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Angiotensin-Converting Enzyme Inhibitor Prevents the Worsening of Renal Function in the Late Phase after Percutaneous Coronary Intervention

Aim : The amount of contrast media and renal atheroemboli are risk factors for acute kidney injury after percutaneous coronary intervention (PCI). However, the chronic kidney injury after PCI has not been fully characterized. The purpose of this study was to investigate factors affecting renal function in the late phase after PCI by measuring serum Cystatin C (CysC). Methods : In 143 consecutive patients who underwent elective PCI, CysC was evaluated at baseline and at 9 months after PCI, and the percent change in CysC (%CysC) was calculated. The association 2016; 23: 233-240.


Introduction
Percutaneous coronary intervention (PCI) is widely performed for the management of ischemic heart disease. The use of statin suppresses the progression of coronary plaques 1) . Novel antiplatelet medicines are developed and have a strong antiplatelet effect in patients undergoing PCI 2) . A recent study has reported that even in patients with diabetes mellitus and multivessel coronary disease, complete revascularization via PCI leads to lower long-term mortality 3) . However, acute kidney injury (AKI) can occur after PCI and is associated with increased mortality 4, 5) . The amount of contrast media and the renal atheroemboli dislodged from the aorta by the guide catheter are major risk factors for AKI after PCI 6,7) . Previous studies have demonstrated that chronic kidney disease (CKD) is an independent risk factor for cardiovascular events and technique. The approach site (transfemoral or transradial) and sheath size were selected on the basis of the operator's judgement. All patients received dual antiplatelet therapy and intravenous heparin before the procedure. In patients with the serum Cr level greater than 1.2 mg/dL, intravenous hydration with normal saline was provided at a rate of 1 ml/kg/h for 12 h before and after PCI. A nonionic iso-osmolar contrast media was used during PCI. All patients underwent follow up coronary angiography at 9 months after PCI.

Assessment of Renal Function
Blood samples were drawn before PCI, and serum CysC and Cr concentrations were measured. The serum CysC was measured using a colloidal gold par-all-cause mortality, and that CKD indicates cardiovascular events as strongly as other established risk factors 8) . However, the phenomenon of chronic kidney injury developing after PCI has not been fully elucidated, and factors affecting renal function in the late phase after PCI are unknown.
The serum creatinine (Cr) concentration is commonly used for the evaluation of renal function. However, the serum Cr concentration is affected by several factors, such as age, gender, and body weight 9, 10) . Therefore, serum Cr concentration may not be accurate for the evaluation of renal function 11) . Serum Cystatin C (CysC) is a new endogenous biomarker of renal function and is less influenced by age, gender, and body weight. Measurement of CysC can also detect AKI after PCI, and serum CysC is more sensitive than the serum Cr in the early stage of renal dysfunction. A previous study suggested that CysC is superior to serum Cr as a marker of renal function and is a stronger predictor of the risk of death and cardiovascular events among the elderly 12) . Furthermore, a recent study has reported that CysC correlated with carotid intima-media thickness, which is an established maker of atherosclerosis in patients without symptoms 13) .

Aim
The purpose of this study was to evaluate the change in renal function in the late phase after PCI by measuring the serum CysC and to investigate factors affecting the change in renal function in the late phase.

Study Population
In this retrospective cohort study, subjects consisted of 143 consecutive patients with stable angina who underwent both elective PCI and 9-month follow-up coronary angiography at Kagoshima University Hospital from January 2010 to July 2013. The serum CysC was measured before PCI and at 9 months after PCI. Patients who underwent cardiogenic shock or in whom intra-aortic balloon pumping was used during PCI were excluded from this study because cardiogenic shock and the use of an intra-aortic balloon pump are risk factors for AKI. Patients treated with hemodialysis were also excluded. The institutional ethic committee of Kagoshima University Hospital approved this retrospective study. All patients provided written informed consent.

PCI Procedure
Elective PCI was performed using a standard female subjects) 14) . The grade of renal function was classified based on the level of eGFR 15) . Nine months after PCI, the serum concentrations of CysC and Cr were reassessed. In our institution, follow-up coronary angiography is performed at 9 months after PCI, and blood test is also performed. Therefore, we evaluated the change in renal function at 9 months after PCI as Values are mean SD. WRF, worsening renal function; Hb, Hemoglobin; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; TG, triglycerides; UA, uric acid, FPG, fasting plasma glucose; HbA1C, hemoglobin A1C; BNP, B-type natriuretic peptide; BUN, blood urea nitrogen; Cr, creatinine; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction. receiving ACEI, those receiving angiotensin II receptor blocker (ARB), and those receiving neither medication]. Steel -Dwass analysis was used for post hoc analysis. Statistical analyses were performed using SAS software (JMP version 11.0). A value of p 0.05 was considered to indicate statistical significance.

