Showing papers in "Pediatric Transplantation in 2005"
TL;DR: One‐year graft and patient survival are better in adolescent transplant recipients (age 11–19 years) than in younger (age < 11’years) pediatric transplant recipients, but several groups found that long‐term outcomes in the adolescent age group are significantly worse than in young transplant recipients.
Abstract: One-year graft and patient survival are better in adolescent transplant recipients (age 11-19 years) than in younger (age i.e. 5 year post-transplant) in the adolescent age group are significantly worse than in younger transplant recipients. A behavioral factor that could explain an important part of the poorer clinical outcome in adolescent transplant recipients is non-compliance with medication taking. Adolescents, like all organ transplant recipients irrespective of their age, must adhere to a life-long immunosuppressive regimen in addition to other aspects of their therapeutic regimen. Therefore, adolescent transplant recipients, as all transplant patients, should be regarded as a chronically ill patient population in whom behavioral and psychosocial management is equally important as state-of-the-art medical management. This paper provides an overview of the current knowledge on prevalence, clinical consequences, and risk-factors for non-compliance with the immunosuppressive regimen in adolescent transplant recipients and offers some suggestions for adolescent-tailored interventions to improve medication adherence.
311 citations
TL;DR: The philosophy of transition and an evidence‐based approach to transitional care in terms of the need for it, proposed models of care and the evidence of the benefits of transitional care programmes are presented.
Abstract: The development of transitional care is one of the major challenges for the twenty-first century as the survival rates and medical outcomes for child and adolescent recipients of transplants continue to improve. Such developments must include both paediatric and adult providers and is likely to require training of professionals in both arenas. Transition is a multidimensional process with transfer to adult care, only one event within that process. The aim of this paper is to present the philosophy of transition and an evidence-based approach to transitional care in terms of the need for it, proposed models of care and the evidence of the benefits of transitional care programmes. Examples of some key clinical aspects of transitional care including communication skills, parenting, self advocacy, vocation will be presented. Adherence issues will be presented in accompanying papers in this journal. Finally, potential barriers to successful transition will be explored.
174 citations
TL;DR: The recommendations to approach the problems of adolescent transplant non‐adherence from the transplant clinician's viewpoint are proposed, and with early identification and appropriate interventions, significant improvement in adolescent graft survival is possible.
Abstract: Recent advancements in immunosuppression and surgical techniques have significantly improved the outcome of kidney transplantation in the pediatric population. Adolescents enjoy the best 1-year graft survival of any age group. However, the long-term transplant outcome in adolescents is disappointing. Non-adherence with immunosuppressive medications is one of the most important contributing factors for graft rejection and loss in teenagers. The impact of non-adherence is perceived to be far more powerful in adolescent transplant recipients than in the transplant population as a whole. To better understand adolescent non-adherence, the process of transplantation must be placed in the context of adolescent development. Adolescents try to establish their identity and autonomy separately from the parents; however at the same time, adolescents with chronic illness require help, support and guidance from adults, including parents and medical personnel. Adolescents have limited ability to anticipate abstractly the long-term consequences of their immediate actions. This inconsistency can create frustration in both adolescents and in the supporting systems around them. Despite the significant consequences of adolescent non-adherence, research in this area is scarce. There are still no established definitions, standardized diagnostic methods and effective interventions to treat and prevent this problem. We propose the recommendations to approach the problems of adolescent transplant non-adherence from the transplant clinician's viewpoint. With early identification and appropriate interventions, significant improvement in adolescent graft survival is possible.
145 citations
TL;DR: Recent data suggest that these patients tolerate lower Tacrolimus trough blood levels than those transplanted for non‐malignant conditions, without increasing the risk of acute rejection, and there is a trend for a better patient survival after living related liver transplantation.
Abstract: In the past 20 yr, a dramatic improvement has been achieved in the outcome of children with hepatoblastoma by combining cisplatin based chemotherapy and surgery. Treatment of patients in the USA is an exception to the rule that all patients should receive neoadjuvant chemotherapy. It is paramount that surgical resection be complete, both macro- and microscopically. Complete tumor resection can be achieved after chemotherapy with a partial hepatectomy when the intrahepatic extent is limited to 1-3 sectors. In multifocal (and solitary) hepatoblastomas invading all four liver sectors, and in centrally located tumors with close proximity to the major veins, the SIOPEL-1 study and an extensive review of the world experience have shown that primary transplantation provides high, long term, disease-free survival rate in the range of 80%. In contrast, the results of rescue transplants for incomplete tumor resection or disease recurrence after partial hepatectomy are disappointing (in the range of 30%). Hazardous attempts at partial hepatectomy in children with extensive hepatoblastoma should be discouraged. Guidelines are provided for early referral of children with extended hepatoblastoma to a transplant surgeon. There is a trend for a better patient survival after living related liver transplantation. Patients who will become candidates to liver transplantation should be treated with chemotherapy following the same protocols as for children undergoing a partial hepatectomy. There is a concern about cumulative nephrotoxicity of calcineurin inhibitors and chemotherapeutic drugs. Recent data suggest that these patients tolerate lower Tacrolimus trough blood levels than those transplanted for non-malignant conditions, without increasing the risk of acute rejection. Due to the rarity of the disease, these children should be treated in specialized centers.
104 citations
TL;DR: Post‐transplant Lymphoproliferative Disorder (PTLD) because of the Epstein–Barr Virus is a major concern after pediatric transplantation, and the group at greatest risk is EBV‐seronegative recipients who receive EBv‐seropositive organs.
