The Impact of Grade 1R Endomyocardial Biopsies on Donor-Derived Cell-Free DNA, Higher-Grade Rejection and Development of Donor Specific Antibodies

Abstract

<h3>Purpose</h3> Recurrent episodes of mild rejection early post-transplant may lead to subsequent higher severity rejections and adverse outcomes, but there is a paucity of data on the prognosis of these patients. Elevations in donor-derived cell-free DNA (dd-cfDNA) and the development of donor specific antibodies (DSA) in kidney, heart, and lung transplantation have been described. We evaluated the association of AlloSure (dd-cfDNA) during episodes of acute cellular rejection (ACR) ISHLT Grade 1R with subsequent development of higher-grade rejections and DSA in heart transplantation. <h3>Methods</h3> This is a retrospective analysis of 484 patients who developed ACR Grade 1R (< 365 days post-transplant) paired with dd-cfDNA in the <i>Surveillance HeartCare® Outcomes Registry</i> (SHORE). dd-cfDNA levels were divided into 4 quartiles (median dd-cfDNA; Q1 = 0.10%, Q2 = 0.12%, Q3 = 0.15%, Q4 = 0.32%). The number of recurrent rejections (ISHLT Grade 2R/3R) and DSA were compared across quartiles using the Cochran-Armitage test (p<0.05). <h3>Results</h3> There were 933 episodes of Grade 1R biopsies. The median dd-cfDNA in 72 for-cause biopsies was 0.16% and in 860 surveillance biopsies was 0.12%, p=0.8979. Grade 1R rejection was not associated with later development of higher grades of ACR or dd-cfDNA quartiles (Table). Sixty-seven patients developed DSA subsequent to a 1R rejection and a higher incidence of DSA was associated with increased dd-cfDNA (median dd-cfDNA in Q1=8.7%, Q2=10.9%, Q3=18.9%, Q4=18.3%) (p = 0.006). <h3>Conclusion</h3> Grade 1R biopsies did not progress to higher grade rejections. There was no significant elevation in dd-cfDNA with Grade 1R biopsies. With increasing dd-cfDNA there was a significant trend toward DSA development following Grade 1R biopsies. Further analysis with longer follow-up to assess recurrent rejection and larger sample size of DSA is warranted.