550
Editorial
Statins and contrast-induced acute kidney injury Carlo Briguoria, Giovanni Napolitanob and Gerolama Condorellic,d Coronary Artery Disease 2014, 25:550–551 a
Laboratory of Interventional Cardiology, Department of Cardiology, Clinica Mediterranea, bDepartment of Cardiology, Ospedale San Giuliano, cDepartment of Molecular Medicine and Medical Biotechnologies, ‘Federico II’ University of Naples and dIEOS, CNR, Naples, Italy
Correspondence to Carlo Briguori, MD, PhD, Laboratory of Interventional Cardiology, Department of Cardiology, Clinica Mediterranea, Via Orazio 2, I-80121 Naples, Italy Tel: + 39 81 7259 764; fax: + 39 81 7259 777; e-mail: [email protected] Received 24 June 2014 Revised 26 June 2014 Accepted 30 June 2014
Over the past few decades application of coronary and peripheral procedures has substantially increased because of the more aggressive approach in the diagnosis and treatment of the different clinical presentations of atherosclerosis. Indeed, recent technical advances in this field have also allowed the successful treatment of patients with complex coronary and peripheral artery disease. The administration of iodinated contrast media is essential for all these procedures. Contrast media are usually well tolerated; however, in some patients they may induce acute kidney injury. Contrast media-induced acute kidney injury (CI-AKI) has become the third cause of hospital-acquired renal failure, with prolongation of hospital stay and consequent increase in healthcare costs [1]. In addition, patients developing CI-AKI are at higher risk for both a further deterioration in kidney function and an unfavourable clinical outcome. Risk factors for a more marked decline in renal function following contrast media exposure are pre-existing chronic kidney disease, diabetic nephropathy, high total dose of contrast media, heart failure, age and anaemia. The risk scores proposed by Mehran et al. [2] or by Gurm et al. [3] are very useful in clinical practice. A general consensus exists on the beneficial effect of hydration in preventing CI-AKI [4]. Hydration represents the cornerstone or prophylaxis of CI-AKI. Thus, adequate hydration should be performed before contrast media exposure. Multiple drugs have been tested in an attempt to prevent CI-AKI. Because of the concept that a key mechanism seems to be alteration in renal dynamics, vasodilators and diuretics have been tested as prophylactic drugs. However, their effectiveness has not been confirmed. In recent times, considerable interest has resulted from the preliminary positive data on the effectiveness of prophylactic administration of antioxidant compounds, such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). In the current issue of Coronary Artery Disease, Xie et al. [5] report the results of an updated meta-analysis to determine whether pretreatment with statins can reduce the risk of CI-AKI and adverse clinical events. Seventeen studies with 6323 patients were included. Pretreatment with statins before angiography significantly reduced the risk of CI-AKI [relative risk 0.50; 95% confidence 0954-6928 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
interval (CI) 0.35–0.71; P < 0.001] and was associated with significantly lower postprocedural serum creatinine levels. Meanwhile, the use of statins resulted in trends of reduced risks of renal replacement therapy and all-cause death within 30 days (relative risk 0.44; 95% CI 0.18–1.08; P = 0.07). Further analyses indicated that highdose statins were more effective than low-dose statins in reducing the risk of CI-AKI and that different types of statins (atorvastatin, rosuvastatin and simvastatin) exhibited similar effects on preventing CI-AKI. Khanal et al. [6] first studied 29 409 patients undergoing percutaneous coronary intervention, and patients on preprocedure statins had a lower incidence of CI-AKI (4.37 vs. 5.93%; P < 0.0001) and renal replacement therapy (0.32 vs. 0.49%; P = 0.03). After adjustments for comorbidities, preprocedure statin use was associated with a significant reduction in CI-AKI (odds ratio 0.87; 95% CI 0.77–0.99; P = 0.03) [6]. Statins are a class of drugs mainly used to control cholesterol levels. Statins have several ‘pleiotropic’ effects through their non-lipid-related mechanisms acting on inflammation responses, endothelial function, plaque stability, thrombus formation and the apoptotic pathway [7,8]. Some observational and randomized studies have investigated the effectiveness of statin pretreatment in reducing the incidence of CI-AKI [6,9–13]. Toso et al. [12]. demonstrated that a high dose (80 mg) of atorvastatin before and after contrast exposure had no effect on CI-AKI prevention when compared with conventional prophylaxis (i.e. hydration plus N-acetyl cysteine). Conversely, the study by Xinwei et al. [14] proved that a high (80 mg) rather than a low (20 mg) dose of simvastatin reduces the incidence of CI-AKI. Recently, Quintavalle et al. [15] have demonstrated that a single high (80 mg) loading dose of atorvastatin administered within 24 h before contrast media exposure is effective in reducing the rate of CI-AKI in patients with CKD. This beneficial effect is observed in patients with and without diabetes mellitus as well as in those with moderate chronic kidney failure. Moreover, another recent investigation confirmed that the administration of a high dose of rosuvastatin in statin-naive patients with acute coronary syndromes scheduled for early invasive procedure can prevent CIAKI and reduce 30-day adverse clinical events [16]. DOI: 10.1097/MCA.0000000000000154
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Statins and contrast-induced AKI Briguori et al. 551
Acknowledgements
Fig. 1
Conflicts of interest
There are no conflicts of interest.
