Pediatric Organ Transplant Research Articles

Pediatric renal transplantation: an overview and update

Transplantation is the preferred method of treatment for end-stage renal disease in children. The rate of pediatric kidney transplantation has been steadily rising over the past decade. The use of increasingly potent immunosuppressive drugs has lessened the risk for acute rejection substantially and improved short-term outcomes; however, the long-term outcomes have remained inadequate. The follow-up of pediatric cohorts and the encouraging results from data registries prompt us to revisit our practices in transplantation so as to devise additional strategies to improve long-term outcomes. This review presents a comprehensive discussion of the major issues in pediatric renal transplantation, the newer immunosuppression approaches to limit toxicities of therapies in children and some critical issues that remain to be addressed, specific to the care of the transplanted child. The ultimate goal of designing optimum conditions for equating graft survival to patient survival still remains a major goal for pediatric organ transplantation.

Meta-Analysis of Medical Regimen Adherence Outcomes in Pediatric Solid Organ Transplantation

Adherence to the medical regimen after pediatric organ transplantation is important for maximizing good clinical outcomes. However, the literature provides inconsistent evidence regarding prevalence and risk factors for nonadherence posttransplant. A total of 61 studies (30 kidney, 18 liver, 8 heart, 2 lung/heart-lung, and 3 with mixed recipient samples) were included in a meta-analysis. Average rates of nonadherence to six areas of the regimen, and correlations of potential risk factors with nonadherence, were calculated. Across all types of transplantation, nonadherence to clinic appointments and tests was most prevalent, at 12.9 cases per 100 patients per year (PPY). The immunosuppression nonadherence rate was six cases per 100 PPY. Nonadherence to substance use restrictions, diet, exercise, and other healthcare requirements ranged from 0.6 to 8 cases per 100 PPY. Only the rate of nonadherence to clinic appointments and tests varied by transplant type: heart recipients had the lowest rate (4.6 cases per 100 PPY vs. 12.7-18.8 cases per 100 PPY in other recipients). Older age of the child, family functioning (greater parental distress and lower family cohesion), and the child's psychological status (poorer behavioral functioning and greater distress) were among the psychosocial characteristics significantly correlated with poorer adherence. These correlations were small to modest in size (r=0.12-0.18). These nonadherence rates provide benchmarks for clinicians to use to estimate patient risk. The identified psychosocial correlates of nonadherence are potential targets for intervention. Future studies should focus on improving the prediction of nonadherence risk and on testing interventions to reduce risk.

O21 Differentially expressed host B cell-associated genes in high/intermediate versus low/undetectable viral load states in Epstein–Barr (EBV) virus infection after pediatric organ transplantation

O21 Differentially expressed host B cell-associated genes in high/intermediate versus low/undetectable viral load states in Epstein–Barr (EBV) virus infection after pediatric organ transplantation

O22 Molecular epidemiology of noroviruses in British Columbia, Canada

Objective: One of the most devastating complications after organ transplantation is EBV-related lymphoproliferation. This condition is predominantly a B-cell disorder that is often associated with antecedent elevation of Epstein-Barr virus (EBV) loads. However, there is no consistent relationship between elevated EBV loads and the risk of progression to post-transplant lymphoproliferative disorder (PTLD). We hypothesized that aspects of the virus-host interaction could be measured to help predict progression to PTLD in settings where viral loads are elevated. Thus, the objective of this study was to examine differentially expressed host B cell-associated genes and their interaction patterns in different EBV viral load settings after pediatric organ transplantation. Specifically, we were interested in the genes expressed in high/intermediate (HI) versus low/undetectable (LU) viral load states. Methods: Gene expression was measured by microarray analysis of RNA from CD19+ B lymphocytes using the Human Genome U133 Plus 2.0 GeneChip. Moderated t-statistics were computed for each gene using a local pooled error (LPE) test. The false discovery rates (FDR) of the differentially expressed genes were evaluated and validated using RT-PCR. In this report, the primary focus was on comparisons between patients with HI and LU viral loads (VL). Using averagelinkage hierarchical clustering analysis, a set of genes with the largest variation, as measured by coefficient of variation, was used to explore the patterns of viral loads. Gene network analysis was also performed. Results: Among samples from 27 transplant recipients, the VL categories were: low or undetectable loads, N = 14; high or intermediate loads, N = 13. There were 7 healthy EBV-seropositive (P) and -seronegative controls (N). The median age of transplant patients was 12.1 yrs (range 1 16.9); Median time post-transplant 0.5 yr (range 0.1 3.8). Using the LPE test, we identified 54 differentially expressed genes with FDR 0.1 when HI was compared with LU. In addition to our comparisons of interest (HI vs LU), we examined other comparisons; HI vs P, LU vs P and P vs N, respectively. Altogether, these comparisons yielded 24 54 differentially expressed genes. Clustering analysis of 563 gene expressions identified 5 clusters aligned with levels of VL. Conclusion: Our results revealed a spectrum of B-cell associated genes that includes several that may be relevant to the pathogenesis of lymphoproliferation after organ transplantation. Further studies using the above methodology will shed further light on gene expression profiles in the setting of different viral load states after organ transplantation.