Baseline Characteristics
The baseline clinical characteristics of the patients are shown in Table 1. Mean age was 67 9 years, and 108 (76%) patients were men. ACEI and ARB were prescribed for 36 (25%) and 66 (46%) patients, respectively, and there were no patients who were taking both ACEI and ARB. In 104 (73%) patients, PCI was performed via the transfemoral approach. The mean volume of contrast media was 160 58 ml. The serum CysC was 1.06 0.27 mg/L, and eGFR was 65.7 17.2 ml/min/1.73 m 2 at baseline. Seventy-six (53%) patients had G2 renal dysfunction classified based on the level of eGFR (Table 1).
the late phase. The percent change in CysC [%CysC (CysC at 9 months CysC at baseline)/CysC at baseline 100] was calculated. The recruited patients were divided into two groups depending on the %CysC. Patients with a %CysC of ≥ 0 were defined as the worsening renal function (WRF) group, and the remaining patients with a %CysC of 0 were defined as the non-WRF group.

Statistical Analysis
Continuous variables are expressed as mean SD. The 2 test was used to compare the incidence of categorical variables. Continuous variables were compared between WRF and non-WRF groups using the Wilcoxon rank-sum test because CysC data were not normally distributed. Logistic regression analysis was applied to investigate the relationship between WRF and factors. When comparing %CysC between patients who received angiotensin-converting enzyme inhibitor (ACEI) and those that did not receive such medication, %CysC data were expressed as median and interquartile ranges. The Kruskal -Wallis ANOVA was used to compare %CysC among three groups [e.g., those  . 2).

Discussion
The current study demonstrated that in patients with stable angina, baseline CysC and ACEI were inversely associated with a deterioration in renal function at 9 months after PCI. In comparison, baseline Cr and eGFR did not correlated with WRF. Furthermore, the %CysC in patients with ACEI was significantly lower than that in patients with ARB or in those who were not taking either medication, suggesting that ACEI has a protective effect against WRF in the late phase after PCI.

Effect of ACEI on Renal Function after PCI
AKI is a critical complication that can occur after PCI and is associated with increased mortality 4, 5) . Previous studies documented that AKI after PCI might be caused by multiple factors, including hemodynamic instability, the amount of contrast media, renal atheroemboli dislodged from the aorta by the guide catheter, and drug toxicity 6, 7) . It has not been determined

Comparison of Patients' Characteristics According to Change in Renal Function
Eighty-six patients had worsening renal function (WRF; %CysC ≥ 0) after PCI, and 57 patients did not (non-WRF; %CysC 0). Table 2 shows the comparison of patient characteristics between WRF and non-WRF groups. There were no significant differences in age, body mass index, gender, or the amount of contrast media between the two groups. The WRF group had a larger proportion of patients with hypertension when compared with the non-WRF group. The use of ACEI in the WRF group was lower than that in the non-WRF group (15 vs. 40%, p 0.001). There was no significant difference in baseline serum Cr between the two groups. In contrast, the baseline CysC in the WRF group was significantly lower than that in the non-WRF group (1.02 0.26 vs. 1.13 0.26 mg/L, p 0.015) ( Table 2).

Influence of Baseline Characteristics on Change in Renal Function after PCI
Logistic analysis was performed to investigate the association between WRF after PCI and baseline patient characteristics, including the use of medications (Table 3). In univariate analysis, the use of ACEI was negatively associated with WRF [odds ratio (OR) 0.26, 95% confidence interval (CI) 0.12 -0.57, p 0.001]. Baseline CysC also had a negative correlation with WRF (OR 0.20, 95%CI 0.05 -0.73, p 0.015). On the other hand, neither the baseline Cr nor the eGFR significantly correlated with WRF. Multivariate analysis revealed that both the use of ACEI and CysC independently correlated with WRF (ACEI: OR 0.26, 95%CI 0.11 -0.57, p 0.001 and CysC: OR 0.20, 95%CI 0.05 -0.74, p 0.016, respectively).

Association between ACEI and Change in Renal Function
The use of ACEI had the strongest negative correlation with WRF after PCI in multivariate analysis. Therefore, an additional analysis was performed between patients with and without ACEI. The %CysC in 36 patients with ACEI was significantly lower than that in 107 patients without ACEI [median, 3.8%; interquartile range (IQR), 11.0% -4.2% vs. median, 3.3%; IQR 2.9% -11.0%; p 0.001] (Fig.1). Of 107 patients who were not taking an ACEI, 66 patients were taking an ARB, and the remaining 41 patients were not taking either medication. %CysC was compared among patients with ACEI (n 36), with ARB (n 66), and without either medication (n 41); %CysC was significantly different among three groups (p 0.013). %CysC in patients with ACEI was significantly lower tion of NO promotes severe and progressive arterial hypertension and renal injury 26,27) and that NO protects the glomerular filtration barrier from injury caused by superoxide 28) . Another possible mechanism is that angiotensin II (Ang II) increases the expression of plasminogen activator inhibitor-1 (PAI-1) via angiotensin IV (Ang IV) 29) . The expression of PAI-1 is increased in renal disease, and PAI-1 participates in the fibrosis of the kidney 30) . ARB directly inhibits the binding of Ang II to Ang II type 1 receptor. Consequently, Ang II levels increase, upregulate Ang IV, and increase the expression of PAI-1. In contrast, ACEIs decrease Ang II levels by blocking angiotensin-converting enzyme. The current study is retrospective; therefore, we could not evaluate the levels of PAI-1 via Ang IV. To confirm the above mentioned possible mechanism, further investigations are necessary to clarify the association between %CysC and PAI-1 levels derived from ACEI or ARB by short or long time-interval observation.

