Circulating nucleic acids as biomarkers for allograft injury after solid organ transplantation: current state-of-the-art

Abstract

Sabrina K Pattar Steven C Greenway 1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; 2Department of Pediatrics and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; 3Department of Cardiac Sciences and Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Abstract: Immune-mediated injury of a transplanted organ can lead to allograft dysfunction and even patient death. Acute cellular rejection typically occurs within the first months post-transplantation but patients are at life-time risk, particularly if there is medication non-compliance or reduction of immunosuppression due to complications. Therefore, safe and accurate monitoring of the donated organ for signs of rejection is essential for long-term survival of the transplanted organ and recipient. The current gold standard for rejection surveillance is through tissue biopsy and histology, which is costly, invasive, and subjective. Thus, efforts to develop non-invasive methods for the detection of rejection post-transplantation are a priority in the field. The first FDA-approved noninvasive assay, AlloMap, was developed in 2006 and monitored the peripheral expression of 11 genes associated with immune system activation. More recently, there has been a shift towards interrogating the status of the transplanted organ directly. Fragments of genomic DNA are released into the blood during cellular apoptosis and levels of cell-free DNA (cfDNA) have been shown to be elevated in the presence of organ injury, including after transplantation. Since the genomic characteristics of DNA are maintained in cfDNA (eg, sequence variants), this circulating molecule represents a promising organ-specific biomarker for allograft injury. DNA sequence variants have been used to distinguish donor and recipient cfDNA with or without a priori donor genotyping in a variety of solid organs post-transplant. Current research has established the groundwork and future multicenter trials will determine if this novel molecular diagnostic tool represents a viable alternative to tissue biopsy. Other nucleic acid molecules released from the transplanted organ (eg, microRNAs) are presently less well developed in comparison to cfDNA but may also represent potential novel biomarkers. This review summarizes current literature and evaluates the promises and pitfalls of circulating nucleic acids as biomarkers for allograft injury post-transplant.