Understanding Donor-derived Cell-free DNA in Kidney Transplantation: An Overview and Case-based Guide for Clinicians

Abstract

Kidney transplant recipients undergo lifelong monitoring of allograft function and evaluation for transplant complications. The current monitoring paradigm utilizes blood, urine, and tissue markers that are insensitive, nonspecific, or invasive to obtain. As a result, problems are detected late, after significant damage has accrued, and often beyond the time at which complete resolution is possible. Indeed, most kidney transplants eventually fail, usually because of chronic rejection and other undetected injury. There is a clear need for a transplant-specific biomarker that enables a proactive approach to monitoring via early detection of reversible pathology. A biomarker that supports timely and personalized treatment would assist in achieving the ultimate goal of improving allograft survival and limiting therapeutic toxicity to the recipient. Donor-derived cell-free DNA (ddcfDNA) has been proposed as one such transplant biomarker. Although the test is presently utilized most in the United States, it is conceivable that its use will become more widespread. This review covers aspects of ddcfDNA that support informed use of the test by general nephrologists, including the basic biology of ddcfDNA, methodological nuances of testing, and general recommendations for use in the kidney transplant population. Clinical contexts are used to illustrate evidence-supported interpretation of ddcfDNA results and subsequent management. Finally, knowledge gaps and areas for further study are discussed.

Donor-Derived Cell-Free DNA for Kidney Allograft Surveillance after Conversion to Belatacept: Prospective Pilot Study

“…While in our study, a recurrent ABMR episode was detected by increase in creatinine and also led to increase of dd-cfDNA, other studies indicate that dd-cfDNA increases also can precede clinical rejection [ 25 ]. Due to its ability to detect vascular graft injury, dd-cfDNA is currently discussed as an activity marker in ABMR [ 26 ]. Therefore, increased dd-cfDNA could indicate underimmunosuppression and active rejection in patients with ABMR who undergo conversion to belatacept for concomitant CNI toxicity.…”

“…The rate of TCMR in our study was comparable to previous studies, although it is important to note that rejection frequency depends on time after transplantation and the proportion of patients with previous TCMR and ABMR [ 13 , 14 , 30 ]. TCMR episodes without vascular lesions are not reliably detected by plasma dd-cfDNA since inflammation occurs predominantly in the tubulointerstitial compartment [ 26 ]. This was shown exemplarily in our study, where an episode of low-grade TCMR (Banff IA) led to slight increase in relative dd-cfDNA but no increase in absolute dd-cfDNA.…”

Circulating donor-derived cell-free DNA as a marker for rejection after lung transplantation

“…In liver transplantation, dd-cell free DNA was elevated significantly after engrafting, followed by a steady decrease to 10% of total cfDNA after 1 week ( 41 ). Moreover, dd-cfDNA accounts for <0.5% of total plasma cell free DNA in renal transplantation recipients without allograft injury, and normal dd-cfDNA could reduce the probability of detecting rejection ( 42 ). Early diagnosis of subclinical rejection might improve the clinical prognosis.…”

Lessons From a Rare Randomized Controlled Trial of Immunosuppressant Management After Kidney Transplantation

“…That is a really important question for the field, especially since the move to noninvasive biomarkers relies upon comparison to a biopsy-driven gold standard-as exemplified by the recent studies of donor-derived cell-free DNA wherein the field remains hampered by lack of wellconstructed and powered RCT data. 5 The challenges associated with innovation using the current immunosuppressive strategies are thus substantial: traditional trials are hard to finance and complex to mount across multiple centers; there is a low tolerance of adverse events in the context of high rates of adverse events from standard of care; there is slow recruitment from hesitant patients not engaged in trial design; there are difficulties in achieving compliance to protocol, especially when interventions such as biopsies and multiple data points are needed; long-term interest and a true state of equipoise among the investigators must be maintained; and finally, journals provide substantial hurdles to rapid publication, such that it can take a year or more to achieve publication of a final manuscript. On the latter point, we can and will do better at Transplantation, by fast-tracking review of all randomized controlled clinical trials.…”

“…That is a really important question for the field, especially since the move to noninvasive biomarkers relies upon comparison to a biopsy-driven gold standard—as exemplified by the recent studies of donor-derived cell-free DNA wherein the field remains hampered by lack of well-constructed and powered RCT data. 5…”