Abstract: Post-transplant Lymphoproliferative Disorder (PTLD) because of the Epstein-Barr Virus (EBV) is a major concern after pediatric transplantation. The group at greatest risk is EBV-seronegative recipients who receive EBV-seropositive organs. Additional risk factors remain to be determined, including those among EBV-seropositive recipients. In this case-control study, PTLD cases were biopsy-proven over a period of 4 yr (1997-2000, inclusive). Each case was matched with 2 controls, based on the type of organ transplanted and the period of transplantation (+/-1 yr). Variables compared between cases and controls included those relating to the clinical and virologic profiles and immunosuppressive therapy. Twenty-two cases of PTLD were diagnosed during the study period. PTLD cases occurred at a median of 22.8 months post-transplantation (range 1-131). The median age of cases was 26.2 months (range 6.1-194) compared with 47.4 months (range 0.8-202.2) for controls (p = 0.93). Cases had a higher mean baseline EBV load compared with controls (3.1 log(10) (s.d. +/- 1.0) vs. 1.6 log(10)/10(6) PBMCs (s.d. +/- 1.4), with every 1 log increase in viral load resulting in a three times increase in the likelihood of PTLD (p < 0.007). Close to one in four cases of PTLD were EBV-seropositive pretransplantation. These seropositive recipients tended to be older patients with a trend to a worse outcome compared with their seronegative counterparts. The occurrence of PTLD was not associated with the use of any specific immunosuppressants. A significant proportion of PTLD cases occurred among EBV-seropositive transplant recipients, with a tendency towards an unfavorable outcome. Besides EBV-seronegative recipients who receive seropositive organs, some EBV-seropositive pediatric patients are at risk of PTLD. Additional studies are warranted to further define the factors associated with PTLD in EBV-seropositive transplant recipients.
96 citations
TL;DR: The evidence presented in this review indicates that BOS is the result of humoral and cellular immune responses developed against major histocompatibility complex molecules expressed by airway epithelial cells of the lung allograft.
Abstract: Lung transplantation is recognized as the only viable treatment option in a variety of end-stage pulmonary diseases. However, the long-term survival after lung transplantation is limited by the development of obliterative bronchiolitis, and its clinical correlate bronchiolitis obliterans syndrome (BOS), which is considered to represent chronic lung allograft rejection. Histopathologically, BOS is an inflammatory process that leads to fibrous scarring of the terminal and respiratory bronchioles and subsequent total occlusion of the airways. The specific etiology and pathogenesis of BOS are not well understood. The current premise is that BOS represents a common lesion in which different inflammatory insults such as ischemia-reperfusion, rejection, and infection can lead to a similar histological and clinical outcome. However, the low incidence of BOS in non-transplanted individuals and the observation that early development of BOS is predicted by the frequency and severity of acute rejection episodes indicate that alloimmune-dependent mechanisms play a crucial role in the pathogenesis of BOS. The evidence presented in this review indicates that BOS is the result of humoral and cellular immune responses developed against major histocompatibility complex molecules expressed by airway epithelial cells of the lung allograft. This process is aggravated by alloimmune-independent mechanisms such as ischemia-reperfusion and infection. Currently, treatment of BOS is frequently unsuccessful. Therefore, a better understanding of the immunopathogenesis of BOS is of paramount importance toward improving long-term patient and graft survival after lung transplantation.
93 citations
TL;DR: Tac was significantly more effective than CyA in preventing acute rejection in pediatric renal recipients and glomerular filtration rate appears to be an useful surrogate marker for long‐term outcome.
Abstract: This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with cyclosporin microemulsion (CyA) in pediatric renal recipients. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 yr) were randomly assigned (1:1) to receive either Tac (n = 103) or CyA (n = 93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection (intent-to-treat). Baseline characteristics were comparable between treatment groups. Excluding deceased patients (n = 9) and patients lost to follow-up (n = 31, mostly transferred to adult care), 95% of 2-yr data (159 of 167 possible patients), 87% of 3-yr data (142 of 163) and 73% of 4-yr data (114 of 156) were retrieved. At 1 yr Tac therapy resulted in a significantly lower incidence of acute rejection (36.9%) compared with CyA (59.1%, p = 0.003). The incidence of corticosteroid-resistant rejection was also significantly lower with Tac (7.8% vs. 25.8%, p = 0.001). At 4 yr, patient survival was similar (94% vs. 92%, p = 0.86) but graft survival significantly favored Tac (86% vs. 69%; p = 0.025, log-rank test), respectively. At 1 yr, the mean glomerular filtration rate (GFR) (Schwartz formula, ml/min/1.73 m(2)) was 64.9 +/- 20.7 (n = 84) vs. 57.8 +/- 21.9 (n = 77, p = 0.0355), at 2 yr 64.9 +/- 19.8 (n = 71) vs. 51.7 +/- 20.3 (n = 66, p = 0.0002), at 3 yr 66.7 +/- 26.4 (n = 81) vs. 53.0 +/- 23.3 (n = 55, p = 0.0022), and at 4 yr 71.5 +/- 22.9 (n = 51) vs. 53.0 +/- 21.6 (n = 44, p = 0.0001) for Tac vs. CyA, respectively. Cholesterol remained significantly higher with CyA throughout follow-up. Three patients in each arm developed post-transplant lymphoproliferative disease. Incidence of insulin-dependent diabetes mellitus was not different. Tac was significantly more effective than CyA in preventing acute rejection in pediatric renal recipients. Renal function and graft survival were also superior with Tac. Glomerular filtration rate appears to be an useful surrogate marker for long-term outcome.
