Development and validation of an optimized integrative model using urinary chemokines for noninvasive diagnosis of acute allograft rejection.

The urinary chemokines CXCL9 and CXCL10 are promising noninvasive diagnostic markers of acute rejection (AR) in kidney recipients, but their levels might be confounded by urinary tract infection (UTI) and BK-virus reactivation. Multiparametric model development and validation addressed these confounding factors in a training set of 391 samples, optimizing the diagnostic performance of urinary chemokines. CXCL9/creatinine increased in UTI and BKV viremia with or without nephropathy (BKVN) (no UTI/leukocyturia/UTI: -0.10/1.61/2.09, P=0.0001 and no BKV/viremia/BKVN: -0.10/1.90/2.29, P<0.001) as well as CXCL10/creatinine (1.17/2.09/1.98, P<0.0001 and 1.13/2.21/2.51, P<0.001, respectively). An optimized 8-parameter model (recipient age, sex, eGFR, DSAs, UTI, BKV blood viral load, CXCL9 and CXCL10) diagnosed AR with high accuracy (AUC: 0.85, 95% CI: 0.80-0.89) and remained highly accurate at the time of screening (AUC: 0.81, 95% CI: 0.48-1) or indication biopsies (AUC: 0.85, 95% CI: 0.81-0.90) and within the first year (AUC: 0.86, 95% CI: 0.80-0.91) or later (AUC: 0.90, 95% CI: 0.84-0.96), achieving AR diagnosis with an AUC of 0.85 and 0.92 (P<0.0001) in two external validation cohorts. Decision curve analyses demonstrated the clinical utility of the model. Considering confounding factors rather than excluding them, we optimized a noninvasive multiparametric diagnostic model for AR of kidney allografts with unprecedented accuracy.