Contrast media ROS
References 1
Statins
2
pJNK
ERK AKT
Statins 3
Caspase 3
4
Apoptosis
Cell survival 5
Statin effects on kidney cell contrast media-induced apoptosis. Contrast media induce the generation of reactive oxygen species (ROS) in tubular kidney cells, which activate the stress kinase phosphorylated Jun-N-terminal-kinase (pJNK). pJNK in turn may activate the intrinsic apoptotic pathway by the activation of caspase 3. Statin treatment prevents contrast media-induced apoptosis by inhibiting pJNK and, in turn, activating survival alternative protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) (which are pathways of cell survival). In the background a galactin-3 staining for tubular renal cells is represented, which is a marker of distal epithelial tubular cells.
6
7
8
9
Contrast media exposure of vasa recta and tubule cells can cause an increase in reactive oxygen species production and consequently induce apoptosis activation. For this reason, compounds with antioxidant properties acting as scavenger molecules for reactive oxygen species (such as N-acetyl cysteine, ascorbic acid and statins) have been investigated. Furthermore, an in-vitro model indicates that pretreatment with atorvastatin prevents contrast media-induced renal cell apoptosis by reducing stress kinase activation, and restores the survival signals mediated by alternative protein kinase B and extracellular signal-regulated kinase signal transduction pathways (Fig. 1) [15]. To conclude, CI-AKI is the major complication following contrast media exposure. It is highly prevalent in patients with several risk factors, including older age, chronic kidney disease, congestive heart failure and diabetes mellitus. Although the administration of limited contrast media volume and hydration (either by saline or by sodium bicarbonate infusion) is the cornerstone of CIAKI prevention, antioxidant compounds (such as statins) seem to be effective by reducing oxidative stress and thus preventing contrast media-induced renal cell apoptosis. Therefore, a high dose of statins should be included in the strategies for CI-AKI prevention.
10
11
12
13
14
15
16
McCullough PA. Contrast-induced acute kidney injury. J Am Coll Cardiol 2008; 51:1419–1428. Mehran R, Aymong ED, Nikolsky E, Lasic Z, Iakovou I, Fahy M, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol 2004; 44:1393–1399. Gurm HS, Seth M, Kooiman J, Share D. A novel tool for reliable and accurate prediction of renal complications in patients undergoing percutaneous coronary intervention. J Am Coll Cardiol 2013; 61:2242–2248. Stacul F, van der Molen AJ, Reimer P, Webb JA, Thomsen HS, Morcos SK, et al. Contrast induced nephropathy: updated esur contrast media safety committee guidelines. Eur Radiol 2011; 21:2527–2541. Xie H, Ye Y, Shan G, Zhang S, Fang Q, Yang D, Zeng Y. Effect of statins in preventing contrast-induced nephropathy: an updated meta-analysis. Coron Artery Dis 2014; 25:565–574. Khanal S, Attallah N, Smith DE, Kline-Rogers E, Share D, O’Donnell MJ, Moscucci M. Statin therapy reduces contrast-induced nephropathy: an analysis of contemporary percutaneous interventions. Am J Med 2005; 118:843–849. Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA 1998; 279:1643–1650. Briguori C, Visconti G, Focaccio A, Golia B, Chieffo A, Castelli A, et al. Novel approaches for preventing or limiting events (naples) II trial: impact of a single high loading dose of atorvastatin on periprocedural myocardial infarction. J Am Coll Cardiol 2009; 54:2157–2163. Lev EI, Kornowski R, Vaknin-Assa H, Ben-Dor I, Brosh D, Teplitsky I, et al. Effect of previous treatment with statins on outcome of patients with STsegment elevation myocardial infarction treated with primary percutaneous coronary intervention. Am J Cardiol 2009; 103:165–169. Patti G, Nusca A, Chello M, Pasceri V, D’Ambrosio A, Vetrovec GW, Di Sciascio G. Usefulness of statin pretreatment to prevent contrast-induced nephropathy and to improve long-term outcome in patients undergoing percutaneous coronary intervention. Am J Cardiol 2008; 101:279–285. Jo SH, Koo BK, Park JS, Kang HJ, Cho YS, Kim YJ, et al. Prevention of radiocontrast medium induced nephropathy using short-term high-dose simvastatin in patients with renal insufficiency undergoing coronary angiography (PROMISS) trial – a randomized controlled study. Am Heart J 2008; 155:499.e1–499.e8. Toso A, Maioli M, Leoncini M, Gallopin M, Tedeschi D, Micheletti C, et al. Usefulness of atorvastatin (80 mg) in prevention of contrast-induced nephropathy in patients with chronic renal disease. Am J Cardiol 2010; 105:288–292. Patti