Assessment of liver fibrosis using a 3-dimensional high-resolution late gadolinium enhancement sequence in children and adolescents with Fontan circulation.

OBJECTIVES: To assess abnormal liver enhancement on 15-20 min delayed 3D high-resolution late gadolinium enhancement (3D HR LGE) sequence in patients with Fontan circulation. METHODS: Retrospective study of pediatric Fontan patients (< 18 years old) with combined cardiac-liver MRI from January 2018 to August 2021. Abnormal hepatic enhancement was graded (0-3) for each lobe, summed for a total liver enhancement score (0-6), and compared to repaired tetralogy of Fallot (rTOF) patients. Correlations with other hepatic imaging biomarkers were performed. Temporal relationships of enhancement compared to traditional early portal venous and 5-7-min delayed phase liver imaging were analyzed. RESULTS: The Fontan group (n = 35, 13 ± 3.4 years old, median time from Fontan 10 (9-12) years) had 23/35 (66%) with delayed 3D HR LGE total liver enhancement score > 0 (range 0-5), with greater involvement of the right lobe (1 (0-1) vs 0 (0-1), p < 0.01). The rTOF group (n = 35, 14 ± 2.6 years old) had no abnormal enhancement. In the Fontan group, total liver enhancement was 3 (2-4) in the early portal venous phase, lower at 1 (1-2) in the 5-7-min delayed phase (p < 0.01), and lowest at 1 (0-2) in the 15-20-min delayed phase (p = 0.03). 3D HR LGE enhancement correlated inversely with portal vein flow (rs = - 0.42, p = 0.01) and positively with left lobe stiffness (rs = 0.51, p < 0.01). The enhancement score decreased in 13/35 (37%) between the 5-7- and 15-20-min delayed phases. CONCLUSIONS: Liver fibrosis can be assessed on 3D HR LGE sequences in patients with Fontan circulation, correlates with other imaging biomarkers of Fontan liver disease, and may add information for hepatic surveillance in this population. KEY POINTS: • Abnormal liver enhancement on 3D HR LGE sequences in Fontan patients likely represents liver fibrosis and is seen in up to 66% of children and adolescents with variable distribution and severity. • The degree of 3D HR LGE liver enhancement correlates with decreased portal vein flow and increased left hepatic lobe stiffness.

Incidence and Risk Factors of Obesity in Childhood Solid-Organ Transplant Recipients.

BACKGROUND: Obesity is a significant public health concern; however, the incidence post solid-organ transplantation is not well reported. METHODS: This study determined the incidence and risk factors of obesity among pediatric solid-organ transplant recipients (heart, lung, liver, kidney, multiorgan) at The Hospital for Sick Children (2002-2011), excluding prevalent obesity. Follow-up occurred from transplantation until development of obesity, last follow-up, or end of study. Incidence of obesity was determined overall, by baseline body mass index, and organ group. Risk factors were assessed using Cox proportional-hazards regression. RESULTS: Among 410 (55% male) children, median transplant age was 8.9 (interquartile range [IQR]: 1.0-14.5) years. Median follow-up time was 3.6 (IQR: 1.5-6.4) years. Incidence of obesity was 65.2 (95% confidence interval [CI]: 52.7-80.4) per 1000 person-years. Overweight recipients had a higher incidence, 190.4 (95% CI: 114.8-315.8) per 1000 person-years, than nonoverweight recipients, 56.1 (95% CI: 44.3-71.1). Cumulative incidence of obesity 5-years posttransplant was 24.1%. Kidney relative to heart recipients had the highest risk (3.13 adjusted hazard ratio [aHR]; 95% CI: 1.53-6.40) for obesity. Lung and liver recipients had similar rates to heart recipients. Those with higher baseline body mass index (z-score; 1.72 aHR; 95% CI: 1.39-2.14), overweight status (2.63 HR; 95% CI: 1.71-4.04), and younger transplant age (y; 1.18 aHR; 95% CI: 1.12-1.25) were at highest risk of obesity. Higher cumulative steroid dosage (per 10 mg/kg) was associated with increased risk of obesity after adjustment. CONCLUSIONS: Among all transplanted children at The Hospital for Sick Children, 25% developed obesity within 5-years posttransplant. Kidney recipients, younger children, those overweight at transplant, and those with higher cumulative steroid use (per 10 mg/kg) were at greatest risk. Early screening and intervention for obesity are important preventative strategies.

