Min Liang, BS 1 Shicheng Yang, MD 2 Naikuan Fu, MD 1,2 Chengzhi Lu, MD 3 Fengshi Tian, MD 4 Xiaochun Xing, MD 4 Wenhua Lin, MD 5 Jingjing Liu, MD 5

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1 Received: 17 May 2017 Revised: 22 August 2017 Accepted: 2 September 2017 DOI: /ccd ORIGINAL STUDIES Efficacy of alprostadil in preventing contrast-induced nephropathy in patients undergoing percutaneous coronary intervention: A multicenter prospective randomized controlled trial Min Liang, BS 1 Shicheng Yang, MD 2 Naikuan Fu, MD 1,2 Chengzhi Lu, MD 3 Fengshi Tian, MD 4 Xiaochun Xing, MD 4 Wenhua Lin, MD 5 Jingjing Liu, MD 5 1 Graduate School of Tianjin Medical University, Tianjin, China 2 Department of Cardiology, Tianjin Chest Hospital, Tianjin, China 3 Department of Cardiology, Tianjin First Central Hospital, Tianjin, China 4 Department of Cardiology, Tianjin Forth Central Hospital, Tianjin, China 5 Department of Cardiology, Teda International Cardiovascular Hospital, Tianjin, China Correspondence Naikuan Fu, MD, Institute of Cardiology Diseases, Tianjin Chest Hospital, Tianjin, China. cdrfnk@163.com Funding information Tianjin Municipal Health and Family Planning Commission, Grant/Award Number: 14KG124 Abstract Background: The role of alprostadil on the prevention of contrast-induced nephropathy (CIN) still remains controversial. The purpose of this study was to examine the effects of short-term alprostadil on the incidence of CIN in patients undergoing elective percutaneous coronary intervention (PCI). Methods: A total of 480 patients with coronary heart disease undergoing PCI were enrolled in our study and randomly assigned to two groups. The control group (n 5 240) was given only hydration therapy and the alprostadil group (n 5 240) received intravenous administration of 20 ug/day (diluted with 100 ml normal saline) from 0.51 hr before to 3 days after operation on the basis of hydration. The primary endpoint of the study was the incidence of CIN, which was defined as an increase in SCr concentration 44.2 umol/l or 25% above baseline within 48 hr72 hr after exposure of contrast media. Results: The incidence of CIN was significantly lower in the alprostadil group than that in the control group (6.25% vs 11.67%, P ). Multivariate logistic regression analysis showed that alprostadil was the protective factor of CIN (OR , 95% CI , P ). The benefits against CIN were consistent in prespecified high-risk patients with diabetes mellitus (P ). In addition, we also found that hs-crp and blood homocysteine values after PCI were significantly lower in the alprostadil group than those in the control group. Conclusion: Prophylactic administration of alprostadil may prevent against CIN in coronary heart disease patients undergoing elective PCI, particularly in high-risk patients with diabetes mellitus. KEYWORDS alprostadil, percutaneous coronary intervention, prostaglandin E1 1 INTRODUCTION Contrast-induced nephropathy (CIN), also known as contrast-induced acute kidney injury (CIAKI), is a frequent complication after intravascular contrast media administration. It is defined as an increase in baseline serum creatinine (SCr) level by 25% or an absolute increase 44.2 umol/l within 48 or 72 hr after contrast media administration [1]. The advanced development in the field of interventional cardiology resulted in an increasing number of CIN patients and CIN has become the third leading cause of hospital-acquired acute kidney injury followed by surgical operation and nephrotoxic drug damage, accounting for 11% [2]. However, the present guideline merely recommends the intravenous Catheter Cardiovasc Interv. 2017;1 9. wileyonlinelibrary.com/journal/ccd VC 2017 Wiley Periodicals, Inc. 1

