Pediatric Heart Transplant Recipients Research Articles

(1162) - Pediatric Heart Transplant Donor and Recipient Factors Associated with Death or Re-Transplantation by One Year

(1162) - Pediatric Heart Transplant Donor and Recipient Factors Associated with Death or Re-Transplantation by One Year

Late outcome after paediatric heart transplantation in Finland.

We studied the long-term survival and rejection episodes of paediatric heart transplant recipients. We included all paediatric patients (≤18 years) who underwent heart transplantation during 1991-2014 in Finland. Data were obtained retrospectively from a paediatric cardiac surgery database. Patient status was received from the Finnish population registry. All patients underwent yearly routine postoperative endomyocardial biopsies and coronary angiographies. Between 1991 and 2014, 68 heart transplantations were performed. The early mortality (<30 days after surgery) rate was 10% and follow-up coverage was 100%. The 10- and 15-year survival rates for all patients were 68% (95% confidence internal, CI, 56-80%) and 65% (95% CI 53-78%), respectively, including early mortality. The 1-year survival rate was 100% when excluding early operative mortality. Indications for heart transplantation were cardiomyopathy in 57% and cardiac malformations in 43% of patients, with similar long-term survival between the groups. During 23 years of follow-up, 43 patients (70%) had at least one rejection episode and 17 patients (29%) at least a grade 1 coronary artery vasculopathy finding. Patients with early rejection episodes (<3 months) had a higher incidence of late rejection episodes (P = 0.025). Older age at operation was a significant risk factor for the development of coronary artery vasculopathy (hazard ratio 1.1, 95% CI 1.0-1.3, P = 0.012). First-year survival was excellent. Asymptomatic rejection episodes were common among patients. Early rejection episodes are a risk factor for late rejection episodes and show a trend towards an increased risk of late death. Coronary artery vasculopathy remains a major challenge for late graft survival.

Modern Outcomes of Mechanical Circulatory Support as a Bridge to Pediatric Heart Transplantation

Pediatric patients awaiting orthotopic heart transplantation frequently require bridge to transplantation (BTT) with mechanical circulatory support. Posttransplant survival outcomes and predictors of mortality have not been thoroughly described in the modern era using a large-scale analysis. The United Network for Organ Sharing database was reviewed to identify pediatric heart transplant recipients from 2005 through 2012. Patients were stratified into three groups: extracorporeal membrane oxygenation (ECMO), ventricular assist device (VAD), and direct transplantation (DTXP). The primary outcome was posttransplant survival. Two thousand seven hundred seventy-seven pediatric patients underwent orthotopic heart transplantation. There were 617 patients who required BTT with mechanical circulatory support (22.2%), of whom there were 428 VAD BTT (69.4%) and 189 ECMO BTT (30.6%). An increase in VAD use was observed during the study period (p < 0.0001). Compared with DTXP, patients in the ECMO BTT group had a lower median age (<1 versus 5 years; p < 0.0001) and were significantly smaller (8 versus 14 kg; p < 0.001), whereas patients in the VAD BTT group were older (8 versus 5 years; p= 0.0002) and larger (24 versus 14 kg; p < 0.001). Actuarial survival was greater in the DTXP group compared with ECMO BTT, but similar to VAD BTT at 30 days and 1, 3, and 5 years. However, this survival difference was lost after censoring the first 4 months after transplant. In multivariable analysis, when restricted to the first 4 months of survival, independent predictors for mortality were ECMO BTT, age, diagnosis, and functional status, whereas VAD BTT was not. Pediatric patients with DTXP or VAD BTT have equivalent posttransplant survival. However, those requiring ECMO BTT have inferior early posttransplant survival compared with those receiving DTXP.