G, Ricottini E, Nusca A, Colonna G, Pasceri V, D’Ambrosio A, et al. Short-term, high-dose atorvastatin pretreatment to prevent contrast-induced nephropathy in patients with acute coronary syndromes undergoing percutaneous coronary intervention (from the ARMYDA-CIN [atorvastatin for reduction of myocardial damage during angioplasty – contrast-induced nephropathy] trial. Am J Cardiol 2011; 108:1–7. Xinwei J, Xianghua F, Jing Z, Xinshun G, Ling X, Weize F, et al. Comparison of usefulness of simvastatin 20 mg versus 80 mg in preventing contrastinduced nephropathy in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Am J Cardiol 2009; 104:519–524. Quintavalle C, Fiore D, De Micco F, Visconti G, Focaccio A, Golia B, et al. Impact of a high loading dose of atorvastatin on contrast-induced acute kidney injury. Circulation 2012; 126:3008–3016. Leoncini M, Toso A, Maioli M, Tropeano F, Villani S, Bellandi F. Early highdose rosuvastatin for contrast-induced nephropathy prevention in acute coronary syndrome: results from the PRATO-ACS study (protective effect of rosuvastatin and antiplatelet therapy on contrast-induced acute kidney injury and myocardial damage in patients with acute coronary syndrome). J Am Coll Cardiol 2014; 63:71–79.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Editorial
Statins and contrast-induced acute kidney injury Carlo Briguoria, Giovanni Napolitanob and Gerolama Condorellic,d Coronary Artery Disease 2014, 25:550–551 a
Laboratory of Interventional Cardiology, Department of Cardiology, Clinica Mediterranea, bDepartment of Cardiology, Ospedale San Giuliano, cDepartment of Molecular Medicine and Medical Biotechnologies, ‘Federico II’ University of Naples and dIEOS, CNR, Naples, Italy
Correspondence to Carlo Briguori, MD, PhD, Laboratory of Interventional Cardiology, Department of Cardiology, Clinica Mediterranea, Via Orazio 2, I-80121 Naples, Italy Tel: + 39 81 7259 764; fax: + 39 81 7259 777; e-mail: [email protected] Received 24 June 2014 Revised 26 June 2014 Accepted 30 June 2014
Over the past few decades application of coronary and peripheral procedures has substantially increased because of the more aggressive approach in the diagnosis and treatment of the different clinical presentations of atherosclerosis. Indeed, recent technical advances in this field have also allowed the successful treatment of patients with complex coronary and peripheral artery disease. The administration of iodinated contrast media is essential for all these procedures. Contrast media are usually well tolerated; however, in some patients they may induce acute kidney injury. Contrast media-induced acute kidney injury (CI-AKI) has become the third cause of hospital-acquired renal failure, with prolongation of hospital stay and consequent increase in healthcare costs [1]. In addition, patients developing CI-AKI are at higher risk for both a further deterioration in kidney function and an unfavourable clinical outcome. Risk factors for a more marked decline in renal function following contrast media exposure are pre-existing chronic kidney disease, diabetic nephropathy, high total dose of contrast media, heart failure, age and anaemia. The risk scores proposed by Mehran et al. [2] or by Gurm et al. [3] are very useful in clinical practice. A general consensus exists on the beneficial effect of hydration in preventing CI-AKI [4]. Hydration represents the cornerstone or prophylaxis of CI-AKI. Thus, adequate hydration should be performed before contrast media exposure. Multiple drugs have been tested in an attempt to prevent CI-AKI. Because of the concept that a key mechanism seems to be alteration in renal dynamics, vasodilators and diuretics have been tested as prophylactic drugs. However, their effectiveness has not been confirmed. In recent times, considerable interest has resulted from the preliminary positive data on the effectiveness of prophylactic administration of antioxidant compounds, such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). In the current issue of Coronary Artery Disease, Xie et al. [5] report the results of an updated meta-analysis to determine whether pretreatment with statins can reduce the risk of CI-AKI and adverse clinical events. Seventeen studies with 6323 patients were included. Pretreatment with statins before angiography significantly reduced the risk of CI-AKI [relative risk 0.50; 95% confidence 0954-6928 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
