New Generation Biomarkers in Organ Transplantation

Recent years have witnessed vast improvements in the survival of renal allografts primarily due to the availability of improved immunosuppression regimens, HLA matching strategies, improvements in antibody detection assays, and better understanding of the immune mechanisms underlying graft rejection. Despite all of this, many questions still require answers in order to maximize the successful graft outcome. For example, it is not clear why some grafts still survive although they express many incompatibilities, while others are lost even though they are well matched and are without evidence of antibody presence in the recipient. It is also not clear why some antibodies are on the spot deterimental, while others take years, if ever, to inflict any harm. With the advent of next generation sequencing, the focus is slowly shifting towards defining the hierarchy of alloresponsiveness by the recipient through full sequencing of both the donor and the recipient so as to define challenging HLA epitopes. At the same time, defining biomarkers as non-invasive indicators of the biologic processes represents a useful tool in the field of solid organ transplantation.

The traditional kidney transplant clinics use conventional markers that primarily include serum creatinine/eGFR, proteinuria, graft histology, and donor-specific antibody (DSA) monitoring. Despite their clinical utility, these markers have inherent problems like low sensitivity and specificity, invasiveness, and lack of consensus for interpretation. In recent years, many candidate biomarkers have been discovered that are in rigorous internal and external validation phases. For example, biomarkers of ischemia-reperfusion injury and of delayed graft function are extremely important for an early diagnosis of post transplant complications and for optimizing the treatment. Further, biological indicators predicting acute rejection, both cell mediated as well as antibody mediated, could permit risk stratification of the recipient and prompt diagnosis in the early phase when the histology is still unremarkable. Similarly, biomarkers that are able to detect chronic allograft dysfunction in an early phase and those that can differentiate the true chronic rejection from other forms of non-immune related nephropathies are a subject of intense investigation. Identifying recipients at high risk of acute, chronic, or subclinical rejection with high level of sensitivity and specificity could go a long way in achieving long-term graft success.

This proposed Research Topic in Frontiers in Medicine on the topic of next generation biomarkers with focus on renal transplantation will provide a general assessment of the current applications and shortcomings of previously proposed biomarkers and an outline of the potential of precision medicine in transplantation. The Research Topic will specifically address diverse biomarkers and their usefulness in clinical practice. This will include biomarkers in chronic kidney disease, discovery of urinary biomarkers, discovery of protein biomarkers for renal diseases, precision transplant medicine, biomarkers as diagnostic tools in kidney transplantation, and recent advances in urinary proteome analysis and biomarker discovery. Further specific topics will address epitope matching to improve graft outcome, KSORT assays to detect acute cellular rejection, sMICA and MICA antibodies, new tool allograft survillance for biopsy pathology, and other similar topics. Noninvasive candidate biomarkers principally include mRNA transcripts, chemokines, lymphocyte phenotypes, microRNA (miRNA), and donor specific antibodies. Major challenges for clinical utility of biomarkers are validation due to known interindividual variations, sensitivity and specificity, predictive scores, and establishing technology platforms.