically improved over the last couple of decades, and currently, over 80% of pediatric patients survive into adolescence and young adulthood. Waiting list mortality has been a concern for liver, heart, and intestinal transplantation, illustrating the importance of transplant as a life-saving therapy. Unfortunately, the success of pediatric transplantation comes at the cost of long-term or late complications that arise as a result of allograft rejection or injury, immunosuppression-related morbidity, or both. As transplant recipients enter adolescence treatment, non-adherence becomes a significant issue, and the medical and psychosocial impacts transition to adulthood not only with regard to healthcare but also in terms of functional outcomes, economic potential, and overall QoL. This review addresses the clinical and psychosocial challenges encountered by pediatric transplant recipients in the current era. A better understanding of pediatric transplant outcomes and adult morbidity and mortality requires further ongoing assessment.     

Pediatric pancreas transplantation,including total pancreatectomy with islet autotransplantation

Unlike other solid-organ transplants, whole pancreas transplantation in children is relatively rare, and it occurs more frequently in the context of multivisceral or composite organ transplantation. Because children only infrequently suffer severe sequelae of type 1 diabetes mellitus, pancreas transplantation is rarely indicated in the pediatric population. More commonly, pediatric pancreas transplant occurs in the setting of incapacitating acute recurrent or chronic pancreatitis, specifically islet autotransplantation after total pancreatectomy. In this clinical scenario, total pancreatectomy removes the nidus of chronic pain and debilitation, while autologous islet transplantation aims to preserve endocrine function. The published experiences with pediatric total pancreatectomy with islet autotransplantation (TPIAT) in children has demonstrated excellent outcomes including liberation from chronic opioid use, as well as improved mental and physical quality of life with good glycemic control. Given the complexity of the operation, risk of postoperative complication, and long-term physiologic changes, appropriate patient selection and comprehensive multidisciplinary care teams are critical to ensuring optimal outcomes.     

Pediatric liver transplantation : The Indian perspective

Liver transplantation is now the accepted treatment for end stage liver disease, hepaticbased inborn errors of metabolism and localised primary hepatic malignancies. In children the commonest indication is biliary atresia. Innovations in surgical techniques, particularly liver reductions/splits and living related transplants have not only shortened the waiting period but have improved the results of surgery as well. The long term survival for pediatric liver transplant recipients in most large series from the Western world is more than 85%. Treatment protocols for ITU care of donors and recipients, anaesthetic care during surgery and post-operative immunosuppression are available. A country like India has a crying need for the development of facilities for liver transplantation in children but a number of factors have hampered the progress. The cost of surgery and post-operative immunosuppression and attitudes on life and death issues have been the greatest impediment. A few organisational details have also to be addressed to in order to minimise interdepartmental clashes of interest. It is hoped that a viable programme would soon be available for the children in India.     

Safety and efficacy of tacrolimus in pediatric liver recipients

Pediatric liver transplantation is now so successful that we expect more than 80% of children to survive into adolescence and adulthood. As the focus of care shifts toward long-term patient management, immunosuppressive regimens should, in addition to preventing acute and chronic rejection, promote good quality of life and be free of significant long-term side effects. Historically, the most effective immunosuppressive regimens have been based on induction with a combination of calcineurin inhibitors (cyclosporin or tacrolimus) and steroids. Usually, maintenance is monotherapy with cyclosporin or tacrolimus or dual therapy with low-dose alternate-day steroids to encourage growth. A number of studies, including long-term follow-up, have shown significantly lower incidences of rejection, hypertension, hyperlipidemia and cosmetic side effects in patients treated initially with tacrolimus compared with cyclosporin. The use of anti-interleukin-2 inhibitors as induction therapy, with low-dose tacrolimus or in combination with mycophenolate mofetil, has a key role in preventing significant renal dysfunction and reducing infection and rejection. Steroid-free immunosuppression is also proving to be an effective option for the management of pediatric liver recipients. The main challenges now facing pediatricians include ensuring long-term quality of life, optimizing immunosuppression while preventing associated adverse events, and managing a smooth transition from childhood to adolescence and adulthood.     

Success of a steroid-minimization immunosuppression protocol for renal transplantation in the presence of donor-specific antibodies

Abstract:  Steroid-minimization regimens have gained tremendous popularity for renal Tx in the recent past since they are associated with lower metabolic complications and other adverse effects related to long-term steroid exposure. Most such protocols have been restricted to low-risk recipients due to the concern for acute rejection with steroid-minimization. Herein, we report our experience in managing a child who received a positive flow cytometry cross-match living donor kidney transplant with low titer DSA and was successfully managed using a steroid-minimization drug regimen. The purpose of our report is to make pediatric transplant care providers aware of the feasibility of using a steroid-minimization immunosuppression regimen even in children who have traditionally been perceived to be at higher risk for immunologic complications, allowing successful avoidance of steroid toxicity.     

