Contrast-induced nephropathy (CIN) is an iatrogenic disease occurring after the intravascular injection of iodinated radiographic contrast media and is a significant cause of acute renal failure.1 The mechanism of CIN is as yet not clearly understood. It is associated with increased in-hospital mortality and subsequently contributes to morbidity and prolonged hospitalization, and increases the costs of health care.2,3 The incidence of CIN varies depending on the study population, although it has decreased in recent years due to use of less nephrotoxic contrast agents and better prevention strategies.4 However, CIN developing after coronary angiography is still a major cause of mortality and morbidity.5 It is therefore clinically important to predict the risk of developing CIN and there is a need to identify new biomarkers for its rapid and accurate diagnosis.

Pituitary vasopressin plays important roles in the regulation of osmotic pressure and homeostasis. Copeptin is the C-terminal part of pro-arginine vasopressin and may serve as a potent biomarker of cardiovascular disease.6 Vasopressin plays an important role in water homeostasis, but has a very short half-life and is unstable in vitro, which makes it difficult to quantify. The function of copeptin remains unknown, but it is secreted in equimolar quantities to vasopressin and has the advantage of high stability in blood samples. Owing to its involvement in the adrenocorticotropic hormone cycle, copeptin has been proposed to be a marker of severe stress reactions as well as of hemodynamic triggers.7,8 In recent years, studies have also found that copeptin may increase albuminuria9 and predict the outcomes of adverse cardiac and renal events.10 We therefore hypothesized that copeptin may be a sensitive biomarker to predict changes in renal function, with clinical importance in the early diagnosis and assessment of progression of CIN in STEMI patients. The association of copeptin and CIN in STEMI patients was also investigated in the present study.

The study population (n=274, mean age 56.69±11.85, 16.4% female) was divided into two groups as follows: 69 (25.1%) CIN+ and 205 (74.8%) CIN-. There was no significant difference in mean age between the groups, but the prevalence of females was significantly higher in the CIN- group than in the CIN+ group (19% vs. 8.6%; p<0.05). No differences were observed between the groups with regard to other demographic characteristics. Copeptin levels (10.68±6.43 vs. 7.07±05.53 pmol/l; p<0.001) and peak creatinine (1.46±1.20 vs. 1.03±0.20 mg/dl; p=0.005) were significantly higher in the CIN+ group compared to the CIN- group. No differences were observed between the groups with regard to other laboratory findings. Previous prescription of diuretics was significantly higher in the CIN+ group (8.6% vs. 2.9%; p=0.047). No significant difference was observed between the groups in quantity of contrast media used (196.75±53.57 vs. 180.65±54.68 cc; p=0.143) (Table 1). Four patients (5.8%) who developed CIN required dialysis in hospital follow-up.

Among the demographic and laboratory findings (Table 1), variables associated with CIN were analyzed as potential risk factors and were assessed by logistic regression analysis. Copeptin level at admission (odds ratio [OR]: 2.36, p=0.005), and peak creatinine (OR: 6.44, p=0.004) were found to be independent predictors of development of CIN. Female gender and diuretic use were not found to be independent predictors of CIN development (Table 2). In ROC curve analysis, admission copeptin above a cut-off of 7.72 pmol/l predicted CIN with sensitivity of 73.9% and specificity of 73.7% (area under the curve: 0.72; 95% confidence interval: 0.65-0.79; p<0.001) (Figure 1).

Figure 1.

Receiver operating characteristic curve of copeptin level and contrast-induced nephropathy. AUC: area under the curve.

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CIN is an important cause of concern for physicians and is a significant cause of iatrogenic acute renal failure.1 A biomarker that predicts CIN development could thus enable measures to be taken to prevent renal failure. In this study, we determined that copeptin is a independent predictor of CIN in patients with STEMI. To the best of our knowledge, this study is the first to determine such a relationship between copeptin and CIN. The results indicate that the CIN rate increases significantly in patients with high copeptin levels who have undergone primary PCI for STEMI.

The mechanism of CIN is not yet fully understood. Reactive oxygen species (ROS)-induced combined hypoxic and toxic injury is important in the development of CIN.12 Renal oxygenation is significantly decreased and medullary hypoxia leads to ROS production and thus increased oxidative stress.13 While ROS trigger vasoconstrictive signals such as angiotensin II and endothelin I,14 they also reduce the bioavailability of nitric oxide.15 There are also studies indicating that contrast administration leads to vasoconstriction in the renal arteries, reducing renal blood flow.16 As is evident, the underlying pathophysiology of CIN is complex and further studies are needed to understand this issue.

The incidence of CIN varies depending on the population. The main risk factors for its development include impaired renal function, heart failure, age (>65 years), diabetes, nephrotoxic drugs, decreased intravascular volume, long-standing hypotension, anemia, renal transplantation, female gender, high doses of contrast medium and multiple contrast injections within 72 hours.17 Contrast-medium osmolality is also important. Use of low-osmolality instead of high-osmolality contrast medium has been shown to be better for prevention of CIN.18 Therefore, in our study we opted to use low-osmolality contrast medium, aimed to maintain sufficient hydration and avoided the use of nephrotoxic drugs.