89 citations
TL;DR: Recent advances in the diagnosis and treatment of AMR has allowed for significant improvements in outcomes of a condition usually associated with rapid graft failure, however, much work needs to be done to better understand the immunologic processes leading to AMR and how current therapies can be best used to effectively prevent and treat it.
Abstract: Antibody-mediated rejection (AMR) has recently been recognized as a significant and unique form of rejection that is not amenable to treatment with standard immunosuppressive medications aimed at modification of T-cell function. Recent interest in AMR and the role of B cells in rejection has been aided by the concomitant discovery that C4d staining of renal biopsy tissue is strongly associated with AMR and a poor prognosis, and the emergence of desensitization protocols for treatment of highly human leukocyte antigen (HLA)-sensitized patients. Treatment options include: (i) the use of high-dose intravenous immunoglobulin (IVIG) which works by blocking anti-HLA antibody activity and through complement inhibition, (ii) the use of Rituxan (anti-CD20 chimeric antibody) to deplete B cells and interfere with antigen-presenting cell (APC) activity of B cells subsequently decreasing T-cell activation, and (iii) the use of plasmapheresis (PE) + anti-cytomegalovirus (CMV) immunoglobulin G (IgG) or IVIG in lower doses. This protocol removes deleterious anti-HLA antibodies and may also allow complexing of anti-HLA with anti-idiotypes in the anti-CMV IgG. Although early, data support the efficacy of all three approaches. Many centers are now designing protocols that utilize a combination of all three agents. In summary, recent advances in the diagnosis and treatment of AMR has allowed for significant improvements in outcomes of a condition usually associated with rapid graft failure. However, much work needs to be done to better understand the immunologic processes leading to AMR and how current therapies can be best used to effectively prevent and treat it.
87 citations
TL;DR: Hepatic complications occur in a significant proportion of children with autosomal recessive polycystic kidney disease (ARPKD), and the implications of hepatic disease need to be considered in the decision‐making regarding renal transplantation in ARPKD.
Abstract: Hepatic complications occur in a significant proportion of children with autosomal recessive polycystic kidney disease (ARPKD). PKHD1/fibrocystin, the defective gene in ARPKD, is expressed in the cilia of bile duct epithelium and leads to abnormalities in the rubric of the ductal plate malformation. Portal hypertension and biliary disease are the major liver problems seen in ARPKD. Complete blood counting, physical examination, ultrasonography and magnetic resonance (MR) cholangiography are indicated as screening procedures for hepatic disease in ARPKD. Medical and surgical interventions are potentially indicated for children with portal hypertension and/or biliary disease. A high index of suspicion for the diagnosis of cholangitis needs to be maintained in children with biliary disease. The implications of hepatic disease need to be considered in the decision-making regarding renal transplantation in ARPKD.
85 citations
TL;DR: The results show an inverse correlation between age and required tacrolimus dose, wide interindividual variation, and greater exposure with steroid‐free regimen despite no change in trough level.
Abstract: Tacrolimus has become an effective alternative to cyclosporine as a component of primary immunosuppression in pediatric renal transplant patients, but the information on the pharmacokinetic characteristics of tacrolimus in young patients is still limited. The primary objective of this study was to determine the effect of patient age, ethnicity, and concurrent steroid administration on tacrolimus pharmacokinetics in pediatric renal transplant patients. The study population consisted of 30 pediatric patients, age 1.5-18.6 yr, who received a kidney transplant between July 1999 and February 2004. After twice daily dosing was stabilized based on clinical judgment, at least 5 days postoperatively, tacrolimus levels were drawn prior to, and 1, 2, 4, 8, and 12 h after the morning dose. The mean dose of tacrolimus was 0.12 mg/kg/dose. Mean trough level was 11.9 +/- 5.0 ng/mL. Mean area under the curve (AUC) was 192 +/- 84 with a range of 78-360 h x (ng/mL). The correlation between trough level and AUC was only fair (r = 0.74); later time points correlated better with AUC, and an excellent correlation (r = 0.96) was obtained between the mean of trough and 2-h level (C(2)) and AUC. There was a negative correlation between age and dose per body weight (r = -0.68). African-American patients had marginally lower drug exposure with similar dosing. Three age groups ( 12 yr) were compared with respect to dosing and AUC. Despite similar AUC in all three groups, the mean dose per kg required to achieve the AUC was 2.7- and 1.9-fold higher in the 12-yr group. Nine of the 30 patients were on a totally steroid-free regimen. Their tacrolimus dose and trough levels were similar to those of steroid-exposed patients, but their mean AUC was 41% higher. Our results show an inverse correlation between age and required tacrolimus dose, wide interindividual variation, and greater exposure with steroid-free regimen despite no change in trough level.
78 citations
TL;DR: Patient-based studies point to a pro‐inflammatory commitment of lymphocytes at the time of diagnosis, and to their potential role in regulating bile duct obstruction, which is the focus of this article.
