Genome Transplant Dynamics

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:

- Individuals 14 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.

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 donor-derived cell-free DNA (%dd-cfDNA) correlate with AR diagnosis and severity as detected by biopsy.

The performance receiver operator curve (ROC) of %dd-cfDNA yielded an area under the curve (AUC) of 0.83. Using this technique, we can diagnose AR by measuring elevations in %dd-cfDNA up to 5 months before EMB-detected pathology. While these findings suggest that monitoring %dd-cfDNA 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 %dd-cfDNA for AR in a multicenter, prospective cohort study of heart and lung transplant patients, recruited through a consortium of 5 transplant centers in 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 %dd-cfDNA characteristics in AMR (antibody-mediated rejection) and ACR (acute cellular rejection), 2) to study early immunological changes associated with a significant rise in %dd-cfDNA, and 3) to examine changes in microbiome architecture and other cell-free nucleic acids in rejection.

Eligibility Criteria:
* INCLUSION CRITERIA:
* Lung and heart transplant candidates. Dual organ transplants such as those 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.
* 14 years and older
* Able to understand and be 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 transplants. 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 Inclusion of Children: Subjects under 14 years of age will not be considered for inclusion in this protocol, because there are very few heart and lung transplantations performed annually on young minors in the DC/MD/VA area. Extension of enrollment to include younger subjects will provide the research samples to test the diagnostic performance of dd-cfDNA in this population, a first step towards adoption of dd-cfDNA for clinical use in pediatric population. Children will only undergo studies with no greater than minimal risk. There is no prospect of direct benefit to individual subjects, but the research is likely to yield generalizable knowledge about the disease or condition under study. Children will be enrolled in this minimum risk protocol in compliance with federal guidelines Title

45 Code of Federal Regulations, Part 46, Subpart D.

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 lung-transplant

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.