Beyond Acute Kidney Injury : Direct Pathways Implicate Inflammatory Mechanisms in Serum NGAL's Mortality Effect in...

Neutrophil gelatinase-associated lipocalin (NGAL) is associated with mortality in critically ill patients, conventionally attributed to its role in acute kidney injury (AKI) detection. However, NGAL is a neutrophil granule protein released during innate immune activation-a process central to acute brain injury (ABI) pathophysiology. Whether the association between NGAL and mortality in neurocritical care operates through AKI-mediated or alternative pathways has not been evaluated. In this prospective cohort of 274 adults with ABI (98 intracerebral hemorrhage, 60 ischemic stroke, 46 subarachnoid hemorrhage, 70 traumatic brain injury) admitted to a neurocritical care unit, serum NGAL was measured within 24 h of admission. Causal mediation analysis with time-varying AKI status decomposed NGAL's mortality effect into direct and AKI-mediated components. High NGAL (≥ 150 ng/mL) was independently associated with in-hospital mortality (adjusted hazard ratio [aHR] 2.94, 95% confidence interval [CI] 1.57-5.51; absolute risk difference 15.0% at 28 days), ICU mortality, 6-month mortality, and worse functional outcomes. Pathway decomposition revealed a significant direct effect not mediated through AKI (aHR 2.15, 95% CI 1.04-4.62, P=.04), whereas the AKI-mediated component was not significant (P=.33). Effects were consistent across injury types. Admission NGAL correlated with subsequent 72-hour systemic inflammatory burden (Spearman ρ = 0.38, P<.001), and within-subject NGAL and interleukin-6 showed concordant temporal trajectories (repeated-measures r = .29, P<.001). These findings indicate that the NGAL-mortality association in ABI includes a significant direct effect not mediated through AKI, implying that NGAL elevation reflects systemic innate immune activation rather than impending renal dysfunction.