Contrast induced nephropathy (CIN) has been the third leading cause of hospital-acquired renal failure,1 and the incidence of CIN is 3%-14% and higher in patients with renal dysfunction and diabetes (>20%).2 Currently, high-dose statins have been confirmed to be protective of kidney injury in patients undergoing percutaneous coronary intervention (PCI), but there is no report showing that statins can reduce the incidence of CIN, and patients seldom use statins at a high dose, such as 80 mg/d.3–5 Alprostadil (prostaglandin E1), as one of the vasodilators, may also be effective treatment for CIN. Pilot studies6,7 showed that prostaglandin E1 was able to lower the rate of serum creatinine (SCr) increase in patients with pre-existing renal impairment who underwent intravascular iodinated radiocontrast media (RCM) injection as compared to patients treated with a placebo. These two drugs can protect the kidneys by different mechanisms. However, whether combined therapy with both alprostadil and statins was more effective than monotherapy with alprostadil or statins alone in preventing CIN in patients with renal failure who underwent coronary angiography is not known.
This study was approved by the Ethics Committee of Shanghai Tenth People's Hospital. A total of 170 consecutive patients were enrolled in the Department of Cardiology, Shanghai Tenth People's Hospital from February 2011 to February 2012. The inclusion criteria were as follows: patients were 18–75 years old, had or had no history of statins treatment, were not treated with prostaglandins (PGs) before this study, and patients were diagnosed with mild to moderate chronic kidney disease (CKD). On the basis of estimated glomerular filtration rate (eGFR) (ml · min-1· 1.73 m-2), mild and moderate CKD was defined at 60–89 ml · min-1· 1.73 m-2 and 30–59 ml · min-1· 1.73 m-2, respectively. eGFR was calculated from serum samples with the “Cockcroft-Gault” formula: 8 creatinine clearance (Ccr) (ml/min) = ((140-age) ×body weight (kg))/ (0.818 × Scr (μmol/L)).
Patients were excluded for the following reasons: acute renal failure, end-stage renal disease requiring dialysis, unstable renal function, uncontrolled diabetes mellitus/ hypertension/hyperthyroidism, New York Heart Association class IV congestive heart failure or left ventricular ejection fraction (LVEF) of <35%, intra-arterial or intravenous administration of iodinated RCM from seven days before to 72 hours after administration of agents in the present study, any medication to prevent CIN (such as N-acetylcysteine (NAC)), or intake of nephrotoxic agents from 24 hours before to 24 hours after administration of agents in the present study. Importantly, patients treated with ascorbic acid within 30 days before the study were excluded.
On admission, patients were fully informed about the study protocol, and informed consent was obtained. Eligible patients were randomly divided into two groups: 85 patients received statins treatment and 85 underwent combined therapy with statins and alprostadil. For patients treated with statins before the study, the drug and dose remained unchanged. For the remaining patients, atorvastatin (40 mg) was administered at 12–24 hours before and seven days after coronary angiography. The statins used in the present study were as follows: 20 mg of atorvastatin in 59, 40 mg of atorvastatin in 40, 10 mg of rosuvastatin in 41, 20 mg of simvastatin in 19, and 40 mg of fluvastatin in 11 patients. In the alprostadil plus statins group, the alprostadil (20 μg/d) was intravenously administered for seven days starting at one day prior to coronary angiography. All patients received standard hydration:9 intravenous infusion of normal saline at 1.0–1.5 ml· kg-1 · h-1 for 3–12 hours before and 6–24 hours after coronary angiography.
Coronary angiography or PCI was performed via the radial or femoral artery, the arterial stenosis was graded by the Coronary Angiogram Analyzing System II (CAAS II; Pie Medical, Maastricht, the Netherlands). 10 Coronary flow over the culprit lesion was graded according to the Thrombolysis in Myocardial Infarction (TIMI) trial criteria, and collateral circulation was classified according to the criteria reported.11 Multi-vessel coronary artery disease (CAD) was defined as the presence of lesions in three or more coronary arteries. The presence of occlusion in major and secondary branches of a coronary artery was defined as single-vessel disease. All patients received iso-osmolar, nonionic iodixanol (a contrast agent) injection (Visipaque, JX20080286, GE Healthcare Ireland).