Usefulness of Diastolic Strain Measurements in Predicting Elevated Left Ventricular Filling Pressure and Risk of Rejection or Coronary Artery Vasculopathy in Pediatric Heart Transplant Recipients

In pediatric heart transplant recipients, elevated pulmonary capillary wedge pressure (PCWP) is associated with rejection and coronary artery vasculopathy. This study aimed to evaluate which echocardiographic parameters track changes in PCWP and predict adverse outcomes (rejection or coronary artery vasculopathy). This prospective single-center study enrolled 49 patients (median 11.4 years old, interquartile range 7.4 to 16.5) at time of cardiac catheterization and echocardiography. Median follow-up was 2.4 years (range 1.2 to 3.1 years), with serial testing per clinical protocol. Ratio of early mitral inflow to annular velocity (E/E'), left atrial (LA) distensibility, peak LA systolic strain, E/left ventricular (LV) diastolic strain, and E/LV diastolic strain rate were measured from echocardiograms. Increase in PCWP ≥3 mm Hg was associated with changes in LA distensibility, E/E', and E/LV diastolic strain, with highest area under the receiver operating characteristic curve for E/LV diastolic strain (0.76). In 9 patients who subsequently developed rejection or coronary artery vasculopathy, E/LV diastolic strain rate at baseline differed from patients without events (median 57.0 vs 43.6, p = 0.02). On serial studies, only change in LV ejection fraction differed in patients with events (median -10% vs -1%, p = 0.01); decrease in LV ejection fraction of -19% had a specificity of 100% and sensitivity of 44%. In conclusion, LV diastolic strain and strain rate measurements can track changes in PCWP and identify patients at risk for subsequent rejection or coronary artery vasculopathy. Further studies are necessary to confirm these data in a larger cohort.

The impact of estimated glomerular filtration rate equations on chronic kidney disease staging in pediatric renal or heart transplant recipients.

BackgroundThe aim of this study was to evaluate the performance of selected pediatric estimated glomerular filtration rate (eGFR) equations in relation to the clinical management of children after renal or heart transplantation or post-chemotherapy treatment.MethodsThis study was a retrospective cross-sectional analysis of 61 children whose glomerular function (GFR) had been determined using a single-dose inulin clearance (iGFR) method. Eight equations for estimating the GFR were evaluated for bias, agreement, accuracy, and clinical stratification.ResultsThe outcome of all eight eGFR equations differed from the value determined using the iGFR method, with the mean bias ranging from −3.4 to 20.7 ml/min/1.73 m2 and 90 % accuracy ranging from 16 to 26 %. All eGFR equations overestimated renal function in patients with decreased kidney function as determined by the iGFR method and underestimated renal function in patients with normal kidney function. Consequently, based on the eGFR values, patients with low GFR values according to the iGFR method were staged in a less severe chronic kidney disease (CKD) category, and patients with normal GFR values according to the iGFR method were staged in a more severe CKD category. The percentage of correctly classified patients ranged from 32.6 to 41.6 %.ConclusionsIn our cohort we found the CKiDIII equation to be the best alternative to calculating the GFR using the inulin clearance method, closely followed by the Hoste and the revised Grubb equations. The performances of all eight eGFR equations assessed were moderate at best and only slightly better than the easy-to-do bedside Schwartz equation.

Dual-Axis Rotational Angiography is Safe and Feasible to Detect Coronary Allograft Vasculopathy in Pediatric Heart Transplant Patients: A Single-Center Experience.

Coronary allograft vasculopathy (CAV) is the leading cause of graft failure in pediatric heart transplant recipients, also adding to mortality in this patient population. Coronary angiography is routinely performed to screen for CAV, with conventional single-plane or bi-plane angiography being utilized. Dual-axis rotational coronary angiography (RA) has been described, mostly in the adult population, and may offer reduction in radiation dose and contrast volume. Experience with this in the pediatric population is limited. This study describes a single-institution experience with RA for screening for CAV in pediatric patients. The catheterization database at our institution was used to identify pediatric heart transplant recipients having undergone RA to screen for CAV. Procedural data including radiation dose, fluoroscopy time, contrast volume, and procedure time were collected for each catheterization. The number of instances in which RA was not successful, ECG changes were present, and CAV was detected were also collected for each catheterization. A total of 97 patients underwent 345 catheterizations utilizing RA. Median radiation dose-area product per kilogram was found to be 341.7 (mGy cm(2)/kg), total air kerma was 126.8 (mGy), procedure time was 69 min, fluoroscopy time was 9.9 min, and contrast volume was 13 ml. A total of 17 (2 %) coronary artery injections out of 690 could not be successfully imaged using RA. A total of 14 patients had CAV noted at any point, 10 of whom had progressive CAV. Electrocardiographic changes were documented in a total of 10 (3 %) RA catheterizations. Procedural characteristics did not differ between serial catheterizations. RA is safe and feasible for CAV screening in pediatric heart transplant recipients while offering coronary imaging in multiple planes compared to conventional angiography.