Pediatric liver transplantation

Liver transplantation has become the accepted standard of care in the treatment of a child with a failing liver. Advances in the management of critical care and immunosuppression along with the development of innovative operative procedures have improved outcome such that 5-year survival rates of 80% to 90% are expected following liver transplantation. Organ allocation schemes have evolved in an effort to better stratify recipient risk thereby more appropriately distributing deceased donor grafts. A persistent shortage of appropriate donors continues to contribute to patient mortality. The consequences of long-term immunosuppression have become increasingly apparent such that health care providers need to be aware of the side effects of chronic immunosuppression. New strategies need to be defined to minimize the need of continuous immunosuppression. The continued success of pediatric liver transplantation will require multi-disciplinary health care teams comprised of general pediatricians, pediatric hepatologists, transplant surgeons, and transplant coordinators who focus on the complex needs of the transplant recipient.     

The use of everolimus in pediatric liver transplant recipients: first experience in a single center

The role of mTOR inhibitors, such as EVL, has not been established for pediatric liver transplant recipients up to now, although data from adult solid organ graft transplantation are very promising. Major complications following pediatric liver transplantation in the long-term course include chronic graft rejection and CNI-derived nephrotoxicity. The purpose of our study was to report first results using EVL as a rescue therapy in pediatric liver transplant recipients for the following indications: chronic graft dysfunction n=12, suspected CNI toxicity n=3, hepatoblastoma n=2, and recurrence of primary sclerosing cholangitis post-Ltx n=1. Four patients with chronic graft dysfunction developed completely normal liver function tests using EVL, six patients showed partial improvement, and two patients did not respond at all. One patient with CNI-induced nephropathy showed a slightly improved GFR. Both patients with hepatoblastoma did not develop any metastasis post-Ltx. First experience with EVL in pediatric liver transplant recipients shows promising results in patients with chronic graft failure when standard immunosuppression has failed. The future role of EVL in immunosuppressive protocols for children post-Ltx has to be proven by controlled clinical trials.     

Pediatric heart and lung transplantation

During the last two decades, several advances have resulted in marked improvement in medium-term survival with excellent quality of life in pediatric heart transplant recipients. These were possible due to better donor and recipient selection, increased surgical experience in transplantation for complex congenital heart disease, development of effective rejection surveillance, and wider choice of immunosuppressive medications. Despite all of these advances, recipients suffer from the adverse effects of non-specific immunosuppression including infections, post-transplant lymphoproliferative disorders and other malignancies, renal dysfunction and other important end-organ toxicities. Furthermore, newer immunosuppressive regimens appear (so far) to have had relatively little impact on the incidence of allograft coronary vasculopathy (chronic rejection). Progress in our understanding of the immunologic mechanisms of rejection and graft acceptance should lead to more targeted immunosuppressive therapy and avoidance of non-specific immunosuppression. The ultimate goal is to induce a state of tolerance, wherein the recipient will accept the allograft indefinitely without the need for long-term immunosuppression and yet remain immunocompetent to other antigens. This quest is currently being realized in many animal models of solid organ transplantation and offers great hope for the future.     

Pediatric transplantation: An international perspective

Abdominal solid-organ transplantation has revolutionized the life of children with end-stage organ failure. The international practice of transplant in the pediatric population is heterogeneous. Global trends in pediatric transplant activity are increasing, with diffusion of transplant activities into developing and emerging economies. The organization of deceased donor programs varies internationally (with strong association to a country’s gross domestic product (GDP) per capita and health spending). While deceased donor programs are well established in advanced economies, emerging and developing countries rely heavily on living donor programs. There are efforts underway to increase availability of pediatric and neonatal donor organs. Prioritization of organs for children exists in different forms throughout the world. Pediatric transplantation as a subspecialty is young but growing around the world with a need to train surgeons and physicians in this discipline. Outreach efforts with multinational and multi-institutional partnerships have enabled resource poor countries to establish new transplant programs for children. Further international collaboration, good quality data collection and audit, prospective research and ongoing mentorship, and education are needed to further improve outcomes of all children receiving solid-organ transplants.     

