Should We Be Comforted by a "Negative" Endomyocardial Biopsy? Risk of Future Events with Donor Derived Cell Free DNA in the Setting of Histologic Quiescence

PurposeEndomyocardial biopsy (EMB) is considered the gold standard for screening for rejection in heart transplant (HT) recipients. Lack of histological evidence of rejection on EMB has typically been reassuring to clinicians, but the interpretation of elevated levels of donor-derived cell free DNA (dd-cfDNA) in the setting of a “negative” biopsy is unclear.MethodsPatients from the multi-center Surveillance Using HeartCare Outcomes Registry (SHORE) database who had dd-cfDNA measured within 30 days of a negative EMB (Grades 2R/AMR1 or higher rejection) within the first 100 days of heart transplant (HT) were reviewed. These patients were followed for the subsequent development of significant rejection and de novo donor-specific antibodies (dnDSA) over the next 365 days.ResultsA total of 648 HT recipients with a mean age 57, 74% male, white 64%, 60% of which had PRA < 1% and had a total of 982 paired biopsies with a median dd-cfDNA of 0.05% for those with a Grade 0R and 0.06% for Grade 1R biopsy (Figure 1a). The dd-cfDNA was measured a median of 112 days post-transplant for Grade 0R and 109 days post-transplant for Grade 1R. Despite negative histology on EMB, those with a cfDNA >= 0.20% were at significantly higher risk for the development of significant rejection (14.3% v 5.2%, p<0.01) and dnDSA (11.3% v. 6.8%, p<0.01) over the subsequent year.ConclusionPatients with elevated dd-cfDNA, but without prior rejection and negative histology in the first 100 days post-transplant are at increased risk for significant rejection and dnDSA in the subsequent year. The use of dd-cfDNA may be a better method to determine true quiescence and call into question the utility of the EMB as the gold standard for cardiac allograft monitoring. Endomyocardial biopsy (EMB) is considered the gold standard for screening for rejection in heart transplant (HT) recipients. Lack of histological evidence of rejection on EMB has typically been reassuring to clinicians, but the interpretation of elevated levels of donor-derived cell free DNA (dd-cfDNA) in the setting of a “negative” biopsy is unclear. Patients from the multi-center Surveillance Using HeartCare Outcomes Registry (SHORE) database who had dd-cfDNA measured within 30 days of a negative EMB (Grades 2R/AMR1 or higher rejection) within the first 100 days of heart transplant (HT) were reviewed. These patients were followed for the subsequent development of significant rejection and de novo donor-specific antibodies (dnDSA) over the next 365 days. A total of 648 HT recipients with a mean age 57, 74% male, white 64%, 60% of which had PRA < 1% and had a total of 982 paired biopsies with a median dd-cfDNA of 0.05% for those with a Grade 0R and 0.06% for Grade 1R biopsy (Figure 1a). The dd-cfDNA was measured a median of 112 days post-transplant for Grade 0R and 109 days post-transplant for Grade 1R. Despite negative histology on EMB, those with a cfDNA >= 0.20% were at significantly higher risk for the development of significant rejection (14.3% v 5.2%, p<0.01) and dnDSA (11.3% v. 6.8%, p<0.01) over the subsequent year. Patients with elevated dd-cfDNA, but without prior rejection and negative histology in the first 100 days post-transplant are at increased risk for significant rejection and dnDSA in the subsequent year. The use of dd-cfDNA may be a better method to determine true quiescence and call into question the utility of the EMB as the gold standard for cardiac allograft monitoring.