Urine Test Biomarker Allows Diagnosis Without Kidney Biopsy

Nancy A. Melville

July 31, 2023

Patients with acute tubulointerstitial nephritis (AIN), a difficult-to-diagnose allergic reaction in the kidneys, show substantial increases in the protein CXCL9 in their urine, suggesting an essential, fast, and easy-to-test biomarker that could replace the more time-consuming kidney biopsy.

"Our data show that in patients with suspected AIN the urine biomarker CXCL9 can significantly improve clinical care by helping to rule in or rule out the disease in a large subset of patients, and kidney biopsy can be reserved for a narrower subset in whom biomarker values are equivocal," report the authors, from Johns Hopkins Medicine in collaboration with the Yale School of Medicine, in research recently published online in the Journal of Clinical Investigation.

AIN, which causes inflammation of the kidney that can potentially lead to acute kidney injury (AKI), is believed to be linked to an allergic reaction to common medications used to treat gastroesophageal reflux disease, bacterial infections, and cancer.

Although the condition can be treated through withdrawal of the suspected drugs and administration of corticosteroid therapy, a major challenge is differentiating AIN from other causes of AKI, as most patients with AIN have no disease-specific signs or symptoms, and currently available diagnostic tests have poor accuracy.

Consequently, a kidney biopsy is often needed, adding risks as well as delays in care, and, in fact, as many as half of patients suffer significant, permanent kidney damage after an episode of AIN, often due, in part, to delayed diagnosis, the authors note.

To avoid those delays, clinicians will often simply assume AIN is the cause rather than go through the risks of a kidney biopsy and move ahead with withdrawing drugs suspected to be the culprits and administering corticosteroid therapy to prevent AKI.

However, if a patient does not indeed have AIN, that course of action can have critical consequences, by discontinuing potentially life-saving medications while introducing the various risks of corticosteroids, which can include hyperglycemia, bone loss, gastrointestinal hemorrhage, and infection.

To try to identify a biomarker that could provide a better means for accurately diagnosing AIN, senior author Chirag Parikh, MBBS, PhD, director of the Division of Nephrology at Johns Hopkins Medicine, in Baltimore, Maryland, and colleagues tested the urine of 204 hospital patients with AKI and evaluated 180 potential biomarkers before validating CXCL9 as a top protein.

Of the patients, 15% were diagnosed with AIN on histology, and among them, levels of urinary CXCL9 were 7.6-fold higher than patients without AIN (P = 1.23 x 10–5). In a further analysis using sandwich immunoassays, the adjusted odds ratio was 6.0 for the highest versus lowest quartiles of CXCL9.

In an additional analysis, the expression of CXCL9 mRNA was 3.9-fold higher in kidney tissue from 19 patients with AIN compared to 52 individuals in the control group (P = 5.8 x 10–6).

The association between AIN and CXCL9 was consistent, regardless of the criteria used to define AIN.

In helping to differentiate from common alternative diagnoses, median CXCL9 levels were as much as eightfold higher in patients with AIN compared with patients with acute tubular injury (60.3 vs 7.7 ng/g; P = .0001).

Of note, CXCL9 is an interferon (IFN)-γ-induced chemokine, but no significant differences were observed between other IFN-γ-induced chemokines, CXCL10, and CXCL11, among patients with AIN and those in the control group.

The previously identified biomarker TNF-α was found to be 2.5-fold higher in participants with AIN than in the control group (P = 1.37 x 10–4), and IL-9 has also been linked to AIN.

Ultimately, the authors conclude that CXCL9, along with TNF-α and IL-9, represent "the optimal combination of biomarkers for AIN diagnosis."

"The future development of clinically useful assays for detection of these biomarkers in urine samples may prospectively assess the utility of biomarker information for prognostication of clinical outcomes," the authors write.

Parikh and co-author Dennis Moledina are co-inventors on a pending patent for a new CXCL9 assay and founders of the company Predict AIN.

J Clin Invest. Published July 3, 2023. Full text

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