Statin Use Influence On The Occurrence Of Acute Kidney Injury in Patients With Peripheral Arterial Disease

Abstract

1. Aim

Acute kidney injury (AKI) is an important clinical issue in the diagnosis and treatment of cardiovascular diseases. The association between pretreatment by statins and the occurrence of AKI in patients with peripheral arterial diseases (PAD) remains unclear. Therefore, we examined the association between statin therapy and the occurrence of AKI in patients with PAD.

2. Methods

We retrospectively analyzed data from the endovascular treatment (EVT) database in our hospital. A total of 295 patients who underwent angiography and/or intervention for PAD between October 2011 and March 2016 were enrolled and divided into two groups: those without statins (control group; N=157) and those with statins (statin group; N=138) for at least 1 month before admission. We examined the occurrence of AKI and its related factors in these patients.

3. Results

The serum creatinine levels, dose of contrast medium, use of a renin-angiotensin system inhibitor, smoking habit, and blood pressure were similar in both groups. The statin group had more diabetes patients, significantly younger patients, patients with a higher body mass index (BMI), and patients with lower low-density lipoprotein cholesterol than the control group. Regarding the occurrence of AKI, there was a significantly lower incidence in the statin group compared with the control group (5% vs. 16%, p＜ 0.05). The result of the multivariate analysis indicated that statin therapy was significantly correlated with lower occurrence rates of AKI (p＜0.05).

4. Conclusions

Our study suggests that statin therapy might prevent the occurrence of AKI after angiography and/or intervention for PAD.

5. Keywords

Statin, Acute kidney injury, Peripheral artery disease.

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Introduction

Acute kidney injury (AKI) is associated with increased morbidity and mortality, and patients with severe kidney injury require maintenance hemodialysis. Moreover, even if kidney function is improved, patients with a history of AKI will still have poor outcomes compared with healthy ones 1, 2). Therefore, patients with AKI need a large healthcare cost and lengthened hospital stays 3). AKI has several risk factors, such as older age, obesity, anemia, chronic kidney disease (CKD), hypertension, diabetes mellitus, heart failure, cardiovascular disease (CVD), surgery, and diuretics. Another important risk factor is the dose of contrast medium4-6). Particularly, in patients with CKD, the prevalence of CVD is very high, and they often face situations that require the use of a contrast medium7, 8). To prevent the occurrence of AKI, several guidelines recommend intravenous hydration with normal saline or sodium bicarbonate before the administration of contrast medium as a standard precaution9-12). However, AKI following contrast medium administration cannot be completely prevented. Multiple meta-analyses reported that the onset of AKI in coronary angiography and intervention was significantly suppressed by pretreatment with statins in addition to hydration by isotonic saline 13-15).

The presence of peripheral arterial disease (PAD) is closely associated with amputation, other CVD, and mortality. The coexistence of PAD and impaired kidney function has been reported to additively increase mortality rates 16, 17). Thus, preserving kidney function in patients with PAD seems to be essential. However, there is no specific information on the prevention of AKI about PAD, and the effectiveness of pretreatment with statins for AKI in patients with PAD has not been fully elucidated.

Therefore, we conducted a retrospective study that investigated whether the use of statins was related to the occurrence of AKI in patients with PAD.

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Methods

1. Study Design and Population

This was a single-center, retrospective, observational study and was conducted by the principles stated in the Declaration of Helsinki. Our study protocol was approved by the appropriate institutional review committee (no. 28005).

A total of 377 patients were hospitalized at our institution between October 2011 and March 2016 who underwent angiography and/or intervention for PAD (Fig.1). PAD was diagnosed by subjective and objective complaints and findings arising from leg ischemia and/or ankle-brachial index ＜0.9. All the patients underwent ultrasound scans, computed tomography, or magnetic resonance angiography to confirm stenosis of the peripheral artery. The severity of PAD was evaluated using the Rutherford classification. Patients who underwent hemodialysis (N=69) and those with insufficient clinical data (N=13) were excluded from the study. Those who took statins for less than 3 months were also excluded. Consequently, 295 patients were included in the analysis. These patients were divided into two groups: those who were taking statins (statin group; N=138) and those who were not taking statins (control group; N=157). All the study patients received standard hydration therapy before and after angiography and/or intervention for PAD. Isotonic saline (0.9% sodium chloride, 1 mL/kg/h) was administered every 12 h before and after the procedure. The low-molar, nonionic contrast medium iopamidol (370 mg iodine/ mL, iopamiron®) was used for all procedures. AKI was defined by the absolute increase in serum creatinine (SCr) of ≥ 0.5 mg/dL or a relative increase of ≥ 25% measured within 1 week after performing the procedures according to the KDIGO guideline10).

