review article
Novel Biomarkers of Acute Kidney Injury After Contrast Coronary Angiography M. Connolly, MB, MRCP,* D. McEneaney, MD, FRCP,* Ian Menown, MD, FRCP,* N. Morgan, PhD, FRCP,† and M. Harbinson, MD, FRCP‡
Abstract: Acute kidney injury (AKI), defined as a rise in serum creatinine of greater than 25% from baseline measured at 48 hours after renal insult, may follow iodinated contrast coronary angiography. Termed contrast-induced nephropathy, it can result in considerable morbidity and mortality. Measurement of serum creatinine as a functional biomarker of glomerular filtration rate is widely used for detection of AKI, but it lacks sensitivity for the early diagnosis of AKI (typically rising 24 hours after functional loss) and, as a solely functional marker of glomerular filtration rate, is unable to differentiate among the various causes of AKI. These intrinsic limitations to creatinine measurement and the recognition that improved clinical outcomes are linked to a more timely diagnosis of AKI, has led investigators to search for novel biomarkers of “early” kidney injury. Several studies have investigated the utility of renal injury biomarkers in a variety of clinical settings including angiography/percutaneous coronary intervention, coronary artery bypass graft surgery, sepsis in intensive care patients, and pediatric cardiac surgery. In this article, we discuss the use of iodinated contrast for coronary procedures and the risk factors for contrast-induced nephropathy, followed by a review the potential diagnostic utility of several novel biomarkers of early AKI in the clinical settings of coronary angiography/percutaneous coronary intervention. In particular, we discuss neutrophil gelatinase associated lipocalin in depth. If validated, such biomarkers would facilitate earlier AKI diagnosis and improve clinical outcomes. Key Words: acute kidney injury, contrast-induced nephropathy, coronary angiography, iodinated contrast, novel biomarkers (Cardiology in Review 2015;23: 240–246)
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ecent advances in cardiovascular and radiological procedures have led to a surge in the use of iodinated contrast media. However, the increased use of contrast has led to a higher risk of acute kidney injury (AKI), which has become a major healthcare issue. Significant AKI markedly increases the risk of death, length of hospital stay, and associated healthcare costs. AKI due to administration of iodinated contrast is termed contrast-induced nephropathy (CIN) and is defined as a rise in baseline creatinine of greater than 25% noted 48 hours after the procedure leading to renal insult, with peak creatinine occurring within 3 to 5 days after contrast administration.1 AKI induced by such agents begins within the first 12 to 24 hours after contrast administration.2 Although iodinated contrast is toxic to renal tubular cells (Fig. 1),3 a suitable alternative media is yet to be
From the *Cardiovascular Research Unit, Craigavon Cardiac Centre, Southern Trust, Northern Ireland, United Kingdom; †Department of Nephrology, Daisy Hill Hospital, Southern Trust, Northern Ireland, United Kingdom; and ‡Centre for Experimental Medicine, Queens University Belfast, Northern Ireland, United Kingdom. Disclosure: The authors have no conflicts of interest to report. Correspondence: M. Connolly, MB, MRCP, Cardiovascular Research Unit, Craigavon Cardiac Centre, Southern Trust, Northern Ireland, United Kingdom. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1061-5377/15/2305-0240 DOI: 10.1097/CRD.0000000000000058
240 | www.cardiologyinreview.com