Measurement of laboratory parameters
Blood samples were collected in the morning on the day prior to and within three days after coronary angiography. SCr was measured by the Jaffe method with an autoanalyzing system in the Department of Laboratory Medicine of our hospital. The normal range of SCr is 44–133 μmol/L. CIN was described as a baseline SCr of ≥25% and/or an absolute increase in SCr of ≥0.5 mg/dl at 48 hours after coronary angiography.12
Blood samples were collected in the morning on the day prior to, and at 6, 24, and 48 hours after coronary angiography to measure the serum cystatin (CysC) and neutrophil gelatinase-associated lipocalin (NGAL). CysC was detected by using turbidimetric immunoassay with a kit (Mike Biotechnology Co., Ltd, Sichuan, China). The normal range of CysC is 0.78–1.90 mg/L. CIN was described as a CysC increase of ≥25% after coronary angiography.13 NGAL was measured by enzyme-linked immunosorbent assay (ELISA) with a kit (BD Biosciences, USA).
Data were collected during the follow-up period in the following ways: reviewing patients' medical records, interviewing patients via telephone, and examining patients in outpatient clinics. The patients' characteristics, history, medications, hospital stay, and the side effects of drugs (such as itching, flushing, transitory rash, vomiting, hypotension, bronchospasm and fever) were recorded during hospitalization. Major adverse cardiovascular events (MACE) including cardiac death, nonfatal myocardial infarction, and ischemic stroke were recorded. Other adverse events were also recorded, such as end-stage kidney disease, revascularization, coronary artery bypass graft surgery, congestive heart failure or pulmonary edema, and need for permanent pacing. The mean follow-up duration was (6±1) months.
The sample size calculation was determined using the estimation of differences in CIN incidence between the two groups. The sample size was selected to demonstrate a 35% incidence of CIN in the statins group and a 50% decrease in the alprostadil plus statins group. Using a 2-sided chi-square test and a significance level of P <0.05, a total sample size of 140 patients (70 in each group) would provide 80% power to detect the difference with an alpha level of 0.05. A sample size of 168 patients (84 patients in each group) was planned, taking into account the likelihood of incomplete data collection, protocol violations, and patients lost to follow up (estimated 20% total).
Quantitative data are expressed as mean ± standard deviation (SD), and qualitative data as frequencies. In univariate analysis, quantitative data were compared using the Student's t-test. Qualitative data were analyzed by using the chi-square test or Fisher's exact test when appropriate. The Kaplan-Meier method was used to analyze the timing of MACE or other adverse events during the follow-up period. Statistical analysis was conducted with SPSS version 13.0 for Windows (SPSS Inc., IL, USA) and a value of P<0.05 was considered statistically significant.
Complete laboratory tests were not available in eight patients (statins group 3 patients, alprostadil plus statins group 5 patients); and six patients were lost to follow up (statins group 2 patients, alprostadil plus statins group 4 patients). These 14 patients were excluded from final analysis. Finally, there were 156 patients with an average age of (65.8±6.9) years.
Baseline characteristics and study population
There were 80 patients in the statins group and 76 patients in the alprostadil plus statins group. There were no significant differences in age, gender, body mass index (BMI), concentrations of hemoglobin, lipid, hypersensitivity C reactive protein (hsCRP), N-terminal pro-brain natriuretic peptide (NT-pro-BNP), eGFR, Scr, CysC, and NGAL on admission, nor in the history of hypertension, diabetes and medications between the two groups (P>0.05, Table 1). There were no significant differences in the types of statins used and in the dose and delivery of statins between the two groups (Table 2). No significant differences were observed in coronary angiography, stent implantation, and total contrast volume (Table 3).
