Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children.

Late graft rejection impairs the long-term function of organ transplants in children. Previous studies suggest patients with wide variation in tacrolimus levels may have higher rates of late kidney and liver graft rejection. The reproducibility of this finding and impact on graft and recipient survival have not been reported. We investigated factors associated with late rejection > 6 months post-transplant in 144 heart, kidney, liver, and lung transplant recipients (ages 8-18, ≥ 1-yr survivors, receiving tacrolimus-based immunosuppression), comparing late rejectors (n = 61, 42%) to non-rejectors (no rejection > 6 months); groups had similar mean tacrolimus concentrations ≤ 6 months post-transplant. For all organ types, increased standard deviation in intrapatient tacrolimus blood levels was an independent risk factor for late rejection (OR 1.6 [CI 1.1-2.1]; p = 0.02). Each 1-point increase in s.d. > 2 of tacrolimus level > 6 months post-transplant associated with 1.58 increase in hazard of graft loss (p = 0.003). Graft survival (conditional on one-yr survival) was significantly better for those with s.d. < 2 at > 6 months post-transplant: 98% at three and five yr, versus 88%, 70%, at three and five yr, in patients with s.d. > 2 (p = 0.003). In conclusion, high s.d. in serial tacrolimus concentrations associated with increased risk of late rejection and graft loss in pediatric organ transplant recipients, providing opportunities for screening and interventions.

Post-transplant lymphoproliferative disorder in pediatric heart transplant recipients.

BACKGROUND: Post-transplantation lymphoproliferative disorder (PTLD) is a major cause of morbidity and mortality after pediatric heart transplantation. METHODS: Heart transplant recipients at The Hospital for Sick Children, Toronto, from 1990 to May 2008, were reviewed. Competing risk hazard analysis was used to model the natural history of the disease. Patients were matched for gender and duration of follow-up to identify potential covariates associated with increased risk of PTLD. RESULTS: A total of 173 heart transplant recipients (42% <1 year old) were reviewed. Twenty-three developed PTLD at a median of 4 years post-transplantation. After transplantation, PTLD affected 9%, 15% and 28% at 3, 5 and 10 years, respectively. Freedom from death or PTLD recurrence was 72%, 58% and 50% at 1, 3 and 5 years, respectively, after PTLD diagnosis. Higher maximum Epstein-Barr viral (EBV) load (hazard ratio [HR]: 2.6, p = 0.004) and longer duration of induction therapy (HR: 1.7, p = 0.02) were associated with increased risks of PTLD. Higher cumulative cyclosporine doses over the first year post-transplantation were associated with increased risks of PTLD (HR: 1.2 per 1 mg/kg/day equivalent, p = 0.03), but higher tacrolimus doses were not (p = 0.38). Patients on cyclosporine at 6 months post-transplantation were at higher risk of PTLD than those on tacrolimus (HR: 5.2, p = 0.003). The use of anti-viral prophylaxis in patients with high EBV load may provide some protection (HR: 7.6 vs 15.4 with no anti-viral, p = 0.02). CONCLUSIONS: PTLD is a major concern in pediatric heart transplant recipients and is associated with high morbidity/mortality. Exposure to EBV and higher intensity of immunosuppression seems to be associated with increased risk.

Child and parental perspectives of multidimensional quality of life outcomes after kidney transplantation.

Kidney transplantation is an optimal therapy for pediatric patients with end-stage kidney disease. This pilot study sought to examine multidimensional QOL outcomes after kidney transplant using VAQOL and General Health, the PedsQL 4.0, PedsQL End Stage Renal Disease Module, and Impact on Family Module. Sample included 12 adolescents aged 13-18 yr and their parent; three children aged eight to 12 yr and their parent; and six parents of children aged two to seven yr. All were 73 months post transplant. The median age at transplant was 9.3 yr and median time since transplant was 3.2 yr. VAQOL mean was 7.7/10 (child report) and 7.3/10 (parent report); the mean general health was 7.4/10. High levels of fatigue (> or =5/10) were reported in 43%. PedsQL subscale mean values were lower than healthy reference scores. PedsQL Renal Module demonstrated great concern with physical appearance and physical symptoms (thirst and headaches), difficulty with peer and family interaction, and school disruption. Low scores on parental emotional function depict the negative impact of transplant on family functioning. Discordance exists between child and parental reports of QOL. Prospective studies are needed to explore multidimensional QOL to improve long-term outcomes after pediatric kidney transplant.

Continuous infusion of thymoglobulin for induction therapy in pediatric heart transplant recipients; experience and outcomes with a novel strategy for administration.