developed. Current therapeutic options are restricted to preventative strategies designed to mitigate CIN risk. The pathophysiology of CIN is only partly understood. Putative mechanisms include intrarenal vasoconstriction, oxidative stress, and a direct cytotoxic effect of iodinated contrast agents (Fig. 2).2,4,5 Iodinated contrast induces enthothelin release and dysregulates local prostaglandins, the result being sustained intrarenal vasoconstriction.6 The ensuing drop in glomerular filtration pressure reduces tubular flow rates, prolongs contrast transit time, and enhances contrast exposure to renal tubular cells. These synergistic effects of contrast produce intramedullary hypoxia. At the cellular level a combination of oxidative stress and inflammation results in ischemic injury and death, leading to AKI. In most cases of CIN, the decline in renal function is mild and transient with recovery typically beginning within 3 to 5 days.7 The strongest risk factor for CIN development is the presence of pre-existent chronic kidney disease [CKD is defined as a glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2)]. Other independent risk factors include increasing age (CIN incidence rises to 15% in patients greater than 65 years), diabetic nephropathy, peripheral vascular disease, advanced cardiac failure, and the use of non iso-osmolar contrast agents.8–10 Demographic shifts toward a more aged population along with the increasing prevalence of diabetes mellitus (with commensurate increases in the prevalence of CKD and coronary artery disease) place detection and prevention of CIN as a key health priority for both cardiac and renal services. The incidence of CKD in the United Kingdom is 5–8% of the population but approximately doubles in patients with atherosclerotic disease undergoing cardiac contrast investigation.11 A recent audit at Craigavon Area Hospital demonstrated that 77 (12.1%) of 634 patients undergoing angiography met the definition for CKD (GFR < 60 mL/min), of whom 9 patients (11.6%) developed AKI postcontrast (author’s unpublished data presented at the Irish Atherosclerotic Society Scientific Session 2012). Within the patient group undergoing cardiac imaging, those patients undergoing percutaneous coronary intervention (PCI) are among the highest risk group for the development of CIN due to the greater contrast volumes required. The absolute risk of CIN varies within the published literature on account of the heterogeneous mix of baseline risk factors in the populations studied. One study of 7230 consecutive patients over a 5-year history assessed CIN risk (when defined as greater than or equal to 25% increase from baseline serum creatinine at 48 hours post-PCI) in relation to the presence of end stage of renal dysfunction. Patients with end-stage renal dysfunction were excluded. There were 1980 patients (27.4%) with baseline CKD and 5250 patients (72.6%) without CKD. CIN developed in 13% of patients with normal renal function and in 19% of patients with baseline CKD. In the CKD CIN-positive group, 70% had hypertension, 80% had hypercholesterolemia, 52% had diabetes, and 43% had cardiac failure (left ventricular ejection fraction 60 mL
140
DM vs non-DM, GFR > 60 mL
AKI Rate 11%
14% (DM) 10% (non-DM)
25
Non-DM GFR > 60 mL
0%
150
GFR > 60 mL
8.7%
208
DM + GFR < 60 mL
18.8%
Main Findings
Statistics
Ref
0, 2, 4, 8, 24
Timepoints (h)
Significant NGAL rises as early as 2 hours
34
0, 2, 4, 8, 24
Significant NGAL rise in both groups, more significant in DM group No patient developed CIN by creatinine definition. Significant NGAL rises as early as 2 hours Significant NGAL rise seen at 24 hours Significant NGAL rise as early as 2 hours
Serum NGAL raised at 2 hours (P < 0.05), 4 hours (P < 0.01), and 8 hours (P < 0.05), urinary NGAL raised at 4 hours (P < 0.05), 8 hours (P < 0.001) and 12 hours (P < 0.05) P < 0.05 for both groups vs precontrast P < 0.001 DM vs non-DM Serum NGAL raised at 2 hours (P < 0.05) and 4 hours (P < 0.01), urinary NGAL raised at 4 and 12 hours (P < 0.05)
37
P < 0.05 vs controls
38
P = 0.03 (2 hours), P = 0.007 (4 hours), P = 0.0015 (12–24 hours)
39
0, 2, 4, 12
0, 24 0, 2, 4, 12–24
36
AKI indicates acute kidney injury; CIN, contrast-induced nephropathy; CKD, chronic kidney disease; DM, diabetes mellitus; GFR, glomerular filtration rate; NGAL, neutrophil gelatinase-associated lipocalin.
