Donor-derived cell-free DNA as a diagnostic tool in transplantation

Abstract

There is a need to improve personalized immunosuppression in organ transplantation to reduce premature graft loss. Biomarkers are needed to better detect rejection, asymptomatic graft injury, and under-immunosuppression. Assessment of minimal necessary exposure to guide tapering and prevent immune activation is also important. There is robust clinical evidence from a large number of published studies supporting the role of dd-cfDNA for monitoring graft integrity and detection or exclusion of rejection. Dd-cfDNA indicates graft cell death without being rejection specific. It can be determined in plasma through droplet digital PCR using preselected SNPs or next generation sequencing. Changes in recipient cfDNA (e.g., by infection) can affect the results of dd-cfDNA fractional determination. This limitation can be overcome using absolute dd-cfDNA quantification. The combination of fractional and absolute determination including total cfDNA is recommended for meaningful interpretation of the results. The value proposition for the patient includes earlier transplant injury detection and intervention, less full blown rejection risk, an alternative to invasive biopsies, and personalized immunosuppression with potential for improved long-term outcome. Transplant physicians benefit from better immunosuppressive guidance and having an alternative when biopsies are refused or contraindicated. Further advantages are improved biopsy interpretation, less trial and error changes in immunosuppression, and less time dealing with complications. The laboratory medicine specialist can provide more effective services. Hospital management and insurance companies could benefit from more cost-effective surveillance of transplant recipients. Potential cost savings would result from fewer biopsies as a result of the tests’ high negative predictive value, fewer re-transplantations, and less organ failure with return to dialysis. A pathway to implementation and metrics is suggested to measure the effectiveness of dd-cfDNA testing.

Immature and activated phenotype of blood NK cells is associated with acute rejection in adult liver transplant

“…[48][49][50] However, as a product of allograft injury, the ddcfDNA is not rejection specific, its elevations can also be observed due to other causes, such as ischemia, trauma, and infection. [51] In renal transplantation, to achieve accurate detection of the alloresponse resulting in graft damage and benefit the individualized IS, the ddcfDNA is being tested in combination with other immunological strategies, including HLA epitope donor matching, T cell receptor sequencing, deep cytometric phenotyping of immune cell subsets, and routine DSA monitoring. Thus, with the potential of screening patients with a high risk of AR preoperative, the peripheral blood NK-cell expression can be combined with ddcfDNA to improve the accuracy of early diagnosis of LTx AR.…”

When performance is not enough—A multidisciplinary view on clinical decision support

“…pharmaceutical industry, physicians, patients) and the targeted medical domain. In the area of kidney transplantation, which we are studying in this article, physicians use a combination of demographic, clinical (including microbiological and medical imaging), and mostly laboratory data to implicitly risk stratify patients according to their risk for rejection, infection, and graft loss and to adapt the immunosuppressive treatment accordingly [ 9 ].…”

Monitoring of Serological, Cellular and Genomic Biomarkers in Transplantation, Computational Prediction Models and Role of Cell-Free DNA in Transplant Outcome

“…The process and evolution of an organ transplant procedure has evolved in the prevention of immunological rejection with the improvement in the determination of immune-response genes, including more important genes, more polymorphism detection, more refinement of the response motifs, the analysis of epitopes and eplets, and PIRCHE (predict indirectly recognizable HLA epitopes). These advancements are capable of fixing complements and post-transplant monitoring with promising new biomarkers [ 1 , 2 , 3 ] and surpassing the classic serum markers, such as creatine and other similar parameters of organ function [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ].…”