Recurrent Acute Cellular Rejection Graded ISHLT 1R Early After Heart Transplantation Negatively Affects Long-Term Outcomes

Background:

The 2004 ISHLT working formulation was developed to resolve inconsistencies between centers and is characterized by grouping former low-grade acute cellular rejection (ACR) to current grade 1R. The 1R classification as guidance on prognosis and treatment has not yet been well studied. We aimed to investigate the implications of early recurrent 1R rejections on the long term outcomes after heart-transplantation (HTx).

Methods:

Data on all patients who underwent HTx between 1991-2017 were reviewed. Excluded were patients who had rejection graded ISHLT 2R or higher on endomyocardial biopsy (EMB) in the first 3 months. Patients with ≥2 EMBs graded 1R in the first 3 months were classified as "recurrent 1R". Outcomes were long term rejections (>3months) assessed by total rejection score (TRS; 0R=0,1R=1,2R=2,3R=3 normalized for total EMBs) and any rejection score (ARS; 0R=0,1R=1,2R=1,3R=1normalized for total EMBs), and the combined endpoint of allograft vasculopathy (CAV) and cardiovascular (CVS) mortality.

Results

Recurrent 1R group included 69 patients, 159 were classified as non-recurrent. Basic clinical characteristics were similar. TRS and ARS were significantly higher in the recurrent 1R group compared to the non-recurrent group (0.51±0.22 vs. 0.37±0.36; 0.46±0.186 vs. 0.3±0.21, p<0.001,respectively). Kaplan-Meier survival analysis showed that CAV/CVS mortality at 10 years of follow-up was significantly higher among the recurrent 1R group (38% vs. 18% p<0.05, Figure). Multivariate analysis showed that early recurrent 1R rejections was associated with 2.5-fold increased risk for CAV/CVS mortality.

Conclusions:

Early recurrent 1R rejections negatively affect long-term outcomes. These data support early ACR detection, and suggest that continuous immunosuppressive adjustments might improve long term outcomes.