Serum neutrophil gelatinase-associated lipocalin at inception of renal replacement therapy predicts survival in critically ill patients with acute kidney injury

Philipp Kümpers, Carsten Hafer, Alexander Lukasz, Ralf Lichtinghagen, Korbinian Brand, Danilo Fliser, Robert Faulhaber-Walter, Jan T Kielstein, Philipp Kümpers, Carsten Hafer, Alexander Lukasz, Ralf Lichtinghagen, Korbinian Brand, Danilo Fliser, Robert Faulhaber-Walter, Jan T Kielstein

Abstract

Introduction: Neutrophil gelatinase-associated lipocalin (NGAL) is a promising novel biomarker that correlates with the severity and outcome of acute kidney injury (AKI). However, its prognostic utility during the late course of AKI, especially in patients that require renal replacement therapy (RRT) remains unknown. The aim of this study was to evaluate the predictive value of serum NGAL in patients with established AKI at inception of RRT in the intensive care unit (ICU).

Methods: Serum NGAL (ELISA methodology) was measured in 109 critically ill patients with AKI at inception of RRT in 7 ICUs of a tertiary care university hospital. The primary outcome studied was 28-day mortality. Secondary outcome measures were ICU length of stay, ventilator-free days, and renal recovery at day 28.

Results: There was a significant difference in serum NGAL between healthy subjects (median [interquartile range] 39.0 [37.5-42.75] ng/mL), critically ill patients with systemic inflammatory response syndrome (SIRS) (297 [184-490] ng/mL), and critically ill patients with sepsis (708 [365-1301] ng/mL; P < 0.0001), respectively. Multiple linear regression showed that NGAL levels were independently related to the severity of AKI and the extent of systemic inflammation. NGAL levels were higher in non-survivors (430 [303-942] ng/mL) compared to survivors (298 [159-506] ng/mL; P = 0.004). Consistently, Cox proportional hazards regression analysis identified NGAL as a strong independent predictor for 28-day survival (hazard ratio 1.6 (95% confidence interval [CI] 1.15 - 2.23), P = 0.005).

Conclusions: This is the first prospective evaluation of serum NGAL as an outcome-specific biomarker in critically ill patients at initiation of RRT. The results from this study indicate that serum NGAL is as an independent predictor of 28-day mortality in ICU patients with dialysis-dependent AKI.

Figures

Figure 1
Figure 1
Correlation of NGAL serum levels. (a and c). Correlation of NGAL serum levels with sepsis and acute kidney injury (AKI). Bar charts (mean ± standard error of the mean) showing serum neutrophil gelatinase-associated lipocalin (NGAL) levels of critically ill patients with AKI at inception of renal replacement therapy (RRT) stratified by (a) the presence (n = 31) or absence (n = 78) of sepsis as according to the SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions [25], or (c) stratified by the renal variable from the Sequential Organ Failure Assessment (SOFA) score (1 point (n = 9), 2 points (n = 27), 3 points (n = 28), 4 points (n = 45)). (b and d) Scatter plot showing the correlation of serum NGAL concentrations with (c) C reactive protein (CRP) levels, and (d) serum cystatin C levels in critically ill patients at initiation of RRT (n = 109).
Figure 2
Figure 2
Survival to day 28 according to serum NGAL. Kaplan-Meier curves of 28-day survival stratified to (a) neutrophil gelatinase-associated lipocalin (NGAL) quartiles (Q) (Log-rank (Mantel-Cox) P = 0.01; Log-rank test for trend P = 0.003), and (b) Sequential Organ Failure Assessment (SOFA) quartiles (total SOFA), respectively (Log-rank (Mantel-Cox) P = 0.01; Log-rank test for trend P = 0.002) at inception of renal replacement therapy in critically ill patients with acute kidney injury (n = 109).
Figure 3
Figure 3
Serum NGAL test characteristics at various cut-off values at initiation of RRT. Receiver-operator characteristic (ROC) curve showing the prognostic sensitivity and specificity of serum neutrophil gelatinase-associated lipocalin (NGAL) at initiation of renal replacement therapy (RRT) with regard to 14-day mortality (area under the curve (AUC) 0.74 (95% confidence interval (CI) 0.64 to 0.84) P < 0.0002). Cuboids indicate the cut-off values between NGAL quartiles (see also Figure 2 and Table 5).

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