M. Kemna

Donors' characteristics and impact on outcomes in pediatric heart transplant recipients.

Organ availability and acceptability limit pediatric HTx. What characteristics define an unacceptable or high‐risk pediatric donor remains unclear. The purpose of this study was to characterize a large cohort of pediatric donors and determine the donor risk factors, including cumulative risk, that affect recipient survival. Data from the PHTS, a prospective multicenter study, were used to examine the impact of donor factors on the outcomes of patients listed <18 yr of age who received a HTx between 1993 and 2009. Donor data were available for 3149 of 3156 HTx (99.8%). Donor cause of death, need for inotropes, or CPR did not affect survival outcomes (p = 0.05). Ischemic time also did not have an impact on overall recipient survival; however, longer ischemic times negatively impacted one‐yr post‐transplant survival (p < 0.0001). There was no impact of cumulative risk factors on survival (p = 0.8). Although used in a minority of cases, hormonal therapy in the donor positively impacted survival (p = 0.03). In multivariate analysis, the only donor factor associated with decreased survival was smaller donor BSA, the other factors being related to the recipient characteristics. When analyzed by recipient age, there were no donor‐related factors that affected survival for those who received a transplant at <6 months of age. Longer ischemic time (p < 0.0001) and greater age difference between the recipient and donor (p = 0.0098) were donor‐related factors impacting early‐phase survival for recipients who received a graft at ≥10 yr of age. Factors perceived to define a marginal or high‐risk pediatric heart donor including inotrope use, CPR and donor cause of death may have less impact on outcomes than previously thought. Longer ischemic times did impact one yr, but not overall survival, and this impact was much greater with older donors. Parameters for accepting a donor heart can potentially be expanded, especially in the infant age group, but strong consideration should always be given to the interaction between ischemic time and donor age.

Valganciclovir dosing using area under the curve calculations in pediatric solid organ transplant recipients

Pediatric valganciclovir dosing recommendations have not been extensively validated for prevention or treatment for CMV infection. As such, we performed a pharmacokinetic study to compare different valganciclovir dosing regimens and the potential benefits of individualized dose adjustments in children following organ transplantation. Ganciclovir AUCs were calculated from four plasma drug levels in pediatric SOT recipients aged six months through three yr receiving valganciclovir suspension by mouth. Of the 28 ganciclovir AUC calculations performed, 11 (39%) were outside the therapeutic target range of 40–60 mcg h/L leading to a valganciclovir dose adjustment. Current manufacturer‐recommended dosing based on BSA and CrCl was estimated to result in therapeutic AUCs in fewer patients than the simple weight‐based formula used in our institution (4 vs. 13; p = 0.017). An AUC calculation using only the two‐ and five‐h measurements was strongly correlated with the AUC using all four time measurements (R2 = 0.846; p < 0.001). A simple weight‐based dosing approach gives a higher probability for therapeutic AUCs compared to the manufacturer‐recommended dosing in pediatric transplant patients aged six months through three yr with normal renal function. An AUC calculated using two sample times might allow for fewer blood draws in the future.

HLA molecular epitope mismatching and long-term graft loss in pediatric heart transplant recipients

BACKGROUND Although evidence links HLA allele mismatching to worse outcomes in pediatric heart transplantation, no studies to our knowledge have applied the quantification of structural HLA differences between donor and recipient to risk evaluation. We examine the association between molecular-level HLA mismatching and long-term graft loss in pediatric recipients of heart transplants. METHODS HLA Matchmaker was used to quantify the number of mismatched class-specific HLA eplets among 4,851 heart transplant recipients ≤18 years of age in the Scientific Registry of Transplant Recipients (1987-2012). Survival analysis was used to compare long-term probabilities of graft loss by number of eplet mismatches and allele mismatches stratified by eplet mismatches. RESULTS Recipients with 10 to 20 or >20 class I (HLA-A and HLA-B) eplet mismatches experienced increased long-term graft loss compared with recipients with <10 class I eplet mismatches (adjusted hazard ratio = 1.23 [95% confidence interval = 1.06-1.42], adjusted hazard ratio = 1.27 [95% confidence interval = 1.08-1.50], respectively). Recipients with 2 to 4 class I allele mismatches had increased long-term graft loss compared with recipients with 0 to 1 class I allele mismatches. Neither class II (HLA-DR) eplet mismatching nor class II allele mismatching was associated with graft loss. On stratification by allele and structural eplet mismatching, only recipients with 2 to 4 class I allele mismatches and ≥10 class I eplet mismatches had an increased probability of graft loss compared with recipients with 0 to 1 class I allele mismatches (adjusted hazard ratio = 1.42 [95% confidence interval = 1.09-1.57]). CONCLUSIONS Molecular-level HLA mismatching may aid in identifying recipients at increased risk of long-term graft loss who could benefit from intensified post-transplant surveillance and management.

