Identification and validation of urinary CXCL9 as a biomarker for diagnosis of acute interstitial nephritis

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Abstract

Background Acute tubulointerstitial nephritis (AIN) is one of the few causes of acute kidney injury with diagnosis-specific treatment options. However, due to the need to obtain a kidney biopsy for histological confirmation, AIN diagnosis can be delayed, missed, or incorrectly assumed. Here, we identify and validate urinary CXCL9, an IFN-γ-induced chemokine involved in lymphocyte chemotaxis, as a diagnostic biomarker for AIN.Methods In a prospectively enrolled cohort with pathologist-adjudicated histological diagnoses, termed the discovery cohort, we tested the association of 180 immune proteins measured by a proximity extension assay with AIN and validated the top protein, CXCL9, using sandwich immunoassay. We externally validated these findings in 2 cohorts with biopsy-confirmed diagnoses, termed the validation cohorts, and examined mRNA expression differences in kidney tissue from patients with AIN and individuals in the control group.Results In a proximity extension assay, urinary CXCL9 was 7.6-fold higher in patients with AIN than in individuals in the control group (P = 1.23 × 10–5). Urinary CXCL9 measured by sandwich immunoassay was associated with AIN in the discovery cohort (n = 204; 15% AIN) independently of currently available clinical tests for AIN (adjusted odds ratio for highest versus lowest quartile: 6.0 [1.8–20]). Similar findings were noted in external validation cohorts, where CXCL9 had an AUC of 0.94 (0.86–1.00) for AIN diagnosis. CXCL9 mRNA expression was 3.9-fold higher in kidney tissue from patients with AIN (n = 19) compared with individuals in the control group (n = 52; P = 5.8 × 10–6).Conclusion We identified CXCL9 as a diagnostic biomarker for AIN using proximity extension urine proteomics, confirmed this association using sandwich immunoassays in discovery and external validation cohorts, and observed higher expression of this protein in kidney biopsies from patients with AIN.Funding This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) awards K23DK117065 (DGM), K08DK113281 (KM), R01DK128087 (DGM), R01DK126815 (DGM and LGC), R01DK126477 (KNC), UH3DK114866 (CRP, DGM, and FPW), R01DK130839 (MES), and P30DK079310 (the Yale O’Brien Center). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Authors

Dennis G. Moledina, Wassim Obeid, Rex N. Smith, Ivy Rosales, Meghan E. Sise, Gilbert Moeckel, Michael Kashgarian, Michael Kuperman, Kirk N. Campbell, Sean Lefferts, Kristin Meliambro, Markus Bitzer, Mark A. Perazella, Randy L. Luciano, Jordan S. Pober, Lloyd G. Cantley, Robert B. Colvin, F. Perry Wilson, Chirag R. Parikh