Brain Natriuretic Peptide for Predicting Contrast-Induced Acute Kidney Injury in Patients with Acute Coronary Syndrome Undergoing Coronary Angiography: A Systematic Review and Meta-Analysis

Objective To assess the diagnostic value of B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) for contrast-induced acute kidney injury (CI-AKI) in patients with acute coronary syndrome (ACS) undergoing coronary angiography. Background ACS remains a major cause of death worldwide. Patients with ACS undergoing coronary angiography are more likely to develop CI-AKI, which correlates highly with poor clinical outcomes. Early diagnosis of CI-AKI remains a challenge. Many recent studies have suggested that BNP or NT-proBNP may be a useful biomarker for the early diagnosis of CI-AKI. Methods We searched databases (PubMed, EMBASE, and Cochrane Library) to identify eligible studies. Two authors independently screened the studies and extracted data. We used the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) criteria to assess the methodological quality of the included studies and STATA to perform all statistical analyses. Results Nine studies including 2832 patients were identified. The pooled sensitivity of 0.73 (95% CI 0.65–0.79), specificity of 0.79 (95% CI 0.70–0.85), and area under the summary receiver operating characteristic curve of 0.81 (95% CI 0.77–0.84) suggested that BNP or NT-proBNP had a good diagnostic value for CI-AKI in patients with ACS undergoing coronary angiography. Conclusions Our findings suggest that BNP or NT-proBNP may be an effective predictive marker for CI-AKI. However, additional high-quality studies are required to find the optimal cutoff value and the diagnostic value of BNP or NT-proBNP in combination with other biomarkers.


Introduction
Acute coronary syndrome (ACS), including unstable angina (UA), non-ST elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI), generally results from atherosclerotic plaque rupture or superficial plaque erosion [1,2]. Despite great progress in the treatment of ACS over the past few decades, ACS is still a major cause of death worldwide [3]. For patients with ACS, coronary angiography plays a key role. Early invasive treatment with cardiac catheterization and revascularization remains the preferred treatment for UA and NSTEMI, and timely percutaneous coronary intervention (PCI) for STEMI is recommended as a first-line treatment when prohibitive comorbidities are absent [4][5][6].
ese treatments can reduce mortality and improve prognosis in patients with ACS.
Acute kidney injury (AKI) is a common and serious complication of inpatients that causes significant mortality and other severe complications [7,8]. Patients with ACS, especially those undergoing coronary angiography or PCI, are more likely to develop AKI due to contrast agent exposure [9,10]. e development of CI-AKI after coronary angiography is highly correlated with poor clinical outcomes, such as mortality [11][12][13], adverse cardiac events [14], and stent restenosis [15]. e ability to identify patients at high risk for developing CI-AKI identified early is important to allow the treating physician to take necessary precautions to prevent it.
Brain natriuretic peptides are released into the circulation in response to myocardial ischemia, pressure overload, or ventricular dilatation [16,17]. Previous studies have found elevated concentrations of B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with ACS and have a prognostic value in patients with ACS [18,19]. Moreover, some studies have found that levels of BNP or NT-proBNP are higher in patients with AKI [20][21][22], especially for those who are diagnosed with ACS and undergo coronary angiography or PCI [23][24][25].
To fully understand the correlation between elevated levels of brain natriuretic peptide and CI-AKI, we performed this meta-analysis to evaluate the diagnostic value of brain natriuretic peptide for CI-AKI in patients with ACS undergoing coronary angiography.

Methods
We conducted this meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA statement) guidelines [26].
ere was no prospectively registered protocol; however, search terms, data extraction, inclusion and exclusion criteria, and data synthesis were applied according to a plan made by our team.

