Genome Transplant Dynamics

Study Overview
=================
Brief Summary
-----------------
Background: - Some people with advanced heart and lung disease have heart and lung transplants. But the organs are often rejected. When this happens, the organ recipients must have repeated biopsies. These are invasive and expensive. Researchers want to see if a blood test can predict rejection and take the place of biopsies. The test shows how much donor DNA is in a recipient s blood. Objective: - To see if a new blood test can be used instead of biopsies to diagnose rejection after transplant. Eligibility: - Adults 18 years and older who are on the lung or heart transplant waitlist. Design: Participants will have about 4 teaspoons of blood drawn from the arm before having their transplant. Researchers will collect demographic data about participants. They will also collect basic medical information about their condition. After surgery, while still in the hospital, participants will have 2 teaspoons of blood drawn twice a week until they go home. At each biopsy visit after the transplant, participants will have 4 teaspoons of blood drawn for testing for up to 5 years.

Detailed Description
-----------------
Acute rejection (AR) occurs within the first 6 months after transplantation in 20 percent of heart transplant patients and in 50 percent of lung-transplant patients. Given the often silent clinical presentation of AR, these patients require monitoring with repeated invasive and costly endomyocardial (EMB) or transbronchial biopsies (TBBx). Since organ transplantation is essentially genomic transplantation, our prior studies leveraged the use of distinctive graft and recipient genotype single-nuclear polymorphisms (SNPs) to barcode donor DNA circulating in recipient serum. We have shown that levels of donor DNA measured as the percentage of circulating cell-free donor-derived DNA (%ccfdDNA) correlate with AR diagnosis and severity as detected by biopsy. The performance receiver operator curve (ROC) of %ccfdDNA yielded an area under the curve (AUC) of 0.83. Using this technique, we can diagnose AR by measuring elevations in %ccfdDNA up to 5 months before EMB-detected pathology. While these findings suggest that monitoring %ccfdDNA may offer a high-performing, non-invasive, and early diagnostic tool of AR, further validation studies are required to determine its clinical utility. The ability to diagnose AR earlier than is possible with a biopsy offers an opportunity to investigate the pathogenesis of rejection as well as to identify potential AR biomarkers. Thus, the primary objective of this study is to validate the predictive accuracy and ROC characteristics of %ccfdDNA for AR in a multicenter, prospective cohort study of heart- and lung-transplant patients, recruited through a consortium of 5 transplant centers in the Washington, DC metropolitan area. The secondary objective is to determine the association between early graft injury caused by acute rejection and infection and the development of chronic rejection, i.e., chronic lung allograft dysfunction (CLAD) or chronic allograft vasculopathy (CAV). The exploratory objectives are: 1) to compare %ccfdDNA characteristics in AMR (antibody-mediated rejection) and ACR (acute cellular rejection), 2) to study early immunological changes associated with a significant rise in %ccfdDNA, and 3) to examine changes in microbiome architecture and other cell-free nucleic acids in rejection.

Official Title
-----------------
Genome Transplant Dynamics

Conditions
-----------------
Thoracic Organ Transplantation

Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA: Lung and heart transplant candidates. Dual organ transplants such as that include lung or heart PLUS any other organ are also considered for enrollment. Subjects who have undergone lung or heart transplants and are within 3 months of transplantation. 18 years and older Able to understand and willing to sign the informed consent form. Subjects undergoing a double transplant will sign a single consent. Retransplant candidates will be considered as a new transplant. These subjects will be approached for enrollment and if they consent to participate, they will be assigned a different SSPIN. EXCLUSION CRITERIA: -Pregnancy INCLUSION OF VULNERABLE POPULATIONS Rationale for the Exclusion of Children: Subjects under 18 years of age will not be considered for inclusion in this protocol, because there are very few heart and lung transplantations performed annually on minors in the DC/MD/VA area. Rationale for the Exclusion of Pregnant Women: Pregnant women are not eligible for this study. Women who are pregnant or lactating will be excluded since these patients are not typically considered for transplantation due to the risk to the developing fetus or nursing infants. For patients enrolled in the study who become pregnant, we will stop all study specific tasks. When the subject is no longer pregnant we will resume the sample collection. Inclusion of Minority Populations: According to the United Network for Organ Sharing (UNOS), about 20 percent of lungtransplant recipients and about 40 percent of heart-transplant recipients in participating centers are minorities. Also, about 40 percent of lung-transplant recipients and 37 percent of heart-transplant recipients are female. In our experience, enrollment rates among minority transplant recipients and female transplant recipients have been similar to the rate in our general transplant population.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort 1<br>Heart and Lung Transplant patients | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To validate the predictive accuracy and ROC characteristics of the percentage of circulating cell-free donor-derived DNA (%ccfdDNA) in a multicenter, prospective cohort study of heart-and lung-transplant patients, recruited through a consortium ... | Fold change in %ccfdDNA at the time of biopsy-proven rejection | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the association between early graft injury caused by acute rejection and infection and the development of chronic rejection, ie.,chronic lung allograft dysfunction (CLAD) or chronic allograft vasculopathy (CAV). | %ccfdDNA in rejection grades 1R, 2R, and 3R, %ccfdDNA at 1 month before biopsy diagnosis of AR, %ccfdDNA after treatment of AR, %ccfdDNA in ACR and AMR, spirometry grade of CLAD, angiographic grade of CAV, and number of AR per year, severity grade of clinically determined graft dysfunction, mean(%ccfdDNA), all-cause mortality. | End of Study | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cell-free DNA, Acute Rejection, Thoracic Organ Transplantation, Non-Invasive Testing, Chronic Rejection, Natural History