Introduction
Contrast-induced acute kidney injury (CI-AKI) is a common and potential severe complication in patient with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) (1). Also it is associated with increased morbidity and mortality (2). The incidence of CI-AKI ranges from 2% to 30% because of different study populations, different clinical settings and CI-AKI definitions (3-6). The pathogenesis of CI-AKI is not yet completely understood; multiple mechanisms may be involved including sustained intrarenal vasoconstriction, direct toxic effect of contrast media, renal medullary hypoxia, ischemic injury, oxidative stress, and inflammation (7).
Blood urea nitrogen (BUN) is a well-known marker of kidney function (8).
BUN may serve as a comprehensive marker reflecting impaired cardiology function and neurohormonal activation (8). It has been shown that BUN was associated with mortality in patients with acute myocardial infarction (9). Left ventricular ejection fraction (LVEF) was found to be predictor for CIN in other risk models (10,11). Several risk scores to identify patients most likely to develop CIN (10,12). The most commonly used risk score was described by Mehran et al. (10) and is based on the presence of 8 factors (hypotension, use of intra-aortic balloon pump, congestive heart failure, chronic kidney disease, diabetes, age >75 years, anemia, and volume of contrast).
The main purpose of this study was to investigate the role BUN to LVEF ratio in predicting of CIN in patients with acute coronary syndromes undergoing percutenous coronary intervention (PCI) and compare with a validated and well-known model developed to predict CIN.
Methods
Study population
We retrospectively evaluated 1140 consecutive patients with ACS treated with PCI from January 2008 and July 2015. We excluded patients who died during coronary angiography/PCI , on chronic dialysis, those without paired serum creatinine determinations, and those without the measurement of contrast volume, patients with absence of echocardiogram during admission and lack of follow-up. The remaining 1058 patients made up final study population. This study was approved by the Institutional Research and Ethics Committee.
Blood sampling and Echocardiographic analysis
Blood samples were collected before PCI as part of routine patient care. Creatinine was measured at baseline and 48–72 h post-procedure. BUN was measured at admission. Echocardiographic examinations were performed early after ACS diagnosis using transthoracic echocardiography for all patients . The left ventricular ejection fraction (LVEF) was calculated after measuring the end-diastolic and end-systolic left ventricul (LV) volumes in the apical four-chamber and two -chamber views using the modified Simpson’s method.
Definitions
According to the criteria of the universal definition of myocardial infarction, diagnosis was established in the detecting of an increasing/decreasing pattern in cardiac troponin I values, with at least one measurement above the 99th percentile of the upper reference limit together with evidence of myocardial ischemia [13]. Morever, myocardial infarction was classified as STEMI or NSTEMI according to current guidelines [14, 15]. STEMI was defined as the presence of (1) ST-segment elevation consistent with myocardial infarction of ≥2 mm in adjacent chest leads and/or ST-segment elevation of ≥1 mm in two or more standard leads or new left bundle branch block (LBBB) and (2) positive cardiac necrosis markers (14). Diagnosis of NSTEMI was established in accordance with current guidelines. NSTEMI was defined as the presence of typical chest pain, serial increased levels of cardiac biomarkers and diagnostic electrocardiographic changes without ST elevation. Morever, UA includes (1) the absence of ST-segment elevation consistent with MI or new LBBB, (2) the presence of negative cardiac necrosis markers, and (3) the presence of angina pectoris (or an equivalent type of ischemic discomfort) with any one of the following three features: (a) prolonged (> 20 min) angina occurring at rest, (b) new-onset angina of at least Canadian Cardiovascular Society (CCS) class III severity, or (c) recent acceleration of angina reflected by an increase in severity of at least one CCS class to at least CCS class III [15]. Cardiovascular risk factors (arterial hypertension, diabetes, hypercholesterolemia, and smoking) were defined according to the accepted current criteria.
The definition of CI-AKI was a raise of 0.3 mg/dL or 50% in post procedure (48–72 h) creatinine compared to baseline, proposed by the Acute Kidney Injury Network (AKIN) as a standardized definition of acute kidney injury [16]. BUNEFr was defined as BUN to LVEF ratio. A BUNEFr of 0.43 was found as threshold value by receiver-operating characteristic (ROC). According to the BUNEFr, the patients were classified into high BUNEFr (≥ 0.43, n = 330) and low BUNEFr (< 0.43, n = 728) groups.