2 2 LIANG ET AL. hydration, use of iso- or low-osmolar contrast media, minimization of contrast volume to prevent the occurrence of CIN and none of other strategies were proved effective in preventing CIN [3]. Therefore, effective strategies need to be explored to prevent the occurrence of CIN. Although the pathophysiological mechanisms of CIN are complex and uncertain, it may be associated with intense vasoconstriction mediated by endothelin, inhibition of nitric oxide-mediated vasodilation, release of reactive oxygen species and direct toxic effects on tubular cells from contrast media, thus leading to ischemic injury of medulla outer area and the occurrence of CIN [4]. In addition, the inadequate production of renal prostaglandin at the crucial time of contrast intaking period may be one of main causes of CIN [4]. Prostaglandin E1 (PGE1) is characterized with potent vasodilator effect, which is stronger than nitic oxide [5], and plays a cytoprotective role in ischemiainduced renal dysfunction [6]. Therefore, PGE1 may be applied to prevention of CIN. Some of recently published articles have focus on the use of PGE1 in high-risk population, including advanced age [7], diabetes mellitus [8], and renal insufficiency patients [9], and the results remains controversial. The purpose of this clinical trial was to examine the effects of alprostadil, an exogenous form of PGE1, on the incidence of CIN in patients undergoing elective percutaneous coronary intervention (PCI), as well as to estimate its preventive effects in various high-risk patients. 2 METHODS 2.1 Patients population All consecutive patients (18 years) with coronary heart disease undergoing elective PCI admitted to department of cardiology, Tianjin Chest Hospital, Tianjin First Central Hospital, Tianjin Fourth Central Hospital and TEDA International Cardiovascular Hospital from January 2015 to December 2016 were considered for enrollment in this study. The present study was approved by the Ethics Committee of the Tianjin Chest Hospital and written informed consent was obtained from all participates. Patients were excluded from the present study when the following criteria were met: (1) ST-elevation acute myocardial infarction receiving emergency PCI; (2) receiving alprostadil or contrast media 7 days before surgery; (3) acute renal damage or chronic renal insufficiency (defined as estimated glomerular filtration rate (egfr) < 30 ml/min/ 1.73 m 2 ); (4) severe cardiac insufficiency (left ventricular ejection fraction (LVEF) < 20%) or cardiogenic shock; (5) hypersensitivity to alprostadil or contrast media;(6) use of any nephrotoxic drugs during the perioperative period; (7) severe liver damage, autoimmune diseases, malignant tumor, pregnancy; (8)infectious diseases or fever; (9) refusal of consent. 2.2 Study protocol The present study is a multicentral, prospective, randomized, controlled, double-blind clinical trial. All participates were randomly assigned to two group: the control group and the alprostadil group according to the method of random number table. The control group was given only hydration therapy and the alprostadil group received intravenous administration of 20 ug/day (diluted with 100 ml normal saline) from 0.51 hr before to 3 days after operation on the basis of hydration. The standard hydration routine was carried out as follows: all patients received intravenous hydration with isotonic saline (0.9% sodium chloride) for 612 hr before and after procedure at the rate of 1 ml/kg/h. Hydration rate was reduced to 0.5 ml/kg/h in both arms for patients with LVEF 45%. All patients were given aspirin, clopidogrel 300 mg or ticagrelor 180 mg load dose before procedure, and continued to take aspirin (100 mg/day) and clopidogrel (75 mg/day) or ticagrelor (90 mg twice a day) for at least 12 months. Both groups received subcutaneous injection of low molecular heparin (enoxaparin) q12 h for 3 days after procedure. And other drugs, including angiotensin converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs), b-blockers, calcium channel blockers (CCBs), diuretics and statin, were left to discretion of the cardiologists according to clinical requirements or recommendations of guidelines. All patients underwent implantation of stents according to interventional guidelines of coronary artery disease, with narrowing >70% of culprit lesions stenosis for revascularization therapeutic threshold [10]. Iso-osmolar (iodixanol) or low-osmolar contrast media was employed during PCI. Contrast media volume/calculated creatinine clearance (CMV/CCC) ratio no less than 3 was defined as high-dose contrast loading according to Gurm study [11]. The subjects and the physicians performing PCI were not aware of the assignment group. 