L-FABP levels were significantly higher in CIN cases after 24 hours of contrast administration (P < 0.01), with no statistically significant changes up to 8 hours postprocedure. Manabe et al43 studied stable CKD patients undergoing electively planned angiography and found an AKI event rate of 8.6%. L-FABP levels were assessed before angiogram and at 1 and 2 days after angiogram. This study found that urinary L-FABP levels were significantly raised preprocedure in those patients who subsequently developed AKI by creatinine criteria, with an AUC of 0.70 for AKI prediction pre procedure, with a sensitivity of 82% and specificity of 69%; P = 0.002. Independent predictors of AKI on multivariate analysis were baseline L-FABP of greater than 24.5 μg/g of creatinine (μg/g Cr), left ventricular ejection fraction less than 40% and use of angiotensin-converting enzyme inhibitors. L-FABP levels at 1 and 2 days postprocedure were also significantly higher in the AKI group, P = 0.014 and P = 0.003, respectively. Nakamura et al44 found similar findings, with L-FABP levels increasing after 1 and 2 days following elective angiography with or without PCI. Levels were still significantly higher after 14 days when creatinine had fallen to baseline, with levels in the non-AKI group remaining low throughout the 14 days postprocedure. This was also mirrored in the Kato et al45 study, where L-FABP levels were only noted to rise at 1 and 2 days postprocedure.
Kidney Injury Marker 1 KIM-1 is a 90 kDa transmembrane glycoprotein belonging to the immunoglobulin gene superfamily and is involved in the differentiation of T helper cells and expressed on the proximal tubule apical membrane cilia following renal injury.22 It is a type one cell membrane glycoprotein with transmembrane, cytoplasmic, and ectodomains. KIM-1 is not expressed within normal healthy kidneys, but is upregulated in ischemia, nephrotoxic drug injury, CKD, and acute/ 244 | www.cardiologyinreview.com
chronic decreased kidney transplant function.26 The exact pathophysiological role of KIM-1 during AKI is not clearly understood but is believed to be related to dedifferentiation, reduction of cast formation and subsequent tubular obstruction, and phagocytosis of proinflammatory necrotic and apoptotic cellular debris. KIM-1 has not been studied in depth in the context of CIN.
Percutaneous Coronary Intervention/Angiography Malyszko et al37 studied 140 patients after contrast angiography assessed KIM-1 as a potential marker for AKI prediction. Levels of KIM-1 were only found to be significantly elevated at 24 hours (P < 0.05) and 48 hours (P < 0.05) following contrast, lagging behind considerably compared with NGAL and IL-18.
Cystatin C CysC is a 13 kDa endogenous cysteine proteinase inhibitor that is produced by nucleated cells at a constant rate, and is filtered by the renal glomerulus, reabsorbed, and completely catabolized by intact renal tubules.22 It has an important role in intracellular catabolism of various peptides and protein.46 It has several important characteristics which are important in its function as an AKI biomarker. CysC is produced at a relatively constant rate and released into the plasma. It has no specific protein binding and is greater than 99% filtered by the glomeruli.47 Levels of CysC are not affected by age, gender, race, muscle mass, steroid therapy, infection, liver disease, or inflammation.48 It is therefore a good marker of renal filtration function.
Percutaneous Coronary Intervention/Angiography When compared with serum creatinine, one prospective study showed CysC had an AUC of 0.93 for AKI prediction (sensitivity 94.7%, specificity 84.8%; P = 0.012).45 Patients who developed AKI postcontrast had a raised baseline CysC before angiogram (CysC © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Cardiology in Review • Volume 23, Number 5, September/October 2015
1.08 ± 0.22 vs 1.36 ± 0.28 mg/L; P = 0.007), thus supporting the view that patients who have CKD are at higher risk for CIN postangiogram or PCI than those with normal baseline renal function.
Interleukin 18 IL-18 is an 18kDa proinflammatory cytokine produced by renal tubular cells and plays an important role in the activation of macrophages. It has an active role in a variety of renal diseases.22 The intracellular cysteine protease, caspase-1, converts the preform of the cytokine to its active form.49 The active form of IL-18 exits the cell and may enter the urine (Fig. 5)26 after being activated by proximal tubules.50 IL-18, in contrast to NGAL, is independent of neutrophils.49
Percutaneous Coronary Intervention/Angiography Ling et al39 assessed IL-18 in 150 patients undergoing coronary angiography. Thirteen patients (8.7%) developed AKI and had a significantly raised IL-18 level at 24 hours postprocedure compared with controls with an AUC of 0.75 (P = 0.011, odds ratio: 10.7). It was also noted in this study that urinary IL-18 at 24 hours contrast postadministration was found to be an independent predictive marker for late major cardiac events [relative risk: 2.09; P < 0.01). Malyszko et al37 found that IL-18 increased significantly within 2 hours after contrast angiography (P < 0.05) and peaked at 24 hours postprocedure (P < 0.01). However, a study by Bulent Gul et al51 of PCI patients identified no statistical difference between IL-18 levels in CIN patients or non-CIN controls at 24 or 72 hours postcontrast (P > 0.05) despite a CIN rate of 9.5%.