Immunization of pediatric solid-organ transplantation candidates: immunizations in transplant candidates

Many children who receive solid-organ transplants have not completed their primary immunizations prior to transplantation. This leaves pediatric transplant recipients susceptible to the vaccine preventable illness of childhood, which if acquired post-transplantation are associated with increased rates of complications, hospitalization, graft rejection and mortality. The administration of vaccines to transplant candidates earlier and more rapidly than in the healthy child will improve vaccination rates among transplant recipients while not compromising immunogenicity. The recommended vaccines and vaccine schedule are discussed in detail.     

Outcomes after liver transplantation: keep the end in mind

Since the advent of transplantation as a life-saving procedure for patients with end-stage liver disease, more than 15,000 children and adolescents have received liver transplants. With the improvements in long-term posttransplant survival offered by advances in medical and surgical therapy, the concept of transplantation outcome has expanded beyond simple patient and graft survival rates. The quality of the life years restored, the long-term complications of transplant immunosuppression, and the overall cost of care have been increasingly recognized as important components of liver transplantation outcome. This review focuses on the efforts of a single pediatric transplant center to examine the incidence of, and risk factors for, common posttransplantation complications, to characterize posttransplantation health-related quality of life, to describe the cost of posttransplant care, and to implement novel programs to improve health care delivery. Together, these projects set the future course for research and care improvement initiatives in this population and encourage us to "keep the end in mind" when considering pediatric liver transplantation.     

BK virus nephropathy in a pediatric heart transplant recipient with post‐transplant lymphoproliferative disorder: A case report and review of literature

BKV is known to cause allograft failure in kidney transplant recipients. It has been recently recognized to cause native kidney nephropathy in non‐kidney transplant recipients. This is a case report BKVN in a 15‐yr‐old HTx recipient who had PTLD and a review of pediatric cases in the literature. The patient was diagnosed with BKVN +189 months after transplantation and died thirty days after diagnosis of BKVN. We identified five other cases of BKVN in pediatric non‐kidney solid organ transplantation, of which all were HTx recipients. Overall, outcome was poor and BKV clearance was not achieved with reduction of immunosuppression and with current therapies. We strongly recommend that pediatric HTx recipients be tested for BKV infection if there is evidence of kidney dysfunction. We also recommend that they have an annual screening for BKV viruria and viremia with the assessment of kidney function.     

Immunosuppression in pediatric solid organ transplantation

This report reviews the immunosuppressive regimens that are used in pediatric transplantation. There are predominant themes developing in the field involving the minimization of the total exposure of immunosuppression through limiting the number of agents and newer pharmacokinetic modeling. Calcineurin inhibitors are the foundation of most immunosuppressive regimens. However, there are new pharmacologic monitoring techniques to reduce the potential for long-term side effects of this class of agents. Although tacrolimus remains one of the mainstays of current protocols, there are strides being made to reduce the patient's long-term exposure to it with transitioning to sirolimus. Corticosteroids are still used predominantly, but there is growing evidence of successful steroid-sparing protocols that are as effective and avoid the chronic morbidity of steroids. Antibody induction therapy remains a standard with clearer evidence of the efficacy of IL-2 receptor antagonists. There is preliminary clinical evidence that polyclonal antibody therapy is efficacious in pediatric transplantation. Future studies will determine the best way to assess the functional immune status of a pediatric transplant recipient to maintain the fine balance and avoid the complications of either excessive or inadequate immunosuppression.     

Practice recommendations for the monitoring of renal function in pediatric non‐renal organ transplant recipients

The management of non‐renal pediatric solid organ transplant recipients has become complex over the last decade with innovations in immunosuppression and surgical techniques. Post‐transplantation follow‐up is essential to ensure that children have functioning allografts for as long as possible. CKD is highly prevalent in these patients, often under recognized, and has a profound impact on patient survival. These practice recommendations focus on the early detection and management of hypertension, proteinuria, and renal dysfunction in non‐renal pediatric solid organ transplant recipients. We present seven practice recommendations. Renal function should be monitored regularly in organ transplant recipients, utilizing assessment of serum creatinine and cystatin C. GFR should be calculated using the new Schwartz formula. Transplant physicians should also monitor blood pressure using automated oscillometric devices and confirm repeated abnormal measures with manual blood pressure readings and ambulatory 24‐h blood pressure monitoring. Proteinuria and microalbuminuria should also be assessed regularly. Referrals to a pediatric nephrologist should be made for non‐renal organ transplant recipients with repeated blood pressures >95th percentile using the Fourth Task Force reference intervals, microalbumin/creatinine ratio >32.5 mg/g (3.7 mg/mmol) creatinine on repeated testing and/or GFR <90 mL/min/1.73 m².