Selection of Studies.
We reviewed PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials Library database through April 2020. e search terms were as follows: ("B-type natriuretic peptide" or "BNP" or "N-terminal pro-Btype natriuretic peptide" or "NT-proBNP") and ("acute kidney injury" or "AKI" or "contrast-induced acute kidney injury" or "CI-AKI" or "contrast-induced nephropathy" or "CIN") and ("acute coronary syndrome" or "ACS" or "acute myocardial infarction" or "AMI" or "ST-elevation myocardial infarction" or "STEMI" or "Non-ST elevation myocardial infarction" or "NSTEMI" or "unstable angina"). We did not impose any language restrictions. To find additional citations, the reference lists of the included studies and recent reviews were manually searched when necessary.
Studies were selected if they met the following criteria: a diagnostic value of BNP or NT-proBNP for CI-AKI morbidity in adult patients (≥18 years old) with ACS undergoing coronary angiography or PCI was reported; a 2 × 2 table of results could be constructed; CI-AKI was clearly defined; and the study type was a prospective or retrospective study. e exclusion criteria were as follows: case report, review, editorial, conference abstract, comment, letter, animal study, involving pediatric patients, and insufficient information to extract a 2 × 2 table of results. Two authors (X. L and C. L) assessed the selected studies for the final analysis independently, and any discrepancies were resolved through consultation with the third author (F. Z).

Data Extraction and Quality Assessment.
e following data were extracted by two authors (X. L and C. L) and checked by the third author (Z. M): the first author, year of publication, study design, sample size, average age, patient population, definition of CI-AKI, measurement method of brain natriuretic peptide, timing of brain natriuretic peptide measurement, cutoff points, area under the curve (AUC), true positives (TP), true negatives (TN), false positives (FP), false negatives (FN), sensitivity (SEN), and specificity (SPE).
We used the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) criteria to evaluate each of these studies in 4 domains: patient selection; index test; reference standard; and flow and test timing [27]. Any disagreements were resolved by discussion.

Statistical Analysis.
e statistical analyses were conducted by STATA (version 14.0) using the MIDAS module [28]. A bivariate random-effects regression model was performed to calculate SEN, SPE, the positive likelihood ratio (PLR), the negative likelihood ratio (NLR), the diagnostic odds ratio (DOR), and the corresponding 95% credible interval (CI). A summary receiver operating characteristic (SROC) curve was drawn to assess the overall diagnostic accuracy [29]. We used the Deek funnel plots to detect publication bias, whereby publication bias may exist if the P value is less than 0.1. e I 2 index was calculated to assess heterogeneity between studies, and I 2 values above 50% were regarded as indicative of substantial heterogeneity. We generated a Fagan nomograph and likelihood ratio scattergram to evaluate clinical applications. Sensitivity and subgroup analyses were conducted to investigate potential sources of heterogeneity among the included studies.

Selection and Characteristics of Studies.
As a result of the literature search, 170 studies were identified, of which 55 duplicate publications were excluded. We excluded 101 studies for various reasons by evaluating the titles and abstracts. e remaining 14 articles were further scrutinized by reading the full text. Four studies were excluded due to an inability to extract a 2 × 2 contingency table [30][31][32][33], and one retrospective study was excluded after discussion between two authors because it used peak NT-proBNP as the cutoff value [34]. In total, nine studies [23][24][25][35][36][37][38][39][40] including 2832 patients fulfilled the inclusion criteria and were ultimately included in this meta-analysis ( Figure 1). Table 1 summarizes the details of the nine included studies (prospective: 7; retrospective: 2). ese studies were published between 2013 and 2020. Different SEN, SPE, and AUC values of BNP or NT-proBNP for the diagnosis of CI-AKI were reported. e AUC values in the studies ranged from 0.65 to 0.92, and the definition of CI-AKI varied. Five studies [23-25, 36, 37] measured NT-proBNP and four [35,[38][39][40] BNP. e decision cutoff value used in the studies varied widely between 42.4 and 676 pg/ml for BNP and between 512 and 2320 pg/ml for NT-proBNP (Table 2). Five studies included patients only with STEMI [24,35,37,38,40]. One study [37] was published in Russian, and the others were published in English.

Study Quality and Publication
Bias. Supplementary material S1 shows the risk of bias in the nine included studies. e results revealed that one study had a high risk of bias in the flow and timing domain [37]. Because that study initially included 103 patients, only 68 patients were assessed. A Deek funnel plot is shown in Figure 2. No significant publication bias was detected (P � 0.27).