N-Acetyl-β-(D)-Glucosaminidase NAG is a high-molecular weight lysosomal enzyme found in many tissues of the body. It is a tubular brush border enzyme.52 It has not been extensively studied in the AKI literature. Because of its high molecular weight, it cannot pass into glomerular ultrafiltrate.53 However, this enzyme shows high activity in renal proximal tubular cells, and leaks into the tubular fluid as the ultrafiltrate passes through proximal tubules. When proximal tubular cells are damaged, such as by the use of radio-contrast agents, urinary NAG levels increase.
COMBINATION OF BIOMARKERS The possibility of combining biomarkers has yet to be fully studied and is an emerging concept in the field of renal biomarker
Contrast Coronary Angiography
analysis, with cost and sampling time posing logistic barriers. Endre and Pickering24 discuss how there are no published simultaneously sampled multiple-biomarker time courses among adults. Failure to demonstrate added benefit from multiple biomarkers may occur due to biomarker combinations selected. Theoretically, combining biomarkers could target different mechanisms of injury; however, if they are equally predictive at the same timepoint, then the rationale for their use is doubtful. Conversely, combining biomarkers in an either/ or approach depending on the biomarker window of opportunity, could be of use and warrants investigation.24 It has been proposed that using a panel of biomarkers simultaneously may increase the sensitivity and AUC for AKI prediction, although this has not been extensively assessed to date. In one such study, Han et al54 found that the combination of NGAL, KIM-1, and NAG significantly improved the AUC for AKI prediction to 0.80 and 0.84 immediately and 3 hours postcardiac surgery, respectively. Together, the combined biomarkers performed much better than any single biomarker in isolation. Further support for such an approach comes from a study comparing the predictive power of CysC for AKI post elective cardiac surgery. CysC used alone demonstrated a sensitivity of 71% and specificity of 92%; however, when all 5 tested biomarkers were used together (CysC, NGAL, IL-18, NAG, and retinol-binding protein), an excellent AUC of 0.98, P < 0.001, was demonstrated.55
CONCLUSION All patients undergoing iodinated contrast studies are at risk of CIN; the absolute number of studies worldwide is vast and expanding as healthcare technology develops alongside an ageing demographic populous carrying a higher burden of atherosclerotic disease. The health-economic challenge is considerable. To address this challenge, patients at highest CIN risk must be clearly identified to mitigate the associated morbidity and mortality. Patients with CKD represent a sizeable and disproportionate subpopulation of patients undergoing coronary angiography and PCI; within the highest risk group they are anticipated to derive the most benefit from timely CIN diagnosis and therapeutic intervention. Clinical research often focuses on the search for novel treatments but we must also develop novel diagnostics; case in point being the ineffectiveness of therapeutic interventions so far developed for CIN contrasted to the emerging potential for biomarkers. The effective management of CIN requires validated novel biomarkers to detect AKI at initiation, enabling timely therapeutic intervention. Currently available markers, such as creatinine fail to meet these requirements but emerging data for novel markers show promise. The authors are currently assessing the clinical utility of NGAL, L-FABP, KIM-1, CysC, IL-18, and NAG in a prospective study of elective patients with established CKD undergoing angiography/PCI. We hope this evidence will add to the available literature in further validating these markers and help bring us closer to their routine adoption in cardiac practice. REFERENCES
