Contrast-induced nephropathy (CIN) is a rare but life-threatening complication of primary percutaneous coronary interventions (pPCI). Preventing the development of CIN is very important for decreased mortality and morbidity after p-PCI. Our study demonstrated that oxidative parameters such as gamma-glutamyltransferase, 4 (UA), total oxidant status and total antioxidant status, as well as inflammatory parameters such as C-reactive protein could be useful prognostic biomarkers in acute myocardial infarction (AMI). Additionally, measurement of the oxidative status may be useful in preventing the development of CIN after pPCI.

Primary percutaneous coronary intervention (p-PCI) is the recommended reperfusion strategy for patients who present acute ST-elevation myocardial infarction (STEMI) within the first few hours after the onset of symptoms.1 However, some life-threatening complications such as contrast-induced nephropathy (CIN) are observed after p-PCI.2,3 Evidence shows a strong correlation between CIN and high mortality and morbidity in patients with STEMI.2 Additionally, these patients tend to be hospitalized for long periods.2 Several clinical and laboratory variables have been associated with the development of CIN, including contrast media volume, presence of diabetes mellitus, chronic congestive heart failure, anemia and decreased renal perfusion.3 Production of reactive oxygen species (ROS) and impaired renal perfusion are the two major mechanisms involved in the pathogenesis of CIN.4,5 In addition, previous studies have suggested that CIN may lead to a decrease in the activity of antioxidant enzymes and cause cytotoxic effects via the release of ROS. Increased reactive oxygen radicals may cause an increase in renal medullary hypoxia.4–6 Additionally, antioxidant supplements such as ascorbic acid and drugs such as N-acetylcysteine (NAC) could lead to the amelioration of CIN.7,8 Although many studies have shown alterations in total oxidant status and antioxidant capacity in various diseases, including end-stage renal disease, atrial fibrillation and hypertension, to the best of our knowledge, none have examined these parameters in predicting CIN in patients with STEMI.9–11

In a clinical setting, serum creatinine level is generally used as a marker of renal function, even though this marker is affected by several factors such as age, gender, muscle mass, weight, and ethnicity.12,13 Additionally, serum creatinine is not a marker of renal damage per se and is elevated only at advanced stages of renal disease. For these reasons, use of serum creatinine as a marker could lead to under-estimation of CIN.13 Patients at high risk of CIN should undergo early prophylactic measures such as hydration and the antioxidant NAC to prevent CIN.8 Additionally, high risk patients should be followed up for progression of serum creatinine levels after the procedure.2 Therefore, there is a need for the development of new laboratory parameters to predict the development of CIN. In this study, we aimed to assess the association between total oxidant status (TOS), total antioxidant capacity (TAC), high-sensitivity C-reactive protein (hs-CRP), gamma-glutamyltransferase (GGT) and uric acid (UA) in the development of CIN in patients presenting with STEMI.

A total of 300 patients (mean age: 62±13 years; range, 23–91 years) were included in this study. During the follow-up period, 50 patients (16.7%) developed CIN. Demographic and clinical characteristics of the patients with and without CIN are listed in Table 1. The patients with CIN were significantly older, predominantly female and with a higher incidence of hypertension when compared to the patients without CIN (p=0.01, p=0.01 and p<0.001, respectively). The incidence of diabetes, obesity and hyperlipidemia were similar between patients with and without CIN (for all parameters p>0.05). There were no statistically significant differences in cholesterol parameters (p>0.05) between patients with and without CIN. Left ventricle ejection fraction (LVEF) was significantly lower in patients with CIN compared to patients without CIN (p<0.001). Initial creatinine levels were significantly higher in patients with CIN compared to patients without CIN.