De Novo Malignancy After Solid Organ Transplantation in Children

The aim of this study was to assess the prevalence of de novo malignancy after solid organ transplantation in childhood. A retrospective questionnaire-based survey was sent to 9 referral centers for pediatric organ transplantation in France. Among 1326 children who underwent solid organ transplantation since 1996, 80 (6%) presented with de novo malignancy posttransplantation during childhood: posttransplant lymphoproliferative disease was the most common (5% of pediatric recipients) comprising 80% of all tumors, with a disproportionately high prevalence among combined liver and small bowel recipients (18%). Various solid tumors were observed mainly among kidney recipients. No skin cancer was reported.

Out with the old, in with the new: immunosuppression minimization in children

To cover the current literature on immunosuppression minimization strategies in pediatric transplantation, with an emphasis on an application of these strategies in renal transplantation. Safe elimination of certain immunosuppressives carry unprecedented advantages for reducing patient morbidity and chronic graft injury, but may also result in unanticipated changes in immunological homeostasis and drug pharmacokinetics. Closer surveillance for posttransplant infections and alterations in drug bioavailability and dosing as well as break-through immunologic responses are required. Immunosuppression minimization strategies, under the umbrella of a newer generation of more powerful induction and maintenance immunosuppressants, are being increasingly applied to pediatric organ transplantation, with the greatest emphasis on minimization of steroids and calcineurin inhibitor agents. The success of some of these protocols may support their immediate application to clinical practice.

Immunizations and infectious diseases in pediatric liver transplantation

Liver transplantation (LTx) is an established and effective treatment for children with end-stage and metabolic liver disease. Improved surgical techniques and immunosuppressive regimens have led to enhanced short-term and long-term survival rates, which now approach or exceed 90%. Consequently, more children are being referred for LTx, and an increasing numbers of pediatric centers routinely perform this procedure. Infectious complications are an important cause of morbidity and mortality in children undergoing LTx. However, improvements in immune suppression management along with the availability of new antimicrobial agents and diagnostic tools have resulted in improved treatment and preventative regimens, thus reducing the impact of infectious complications on these children. This review provides an overview of the infectious complications and prevention strategies for children undergoing LTx.

The Need for Tolerance in Pediatric Organ Transplantation

Transplantation is the preferred therapy for pediatric end stage diseases of a variety of solid organs. Unfortunately, however, transplantation does not restore patients to a normal life, because they are left on lifelong immunosuppression with its associated complications. In addition, even when immunosuppression is properly administered, there is progressive loss of allograft function through a process called “chronic allograft dysfunction” that leads to loss of ∼4% of transplanted organs per year. Exciting new findings in adult transplant patients now offer the hope that both the need for chronic immunosuppression and the loss of organs to chronic rejection may be avoided by the induction of transplantation tolerance—the specific elimination of the rejection response through modification of the immune system. Below, we will outline the history of immunosuppression and its problems and provide some insights into how we believe that the induction of tolerance will be of special benefit to children.

