We enrolled 307 consecutive incident patients to an adult medical-surgical ICU. We excluded 5 patients with endstage renal disease on chronic RRT and 1 patient for uninterpretable NGAL result, leaving 301 patients for analysis. Patient characteristics are shown in Table 1. Two hundred twenty patients (73%) had an eGFR <90 ml/min/1.73 m2, of whom 20 (6.6%) had an eGFR <60 ml/min/1.73 m2. The most common diagnostic categories for ICU admission were Neurologic, Respiratory, Cardiovascular, Trauma and Gastrointestinal, accounting for 89% of admissions. Median ICU length of stay was 7 days (IQR 3, 13). Crude ICU and hospital mortalities were 17.3 and 25.5%, respectively, and 58 (19.3%) patients met the composite RRT or ICU death endpoint.
Acute kidney injury
Of 301 patients, 133 (44%) had AKI during their ICU stay; 90 patients had AKI within 24 h of ICU admission, while 43 developed it later during their ICU stay (median 3rd day, IQR 2–5) (see ESM File 1, ESM Table 1). RIFLE-initial class was Risk in 92 patients (30.6%), Injury in 17 (5.6%) and Failure in 24 (8.0%). Progression of AKI to a worse RIFLE class was seen in 37 patients (28% of AKI patients). The maximum RIFLE class reached (RIFLE-max) was Risk in 57 patients (18.9%), Injury in 42 (14%) and Failure in 34 (11.3%). Fifteen patients (5%) were treated with RRT in the ICU. AKI patients were older, less likely to have a neurologic diagnosis and more likely to have a respiratory diagnosis on ICU admission, had higher APACHE II, SAPS II and SOFA scores, and higher baseline and admission SCr values. They were more likely to have had exposure to potential nephrotoxins prior to their ICU admission, and to have received diuretics during their ICU stay. Sixty-six AKI patients (49.6%) fulfilled criteria for sepsis during their ICU stay, compared to 49 (29.2%) of non-AKI patients (P < 0.001), whereas 83 AKI patients (62.4%) fulfilled criteria for SIRS or sepsis during their ICU stay, as compared to 80 (47.6%) of non-AKI patients (P = 0.014).
AKI patients had a higher crude ICU mortality (27.8% vs. non-AKI 8.9%, P < 0.001) and longer ICU length of stay [median 9 days vs. 5 days (non-AKI), P < 0.001]. Sixty-four patients (48% of AKI patients) had complete recovery of renal function, with a SCr at time of ICU discharge that was <150% of baseline; an additional 27 AKI patients (20%) had partial renal recovery.
NGAL in AKI and non-AKI
The median first pNGAL in the study population was 117.0 (IQR 68.2, 213.8) ng/ml, which was significantly higher than 61.2 (IQR 60.0–78.5) ng/ml observed in apparently healthy adults (P < 0.001). Even ICU patients without AKI had significantly higher pNGAL levels (82.0 ng/ml, IQR 49.7, 134.1) compared to healthy adults (P = 0.004). A summary of first pNGAL values in the study population is shown in Fig. 1. Compared to non-AKI patients, pNGAL values were higher among patients who already had AKI at the time of first pNGAL measurement (213.7 ng/ml, IQR 110.4, 553.3; P < 0.001 vs. non-AKI), as well as in patients who developed AKI within 48 h (209.0 ng/ml, IQR 101.4, 268.2; P < 0.001 vs. non-AKI). Patients who developed AKI within 24 h had a median pNGAL of 225.3 ng/ml (IQR 163.0, 279.5; P < 0.001 vs. non-AKI), whereas those who developed it within 24–48 h had a median pNGAL of 140.7 ng/ml (IQR 95.8, 218.3; P = 0.13 vs. non-AKI). In contrast, patients who developed AKI after >48 h had pNGAL similar to non-AKI patients (79.8 ng/ml, IQR 52, 143.9; P = 0.81). The proportion of AKI patients was higher with progressive quartiles of first pNGAL measurement (see ESM file 1, ESM Fig. 1, P < 0.001).