There were no statistically significant differences in previous treatments including renin-angiotensin system (RAS) blockers, acetyl salicylic acid, clopidogrel or statins between patients with and without CIN (for all parameters p>0.05). Among in-hospital treatments, the use of BB and RAS blockers was lower in patients with CIN but use of other medications was similar among patients with and without CIN. Patients with CIN spent longer in the coronary care unit than patients without CIN (2.6±1.2 vs. 2.0±0.5 days; p<0.001). There were no statistically significant differences in the initial and peak cardiac enzymes including troponin and creatine kinase myocardial bundle between patients with and without CIN (for all parameters p>0.05). The mean Mehran risk score (6.9±6.2 vs. 3.0±3.5, p<0.001), contrast media volume (78.3±17.4 cc vs. 72.5±9.3 cc, p<0.001) and contrast media volume/glomerular filtration ratio (eGFR) (1.5±1.0 versus 1.0±0.4; p<0.001) were significantly higher in patients with CIN compared to patients without CIN.

Oxidative status and inflammation parameters are presented in Table 2. In patients with CIN, plasma TOS and OSI values were significantly higher (33.0±5.5 mmol H2O2 equiv./L vs. 27.7±5.0 mmol H2O2 equiv./L, p<0.001 and 28.9±6.8 vs. 19.2±4.5, p<0.001, respectively) and plasma TAC levels were significantly lower compared to those without CIN (1.1±0.2 mmol Trolox equiv./L vs. 1.4±0.2 mmol Trolox equiv./L p<0.001). Hs-CRP, UA and GGT levels were significantly higher in patients with CIN compared to patients without CIN (49.7±35.8 mg/L vs. 22.5±26.0 mg/L, p<0.001; 7.1±1.9 mg/dl vs. 6.0±1.2 mg/dl, p<0.001 and 43.8±48.09 U/L vs. 31.8±23.2 U/L, p=0.01; respectively)

Prediction of contrast-induced nephropathy

Univariate analyses showed that TOS, TAC, OSI, LVEF, age, contrast media volume, contrast media volume/eGFR ratio, female gender, hypertension, initial glucose level, initial creatine level, Mehran score, UA level, hs-CRP level and GGT level were significantly associated with a higher risk of development of CIN (Table 3).

Table 3.

Univariate and multivariate regression analyses of predictors of contrast-induced nephropathy in the study population.

	Unadjusted odds ratio	CI	p value	Adjusted odds ratio	Confidence interval	p value
TOS	1.18	1.11-1.25	<0.001
TAS	0.009	0.002-0.043	<0.001
OSI	1.35	1.24-1.45	<0.001	1.39	1.25-1.56	<0.001
Age	1.03	1.00-1.05	0.01
Gender (female)	3.04	1.55-5.95	0.001
Hypertension	3.16	1.67-5.99	<0.001
Initial creatinine	9.79	3.40-28.1	<0.001
Initial glucose level	1.00	1.003-1.009	<0.001	1.006	1.00-1.01	0.02
LV ejection fraction	0.93	0.90-0.97	<0.001
Opaque amount/GFR ratio	2.8	1.7-4.4	<0.001	5.88	1.4-23.08	0.011
Contrast media volume	1.04	1.01-1.06	0.002
Mehran score	1.19	1.11-1.27	<0.001
Uric acid	1.66	1.32-2.07	<0.001	1.36	0.94-1.96	0.09
GGT	1.01	1.00-1.01	0.03
Hs-CRP	1.02	1.01-1.03	<0.001	1.023	1.00-1.04	0.009

CI: confidence interval; GFR: glomerular filtration rate; GGT: gamma-glutamyltransferase; Hs-CRP: high-sensitivity C-reactive protein; LV: left ventricle; OSI: oxidative stress index; TAS: total anti-oxidative status; TOS: total oxidative status.

