Pediatric Heart Transplantation, Pediatric Heart Transplant Recipients
Conditions
Keywords
alloantibodies, donor specific antibodies (DSA)-preformed, de novo, self-antigens, chronic allograft function
Brief summary
This is a multi-center, prospective, single cohort, observational study of pediatric heart transplant recipients designed to determine the impact of preformed versus de novo human leukocyte antigen (HLA) donor-specific antibodies (DSA), and antibodies to the self-antigens cardiac myosin and vimentin, on chronic allograft function. In addition, the investigators will explore mechanisms of action and predictors of DSA, rejection and altered pathophysiology.
Detailed description
Participants that were enrolled in the CTOTC-04 study (ClinicalTrials.gov Identifier NCT01005316) are invited to enroll in this CTOTC-09 study. Conversion from the CTOTC-04 to CTOTC-09 study will occur in such a manner as to avoid/minimize discontinuity of follow-up between the planned CTOTC-04 and CTOTC-09 study visits. In addition, subjects added to the United Network for Organ Sharing (UNOS) system-or Canadian equivalent agency-at a participating study site, who are less than 21 years of age and fulfill all study eligibility criteria, will be invited to enroll in CTOTC-09. This study focuses on the importance of antibodies against the newly transplanted heart in pediatric heart transplant recipients. The investigators aim to determine if certain antibodies lead to problems with the heart transplant. Antibodies are small proteins in the blood that the body makes to fight off infections, for example with bacteria or viruses. Since a new heart is foreign to the recipient's body, their immune system might try to attack it with antibodies, as if it were an infection. For many years it was thought that only white blood cells attacked the new heart, causing rejection. Now there is new information showing that antibodies may also cause rejection or long-term damage to the heart. At this time, very little is known about how antibodies might cause problems after heart transplantation in transplant recipients younger than 21 years at the time of transplant. This study will collect a medical history and blood samples at specified times for research. The blood samples will be used to measure antibodies in the blood, and to perform special tests to see how these antibodies might damage the heart. Participant follow-up is from the day of the heart transplant to year 5 post-transplant.
Interventions
None listed
Sponsors
Clinical Trials in Organ Transplantation in Children
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
No minimum to 20 Years
Healthy volunteers
No
Inclusion criteria
* Subject and/or parent guardian able to understand and provide informed consent and where applicable assent * Planned long-term follow-up at one of the study sites AND either: -Enrolled in the CTOTC-04 study and actively followed at one of the study sites OR -Listed at participating study sites, less than 21 years of age and not yet transplanted. The inclusion criteria for enrollment of new study patients in the CTOTC-09 Protocol will be the same as the CTOTC-04 study (refer to ClinicalTrials.gov ID NCT01005316).
Exclusion criteria
* Parental withdrawal of consent from the CTOTC-04 study * Past or current medical problems or findings from physical examination or laboratory testing that, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or may impact the quality or interpretation of the data obtained from the study * Listed for simultaneous multiple organ transplant.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Pulmonary capillary wedge pressure at heart catheterization | 3 years post-transplantation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to recurrent late acute rejections | Up to 5 years post-transplantation | Recurrent defined as two or more late acute rejection episodes |
| Proportion of participants with angiographic evidence of coronary artery disease | 3 and 5 years post-transplantation | — |
| Time to graft loss (death or retransplantation) after first late rejection | Up to 5 years post-transplantation | — |
| Medication Adherence Measure (MAM) after hospital discharge | Up to 5 years post-transplantation | — |
| Variability of maintenance tacrolimus levels | Up to 5 years post-transplantation | — |
| Other invasive cardiac hemodynamic findings at cardiac catheterization | 3 and 5 years post-transplantation | Cardiac hemodynamic findings: right and left ventricular end diastolic pressures, right atrial pressure, pulmonary artery pressure and cardiac index |
| Frequency of development of post-transplant de novo DSA and autoantibodies to cardiac myosin and vimentin | 3 years post-transplantation | — |
| Time course of development of post-transplant de novo DSA and autoantibodies to cardiac myosin and vimentin. | 3 years post-transplantation | — |
| Frequency of first episode of late acute rejection | From >1 year to 5 years post-transplantation | — |
| Time to first episode of late acute rejection | From >1 year to 5 years post-transplantation | Late acute rejection is defined as occurring \>1 year post-transplantation |
| Frequency to recurrent (two or more) late acute rejections | Up to 5 years post-transplantation | — |
| Frequency to first episode of late acute rejection with hemodynamic compromise | Up to 5 years post-transplantation | — |
| Time to first episode of late acute rejection with hemodynamic compromise | Up to 5 years post-transplantation | — |
| Time to graft loss (death or retransplantation) conditional to surviving one year post-transplantation | One year and up to 5 years post-transplantation | — |
| N-terminal pro-brain Natriuretic Peptide (NT-proBNP)/Brain Natriuretic Peptide (BNP) | 3 and 5 years post-transplantation | — |
| Systolic and diastolic graft function | 3 and 5 years | Graft function as assessed by echocardiography |
Other
| Measure | Time frame | Description |
|---|---|---|
| Exploratory: Cellular immune responses to allo-antigens and self-antigens (vimentin and myosin) | 24 hours prior transplantation, Months 3 and 6 post transplantation | Cellular immune responses to allo-antigens and self-antigens (vimentin and myosin) will be measured by: * ELISPOT for Interleukin 17 (IL17) and Interleukin 10 (IL10) producing T cells * Plasma cytokines by Luminex (IL-6, IL-1beta, IL-17, Cxcl12, IL-10 and Transforming Growth Factor-beta (TGF-beta) |
| Exploratory: Role of Interleukin-33 (IL-33) and its Receptor (ST2) in cardioprotection against effects of DSA | Month 5 post transplantation | Role of IL-33 and its Receptor (ST2) in cardioprotection against effects of DSA will be measured by: * IL33 and ST2 expression in graft biopsies * Soluble ST2 in serum |
| Exploratory: Microvascular pathology | Up to 5 years post-transplantation | Microvascular pathology as defined by: * cytoprotective intracellular signaling (bcl2, Heme Oxygenase-1(HO-1)) * interstitial capillary network * endothelial cell progenitor influx and premature senescence * obliterative microvasculopathy (arteriolopathy) |
| Exploratory: Expression of cytoprotective genes Bcl2 and HO-1, ICAM, VCAM and selectins, Complement inhibitory proteins CD55, CD59, CR1, CR2 and CR3. | After exposure to alloantibody (or control) (At Year 1) | Endothelial Cell (EC) Culture Model is used to study factors that will predict and contribute to the protection of the graft following transplantation across sub-threshold concentrations of DSA. Exploratory: Expression of cytoprotective genes Bcl2 and HO-1, Intercellular adhesion molecules (ICAM), Vascular Cell Adhesion Molecule (VCAM) and selectins, Complement inhibitory proteins (cluster of differentiation antigen 55 (CD55), cluster of differentiation antigen 59 (CD59), Complement Receptor 1 (CR1), (CR2) and (CR3). |
Countries
Canada, United States
Outcome results
None listed