2.3 Laboratory parameters Blood samples were collected to measure SCr concentration before alprostadil administration and at 48 and 72 hr after contrast media exposure. Level of hypersensitive C-reactive protein (hs-crp) and blood homocysteine were also measured using commercial kits before and 72 hr after PCI. Estimated glomerular filtration rate (egfr) was calculated using the equation from the study by Levey [12]. 2.4 Study endpoints and definitions The primary endpoint was CIN, defined as an increase in SCr concentration 44.2 umol/l or 25% above baseline within 48 hr72 hr after exposure of contrast media. Furthermore, contrast induced nephropathy was classified into three grades as follows: grade 0-no CIN; grade 1-increase in SCr 25% but<44.2 umol/l; grade 3-increase in SCr 44.2 umol/l. Additional endpoints were: (1) CIN defined by other criteria; (2) the efficacy of alprostadil on prevention of incidence of CIN in prespecified subgroups (age<or 70 years, sex, diabetes mellitus, acute myocardial infarction (AMI), LVEF or>45%, CMV/CCC<or 3, type of contrast media, baseline egfr 60 or or>90 ml/min/ 1.73 m 2, CIN risk score or>5).the CIN risk score was calculated as specified by Mehran et al. [13]. (3) a composite of adverse events in hospitalization, including major adverse cardiovascular events

3 LIANG ET AL. 3 FIGURE 1 Trial flowchart (recurrent myocardial infarction, acute heart failure, cardiogenic shock, left ventricular fibrillation), acute renal failure requiring dialysis and allcause mortality. 3 STATISTICAL ANALYSIS Normally distributed continuous variables, expressed as means 6 standard deviation (SD), were performed using Student t tests. Nonnormally distributed continuous variables, expressed as medians and interquartile ranges, were analyzed using nonparametric tests. Categorical data, expressed as percentages, were analyzed using chi-square or Fisher exact tests. Unconditional logistical regression analysis was performed to evaluate the efficacy of alprostadil treatment on CIN, adjusting for various potential prognostic and confounding factors (age, sex, BMI, acute myocardial infarction, diabetes mellitus, hemoglobin, baseline LVEF, statin, contrast volume, type of contrast media, baseline egfr). The association between treatment and CIN was expressed as odds ratio (OR) and 95% confidence interval (CI). The efficacy of alprostadil was also evaluated in prespecified subgroups (age, sex, diabetes mellitus, acute myocardial infarction, baseline LVEF, CMV/CCC, type of contrast media, baseline egfr, CIN risk score). A p value less than 0.05 was considered significant (2-sided) and a total of 400 patients would give the study 80% power. All statistical analyses were carried out using SPSS software version 20.0 (SPSS, Inc., Chicago, IL, USA). 4 RESULTS The present trial flow chart was shown in Figure patients, 17 of whom did not undergo PCI and 4 of whom had no postoperative SCr values, were excluded. Finally, 240 patients were randomly assigned to the control group and 240 to the alprostadil group. Demographic, clinical, biochemical, procedural variables were presented in Table 1. There were no significant differences between two groups regarding age, diabetes mellitus, clinical presentation, renal function, baseline LVEF, contrast volume and CIN risk score. 4.1 Laboratory test results Changes in SCr, egfr, homocysteine, and hs-crp values before and after PCI were presented in Table 2. There were no significant differences in baseline of laboratory parameters. There were no significant differences in postoperative SCr and egfr values between the two groups. However, postoperative SCr values were significantly higher than preoperative SCr and postoperative egfr values were significantly lower than preoperative egfr in both arms. Postoperative hs- CRP and homocysteine values in the alprostadil group were significantly lower than those in the control group. 