Measurement of CysC for the Assessment of Renal Function
Cystatin C is a novel endogenous marker of renal whether treatment with reninangiotensinaldosterone system (RAAS) blockers, such as ACEI and ARB, decreases the frequency of AKI after PCI 16,17) . Dangas, et al. reported that the use of ACEI might have a protective effect against AKI after PCI in patients with CKD 5) . On the other hand, a few studies concluded that taking RAAS blockers is an independent risk factor for AKI 18,19) . Considering the preventive effect of ACEI on the decline in renal function in patients with CKD in previous long-term follow-up studies in which patients were not treated with PCI 20,21) , ACEI might contribute to the prevention of renal dysfunction in the acute phase after PCI. However, it is speculated that the hemodynamic instability, the amount of contrast media, and the occurrence of renal atheroemboli have a more powerful adverse effect on renal function when compared with the protective effect of ACEI on renal function in the acute phase after PCI. The present study demonstrated the protective effect of ACEI on renal function in the late phase after PCI, which is consistent with the preventive effect of ACEI on renal function seen in previous studies 20,21) . The renal protective effect of ACEI after PCI might be more prominent in the long-term, at a point at which the effect of hemodynamic instability, the amount of contrast media, and the occurrence of renal atheroemboli has waned.

Different effects of ACEI and ARB on Renal Function
RAAS blockers inhibit the reninangiotensin system and have renal protective effects. These drugs are first-line agents for the treatment of CKD 22) . RAAS blockers expand the efferent glomerular arteriole and lead to a decrease in urine protein by reducing internal pressure of the glomerulus. As a result, these drugs might restrain the progression of renal dysfunction in the long term. Several studies reported that there were no significant differences in the prevention of renal dysfunction when comparing ACEIs and ARBs 23,24) . On the other hand, although Ramipril is not available in Japan and its dose was extremely high, an ONTAR-GET study, which included patients with high vascular risks, demonstrated that the degree of the drop of eGFR in the ARB group was significantly bigger than that in the ACEI group at the 2-year follow-up time point 25) . Similarly, the current study suggested that ACEI has a stronger protective effect on renal function in the late phase after PCI when compared with that of ARB. This difference may be derived from the fact that ACEIs increase serum and tissue bradykinin levels, thereby leading to an increase in nitric oxide (NO). Previous studies demonstrated that the inhibi- ration of renal function at 9 months after PCI. These data suggest that ACEI protects against WRF in the late phase after PCI.

Conflict of Interests
The authors declare that they have no conflicts of interest.  31) . Furthermore, several studies reported that CysC is more accurate than serum Cr in estimating renal function, particularly in patients with mild to moderate chronic renal failure 32,33) . In the present study, we estimated renal function at 9 months after PCI by measuring serum CysC. Baseline CysC is independently associated with WRF, but baseline Cr had no significant association with WRF. We speculate that the use of CysC for renal function might result in a more accurate evaluation of renal function when compared with serum Cr because patients had mild to moderate renal dysfunction in our study. Microalbuminuria also seems to be a sensitive marker for mild renal function compared with serum Cr, and microalbuminuria might have a stronger correlation with WRF after PCI than serum CysC. However, we could not investigate this association because of the lack of data regarding microalbuminuria.

Limitations
Several limitations of this study must be considered. First, CysC was measured before and at 9 months after PCI, and we demonstrated an independent association between ACEI and WRF. However, it is unknown whether ACEI has a protective effect on AKI after PCI because CysC was not measured in the acute phase after PCI in this study. Second, this study included patients with mild to moderate renal function. In this setting, ACEI had a protective effect on renal function at 9 months after PCI. However, the protective effect of ACEI for patients with severe renal function was not elucidated in this study. Third, this study was retrospective and contained a relatively small number of patients. Thus, we could not analyze the association between the type or the dose of ACEI and renal function after PCI. In the future, we must assess the protective effect of ACEI on renal function in a longer time-interval after PCI in a large scale prospective study. Fourth, in this study, only patients with stable angina are recruited. However, acute coronary syndrome is thought to be one of factors deteriorating renal function. Therefore, it is needed to investigate the impact of ACEI on renal function in the late phase after PCI in patients with acute coronary syndrome.

Conclusion
Use of ACEI was inversely related to the deterio-