Behavioral economics-A framework for donor organ decision-making in pediatric heart transplantation.

The high discard rate of pediatric donor hearts presents a major challenge for children awaiting heart transplantation. Recent literature identifies several factors that contribute to the disparities in pediatric donor heart usage, including regulatory oversight, the absence of guidelines on pediatric donor heart acceptance, and variation among transplant programs. However, a likely additional contributor to this issue are the behavioral factors influencing transplant team decisions in donor offer scenarios, a topic that has not yet been studied in detail. Behavioral economics and decision psychology provide an excellent foundation for investigating decision-making in the pediatric transplant setting, offering key insights into the behavior of transplant professionals. We conducted a systematic review of published literature in pediatric heart transplant related to behavioral economics and the psychology of decision-making. In this review, we draw on paradigms from these two domains in order to examine how existing aspects of the transplant environment, including regulatory oversight, programmatic variation, and allocation systems, may precipitate potential biases surrounding donor offer decisions. Recognizing how human decision behavior influences donor acceptance is a first step toward improving utilization of potentially viable pediatric donor hearts.

Equally Interchangeable? How Sex and Gender Affect Transplantation.

Organ transplantation as an option to overcome end-stage diseases is common in countries with advanced healthcare systems and is increasingly provided in emerging and developing countries. A review of the literature points to sex- and gender-based inequity in the field with differences reported at each step of the transplant process, including access to a transplantation waiting list, access to transplantation once waitlisted, as well as outcome after transplantation. In this review, we summarize the data regarding sex- and gender-based disparity in adult and pediatric kidney, liver, lung, heart, and hematopoietic stem cell transplantation and argue that there are not only biological but also psychological and socioeconomic issues that contribute to disparity in the outcome, as well as an inequitable access to transplantation for women and girls. Because the demand for organs has always exceeded the supply, the transplant community has long recognized the need to ensure equity and efficiency of the organ allocation system. In the spirit of equity and equality, the authors call for recognition of these inequities and the development of policies that have the potential to ensure that girls and women have equitable access to transplantation.

Sensitization in Transplantation: Assessment of Risk (STAR) 2017 Working Group Meeting Report.

The presence of preexisting (memory) or de novo donor-specific HLA antibodies (DSAs) is a known barrier to successful long-term organ transplantation. Yet, despite the fact that laboratory tools and our understanding of histocompatibility have advanced significantly in recent years, the criteria to define presence of a DSA and assign a level of risk for a given DSA vary markedly between centers. A collaborative effort between the American Society for Histocompatibility and Immunogenetics and the American Society of Transplantation provided the logistical support for generating a dedicated multidisciplinary working group, which included experts in histocompatibility as well as kidney, liver, heart, and lung transplantation. The goals were to perform a critical review of biologically driven, state-of-the-art, clinical diagnostics literature and to provide clinical practice recommendations based on expert assessment of quality and strength of evidence. The results of the Sensitization in Transplantation: Assessment of Risk (STAR) meeting are summarized here, providing recommendations on the definition and utilization of HLA diagnostic testing, and a framework for clinical assessment of risk for a memory or a primary alloimmune response. The definitions, recommendations, risk framework, and highlighted gaps in knowledge are intended to spur research that will inform the next STAR Working Group meeting in 2019.

Prelisting predictions of early postoperative survival in infant heart transplantation using classification and regression tree analysis.

