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.