FIGURE 5. IL-18 release from proximal tubules. IL-18 indicates interleukin 18. Adapted from Am J Kidney Dis 2011;57:930–940. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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31. Mishra J, Ma Q, Prada A, et al. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol. 2003;14:2534–2543. 32. Goetz DH, Holmes MA, Borregaard N, et al. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol Cell. 2002;10:1033–1043. 33. Yang J, Goetz D, Li JY, et al. An iron delivery pathway mediated by a lipocalin. Mol Cell. 2002;10:1045–1056. 34. Haase M, Mertens PR. Urinary biomarkers–silver bullets to faster drug development and nephron protection. Nephrol Dial Transplant. 2010;25:3167–3169. 35. Bagshaw SM, Bennett M, Haase M, et al. Plasma and urine neutrophil gelatinase-associated lipocalin in septic versus non-septic acute kidney injury in critical illness. Intensive Care Med. 2010;36:452–461. 36. Bachorzewska-Gajewska H, Malyszko J, Sitniewska E, et al. Could neutrophil-gelatinase-associated lipocalin and cystatin C predict the development of contrast-induced nephropathy after percutaneous coronary interventions in patients with stable angina and normal serum creatinine values? Kidney Blood Press Res. 2007;30:408–415. 37. Malyszko J, Bachorzewska-Gajewska H, Poniatowski B, et al. Urinary and serum biomarkers after cardiac catheterization in diabetic patients with stable angina and without severe chronic kidney disease. Ren Fail. 2009;31:910–919. 38. Bachorzewska-Gajewska H, Poniatowski B, Dobrzycki S. NGAL (neutrophil gelatinase-associated lipocalin) and L-FABP after percutaneous coronary interventions due to unstable angina in patients with normal serum creatinine. Adv Med Sci. 2009;54:221–224. 39. Ling W, Zhaohui N, Ben H, et al. Urinary IL-18 and NGAL as early predictive biomarkers in contrast-induced nephropathy after coronary angiography. Nephron Clin Pract. 2008;108:c176–c181. 40. Qureshi AC, Rampat R, Harwood SM et al. Serum NGAL identifies contrast nephropathy early in patients with diabetes mellitus and chronic kidney disease undergoing coronary angiography and angioplasty. Heart. 2011;97:A17–A18. 41. McMahon BA, Murray PT. Urinary liver fatty acid-binding protein: another novel biomarker of acute kidney injury. Kidney Int. 2010;77:657–659. 42. Portilla D, Dent C, Sugaya T, et al. Liver fatty acid-binding protein as a biomarker of acute kidney injury after cardiac surgery. Kidney Int. 2008;73:465–472. 43. Manabe K, Kamihata H, Motohiro M, et al. Urinary liver-type fatty acid-binding protein level as a predictive biomarker of contrast-induced acute kidney injury. Eur J Clin Invest. 2012;42:557–563. 44. Nakamura T, Sugaya T, Node K, et al. Urinary excretion of liver-type fatty acid-binding protein in contrast medium-induced nephropathy. Am J Kidney Dis. 2006;47:439–444. 45. Kato K, Sato N, Yamamoto T, et al. Valuable markers for contrast-induced nephropathy in patients undergoing cardiac catheterization. Circ J. 2008;72:1499–1505. 46. Barrett AJ, Davies ME, Grubb A. The place of human gamma-trace (cystatin C) amongst the cysteine proteinase inhibitors. Biochem Biophys Res Commun. 1984;120:631–636. 47. Grubb AO. Cystatin C–properties and use as diagnostic marker. Adv Clin Chem. 2000;35:63–99. 48. Zhu J, Yin R, Wu H, et al. Cystatin C as a reliable marker of renal function following heart valve replacement surgery with cardiopulmonary bypass. Clin Chim Acta. 2006;374:116–121. 49. Melnikov VY, Ecder T, Fantuzzi G, et al. Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J Clin Invest. 2001;107:1145–1152. 50. Coca SG, Yalavarthy R, Concato J, et al. Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review. Kidney Int. 2008;73:1008–1016. 51. Bulent Gul CB, Gullulu M, Oral B, et al. Urinary IL-18: a marker of contrastinduced nephropathy following percutaneous coronary intervention? Clin Biochem. 2008;41:544–547. 52. Wellwood JM, Ellis BG, Price RG, et al. Urinary N-acetyl- beta-D-glucosaminidase activities in patients with renal disease. Br Med J. 1975;3:408–411. 53. Kavukçu S, Soylu A, Türkmen M. The clinical value of urinary N-acetylbeta-D-glucosaminidase levels in childhood age group. Acta Med Okayama. 2002;56:7–11. 54. Han WK, Wageber G, Zhu Y et al. Urinary biomarkers in the early detection of acute kidney injury after cardiac surgery. Kidney Int. 2008;73:873–882. 55. Che M, Xie B, Xue S, et al. Clinical usefulness of novel biomarkers for the detection of acute kidney injury following elective cardiac surgery. Nephron Clin Pract. 2010;115:c66–c72.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Novel Biomarkers of Acute Kidney Injury After Contrast Coronary Angiography M. Connolly, MB, MRCP,* D. McEneaney, MD, FRCP,* Ian Menown, MD, FRCP,* N. Morgan, PhD, FRCP,† and M. Harbinson, MD, FRCP‡
