The Landscape of Biomarkers in ICU ‐Associated AKI : From Protein Markers to Cell‐Free Nucleic Acids

Abstract

BACKGROUND: Acute kidney injury (AKI) affects approximately 30%-60% of intensive care unit (ICU) admissions, but early detection remains difficult because creatinine- and urine-output-based KDIGO criteria are delayed and confounded in critical illness. OBJECTIVE: To summarize the biomarker landscape for ICU-associated AKI, focusing on kidney-targeted injury/stress proteins and circulating cell-free DNA (cfDNA), including mitochondrial DNA (mtDNA). METHODS: PubMed/MEDLINE and Embase were searched from inception to December 31, 2025, using terms related to AKI, critical illness, NGAL, KIM-1, IL-18, L-FABP, [TIMP-2]·[IGFBP7], cfDNA, mtDNA, and damage-associated molecular patterns. Adult ICU studies reporting diagnostic performance, risk stratification, or clinically relevant outcomes were prioritized, especially in sepsis, cardiac surgery, shock, and trauma. RESULTS: NGAL, KIM-1, IL-18, L-FABP, and [TIMP-2]·[IGFBP7] often rise before creatinine or urine-output changes, providing early kidney-proximal signals of tubular injury or stress. cfDNA/mtDNA instead reflects systemic cell death, mitochondrial damage, and innate immune activation, capturing multi-organ injury and adding prognostic information beyond clinical scores and creatinine. Across ICU phenotypes, combining clinical risk, an early kidney-targeted marker, and cfDNA/mtDNA may improve identification of patients at risk for severe AKI, renal replacement therapy, and death. CONCLUSIONS: Multimarker strategies may widen the diagnostic window and sharpen prognostication in ICU-associated AKI. Routine implementation will require standardized pre-analytical handling, assay harmonization, biomarker-guided pragmatic trials, and trajectory-based decision tools that demonstrate clinical benefit.