A multivariate binary logistic regression analysis was carried out by including all the parameters that were associated with the development of CIN in the univariate analysis. This analysis showed that OSI (OR: 1.39; CI 95: 1.25-1.56, p<0.001), initial glucose level (OR: 1.006; CI 95%: 1.00-1.01, p=0.02), hs-CRP (OR: 1.023; CI 95: 1.00-1.04, p=0.009), contrast media volume/eGFR ratio (OR: 5:88; CI 95%: 1.4-23.08, p=0.011), and UA level (OR: 1.36; CI 95%: 0.94-1.96, p=0.09) remained as independent factors for CIN development (Table 3). ROC curve analysis showed that OSI (C-statistic: 0.81; CI 95%: 0.76-0.86, p<0.001), TAC (C-statistic: 0.80; CI 95%: 0.75-0.85, p<0.001) and TOS (C-statistic: 0.76; CI 95%: 0.68-0.83, p<0.001) were significant predictors of CIN following STEMI (Table 4, Figure 1). We calculated that a cut-off point of 30.5 for TOS, 1.2 for TAC and 26 for OSI could estimate the presence of CIN with a sensitivity of 72%, 76% and 74%, a specificity of 77%, 81% and 94%, respectively (Table 4).

Table 4.

Receiver operating characteristics curve analysis of oxidative parameters.

	C-statistic	95% CI	p value	Cut-off value	Sensitivity	Specificity
TOS	0.760	0.68-0.83	<0.001	>30.5	72	77
TAS	0.808	0.75-0.85	<0.001	≤1.2	76	81
OSI	0.816	0.765-0.860	<0.001	>26	74	94

CI: confidence interval; OSI: oxidative status index; TAS: total anti-oxidative status; TOS: total oxidative status.

Figure 1.

Receiver operating characteristics curve with calculated area under the curve and optimal cut-off point for oxidative stress index, total antioxidant capacity, and total oxidant status to identify the presence of contrast-induced nephropathy. OSI: oxidative stress index; TAS: total antioxidant status; TOS: total oxidant status.

(0.07MB).

In correlation analysis, Mehran score correlated positively with OSI, hs-CRP, UA, contrast media volume/eGFR ratio levels and negatively correlated with TAC levels, while hs-CRP levels correlated positively with UA, GGT, OSI and TOS (Table 5).

Table 5.

Correlation analysis of study variables.

	hs-CRP		Uric acid		GGT		OSI		TAC		TOS		Contrast media volume/eGFR ratio
	r	p	r	p	r	p	r	p	r	p	r	p	r	p
MEHRAN score	0.297	<0.001	0.158	0.009	0.00	ns	0.175	0.002	-0.127	0.028	0.092	ns	0.516	<0.001
Hs-CRP (mg/L)			0.210	0.001	0.296	<0.001	0.168	0.006	-0.085	ns	0.162	0.009	0.109	0.07
Uric Acid(mg/dl)					0.244	<0.001	0.165	0.006	-0.166	0.006	0.060	ns	0.105	ns
GGT (U/L)							0.072	ns	-0.023	ns	0.107	ns	-0.110	ns
OSI									-0.737	<0.001	0.692	<0.001	0.092	ns
TAC (mmol/Trolox Equiv./L)											-0.063	ns	-0.097	ns
TOS (lmol H2O2 Eq/L)													0.000	ns

GGT: Gamma-glutamyltransferase; OSI: oxidative stress index; Hs-CRP: high-sensitivity C-reactive protein; ns: not statistically significant; TAC: total antioxidative capacity; TOS: total oxidative status.

The main findings of this study suggest that oxidative stress and inflammation parameters are associated with the development of CIN in patients presenting with acute STEMI. Oxidative stress is caused by increased ROS production and is associated with poor outcomes in cardiovascular diseases such as coronary artery disease (CAD) and CIN.4,9,19–22

Borekci et al.,20 demonstrated that OSI, UA and neutrophil to lymphocyte ratio were associated with spontaneous reperfusion in patients with STEMI. Similarly, Turan et al.21 reported that plasma TOS and OSI were significant factors associated with CAD complexity and severity in patients with acute coronary syndrome. Korkmaz et al.22 showed that thiol/disulfide homeostasis, a new oxidative marker, could be a good biochemical risk marker for CIN in STEMI patients who underwent p-PCI. Additionally, we have reported a positive association between atrial fibrillation development after STEMI and TAC, TOS and OSI.9 In these studies, the relationship between CIN and oxidative stress markers in patients with STEMI was not determined. Data from the current study suggest that plasma TAC, TOS and OSI were increased in patients with CIN when compared to those without CIN in a STEMI patient population. Thus, increased oxidative stress may contribute to pathogenesis in these patients.

