Detection of Kidney Allograft Rejection Using Urinary Chemokines

KEY POINTS: Urinary C-X-C motif ligand 9 demonstrated moderate clinical utility beyond standard-of-care monitoring in detecting overall allograft rejection. Urinary C-X-C motif ligand 10 did not show additional value in detecting overall allograft rejection beyond standard-of-care monitoring. In sensitivity analyses limited to acute/active rejection and single biopsies per patient, urinary C-X-C motif ligand 9 and C-X-C motif ligand 10 showed no added value. BACKGROUND: Urinary chemokines C-X-C motif ligand 9 (CXCL9) and C-X-C motif ligand 10 (CXCL10) have shown promise for detecting kidney allograft rejection, but the demonstration of their added value beyond standard-of-care patient monitoring requires further study. METHODS: We prospectively enrolled adult patients who underwent kidney transplantation in seven transplant referral centers between July 2018 and December 2019 (ClinicalTrials.gov, NCT03582436 ). We quantified urinary CXCL9 and CXCL10 protein levels at the time of kidney allograft biopsies in the first year post-transplantation using an automated immunoassay platform. The primary outcome was allograft rejection defined according to the international Banff 2019 classification. RESULTS: Overall, 733 kidney transplant patients (64% male, 36% female) were included in the main analysis, with 1549 biopsies paired with a urine sample. The cumulative incidence of rejection was 10%. For detecting allograft rejection, urinary CXCL9 and CXCL10 demonstrated areas under the receiver operating characteristic curve (AUROC) of 0.70 (95% confidence interval CI, 0.64 to 0.75) and 0.64 (95% CI, 0.58 to 0.71), respectively. Adding urinary CXCL9 to a standard-of-care model improved discrimination for allograft rejection (AUROC 0.75 percentile bootstrap CI, 0.70 to 0.79 to 0.78 percentile bootstrap CI, 0.73 to 0.83), while urinary CXCL10 did not. There was no improvement of overall fit with the addition of urinary CXCL9 (Brier score changed from 0.056 95% CI, 0.046 to 0.067 to 0.054 95% CI, 0.045 to 0.064), as this tended to overestimate the risk for allograft rejection. In sensitivity analyses restricting to only acute/active forms of rejection or to a single randomly selected biopsy per patient, urinary chemokines did not show additional value beyond the standard of care. In addition, existing chemokine-based models showed low-to-moderate performance for the detection of allograft rejection. CONCLUSIONS: Urinary CXCL9 demonstrated limited clinical utility, while urinary CXCL10 provided no additional value beyond standard-of-care monitoring for detecting allograft rejection within the first year after kidney transplantation. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov, NCT03582436 .