Hypoxia-Responsive Artificial Urinary Biomarker Probe for Early Detection of Drug-Induced Acute Kidney Injury

Drug-induced acute kidney injury (AKI), associated with high morbidity and mortality, remains challenging to diagnose in clinical settings and is inadequately assessed during drug discovery due to its reliance on insensitive late-stage blood and urinary biomarkers. Herein, we report a hypoxia-responsive artificial urinary biomarker probe (NCD) for the noninvasive urinalysis-based detection of drug-induced AKI. NCD demonstrates sensitive and specific fluorescence enhancement in response to nitroreductase (NTR), which is overexpressed under hypoxia─an early pathological event that is detectable earlier than the elevation of kidney injury molecule-1, activation of cellular apoptosis, renal functional decline, and tissue damage in drug-induced AKI. Owing to its high renal clearance efficiency (>90% of the injected dose within 24 h), NCD detects elevated NTR levels as early as 6 h after cisplatin induction, as evidenced by a significantly intensified urinary fluorescence signal that can be directly visualized using a hand-held fluorometer. Although the visible-light emission of the probe limits its applicability for direct in vivo imaging, this property is highly advantageous for its use as an artificial urinary biomarker probe in ex vivo urine detection, where signal changes are visually discernible. Notably, this urinalysis-based approach enables noninvasive detection and advances the diagnostic window by at least 18 h compared to the conventional clinical assays, highlighting its significant potential for early AKI diagnosis.