Inflammatory Cytokines, Endothelial Function, and Chronic Allograft Vasculopathy in Children: An Investigation of the Donor and Recipient Vasculature After Heart Transplantation.

Chronic allograft vasculopathy (CAV) limits the lifespan of pediatric heart transplant recipients. We investigated blood markers of inflammation, endothelial dysfunction, and damage to both the native and transplanted vasculature in children after heart transplantation. Serum samples were taken from pediatric heart transplant recipients for markers of inflammation and endothelial activation. The systemic vasculature was investigated using brachial artery flow-mediated dilatation and carotid artery intima-medial hyperplasia. CAV was investigated using intravascular ultrasound. Mean intima-media thickness (mIMT) > 0.5 mm was used to define significant CAV. Forty-eight children (25 male) aged 8-18 years were enrolled in the study. Patients were a median (interquartile range) 4.1 (2.2-8.7) years after transplant. Patients had increased levels of circulating IL6 (3.86 [2.84-4.95] vs. 1.66 [1.22-2.63] p < 0.0001), vascular cell adhesion molecule 1 (539 [451-621] vs. 402 [342-487] p < 0.001), intracellular adhesion molecule 1 305 (247-346) vs. 256 (224-294) p = 0.002 and thrombomodulin (7.1 [5.5-8.1] vs. 3.57 [3.03-4.71] p < 0.0001) and decreased levels of tumor necrosis factor-α, E selectin, and P selectin, compared with controls. The systemic vasculature was unaffected. Patients with severe CAV had raised serum von Willebrand factor and decreased serum thrombomodulin. Posttransplant thrombomodulin levels are elevated after transplant but significantly lower in those with mIMT > 0.5 mm. This suggests that subclinical inflammation is present and that natural anticoagulant/thrombomodulin activity is important after transplant.

Longitudinal Strain and Strain Rate Abnormalities Precede Invasive Diagnosis of Transplant Coronary Artery Vasculopathy in Pediatric Cardiac Transplant Patients.

Transplant coronary artery vasculopathy (TCAV) is the primary cause of late graft loss in pediatric heart transplant recipients. TCAV is diagnosed using angiography or intravascular ultrasound; however, noninvasive methods remain elusive. We sought to define patterns of myocardial mechanics in patients with TCAV and to determine whether this can detect TCAV before invasive methods. In this retrospective study, we queried our heart transplant database to identify all recipients with TCAV since 2006 (n = 41). Echoes were reviewed from the last normal catheterization and at TCAV diagnosis, and from time-matched transplant controls (n = 33) without TCAV. Peak global circumferential and longitudinal strain and systolic and diastolic strain rate (SSR and DSR) of the left ventricle were derived using velocity vector imaging. T tests were used to compare both groups longitudinally and between groups at both time points. Longitudinal strain, SSR, and DSR were diminished in the TCAV group compared to the transplant control group at both time points. No differences were found across time points in either group. Retrospective modeling using a longitudinal strain cutoff of 15 % on echoes 2 years prior to TCAV diagnosis predicted development or exclusion of TCAV with sensitivity of 53 %, specificity of 89 % with an area under the curve of 0.8. Decreases in longitudinal strain measurements demonstrate that alterations in myocardial mechanics occur in patients with TCAV at least 2 years prior to invasive diagnosis. These early changes may be due to microvascular disease. This modality could aid in earlier treatment and intervention for this challenging problem .

Persistent Epstein-Barr viral load in Epstein-Barr viral naïve pediatric heart transplant recipients: Risk of late-onset post-transplant lymphoproliferative disease.

