The NGAL-mortality association in acute brain injury includes a significant direct effect not mediated through AKI, implying that NGAL elevation reflects systemic innate immune activation rather than impending renal dysfunction.
High serum NGAL at admission was independently associated with in-hospital mortality in acute brain injury patients.
High NGAL was associated with ICU mortality, 6-month mortality, and worse functional outcomes in addition to in-hospital mortality.
Causal mediation analysis revealed that the majority of NGAL's mortality effect in acute brain injury operates through a direct pathway not mediated by acute kidney injury.
Admission NGAL levels correlated with subsequent 72-hour systemic inflammatory burden.
NGAL is a neutrophil granule protein released during innate immune activation, a process central to acute brain injury pathophysiology, which may explain its AKI-independent mortality association.
The study used a prospective cohort design enrolling adults with four distinct types of acute brain injury admitted to a neurocritical care unit.
This research suggests that a protein called NGAL (neutrophil gelatinase-associated lipocalin), measured in the blood shortly after a patient is admitted with a serious brain injury, is a strong predictor of death. Historically, doctors have interpreted high NGAL levels as a warning sign of kidney damage (acute kidney injury, or AKI), which is itself a known complication that worsens outcomes. However, this study found that NGAL's link to mortality in brain injury patients is mostly explained by pathways that have nothing to do with kidney injury — instead, high NGAL appears to reflect widespread activation of the body's immune system (innate immune activation). The researchers studied 274 patients with various types of acute brain injury — including strokes, brain bleeds, and traumatic brain injuries — and used advanced statistical methods (causal mediation analysis) to separate NGAL's effect into two parts: the portion that works through kidney injury and the portion that does not. The direct, non-kidney-related effect was statistically significant, while the kidney-mediated effect was not. They also found that high NGAL levels at admission correlated with elevated inflammatory markers (including interleukin-6) in the days that followed, further supporting the idea that NGAL is tracking immune system activity rather than kidney function alone. This research suggests that clinicians caring for brain injury patients should not interpret a high NGAL reading solely as a kidney problem. Instead, elevated NGAL may signal a broader systemic inflammatory response that independently drives poor outcomes. This could have implications for how brain injury patients are monitored and may point toward inflammation as a therapeutic target, though further research would be needed to confirm and extend these findings.
Guk H, Kim Y, Kang D, Han S, Kim M, Han M, et al.. (2026). Beyond Acute Kidney Injury : Direct Pathways Implicate Inflammatory Mechanisms in Serum NGAL's Mortality Effect in Acute Brain Injury.. Translational stroke research. https://doi.org/10.1007/s12975-026-01489-8