4.2 Incidence of CIN The primary endpoint of CIN occurred in 43 patients (8.96%): 15 (6.25%) in the alprostadil group and 28 (11.67%) in the control group, with a crude OR of (95% CI: , P ). Even adjusting for age, sex, diabetes, hypertension, AMI, LVEF, baseline LDL-C, baseline SCr, contrast volume and CIN risk score, this OR remained highly significant (adjusted OR (OR adj : 0.425, 95% CI: , P ). Furthermore, CIN was observed in 225 patients for grade 0, 12 for grade 1, 3 for grade 2 in the aloprostadil group, and 212 for grade 0, 24 for grade 1, 4 for grade 2 in the control group. On the basis of these results, 18.5 patients would need to be treated (NNT) with alprostadil for 3 days to prevent the occurrence of 1 case of CIN. Moreover, alprostadil treatment was correlated with a consistent reduction in the incidence of CIN when other CIN criteria were applied. (Table 3) The multivariable logistic regression analysis (Table 4) revealed that alprostadil treatment was a protective factor of CIN (OR , 95% CI , P ). And low-osmolar contrast media were also independently associated with a decreased risk of CIN. The

4 4 LIANG ET AL. TABLE 1 Baseline characteristics Parameters Control group (n 5 240) Alprostadil group (n 5 240) P Value Age, year Age70 years 54 (22.5) 59 (24.6) Male 158 (65.8) 153 (63.8) BMI, kg/m Clinical presentation AMI 40 (16.7) 28 (11.7) Unstable angina 200 (83.3) ) Hypertension 153 (63.8) 167 (69.6) Diabetes mellitus 74 (30.8) 92 (38.3) Hyperlipidemia 95 (39.6) 94 (39.2) Smoking 108 (45.0) 113 (47.1) Prior MI 45 (18.8) 52 (21.7) Previous PCI 89 (37.1) 86 (36.5) Baseline LVEF, % LVEF45% 20 (8.3) 17 (7.1) Baseline laboratory variables Hemoglobin, mg/dl WBC count, 10 9 /L RBC count, /L Platelet count, 10 9 /L Total cholesterol, mmol/l Triglyceride, mmol/l LDL cholesterol, mmol/l HDL cholesterol, mmol/l Blood glucose, mmol/l CK, U/L 77 (53 109) 79 (62 101) CK-MB, U/L 14 (12 18) 14 (11 18) 0.1 ctnt, ng/ml 0.01 ( ) 0.01 ( ) Serum creatinine, umol/l egfr, ml/min/1.73 m ml/min/1.73 m 2 17 (7.1) 16 (6.7) ml/min/1.73 m 2 86 (35.8) 102 (42.5) >90 ml/min/1.73 m (57.1) 122 (50.8) Hs-CRP, mg/l 1.60 ( ) 1.41 ( ) Homocysteine, umol/l ( ) ( ) Medications at PCI Diuretic 45 (18.8) 33 (13.8) Calcium channel blockers 58 (24.2) 52 (21.7) Beta-blockers 182 (75.8) 187 (77.9) Statins 226 (94.2) 234 (97.5) ACEI 81 (33.8) 89 (37.1) ARB 65 (27.1) 69 (28.8) GP IIb/IIIa inhibitors 26 (10.8) 51 (21.2) PCI data Number of targeted vessels (73.3) 173 (72.1) 2 64 (26.7) 67 (27.9) Number of stents (55.8) 140 (58.3) (44.2) 100 (41.7) Contrast volume, ml CMV/CCC 1.74 ( ) 2.50 ( ) (11.2) 26 (10.8) <3 213 (88.8) 214 (89.2) (Continues)

5 LIANG ET AL. 5 TABLE 1 (Continued) Parameters Control group (n 5 240) Alprostadil group (n 5 240) P Value Type of contrast medium LOCM 211 (87.9) 217 (90.4) IOCM 29 (12.1) 23 (9.6) CIN risk score 4 (1 5) 2.5 (1 4) 0.89 Score distribution (78.7) 195 (81.3) (19.6) 38 (15.8) (1.3) 6 (2.5) 16 1 (0.4) 1 (0.4) Hospital stay, day Data were expressed as mean 6 SD, n (%) or median (interquartile range). ACEI, angiotensin-converting enzyme inhibitor; AMI, acute myocardial infarction; ARB, angiotensin receptor blocker; BMI, body mass index; CIN, contrast-induced nephropathy; CK, creatine kinase; CMV/CCC, contrast media volume/calculated creatinine clearance; ctnt, cardiac troponin; egfr, estimated glomerular filtration; HDL, high density lipoprotein; Hs-CRP, hypersensitive c-reactive protein; GP, glycoprotein; IOCM, iso-osmolar contrast media; LDL, low density lipoprotein; LOCM, low-osmolar contrast media; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; RBC, red blood cell; WBC, white blood cell. independent predictors of CIN included contrast dose, diabetes mellitus and AMI. The advanced age (P ) and a decreased baseline egfr (P ) also intended to increase the risk of CIN. The benefit of alprostadil on prevention CIN in all the prespecified subgroups was presented in Figure 2. A significant reduction of CIN was observed in patients with diabetes mellitus (P ) and in those received lowosmolar contrast media (P ). Moreover, a positive trend also was observed in female patients (P ). On the contrary, the effect of alprostadil was attenuated in the subgroups with acute myocardial infarction (P ), low baseline LVEF (P ) and baseline egfr 60 ml/min/1.73 m 2 (P ). 