AIMTo examine the risk of late-onset post-transplant lymphoproliferative disorder (PTLD) in the presence of persisting high Epstein-Barr virus (EBV) in EBV naïve pediatric heart transplant (HT) recipients.METHODSA retrospective review of the medical records of the 145 pediatric HT recipients who had serial EBV viral load monitoring at our center was performed. We defined EBV naive patients whose EBV serology either IgM or IgG in the blood were negative at the time of HT and excluded passive transmission from mother to child in subjects less than 6 mo of age.RESULTSPTLD was diagnosed in 8 out of 145 patients (5.5%); 6/91 (6.5%) in those who were EBV seropositive and 2/54 (3.7%) in the EBV naïve group at the time of HT (P = 0.71). We found 32/145 (22%) patients with persistently high EBV load during continuing follow-up; 20/91 (22%) in EBV seropositive group vs 12/54 (22%) in EBV naïve group (P = 0.97). There was no significant association between pre-HT serostatus and EBV load after transplant (P > 0.05). In the EBV seropositive group, PTLD was diagnosed in 15% (3/20) of patients with high EBV vs 4.2% (3/71) of patients with low or undetectable EBV load (P = 0.14) whereas in EBV naïve patients 8.3% (1/12) of those with high EBV load and 2.3% (1/42) with low or undetectable EBV load (P = 0.41). There was a highly significant association between occurrence of PTLD in those with high EBV load and duration of follow up (4.3 ± 3.9 years) after HT by Cochran-Armitage test for the entire cohort (P = 0.005). At least one episode of acute rejection occurred in 72% (23/32) of patients with high EBV vs 36% (41/113) patients with low or undetectable EBV after HT (P < 0.05).CONCLUSIONThere is an association between persistently high EBV load during post-HT follow up and the occurrence of late-onset PTLD in pediatric HT recipients irrespective of serostatus at the time of transplant. The occurrence of allograft rejection increased in patients with high EBV load presumably due to reduction in immunosuppression.

Acute cellular rejection in pediatric heart transplant recipients is associated with abnormal left ventricular mechanics by CMR

Acute cellular rejection in pediatric heart transplant recipients is associated with abnormal left ventricular mechanics by CMR

Magnetic resonance imaging of the transplanted pediatric heart as a potential predictor of rejection.

AIMTo evaluate cardiac magnetic resonance imaging (CMR) as a non-invasive tool to detect acute cellular rejection (ACR) in children after heart transplant (HT).METHODSThirty pediatric HT recipients underwent CMR at the time of surveillance endomyocardial biopsy (EMB) and results were compared to 14 non-transplant controls. Biventricular volumes, ejection fractions (EFs), T2-weighted signal intensities, native T1 times, extracellular volumes (ECVs) and presence of late gadolinium enhancement (LGE) were compared between patients and controls and between patients with International Society of Heart and Lung Transplantation (ISHLT) grade ≥ 2R rejection and those with grade 0/1R. Heart rate (HR) and brain natriuretic peptide (BNP) were assessed as potential biomarkers.RESULTSSignificant ACR (ISHLT grade ≥ 2R) was an infrequent event in our population (5/30, 17%). Ventricular volumes, EFs, LGE prevalence, ECVs, native T1 times, T2 signal intensity ratios, HR and BNP were not associated with the presence of ≥ 2R ACR.CONCLUSIONIn this pilot study CMR did not reliably identify ACR-related changes in pediatric HT patients.

Status on Heart Transplantation in China.

Status on Heart Transplantation in China.

Clinical Characteristic and Prognosis of Post-Transplant Lymphoproliferative Disorder in Pediatric Heart Transplant Recipients in Japan

Purpose: Post-transplant lymphoproliferative disorder (PTLD) caused by Epstein-Barr virus (EBV) has recently has been recognized as a serious complication of various organ transplantations. In our institute, we have followed-up 34 pediatric patients after heart transplantation. We retrospectively investigated clinical features of PTLD in heart transplant recipients.Methods: The evaluation period was from July 2004 to June 2015. Six patients with PTLD (4 boys, 2 girls) were diagnosed by blood examination, lymph node histology and EBV viral load in peripheral blood and invasive organ.Results: Median age at onset of PTLD was 4.5 years old (range, 3.2-16.2 years). Median time from transplantation to onset was 18 months (range, 7-45 months). Bone marrow and central nervous system invasion were not detected in all cases. Four patients were EBV-seronegative recipients for EBV-seropositive donors. We performed the lymphoma-based chemotherapy combined with the anti-CD20 monoclonal antibody rituximab and achieved remission. As a result, five patients remained alive in remission, and one patient died of therapy-related toxicity. Although one patient relapsed after chemotherapy, she achieved second remission after multimodal chemotherapy combined with rituximab. Abdominal lymph node involvement was detected in four cases, and one patient experienced severe abdominal symptoms including intestinal perforation.Conclusion: EBV serostatus and the period from transplantation to onset of PTLD appear to represent important prognostic factors. Early detection followed by pre-emptive reduction of immunosuppressive agents is essential to the management of PTLD, but may increase the risk of fatal rejection. We administered chemotherapy combined with rituximab, and this treatment strategy might be effective. However, severe fatal toxicity developed in one patient, and severe abdominal symptoms due to tumor lysis were noted in many cases. These findings suggested the importance of carefully selecting the induction treatment and perform various supportive therapies. We should establish appropriate treatment strategies according to prognostic factors because of the distinctive characteristics of PTLD by accumulating more cases. DisclosuresNo relevant conflicts of interest to declare.