Abstract: Acute kidney injury (AKI), defined as a rise in serum creatinine of greater than 25% from baseline measured at 48 hours after renal insult, may follow iodinated contrast coronary angiography. Termed contrast-induced nephropathy, it can result in considerable morbidity and mortality. Measurement of serum creatinine as a functional biomarker of glomerular filtration rate is widely used for detection of AKI, but it lacks sensitivity for the early diagnosis of AKI (typically rising 24 hours after functional loss) and, as a solely functional marker of glomerular filtration rate, is unable to differentiate among the various causes of AKI. These intrinsic limitations to creatinine measurement and the recognition that improved clinical outcomes are linked to a more timely diagnosis of AKI, has led investigators to search for novel biomarkers of “early” kidney injury. Several studies have investigated the utility of renal injury biomarkers in a variety of clinical settings including angiography/percutaneous coronary intervention, coronary artery bypass graft surgery, sepsis in intensive care patients, and pediatric cardiac surgery. In this article, we discuss the use of iodinated contrast for coronary procedures and the risk factors for contrast-induced nephropathy, followed by a review the potential diagnostic utility of several novel biomarkers of early AKI in the clinical settings of coronary angiography/percutaneous coronary intervention. In particular, we discuss neutrophil gelatinase associated lipocalin in depth. If validated, such biomarkers would facilitate earlier AKI diagnosis and improve clinical outcomes. Key Words: acute kidney injury, contrast-induced nephropathy, coronary angiography, iodinated contrast, novel biomarkers (Cardiology in Review 2015;23: 240–246)
R
ecent advances in cardiovascular and radiological procedures have led to a surge in the use of iodinated contrast media. However, the increased use of contrast has led to a higher risk of acute kidney injury (AKI), which has become a major healthcare issue. Significant AKI markedly increases the risk of death, length of hospital stay, and associated healthcare costs. AKI due to administration of iodinated contrast is termed contrast-induced nephropathy (CIN) and is defined as a rise in baseline creatinine of greater than 25% noted 48 hours after the procedure leading to renal insult, with peak creatinine occurring within 3 to 5 days after contrast administration.1 AKI induced by such agents begins within the first 12 to 24 hours after contrast administration.2 Although iodinated contrast is toxic to renal tubular cells (Fig. 1),3 a suitable alternative media is yet to be
From the *Cardiovascular Research Unit, Craigavon Cardiac Centre, Southern Trust, Northern Ireland, United Kingdom; †Department of Nephrology, Daisy Hill Hospital, Southern Trust, Northern Ireland, United Kingdom; and ‡Centre for Experimental Medicine, Queens University Belfast, Northern Ireland, United Kingdom. Disclosure: The authors have no conflicts of interest to report. Correspondence: M. Connolly, MB, MRCP, Cardiovascular Research Unit, Craigavon Cardiac Centre, Southern Trust, Northern Ireland, United Kingdom. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1061-5377/15/2305-0240 DOI: 10.1097/CRD.0000000000000058
240 | www.cardiologyinreview.com