Minimal data exist on the perioperative use of TG for induction in pediatric HTx recipients. We report our experience using continuous infusion of TG on (i) perioperative adverse events, (ii) rejection, (iii) CAV, and (iv) PTLD. TG was infused via peripheral intravenous intra- and perioperatively as a continuous infusion (24 h/day). Starting dose was 1.5 mg/kg/day titrated to achieve target lymphocyte count of 0.1-0.3 x 10(9)/L. Fifty-five patients received TG; mean age at HTx was 4.4 yr (1 day-17.8 yr). The mean duration of TG was three and a half days (2-7 days). Median platelet count during TG infusion was 95 x 10(9)/L (28-228). Five patients had TG stopped for low platelets (at 4-6 days post-HTx) - all started maintenance immunosuppression. There was no perioperative mortality due to infection. Mean follow-up of 46 survivors was 2.3 yr (0.6-5.8 yr). Fifty-one percent had > or = ISHLT 2R rejection at a median time of 33 days post-HTx (7 days-2 yr). One patient developed PTLD 1.4 yr post-HTx; three patients developed mild-moderate CAV. TG as a continuous infusion appears to have a good safety profile. Though mild thrombocytopenia was prevalent, there was no bleeding attributable solely to TG. Whether early depletion of T-cell function will translate into long-term benefits remains to be determined.

Competing outcomes after neonatal and infant wait-listing for heart transplantation.

BACKGROUND: Neonatal and infant heart transplantation is a therapeutic option for patients with end-stage cardiac lesions, yet infants continue to face a considerable shortage of donor organs. We sought to ascertain outcomes after listing for heart transplantation using a competing outcomes methodology, and to identify factors predicting each outcome. METHODS: Review of the Toronto cardiac transplant database was undertaken to identify infant patients (

Pediatric heart transplantation in human leukocyte antigen sensitized patients: evolving management and assessment of intermediate-term outcomes in a high-risk population.

BACKGROUND: There is an elevated risk for poor outcomes after heart transplant (HTx) in patients sensitized to human leukocyte antigens including graft dysfunction, acute cellular and antibody-mediated (AMR) rejection, and cardiac allograft vasculopathy. We report our experience with human leukocyte antigens-sensitized pediatric HTx recipients. METHODS AND RESULTS: We identified pediatric HTx patients with elevated pre-HTx Panel Reactive Antibody (Class I/II; > 10%), or a positive T- or B-cell crossmatch. Thirteen patients met criteria (5 female, 39%). The median age at HTx was 7 months (3.5 months to 15.5 years). Nine were infants who had prior palliation for congenital heart disease. Four were older patients (median 7.3 years; 4.8 to 15.5 years): 2 had congenital heart disease (Fontan), 2 were re-HTx. B-cell therapies were used in all patients, guided by assessment of CD19+ and CD20+ cells. Immunosuppression included thymoglobulin induction, and tacrolimus, mycophenolate mofetil, and steroids. Daily plasmapheresis +/- intravenous immunoglobulin G was used if there was a positive crossmatch on day 1, with a gradual, biopsy-guided weaning schedule. Rituximab was used when AMR was detected on biopsy: more recently (n=3), used empirically perioperatively. AMR was confirmed in 9 patients within median 0.9 months post-HTx. Seven had early acute cellular rejection (> or = ISHLT Grade 2 R) with no hemodynamic compromise or graft dysfunction. There were 4 deaths post-HTx (range, 11 days to 9 months). The median follow-up of 9 survivors was 1.7 years (0.3 to 3.7 years). Of 7 patients > 6 months post-HTx, no AMR or cardiac allograft vasculopathy was observed at a mean of 1.9+1.1 years post-HTx and no cardiac allograft vasculopathy. CONCLUSIONS: Despite aggressive management, acute cellular rejection and AMR occurred frequently early post-HTx. An algorithm of B cell-directed strategies can be effective in managing these patients with reasonable intermediate-term outcomes.

Impact on outcomes after listing and transplantation, of a strategy to accept ABO blood group-incompatible donor hearts for neonates and infants.