Abstract: Biliary atresia is the most common cause of neonatal cholestasis and the leading indication for pediatric liver transplantation worldwide. The disease is caused by a progressive inflammatory and fibrosing obliteration of the extrahepatic bile ducts. Although the cause of this obstruction is largely unknown, patient-based studies have identified environmental and genetic factors that may interact and orchestrate disease pathogenesis. Chief among these factors are infectious and immunologic processes. While infectious agents have varied in different patient populations, studies of liver specimens at different phases of disease point to a pro-inflammatory commitment of lymphocytes at the time of diagnosis, and to their potential role in regulating bile duct obstruction. A review of these studies is the focus of this article.
TL;DR: After renal transplantation, varicella vaccine is safe with a 66% rate of conversion to high antibody titers.
Abstract: The severity of varicella-zoster virus (VZV) in immunocompromised children, especially in those receiving renal transplants, is well known. However, the use of live attenuated virus vaccine in this population is controversial. This study aimed to: (i) assess the immunization status of pediatric renal transplant recipients at our center; (ii) determine the anti-VZV antibody titers in such patients; (iii) evaluate the response to VZV vaccine in seronegative children and in those who present low antibody titers (defined as /=500 mAU/mL in 37 (75.5%). Of the 12 children who were eligible for vaccination and had antibody titers /=500 mAU/mL 6-8 wk after vaccination. In conclusion, after renal transplantation, varicella vaccine is safe with a 66% rate of conversion to high antibody titers.
TL;DR: The adjusted relative risk (aRR) for development of post‐transplant lymphoproliferative disorder (PTLD) is higher in kidney transplant recipients receiving monoclonal antibody induction therapy, but the aRR between the different available polyclonal agents has not been investigated in detail.
Abstract: The adjusted relative risk (aRR) for development of post-transplant lymphoproliferative disorder (PTLD) is higher in kidney transplant recipients receiving monoclonal antibody induction therapy, but the aRR between the different available polyclonal agents has not been investigated in detail. We analyzed data from the United Network of Organ Sharing registry on all kidney transplants performed between 1987 and 2003. The aRR for PTLD development was calculated using SAS 9.0 statistical software and Cox proportional hazards modeling, adjusting for multiple covariates. There were 539 cases of PTLD among 84 907 kidney transplant recipients, who received either polyclonal antibody induction or no induction therapy. In adjusted analysis, the aRR for PTLD development (vs. no induction) was significantly higher with use of equine anti-thymocytic globulin (E-ATG; aRR = 1.61, p = 0.0003) or anti-lymphocytic globulin (ALG; aRR = 1.35, p = 0.0055) but not with rabbit anti-thymocytic globulin (R-ATG; aRR = 1.17, p = 0.29, NS). Median follow up times were significantly shorter in the R-ATG cohort than the ALG or E-ATG cohort (median 368 vs. 1433 and 2055 day). However, in an analysis restricted to pediatric recipients, where median times to PTLD are less than 200 days, only E-ATG was associated with a higher aRR for PTLD (aRR = 2.16, p = 0.0078), while R-ATG and ALG were not. There is a higher aRR for PTLD after kidney transplantation with E-ATG, but not R-ATG. This may only partially be explained by shorter follow up time and may represent differential hazard for PTLD among the agents.
TL;DR: An overview of recent data on emerging viruses after hematopoietic cell transplantation (HCT), including adenovirus, BK virus, human metapneumovirus (hMPV), and human herpesvirus (HHV) 6 is summarized.
Abstract: This overview summarizes recent data on emerging viruses after hematopoietic cell transplantation (HCT), including adenovirus, BK virus, human metapneumovirus (hMPV), and human herpesvirus (HHV) 6. The increased recognition of these infections is due to improved molecular detection methods, increased surveillance and more profound immunosuppression in the host. Adenovirus can cause serious disease especially in T-cell depleted transplant recipients. Adenovirus viremia is an important risk factor for disease in this setting. BK virus has been associated with hemorrhagic cystitis in HCT recipients. BK viremia is significantly associated with hemorrhagic cystitis. hMPV shows a seasonal distribution and can cause fatal pneumonia in HCT recipients. hMPV may be the etiology of some cases previously categorized as idiopathic pneumonia syndrome. HHV-6 commonly leads to viremia in HCT recipients. HHV-6 has been strongly associated with encephalitis and delayed platelet engraftment. Prospective studies are needed to further examine epidemiology, disease associations, and management strategies for these viruses.
TL;DR: The rationale for neonatal screening and the profound effect that such screening would have on the therapy of X‐ALD, including the role of HCT are discussed, with emphasis on the asymptomatic, childhood cerebral, and adrenomyeloneuropathy phenotypes.
Abstract: X-linked adrenoleukodystrophy (X-ALD) in males can present with eight distinct phenotypes, which vary greatly in respect to phenotypic expression, age of onset and rate of progression and therapy. The plasma very long chain fatty acid assay permits precise diagnosis and is already abnormal at birth. The clinical features, molecular biology, pathogenesis, and therapeutic approaches, including the indications for Hematopoietic Stem Cell Transplants (HCT) and dietary therapy are discussed, with emphasis on the asymptomatic, childhood cerebral, and adrenomyeloneuropathy phenotypes. The rationale for neonatal screening and the profound effect that such screening would have on the therapy of X-ALD, including the role of HCT, are discussed.
TL;DR: 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.
Abstract: 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.
TL;DR: The biological and psychological developmental changes that occur during adolescence place the transplanted adolescent at an even higher risk of non‐adherence and poor outcome than other age groups, so further studies are needed to formulate therapeutic interventions that would improve adherence and patient outcomes.
