Pathologist interrater reliability and clinical implications of elevated donor-derived cell-free DNA beyond heart transplant rejection, on behalf of the GRAfT investigators

Background

There is significant variability among pathologists in the histopathological interpretation of the endomyocardial biopsy (EMB) for acute cellular rejection (ACR), and assessment of variability in the interpretation of antibody-mediated rejection (AMR) has not been reported. In contemporary practice, the strategy of allograft surveillance with donor-derived cell-free DNA (dd-cfDNA) compared to EMB has not been compared with a focus on long-term clinical outcomes beyond acute rejection (AR).

Methods

The Genomic Research Alliance for Transplantation is a multicenter, prospective cohort study that enrolled patients from 2015 to 2020. The center pathologist read was compared to 2 blinded core cardiac pathologists. ACR and AMR were graded based on the International Society for Heart and Lung Transplantation criteria. Weighted Cohen’s kappa (κ) was used to evaluate interrater reliability between the center and core reads. To assess long-term outcomes, we evaluated a composite of AR, allograft dysfunction, and mortality within 1 year.

Results

The study included 94 patients (median age 55 years [interquartile range (IQR) 45, 62]), 30% female sex, 41% Black race), with 429 paired EMBs and dd-cfDNA measures. The concordance rate between center and core pathologists was 77% for ACR (95% confidence interval [CI]: 66%-89%) and 63% for AMR (95% CI: 53%-74%). Forty-six patients had an elevation in dd-cfDNA without AR by EMB. The median dd-cfDNA was 0.49% (IQR: 0.35, 1.01), and subsequent AR, allograft dysfunction, or mortality occurred in 59% of these patients at 1 year. In patients with AR by EMB and negative dd-cfDNA (n = 5), the composite outcome occurred in 20% of patients at 1 year. At baseline, the positive likelihood ratio (LR+) of dd-cfDNA to detect AR by the center pathologist was 3.74 (95% CI 3.01-4.64) and by core pathologist was 2.59 (95% CI: 1.95-3.45). If the composite outcome was included as a true positive, the LR+ of dd-cfDNA improved to 9.82 (95% CI: 7.04-13.69) and 7.63 (95% CI: 5.61-10.38) at 1 year, respectively.

Conclusions

Pathologists’ interrater reliability is limited in AMR similar to what has been reported in ACR. The LR+ of dd-cfDNA when compared with traditional histopathology is limited, but when longitudinal clinical outcomes are included to assess diagnostic performance, the LR+ improves significantly. The value of dd-cfDNA extends beyond the diagnosis of AR to include other clinically meaningful outcomes for patients after heart transplant.