On the relative relevance of donor-derived cell-free DNA and urinary chemokines as noninvasive biomarkers for the diagnosis of kidney allograft rejection

Donor-derived cell-free deoxyribonucleic acid (DNA) (dd-cfDNA) and urinary chemokines are promising noninvasive biomarkers for kidney allograft rejection, but direct comparative data are lacking. In this prospective pilot study, we analyzed 194 biopsies (101 for-cause, 93 surveillance) paired with dd-cfDNA and urinary chemokine (CXCL9, CXCL10, CCL2, VEGF-A) concentrations in kidney transplant recipients. We evaluated their correlation, diagnostic accuracy for rejection phenotypes, and integration into diagnostic models with clinical and immunologic variables. Rejection was diagnosed in 32.5% of biopsies, predominantly antibody-mediated. dd-cfDNA showed strong diagnostic performance in both for-cause (area under the receiver operating characteristic curve [AUC] 0.85) and surveillance (AUC 0.91) biopsies. Conversely, urinary chemokines, particularly the composite Score4, showed accuracy mainly in for-cause biopsies (AUC 0.76). Remarkably, Score4 combined with donor-specific antibodies showed similar performance as dd-cfDNA + donor-specific antibodies (AUC 0.90) in for-cause biopsies. Internal bootstrap validation, including calibration metrics, confirmed the consistency of the models. dd-cfDNA provides robust diagnostic accuracy for kidney allograft rejection across distinct clinical settings. Urinary chemokine measures, especially Score4, may offer valuable diagnostic utility in for-cause biopsies. These findings support context-specific integration of noninvasive biomarkers and represent the first direct comparison of dd-cfDNA and urinary chemokines, informing personalized approaches to rejection monitoring.