The outcome of neutrophil gelatinase-associated lipocalin-positive subclinical acute kidney injury: a multicenter pooled analysis of prospective studies

Abstract

Objectives: The aim of this study was to test the hypothesis that, without diagnostic changes in serum creatinine, increased neutrophil gelatinase-associated lipocalin (NGAL) levels identify patients with subclinical acute kidney injury (AKI) and therefore worse prognosis.

Background: Neutrophil gelatinase-associated lipocalin detects subclinical AKI hours to days before increases in serum creatinine indicate manifest loss of renal function.

Methods: We analyzed pooled data from 2,322 critically ill patients with predominantly cardiorenal syndrome from 10 prospective observational studies of NGAL. We used the terms NGAL(-) or NGAL(+) according to study-specific NGAL cutoff for optimal AKI prediction and the terms sCREA(-) or sCREA(+) according to consensus diagnostic increases in serum creatinine defining AKI. A priori-defined outcomes included need for renal replacement therapy (primary endpoint), hospital mortality, their combination, and duration of stay in intensive care and in-hospital.

Results: Of study patients, 1,296 (55.8%) were NGAL(-)/sCREA(-), 445 (19.2%) were NGAL(+)/sCREA(-), 107 (4.6%) were NGAL(-)/sCREA(+), and 474 (20.4%) were NGAL(+)/sCREA(+). According to the 4 study groups, there was a stepwise increase in subsequent renal replacement therapy initiation-NGAL(-)/sCREA(-): 0.0015% versus NGAL(+)/sCREA(-): 2.5% (odds ratio: 16.4, 95% confidence interval: 3.6 to 76.9, p < 0.001), NGAL(-)/sCREA(+): 7.5%, and NGAL(+)/sCREA(+): 8.0%, respectively, hospital mortality (4.8%, 12.4%, 8.4%, 14.7%, respectively) and their combination (4-group comparisons: all p < 0.001). There was a similar and consistent progressive increase in median number of intensive care and in-hospital days with increasing biomarker positivity: NGAL(-)/sCREA(-): 4.2 and 8.8 days; NGAL(+)/sCREA(-): 7.1 and 17.0 days; NGAL(-)/sCREA(+): 6.5 and 17.8 days; NGAL(+)/sCREA(+): 9.0 and 21.9 days; 4-group comparisons: p = 0.003 and p = 0.040, respectively. Urine and plasma NGAL indicated a similar outcome pattern.

Conclusions: In the absence of diagnostic increases in serum creatinine, NGAL detects patients with likely subclinical AKI who have an increased risk of adverse outcomes. The concept and definition of AKI might need re-assessment.

Figure 1

Flow of study selection. NGAL, neutrophil gelatinase-associated lipocalin; RRT, renal replacement therapy.

Figure 2

Figure 2A Proportion of patients according to biomarker states. NGAL, neutrophil gelatinase-associated lipocalin; sCREA, serum creatinine; u, urine; p, plasma. Figure 2B. Proportion of NGAL(+) / sCREA(−) patients in relation to the proportion of patients diagnosed to have AKI by conventional creatinine-based criteria (RIFLE classification [1]) and NGAL positivity. Neutrophil Gelatinase-associated Lipocalin, NGAL; u, urine; p, plasma. The formula used was: $$\frac{(\text{NGAL}+/\text{sCREA}-)=\text{renal}\text{impairment}\text{identified}\text{by}\text{NGAL}}{(\text{NGAL}+/\text{sCREA}-)+(\text{NGAL}-/\text{sCREA}+)+(\text{NGAL}+/\text{sCREA}+)=\text{all}\text{renal}\text{impairment}}$$

Figure 3

Incidence of renal replacement therapy (RRT) initiation, in-hospital morality and a combination of both according to Neutrophil Gelatinase-associated Lipocalin (NGAL) and serum creatinine. There was a stepwise increase in all outcomes.

Figure 4

Length of stay (LOS) stratified by Neutrophil Gelatinase-associated Lipocalin (NGAL) and serum creatinine in the Intensive Care Unit (ICU) (A) and in-hospital (B). There was a stepwise increase in median LOS in ICU and in-hospital.

Figure 4

Length of stay (LOS) stratified by Neutrophil Gelatinase-associated Lipocalin (NGAL) and serum creatinine in the Intensive Care Unit (ICU) (A) and in-hospital (B). There was a stepwise increase in median LOS in ICU and in-hospital.