Current status and impact of CMV prevention following pediatric organ transplantation

Current status and impact of CMV prevention following pediatric organ transplantation

Higher Mycophenolate Dose Requirements in Children Undergoing Hematopoietic Cell Transplant (HCT)

Little is known about dosing of mycophenolate mofetil in pediatric hematopoietic cell transplant recipients; therefore, dosing strategies using other settings have been extended to this population. The authors studied pharmacokinetics in 19 children (median 17 months) undergoing myeloablative hematopoietic cell transplant and receiving prophylactic mycophenolate and cyclosporine. All subjects except 2 received mycophenolate 15 mg/kg intravenously every 8 hours. The median (range) total mycophenolic acid area under the concentration-time curve (AUC)(0-8) was 12.6 mcg.h/mL (4.9-49.2), and unbound mycophenolic acid AUC(0-8) was 0.274 mcg.h/mL (0.037-1.4). Total and unbound mycophenolic acid trough concentrations were 0.27 (0.03-2.9) and 0.005 (0-0.034) mcg/mL, respectively. Mycophenolic acid trough concentrations were not good surrogates for overall exposure (AUC(0-8)), r(2) < or = 0.55. Mycophenolate dose requirements are higher in pediatric hematopoietic cell transplant recipients relative to pediatric organ transplant recipients. Children undergoing hematopoietic cell transplant should receive a mycophenolate mofetil dose of at least 15 mg/kg intravenously every 8 hours when used in combination with cyclosporine to achieve systemic concentrations near those proposed to be therapeutic in the adult hematopoietic cell transplant population.

Pediatric Transplantation in the United States, 1997–2006

This article represents the sixth annual review of the current state of pediatric transplantation in the United States from the Scientific Registry of Transplant Recipients (SRTR). It presents updated trends, discussion of analyses presented during the year by the SRTR to the committees of the Organ Procurement and Transplantation Network (OPTN) and discussion of important issues currently facing pediatric organ transplantation. Unless otherwise stated, the statistics in this article are drawn from the reference tables of the 2007 OPTN/SRTR Annual Report. In this article, pediatric patients are defined as candidates, recipients or donors aged 17 years or less. Data for both graft and patient survival are reported as unadjusted survival, unless otherwise stated (adjusted patient and graft survival are available in the reference tables). Short-term survival (3 month and 1 year) reflects outcomes for transplants performed in 2004 and 2005; 3-year survival reflects transplants from 2002 to 2005; and 5-year survival reports on transplants performed from 2000 to 2005. Details on the methods of analysis employed may be found in the reference tables themselves or in the technical notes of the 2007 OTPN/SRTR Annual Report, both available online at http://www.ustransplant.org.

Pediatric Transplant Rating Instrument – A scale for the pretransplant psychiatric evaluation of pediatric organ transplant recipients

Although the majority of pediatric solid organ transplant centers in the United States employ psychosocial criteria to assess the suitability of potential transplant candidates, there are no standardized pretransplant psychosocial assessment measures. Assessment scales that have been developed were designed for adult transplant recipients and are not suitable for use in the pediatric population. The P-TRI was developed to address this gap in the pediatric pretransplant psychosocial evaluation. It is intended to identify areas of psychosocial vulnerability that may be associated with poor treatment adherence and to facilitate the development of informed and focused psychosocial interventions for pediatric patients before and after transplant surgery. Items on the rating instrument were generated based on a review of the major correlates of treatment adherence in the pediatric population. Data are currently being collected for further reliability and validity analyses.

Higher Mycophenolate Dose Requirements in Children Undergoing Hematopoietic Cell Transplant (HCT).