Elevated pre-transplant pulmonary vascular resistance is not associated with mortality in children without congenital heart disease: A multicenter study

BACKGROUND Traditionally, an elevated pulmonary vascular resistance index (PVRI) has been a relative contraindication to pediatric orthotopic heart transplantation. This study examined the risk of elevated pre-transplant PVRI on early (30-day) and intermediate-term mortality in pediatric heart transplant recipients without congenital heart disease (CHD). METHODS A review of the prospective multicenter Pediatric Heart Transplant Study registry identified all patients without CHD in whom a pre-transplant PVRI was recorded. Of 35 participating centers, 29 reported heart transplants in children with a markedly elevated PVRI (> 5 WU × m(2), corresponding to the highest quartile). Multiphase parametric analysis was performed, adjusting for potential risk factors to assess the association of PVRI with early and intermediate-term mortality. RESULTS Between 1993 and 2011, 1,909 children without CHD underwent heart transplantation at a median age of 9.7 years (range, 1.6 months-18 years). Of those, 795 (42%) had a recorded or calculable pre-transplant PVRI, and PVRI > 5 WU × m(2) was present in 193 patients (24%). For all recipients, median pre-transplant PVRI was 3.15 WU × m(2) (range, 0.4-23 WU × m(2)); 2.8 WU × m(2) in infants < 1 year, 3.5 WU × m(2) in patients aged 1 to 10 years, and 3.0 WU × m(2) in patients aged > 10 years (p = 0.03). Multivariable hazard analysis controlling for graft ischemic time and pre-transplant ventilation showed no association of elevated PVRI with early mortality (relative risk, 1.2; p = 0.66), nor with intermediate mortality when controlled for year of transplant, age, race, and pre-sensitization (relative risk, 0.7; p = 0.27). CONCLUSIONS Elevation of PVRI did not affect post-transplant survival in this large, multicenter cohort of pediatric heart transplant recipients without CHD, suggesting that the barrier of elevated PVRI can be successfully overcome in this population.

Feasibility and interpretation of global longitudinal strain imaging in pediatric heart transplant recipients

Evaluation of myocardial mechanics after heart transplant is important in monitoring allograft function and identifying rejection. Speckle tracking global longitudinal strain (GLS) may be more sensitive to early regional changes from rejection. This study aimed to determine feasibility of GLS in pediatric hearts during surveillance echocardiograms, compare their GLS to published norms (−18% to −22%), and assess association of GLS with other indices of graft function. Retrospective review of transplant echocardiograms from 2013 to 2014. Philips QLAB was used for post‐acquisition GLS analysis. Multiple linear regression was used to assess the association of GLS with echocardiographic/catheterization indices, and B‐type natriuretic peptide (BNP). Forty‐seven patients (84 studies) were included. Calculation of GLS was feasible in 82 studies (97%) with inter‐ and intra‐observer variability of 0.71 and 0.69. Patients (n=9) with rejection had GLS of −16.4% (SD=3.5%) compared to those without [−16.8% (SD=3.7%)]. GLS worsened linearly with increasing Ln(BNP) (P=<.001), left ventricular volume in diastole (P=<.001), septal a’ wave (P=<.001), and pulmonary capillary wedge pressure (P=<.001). Speckle tracking‐based GLS is feasible and reproducible in pediatric heart recipients and is reduced at baseline. The role of GLS and BNP in detecting early systolic dysfunction warrants further investigation.

