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Cited by 80Acute Kidney Injury ResearchNephrotoxicity and Medicinal PlantsRenal Diseases and Glomerulopathies

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

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Moledina, Dennis G., Obeid, Wassim, Smith, Rex N., Rosales, Ivy, Sise, Meghan E., Moeckel, Gilbert, Kashgarian, Michael, Kuperman, Michael +11 more·2023·Journal of Clinical Investigation
DOI 10.1172/jci168950PMC PMC10313360
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Abstract

BackgroundAcute 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.MethodsIn a prospectively enrolled cohort with pathologist-adjudicated histological diagnoses, termed the discovery cohort, we tested the association of 180 immune proteins measured by an aptamer-based 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.ResultsIn aptamer-based 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).ConclusionWe identified CXCL9 as a diagnostic biomarker for AIN using aptamer-based 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.FundingThis 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.

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  • Moledina et al. observed higher levels of urinary CXCL9, IL-9 and TNF-α in patients with AIN.

    “Despite the findings of Moledina et al. [60, 62, 94], who observed a higher level of urinary C-X-C motif ligand 9 (CXCL9), interleukin-9 (IL-9) and tumor necrosis factor-α (TNF-α) levels in patients with AIN”

    From The diagnosis of acute interstitial nephritis caused by infection versus antibiotic-induced interstitial nephritis: a narrative review (2024) · cites this paper as [62]

    The Results section on urine proteomics reports higher urinary CXCL9 and TNF-α in patients with AIN than in controls. The Introduction says urinary IL-9 differentiated patients with AIN from controls, but our copy does not state that IL-9 levels were higher in the AIN group. Page numbers were not available in the indexed passages. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Moledina et al. observed a higher level of CCL3 in patients with AIN compared with the control group.

    “For instance, Moledina et al. [62] observed a higher level of the major eosinophilic attractant C-C motif ligand 3 (CCL3) in patients with AIN compared with the control group.”

    From The diagnosis of acute interstitial nephritis caused by infection versus antibiotic-induced interstitial nephritis: a narrative review (2024) · cites this paper as Moledina et al. [62]

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Authors
Moledina, D. G., Obeid, W., Smith, R. N., Rosales, I., Sise, M. E., Moeckel, G., Kashgarian, M., Kuperman, M., Campbell, K. N., Lefferts, S., Meliambro, K., Bitzer, M., Perazella, M. A., Luciano, R. L., Pober, J. S., Cantley, L. G., Colvin, R. B., Wilson, F. P., & Parikh, C. R.
Affiliations
  • Yale University (US)
  • Johns Hopkins University (US)
  • Harvard University (US)
  • Massachusetts General Hospital (US)
  • Arkana Laboratories (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • University of Michigan (US)
Corresponding author
  • Moledina, Dennis G.
  • Parikh, Chirag R.
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2023-07-03
Volume
133
Issue
13
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci168950
PMC
PMC10313360
OpenAlex
W4382893775
Cited by
80
References
4
Citations by year
2026: 18 · 2025: 26 · 2024: 30 · 2023: 6
FWCI
15.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Clinical Investigation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (K23DK117065,K08DK113281,R01DK128087,R01DK126815,R01DK126477,UH3DK114866,R01DK130839,P30DK079310)
Topics
  • Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Nephrotoxicity and Medicinal Plants
  • Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
Keywords
acute interstitial nephritis, diagnostic biomarkers, acute kidney injury, chemokines, interferon-gamma, renal biopsy, non-invasive diagnosis, lymphocyte chemotaxis, external validation, discovery cohort, validation cohort, sandwich immunoassay
MeSH terms
Humans, Kidney, Nephritis, Interstitial, RNA, Messenger, Biomarkers, Chemokine CXCL9

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