Molecular immune monitoring in kidney transplant rejection: a state-of-the-art review

Abstract

Although current regimens of immunosuppressive drugs are effective in renal transplant recipients, long-term renal allograft outcomes remain suboptimal. For many years, the diagnosis of renal allograft rejection and of several causes of renal allograft dysfunction, such as chronic subclinical inflammation and infection, was mostly based on renal allograft biopsy, which is not only invasive but also possibly performed too late for proper management. In addition, certain allograft dysfunctions are difficult to differentiate from renal histology due to their similar pathogenesis and immune responses. As such, non-invasive assays and biomarkers may be more beneficial than conventional renal biopsy for enhancing graft survival and optimizing immunosuppressive drug regimens during long-term care. This paper discusses recent biomarker candidates, including donor-derived cell-free DNA, transcriptomics, microRNAs, exosomes (or other extracellular vesicles), urine chemokines, and nucleosomes, that show high potential for clinical use in determining the prognosis of long-term outcomes of kidney transplantation, along with their limitations.

Keywords: MicroRNAs; chemokine; donor-derived cell-free DNA; exosomes; extracellular vesicles; molecular immune monitoring; nucleosome; transcriptomics.

Figure 1

The illustration of renal allograft rejection and the application of biomolecular biomarkers from immunological pathogenesis. While the main pathogenesis of acute cellular mediated rejection (TCMR) is epithelial cell injury enhancement leading to adaptive immune system amplification, acute antibody-mediated rejection (AMR) is endothelial cell injury through antibody and complement enhancement. As a result, the culprit pathologic characteristic of TCMR is tubulitis compared to glomerulitis and peritubular capillaritis in AMR. Both patterns can be concurrently found in severe combined TCMR and AMR case. During renal allograft rejection process, both innate and adaptive immune system are activated from the imbalance differentiation between donor and recipient cell-free deoxyribonucleic acid (cfDNA) molecules ❶ (left panel). The final products of both T cell and B cell activation can be detected their signals and cellular origin of either peripheral blood or renal allograft tissue by transcriptomic profiles ❷. Indeed, plenty of mediators are produced during overwhelming inflammatory process from both TCMR and AMR, including the production of miRNAs ❸ within extracellular vesicles and exosomes ❹, and soluble mediators (cytokines and chemokines) ❺. Interestingly, the epigenetic control of gene expression by circulating cell-free nucleosome may play as a crucial step of renal allograft rejection activation ❻. Imbalance between donor- and recipient-derived nucleosomes with histone alteration is currently postulated as one of pathogenesis in renal allograft rejection. ICAM, intracellular adhesion molecule; IL, interleukin; MHC, major histocompatibility complex; VCAM, vascular cell adhesion molecule; TNF, tumor necrosis factor. Picture is created by BioRender.com.