Quantitative Detection of Circulating Donor-Specific DNA in Organ Transplant Recipients (DTRT-Multi-Center Study)

Early detection of rejection is a major focus of organ transplant care. The use of aggressive
immunosuppressive therapy has been shown to alter the prognosis of heart transplant patients
who have acute rejection1. There are many modalities utilized in the routine surveillance of
heart transplant patients, each with limitations. Screening transthoracic echocardiography
focusing on indices of systolic and diastolic dysfunction, along with regional wall
abnormalities, has been shown to have poor sensitivity and does not effectively discriminate
between patients with and without rejection. Newer echocardiographic parameters including
myocardial performance or diastolic velocity indices may be a better means of detecting
subtle changes in cardiac function in the setting of heart transplant, but these tools are
most helpful after the insult caused by rejection has already occurred. Hemodynamic changes
measured during heart catheterization have also been evaluated as a means of detecting
rejection. Rosenthal et al found that although there were statistically significant
differences between patients with higher or lower grades of rejection scores, heart
catheterization did not permit effective discrimination of patients with moderate to severe
rejection. Heart biomarkers, including c-reactive protein, brain natriuretic peptides, and
troponin, have been studied as non-invasive measures of determining heart dysfunction or
rejection. These surrogates are weakly associated with different rejection grades on biopsy
and have a poor predictive capacity for biopsy-detected rejection3. Recently, microarray
technology has been used to screen for genes expressed in heart allograft rejection using
peripheral leukocytes from blood samples obtained at the time of endomyocardial biopsy. This
technique was shown to have a high negative predictive value for the diagnosis of acute
cellular rejection but it is unable to detect low grades of rejection4. Overall, these
technologies are limited in the ability to consistently and accurately predict the presence
of rejection and have low positive predictive values when compared to biopsy.

The current gold standard in detection of rejection is the use of endomyocardial biopsy.
Attaining these samples is invasive and long term repeated central venous access can be
difficult. Risk of endomyocardial biopsy includes perforation leading to cardiac tamponade,
arrhythmias including atrial fibrillation, pneumothorax, hemothorax, and valvular
regurgitation secondary to rupture of chordae or damage to valve leaflets themselves. There
is variability in pathological interpretation of histologic grades, especially at higher
grades of rejection due to the difficulty in interpretation of nodular infiltrates. The 2005
revised ISHLT grading system has simplified the grading system of cellular rejection and now
includes assessment of antibody mediated rejection. This may improve the utility of
endomyocardial biopsy, but much controversy still exists on the method of grading rejection
and its clinical implications. Thus, the development of a noninvasive, relatively inexpensive
method that accurately predicts the presence of rejection is critical.

Inclusion Criteria:

Any patient who is "listed" to undergo or has in the past undergone heart transplantation.

Exclusion Criteria:

Any patient who is not currently listed to undergo heart transplantation or has not
previously received a heart transplant;

Any patient who is not anticipated to be available for follow-up of at least 1 year;

Any patient who is unable or unwilling to provide documented informed consent for self or
through a legally authorized representative.