Mycophenolate mofetil (MMF), a pro-drug of mycophenolic acid (MPA), is commonly used as part of the immunosuppressive regimen after hematopoietic cell transplantation (HCT). Although MMF is widely used in HCT transplant recipients, systemic exposure has not been thoroughly studied in pediatric HCT recipients. Hence, the dosing strategies used in children undergoing kidney transplantation have been adopted or the adult dose has been extended to HCT children. Therefore, we studied mycophenolate pharmacokinetics in 19 children with median age of 17 (3–140) months with nonmalignant diseases undergoing myeloablative HCT who received mycophenolate in combination with cyclosporine for graft-versus-host disease prophylaxis. All subjects, except two, received 15 mg/kg mycophenolate intravenously every 8 hours. Pharmacokinetics were studied once between days 3–7 and again between days 10–14 post-transplant. The median [range] MPA total area under the curve (AUC)0-8 was 12.6 mcg hr/ml [4.9–49.2] and unbound AUC0-8 was 0.274 mcg hr/ml [0.037–1.4]. Unbound MPA fraction was 1.7% [0.76–5.1]. The median total mycophenolic acid glucuronide (MPAG) AUC0-8 was 269.1 mcg hr/mL [127.6–957.0]. Total and unbound MPA trough concentrations were 0.24 [0.03–2.9] and 0.005 [0–0.034] mcg/mL, respectively, with 8 hour dosing. MPA troughs were not good surrogates for overall exposure (AUC)0-8,[r2≤0.55]. MPA exposures did not change significantly between weeks 1 and 2 (p≤0.51), although several patients had an increase or decrease in AUC by 50% or more. SCr, CrCl, bilirubin, age, weight and albumin were poorly correlated with MPA AUC0-8 (all r2<0.40). Twenty % of the AUC's achieved a total MPA target previously associated with better donor chimerism and 54% met the unbound MPA targets associated with reduced acute GVHD risk in adults undergoing nonmyeloablative transplant. These data suggest that 15 mg/kg every 8 hours may be too low. However, whether these targets are relevant in the pediatric myeloablative setting is not known. MMF given 15 mg/kg every 8 hours intravenously in our patients achieved an exposure similar to that previously observed in adult nonmyeloablative HCT recipients receiving 1gm every 12 hours intravenously. MPA exposure in pediatric HCT recipients is lower than pediatric organ transplant recipients despite receiving a 33% higher dose. Children undergoing HCT should receive an MMF dose of at least 15 mg/kg intravenously every 8 hours to achieve systemic concentrations near those proposed to be therapeutic in the adult HCT population. The optimal MPA exposure target, particularly the upper limit of safety, in children undergoing myeloablative HCT has yet to be determined.

Immunoglobulin E-Mediated Allergies in Lung-Transplanted Adults

Immunoglobulin E (IgE)-mediated allergy has repeatedly been reported after solid organ transplantation, apparently affecting approximately 10% of pediatric organ transplant recipients. Interestingly, type 1 allergy has not been described in transplanted adults, suggesting a particular propensity in childhood. The present cross-sectional study assessed the prevalence of type 1 allergy in 42 adult lung transplant recipients aged 25 to 50 years. Instruments included standardized interviews, skin prick tests, and serum IgE measurements. Ten of 42 patients (23.8%) displayed elevated specific IgE levels or positive skin prick test results against one or more allergens. Five individuals (11.9%) additionally reported corresponding clinical symptoms of type 1 allergy. No statistically significant association of sensitization or allergy prevalence with patient age, kind of immunosuppressive therapy, and time since transplantation was found. The phenomenon of transplantation-associated allergy is not age-restricted and thus should be assessed more thoroughly in all age groups.

Severe cold agglutinin disease caused by recurrent monomorphic Epstein–Barr virus (EBV)‐associated post‐transplant lymphoproliferative disorder (PTLD), clonally related to an EBV‐negative plasmacytic hyperplasia in a pediatric multivisceral organ transplant recipient

PTLD represent major post-transplant complications. The major etiologic factor is EBV. Association with cold agglutinin disease has not been described so far. We report a three-yr-old girl who developed oligoclonal EBV-negative plasmacytic hyperplasia as well as Coombs test-positive anemia one yr after multivisceral organ transplantation, performed after subtotal bowel resection for colointestinal aganglionosis and liver cirrhosis resulting from long-term parenteral nutrition. The patient was treated for plasmacytic hyperplasia with cyclophosphamide and prednisolone and achieved clinical remission. One yr later PTLD progressed possibly driven by EBV to DLBCL. The migration patterns of the amplified Ig heavy chain genes demonstrated a probable clonal relationship of the DLBCL to a clone almost present in the plasmacytic hyperplasia. This progression was accompanied by a rapid rise of cold agglutinin titers with symptoms of severe cold agglutinin disease, leading to right femoral and extern iliac vein thromboses requiring partial leg amputation. After four cycles of rituximab, cyclophosphamide, and prednisolone, the patient achieved complete PTLD remission and the cold agglutinins disappeared. Summarizing, PTLD may be accompanied by cold agglutinin disease, and both may be successfully treated by immuno-chemotherapy. The appearance of cold agglutinins in transplant patients may indicate PTLD development.