Changes in SCr
Preoperative and postoperative SCr concentrations were comparable between the two groups. SCr concentrations were significantly elevated at 24 hours when compared with baseline. SCr concentrations reached their peak at 48 hours, and fell off by 72 hours, but the level was still higher at 72 hours than the preoperative concentration (Table 4, Figure 1).
Changes in serum CysC and NGAL
Preoperative CysC and NGAL concentrations were similar between the two groups. CysC concentrations were elevated markedly at 6 hours, peaked at 24 hours, and began to recede at 48 hours. Postoperative CysC concentrations were dramatically lower in the alprostadil plus statins group at 24 and 48 hours than in the statins group (P=0.012 and P=0.006) (Table 4, Figure 1). Serum NGAL was significantly elevated and reached a maximal level at 6 hours after coronary angiography. The serum NGAL was significantly lower in the alprostadil plus statins group than in the statins group (P=0.002) (Table 4, Figure 1).
Incidence of CIN
The incidence of CIN was 7.5% (6/80) in the statins group and 6.6% (5/76) in the alprostadil plus statins group according to SCr increases of ≥25%, and 11.2% (9/80) and 9.2% (7/76) based on CysC increase of ≥25%. The proportion of patients with CIN in the alprostadil plus statins group was slightly lower than the statins group, but the difference was not significant.
Tolerance during hospitalization
There were no serious adverse events during hospitalization; most events were resolved without specific treatments. The hypotension and dizziness were relieved through slowing the infusion rate. No serious cardiac adverse events (recatheterization, acute myocardial infarction, pulmonary edema, sudden death, etc) were recorded during the study.
Incidence of adverse events
Twenty-seven (17.3%) of the 156 patients experienced 36 adverse events. Eight patients in the statins group and three patients in the alprostadil plus statins group experienced a major event: cardiac death, nonfatal myocardial infarction, or ischemic stroke. Eighteen patients in the statins group and seven patients in the alprostadil plus statins group experienced other adverse events during the period of follow-up: such as end-stage kidney disease, revascularization, coronary artery bypass graft surgery, congestive heart failure or pulmonary edema, need for permanent pacing. The incidence of adverse events within six months after coronary angiography in the alprostadil plus statins group was significantly lower when compared with the statins group: 23.7% (19/80) vs. 10.5% (8/76) (P=0.035). The Kaplan-Meier survival curves of adverse events in the two groups are shown in Figure 2.
CIN associated with long-term adverse events
Sixteen patients suffered from CIN, and 27 patients experienced adverse events. The incidence of adverse events was statistically higher in CIN patients than in non-CIN patients: 37.5% (6/16) vs. 15.0% (21/140); P=0.036.
CIN has become a hot focus topic in cardiovascular medicine. Patients with CIN have a high incidence of vascular complications. Levy et al13 found that CIN patients had longer hospital stays and higher intra-hospital mortality. Even mild changes in SCr were found to be associated with poor outcomes.14 Hydration has been confirmed as an effective measure to prevent CIN, but the application of other prophylactic agents such as N-acetylcysteine, calcium channel blockers, vitamin-C, hypotonic or isotonic contrast agent remains controversial.15–18 Despite the clinical importance of CIN, the effective preventive strategies for CIN are largely unknown.
Our study examined for the first time combined therapy with alprostadil and statins in CIN patients. SCr, CysC and NGAL were employed as markers to evaluate the renal function, and patients were followed up for six months to monitor adverse events. Results demonstrated a synergistic effect of statins and alprostadil on renal failure in patients undergoing coronary angiography or PCI. The incidence of adverse events within six-month after coronary angiography was also lower in the alprostadil plus statins group.
Previous studies have found that several conditions contribute to the development of CIN, such as vasoconstrictive factors resulting in medullary ischemia, compromised local prostaglandin-mediated vasodilatation, and oxygen radical induced damage.19 However, the complex pathophysiology of CIN suggests that combined measures might be more effective than a single strategy in preventing CIN.