4.3 In-hospital complications The control group occurred 5 cases adverse events, including 1 case cardiogenic shock, 2 cases nonfatal myocardial infarction, 1 case acute heart failure and 1 case death, and the alprostadil group occurred 2 cases adverse events, including 1 cases nonfatal myocardial infarction TABLE 2 Changes in SCr, egfr, homocysteine and hs-crp Variables Control group Alprostadil group P Value SCr (umol/l) Baseline Day 2 postprocedure a a Day 3 postprocedure a a egfr (ml/min/1.73 m 2 ) Baseline Day 2 postprocedure a a Day 3 postprocedure a a Homocysteine (umol/l) Baseline ( ) ( ) Day 2 postprocedure ( ) a ( ) b Hs-CRP (mg/l) Baseline 1.60 ( ) 1.41 ( ) Day 2 postprocedure 5.74 ( ) a 4.11 ( )ab 0.05 Abbreviations as in Table 1. a P<0.05 compared with baseline. b P <0.05 compared with the same period of the control group.

6 6 LIANG ET AL. TABLE 3 The incidence of primary and additional CIN endpoint Primary CIN endpoint Alproatadil group Control group ORc (95% confidence interval) P value ORadj (95% confidence interval) P value SCr25% or44.2 umol/l within 72 hr 15 (6.2) 28 (11.7) ( ) ( ) CIN classification Grade 0 (SCr<25% and<44.2 umol/l within 72 hr) 225 (93.8) 212 (88.3) ( ) ( ) Grade 1 (SCr25% and<44.2 umol/l within 72 hr) 12 (5.0) 24 (10.0) ( ) ( ) Grade 2 (SCr44.2 umol/l within 72 hr) 3 (1.2) 4 (1.7) ( ) ( ) Additional CIN endpoints SCr25% or44.2 umol/l within 48 hr 13 (5.4) 25 (10.4) ( ) ( ) SCr 26.5 umol/l within 48 hr 7 (2.9) 17 (7.1) ( ) ( ) SCr 26.5 umol/l within 72 hr 10 (4.2) 22 (9.2) ( ) ( ) egfr25% within 72 hr 8 (3.3) 18 (7.5) ( ) ( ) Unconditional logistic model was applied and crude odds ratio (OR c ) with 95% confidence interval was reported. Adjusted OR was controlled (OR adj ) for age, sex, diabetes, hypertension, NSTEMI, LVEF, baseline LDL-C, baseline SCr, contrast volume and CIN risk score. Abbreviations as in Table 1. and 1 cases acute heart failure. There were no significant differences between two groups (2.1% vs 0.8%, P ). 5 DISCUSSION This multicenter, prospective, randomized, controlled trial showed that alprostadil significantly decreased the incidence of CIN in patients undergoing PCI, particularly in high-risk patients with diabetes mellitus. CIN is a frequent complication after intravascular contrast media administration and is closely correlated with prolonged hospitalization, increased costs and increased short and long-term morbidity and mortality [1]. Currently recognized risk factors include pre-existing renal insufficiency, diabetes mellitus, old age and high dose of contrast medium and the incidence of CIN in these high-risk patients is greatly increased [4]. Therefore, it is crucial to preoperatively apply prophylactic interventions to those. The main component of alprostadil is PGE1 and the role of it in renoprotection can be explained as follow. (1) PGE1 can inhibit the transcription of endothelin [14], whereas endothelin-induced vasoconstriction is an important part of the pathogenesis of CIN [4], and PGE1 may exert stronger vasodilatory effects than nitric oxide [5]. (2) PGE1 is also likely to exert reno-protective effects by reducing the inflammatory response and it is believed that inflammation may play a significant role in the progression of CIN. For example, Fan et al. [15] performed a randomized controlled clinical trial and demonstrated that PGE1 decreased inflammatory factors including plasma high-sensitivity C- reactive protein, tumor necrosis factor a and interleukin 6 in patients with unstable angina undergoing PCI, which was similar to our findings TABLE 4 Multi-variables analysis for predictors of CIN Variables Odds ratio 95% confidence interval P value Alprostadil ( ) Male ( ) Age 1.04 ( ) BMI (kg/m 2 ) ( ) AMI ( ) Diabetes mellitus 2.82 ( ) Hemoglobin (mg/dl) ( ) Statin ( ) Contrast volume (ml) ( ) Contrast media type ( ) Baseline LVEF (%) ( ) Baseline egfr (ml/min/1.73 m 2 ) ( ) Abbreviations as in Table 1.

