Genome Transplant Dynamics

Overview

Study Description: Heart and lung transplants can save lives, but long-term success is often limited by organ rejection that is hard to detect early. This study is testing a new, non-invasive blood test that looks for small pieces of DNA from the donor organ in the patient s blood. We believe higher levels of this donor DNA may signal early rejection before damage becomes permanent. Hypothesis: We believe that measuring donor-derived DNA in the blood can help detect early signs of rejection and improve outcomes for transplant patients. The study also collects genetic and biological samples to explore why some people are more at risk of complications after transplant. This may help guide future research and treatments. Who Can Join the Study: People receiving a heart or lung transplant (or both), age 14 and older People who are within three months of their transplant People who can understand and agree to take part in the study Participants will be asked to provide blood and other samples, and some of these will be used in lab research to explore new ideas about how and why transplant rejection happens. This research could lead to better ways to monitor and treat patients after a heart or lung transplant - and help improve long-term survival and quality of life.

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 donor-derived cell-free DNA (cfDNA) correlate with AR diagnosis and severity as detected by biopsy. The performance receiver operator curve (ROC) of cfDNA yielded an area under the curve (AUC) of 0.83. Using this technique, we can diagnose AR by measuring elevations in cfDNA up to 5 months before EMB-detected pathology. While these findings suggest that monitoring 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 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 cfDNA characteristics in AMR (antibody-mediated rejection) and ACR (acute cellular rejection), 2) to study early immunological changes associated with a significant rise in cfDNA, and 3) to examine changes in microbiome architecture and other cell-free nucleic acids in rejection, 4) to determine if cfDNA trends correlate with treatment response for transplant complications, 5) to determine if the level of pre-transplant cfDNA identify patients at high risk of rejection post-transplant, 6) to determine genetic variants associated with post-transplant risk of rejection, high cfDNA levels and other complications.

Primary outcome measures

• To validate the predictive accuracy and ROC characteristics of circulating cell- free donor derived DNA (cfDNA) in multicenter, prospective cohort study of heart and lung transplant patients, recruited through a consortium of 5 transplant center... [Time frame: At the time of biopsy-proven rejection]

Secondary outcome measures (1)

• 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). [Time frame: End of Study]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

United States · 6 centers

• MedStar Washington Hospital Center — Washington D.C.
• Johns Hopkins University — Baltimore
• University of Maryland — Baltimore
• National Institutes of Health Clinical Center — Bethesda
• INOVA Fairfax Medical — Falls Church
• Virginia Commonwealth University — Richmond

Publications

• Angelini A, Andersen CB, Bartoloni G, Black F, Bishop P, Doran H, Fedrigo M, Fries JW, Goddard M, Goebel H, Neil D, Leone O, Marzullo A, Ortmann M, Paraf F, Rotman S, Turhan N, Bruneval P, Frigo AC, Grigoletto F, Gasparetto A, Mencarelli R, Thiene G, Burke M. A web-based pilot study of inter-pathologist reproducibility using the ISHLT 2004 working formulation for biopsy diagnosis of cardiac allogr PMID 21816625
• De Vlaminck I, Khush KK, Strehl C, Kohli B, Luikart H, Neff NF, Okamoto J, Snyder TM, Cornfield DN, Nicolls MR, Weill D, Bernstein D, Valantine HA, Quake SR. Temporal response of the human virome to immunosuppression and antiviral therapy. Cell. 2013 Nov 21;155(5):1178-87. doi: 10.1016/j.cell.2013.10.034. PMID 24267896
• Pham MX, Teuteberg JJ, Kfoury AG, Starling RC, Deng MC, Cappola TP, Kao A, Anderson AS, Cotts WG, Ewald GA, Baran DA, Bogaev RC, Elashoff B, Baron H, Yee J, Valantine HA; IMAGE Study Group. Gene-expression profiling for rejection surveillance after cardiac transplantation. N Engl J Med. 2010 May 20;362(20):1890-900. doi: 10.1056/NEJMoa0912965. Epub 2010 Apr 22. PMID 20413602
• Goldberg JF, Bagchi P, Mercado A, Shah KB, Najjar SS, Tchoukina I, Rodrigo ME, Hsu S, Jang M, Kong H, Marboe CC, Berry GJ, Valantine HA, Agbor-Enoh S, Shah P; GRAfT Investigators. Identification of Heart Transplant Rejection Subtypes With Circulating MicroRNAs. Circ Heart Fail. 2026 May;19(5):e013141. doi: 10.1161/CIRCHEARTFAILURE.124.013141. Epub 2026 Jan 12. PMID 41521923
• Alnababteh M, Keller MB, Kong H, Phipps K, Namian J, Ponor L, Shah P, Mathews J, Andargie T, Park W, Orens JB, Aryal S, Nathan SD, Bush E, Redekar N, Hill T, Jang M, Tian X, Agbor-Enoh S. Early post-transplant recipient tissue injury predicts allograft function, rejection and survival in lung transplant recipients: evidence from cell-free DNA. Eur Respir J. 2026 Apr 16;67(4):2402537. doi: 10.1183/ PMID 40744691
• Shah P, Agbor-Enoh S, Lee S, Andargie TE, Sinha SS, Kong H, Henry L, Park W, McNair E, Tchoukina I, Shah KB, Najjar SS, Hsu S, Rodrigo ME, Jang MK, Marboe C, Berry GJ, Valantine HA; GRAfT Investigators. Racial Differences in Donor-Derived Cell-Free DNA and Mitochondrial DNA After Heart Transplantation, on Behalf of the GRAfT Investigators. Circ Heart Fail. 2024 Apr;17(4):e011160. doi: 10.1161/CIRC PMID 38375637
• Keller MB, Tian X, Jang MK, Meda R, Charya A, Berry GJ, Marboe CC, Kong H, Ponor IL, Aryal S, Orens JB, Shah PD, Nathan SD, Agbor-Enoh S. Higher Molecular Injury at Diagnosis of Acute Cellular Rejection Increases the Risk of Lung Allograft Failure: A Clinical Trial. Am J Respir Crit Care Med. 2024 May 15;209(10):1238-1245. doi: 10.1164/rccm.202305-0798OC. PMID 38190701
• Keller M, Bush E, Diamond JM, Shah P, Matthew J, Brown AW, Sun J, Timofte I, Kong H, Tunc I, Luikart H, Iacono A, Nathan SD, Khush KK, Orens J, Jang M, Agbor-Enoh S. Use of donor-derived-cell-free DNA as a marker of early allograft injury in primary graft dysfunction (PGD) to predict the risk of chronic lung allograft dysfunction (CLAD). J Heart Lung Transplant. 2021 Jun;40(6):488-493. doi: 10.101 PMID 33814284

Identifiers

NCT: NCT02423070 · 999915115 · 15-H-N115

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