BACKGROUND: Recent data suggest that ABO blood group-incompatible donor hearts are immunologically well tolerated in infants undergoing transplantation. METHODS: Competing-risks methodology was used to assess outcomes after listing and the impact of a strategy to accept heart grafts from any blood group donor for infants less than 18 months of age. RESULTS: From 1992 to 2002, there were 91 listing episodes in 84 patients (including 20 fetuses; 50% were male and 63% had congenital heart disease). Beginning in 1995, a strategy to accept ABO-incompatible organs was adopted. Competing-risks analysis showed that after 20 months 60% underwent transplantation, 18% died, and less than 1% were still listed; the remaining 21% were de-listed because of a change of surgical strategy (9%), improved clinical condition (8%), and deterioration to ineligibility (4%). Risk factors for transplantation included only a strategy to accept ABO-incompatible organs (P <.001). Risk factors for death included failure to accept ABO-incompatible organs (P =.002) and Canadian listing status 3 (P =.085) or 4 (P <.001). Multivariable parametric models were used to create competing risk predictions for outcomes specific to status and ABO-incompatible strategy. Higher status resulted in greater mortality regardless of strategy, although for any status, more patients underwent transplantation and fewer died using a strategy to accept ABO-incompatible organs. Parametric modeling of time-related freedom from death or retransplantation demonstrated no significant difference at 4 years posttransplantation (P =.78) for ABO-incompatible (74%) versus ABO-compatible transplants (72%). CONCLUSIONS: A strategy to accept ABO-incompatible donor hearts for infant transplantation significantly improves the likelihood of transplantation and reduces waiting list mortality while not adversely altering outcomes after transplantation.

Patients' perceptions versus medical testing of function in women with lymphangioleiomyomatosis (LAM).

Lymphangioleiomyomatosis (LAM), a rare pulmonary disease that occurs primarily in women is characterized by progressive cystic lung lesions causing respiratory failure, which may require lung transplantation. It has been observed that in diseases of the lungs, objective medical tests frequently do not translate to subjective functional status. However, patient's perceptions of functional status directly impact quality of life. In order to evaluate this relationship in LAM, a cross sectional study of 31 lung transplant candidates and 43 lung transplant recipients with LAM was conducted to evaluate functional status. Objective tests (Pulmonary function tests, PFTs, 6 min walk) were obtained in 19 candidates and 23 recipients, and subjective function was assessed in all women using the Functional Performance Inventory. For both groups statistically significant relationships emerged between forced vital capacity with subjective measures of function including total, social and recreational function (P < 0.05). As well diffusing capacity related significantly to total function, ability to maintain household chores, body care, and social function (P < 0.05), where higher scores were associated with better subjective function. Forced expiratory volume in one second was not found to significantly relate to subjective function in these groups, except the physical exercise domain in transplant recipients. However, despite better PFT results in double lung transplant recipients, no differences were found in subjective measures of function between single and double lung recipients. Results suggest that clinicians need to better recognize that certain aspects of spirometry/6 min walk tests do not necessarily correlate well with patient's perceptions of their function. This has implications for the assessment and follow-up of women living with LAM; considering subjective aspects of function may help focus interventions and improve quality of life.

Personality factors and disordered eating in young women with type 1 diabetes mellitus.

The authors examined the association between the presence of personality variables implicated in the pathogenesis of eating disorders and the presence of eating disorder symptoms in 51 women with type 1 diabetes. Subjects were assessed with interview instruments and self-report questionnaires, including scales measuring eating disorder symptoms, borderline personality characteristics, and perfectionism. Fourteen subjects displayed moderate to severe eating disorder symptoms. Perfectionism was related to attitudinal aspects of eating disorders (e.g., weight preoccupation), and borderline personality characteristics were related to disordered behaviors (e.g., insulin omission) and poor glycemic control. The results suggest that personality factors are related to disordered eating and poor glycemic control in diabetic women.

Randomized clinical trial of tacrolimus- vs cyclosporine-based immunosuppression in pediatric heart transplantation: preliminary results at 15-month follow-up.

BACKGROUND: While Tacrolimus (Tac) and Cyclosporine (Cya) immunosuppression are used after cardiac transplantation (tx), few studies have evaluated their use in pediatric patients. METHODS: We randomized 26 heart transplant recipients (pts) in a prospective, open-label trial to Tac (n = 14) or Cya (n = 12) to compare their efficacy and side-effects. Mean age at tx was 4.2 years for Tac and 5.8 years for Cya. Mean follow-up was 26 months (range: 11-39 months) for Tac and 24 months for Cya (range: 33-13 months). RESULTS: Our data suggest that both regimens are efficacious in the pediatric population. Conversion from Cya to Tac was useful for dealing with persistent rejection, although this sample did not suggest lower incidence of acute cellular rejection in the Tac group. CONCLUSIONS: Further studies are required to establish pharmacokinetic parameters to enhance therapeutic monitoring of these patients to minimize side effects and enhance outcomes.

Sirolimus immunosuppression in pediatric heart transplant recipients: a single-center experience.