Diagnostic Value of Brain Natriuretic Peptide for CI-AKI Prediction.
e pooled SEN and SPE values were 0.73 (95% CI 0.65-0.79) and 0.79 (95% CI 0.70-0.85), respectively ( Figure 3). DOR was 10 (95% CI 6-17); PLR and NLR were 3.5 (95% CI 2.4-4.9) and 0.35 (95% CI 0.27-0.44), respectively (supplementary material S2). e SROC curve is depicted in Figure 4. e AUC of brain natriuretic peptide for the diagnosis of CI-AKI was 0.81 (95% CI 0.77-0.84), indicating a high diagnostic value. Based on the Fagan nomogram (Figure 5), if the pretest probability was set to 50%, the use of BNP or NT-proBNP for the detection of CI-AKI increased the posttest probability to 78% when the brain natriuretic peptide results were positive; the posttest probability decreased to 26% when the brain natriuretic peptide results were negative. e above results suggest that BNP or NT-proBNP is a useful biomarker for the diagnosis of CI-AKI in patients with ACS undergoing coronary angiography.

reshold Effect and Heterogeneity Analysis.
e overall I 2 value for the bivariate model was 90% (95% CI 81-100). e proportion of heterogeneity likely caused by the threshold effect was not significant (P � 0.08). For the pooled SEN and SPE, the I 2 values were 58.95% and 93.92%, respectively. Subgroup analysis based on the patient's condition ("STEMI" subgroup or "ACS" subgroup) revealed that heterogeneity in SEN may be caused by the patient's condition. e pooled I 2 values for SEN in the "STEMI" subgroup and "ACS" subgroup were 9.1% and 0, respectively, though significant heterogeneity in SPE was observed. e results failed to show that different biomarkers or study types were the sources of the potential heterogeneity in SEN and SPE (Table 3).

Discussion
is is the first meta-analysis to evaluate the value of brain natriuretic peptide for CI-AKI in patients with ACS undergoing coronary angiography. Overall, the results    CI-AKI is a frequent complication in patients who receive iodinated contrast agent [41], and it is a common cause of hospital-acquired AKI and accounts for approximately 11% of hospital-acquired renal failure [42]. Previous studies have indicated that CI-AKI is associated with adverse clinical outcomes, including prolonged hospitalization, an increased risk of mortality, stent restenosis, and cardiovascular and cerebrovascular events in patients with ACS undergoing coronary angiography [43,44]. At present, the diagnosis of CI-AKI is based on the increased serum creatinine concentration after a contrast agent injection. However, changes in serum creatinine lack sensitivity because in healthy people, nearly 50% of the glomerular filtration rate (GFR) must be lost before changes in serum creatinine can be detected [7,45]. Moreover, there are no consistent thresholds of serum creatinine levels for the diagnosis of CI-AKI [41]. us, finding new biomarkers is of great significance for the early prediction of CI-AKI.
CI-AKI in ACS is a multifactorial phenomenon. First, the contrast agent is completely excreted by the kidney, and the concentration of the contrast agent increases as it passes through the renal tubules, possibly reaching a level toxic to tubular cells [41]. Toxins can have direct cytotoxic effects on endothelial cells or renal tubular epithelial cells, impair renal hemodynamics, and lead to the precipitation of metabolites or crystals, among others [7]. In addition, the impaired cardiac output and increased venous congestion lead to systemic and renal hemodynamic changes, which result in a decrease in GFR.
is may be a key mechanism in the pathogenesis of AKI. Moreover, patients with ACS are characterized by progressive activation of several neurohormonal systems, involving an imbalance of endogenous vasodilating and vasoconstrictive factors and exerting profound effects on kidney perfusion and function [46]. Although the mechanism underlying the relationship between brain natriuretic peptide and CI-AKI has not been explained completely, the following reasons might be involved it to some extent. First, renal hemodynamic impairment in the context of ACS may decrease the clearance of brain natriuretic peptide [47]. Second, Vila et al. found that in healthy people with normal heart function, plasma brain natriuretic peptides were elevated in a model of systemic inflammation [48], and brain natriuretic peptide is accepted as an acutephase reactant [49]. erefore, brain natriuretic peptide may be an indicator of increased inflammation and immune response in ACS, which plays an important role in the occurrence and development of CI-AKI [50,51]. Furthermore, AKI primarily presents as a sharp decrease in GFR and water and sodium retention, which accelerate the overall progression of cardiovascular disease and heart failure, followed by an increase in BNP or NT-proBNP [52]. Nonetheless, more research are needed to identify the potential mechanism between brain natriuretic peptides and CI-AKI.
BNP or NT-proBNP elevation in AKI patients was found in clinical practice, and recent data suggest that baseline BNP or NT-proBNP may help to identify ACS patients at risk for CI-AKI after coronary angiography. e results from our meta-analysis confirm the role of BNP or NT-proBNP in predicting CI-AKI. Furthermore, we built a Fagan nomogram and a likelihood ratio scattergram to evaluate the clinical application value.
ere was considerable heterogeneity among the included studies. Although we conducted sensitivity and subgroup analyses, the heterogeneity was not significantly decreased. is may be caused by different cutoff values, different definitions of CI-AKI, different conditions of patients, or different study designs among the included studies. Some studies measured NT-proBNP, whereas others measured BNP, and the number of participants in the different studies varied greatly, which may also lead to heterogeneity. More high-quality studies are required to shed light on the role of brain natriuretic peptide in the diagnosis of CI-AKI for ACS patients undergoing coronary angiography.
Measuring brain natriuretic peptide is inexpensive, repeatable, and easy to achieve. For patients with ACS, monitoring brain natriuretic peptide is important and essential. Combining brain natriuretic peptide, creatinine, urine output, and other novel biomarkers, such as neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C, which have been identified as potential biomarkers of CI-AKI [53,54], can improve early diagnostic precision for CI-AKI. Moreover, early detection, intervention, and treatment contribute to a favorable prognosis in CI-AKI.    ere are several limitations in our meta-analysis. First, the definition of CI-AKI was not completely consistent among the included studies. Second, in terms of sample size, brain natriuretic peptide assays, cutoff values, and study type differed across the included studies, which may have led to heterogeneity. Finally, substantial heterogeneity existed, and additional subgroup analyses could not be performed to reduce and interpret the heterogeneity because a limited number of studies were included in the meta-analysis.  Figure 5: Fagan nomogram of brain natriuretic peptide for the diagnosis of contrast-induced acute kidney injury in patients with acute coronary syndrome undergoing coronary angiography. e pretest probability was set to 50%. e use of brain natriuretic peptide for the detection of contrast-induced acute kidney injury increased the posttest probability to 78% when the brain natriuretic peptide results were positive; the posttest probability decreased to 26% when the brain natriuretic peptide results were negative.