7 LIANG ET AL. 7 FIGURE 2 Effects of Alprostadil on CIN According to Prespecified Subgroups that the hypersensitivity C-reactive protein in the alprostadil group was significantly lower than that in the control group. (3) PGE1 plays a cytoprotective role in ischemia-induced renal dysfunction [6] and is resistant to the direct toxic effects of contrast media on renal tubular epithelial cell [16]. (4) Alprostadil may play a role in protecting renal function by reducing proteinuria and its mechanism may be through down-regulation of angiopoietin-2 and Interleukin-18 expression [17]. For patients with chronic kidney disease (CKD) and diabetes mellitus, they are more prone to outer medulla ischemic injury induced by iodinated contrast media [18] and pre-existing renal insufficiency and diabetes mellitus are also recognized as risk factors [4]. Koch et al. [19] first explored the preventive effect of alprostadil on CIN in patients with renal impairment (SCr 1.5 mg/dl) and found that SCr in the alprostadil group was significantly lower than that in the placebo group after contrast administration. In our subgroup analysis, alprostadil showed a beneficial prophylactic effect in patients with egfr 60 ml/ min/1.73 m 2 (12.5% vs 35.3%) or 61 egfr 90 ml/min/1.73 m 2 (4.9% vs 8.1%), but it not arrived at statistical difference, which was responsible for this phenomenon was that the proportion of patients with renal insufficiency was so small that we could not draw a positive conclusion. In addition, previous studies have demonstrated that alprostadil showed a prophylactic advantage for CIN in patients with diabetes mellitus. Zhang et al. [8] conducted a randomized controlled clinical trial involving 120 patients with coronary heart disease combined with diabetic mellitus undergoing coronary artery intervention therapy and indicated that alprostadil could significantly improve egfr and effectively prevent the occurrence of CIN in such people. Similarly, in the diabetes mellitus subgroup analysis of the present study, it was also confirmed that the effect of alprostadil on the prevention of CIN was more beneficial in the patients with diabetes mellitus (OR , 95% CI , P ).A recently published meta-analysis, involving 969 patients with diabetes mellitus undergoing PCI, also demonstrated that alprostadil could significantly decreased the incidence of CIN and adverse reactions [20]. Therefore, alprostadil may become a promising candidate for prevention of CIN. Advanced age is also considered as risk factors of CIN [4]. In 2013, Xu et al. [21] and Miao et al. [7] demonstrated that alprostadil effectively reduced the occurrence of CIN in elderly patients (age 60 years, age 70 years, respectively). In the subgroup analysis of age 70 years of this study, it was also found that alprostadil showed positive effects on the prevention of CIN in elderly patients, although not reaching statistical differences. Other factors, such as receiving high doses of contrast media, acute myocardial infarction, heart failure, also increase the risk of CIN, which were consistent with our logistic regression results that AMI, diabetes, and contrast volume were independent predictors for CIN. Unluckily, our study included only 68 patients with AMI and 53 patients with CMV/ CCC 3 and the advantages of alprostadil on the prevention of CIN in such patients were not observed. However, in the subgroup analyses of our high-risk patients, the forest plot showed that the effect of alprostadil on the prevention of CIN appeared to be consistent in the subgroups and it was confirmed that there were no interaction effects between alprostadil and control therapy for the incidence of CIN. The main reason of this phenomenon is that most of patients included in this study were at low to medium risk and the proportion of high-risk patients so small that they were underpowered to assess the effect of alprostadil in these high-risk populations. Therefore, whether

