Keywords

Contrast induced nephropathy; Percutaneous coronary intervention; Coronary angiography

Introduction

Contrast Induced Nephropathy (CIN) is a generally reversible form of Acute Kidney Injury (AKI) that takes place soon after the administration of radio-contrast media [1]. The data from animal models best describe the pathogenesis of CIN [2]. The reported incidence of CIN show wide variations, largely depending upon the presence or absence of risk factors, like underlying Chronic Kidney Disease (CKD) and varies between 8% to 16% depending upon age and comorbidities [3,4].

Various researches showed evidence of Acute Tubular Necrosis (ATN), mainly due to cytotoxic effects of contrast agents. However, this mechanism is not well understood. Another theory is that ATN is caused by renal vasoconstriction resulting in medullary hypoxia, possibly mediated by changes in nitric oxide, endothelin and/or adenosine [5]. However, unlike other types of ATN, CIN is usually characterized by relatively rapid recovery of renal function [6].

Acetylcysteine is a thiol compound with antioxidant and vasodilatory properties which is found effective in the prevention of CIN [7]. Given the conflicting data regarding benefit, researchers cannot make a strong recommendation regarding the use of acetylcysteine in routine clinical practice. Since the agent is potentially beneficial, well tolerated and relatively inexpensive, the 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend its use in subjects who are at high risk of developing CIN [8]. The overall preventive effects of NAC have been evaluated in multiple pooled analyses. Some have suggested a considerable beneficial effect, with reported risk reductions of up to 50% [9,10]. In one pooled analysis, it was reported that N-Acetylcysteine significantly lowered the risk for CIN when compared with saline only (RR 0.62, 95% CI 0.44-0.88) [11]. Pezeshgi et al. assessed the protective effect of N-acetylcysteine on CIN in diabetic patients and found mean baseline serum creatinine of 1.21 ± 0.35 mg/dL in the control group and 1.17 ± 0.35 mg/dL in NAC group while after 3 days values were 1.34 ± 0.44 mg/dL and 1.08± 0.34 mg/dL respectively (P<0.05) [11].

There is enormous variation and contradictory results in the available clinical studies and pooled analyses examining the effectiveness of acetylcysteine in preventing CIN [10,11]. It was intended to gather the data about its protective role in the local settings. If any favorable results are observed in terms of clinical response, NAC may be recommended for further routine clinical use. This would be beneficial in reducing the renal morbidity associated with the contrast media. The study aim was to determine the mean change in serum creatinine levels before and after coronary angiography in diabetic patients treated with N-Acetylcysteine in comparison with placebo.

Materials and Methods

This Randomized Controlled Trial (RCT) was carried out in Cardiology Department, PIMS and Islamabad in a period of sixmonths from 30-12-2020 to 29-06-2021. A total of 286 adult patients diagnosed with diabetes mellitus undergoing PCI or coronary angiography were selected for this study.

Patients were randomly assigned to two groups. Patients were hydrated with saline, in control group (group A) normal saline only was given while the case group (group B) received normal saline and oral NAC 600 mg twice daily given a day before angiography and continued until the 2^nd day after angiography. All patients received low-osmolal contrast media. Exact estimates of the doses of contrast agent administered were not available. Patients were allowed to continue to take their previously used medications.

Patients who were on anti-diabetic medicine and planned for coronary angiography for evaluation and management of coronary artery disease having age >18 years and of both genders were included. Patients with H/O allergy to iodinated contrast media and who had baseline creatinine more than 1.8 mg/dl were excluded. Ethical clearance was obtained and a written informed consent was taken.

The information regarding demographic characteristics and clinical presentation was recorded. Serum creatinine was estimated before and 3 days of coronary angiography. All patients received low-osmolal contrast media. All the information was recorded on the prescribed proforma.

Data was entered and analyzed using SPSS software version 22.0. The continuous numerical variables were described as mean ± SD. Categorical variables were recorded as frequency and percentage in both groups. Mean difference between baseline and 3 days post angiography creatinine levels was determined in both groups. Student-t test was applied to assess the significance of mean difference pre and post angiography in both groups. A P-value of ≤ 0.05 considered significant.

Results

The mean age was 58.1 ± 9.4 years in group A and 57.5 ± 9.9 years in group B. In group A, there were 40 (28.0%) patients between 18 to 50 years of age and 103 (72.0%) had age more than 50 years while in group B, there were 35 (24.5%) and 10 (75.5%) in these age groups respectively. This distribution was similar in both groups (P=0.501). There were 88 (61.5%) males in group A (control) and 92 (64.3%) in group B NAC while 55 (38.5%) females in group A and 51 (35.7%) in group B and this difference in gender distribution among two groups was not statistically significant (p-value, 0.624) (Table 1).

Table 1: Demographic characteristics of patients in two groups.

Analysis of duration of diabetes at baseline showed that in group A 68 (47.6%) patients had duration of diabetes less than 5 years, 48 (33.6%) reported duration of 6-10 years, 19 (13.3%) reported duration of 11-15 and 8 (5.6%) reported duration of more than 15 years while in group B, 69 (48.3%), 40 (28.0%), 18 (12.6%) and 16 (11.2%) were found in these age categories respectively. The age distribution was similar in both groups (P=0.330). There were 95 (66.4%) patients in group A, who had undergone coronary angiography and 48 (33.6%) underwent PCI while in group B, 94 (65.7%) and 49 (34.3%) were found so, respectively. The distribution was similar in both groups (P=0.901) (Table 2).

Table 2: Clinical details of patients in the two groups.

