Prognostic value of neutrophil gelatinase-associated lipocalin in patients with acute ST-segment elevation myocardial infarction: A meta-analysis

Acute myocardial infarction (AMI) remains a life-threatening disease worldwide. Among AMI patients who survive, 20% suffer a second cardiovascular event within the first year.1 Therefore, early risk stratification and patient selection is urgently needed for more aggressive secondary prevention.2 Biomarkers play an important role to predict adverse outcomes in patients with AMI.3 Acute kidney injury (AKI) is one of the common complications of AMI patients, with a clear effect on the prognosis.4 Neutrophil gelatinase-associated lipocalin (NGAL), an acute phase protein, has emerged as an early biomarker of AKI.5 In addition to being a sensitive marker of AKI, the circulating NGAL level has been used as a biomarker in risk stratification among AMI patients. However, the prognostic value of NGAL in patients with ST-segment elevation myocardial infarction (STEMI) is still under debate. Nevertheless, the magnitude of the prognostic significance of NGAL varied considerably among studies. The current meta-analysis was designed to systematically assess the prognostic value of increased circulating NGAL level in STEMI patients. We searched relevant articles in PubMed and Embase databases up to 5 May 2018 using a combination of the following keywords: ‘neutrophil gelatinase-associated lipocalin’ AND ‘acute myocardial infarction’ OR ‘ST-segment elevation myocardial infarction’ OR ‘acute coronary syndrome‘ AND ‘death’ OR ‘mortality’ OR ‘major adverse cardiovascular events (MACEs)’ OR ‘prognosis’ OR ‘prognostic’. Studies meeting the following inclusion criteria were eligible: 1) observational studies; 2) patients were clinically diagnosed with STEMI; 3) plasma or serum NGAL as exposure; 4) outcome measures were MACEs or all-cause mortality; and 5) reported at least age-adjusted risk estimate of the prognostic value for the higher versus lower NGAL level. Studies were excluded when: 1) the studied population was not restricted to STEMI patients; and 2) in-hospital mortality as outcome. Methodological quality was checked according to the Newcastle–Ottawa Scale (NOS). A study with a score of 7 or over indicated good quality. All data were analyzed using STATA 12.0. The pooled multivariate-adjusted risk ratio (RR) with 95% confidence intervals (CIs) was calculated for the higher versus lower NGAL level. A total of five studies6–10 from 168 relevant articles were identified and analyzed. Three studies6–8 were consecutively enrollment of patients and two studies9,10 were prospective designs. The sample sizes of the selected study ranged from 106 to 1121, with a total of 2462 STEMI patients. The mean age of patients ranged from 51.8 to 65.0 years. The patients in the selected studies were mainly male. Mean follow-up duration was up to 13.9 years. Based on the NOS scale, four studies with a score of 7 were classified into high quality. Four studies6,8–10 evaluated the NGAL for prediction of all-cause mortality and three studies6,7,9 evaluated the NGAL for predicting MACEs. As depicted in Figure 1, STEMI patients who had a higher circulating NGAL level had poor prognosis for all-cause mortality (RR 1.47; 95% CI 1.13–1.91) and MACEs (RR 1.52; 95% CI 1.00–2.30) in a random effect model. A leave-out-one study sensitivity analysis did not significantly alter the pooled effect size. We did not make the funnel plot for the visual assessment of publication bias due to the small number of studies analyzed. Forest plots showing risk ratio (RR) and 95% confidence interval (CI) of all-cause of mortality and major adverse cardiovascular events for the higher versus lower neutrophil gelatinase-associated lipocalin level. The principal finding of this meta-analysis suggested that STEMI patients who had a higher NGAL level had a significantly increased risk of all-cause mortality and MACEs. STEMI patients with higher NGAL level had an approximately 47% and 52% greater risk of all-cause mortality and MACEs, respectively. In contrast to non-ST-segment elevation myocardial infarction (NSTEMI), patients with acute STEMI were facing considerable risk for cardiovascular complications. NGAL plays an important role for early detection of AKI. However, adjustment for renal function in the multivariate analyses did not alter the relation of NGAL level with adverse outcomes. This finding revealed that the prognostic value of NGAL level did not simply reflect kidney dysfunction. One possible interpretation of the prognostic value is that NGAL level reflects impaired kidney function. Furthermore, NGAL indirectly contributes to the inflammatory processes, which can cause increased death and MACE incidences. However, the exact mechanisms underlying the prognostic role of increased NGAL level and worse prognosis should be defined in future studies. This meta-analysis had several limitations. First, NGAL level was detected at a single time point and timing of blood samples may affect the results. Second, the optimal cutoff value for NGAL remains to be defined due to divergent NGAL thresholds reported in the included studies. Third, we failed to conduct the publication bias test and subgroup analysis because of the small number of studies analyzed. Finally, all the included studies consisted of STEMI patients, which may restrict generalizability to NSTEMI and unstable angina cases. In conclusion, STEMI patients who had higher NGAL level independently had increased risk of all-cause mortality and MACEs. Serum/plasma NGAL level may be used for stratification among STEMI patients in daily clinical practice. However, more well-designed prospective studies are necessary to confirm these findings. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article.