Mariska S. Kemna

Donor‐specific antibodies: Can they predict C4d deposition in pediatric heart recipients?

There is limited evidence regarding the utility of circulating DSA in surveillance for AMR of pediatric heart recipients. Our hypothesis is that quantitation of DSA improves their power for predicting a C4d+, an integral component in the current diagnostic criteria of AMR. All pediatric recipients transplanted between 10/2005 and 1/2011 were retrospectively reviewed for DSA determined within 48 h of EMB. C4d+ was defined as >25% endothelial cell staining by immunohistochemical methods. A total of 183 paired DSA–EMB determinations were identified in 60 patients, a median of three paired studies per patient (range: 1–9). DSA were detected in 60 of these determinations. A receiver‐operating characteristic plot identified a threshold single‐antibody MFI of >6000 that strongly correlated with C4d+ (p < 0.0001) with a high negative predictive value (0.97) and specificity (0.95). The sensitivity and positive predictive values were 0.71 and 0.60, respectively. The predictive power of single‐antigen DSA for C4d deposition was improved in pediatric heart recipients using an institution‐specific MFI threshold value. In post‐transplant care, quantitative DSA should be an essential component in the surveillance for AMR.

Eosinophil count, allergies, and rejection in pediatric heart transplant recipients

BACKGROUND Allograft rejection and long-term immunosuppression remain significant challenges in pediatric heart transplantation. Pediatric recipients are known to have fewer rejection episodes and to develop more allergic conditions than adults. A T-helper 2 cell dominant phenotype, manifested clinically by allergies and an elevated eosinophil count, may be associated with immunologic quiescence in transplant recipients. This study assessed whether the longitudinal eosinophil count and an allergic phenotype were associated with freedom from rejection. METHODS This single-center, longitudinal, observational study included 86 heart transplant patients monitored from 1994 to 2011. Post-transplant biannual complete blood counts, allergic conditions, and clinical characteristics related to rejection risk were examined. RESULTS At least 1 episode of acute cellular rejection (ACR) occurred in 38 patients (44%), antibody-mediated rejection (AMR) occurred in 11 (13%), and 49 patients (57%) were diagnosed with an allergic condition. Patients with ACR or AMR had a lower eosinophil count compared with non-rejectors (p = 0.011 and p = 0.022, respectively). In the multivariable regression analysis, the presence of panel reactive antibodies to human leukocyte antigen I (p = 0.014) and the median eosinophil count (p = 0.011) were the only independent covariates associated with AMR. Eosinophil count (p = 0.010) and female sex (p = 0.009) were independent risk factors for ACR. Allergic conditions or young age at transplant were not protective from rejection. CONCLUSIONS This study demonstrates a novel association between a high eosinophil count and freedom from rejection. Identifying a biomarker for low rejection risk may allow a reduction in immunosuppression. Further investigation into the role of the T-helper 2 cell phenotype and eosinophils in rejection quiescence is warranted.

Iron Laboratory Studies in Pediatric Patients With Heart Failure from Dilated Cardiomyopathy

Iron deficiency (FeD), with or without anemia, in adults with heart failure (HF) is associated with poor outcomes, which can be improved with replacement therapy. A similar therapeutic opportunity may exist for children; however, iron laboratory measurements and FeD have not been described in pediatric patients with HF. A single-center, retrospective study was conducted on 28 patients <21 years old with a diagnosis of dilated cardiomyopathy and HF who had iron laboratories (serum iron, iron saturation, and ferritin) performed. The mean (standard deviation) age at time of laboratory collection was 10.3 (5.5) years. Twenty-seven patients (96.4%) met the criteria for FeD. Serum iron and iron saturation were significantly associated with inpatient hospitalization, being on inotropic medications, or having stage D HF. Low-serum iron was associated with a higher left ventricular end-diastolic dimension and left ventricular end-systolic dimension z-score by echocardiography ((β -2.58, 95% confidence interval [CI] -4.76, -0.40, p = 0.02) and (β -2.43, 95% CI -4.70, -0.17, p = 0.04)), respectively. Low ferritin was associated with higher mortality (relative risk 0.29, 95% CI 0.12, 0.70, p = 0.006). In conclusion, FeD was common in this pediatric cohort with more advanced HF. Iron profile abnormalities were associated with worse HF severity and outcomes including mortality.

Outcome of antibody-mediated rejection compared to acute cellular rejection after pediatric heart transplantation

Outcomes of ACR after pediatric HTx have been well described, but less has been reported on outcomes of AMR. We compared the clinical characteristics and cardiovascular outcomes (composite end‐point of death, retransplantation, or allograft vasculopathy) of pediatric HTx recipients with AMR, ACR, and no rejection in a retrospective single‐center study of 104 recipients. Twenty were treated for AMR; 15 were treated for ACR. Recipients with AMR had an increased frequency of congenital heart disease (90% vs ACR 67% vs no rejection 59%, P = .03), homograft (68% vs 7% vs 18%, P < .001), HLA sensitization (45% vs 13% vs 13%, P = .008), and positive cross‐match (30% vs 7% vs 9%, P = .046). AMR caused hemodynamic compromise more often than ACR (39% vs 4%, P = .02). AMR recipients had worse cardiovascular outcome than recipients with ACR or no rejection (40% vs 20% vs 8.6%, P = .003). In bivariate Cox analysis, AMR (HR 4.1, CI 1.4‐12.0, P = .009) and ischemic time (HR 1.6, CI 1.1‐2.3, P = .02) were associated with worse cardiovascular outcome; ACR was not. In summary, pediatric HTx recipients who develop AMR have worse cardiovascular outcome than recipients who develop only ACR or experience no rejection at all.