Posterior reversible encephalopathy syndrome after pediatric heart transplantation: Increased risk for children with preexisting Glenn/Fontan physiology

Identification of risk factors for PRES after organ transplant can improve early detection and avoid permanent neurological injury. High calcineurin‐inhibitor levels and hypertension are recognized risk factors for PRES in adult transplant recipients. Limited data exist regarding PRES after pediatric HTx, with studies limited to case reports. We performed a retrospective review of 128 pediatric HTx recipients to identify risk factors for PRES. Seven of 128 (5.5%) recipients developed PRES at a median of 10 days (5–57) after HTx. The median age of recipients with PRES was 10.0 yr (5.7–19.0), compared to 1.4 yr (0.0–19.8) for recipients without PRES (p = 0.010). Fewer than half of recipients with PRES had elevated post‐transplant calcineurin‐inhibitor levels (n = 3) and/or preceding severe hypertension (n = 3). Four of seven who developed PRES (57%) had pretransplant Glenn or Fontan physiology (G/F). G/F was a significant risk factor for PRES (RR 4.99, 95% CI: 1.19–21.0, p = 0.036). Two recipients (29%), both with severe PRES, had residual neurological symptoms. In summary, PRES occurred in 5.5% of pediatric HTx recipients and presented early after HTx. All recipients with PRES were > 5 yr. Patients with pretransplant G/F were at increased risk, a risks factor not previously described.

Diastolic pressure indices offer a novel approach to predicting risk of graft loss after pediatric heart transplant

PH is a risk factor for GL after HTx. However, traditional parameters are not reliable predictors of risk in children. We hypothesized that DPI (dPAP and DPG) are predictive of GL in pediatric HTx recipients. The UNOS/SRTR database was reviewed to identify pediatric HTx recipients (age <18 years) between 1994 and 2013. Recipients with pretransplant hemodynamic data were grouped by diagnosis (CMP or CHD), and the groups were analyzed separately. Bivariate Cox regression analysis examined the association between hemodynamic variables and GL. DPI showed the strongest association with early GL in recipients with CMP (dPAP: HR = 1.25 [1.09‐1.42]; DPG: 1.24 [1.11‐1.38]). Among CHD recipients, DPI were associated with early GL in those with preexisting PH (dPAP: HR = 1.16 [1.01‐1.33]; DPG: HR = 1.10 [1.00‐1.21]). No cutoff values for “high‐risk” DPI were identified, but a continuous relationship between higher DPI and risk of early GL was observed. DPI are associated with early GL in select pediatric HTx recipients. Our findings suggest that DPI should be considered as part of routine hemodynamic assessment for pediatric HTx candidates.

A tale of two cases of pulmonary arteriovenous malformation: How they fared after cardiac transplantation

In single ventricle patients, aortopulmonary collaterals (APCs) and pulmonary arteriovenous malformations (PAVMs) following superior cavopulmonary shunt (CPS) can complicate orthotopic heart transplant (OHT) by cyanosis and hemoptysis. Although PAVMs can regress with the restoration of hepatic venous flow to the pulmonary circulation, the effects of hypoxemia on the “unconditioned” allograft are not known.

GLOBAL LONGITUDINAL ECHOCARDIOGRAPHIC STRAIN IMAGING IN PEDIATRIC HEART TRANSPLANT RECIPIENTS

Evaluation of myocardial mechanics in heart transplant is important in monitoring allograft function and identifying acute rejection. Speckle tracking based global longitudinal strain (GLS) detects global and regional abnormalities and may detect rejection. This study aimed to compare GLS to other

Immune cell function assay in pediatric heart transplant recipients

The ImmuKnow® ICFA reports ex vivo CD4 lymphocyte activation to quantify immunosuppression. Limited organ and age‐specific data exist for pediatric heart transplant recipients. We sought to examine their normative values and ICFAs association with rejection/infection. A total of 380 ICFAs from 58 heart transplant recipients (6.5/recipient) were studied retrospectively. The median age at the time of their first ICFA was 5.3 yr (IQR 2.4–12.1 yr). ICFA levels during immunologic stability (n = 311) were a median of 305 (IQR: 172–483) and mean of 353 (s.d. ± 224) ng ATP/mL. ICFA levels trended lower with advancing age. ICFA levels during immunologic stability increased over time from transplant after the first six months but were not correlated with calcineurin inhibitor levels or the type used. There is no association between ICFA values during stability and rejection (median 368 ATP ng/mL; IQR 153–527) or infection (median 293 ATP ng/mL; IQR 198–432). In contrast to the manufacturers suggested ranges, the immunologic stable ranges in pediatric cardiac recipients were very different. ICFA values during immunologic stability are related to time from transplant in pediatric heart recipients. ICFAs ability to discriminate rejection or infection from immunologic stability was not demonstrated.