Diagnostic value of serum miR-144-3p for the detection of acute cellular rejection in heart transplant patients

Abstract

The development of noninvasive approaches for the early diagnosis of acute cellular rejection (ACR), an important complication of cardiac transplantation, is of great importance in clinical practice. We conducted a nontargeted transcriptomic study focused on identifying serum miRNAs to evaluate their diagnostic accuracy for detecting rejection episodes. We included consecutive serum samples from transplant recipients undergoing routine endomyocardial biopsies. In the discovery phase (n=40), an RNA sequencing analysis (Illumina HiSeq 2500 sequencer) was performed. We focused on the validation of miR-144-3p in a larger patient cohort (n=212), selected based on the criteria of higher accuracy for ACR detection. ACR was assessed according to the International Society for Heart and Lung Transplantation. In the discovery phase, 26 altered miRNAs were identified as potential markers for detecting ACR. miR-144-3p showed the best results, it was the only molecule with an AUC greater than 0.95 to detect Grade ≥2R ACR and it showed significant differences in its levels when we compared Grade 1R ACR with the nonrejection group. In the validation phase, we confirmed this finding, and it had an excellent diagnostic capacity for clinically relevant rejection (Grade ≥2R AUC=0.801, p < 0.0001), detecting mild rejection (Grade 1R AUC= 0.631, p < 0.01) and was an independent predictor for the presence of ACR (odds ratio of 14.538, p < 0.01). ACR is associated with the differential expression of specific serum miRNAs that correlate with the severity of the episode. Circulating miR-144-3p is a candidate noninvasive ACR biomarker that could contribute to improving the surveillance of cardiac transplanted patients.