CIN is a serious complication of p-PCI after STEMI and is associated with poor clinical outcomes such as prolonged hospital stays, rising costs, and increased short- and long-term morbidity and mortality.2,23 It is, therefore, important to estimate which patients may develop CIN. There are several established parameters for predicting CIN development. Yildiz et al.24 showed that serum osmolality is a predictive factor for CIN development, while Gohbara et al.25 determined that acidosis was associated with CIN development in patients with STEMI. Our results showed that OSI, initial glucose levels, contrast media volume/eGFR ratio, UA and hs-CRP levels were associated with CIN development in patients with STEMI after p-PCI. Previous studies have also shown similar results.26–28 Contrast volume and basal renal insufficiency are important risk factors for CIN29; accordingly, the contrast media volume/eGFR ratio is a good indicator for CIN.28 Our study also indicated that contrast media volume/eGFR ratio was a powerful predictor of CIN development.

There is a demonstrated association between inflammation and CIN in the literature.28,30–33 Liu et al.32 showed that an increase in hs-CRP was a significant and independent predictor of CIN in patients with STEMI after p-PCI. Oweis et al.34 showed that interleukin-33 levels were elevated in patients with CIN. Gu et al.33 reported that an elevation of the inflammatory biomarkers hs-CRP and procalcitonin was a risk factor for postoperative CIN. Similarly, in the present study, hs-CRP levels were significantly higher in patients with CIN compared to patients without CIN. This indicates that higher hs-CRP may be associated with the development of CIN in patients presenting with STEMI.

Although several studies have shown that pharmacological agents such as theophylline, fenoldopam, mannitol, iloprost, furosemide, dopamine, hemofiltration, ascorbic acid, NAC and sodium bicarbonate (NaHCO3) could prevent the development of CIN, it is still unclear which are the best agents for the prevention of CIN.35 Among these agents, the use of NAC and NaHCO3 with physiological saline was recommended as a good strategy to prevent CIN.35 Additionally, statins that have pleiotropic effects such as a decrease in free oxygen radicals, increase in nitrous oxide production and increment of vascular smooth muscle relaxation, can also prevent CIN.36 The present study supported the beneficial effects of the above mentioned agents. In future studies, there is a need to focus on agents and foods with antioxidant effects; individuals should also be advised to increase the amount of antioxidants in their diets.

In this study we have demonstrated lower antioxidant capacity and higher oxidative and inflammatory status in STEMI patients. During the acute phase of STEMI, the oxidative and inflammatory response may influence the patient's baseline cardio-renal reserves. The addition of oxidative and inflammatory parameters to the current risk models derived from clinical, angiographic, and laboratory-based variables and to the previously validated Mehran risk score13 may result in significant improvement in the prediction of CIN.

Our study has several limitations: the study population consisted of patients treated with different modes of STEMI and the number of CIN patients was too small for definitive conclusions. Additional oxidative stress parameters such as serum prolidase activity, malondialdehyde, superoxide dismutase etc., were not examined, and markers for the detection of renal failure, such as NGAL, cystatin C, urinary Kim-1 were also not analyzed.

The present study suggests that in a patient population with STEMI, oxidative stress and inflammation were significantly higher in patients with CIN when compared to patients without CIN. Further studies are needed to establish the pathophysiological and clinical significance of increased oxidative stress and inflammation, and to investigate the effect of antioxidant and anti-inflammatory agents in patients with AMI.

The authors have no conflicts of interest to declare.