BACKGROUND: Sirolimus has been used in heart transplant recipients for treatment of rejection, alternative immunosuppression (IS) and promotion of regression and prevention of graft vasculopathy (coronary artery disease [CAD]). This study reports on our center's experience with 16 children who underwent heart transplantation. METHODS: Data were obtained by retrospective review. RESULTS: Median age at time of review was 12.3 years (n = 16, 5.1 to 18.0 years; 9 boys, 7 girls), and at time of transplant 7.5 years (6 months to 18.0 years). Median time of sirolimus introduction was 2.7 years (1 month to 8.2 years) post-transplant. Fifteen patients were on steroids, 10 on tacrolimus (FK) and mycophenolate mofetil (MMF), 5 on FK and 1 on MMF with no calcineurin inhibitors (CNIs). The average dose of sirolimus was 0.25 mg/kg or 7.0 mg/m(2) to maintain a target level of 5 to 15 mug/liter. Sirolimus was started for CAD in 6 patients (38%), rejection in 5 (31%), and in 5 with combinations of CNI intolerance, CAD, renal dysfunction and rejection. All 6 who received sirolimus for rejection (International Society for Heart and Lung Transplantation [ISHLT] Grade 3A) showed improvement on follow-up biopsies. Two of 3 who received sirolimus for renal dysfunction showed improvement (glomerular filtration rate [GFR] 43 to 67 and 32 to 106 ml/min per 1.73 m(2), respectively). Side effects included hyperlipidemia (38%), abdominal pain (31%), mouth ulcers (26%), anemia or neutropenia (12.5%), persistent pericardial effusion (6%) and interstitial lung disease (6%). Sirolimus therapy was discontinued in 3 patients due to side effects. CONCLUSIONS: In this study sirolimus was found to be a valuable IS agent for the management of rejection, significant renal dysfunction and CNI side effects. These results support the need for prospective studies of the role of sirolimus in primary rejection prophylaxis, primary CAD prophylaxis and CAD regression. There also exists a need to establish an adverse event profile for this drug.

Donor-specific B-cell tolerance after ABO-incompatible infant heart transplantation.

Although over 50 years have passed since its first laboratory description, intentional induction of immune tolerance to foreign antigens has remained an elusive clinical goal. We previously reported that the requirement for ABO compatibility in heart transplantation is not applicable to infants. Here, we show that ABO-incompatible heart transplantation during infancy results in development of B-cell tolerance to donor blood group A and B antigens. This mimics animal models of neonatal tolerance and indicates that the human infant is susceptible to intentional tolerance induction. Tolerance in this setting occurs by elimination of donor-reactive B lymphocytes and may be dependent upon persistence of some degree of antigen expression. These findings suggest that intentional exposure to nonself A and B antigens may prolong the window of opportunity for ABO-incompatible transplantation, and have profound implications for clinical research on tolerance induction to T-independent antigens relevant to xenotransplantation.

Canadian respirologists' experience with lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare pulmonary disease occurring primarily in women. A literature review of LAM in Canada found sporadic mention of LAM in case reports or within lung transplant studies. The LAM Foundation, a patient support and research funding organization, lists 23 Canadian patients in its database. The present study was designed to assess the scope of LAM across Canada and to identify potential patients for further evaluation. OBJECTIVES: To ascertain Canadian respirologists' experience with patients with LAM (current and historical), lung transplantation (single or bilateral) and deaths due to LAM, and awareness of the LAM Foundation. METHODS: Four hundred twelve brief surveys were sent anonymously to members of the Canadian Lung Association (inserted in their newsletters) to ascertain the experience of Canadian respirologists with LAM. RESULTS: One hundred twelve surveys were returned (27%). Fifty-one respondents had "ever" been involved in the care of at least one patient with LAM; eight had cared for three or more patients. At the time of the study, 26 respondents were following a total of 46 patients with LAM; 22 of the 51 respirologists (43%) who had ever cared for a patient with LAM reported the death of a patient. Thirty-three patients had been put on wait lists for transplantation; six died while on the wait list. Nineteen patients underwent lung transplantation--six single-lung recipients and 13 bilateral lung recipients. Of the 51 respirologists who had ever cared for a patient with LAM, only 30 (61%) were aware of the LAM Foundation's services. Of the 112 respondents, only 47 (43%) were aware of the LAM Foundation. CONCLUSIONS: This study identified a moderate level of awareness of a significant existing patient support and research service (the LAM Foundation). There were many patients with LAM who were unknown to the LAM Foundation and could benefit from its resources. Results suggest that there may be more patients with LAM in Canada than are reported in the existing literature.