Cell-Free Dna To Monitor Immunosuppression Adequacy In Lung Transplantation

PurposeTacrolimus 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.Methods96 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).ResultsOver 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<0.0001) (Figure 1b). 27% of patients experienced at least one episode of ACR. During the study follow-up, their %ddcfDNA levels were higher (p=0.049) and their percentage of non-therapeutic trough levels was higher (p=0.006) compared to patients with no ACR. However, even when tacrolimus trough levels were therapeutic, patients with ACR showed higher %ddcfDNA levels compared to patients without ACR (p=0.020).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. 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. 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). 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<0.0001) (Figure 1b). 27% of patients experienced at least one episode of ACR. During the study follow-up, their %ddcfDNA levels were higher (p=0.049) and their percentage of non-therapeutic trough levels was higher (p=0.006) compared to patients with no ACR. However, even when tacrolimus trough levels were therapeutic, patients with ACR showed higher %ddcfDNA levels compared to patients without ACR (p=0.020). %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.