Infants listed for heart transplantation experience high waitlist and early post-transplant mortality, and thus, optimal allocation of scarce donor organs is required. Unfortunately, the creation and validation of multivariable regression models to identify risk factors and generate individual-level predictions are challenging. We sought to explore the use of data mining methods to generate a prediction model. CART analysis was used to create a model which, at the time of listing, would predict which infants listed for heart transplantation would survive at least 3 months post-transplantation. A total of 48 infants were included; 13 died while waiting, and six died within 3 months of heart transplant. CART analysis identified RRT, blood urea nitrogen, and hematocrit as terminal nodes with alanine transaminase as an intermediate node predicting death. No patients listed on RRT (n = 10) survived and only three of 12 (25%) patients listed on ECLS survived >3 months post-transplant. CART analysis overall accuracy was 83%, with sensitivity of 95% and specificity 76%. This study shows that CART analysis can be used to generate accurate prediction models in small patient populations. Model validation will be necessary before incorporation into decision-making algorithms used to determine transplant candidacy.

Generic immunosuppression in solid organ transplantation: a Canadian perspective.

The introduction of generic immunosuppressant medications may present an opportunity for cost savings in solid organ transplantation if equivalent clinical outcomes to the branded counterparts can be achieved. An interprofessional working group of the Canadian Society of Transplantation was established to develop recommendations on the use of generic immunosuppression in solid organ transplant recipients (SOTR) based on a review of the available data. Under current Health Canada licensing requirements, a demonstration of bioequivalence with the branded formulation in healthy volunteers allows for bridging of clinical data. Cyclosporine, tacrolimus, and sirolimus are designated as "critical dose drugs" and are held to stricter criteria. However, whether this provides sufficient guarantee of therapeutic equivalence in SOTR remains controversial, and failure to maintain an appropriate balance of immunosuppression may have serious consequences, including rejection, graft loss, and death. Published evidence supporting therapeutic equivalence of generic formulations in SOTR is lacking. Moreover, in the setting of multiple generic formulations the potential for uncontrolled product switching is a major concern, since generic preparations are not required to demonstrate bioequivalence with each other. Although close monitoring is recommended with any change in formulation, drug product switches are likely to occur without prescriber knowledge and may pose a significant patient safety risk. The advent of generic immunosuppression will require new practices including more frequent therapeutic drug and clinical monitoring, and increased patient education. The additional workload placed on transplant centers without additional funding will create challenges and could ultimately jeopardize patient outcomes. Until more robust clinical data are available and adequate regulatory safeguards are instituted, caution in the use of generic immunosuppressive drugs in solid organ transplantation is warranted.

A prospective study of dobutamine stress echocardiography for the assessment of cardiac allograft vasculopathy in pediatric heart transplant recipients.

Transplant CAV is the leading cause of graft loss beyond one yr post-heart transplant. Diagnosis can be challenging and the previous "gold standard," coronary ANG, tends to underestimate disease. The purpose of this study was to relate DSE to ANG for the diagnosis of CAV. Prospective annual DSE at a single centre on all heart transplant patients (1999-2006) were compared with results from routine coronary angiograms. Progression of CAV over time as determined by DSE and ANG and associated factors were sought through logistic regression models adjusted for repeated measures. There were 102 heart transplant patients (54 males) transplanted between 1989 and 2006. Median age at transplant was 17 months (0-16.6 yr). The initial DSE was at a median of 10-months post-transplantation. There was a high correlation between an abnormal DSE and an abnormality on ANG (p = 0.002). There was an increased probability of an abnormal DSE with increasing grade of CAV as assessed by ANG (p < 0.001). Factors associated with an abnormal DSE included older age at transplant (p = 0.04), higher grade of rejection (p = 0.002), higher total cholesterol (p = 0.04), higher LDL (p < 0.05), and older age at the time of DSE (p = 0.002). DSE result was not related to HDL, triglyceride or homocysteine levels, or to steroid or statin use. The probability of an abnormal DSE result increases with increasing angiographic grade of CAV, and thus DSE may be used for initial screening for CAV with ANG reserved for confirmation and grading. Patients transplanted at an older age and those with a greater history of rejection were at higher risk of a positive DSE and may require increased surveillance for CAV.

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.