Statin therapy is not associated with improved outcomes after heart transplantation in children and adolescents

Although used routinely, the pleiotropic benefits of statins remain understudied in children after heart transplantation. We hypothesized that statin therapy would reduce the incidence of rejection, cardiac allograft vasculopathy (CAV) and post-transplant lymphoproliferative disease (PTLD). This study was a retrospective review of 964 pediatric (ages 5 to 18 years) heart transplant recipients in the multicenter Pediatric Heart Transplant Study registry from 2001 to 2012. Patients were excluded if they were undergoing re-transplantation, survived <1 year post-transplant, or had missing data regarding statin use. The effects of statins beyond the first year were estimated by Kaplan-Meier and Cox regression multivariable analysis for freedom from PTLD, rejection requiring treatment, any severity of CAV, and survival. Statin use was variable among participating centers with only 30% to 35% of patients ≥10 years of age started on a statin at <1 year post-transplant. After the first year post-transplant, statin-treated children (average age at transplant 13.24 ± 3.29 years) had significantly earlier rejection (HR 1.42, 95% CI 1.11 to 1.82, p = 0.006) compared with untreated children (transplanted at 12 ± 3.64 years) after adjusting for conventional risk factors for rejection. Freedom from PTLD, CAV and overall survival up to 5 years post-transplant were not affected by statin use, although the number of events was small. Statin therapy did not confer a survival benefit and was not associated with delayed onset of PTLD or CAV. Early (<1 year post-transplant) statin therapy was associated with increased later frequency of rejection. These findings suggest that a prospective trial evaluating statin therapy in pediatric heart transplant recipients is warranted.

Abstract 16838: Circulating miRNAs Can Predict Cardiac Allograft Vasculopathy in Pediatric Heart Transplant Recipients in a Sex-dependent Manner

Introduction: MicroRNAs (miRs) are small noncoding ~22 nucleotide RNAs capable of modulating the expression of many genes. Our hypothesis was that circulating miRs are useful biomarkers of cardiac allograft vasculopathy (CAV) in pediatric heart transplant recipients (PHTR). Methods: An array for 765 miRs was performed using the Applied Biosystems technology normalized by a global normalization method as determined by the Expression Suite Software. Serum was obtained from 132 PHTR at the time of routine surveillance catheterization with coronary evaluation (intravascular ultrasound [IVUS] performed if ≥ 25 kg). Rejection free CAV+ patients were matched by age at transplant and time since transplant to CAV- controls. Statistical analysis was performed using the Wilcoxon test. Results: Samples were analyzed from 32 CAV+ PHTR matched to 17 CAV-controls. There were no significant differences between expression of miRs between CAV+ and CAV- PHTR alone, but differences in expression were found when PHTR were separated by sex. miRs significantly upregulated in females (F) included miRs-636 (F with both IVUS and angiographic CAV; p=0.008), -636 and -523 (F with a maximal intimal thickness [MIT] of ≥ 0.5mm; p=0.008 and 0.01, respectively), and -509 and -636 (F with any diagnosis of CAV; p=0.01 and p=0.01, respectively). miRs significantly upregulated in males (M) included miRs-422a (M with both IVUS and angiographic CAV; p=0.007), -422a and let-7e (M with a MIT of ≥ 0.5mm; p=0.003 and p=0.01, respectively), and -422a (M with any diagnosis of CAV; p=0.002). miR-19a was significantly downregulated in in M with any diagnosis of CAV (p=0.04). Boxplots highlighting differential expression of miRs by sex in CAV are shown in Figure 1. Conclusions: miRs are differentially expressed between PHTR with CAV on the basis of sex. A unique biomarker signature of miRs that are specific to PHTR with CAV would be valuable in the risk stratification of this challenging patient population.