Hypotension was defined as systolic blood pressure < 80 mmHg for at least 1 h requiring inotropic support with medications or intra-aortic balloon pump (IABP) within 24 h periprocedurally. Anemia was defined according to World Health Organization criteria: baseline hematocrit value < 39% for men and < 36% for women. Previous chronic kidney disease (CKD) was defined as creatinine at baseline >1.5 mg/dL1.5 mg/dL. Mehran score [10] included 8 clinical and procedural variables and its weighted integers: hypotension (5 points), intra-aortic balloon pump (IABP) (5 points), congestive heart failure (5 points), creatinine at baseline >1.5 mg/dL1.5 mg/dL(4 points) age [75 years (4 points), diabetes (3 points), anemia (3 points) and volume of contrast (1 point for each 100 cc3).
Treatment
All coronary angiography and PCI procedures were performed via the transfemoral approach by experienced interventional cardiologists. Coronary angiography with subsequent PCI were performed in both the UA and NSTEMI patients within the first 48 h. Primary PCI for STEMI was made according to the current guidelines [14]. The diagnosis of CAD was confirmed by coronary angiography in all patients and consisted of documentation of a significant disease (defined as coronary stenoses ≥ 50% luminal narrowing in at least one of the major coronary arteries, or an infarct-related artery). Multivessel disease was defined as at least 50% diameter stenosis of two or more epicardial coronary arteries, or left main by visual estimation. Angiographic data of the patients were evaluated from catheter laboratory records. All patients were treated according to good clinical practice and the current guidelines [14,15]. The type of stent and the use of thrombectomy devices, predilation, poststenting adjunctive balloon inflation, intravascular ultrasound, intra-aortic balloon counterpulsation, or glycoprotein IIb/IIIa inhibitors were all left to the operators' discretion. Both aspirin (100 mg/day) and clopidogrel (75 mg /day) or prasugrel (10 mg /day) or tigacrelor (90 mg twice daily) were maintanied for at least 12 months, followed by indefinite single antiplatelet theraphy in our study. Beta-blockers, angiotensin-converting enzyme inhibitors, and statins were administered according to the European Society of Cardiology guidelines [14,15].
Statistical analysis
Continuous variables were presented as mean ± standard deviation, and categorical variables were displayed as counts and percentages. Comparison of parametric values between the two groups was performed using Student's t-test when distribution was normal or the Mann-Whitney U-test as appropriate. A chi-squared test was used in comparing of categorical variables between the groups. A multivariate logistic regression analysis was performed to evaluate whether high BUNEFr was an independent predictor for CIN. Factors with a P value of < 0.1 by univariate analysis were included in multivariate regression analysis. The predictive values of BUN, LVEF, BUNEFr and Mehran score were estimated by comparing the areas under the receivers operating characteristic (ROC) curve. We used DeLong's test to compare the AUC from each of models [17], which were evaluated by use of Analyse-it software programme. Differences were considered significant at the 2-sided P < .05 level. All statistical analyses were performed using SPSS version 16 (SPSS Inc., Chicago, IL, USA).
Results
Baseline characteristics
A total of 81 patients developed CIN (7.7%). The mean age was 61.5 ± 12.2 years. Of the 1058 patients, 774 (73%) were males and 284 (27%) were females. The baseline characteristics of the study patients are presented Table 1.
The patients in the high BUNEFr group were significantly older, with a higher prevalence of hypertension than in the low BUNEFr group. Compared with low BUNEFr group, histories of heart failure, diabetes mellitus, CAD, and higher Killip class were more frequent in the high BUNEFr group. The usages of IABP and inotropic support or hypotension were more common in the high BENEFr group compared with low BUNEFr group (Table 1). Patients with high BUNEFr had higher rates of anemia and renal dysfunction.
Laboratory findings
The laboratory variables of the groups are shown in Table 2. LVEF was significantly lower in high BUNEFr group than low BUNEFr group (42 ± 10% vs 51 ± 8%, p < 0.001.). Patients with high BUNEFr had higher levels of BUN than those with BUNEFr (26.3 ± 10.3 vs 14.6 ± 3.8, p < 0.001). Moreover, Mehran score was higher in high BUNEFr group compared with low BUNEFr group. (Table 2).
Angiographic and procedural characteristics
The angiographic and procedural characteristics of the patients are provided in Table 1. Stent use, stent type, and tirofiban use did not differ significantly between the two groups, whereas the rate of multivessel disease, and use of furosemide were higher in high BUNEFr group than low BUNEFr group (46% vs 30%, p < 0.001; 23% vs 6%, p < 0.001, respectively). Also, contrast volume was higher in patient with high BUNEFr compared with low BUNEFr group (170 ± 64 cc vs 158 ± 53cc, p < 0.001, Table 2).
