Donor-derived cell-free DNA (dd-cfDNA) is a widely used biomarker in kidney transplantation, reported mainly as either percentage of total cfDNA or copies/mL. We hypothesized that combining both metrics into a continuous composite score would reduce false classifications thus improving the accuracy of rejection diagnosis. We analyzed 443 dd-cfDNA measurements in 361 patients from five independent kidney transplant cohorts with both percentage and copies/mL. A random discovery set of 25 biopsy-proven rejections and 26 non-rejections was used to derive a composite score (CM-Score), integrating dd-cfDNA (%) and copies/mL. Diagnostic performance was validated in 81 rejections and 282 non-rejections and compared to 11 published cohorts. For all evaluations, CM-Score was better than dd-cfDNA in copies/mL, which was better than dd-cfDNA in percent. The CM-Score retained a high NPV of 91% (89–93%), while significantly improving PPV to 81% (72–89%; P<0.0001, prevalence: 25%), compared to published values (weighted average NPV: 90% (89–92%); PPV: 54% (52–55%), N=6,536). Decision curve analysis yielded a significantly higher net benefit for the CM-Score (P<0.003). The dd-cfDNA CM-Score is a robust and clinically meaningful tool improving diagnostic accuracy for ruling-out and ruling-in rejection using dd-cfDNA as stand-alone metric with high potential to improve decision-making in kidney transplantation.
Benning et al. (Mon,) studied this question.