Impact of donor-specific anti-HLA antibody on cardiac hemodynamics and graft function 3 years after pediatric heart transplantation: First results from the CTOTC-09 multi-institutional study

Abstract

The aim of this study (CTOTC-09) was to assess the impact of "preformed" (at transplant) donor-specific anti-HLA antibody (DSA) and first year newly detected DSA (ndDSA) on allograft function at 3 years after pediatric heart transplantation (PHTx). We enrolled children listed at 9 North American centers. The primary end point was pulmonary capillary wedge pressure (PCWP) at 3 years posttransplant. Of 407 enrolled subjects, 370 achieved PHTx (mean age, 7.7 years; 57% male). Pre-PHTx sensitization status was nonsensitized (n = 163, 44%), sensitized/no DSA (n = 115, 31%), sensitized/DSA (n = 87, 24%), and insufficient DSA data (n = 5, 1%); 131 (35%) subjects developed ndDSA. Subjects with any DSA had comparable PCWP at 3 years to those with no DSA. There were also no significant differences overall between the 2 groups for other invasive hemodynamic measurements, systolic graft function by echocardiography, and serum brain natriuretic peptide concentration. However, in the multivariable analysis, persistent first-year DSA was a risk factor for 3-year abnormal graft function. Graft and patient survival did not differ between groups. In summary, overall, DSA status was not associated with worse allograft function or inferior patient and graft survival at 3 years, but persistent first-year DSA was a risk factor for late graft dysfunction.

Keywords: allograft function; donor-specific antibodies; heart transplant; pediatric.

Figure 1.. Consort diagram.

Flow of all enrolled patients through the study. 194 patients previously enrolled in CTOTC-04 and 213 newly enrolled patients participated in the study. Reasons for discontinuation pre-transplant and post-transplant, but prior to year 3 visit, are provided. 370 transplanted patients were classified based on central laboratory-determined sensitization status at transplant. Five out of 370 patients had insufficient data to determine their baseline sensitization status.

Figure 2.. Boxplots of hemodynamic measurements by preformed and/or newly detected DSA in first year post-transplant.

Hemodynamic measurements at 3 years post-transplant are plotted for (A) mean pulmonary capillary wedge pressure (mmHg) (291 patients with available data), (B) ejection fraction (%) (292 patients with available data), and (C) log₁₀ BNP (pg/mL) (131 patients with available data). Each figure (A), (B), and (C) includes 2 panels. The left-hand panel presents 1 box plot of all transplanted patients who had the specific measurement available at year 3, and the right-hand panel presents the measurement stratified by whether or not the patient had preformed and/or newly detected DSA in the first-year post-transplant (labeled as ‘Had DSA in 1Y’ vs. ‘No DSA in 1Y’). The length of the box represents the interquartile range of 25^th and 75^th percentiles, the circle in the box represents the group mean, the horizontal line in the box represents the group median, and the whiskers from the box represents the 5^th and 95^th percentiles. The means of 2 groups were connected by a line. 9 patients who had acute rejection at the time of collection of their 3-year hemodynamic measurements are highlighted in red. The P-values result from t-tests to compare the mean difference between 2 groups. DSA, donor specific antibody.

Figure 3.. Boxplots of Hemodynamic measurements by sensitized status at transplant and newly formed DSA in 1-year post-transplant.

Hemodynamic measurements at 3 years post-transplant are plotted for (A) mean pulmonary capillary wedge pressure (mmHg) (291 patients with available data), (B) ejection fraction (%) (292 patients with available data), and (C) log₁₀ BNP (pg/mL) (131 patients with available data). Each figure (A), (B), and (C) includes 2 panels. The left-hand panel presents 1 box plot of all transplanted patients who had the specific measurement available at year 3, and the right-hand panel presents the measurement stratified by 3 groups of sensitization status at transplantation; sensitized with DSA, sensitized without DSA, and non-sensitized (labeled as ‘Sens, DSA at Tx’ vs. ‘Sens, No DSA at Tx’ vs. ‘Non-Sens at Tx’) and within each sensitization status group, patients were stratified by whether or not the patient had newly detected DSA in the first year post-transplant (labeled as ‘ndDSA+’ vs. ‘ndDSA−’). The length of the box represents the interquartile range of 25^th and 75^th percentiles, the circle in the box represents the group mean, the horizontal line in the box represents the group median, the whiskers from the box represents the 5^th and 95^th percentiles. The means of 2 groups were connected by a line. 9 patients who had acute rejections at the time of 3 years hemodynamic measurements were collected are highlighted in red. The P-values result from general linear regression models to test the mean difference between 2 sub-groups are at the top of each panel.

Figure 4.. Freedom from the composite of death, re-transplantation or rejection with hemodynamic compromise stratified by sensitization status and highest MFI of DSA at transplantation based on Alloantibody Core Laboratory testing

Probability of freedom from the composite of death, re-transplantation or rejection with hemodynamic compromise (A) and its constituent components (panels B- D) stratified by sensitization status and highest MFI of DSA at transplantation based on Alloantibody Core Laboratory testing. The number of patients at risk is presented annually post-transplant. Kaplan-Meier survival analysis was used to produce the estimates with a 95% confidence interval for each group; P-values reported from the log-rank test shown in bottom left corner of each panel. An additional P-value (P=0.005) is shown for pairwise comparison of rejection with hemodynamic compromise comparing subjects sensitized with one or more DSA with MFI 4000+ to non-sensitized subjects (panel C). DSA, donor specific antibody; CI, confidence interval.

Figure 5.. Freedom from acute antibody mediated rejection and acute cellular rejection stratified by sensitization status and highest MFI of DSA at transplantation based on Alloantibody Core Laboratory testing

Probability of freedom from acute antibody mediated rejection (A) and acute cellular rejection (B) stratified by sensitization status and highest MFI of DSA at transplantation based on Alloantibody Core Laboratory testing. The number of patients at risk is presented annually post-transplant. The Kaplan-Meier survival analysis was used to produce the estimates with 95% confidence intervals for each group; p-values reported from the log-rank test comparing across all 4 groups and pairwise comparisons vs. the non-sensitized group.