Abstract: Solid organ transplantation has become accepted therapy for the treatment of end-stage organ dysfunction in children. As early management of the pediatric transplant recipient has improved, important age-related differences in long-term patient outcomes have become apparent. Late morbidity and mortality can, in most cases, be attributed to the consequences of long-term immunosuppression: graft loss from under-immunosuppression or an increased incidence of cancer, hypertension, renal failure or diabetes from over-immunosuppression. Age-related differences in both biological and psychological factors play an important role in the optimization of therapy in the transplanted child. Important age-related differences have been demonstrated in all phases of pharmacokinetics: absorption, distribution, metabolism and elimination. Information regarding specific age-related pharmacokinetic differences is lacking for many immunosuppressive medications. Further study using physiologically based pharmacokinetic (PBPK) models will lead to more specific recommendations for age-based immunosuppression protocols. Non-adherence is common among solid organ transplant recipients of all ages and the consequences of non-adherence include increased rejection, late graft loss and death. The biological and psychological developmental changes that occur during adolescence place the transplanted adolescent at an even higher risk of non-adherence and poor outcome than other age groups. Further studies to elucidate the importance of both age-related pharmacokinetic and behavioral factors are needed to formulate therapeutic interventions that would improve adherence and patient outcomes.
TL;DR: Early steroid withdrawal in pediatric renal transplant recipients is efficacious and safe and does not increase risk of rejection, preserving optimal growth and renal function, and reducing cardiovascular risk factors.
Abstract: In pediatric kidney transplantation, steroid induced growth retardation and cushingoid features are of particular concern. In children, gradual steroid withdrawal late after kidney transplantation increases the risk of rejection. In this pilot study, we investigated the outcome of pediatric renal transplantation with an early steroid withdrawal protocol. This is a retrospective case-control study of pediatric renal transplants with age-matched historical control. Groups were comparable in terms of HLA matching, donor type and graft ischemia time. In the steroid withdrawal group (SWG, n = 13), induction therapy included mycophenolate mofetil (MMF) and a 5-day course of steroids with Thymoglobulin in 11 and basiliximab in two other patients. In the steroid group (SG, n = 13), in addition to steroids, four patients were given basiliximab, eight were given Thymoglobulin, and one OKT3. Maintenance therapy included tacrolimus (SWG n = 11, SG n = 3) or cyclosporine (SWG n = 2, SG n = 10). Azathioprine was given to all the patients in the SG, except the last two patients of this series who were prescribed MMF. MMF was given to all in the SWG. Patient and graft survival rates were 100% in both groups. In the SWG, no acute rejection episode was detected. In the steroid group, three patients (25%) presented with an acute rejection episode. All but one patient in either group showed immediate graft function. Patients in the steroid-withdrawal group exhibited a significantly higher creatinine clearance at 6 and 12 months post-transplant (95.8 +/- 23.3 vs. 71.3 +/- 21.9, p = 0.03; and 91.3 +/- 21.6 vs. 69.6 +/- 28.6, p = 0.04). In the SWG delta BMI was significantly lower and delta height Z score was significantly higher, and we observed significantly less hyperlipidemia, body disfigurement, and need for anti-hypertensive medication. Early steroid withdrawal in pediatric renal transplant recipients is efficacious and safe and does not increase risk of rejection, preserving optimal growth and renal function, and reducing cardiovascular risk factors.
TL;DR: It is concluded that basiliximab provides safe and effective induction immunosuppression in pediatric liver graft recipients and short‐ and even long‐term results are excellent.
Abstract: It has been shown that an induction therapy with the monoclonal anti-interleukin-2 receptor antibody basiliximab (Simulect) is capable to reduce the incidence of acute graft rejection in adult and pediatric liver transplantation (Ltx). However, data on long-term results using basiliximab in children post-Ltx are still pending. Therefore, the objective of our study was to report on the long-term results of basiliximab induction therapy in pediatric liver transplant recipients. A total of 54 children received two single doses of basiliximab in addition to cyclosporine and prednisolone following Ltx. We analyzed the incidence of acute and chronic graft rejection that of post-transplant lymphoproliferative disease (PTLD), and patient and graft survival. The follow-up was 22-46 months. The historical control group (matched controls) consisted of 54 patients treated with a cyclosporine and prednisolone dual therapy. Patient survival was 53 of 54 in the treatment group and 51 of 54 in the controls. One patient was retransplanted in the treatment group vs. three patients in the control group. The incidence of acute graft rejection was 16.6% compared with 53.7% in the control group (p < 0.001), that of chronic rejection was comparable in both groups (one of 54 vs. one of 54). The incidence of steroid resistant rejection was four of 54 vs. six of 54 that of PTLD were one of 54 vs. zero of 54. There were no adverse effects observed, which could be related to the antibody treatment. We conclude that basiliximab provides safe and effective induction immunosuppression in pediatric liver graft recipients. Short- and even long-term results are excellent.
TL;DR: The independent determinants of graft survival in live‐donor pediatric and adolescent renal transplant recipients are acute rejection and post‐transplant hypertension.