interval (CI) 0.35–0.71; P < 0.001] and was associated with significantly lower postprocedural serum creatinine levels. Meanwhile, the use of statins resulted in trends of reduced risks of renal replacement therapy and all-cause death within 30 days (relative risk 0.44; 95% CI 0.18–1.08; P = 0.07). Further analyses indicated that highdose statins were more effective than low-dose statins in reducing the risk of CI-AKI and that different types of statins (atorvastatin, rosuvastatin and simvastatin) exhibited similar effects on preventing CI-AKI. Khanal et al. [6] first studied 29 409 patients undergoing percutaneous coronary intervention, and patients on preprocedure statins had a lower incidence of CI-AKI (4.37 vs. 5.93%; P < 0.0001) and renal replacement therapy (0.32 vs. 0.49%; P = 0.03). After adjustments for comorbidities, preprocedure statin use was associated with a significant reduction in CI-AKI (odds ratio 0.87; 95% CI 0.77–0.99; P = 0.03) [6]. Statins are a class of drugs mainly used to control cholesterol levels. Statins have several ‘pleiotropic’ effects through their non-lipid-related mechanisms acting on inflammation responses, endothelial function, plaque stability, thrombus formation and the apoptotic pathway [7,8]. Some observational and randomized studies have investigated the effectiveness of statin pretreatment in reducing the incidence of CI-AKI [6,9–13]. Toso et al. [12]. demonstrated that a high dose (80 mg) of atorvastatin before and after contrast exposure had no effect on CI-AKI prevention when compared with conventional prophylaxis (i.e. hydration plus N-acetyl cysteine). Conversely, the study by Xinwei et al. [14] proved that a high (80 mg) rather than a low (20 mg) dose of simvastatin reduces the incidence of CI-AKI. Recently, Quintavalle et al. [15] have demonstrated that a single high (80 mg) loading dose of atorvastatin administered within 24 h before contrast media exposure is effective in reducing the rate of CI-AKI in patients with CKD. This beneficial effect is observed in patients with and without diabetes mellitus as well as in those with moderate chronic kidney failure. Moreover, another recent investigation confirmed that the administration of a high dose of rosuvastatin in statin-naive patients with acute coronary syndromes scheduled for early invasive procedure can prevent CIAKI and reduce 30-day adverse clinical events [16]. DOI: 10.1097/MCA.0000000000000154
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Statins and contrast-induced AKI Briguori et al. 551
Acknowledgements
Fig. 1
Conflicts of interest
There are no conflicts of interest.
Contrast media ROS
References 1
Statins
2
pJNK
ERK AKT
Statins 3
Caspase 3
4
Apoptosis
Cell survival 5
Statin effects on kidney cell contrast media-induced apoptosis. Contrast media induce the generation of reactive oxygen species (ROS) in tubular kidney cells, which activate the stress kinase phosphorylated Jun-N-terminal-kinase (pJNK). pJNK in turn may activate the intrinsic apoptotic pathway by the activation of caspase 3. Statin treatment prevents contrast media-induced apoptosis by inhibiting pJNK and, in turn, activating survival alternative protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) (which are pathways of cell survival). In the background a galactin-3 staining for tubular renal cells is represented, which is a marker of distal epithelial tubular cells.
6
7
8
9
Contrast media exposure of vasa recta and tubule cells can cause an increase in reactive oxygen species production and consequently induce apoptosis activation. For this reason, compounds with antioxidant properties acting as scavenger molecules for reactive oxygen species (such as N-acetyl cysteine, ascorbic acid and statins) have been investigated. Furthermore, an in-vitro model indicates that pretreatment with atorvastatin prevents contrast media-induced renal cell apoptosis by reducing stress kinase activation, and restores the survival signals mediated by alternative protein kinase B and extracellular signal-regulated kinase signal transduction pathways (Fig. 1) [15]. To conclude, CI-AKI is the major complication following contrast media exposure. It is highly prevalent in patients with several risk factors, including older age, chronic kidney disease, congestive heart failure and diabetes mellitus. Although the administration of limited contrast media volume and hydration (either by saline or by sodium bicarbonate infusion) is the cornerstone of CIAKI prevention, antioxidant compounds (such as statins) seem to be effective by reducing oxidative stress and thus preventing contrast media-induced renal cell apoptosis. Therefore, a high dose of statins should be included in the strategies for CI-AKI prevention.
