Allo-antibodies in Pediatric Heart Transplantation

• Composite endpoint of the incidence of death, retransplantation or rejection with hemodynamic compromise [ Time Frame: At month 12 post-transplantation ] [ Designated as safety issue: Yes ]
  

• To determine the incidence of de novo alloantibody production post-transplantation and assess the impact on graft and participant outcomes [ Time Frame: study enrollment to end of study ] [ Designated as safety issue: Yes ]
  Cohort A
  
  
• To determine the specificity and time course of production of post-transplant de novo allo-antibodies and risk factors for their development [ Time Frame: study enrollment to end of study ] [ Designated as safety issue: Yes ]
  Cohort A
  
  
• Wait-list mortality [ Time Frame: study enrollment to time of transplant ] [ Designated as safety issue: Yes ]
  Cohort A and Cohort B: Pre-transplant
  
  
• Time from listing to transplantation, death or delisting [ Time Frame: study enrollment to time of transplant ] [ Designated as safety issue: Yes ]
  Cohort A and Cohort B: Pre-transplant
  
  
• Presence and quantification of anti-HLA IgG antibodies by Luminex SA testing [ Time Frame: study enrollment to time of transplant ] [ Designated as safety issue: Yes ]
  Cohort A and Cohort B: Pre-transplant
  
  
• Presence of anti-MICA antibodies by LuminexTM assay [ Time Frame: study enrollment to time of transplant ] [ Designated as safety issue: Yes ]
  Cohort A and Cohort B: Pre-transplant
  
  
• Overall participant and graft survival [ Time Frame: time of transplant to end of study ] [ Designated as safety issue: Yes ]
  Cohort A and Cohort B: Post-transplant
  
  
• C4d on endomyocardial biopsy (EMB) [ Time Frame: time of transplant to end of study ] [ Designated as safety issue: Yes ]
  Cohort A and Cohort B: Post-transplant
  
  
• Incidence of Rehospitalizations [ Time Frame: time of transplant to end of study ] [ Designated as safety issue: Yes ]
  Cohort A and Cohort B: Post-transplant
  
  
• Incidence of Severe infections [ Time Frame: time of transplant to end of study ] [ Designated as safety issue: Yes ]
  Cohort A and Cohort B: Post-transplant
  
  
• Time to diagnosis of chronic rejection (graft coronary artery disease) [ Time Frame: time of transplant to end of study ] [ Designated as safety issue: Yes ]
  Cohort A and Cohort B: Post-transplant
  
  
• Time to post-transplantation lymphoproliferative disorder [ Time Frame: time of transplant to end of study ] [ Designated as safety issue: Yes ]
  Cohort A and Cohort B: Post-transplant
  
  
• Time to new-onset diabetes mellitus [ Time Frame: time of transplant to end of study ] [ Designated as safety issue: Yes ]
  Cohort A and Cohort B: Post-transplant
  
  
• Frequency and time to acute rejection [ Time Frame: time of transplant to end of study ] [ Designated as safety issue: Yes ]
  Cohort A and Cohort B: Post-transplant
  
  
• Survival/ 'cytoprotective' genes: Bcl-xl, Bcl-2, HO-1 [ Time Frame: from day of transplant to end of study ] [ Designated as safety issue: No ]
  In EMB samples and EC culture
  
  
• Adhesion molecules: ICAM-1, VCAM-1 [ Time Frame: from day of transplant to end of study ] [ Designated as safety issue: No ]
  In EMB samples and EC culture
  
  
• Endothelial cell chimerism [ Time Frame: from day of transplant to end of study ] [ Designated as safety issue: No ]
  In EMB samples
  
  
• Complement regulatory proteins: CD55, CD59 [ Time Frame: from day of transplant to end of study ] [ Designated as safety issue: No ]
  In EMB samples
  
  
• Complement receptors: CR1 and CR3 [ Time Frame: from day of transplant to end of study ] [ Designated as safety issue: No ]
  In EMB samples
  
  
• Phospho-S6 ribosomal protein [ Time Frame: from day of transplant to end of study ] [ Designated as safety issue: No ]
  In EMB samples
  
  
• Circulating precursor and mature endothelial cells [ Time Frame: from day of enrollment to end of study ] [ Designated as safety issue: No ]
  In Peripheral blood
  
  
• Erythropoietin (EPO) levels [ Time Frame: from day of enrollment to end of study ] [ Designated as safety issue: No ]
  In Peripheral blood
  
  
• Vascular endothelial growth factor (VEGF) [ Time Frame: from day of enrollment to end of study ] [ Designated as safety issue: No ]
  In Peripheral blood
  
  
• pAkt activity in circulating PBMC [ Time Frame: from day of enrollment to end of study ] [ Designated as safety issue: No ]
  In Peripheral blood
  
  
• Cell-bound complement activation product levels as a potential biomarker for AMR [ Time Frame: from day of enrollment to end of study ] [ Designated as safety issue: No ]
  In Peripheral blood
  
  

There is currently a renewed interest in allo-antibodies in transplantation. In 1966, Kissmeyer and colleagues reported that pre-existing antibodies directed against donor cells could cause hyperacute rejection of the renal allograft. Three years later, in a landmark study, Patel and Terasaki showed that a lymphocytotoxic assay to identify donor-specific antibodies was highly predictive of acute graft failure. These observations led to the practice of performing prospective, donor-specific cross-matches by lymphocytotoxicity assay for all kidney transplants and for heart and lung transplants when the candidate has a positive panel reactive antibody (PRA) assay. A concept evolved that transplantations should not be performed across a positive cytotoxicity cross-match. The purpose of this study is to determine the clinical outcomes of sensitized pediatric heart transplant recipients with a positive donor-specific cytotoxicity cross-match and to compare them with outcomes in nonsensitized heart transplant recipients.

This study will enroll 370 pediatric heart transplant recipients over a period of 3 years. The follow-up period will last up to 3 years. All participants will be enrolled pretransplant. In the pretransplant phase, visits will occur every 6 months. These routine visits will continue until transplant or the end of the study. They will coincide with routine pretransplant status visits. At the time of transplant, the participants will be assigned to one of two groups. Group A participants will be allo-antibody negative (less than 10% by AHG CDC-PRA and ELISA in all DTT-treated serum samples). Group B participants will have the presence of a DTT-treated AHG CDC-PRA of greater than or equal to 10% and/or an ELISA-PRA greater than or equal to 10% in any pretransplant sample.

Both groups will receive standard transplantation care. This study has no interventions. All participants will undergo regular blood tests, but those in the sensitized group will have additional blood testing done after the transplant and lasting until the end of the study. Post-transplant visits will occur while participants are recovering in the hospital; at Months 1, 3, and 6; and annually until the study closes.

The information collected for the study include data from a physical exam, routine testing, adverse and serious adverse events assessments, and blood collection. Each time a biopsy is done, the study will ask to review the biopsy tissue and to collect a sample. If stored tissue is not available, none will be collected.