Abstract 14567: Detection of Acute Cellular Rejection in Pediatric Heart Transplantation: A Pilot Cardiac Magnetic Resonance Imaging Study

Introduction: The diagnosis of significant acute cellular rejection (ACR) after heart transplantation (HT) prompts an immediate change in management and is associated with adverse outcome. Endomyocardial biopsy (EMB) is the gold standard for the detection of ACR but has important limitations. The purpose of this study was to evaluate cardiac magnetic resonance imaging (CMR) as a non-invasive tool to detect ACR in pediatric patients after HT. Methods: In this single centre prospective cohort study, 30 pediatric HT recipients underwent CMR at the time of surveillance EMB. Their CMR results were compared to 14 non-HT pediatric controls. Ventricular volumes and ejection fraction, native T1 times and T2-weighted signal intensities were compared between patients and controls and between patients with (grade 2 R) and without (grade 0 R/1 R) significant ACR according to standard criteria. Extracellular volumes (ECV) and the presence of late gadolinium enhancement (LGE) were compared between the two HT groups. Results: There were no significant demographic differences between the patient groups. Transplant patients were on average 11 ± 6.1 years of age and were 31.5 ± 41.3 months post-transplant. Significant (grade 2 R) ACR was an infrequent event in our population (5/30, 17%). Compared to controls, heart rate (100.3 ± 16.4 bpm) and brain natriuretic peptide (60.8 ± 100.7 ng/L) were significantly elevated post-HT but did not differentiate between grades of ACR. Ventricular volumes, ejection fractions, LGE prevalence, ECVs, native T1 times and T2 signal intensities were not significantly altered by ACR. Conclusions: We describe the myocardial characteristics of pediatric HT recipients by CMR. Although limited by the small number of patients with significant ACR the results of this pilot study suggest that current CMR imaging protocols are insufficient to reliably identify ACR-related changes in pediatric HT.

Transition from brand to generic tacrolimus is associated with a decrease in trough blood concentration in pediatric heart transplant recipients.

There are limited data available on the bioequivalence of generic and brand-name tacrolimus in pediatric and heart transplant patients. We characterized changes in 12-hour trough concentrations and clinical outcomes after transition from brand to generic tacrolimus in pediatric thoracic organ transplant recipients. Patients with a pharmacy-confirmed date of switch between generic and brand tacrolimus were identified, as well as a matched control group that did not switch for comparison. We identified 18 patients with a confirmed date of switch, and in 12 patients that remained on the same dose, trough concentrations were 14% less than when they were on brand (p = 0.037). The average change was -1.15 ± 1.76 ng/mL (p = 0.045). The control group did not experience a change in trough concentration and was different than the switched group (p = 0.005). There were no differences in dosage changes or kidney or liver function. In the year after switch, 24% of patients who were switched to generic experienced a rejection event vs. 18% in the patients on brand. We suggest a strategy of monitoring around the time of transition, and education of the patient/family to notify the care team when changes from brand to generic or between generics occur.

Donor-specific HLA alloantibodies: Impact on cardiac allograft vasculopathy, rejection, and survival after pediatric heart transplantation

There is increasing evidence that donor-specific anti-HLA antibodies (DSA) are associated with poor outcomes after cardiac transplantation in adults, but data are limited in children. The objective of this study was to examine the development and consequences of de novo DSA in pediatric recipients of heart transplants. We analyzed 105 pediatric patients who received heart transplants at our center from January 2002 to December 2012. All patients had negative T-cell and B-cell post-transplant crossmatches. Patients underwent HLA antibody screening at 1, 2, 3, 6, and 12 months post-transplant and annually thereafter unless there was suspicion for rejection. HLA class I and II antibodies were identified using Luminex assay. Coronary angiography was performed at 1 year and annually thereafter. Acute cellular rejection, antibody-mediated rejection, and treated clinical rejections were included together as rejection events. Of 105 patients, 45 (43%) developed de novo DSA. DSA-positive patients had significantly higher rates of coronary artery vasculopathy (CAV) compared with DSA-negative patients (36% vs 13%). CAV-free survival at 1 year and 5 years post-transplant for DSA-negative patients was 90% and 25%, respectively, compared with 70% and 0%, respectively, for DSA-positive patients (p < 0.01). DSA-positive patients had 2.5 times more rejection events per year than DSA-negative patients. The 5-year graft survival rate was 72.4% for DSA-negative patients and 21% for DSA-positive patients (p < 0.001). De novo DSA has a strong negative impact on CAV, rejection, and graft survival in pediatric recipients of heart transplants.