The incidence of CIN is higher in patients who undergo coronary angiography than in outpatients (10-15% vs. <5%),17 and previous studies have shown rates up to 25% in STEMI patients.18 The higher incidence in this group may be associated with the high-risk profile of these patients.19 The rate was found to be 25.1% in our study. We consider that this high rate may be related to the fact that our study population was composed of high-risk patients with many comorbidities. It also appears that the use of intra-arterial contrast administration is one of the causes of the high CIN rate in patients undergoing coronary intervention; intra-arterial administration is associated with more risk than intravenous administration.20 In addition, timing is important in determining the incidence of CIN, since creatinine elevation is relatively slow, 48-72 hours being required to identify many cases of CIN, and therefore studies assessing CIN at 24-48 hours after contrast exposure underestimate its rate.21 CIN incidence may be assumed to be low in patients undergoing elective PCI, due to early discharge of these patients and lack of blood tests in the early post-discharge period.22 Our study has shown that CIN is still common among hospitalized patients, but its development can be predicted and its incidence can be decreased if appropriate measures are taken. The current European guidelines on myocardial revascularization recommend risk assessment for acute renal damage for prevention of CIN.25 This indicates the importance of risk detection for CIN.

We believe that copeptin, which has been associated with cardiovascular and renal disease in previous studies, can help in this regard. The close relationship between copeptin and renal disease has been revealed in many studies. Copeptin was found to be affected by mean blood pressure and blood volume and is elevated during pre-dialysis and dialysis periods,23 and is an early indicator of reduced glomerular filtration rate and renal function in diabetic patients.24,25 In addition, a community-based cohort study revealed an independent positive relationship between plasma copeptin level and progression to chronic kidney disease (CKD), demonstrating that its close relationship with renal function is valid not only in patients with CKD, but also in the general population,26 and copeptin is associated with increased risk of CKD even in the general population.27 Furthermore, elevated copeptin has proved a valuable prognostic factor for mid-term mortality in patients with both coronary artery disease and kidney disease.28 The relationship between copeptin and cardiac disorders such as heart failure, coronary artery disease and hypertension has been shown in many previous studies.29–31 Copeptin has been shown to be an independent marker for long-term prognosis in heart failure,32,33 it may be a marker for diagnosis of left ventricular dysfunction in hemodialysis patients,34 and is associated with coronary atherosclerosis in diabetic patients35,36 and with resistant hypertension.37 A rise in copeptin levels two days after STEMI has also been shown to be related to larger acute and chronic infarct size, and initially elevated copeptin level is related to myocardial function and remodeling four months after STEMI. These results highlight the role of copeptin as a biomarker of negative post-STEMI results.38 Copeptin has also been shown to be useful for diagnosing or excluding acute coronary syndrome (ACS) and for safe and early discharge or shortening duration of emergency room stay in low- or moderate-risk patients suspected of suffering ACS when the results of copeptin and troponin are used in combination, as copeptin is elevated in the early period of ACS.39,40 In addition to these findings, rapid copeptin measurement is suggested as a practical and useful tool for medium- and long-term risk assessment in the emergency room.41

In a study assessing acute renal damage in STEMI patients, Guerchicoff et al. investigated the relationship between acute renal damage and B-type natriuretic peptide (BNP), chemokine (C-C motif) ligand 23, D-dimer, endothelial cell-selective adhesion molecule, C-reactive protein, cystatin C, adiponectin and von Willebrand factor.22 Levels of these biomarkers on admission were not found to be significant predictors for CIN development, except for BNP. Although a significant relationship was seen between these biomarkers and CIN during hospital stay and after discharge, we consider that, except for BNP, they have limited benefit in predicting CIN development, and taking measurements within 48-72 hours of contrast administration is important for preventing CIN development. Our study differs from that of Guerchicoff et al., as it investigates the relationship between copeptin and CIN, and our study has revealed that copeptin levels on admission can predict CIN. This may help clinicians to assess the risk and to take appropriate measures. In addition, a statistically significant relationship was found between CIN and peak creatinine level in our study. However, since CIN has already developed by the time peak creatinine is detected, peak creatinine is not a predictive marker, but has only diagnostic value, and is not useful for taking measures to prevent CIN development. As in Guerchicoff et al., no relationship was found between adinopectin level on admission and CIN development in our study. We therefore consider that copeptin is a more valuable marker than adinopectin for prediction of CIN. Copeptin levels also have the advantage of being detected rapidly and easily.

Our findings indicate that physicians should be aware of the possibility of CIN development in patients with high copeptin levels and that preventive measures should start early.

The present study has some limitations. It was based on a single center, included only STEMI patients and not those with other forms of MI, and did not fully analyze potential nephrotoxic agents. Another limitation is that this study did not include long-term results such as copeptin level after reversal of contrast nephropathy.

Copeptin level is an independent predictor of CIN development in patients with acute STEMI. One of the advantages of measuring copeptin compared to other biomarkers is that copeptin at admission can predict CIN at an early stage. Assessment of copeptin level may be helpful for taking measures to prevent CIN development in patients who are to undergo PCI.

The authors received no financial support for the research, authorship, and/or publication of this article.

The authors have no conflicts of interest to declare.