Discussion
ABMR, allograft dysfunction, TCMR, acute injury or atrophy fibrosis
BLOOM, HILDENBRAND
In this prospective study, we assessed the diagnostic usefulness of dd-cfDNA in a cohort of German kidney transplant recipients with indication biopsy. We found that dd-cfDNA levels were significantly higher in patients with active rejection compared to patients with no rejection. dd-cfDNA discriminated active rejection (including borderline changes diagnosed during allograft dysfunction) from no rejection with an AUC of 0.72. This is in line with results of Bloom et al. who validated dd-cfDNA in the DART study and found an AUC of 0.74 to discriminate between biopsy showing any rejection (ABMR or TCMR) vs. no histopathological signs of rejection [Next, we identified that a dd-cfDNA level of 0.57% was best to distinguish rejection (including borderline changes) from no rejection, yielding a specificity of 81%, a sensitivity of 53%, a PPV of 58%, and an NPV of 77%. The cutoffs ≥1.0% and ≥0.74%, as suggested by Bloom et al. [On the contrary, 8/24 (33%) patients with dd-cfDNA levels of ≥1% had no histopathological signs of rejection but other causes of graft injury, such as ATI, BKVAN, IFTA, or CNI-Toxicity. Regarding higher levels of dd-cfDNA in patients with no molecular or histologic rejection, Halloran et al. argued that dd-cfDNA may also be released if parenchymal injury is present, such as in acute injury or atrophy fibrosis [Another potential benefit of dd-cfDNA lies in its ability to identify patients with rejection in whom injury does not resolve upon corticosteroid pulse therapy, warranting closer monitoring, re-biopsies, and possibly more aggressive therapeutic interventions. This hypothesis is supported by Stites et al. who found that higher levels of dd-cfDNA identified patients with TCMR 1A rejection and borderline changes with more unfavorable clinical outcomes, such as eGFR decline, In addition to helping the clinician to identify patients at risk for rejection or with severe injury, dd-cfDNA may also be of use to assess response to therapy. In agreement with the findings of Wolf-Doty et al. and Hinojosa et al., we observed decreasing levels of dd-cfDNA in patients receiving anti-rejection therapy [Another limitation of our study is the relatively small number of cases with ABMR (In conclusion, our prospectively designed study verified the good performance of dd-cfDNA to discriminate kidney transplant recipients with active rejection, particularly patients with ABMR, from those with histopathological findings other than rejection. Based on our results, we hypothesize that dd-cfDNA may aid the clinician in monitoring patients at risk, for example, those with We thank Tina Hildenbrand, Evelina Kudlek, and Verena Backendorf at the Department of Immunology for their technical support. The graphical abstract was composed using icons from 