Fig.1. Enrollment flow diagram for the present study

2. Statistical Analysis

Data for continuous variables are expressed as values±standard deviation, whereas non-normally distributed variables were expressed as median (quartile). The differences between the groups were analyzed using Student's t-test or the Mann–Whitney U test. Categorical variables were expressed as frequencies and percentages, and comparisons were performed using the chi-squared test. Multivariate logistic regression analysis was also performed. For the matching of the clinical characteristics between the two groups, the propensity score was calculated using a logistic regression model from the following factors: sex, age, body mass index (BMI), hypertension, diabetes mellitus, creatinine, use of renin-angiotensin system inhibitors, and dose of contrast medium. Propensity score matching was performed using a nearest-neighbor 1:1 matching between the statin and control groups. P values ＜ 0.05 were considered statistically significant. Statistical analyses were conducted using the JMP software version 9.0.3 (SAS Institute Inc., Cary, NC).

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Discussion

The present study demonstrated that (1) the use of statin was significantly associated with a lower prevalence of AKI following angiography and/or intervention for PAD, and (2) the dose of contrast medium was significantly correlated with the changes in the eGFR.

PAD is an important complication as its progression is related to critical problems, such as claudication, rest pain, ischemic ulcers, amputation, and hospitalization11). Since most patients with PAD have diabetes and dyslipidemia, they are at high risk for atherosclerotic CVD progression18). It has been reported that patients with PAD have a higher risk for myocardial infarction, stroke, and mortality compared with those without PAD19-21). Our study participants also frequently had complications associated with CVD, such as coronary artery disease, stroke, and aortic disease. Furthermore, although kidney function is also an important risk factor for CVD, this study included 152 patients with CKD at baseline (51.5%). Therefore, preventing the further progression of kidney dysfunction seems to be very important to improve the patient's quality of life and prognosis.

Although several etiologies of AKI following angiography and/or intervention in patients with PAD have been proposed, its pathophysiological mechanisms are very complex. The dose of contrast media, cholesterol embolization, infection, and anemia due to bleeding has been suggested to contribute to the occurrence of AKI following angiography and/or intervention22-26). Among them, the dose of contrast media is the most crucial risk factor in clinical settings. The mechanisms of AKI due to the dose of contrast media involve endothelial cell injury, tubular epithelial cell injury, and impaired kidney microcirculation by exerting direct toxic effects and altering the kidney hemodynamics27-29). The dose of contrast media is reported to enhance the formation of reactive oxygen species and thereby reduce microcirculation by decreasing nitric oxide production30). Furthermore, many studies reported that the dose of contrast media is associated with the occurrence of AKI 31, 32). Therefore, contrast media reduction is recommended by current guidelines 10-12). Our data also indicated that the dose of contrast media was significantly associated with changes in the eGFR. Furthermore, this significant correlation was observed in both the control and statin groups.

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Statins are commonly used medications and are prescribed extensively for lowering cholesterol levels to prevent CVD. Several recent studies showed that statins did not only have lipid-lowering effects but also pleiotropic effects 33-35). Several randomized controlled trials demonstrated the effectiveness of statins in the prevention of AKI after contrast media-induced nephropathy in patients undergoing coronary angiography36-38). The occurrence rates of AKI in patients with and without statins were 3.7% and 8.3%, respectively. Nevertheless, there were no reports on the prevention of AKI following angiography and/ or intervention using statins in patients with PAD. Thus, we investigated the possible effects of statins on the occurrence of AKI in these patients. The result of our study indicated that the occurrence rates of AKI in patients with and without statins were 5.0% and 15.0%, respectively. The number of patients with AKI who were undergoing coronary angiography was greater in the present study than in the previous studies. A previous systematic review that included 11,311 patients with PAD has reported that the median incidence of AKI in the studies was 10%39). This result corresponded with our study results. We speculated that the difference in the AKI rate was caused by the other underlying diseases experienced by these patients because patients with PAD might have more severe atherosclerotic lesions 18). In addition, the dose of statins was lower in this study than in other previous studies, given that the dose admitted by health insurance providers in Japan is different from that in other countries. Therefore, this finding would be valuable because the findings from our study suggested that low-dose statin therapy might prevent the occurrence of AKI even in patients with PAD who are undergoing angiography and/or intervention.

This study had several limitations. The number of enrolled patients was relatively small. Therefore, there was a possibility that we could not perform statistically sufficient adjustments. In addition, long-term evaluation was not conducted in this study. A long-term study is needed to ascertain the influence of statins on kidney function.

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Conclusions

Our data suggest that the use of statins might reduce the occurrence of AKI after angiography and/ or intervention for PAD. However, a further detailed study is needed to prove the reno-protective effects of statins.

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Daisuke Kanai1, 2, Hideki Fujii1 , Kentaro Nakai2 , Keiji Kono1 , Kentaro Watanabe1 , Shunsuke Goto1 and Shinichi Nishi1

1 Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan

2 Department of Nephrology and Kidney Center, Kakogawa Central City Hospital, Hyogo, Japan