Validation of a Simple Score to Determine Risk of Early Rejection After Pediatric Heart Transplantation

ObjectivesThis study aimed to develop a reliable and feasible score to assess the risk of rejection in pediatric heart transplantation recipients during the first post-transplant year. BackgroundThe first post-transplant year is the most likely time for rejection to occur in pediatric heart transplantation. Rejection during this period is associated with worse outcomes. MethodsThe United Network for Organ Sharing database was queried for pediatric patients (age <18 years) who underwent isolated orthotopic heart transplantation from January 1, 2000 to December 31, 2012. Transplantations were divided into a derivation cohort (n = 2,686) and a validation (n = 509) cohort. The validation cohort was randomly selected from 20% of transplantations from 2005 to 2012. Covariates found to be associated with rejection (p < 0.2) were included in the initial multivariable logistic regression model. The final model was derived by including only variables independently associated with rejection. A risk score was then developed using relative magnitudes of the covariates’ odds ratio. The score was then tested in the validation cohort. ResultsA 9-point risk score using 3 variables (age, cardiac diagnosis, and panel reactive antibody) was developed. Mean score in the derivation and validation cohorts were 4.5 ± 2.6 and 4.8 ± 2.7, respectively. A higher score was associated with an increased rate of rejection (score = 0, 10.6% in the validation cohort vs. score = 9, 40%; p < 0.01). In weighted regression analysis, the model-predicted risk of rejection correlated closely with the actual rates of rejection in the validation cohort (R2 = 0.86; p < 0.01). ConclusionsThe rejection score is accurate in determining the risk of early rejection in pediatric heart transplantation recipients. The score has the potential to be used in clinical practice to aid in determining the immunosuppressant regimen and the frequency of rejection surveillance in the first post-transplant year.

The utility of circulating donor specific antibody to predict biopsy-proven antibody-mediated rejection and to provide prognostic value after heart transplantation in children

Aim Heart transplantation (HT) is a life-saving option for children with end-stage heart failure. Antibody-mediated rejection (AMR) is a significant cause of morbidity and mortality in HT. The current diagnostic criteria for AMR are based on endomyocardial biopsy (EMB) showing evidence of C4d and C3d deposition, and capillary endothelial changes, including neutrophil and macrophage infiltration, and interstitial edema. Although the presence of donor specific antibody (DSA) is a risk factor for the development of AMR after HT, it is currently not required for diagnosis of AMR. In this study, we aimed to investigate the sensitivity, specificity, predictive values and prognostic implications of circulating DSA using EMB as the gold standard for AMR diagnosis in a cohort of pediatric HT recipients. Methods Retrospective study in pediatric HT patients that had follow-up care between 2009–2013 and had at least one EMB paired with DSA testing within 3 days of the biopsy. Positive DSA was defined at a mean fluorescent intensity (MFI) ⩾ 2000 using single antigen bead testing. Results Of the 66 patients included, 26 (39%) had at least 1 HLA DSA positive test. Of the 26 patients with positive DSA, 18 (69%) had at least one antibody against HLA-DQ. In 7 (27%) of the 26 patients with positive DSA, the only antibody detected was against HLA-DQ. Of 236 DSA EMB pairs analyzed, 132 (56%) pairs were negative for DSA, 23 (10%) pairs had HLA DSA Class I only, 59 (25%) pairs had HLA DSA Class II only, and 22 (9%) pairs had both HLA class I and II DSA. HLA DSA testing had a sensitivity = 92.6%, specificity = 62.2%, PPV = 24.0%, and NPV = 98.5% for biopsy-proven AMR. Kaplan–Meier analysis showed that patients with positive HLA DSA results and biopsy-proven AMR trended toward a higher incidence of cardiovascular mortality, and coronary artery vasculopathy after 3 years compared to patients without circulating DSA and a negative biopsy. Conclusions The results of HLA-DSA testing in this cohort, showing excellent sensitivity and NPV for biopsy-proven AMR suggest for the first time, that DSA testing could be used for non-invasive prediction of AMR absence in heart transplantation, and avoid unnecessary biopsies. The value of DSA testing for biopsy-proven AMR and outcome prognosis in HT is important to study in future multi-center prospective studies.