69: Therapeutic monitoring of sirolimus is essential in pediatric BMT recipients

Limited data on sirolimus (SRL) in adult BMT patients is consistent with a long elimination half-life (t1/2; 57-63 h) and little effect of an occasional missed dose on overall drug exposure. Pharmacokinetic (PK) studies in pediatric organ transplant recipients suggest that SRL may be metabolized more rapidly in children. BMT patients may have variable SRL exposure due to gastrointestinal toxicity, and interactions with calcineurin inhibitors and imidazole antifungaldrugs.

Sirolimus-related pulmonary toxicity mimicking 'asthma like' symptoms

Sirolimus is an immunosuppressant with expanding use in pediatric organ transplantation, dermatology and rheumatology. We report two cases of children who developed asthma like symptoms and were diagnosed with interstitial lung disease, which responded to discontinuation of sirolimus. Pediatricians should be aware about the pulmonary side effects of sirolimus.

The Comprehensive Assessment of Physical Fitness in Children Following Kidney and Liver Transplantation

Pediatric organ transplant recipients may have elevated cardiovascular (CV) risk. Low cardiorespiratory fitness (CRF) may contribute to CV risk; however, studies of CRF in children following kidney transplantation (KTx) and liver transplantation (LTx) are limited. Laboratory testing included assessment of CRF (VO2peak), muscle strength, and body composition (%fat). Field testing (FITNESSGRAM) included the PACER, curl-up, and sit-and-reach tests. Values obtained were compared to sex- and age-based criterion-referenced standards (Healthy Fitness Zone, HFZ). The Previous Day Physical Activity Recall was used to assess after-school physical activity (PA) participation. Independent t tests were used to compare groups. Twenty-five KTx and 11 LTx recipients were tested. The groups were similar in all measures. Both groups demonstrated below normative values for VO2peak and muscle strength. Only 4% of the KTx and 9% of the LTx recipients achieved the HFZ for the PACER and 24% of the KTx and 45% of the LTx attained the HFZ for the curl-up test. Approximately 44% of both groups had percent fat greater than the upper criterion value of the HFZ. Both groups reported spending only 8% of their after-school time participating in physical activity. Pediatric KTx and LTx recipients have significantly reduced CRF, muscle strength, and physical activity. Routine counseling and encouragement for increased physical activity is recommended as a part of routine care. A randomized clinical exercise intervention trial after pediatric solid organ transplantation is warranted to determine the impact of such lifestyle intervention on improving physical fitness and cardiovascular health.

Pediatric Transplantation in the United States,1995–2004

This article reviews trends in pediatric solid organ transplantation over the last decade, as reflected in OPTN/SRTR data. In 2004, children younger than 18 years made up nearly 3% of the 86,378 candidates for organ transplantation and nearly 7% of the 27,031 organ transplant recipients. Children accounted for nearly 14% of the 7152 deceased organ donors. The transplant community recognizes important differences between pediatric and adult organ transplant recipients, including different etiologies of organ failure, surgical procedures that are more complex or technically challenging, effects of development on the pharmacokinetic properties of common immunosuppressants, unique immunological aspects of transplant in the developing immune system and increased susceptibility to posttransplant complications, particularly infectious diseases. For these reasons, and because of the impact of end-stage organ failure on growth and development, the transplant community has generally provided pediatric candidates with special consideration in the allocation of deceased donor organs. Outcomes following kidney, liver and heart transplantation in children often rank among the best. This article emphasizes that the prospects for solid organ transplantation in children, especially those aged 1-10 years are excellent. It also identifies themes warranting further consideration, including organ availability, adolescent survival and challenges facing pediatric transplant clinical research.

Recent Trends and Results for Organ Donation and Transplantation in the United States, 2005

Recent Trends and Results for Organ Donation and Transplantation in the United States, 2005