10
11
12
13
14
15
16
McCullough PA. Contrast-induced acute kidney injury. J Am Coll Cardiol 2008; 51:1419–1428. Mehran R, Aymong ED, Nikolsky E, Lasic Z, Iakovou I, Fahy M, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol 2004; 44:1393–1399. Gurm HS, Seth M, Kooiman J, Share D. A novel tool for reliable and accurate prediction of renal complications in patients undergoing percutaneous coronary intervention. J Am Coll Cardiol 2013; 61:2242–2248. Stacul F, van der Molen AJ, Reimer P, Webb JA, Thomsen HS, Morcos SK, et al. Contrast induced nephropathy: updated esur contrast media safety committee guidelines. Eur Radiol 2011; 21:2527–2541. Xie H, Ye Y, Shan G, Zhang S, Fang Q, Yang D, Zeng Y. Effect of statins in preventing contrast-induced nephropathy: an updated meta-analysis. Coron Artery Dis 2014; 25:565–574. Khanal S, Attallah N, Smith DE, Kline-Rogers E, Share D, O’Donnell MJ, Moscucci M. Statin therapy reduces contrast-induced nephropathy: an analysis of contemporary percutaneous interventions. Am J Med 2005; 118:843–849. Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA 1998; 279:1643–1650. Briguori C, Visconti G, Focaccio A, Golia B, Chieffo A, Castelli A, et al. Novel approaches for preventing or limiting events (naples) II trial: impact of a single high loading dose of atorvastatin on periprocedural myocardial infarction. J Am Coll Cardiol 2009; 54:2157–2163. Lev EI, Kornowski R, Vaknin-Assa H, Ben-Dor I, Brosh D, Teplitsky I, et al. Effect of previous treatment with statins on outcome of patients with STsegment elevation myocardial infarction treated with primary percutaneous coronary intervention. Am J Cardiol 2009; 103:165–169. Patti G, Nusca A, Chello M, Pasceri V, D’Ambrosio A, Vetrovec GW, Di Sciascio G. Usefulness of statin pretreatment to prevent contrast-induced nephropathy and to improve long-term outcome in patients undergoing percutaneous coronary intervention. Am J Cardiol 2008; 101:279–285. Jo SH, Koo BK, Park JS, Kang HJ, Cho YS, Kim YJ, et al. Prevention of radiocontrast medium induced nephropathy using short-term high-dose simvastatin in patients with renal insufficiency undergoing coronary angiography (PROMISS) trial – a randomized controlled study. Am Heart J 2008; 155:499.e1–499.e8. Toso A, Maioli M, Leoncini M, Gallopin M, Tedeschi D, Micheletti C, et al. Usefulness of atorvastatin (80 mg) in prevention of contrast-induced nephropathy in patients with chronic renal disease. Am J Cardiol 2010; 105:288–292. Patti G, Ricottini E, Nusca A, Colonna G, Pasceri V, D’Ambrosio A, et al. Short-term, high-dose atorvastatin pretreatment to prevent contrast-induced nephropathy in patients with acute coronary syndromes undergoing percutaneous coronary intervention (from the ARMYDA-CIN [atorvastatin for reduction of myocardial damage during angioplasty – contrast-induced nephropathy] trial. Am J Cardiol 2011; 108:1–7. Xinwei J, Xianghua F, Jing Z, Xinshun G, Ling X, Weize F, et al. Comparison of usefulness of simvastatin 20 mg versus 80 mg in preventing contrastinduced nephropathy in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Am J Cardiol 2009; 104:519–524. Quintavalle C, Fiore D, De Micco F, Visconti G, Focaccio A, Golia B, et al. Impact of a high loading dose of atorvastatin on contrast-induced acute kidney injury. Circulation 2012; 126:3008–3016. Leoncini M, Toso A, Maioli M, Tropeano F, Villani S, Bellandi F. Early highdose rosuvastatin for contrast-induced nephropathy prevention in acute coronary syndrome: results from the PRATO-ACS study (protective effect of rosuvastatin and antiplatelet therapy on contrast-induced acute kidney injury and myocardial damage in patients with acute coronary syndrome). J Am Coll Cardiol 2014; 63:71–79.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