Impact of donor–recipient sex match on long‐term survival after heart transplantation in children: An analysis of 5797 pediatric heart transplants

The effect of donor–recipient sex matching on long‐term survival in pediatric heart transplantation is not well known. Adult data have shown worse survival when male recipients receive a sex‐mismatched heart, with conflicting results in female recipients. We analyzed 5795 heart transplant recipients ≤18 yr in the Scientific Registry of Transplant Recipients (1990–2012). Recipients were stratified based on donor and recipient sex, creating four groups: MM (N = 1888), FM (N = 1384), FF (N = 1082), and MF (N = 1441). Males receiving sex‐matched donor hearts had increased unadjusted allograft survival at five yr (73.2 vs. 71%, p = 0.01). However, this survival advantage disappeared with longer follow‐up and when adjusted for additional risk factors by multivariable Cox regression analysis. In contrast, for females, receiving a sex‐mismatched heart was associated with an 18% higher risk of allograft loss over time compared to receiving a sex‐matched heart (HR 1.18, 95% CI: 1.00–1.38) and a 26% higher risk compared to sex‐matched male recipients (HR 1.26, 95% CI: 1.10–1.45). Females who receive a heart from a male donor appear to have a distinct long‐term survival disadvantage compared to all other groups.

Hybrid stage 1 palliation as a bridge to cardiac transplantation in patients with high-risk single ventricle physiology

The hybrid stage 1 palliation for hypoplastic left heart syndrome (HLHS) was first described in 1993 as a bridge to heart transplant for HLHS. There are limited data on this strategy as primary heart transplantation for HLHS has become less common.

Fontan-associated protein-losing enteropathy and post-heart transplant outcomes: a multicenter study

BACKGROUND The influence of Fontan-associated protein-losing enteropathys (PLE) severity, duration, and treatment on heart transplant (HTx) outcomes is unknown. We hypothesized that long-standing PLE and PLE requiring more intensive therapy are associated with increased post-HTx mortality. METHODS This 12-center, retrospective cohort study of post-Fontan patients with PLE referred for HTx from 2003 to 2015 involved collection of demographic, medical, surgical, and catheterization data, as well as PLE-specific data, including duration of disease, intensity/details of treatment, hospitalizations, and complications. Factors associated with waitlist and post-HTx outcomes and PLE resolution were sought. RESULTS Eighty patients (median of 5 per center) were referred for HTx evaluation. Of 68 patients listed for HTx, 8 were removed due to deterioration, 4 died waiting, and 4 remain listed. In 52 patients undergoing HTx, post-HTx 1-month survival was 92% and 1-year survival was 83%. PLE-specific factors, including duration of PLE pre-HTx, pre-HTx hospitalizations, need for/frequency of albumin replacement, PLE therapies, and growth parameters had no association with post-HTx mortality. Immunosuppressant regimen was associated with mortality; standard mycophenolate mofetil immunotherapy was used in 95% of survivors compared with only 44% of non-survivors (p = 0.03). Rejection (53%) and infection (42%) post-HTx were common, but not associated with PLE-specific factors. PLE resolved completely in all but 1 HTx survivor at a median of 1 month (interquartile range 1 to 3 months); resolution was not affected by PLE-specific factors. CONCLUSIONS PLE severity, duration, and treatment do not influence post-HTx outcome, but immunosuppressive regimen may have an impact on survival. PLE resolves in nearly all survivors.

Dose conversion factor between cyclosporine and tacrolimus in pediatric heart transplant recipients

Calcineurin inhibitors (CNIs) are the cornerstone of immunosuppression after pediatric heart transplantation (HTx). However, many patients require conversion from one drug to another because of undesired adverse effects or breakthrough rejection. After conversion, it is important to achieve stable target blood levels of the newly introduced CNI as soon as possible to limit the risk of rejection, graft loss, and drug toxicity. Current guidelines direct clinicians converting patients between cyclosporine A (CyA) and tacrolimus (TAC) to dose pediatric patients according to weight (mg/kg), then adjust the dose relative to blood levels. However, dose requirements between patients vary widely because of individual differences in metabolism. Because both drugs are metabolized through the cytochrome P-450 pathway, dose requirements are strongly associated with each other as shown in adults after kidney transplant. Our primary aim was to examine the relationship between CyA and TAC dosing in pediatric HTx patients, seeking a conversion factor between CNIs that would account for individual differences in drug metabolism. This conversion factor could be used to dose the new drug relative to each patient’s unique, stable dosing of the previous drug and might provide more accurate dosing than the traditional mg/kg guidelines. A conversion factor for CNIs is defined as a patient’s stable 24-hour CyA dose/stable 24-hour TAC dose. For adult kidney transplant patients, conversion factors have been determined to be 25 and 30. These conversion factors may not apply to children because their drug metabolism is different from adults. CNI dosing at 1 year post-HTx was also compared with current mg/kg dosing recommendations. The mean CNI dose at 1 year post-HTx was recorded for all HTx patients aged r18 years receiving post-HTx care at Seattle Children’s Hospital. All patients who were switched from a stable CyA dose to TAC, or vice versa, were