Abstract: To study the independent determinants of graft survival among pediatric and adolescent live donor kidney transplant recipients. Between March 1976 and March 2004, 1600 live donor kidney transplants were carried out in our center. Of them 284 were 20 yr old or younger (mean age 13.1 yr, ranging from 5 to 20 yr). Evaluation of the possible variables that may affect graft survival were carried out using univariate and multivariate analyses. Studied factors included age, gender, relation between donor and recipient, original kidney disease, ABO blood group, pretransplant blood transfusion, human leukocyte antigen (HLA) matching, pretransplant dialysis, height standard deviation score (SDS), pretransplant hypertension, cold ischemia time, number of renal arteries, ureteral anastomosis, time to diuresis, time of transplantation, occurrence of acute tubular necrosis (ATN), primary and secondary immunosuppression, total dose of steroids in the first 3 months, development of acute rejection and post-transplant hypertension. Using univariate analysis, the significant predictors for graft survival were HLA matching, type of primary urinary recontinuity, time to diuresis, ATN, acute rejection and post-transplant hypertension. The multivariate analysis restricted the significance to acute rejection and post-transplant hypertension. The independent determinants of graft survival in live-donor pediatric and adolescent renal transplant recipients are acute rejection and post-transplant hypertension.
TL;DR: The use of high dose IVIG as an option for treatment of AMR is discussed and it is suggested that IVIG has the unique ability to block complement‐mediated injury through inhibition of C3 activation.
Abstract: B-cells and their products (antibodies) are now recognized as important mediators of allograft rejection. This represents a significant departure from previous doctrine where the T-cells were felt to be of paramount importance. Antibody-mediated rejection (AMR) has emerged as a significant and common complication of transplantation. The development of donor-specific (anti-HLA class I and class II) antibodies is known to correlate strongly with the development of AMR. Recognition of the unique features of AMR that were often confused with non-specific acute tubular injury is aided considerably by improvements in monitoring of anti-HLA antibodies and the immunopathologic demonstration of C4d staining in affected capillary beds. Although imperfect, the demonstration of C4d (a complement breakdown product) staining in an allograft, especially accompanied by the presence of anti-HLA antibodies in the recipient sera, strongly suggests a diagnosis of AMR. Thus, AMR is a complement-dependent, antibody-mediated disorder. AMR can occur as a de novo complication of transplantation in individuals not previously recognized to be sensitized to HLA antigens, but more often occurs as a complication of desensitization therapies in highly-HLA sensitized patients. AMR may also constitute a significant portion of what is now referred to as chronic allograft nephropathy (CAN). The prognosis of C4d (+) AMR is poor as current therapies for treatment of AR are directed primarily at the T-cell. Until recently, no therapeutic options existed to address this problem from a primary etiological standpoint. Here we discuss the use of high dose IVIG as an option for treatment of AMR. We have significant experience with this approach which is outlined here. IVIG has many ideal advantages as a therapy for AMR. First, it can down regulate B-cell activation and antibody production, second, it can induce anti-inflammatory cytokines and contains blocking antiidiotyic antibodies to anti-HLA antibodies and third, IVIG has the unique ability to block complement-mediated injury through inhibition of C3 activation. Further clinical trials are necessary to prove efficacy for treatment of AMR.
TL;DR: A sirolimus‐based regimen that is combined with both an interleukin‐2 receptor antibody and a calcineurin inhibitor may be excessive immunosuppression for pediatric renal transplant recipients.
Abstract: We report our experience with sirolimus in children during the first 6 months after renal transplantation. From July 2000 to January 2004, 66 children received 33 deceased donor and 33 living donor transplants. Maintenance immunosuppression included sirolimus 3 mg/m(2) in addition to prednisone and tacrolimus or cyclosporine. Patient survival was 100% and graft survival was 65 of 66. Seven children experienced acute rejection episodes. All were reversible with increased doses of corticosteroid. One case of graft failure was caused by ischemic renal injury. Adverse events included Epstein-Barr viremia (8 patients) with three cases of post-transplant lymphoproliferative disease (PTLD), cytomegalovirus viremia (4 patients), poor wound healing (4 patients), pneumonitis (3 patients), nephrotic syndrome (3 patients), perinephric abscess (1 patient) and insulin-dependant diabetes (2 patients). Sirolimus was discontinued in 13 children for adverse events predominantly for wound dehiscence and pneumonitis. Cholesterol levels >200 mg/dL were observed in 33 children. Thrombocytopenia (platelet count <140 000) was not observed. We concluded that early outcomes with sirolimus were acceptable with 98% graft survival and 11% incidence of acute rejection. Medication was discontinued in 20% for adverse events which included poor wound healing and non-infectious pneumonitis. Infections with cytomegalovirus and Epstein-Barr virus, and PTLD were also significant early complications. Therefore, a sirolimus-based regimen that is combined with both an interleukin-2 receptor antibody and a calcineurin inhibitor may be excessive immunosuppression for pediatric renal transplant recipients.
TL;DR: Sirolimus represents a major advancement in the field of solid organ transplantation and is being used as a rescue agent for acute and chronic rejection as well as for primary immunosuppression with good graft outcome.
Abstract: Sirolimus represents a major advancement in the field of solid organ transplantation and is being used as a rescue agent for acute and chronic rejection as well as for primary immunosuppression with good graft outcome. Although initial studies with sirolimus were in adults, now significant data have accumulated on the role of sirolimus in pediatric solid organ transplantation. This article reviews the current status of sirolimus in pediatric transplantation.
TL;DR: Improvement in renal function and hypertension management, and absence of sirolimus‐related adverse events argue for prospective evaluation of regimens in which mTOR inhibitors are used without calcineurin inhibitors in children.