The mean serum creatinine levels at baseline in group A was 1.021 ± 0.235 mg/dL and it was 1.015 ± 0.238 mg/dL in group B and no difference was observed in these levels (P=0.834). The mean serum creatinine levels post procedure in group A was 1.0213 ± 0.235 mg/dL and it was 1.016 ± 0.239 mg/dL in group B. No significant difference was observed in the post procedure serum creatinine levels in both groups (P=0.857). Overall the change in mean serum creatinine levels post procedure in group A and group B were similar and no significant difference was observed in both groups (P=0.338) (Table 3).

Table 3: Comparison of serum creatinine between two groups.

Discussion

This study has found that N-Acetylcysteine (NAC) has a significant preventive role against emergence of contrast induced nephropathy. Historically, there is enormous variation and contradictory findings in the available evidence from clinical studies and pooled analysis evaluating the effects of NAcetylcysteine (NAC) in the prevention of CIN. The protective findings of NAC in CIN have been witnessed in many trials before as well.

There was no difference in the level of serum creatinine from baseline to 3 days post intervention among the controls and NAcetylcysteine (NAC) in the current study. The average decrease in serum creatinine levels was minimal in both groups after 3 days of PCI or CABG procedures. The published incidences of CIN show wide variations that depend on how AKI is defined and whether the risk factors (CKD, type and dose of contrast agent, type of radiological procedure etc.) are present or absent. Studies have demonstrated that risk of AKI depends on the dose and type of the contrast agent with low osmolal agents and lower doses of contrast being safer [12]. In the present study a low osmolal agent was used in all the patients, however, exact estimates of the doses of contrast agent administered were not available.

Many studies and meta-analysis have been found in the literature showing mixed results some have approved while others have rejected the effect of NAC on intravenous CIN. Bagshaw et al., in their meta-analysis on 1261 patients in 14 studies reported that only in 5 studies the risk of contrast induced nephropathy was lower after administration of NAC while other studies showed no effect [13]. van den Berk et al., analyzed 16 studies in a meta-analysis, they found that five of them showed significant effects of NAC [14]. In another study on different doses of NAC authors reported that the protective effect of NAC with a dose of 1200 mg twice daily was more than that with a dose of 600 mg [15]. Liu et al., in their pooled analysis which included 9 RCTs reported that NAC was effective for the prevention of CIN because it was low-risk and low cost, and was advisable to use [16]. In another meta-analysis, Gonzales et al. analyzed 22 studies with 2746 patients and reported that no protective effects of NAC on CIN were observed [17]. In a large multicenter ACT randomized controlled trial, from Brazil, 2300 high-risk patients were assessed for CIN and underwent coronary angiography. The patients who received 1200 mg of oral NAC were compared with the placebo. It was demonstrated that incidence of CIN was lower in NAC group. Pezeshgi et al., in their prospectively designed clinical study determined the effect N-acetylcysteine in reducing the incidence of CIN in patients who underwent coronary angiography [9,11]. The intervention group showed a statistically significant drop in creatinine levels compared with control (P<0.05). Incidence of CIN was more in control group compared with NAC (P<0.05). They concluded that Nacetylcysteine does have the protective effects in preventing CIN. Additionally in a meta-analysis by Kwok et al. a significant reduction of CIN risk was reported by administration of NAC, which supported its protective effect [18]. Compared to these evidences of protective effect of NAC, the current study also found that mean change in creatinine levels pre and post intervention were not statistically significant.

In many instances, the related factors and comorbidities have been witnessed having variable effect over the patient outcomes. The reported incidences of CIN show wide variations, largely depending upon the presence or absence of risk factors [19]. The management is not yet specified once contrastinduced Acute Kidney Injury (AKI) develops, rather these patients are managed as for the etiology with the aim of preserving fluid and electrolyte balance. In most cases, there are no permanent consequences, however, it has been reported that its development may be associated with adverse outcomes [20]. Acetylcysteine is a thiol compound having antioxidant and vasodilatory characteristics. A likely mechanism of action that is involved in preventing CIN is to minimize both vasoconstriction and production of oxygen-free radical after administration of radio-contrast agent [21]. There is also enormous variation and contradictory findings regarding the effects of N-Acetylcysteine (NAC) in preventing CIN. It has been published in several reports that incidence of CIN is higher among patients with CKD, and the degree of the risk is directly related with the severity of renal dysfunction [22].

It has been reported that in patients with CKD, diabetic patients are at higher risk for contrast nephropathy compared with non-diabetic patients [23]. Among subjects with normal kidney function, diabetes does not enhance the risk of contrast nephropathy [24]. The same effect has been observed in the current study, as all patients had baseline creatinine levels ≤ 1.8 mg/dL and only few had creatinine levels between 1.5 mg/dL to 1.8 mg/dL. Magnitude of change in post-procedure creatinine levels did not appear to be in statistically significant range between both groups.

The advantages of this study are numerous as firstly, there were no or very few attempts done in the local settings. Secondly, a comparative trial was accomplished with a control group, thus, providing a true effect of the NAC intervention in preventing CIN.

This study has some limitations as well, firstly, the exact dose of the contrast agent administered was not measured. Secondly, the subjects with serum creatinine levels >1.8 mg/dL were not enrolled in the study. And thirdly due to limited study duration, the sample size was relatively small.

In brief, reported incidences of CIN show wide variations that depend on how AKI is defined and whether the risk factors (CKD, type and dose of contrast agent, type of radiological procedure etc.) are present or absent. Studies on protective role of NAC also show mixed results with evidence more in favor of no significant protective effect of NAC on CIN.

Conclusion

No statistically significant change in serum creatinine levels was observed in this study before and after coronary angiography in diabetic patients treated with N-Acetylcysteine in comparison with placebo. Before generalization of these findings, it is recommend that further large scale studies including patients with serum creatinine levels more than 1.8 mg/dL should be conducted.

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