8 8 LIANG ET AL. alprostadil was beneficial to these high-risk population still needed to be proved by plentiful well-designed prospective randomized controlled trials. Homocysteine is mainly metabolized by the kidney and clearly correlated with renal function. Elevated levels of homocysteine not only increased risk of atherosclerosis and thrombosis, but also induced vascular damage [22]. In addition, hyperhomocysteine was also associated with direct endothelial damage, decreased bioavailability of nitric oxide, generation of free radicals, increased oxidative stress, dysfunction of the vascular endothelium, and proliferation of vascular smooth muscle cells, which share the proposed pathophysiologic mechanisms of CIN [23]. Furthermore, several studies have demonstrated that hyperhomocysteinemia was independent predictor for CIN [24,25]. In our result, we found that blood homocysteine concentration 48 hr after PCI was significantly lower in the alprostadil group than that in the control group, suggesting that alprostadil may decreased the incidence of CIN by reducing homocysteine. To our knowledge, this study may be the first to detect that alprostadil could decrease homocysteine, thereby preventing the occurrence of CIN. Moreover, this study also found that hs-crp concentration 48 hr after PCI was significantly lower in the alprostadil group than that in the control group, indicating that alprostadil may play an anti-inflammatory effect in the prevention of CIN development by reducing hs-crp. 6 STUDY LIMITATIONS The present study had several limitations. (1) This study excluded patients with renal insufficiency (egfr 30 ml/min/1.73 m 2 ) and hemodynamic instability (systolic blood pressure 90 mmhg), which leaded to low CIN risk score and made our study not to observe the effect of alprostadil on the prevention in patients with high CIN risk score. (2) In this study, the proportions of patients with renal insufficiency (egfr 60 ml/min/1.73 m 2 )and AMI were so small that we failed to draw a positive conclusion on the role of alprostadil in such patients. (3) Moreover, this study excluded patients with adverse cardiac insufficiency (LVEF<20%), defined LVEF 45% as left ventricular failure, and did not add heart failure with preserved ejection fraction to the heart failure queue, which might affect the results of alprostadil on the prevention in the subgroup analysis of heart failure. (4) The SCr values were only monitored before alprostadil administration and at 48 and 72 hr after contrast media exposure, which may miss the peak values and resulted in underestimating the incidence of CIN. (5) We only measured the inflammatory makers of hs-crp and other inflammatory, such as interleukin-6, were not be measured, so the anti-inflammatory mechanism of alprostadil remained to be further studied. 7 CONCLUSION In conclusion, alprostadil treatment was associated with a significantly lower incidence of CIN through multiple mechanisms in patients undergoing elective PCI, and the advantages of alprostadil seems to be beneficial in patients at low to medium risk. Therefore, in order to verify the efficacy of alprostadil in high-risk patients, a large number of welldesigned prospective randomized controlled trials needed performing in high-risk patients. ACKNOWLEDGMENTS This study was supported by a grant of Tianjin Municipal Health and Family Planning Commission (14KG124). CONFLICT OF INTERESTS The authors declared no conflicts of interest with respect to the authorship and/or publication of this article. ORCID Naikuan Fu MD REFERENCES [1] McCullough PA. Contrast-Induced Acute Kidney Injury. J Am Coll Cardiol 2008;51: [2] Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis 2002;39: [3] Windecker S, Kolh P, Alfonso F, et al ESC/EACTS Guidelines on myocardial revascularization. EuroIntervention 2015;10: [4] Wong PCY, Li Z, Guo J, et al. Pathophysiology of contrast-induced nephropathy. Int J Cardiol 2012;158: [5] Prasad PV, Priatna A, Spokes K, et al. Changes in intrarenal oxygenation as evaluated by BOLD MRI in a rat kidney model for radiocontrast nephropathy. J Magn Reson Imaging 2001;13: [6] Paller MS, Manivel JC. Prostaglandins protect kidneys against ischemic and toxic injury by a cellular effect. Kidney Int 1992;42: [7] Miao Y, Zhong Y, Yan H, et al. 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