Abstract: A highly selected subject group comprising pediatric recipients of liver (n = 36) and small intestine alone (n = 1) or multivisceral graft (n = 2) were converted to sirolimus maintenance therapy for tacrolimus-related side effects (n = 32) or by primary intent (n = 7). Indications were nephrotoxicity (n = 14), primary intent (n = 7), post-transplant lymphoproliferative disorder (n = 6), seizures (n = 4), recurrent acute rejection (n = 2), and cardiomyopathy (n = 1). Thirty subjects (78%) experienced successful conversion, with one subject requiring atorvastatin for hypercholesterolemia and hypertriglyceridemia. Nine subjects (22%) were converted back to tacrolimus for serious adverse events including acute rejection (n = 2), elevated liver function tests (n = 1), severe leucopenia (n = 1), non-compliance (n = 2), recurrent malignancy/death (n = 1), steatohepatitis (n = 1), and thrombocytopenic thrombotic purpura (n = 1). Among subjects with nephrotoxicity, significant benefit was seen only in those subjects with shorter time to rescue after transplantation (n = 8 of 14 subjects). Additional benefits included a significant decrease in mean serum creatinine from pretransplant values for the entire population, and elimination of antihypertensive treatment in all five subjects receiving it prior to conversion. Hemoglobin, serum cholesterol and triglycerides, white cell counts and platelets remained within normal limits for the duration of follow-up (36 month). Conversion from tacrolimus to sirolimus is successful in selected pediatric liver and intestine recipients. Chronic nephrotoxicity may be ameliorated by early conversion. Improvement in renal function and hypertension management, and absence of sirolimus-related adverse events argue for prospective evaluation of regimens in which mTOR inhibitors are used without calcineurin inhibitors in children.
TL;DR: A high performance liquid chromatography tandem mass spectrometry (HPLC T‐MS) methodology which measures whole blood tacrolimus levels using a 10 μL sample, thus allowing the use of fingerprick blood sampling, allowing the two to be used interchangeably for routine clinical purposes.
Abstract: Regular monitoring of tacrolimus levels is an essential component of post-transplantation follow up in children receiving this drug. We have developed a high performance liquid chromatography tandem mass spectrometry (HPLC T-MS) methodology which measures whole blood tacrolimus levels using a 10 microL sample, thus allowing the use of fingerprick blood sampling. The aim of this study was to determine the degree of relationship between fingerprick and venous tacrolimus levels measured by HPLC T-MS and venous levels measured using the Abbott IMx tacrolimus II assay (IMx). This has not previously been investigated. Blood samples were collected from children on five separate occasions. In addition to the routine venous IMx sample, a further venous and fingerprick sample were collected for tacrolimus level measurement by HPLC T-MS. These were mailed to the central laboratory. One hundred and seventy-two sets of triplicate samples were collected from 36 children (33 kidney, two kidney-pancreas and one kidney-heart). Linear regression analysis showed highly significant relationships between HPLC T-MS venous and IMx venous levels (r(2) = 0.83), HPLC T-MS fingerprick and HPLC T-MS venous levels (r(2) = 0.85) and HPLC T-MS fingerprick and IMx venous levels (r(2) = 0.71) (all p < 0.0001). Bland Altman analysis showed a small, although statistically significant difference between measured values, fingerprick HPLC T-MS levels being lower than venous IMx levels, the mean difference being 0.58 ng/mL (95% CI 0.26-0.91, t = 3.54, d.f. = 168, p = 0.0005 one sample t-test). Precise conversion between the two techniques could be achieved using the regression formula; IMx venous level = 0.751 + 0.978. HPLC T-MS fingerprick level. There is a strong significant relationship between fingerprick blood tacrolimus levels measured by HPLC T-MS and venous blood levels measured by IMx, allowing the two to be used interchangeably for routine clinical purposes.
TL;DR: Rapid evaluation of new SCT preparative regimens would be useful in improving both short‐term and long‐term results.
Abstract: Patients with Fanconi's Anemia (FA) have high rates of congenital physical abnormalities, bone marrow failure, leukemia, and solid tumors. Stem cell transplant (SCT) is often effective in curing bone marrow failure, but high-risk patients, particularly those whose donor is not a human leukocyte antigen matched sibling, are vulnerable to early mortality from transplant-related complications. Long-term survivors of SCT have risks of solid tumors (particularly of the oral cavity), which are even higher than the already high ‘baseline’ risk of neoplasia in untransplanted FA patients. In this group, the major types of cancer are head and neck squamous cell carcinomas, and gynecologic malignancies. Rapid evaluation of new SCT preparative regimens would be useful in improving both short-term and long-term results.
TL;DR: It is concluded that hepatic venous reconstruction in pediatric living donor liver transplantation must be preferentially performed by using a wide triangulation on the recipient inferior vena cava, including the orifices of the three hepatic veins.