developed. Current therapeutic options are restricted to preventative strategies designed to mitigate CIN risk. The pathophysiology of CIN is only partly understood. Putative mechanisms include intrarenal vasoconstriction, oxidative stress, and a direct cytotoxic effect of iodinated contrast agents (Fig. 2).2,4,5 Iodinated contrast induces enthothelin release and dysregulates local prostaglandins, the result being sustained intrarenal vasoconstriction.6 The ensuing drop in glomerular filtration pressure reduces tubular flow rates, prolongs contrast transit time, and enhances contrast exposure to renal tubular cells. These synergistic effects of contrast produce intramedullary hypoxia. At the cellular level a combination of oxidative stress and inflammation results in ischemic injury and death, leading to AKI. In most cases of CIN, the decline in renal function is mild and transient with recovery typically beginning within 3 to 5 days.7 The strongest risk factor for CIN development is the presence of pre-existent chronic kidney disease [CKD is defined as a glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2)]. Other independent risk factors include increasing age (CIN incidence rises to 15% in patients greater than 65 years), diabetic nephropathy, peripheral vascular disease, advanced cardiac failure, and the use of non iso-osmolar contrast agents.8–10 Demographic shifts toward a more aged population along with the increasing prevalence of diabetes mellitus (with commensurate increases in the prevalence of CKD and coronary artery disease) place detection and prevention of CIN as a key health priority for both cardiac and renal services. The incidence of CKD in the United Kingdom is 5–8% of the population but approximately doubles in patients with atherosclerotic disease undergoing cardiac contrast investigation.11 A recent audit at Craigavon Area Hospital demonstrated that 77 (12.1%) of 634 patients undergoing angiography met the definition for CKD (GFR < 60 mL/min), of whom 9 patients (11.6%) developed AKI postcontrast (author’s unpublished data presented at the Irish Atherosclerotic Society Scientific Session 2012). Within the patient group undergoing cardiac imaging, those patients undergoing percutaneous coronary intervention (PCI) are among the highest risk group for the development of CIN due to the greater contrast volumes required. The absolute risk of CIN varies within the published literature on account of the heterogeneous mix of baseline risk factors in the populations studied. One study of 7230 consecutive patients over a 5-year history assessed CIN risk (when defined as greater than or equal to 25% increase from baseline serum creatinine at 48 hours post-PCI) in relation to the presence of end stage of renal dysfunction. Patients with end-stage renal dysfunction were excluded. There were 1980 patients (27.4%) with baseline CKD and 5250 patients (72.6%) without CKD. CIN developed in 13% of patients with normal renal function and in 19% of patients with baseline CKD. In the CKD CIN-positive group, 70% had hypertension, 80% had hypercholesterolemia, 52% had diabetes, and 43% had cardiac failure (left ventricular ejection fraction 60 mL
140
DM vs non-DM, GFR > 60 mL
AKI Rate 11%
14% (DM) 10% (non-DM)
25
Non-DM GFR > 60 mL
0%
150
GFR > 60 mL
8.7%
208
DM + GFR < 60 mL
18.8%
Main Findings
Statistics
Ref
0, 2, 4, 8, 24
Timepoints (h)
Significant NGAL rises as early as 2 hours
34
0, 2, 4, 8, 24
Significant NGAL rise in both groups, more significant in DM group No patient developed CIN by creatinine definition. Significant NGAL rises as early as 2 hours Significant NGAL rise seen at 24 hours Significant NGAL rise as early as 2 hours
Serum NGAL raised at 2 hours (P < 0.05), 4 hours (P < 0.01), and 8 hours (P < 0.05), urinary NGAL raised at 4 hours (P < 0.05), 8 hours (P < 0.001) and 12 hours (P < 0.05) P < 0.05 for both groups vs precontrast P < 0.001 DM vs non-DM Serum NGAL raised at 2 hours (P < 0.05) and 4 hours (P < 0.01), urinary NGAL raised at 4 and 12 hours (P < 0.05)
37
P < 0.05 vs controls
38
P = 0.03 (2 hours), P = 0.007 (4 hours), P = 0.0015 (12–24 hours)
39
0, 2, 4, 12
0, 24 0, 2, 4, 12–24
36
AKI indicates acute kidney injury; CIN, contrast-induced nephropathy; CKD, chronic kidney disease; DM, diabetes mellitus; GFR, glomerular filtration rate; NGAL, neutrophil gelatinase-associated lipocalin.
