Cell-Free DNA to Monitor Immunosuppression Adequacy in Lung Transplantation

Purpose Tacrolimus is a primary immunosuppressive drug used in lung transplantation (LTx). Unfortunately, significant variability in drug level monitoring and dosing makes it challenging to determine immunosuppression adequacy. Furthermore, the relationship between drug levels and allograft injury remain poorly defined. This study examines the relationship between tacrolimus blood and donor-derived cell-free DNA (ddcfDNA), a biomarker of allograft injury. Methods 96 LTx from a multicenter cohort were included. Periodic tacrolimus blood levels (n= 4,204) were obtained. Serial plasma samples (n=2,122) were assayed for %ddcfDNA by shotgun sequencing. %ddcfDNA was log-transformed to adjust for skewness. Tacrolimus trough levels were dichotomized to “therapeutic” and “non-therapeutic” based on clinically desirable trough ranges. Tacrolimus trough and %ddcfDNA trends were analyzed. Separate analysis was performed in patients with and without ACR (> Grade 1 per ISHLT criteria). Results Over a 24-month follow up period, %ddcfDNA showed an inverse relationship to tacrolimus tough levels (Figure 1a); patients showed higher %ddcfDNA with non-therapeutic tacrolimus trough levels than with therapeutic levels (p Conclusion %ddcfDNA levels vary inversely with tacrolimus blood trough levels in LTx. Even in patients with therapeutic trough levels, those with ACR demonstrate higher %ddcfDNA levels. Further studies should examine whether sensitive biomarkers such as ddcfDNA can be used to augment immunosuppression monitoring in LTx rather than trough levels alone.