Abstract: In pediatric patients submitted to living related liver transplantation, hepatic venous reconstruction is critical because of the diameter of the hepatic veins and the potential risk of twisting of the graft over the line of the anastomosis. The aim of the present study is to present our experience in hepatic venous reconstruction performed in pediatric living related donor liver transplantation. Fifty-four consecutive transplants were performed and two methods were utilized for the reconstruction of the hepatic vein: direct anastomosis of the orifice of the donor left or left and middle hepatic veins and the common orifice of the recipient left and middle hepatic veins (group 1-26 cases), and wide triangular anastomosis after creating a wide triangular orifice in the recipient inferior vena cava at the confluence of all the hepatic veins with an additional longitudinal incision in the inferior angle of the orifice (group 2-28 cases). In group 1, eight patients were excluded because of graft problems in the early postoperative period and five among the remaining 18 patients (27.7%) presented stricture at the site of the hepatic vein anastomosis. All these patients had to be submitted to two or three sessions of balloon dilatations of the anastomoses and in four of them a metal stent had to be placed. The liver histopathological changes were completely reversed by the placement of the stent. Among the 28 patients of the group 2, none of them presented hepatic vein stenosis (p = 0.01). The results of the present series lead to the conclusion that hepatic venous reconstruction in pediatric living donor liver transplantation must be preferentially performed by using a wide triangulation on the recipient inferior vena cava, including the orifices of the three hepatic veins. In cases of stenosis, the endovascular dilatation is the treatment of choice followed by stent placement in cases of recurrence.
TL;DR: This review will address fetal liver disease that leads to liver failure in the fetus or newborn and the lack of known preexisting liver disease.
Abstract: Acute liver failure in the newborn is relatively rare but often fatal. The broadest definition of acute liver failure is failure of the vital functions of the liver occurring within weeks or a few months of the onset of clinical liver disease. Therefore, by definition, any liver failure in the newborn can be construed to be acute liver failure. A second component of the general definition of acute liver failure is the lack of known preexisting liver disease. In the case of neonatal acute liver failure, preexisting disease would by definition be liver disease that affects the fetus. Almost nothing is known about fetal onset liver failure, and there is no literature addressing the subject. This review will address fetal liver disease that leads to liver failure in the fetus or newborn.
TL;DR: The aim of this study was to determine the long‐term outcome of renal function in children receiving OLT and the nephrotoxicity of cyclosporine predicts the long-term outcomes of adult patients receiving a liver transplant.
Abstract: The orthotopic liver transplantation (OLT) allows survival of children followed for severe hepatic injury, provided that the immunosuppressive treatment is prolonged. The nephrotoxicity of cyclosporine predicts the long-term outcome of the adult patients receiving a liver transplant. The aim of this study was to determine the long-term outcome of renal function in children receiving OLT.
This study included 12 children, with a median for age of 7.1 yr (2–15 yr) at the time of OLT. The duration of follow-up was at least 4 yr, being 7 yr in 10 patients and more than 10 yr in seven. Renal function was evaluated with the serum level of creatinine, calculated glomerular filtration rate (cGFR), and measurement of glomerular filtration rate using chrome 51 ethylenediaminetetraacetate (51Cr EDTA) clearance performed at least once during follow-up. The doses and the serum concentrations (C0) of cyclosporine were reported at each study time.
The cGFR decreased significantly 2 yr after the OLT [median (range): 106 mL/min/1.73 m2 (71–150) at the time of OLT vs. 85 mL/min/1.73 m2 (57–128) 2 yr after the OLT, p = 0.03], and decreased again between 7 and 10 yr after OLT [median (range): 99 mL/min/1.73 m2 (76–125) 7 yr after OLT vs. 81 mL/min/1.73 m2 (66–140) 10 yr after OLT, p = 0.04]. Six patients developed chronic renal failure (cGFR from 57 to 80 mL/min/1.73 m2) 2 yr after OLT associated with high doses of cyclosporine [median (range): 8.8 mg/kg/day (3.5–13)]. The cGFR overestimated renal function by 16% compared with the isotopic measurement of GFR (p = 0.03). Using the 51Cr EDTA measurement, six of seven patients followed up more than 10 yr after OLT presented mild (n = 3) or moderate (n = 3) chronic renal failure. In our study, the majority of OLT recipients developed a chronic renal failure 10 yr after transplantation. Cyclosporine seems to be the most important factor responsible for the impairment of renal function. The use of the mycophenolate mofetil, a new immunosuppressive agent, allowing a reduction in the dose of cyclosporine, could minimize renal dysfunction. While awaiting the results of a prospective long-term study, close drug monitoring is advised.
TL;DR: HAT with subsequent graft loss may be minimized in PLT with the use of surgical loupes only, anticoagulation utilizing aspirin, alprostadil, and daily ultrasounds.
Abstract: The risk of hepatic artery thrombosis (HAT) after pediatric liver transplantation (PLT) has been reported to range from 0 to 25%. We report our experience focusing on the interrelationships between risk factors, surgical technique and the incidence of HAT after liver transplantation in the pediatric age group. From February 18, 1997 to December 31, 2003, 150 consecutive liver transplants were performed in 132 pediatric patients. There were similar numbers of whole grafts when compared with partial grafts, 80 (53.3%) vs. 70 (46.7%), p = 0.30. Four grafts (2.7%) developed HAT. Of the grafts with HAT, three were successfully revascularized within the first 24 h. Only one graft (0.66%) was lost to HAT. A single surgeon utilizing 3.5-6.0 magnification loupes performed all but one hepatic arterial anastomoses. All patients were followed postoperatively by a daily ultrasound protocol and with anticoagulation of aspirin and alprostadil only. Living and deceased donor left lateral segment grafts had an increased rate of HAT when compared with whole liver grafts. HAT with subsequent graft loss may be minimized in PLT with the use of surgical loupes only, anticoagulation utilizing aspirin, alprostadil, and daily ultrasounds.