This study aimed to compare and analyse the NGAL levels at ROSC and 3 hours post ROSC in AKI among patients who underwent TTM, and to evaluate the clinical utility of NGAL as a predictive marker for AKI. Moreover, the study aimed to verify the association between neurologic outcome and the ROSC-NGAL and 3 h-NGAL levels.
AKI is associated with poor clinical outcome in PCAS patients, and the incidence of AKI in PCAS patients ranges from 12–80% [3–7]. In a study by Oh et al. that was published in 2019, AKI occurred in 348 (60%) of 583 patients who underwent TTM and was associated with poor neurologic outcome at 6 months (adjusted OR 0.206; 95% CI 0.099–0.426; p < 0.001). In a 2015 study by Geri et al. , Stage 3 AKI occurred in 280 out of 580 OHCA patients (48.3%) and was associated with the 30-day mortality rate (OR 1.60; 95% CI 1.05–2.43; p = 0.03). A similar tendency was identified in this study, wherein a comparison of survival at discharge, CPC at discharge, and the 1- and 6-month survival in the AKI (+) and AKI (-) groups showed a significantly higher frequency of poor outcome in the AKI (+) group.
The appropriate management of AKI, which has an effect on poor prognosis in PCAS patients, requires the prediction and early management of AKI. In the results reported from a study by Choi et al.  in 2020, AKI occurred in 55.5% of 1,373 patients who underwent TTM after OHCA, and 78.1% of those patients developed AKI within 3 days after OHCA. In the clinical practice guidelines for AKI in 2012, the KDIGO Acute Kidney Injury Work Group emphasised the importance of studies on biomarkers for the early diagnosis, prognosis, and differential diagnosis of AKI . Thus, additional studies are needed on biomarkers for the early diagnosis or risk prediction of AKI, as well as the prediction of mortality or long-term renal replacement therapy in AKI patients. The factors that are being studied as biomarkers for AKI include NGAL, cystatin C, interleukin-18, kidney injury molecule-1, and plasma interleukin-6. Based on the criteria specified for the evaluation of novel markers of cardiovascular risk in the American Heart Association Scientific Statement , the evaluation phases for clinical biomarkers could be divided into six stages as follows: from proof-of-concept studies (Phase 1) that demonstrate differences in biomarker levels between patients with and without the outcome of interest (i.e., AKI) to whether biomarker use causes changes in therapy for at-risk patients, improves outcomes, and is cost-effective (phases 4–6) . Among the biomarkers of AKI, both NGAL and gamma-glutamyl transpeptidase/alkaline phosphatase have evidence from Phase 4 or higher studies .
Human NGAL was originally identified as a novel protein that was isolated from the secondary granules of human neutrophils . Preclinical transcriptome profiling in a number of AKI models revealed NGAL to be one of the most robustly upregulated genes in the kidney post injury [23, 24]. The NGAL has been identified as a useful marker for the early prediction of AKI in situations that confer a potential risk of kidney injury, such as cardiopulmonary bypass, contrast administration, and kidney transplantation . Cardiac surgery-associated AKI is indicated by a more than 10-fold elevation in the urinary and serum levels of NGAL within 2–6 hours after surgery. Many prospective studies have reported that patients with AKI showed significantly increased NGAL levels at 1–3 hours after surgery [25–28]. Contrast-induced AKI could be predicted by NGAL measurement at 2 hours after contrast administration [18, 29–31]. In studies that analysed the association of NGAL in patients with post-OHCA AKI, the timepoint of NGAL varied from immediately after ROSC to several days later, and there were differences in AUROCs or ORs of NGAL for AKI depending on the time of measurement [11–14]. However, no studies have comparatively evaluated NGAL values that were measured immediately after ROSC with those measured hours later. This study focused on the early prediction of AKI, and compared ROSC-NGAL and 3 h-NGAL to determine the clinical utility of NGAL as a predictor of AKI. The results showed that 3 h-NGAL is a more accurate predictor of AKI than ROSC-NGAL.
Research has been actively undertaken on NGAL and clinical outcomes in OHCA patients. In a 2019 study by Lee et al. , the plasma NGAL measured 4 hours after ROSC among adult OHCA patients who were treated with TTM was associated with both the neurologic outcome at the time of discharge (adjusted OR 1.004; 95% CI 1.001–1.007) as well as the 28-day mortality rate (adjusted OR 1.003; 95% CI 1.001–1.004). In 2018, Park et al.  reported that the NGAL level was measured immediately and 24, 46, and 72 hours after ROSC and was analysed to predict the long-term outcome and survival in 76 OHCA patients who underwent TTM; the results showed that the NGAL value measured after 72 hours was the optimal predictive indicator for the outcome and survival (AUROC = 0.72; p = 0.02). In a 2017 study, Kaneko et al.  analysed the neurologic outcome at discharge based on NGAL measurements at 1 and 2 days after ROSC; the NGAL level after 2 days showed a comparable predictive value as the 2-day neuron-specific enolase, which has widespread application in the prediction of the neurologic outcome. In this study, the results of multivariate regression analysis of ROSC-NGAL and 3 h-NGAL measurements did not identify them as significant risk factors for poor neurologic outcome (ROSC-NGAL: OR 1.017; 95% CI 0.998–1.036; p = 0.084, 3 h-NGAL: OR 0.997; 95% CI 0.992–1.001; p = 0.113). The neuroprognostic value of NGAL measured within 24 hours is remains controversial ; therefore, additional studies are necessary to determine the optimal timepoints for NGAL measurement after ROSC.
This study had several limitations. In patients with missing data for the serum creatinine level, we used the creatinine level on the first day of hospitalisation as the baseline value. Moreover, the study did not consider the potential effect of the history of concurrent medications and the radiocontrast procedure on renal function, volume status after admission, and the onset of complications. Moreover, the single-centre study design is another limitation of this study.