Statins, mainly used as cholesterol-lowering agents, are known to have pleiotropic effects: such as anti-oxidative and anti-inflammatory properties.20 Given the potential role of oxidative stress in the pathophysiology of CIN, statins might reduce the RCM induced nephrotoxicity by removing free radicals. To date, most studies have suggested that long-term use of statins is protective against CIN, but whether statins can prevent the development of CIN is poorly understood. 21 A meta-analysis5 supports the effectiveness of pretreatment with short-term high-dose statins in decreasing serum creatinine and reducing the incidence of CIN in patients who underwent diagnostic and interventional procedures requiring contrast media.
Alprostadil, mainly used in the treatment of pulmonary hypertension, can inhibit platelet aggregation and thrombosis, improve microcirculatory perfusion, inhibit the transcription of endothelin and exert cytoprotective effects. Prostaglandins have also been shown to ameliorate renal impairment. Studies have shown that alprostadil may improve renal function; dilate renal vessels, increase renal blood flow, inhibit platelet aggregation, prevent thrombosis, reduce blood viscosity and erythrocyte aggregation, decrease inflammatory mediators, and suppress inflammatory cell infiltration.22,23 A pilot study on 117 patients receiving three separate doses of alprostadil or placebo suggested that RCM-induced nephropathy was improved in the prostaglandin group, but alprostadil at higher doses caused frequent hypotension and a higher incidence of nephropathy. Alprostadil lowers blood pressure by dilating blood vessels contributing to its protective effect.24
In our study, patients who were treated with 20 μg/d alprostadil in combination with statins were monitored for further analysis. Results confirmed that the combined treatment was more effective than single agent treatment in preventing CIN. Moreover, few adverse events were observed during hospitalization in the statins group. Patients who developed CIN may experience more long-term adverse events because of this comorbidity. However, the pathophysiologic relationship between CIN and adverse clinical events was not investigated in the present study, which may undermine the biologic plausibility of this association.
In clinical practice, the detection of acute renal failure (ARF), which is characterized by a rapid decline in glomerular filtration rate (GFR), is based on an increase in SCr.25 However, there are limitations in the application of Cr for evaluating GFR. Scr cannot accurately reflect GFR in the unsteady state of ARF. Thus, minor changes in Cr, as seen in early ARF, may reflect a substantial decline in GFR. Furthermore, tubular secretion and reabsorption of creatinine, and non-renal factors in critically ill ARF patients, may influence the evaluation of GFP with Cr.26 CysC is freely filtered by glomeruli, reabsorbed, and catabolized, but it is not secreted by tubules.27 CysC is not susceptible to the influence of age, gender, muscle index and tubular secretion, especially the mild GFR reduction.28 Cystatin C permits the identification of ARF 1–2 days earlier than SCr does. NGAL also markedly increases in renal tubular cells and is easy to detect in plasma and urine of animals with ischemic and nephrotoxic AKI.29 NGAL also dramatically increases in renal tubules of patients with ischemia, sepsis, and AKI who undergo cardiac catheterization and angiography with RCM.30
Our results confirmed that cystatin C and NGAL can identify ARF much earlier and more accurately than SCr does. Due to the relatively small sample size, a definite conclusion could not be drawn about the incidence of CIN in patients of our study. In addition, this was a singlecenter study, which limits the extrapolation of our findings. More comprehensive, multi-centered, prospective, and randomized studies are required to confirm our findings.
In conclusion, our findings suggest that combined therapy with alprostadil and statins may exert a synergistic effect on CIN in patients with mild to moderate renal dysfunction who undergo coronary angiography and/or PCI. Combined therapy is also helpful to reduce the adverse events within six months after coronary angiography and/or PCI.
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Keywords:© 2013 Chinese Medical Association
alprostadil; statins; renal failure; coronary angiography