Urinary C-X-C-motif ligand 9 (CXCL9) in immune checkpoint inhibitor-associated acute interstitial nephritis

Immune checkpoint inhibitor-associated acute interstitial nephritis presents significant clinical challenges. There are no reliable non-invasive biomarkers and kidney biopsy remains the gold standard for diagnosis. Prior studies have shown that urinary C-X-C-motif ligand 9 (CXCL9) is upregulated in patients with acute interstitial nephritis. However, its utility, specifically in patients with cancer treated with immune checkpoint inhibitors, is not well-understood.

We used proteomics followed by sandwich immunoassay to analyze urinary proteins among a multicenter cohort of prospectively enrolled participants with and without immune checkpoint inhibitor-associated acute interstitial nephritis.

Among 79 participants receiving immune checkpoint inhibitors, proteomics identified urine CXCL9 as the top-performing urinary biomarker differentiating 38 patients with biopsy-proven acute interstitial nephritis from other forms of acute kidney injury. We validated these results using immunoassay in an expanded cohort of 116 patients, observing higher CXCL9 levels in immune checkpoint inhibitor-associated acute interstitial nephritis compared to several control groups. Urinary CXCL9 was strongly associated with immune checkpoint inhibitor-associated acute interstitial nephritis, with a receiver operating characteristic curve of 0.84, interquartile range [0.74, 0.93] when compared to other forms of acute kidney injury, and an even higher discrimination when compared with all control groups (0.90, [0.83-0.96]).

Urinary CXCL9 demonstrated high discrimination for differentiating acute interstitial nephritis from other forms of acute kidney injury in participants on immune checkpoint inhibitor therapy. Our findings demonstrate the significant potential of this biomarker for non-invasive diagnosis of immune checkpoint inhibitor-associated acute interstitial nephritis.