BUNEFr and CIN
Independent risk factors for CIN were age, history of stroke/TIA, IABP, contrast volume, hypotension or positive inotropic support, and high BUNEFr group (OR: 3.849, 95% CI:2.073-7.145, p < 0.001) (Table 3). Also, Mehran score was independent predictor of CIN (OR:1.162, 95%CI:1.098-1.230, p < 0.001). The predictive performance of BUNEFr was similar to the Mehran score for predicting CIN (BUNEFr vs Mehran score : AUC: 0.760 vs 0.783, z = 0.704, p = 0.481), but better than both BUN alone (BUNEFr vs BUN: AUC: 0.760 vs 0.724, z = 2.258, p = 0.0239), and LVEF alone (BUNEFr vs LVEF: AUC: 0.760 vs 0.667, z = 3.410, p = 0.0006) in predicting of CIN in these patients.
Discussion
This study demonstrated that BUNEFr is an independent predictor of CIN in ACS patients treated with PCI. To the best of our knowlodge, this is the first study investigating the BUNEFr for predicting CIN in these patients. Morever, the present study showed that the BUNEFr was better able to predict CIN compared with both the BUN and LVEF. The predictive accuracy of this parameter was similar to Mehran score to identify patients with an increased risk of CIN in ACS patients undergoing PCI.
BUN is one of the marker of renal function, and its concentration is determined via balance and absorption in the kidneys. Its reabsorption is operated with water absorption at the distal nephron under the influence of antidiuretic hormone (18). It has been shown that Norepinephrine may also increase in patients with high BUN levels (19). There was a relationship between a high BUN level and activation of the renin-angiotensin-aldosterone and sympathetic nerve systems showing renal hypoperfusion from hypovolemia, renovascular disease, and reduced cardiac output in addition to reduced glomerular filtration rate (GFR). Thus BUN may serve as an indicator both cardiorenal dysfunction and neurohumoral activation.
LVEF is most commonly used tool to assess the cardiac functions related to hemodynamic instability and ultimately leads to deterioration of renal perfusion. Shacham et al. showed that low LVEF was associated with CIN in patients undergoing PCI (23). In that study, also worsened LVEF was independent predictor of CIN (23). A risk score named AGEF including age, low LVEF, and reduced GFR showed to be a relationship between low EF and risk of CIN (24). The Chen risk score includes LVEF and other vital risk factors for CIN. Gohbaraet al. found that low LVEF was associated with CIN in STEMI patients (25). A reduced left ventricular ejection fraction may imply diuretic therapy and low output states, possible factors involved in CIN.
IABP as a marker of significant hemodynamic disturbances during PCI may be associated with the developement of CIN. The use of IABP is generally required to provide hemodynamic support to patients with cardiogenic shock in the event of unexpected hypotension and hemodynamic deterioration during complex and high-risk PCI. It has been shown that hypotension and IABP without hypotension was associated with the development of CIN (10). In our study, IABP and furosemide usages were more common in high BUNEFr group. Compared with low BUNEFr group, the rates of high Killip class, history of heart failure and hypotension/inotropic support usage were higher in the high BUNEFr group. These unfavorable hemodynamic settings may lead to activation of the renin-angiotensin-aldosterone and sympathetic nerve systems, and cause reabsorption of BUN at distal nephron. Therefore, a high BUNEFr at admission may be mark of impaired cardiorenal functions and negative neurohormonal activation. Morever, the frequencies of hypertension and anemia which are known risk factors for CIN were more common in high BUNEFr group. Also, high BUNEFr group was older. All of them may cause the development of CIN in these patients.
As the treatment of CI-AKI is rather limited and CI-AKI always leads to prolonged hospital stay, worse in-hospital and long-term clinical outcomes, a practical and effective solution to this complication is its prevention (26). Therefore, the prediction of CIN is pivotal role in ACS patients treated with PCI. Mehran risk score is commonly used to identify patients who are at risk for developing CIN after PCI (10). The predictive value of BUNEFr in predicting of CIN was similar to that of Mehran’s score (according to ROC analysis), but with simple application for risk stratification. BUNEFr as reflection of both kidney and non-kidney pathophysiological pathways may help the interventional team to prevent the development of CIN via some procedures such as reduced dose of contrast volume following with sufficient hydration or combined with pharmacological prophylaxis.
The current study has several limitations. First, this analysis was a retrospective study and it is possible that identified or unidentified cofounders were not fully adjusted and influenced the result of this study. Second, several factors that can affect BUN level, such as diet, muscle mass, and fluid administration before the assessment of BUN, were not recorded.
Third, we did not study the use of baseline medications which may impact the incidence of CIN.
Conclusion
The BUNEFr could be a useful predictor for early prediction of CI-AKI in patients with ACS who were treated PCI. Our data showed that this parameter exhibited good predictive ability on CIN, similar to Mehran’s score,
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