A graphical representation of the kinetics of pNGAL is shown in Fig. 2. For AKI patients, the X-axis shows AKI Day [4, 8]. AKI Day 0 is the day in which the diagnosis of AKI was made based on the RIFLE criteria. One day prior to AKI, pNGAL was higher in these patients compared to non-AKI, and increased further on AKI Day 0. Patients who never developed AKI had comparatively lower pNGAL values without notable variation during the study period (P < 0.001 at each time point).
NGAL and prediction of clinical outcome
Performance characteristics of pNGAL for prediction of AKI and secondary outcomes are shown in Fig. 3 and Table 2. Plasma NGAL was a good diagnostic marker for AKI development within the next 48 h from the first measurement (Fig. 3), with an area under ROC (AuROC) of 0.78 (95% CI 0.65–0.90). Using a threshold value of 150 ng/ml for pNGAL, the sensitivity was 73%, and specificity was 81% (Table 2). Plasma NGAL levels >150 ng/ml were associated with increased odds of AKI of 11.8 (95% CI 3.5–39.2). Furthermore, pNGAL was also a good predictor for RRT use during the ICU stay (AuROC 0.82, 95% CI 0.70–0.95). However, its performance was comparatively weaker with regards to prediction of AKI occurring within the next 5 days, ICU mortality, and the composite endpoint of RRT and ICU mortality (AuROC 0.67, 0.67 and 0.68, respectively).
We also described the cohort with respect to the ascertained threshold pNGAL value (see ESM File 1, ESM Table 2). The findings are similar to Table 1, reflecting the association between AKI and elevated pNGAL levels. Patients with first pNGAL >150 ng/ml were older, were more likely to have CKD, have higher APACHE II and SOFA scores and SCr on ICU admission, and were more likely to have had exposure to potential nephrotoxins. Over 70% of these patients had AKI during their ICU stay. Also, this group had higher RRT use (11.7%) and ICU mortality (27%). The duration of AKI among survivors was longer in patients with first pNGAL >150 ng/ml versus those with first pNGAL <150 ng/ml (4 days, IQR 2,7 vs. 2 days, IQR 1,6, respectively, P = 0.013).
NGAL and severity of illness and AKI
All blood specimens were used to calculate peak and mean pNGAL values . Peak pNGAL concentrations increased with worsening severity of AKI (Table 3). There was a similar relationship between mean pNGAL levels and RIFLE-max class (Non-AKI 71.4 ng/ml, IQR 43.9, 124.3; Risk 139.9 ng/ml, IQR 67.4, 185.0; Injury 161.6 ng/ml, IQR106.9–286.1; Failure 522.0 ng/ml, IQR 288.2–1061.8; P < 0.001 by Kruskal–Wallis test). Peak pNGAL levels also correlated well with RIFLE-max class (R = 0.554, P < 0.001). Patients were further grouped according to APACHE II, SAPS II and SOFA scores, and by presence of sepsis. In general, pNGAL levels were higher among patients with higher severity of illness scores, whether expressed as peak pNGAL (Table 3), mean pNGAL or first pNGAL levels (data not shown). There were weak but highly statistically significant correlations between peak NGAL levels and APACHE II (R = 0.287, P < 0.001), SAPS II (R = 0.215, P < 0.001) and SOFA scores (R = 0.289, P < 0.001). There was no significant difference in pNGAL among patients with and without sepsis or SIRS (Table 3).
Table 4 shows the results of posthoc univariate and multivariate logistic regression analysis using age, APACHE II scores and first pNGAL concentration as independent variables to predict AKI within 48 h of admission. Age was not significant in either the univariate or multivariate model, whereas APACHE II was marginally significant, and NGAL was highly significant. The adjusted odds ratio for pNGAL did not depend significantly on which ICU severity score was used (APACHE II, SAPS II or SOFA) in the model; the best model was that using the APACHE II.