Urinary CXCL-9 Outperforms TNF-α for Non-invasive Diagnosis of Immune Checkpoint Inhibitor-Associated Acute Interstitial Nephritis

Abstract Background and hypothesis Although kidney biopsy remains the gold standard for diagnosing immune checkpoint inhibitors-associated acute interstitial nephritis (ICI-AIN), several promising urinary biomarkers have emerged as potential non-invasive diagnostics. Notably, recent studies have highlighted tumor necrosis factor alpha (TNF-α), CXC motif chemokine ligand 9 (CXCL-9) and others as potential biomarkers to help distinguish ICI-AIN from other causes of acute kidney injury (AKI). However, a direct systematic comparison between these two biomarkers in a cohort of patients undergoing immunotherapy has not been performed. Methods We prospectively enrolled a cohort of ICI-treated cancer patients who developed AKI (including both ICI-AIN and ICI-Non-AIN AKI), as well as those without AKI, referred to as the internal validation cohort. Urinary CXCL-9 and TNF-α were measured across all groups using the human Quantikine ELISA Kit. We externally validated our findings in a cohort of biopsy proven ICI-AIN patients from Spain, referred to as the external validation cohort. Results Urinary CXCL-9 levels were significantly higher in ICI-AIN patients from Mayo (n=40) compared to those with ICI-Non-AIN AKI (n=36) and ICI-treated patients without AKI (n=16) (both p≤0.0001), these findings were confirmed in the validation cohort from Spain (n=19) with p-values of 0.0008 and 0.0001, respectively. The area under the curve (AUC) for urinary CXCL-9 distinguishing ICI-AIN biopsy proven (combined from both cohorts, n= 45) from ICI-Non-AIN AKI was 0.83 (95% CI: 0.74-0.92), while for urinary TNF-α the AUC was 0.63 (95% CI: 0.51-0.75). Conclusions Increased urinary CXCL-9 was superior to TNF-α as a biomarker for the non-invasive diagnosis of ICI-AIN, even after prior corticosteroid exposure, highlighting its promise as clinical diagnostic tool.