Conclusions
is study is the first meta-analysis to evaluate the diagnostic value of brain natriuretic peptide for CI-AKI in patients with ACS undergoing coronary angiography, and the results suggest that BNP or NT-proBNP can serve as an effective predictive marker for CI-AKI. However, additional highquality studies are required to find the optimal cutoff value and the diagnostic value of BNP or NT-proBNP in combination with other biomarkers.

ACS:
Acute coronary syndrome AKI: Acute kidney injury AUC: Area under curve BNP: B-type natriuretic peptide CI-AKI: Contrast-induced acute kidney injury CI: Credible interval DOR: Diagnostic odds ratio FN: False negatives FP: False positives NT-proBNP: N-terminal pro-B-type natriuretic peptide NLR: Negative likelihood ratio NSTEMI: Non-ST elevation myocardial infarction PLR: Positive likelihood ratio PCI: Percutaneous coronary intervention PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses QUADAS-2: Quality Assessment of Diagnostic Accuracy Studies-2 SEN: Sensitivity STEMI: ST-elevation myocardial infarction SPE: Specificity SROC: Summary receiver operating characteristic TP: True positives TN: True negatives UA: Unstable angina.

Data Availability
e data used to support the findings of this study are included within the article and its supplementary material files.

Authors' Contributions
XML and CL contributed equally to this work. XML and CL conceived the study, participated in the design, collected the data, performed statistical analyses, and drafted the manuscript. ZM performed statistical analyses and helped to draft the manuscript. RJS and SQ collected the data and revised the manuscript critically for important intellectual content. FHZ collected the data, performed statistical analyses, and helped to revise the manuscript critically for important intellectual content. All authors read and approved the final manuscript.