L-FABP levels were significantly higher in CIN cases after 24 hours of contrast administration (P < 0.01), with no statistically significant changes up to 8 hours postprocedure. Manabe et al43 studied stable CKD patients undergoing electively planned angiography and found an AKI event rate of 8.6%. L-FABP levels were assessed before angiogram and at 1 and 2 days after angiogram. This study found that urinary L-FABP levels were significantly raised preprocedure in those patients who subsequently developed AKI by creatinine criteria, with an AUC of 0.70 for AKI prediction pre procedure, with a sensitivity of 82% and specificity of 69%; P = 0.002. Independent predictors of AKI on multivariate analysis were baseline L-FABP of greater than 24.5 μg/g of creatinine (μg/g Cr), left ventricular ejection fraction less than 40% and use of angiotensin-converting enzyme inhibitors. L-FABP levels at 1 and 2 days postprocedure were also significantly higher in the AKI group, P = 0.014 and P = 0.003, respectively. Nakamura et al44 found similar findings, with L-FABP levels increasing after 1 and 2 days following elective angiography with or without PCI. Levels were still significantly higher after 14 days when creatinine had fallen to baseline, with levels in the non-AKI group remaining low throughout the 14 days postprocedure. This was also mirrored in the Kato et al45 study, where L-FABP levels were only noted to rise at 1 and 2 days postprocedure.
Kidney Injury Marker 1 KIM-1 is a 90 kDa transmembrane glycoprotein belonging to the immunoglobulin gene superfamily and is involved in the differentiation of T helper cells and expressed on the proximal tubule apical membrane cilia following renal injury.22 It is a type one cell membrane glycoprotein with transmembrane, cytoplasmic, and ectodomains. KIM-1 is not expressed within normal healthy kidneys, but is upregulated in ischemia, nephrotoxic drug injury, CKD, and acute/ 244 | www.cardiologyinreview.com
chronic decreased kidney transplant function.26 The exact pathophysiological role of KIM-1 during AKI is not clearly understood but is believed to be related to dedifferentiation, reduction of cast formation and subsequent tubular obstruction, and phagocytosis of proinflammatory necrotic and apoptotic cellular debris. KIM-1 has not been studied in depth in the context of CIN.
Percutaneous Coronary Intervention/Angiography Malyszko et al37 studied 140 patients after contrast angiography assessed KIM-1 as a potential marker for AKI prediction. Levels of KIM-1 were only found to be significantly elevated at 24 hours (P < 0.05) and 48 hours (P < 0.05) following contrast, lagging behind considerably compared with NGAL and IL-18.
Cystatin C CysC is a 13 kDa endogenous cysteine proteinase inhibitor that is produced by nucleated cells at a constant rate, and is filtered by the renal glomerulus, reabsorbed, and completely catabolized by intact renal tubules.22 It has an important role in intracellular catabolism of various peptides and protein.46 It has several important characteristics which are important in its function as an AKI biomarker. CysC is produced at a relatively constant rate and released into the plasma. It has no specific protein binding and is greater than 99% filtered by the glomeruli.47 Levels of CysC are not affected by age, gender, race, muscle mass, steroid therapy, infection, liver disease, or inflammation.48 It is therefore a good marker of renal filtration function.
Percutaneous Coronary Intervention/Angiography When compared with serum creatinine, one prospective study showed CysC had an AUC of 0.93 for AKI prediction (sensitivity 94.7%, specificity 84.8%; P = 0.012).45 Patients who developed AKI postcontrast had a raised baseline CysC before angiogram (CysC © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Cardiology in Review • Volume 23, Number 5, September/October 2015
1.08 ± 0.22 vs 1.36 ± 0.28 mg/L; P = 0.007), thus supporting the view that patients who have CKD are at higher risk for CIN postangiogram or PCI than those with normal baseline renal function.
Interleukin 18 IL-18 is an 18kDa proinflammatory cytokine produced by renal tubular cells and plays an important role in the activation of macrophages. It has an active role in a variety of renal diseases.22 The intracellular cysteine protease, caspase-1, converts the preform of the cytokine to its active form.49 The active form of IL-18 exits the cell and may enter the urine (Fig. 5)26 after being activated by proximal tubules.50 IL-18, in contrast to NGAL, is independent of neutrophils.49
Percutaneous Coronary Intervention/Angiography Ling et al39 assessed IL-18 in 150 patients undergoing coronary angiography. Thirteen patients (8.7%) developed AKI and had a significantly raised IL-18 level at 24 hours postprocedure compared with controls with an AUC of 0.75 (P = 0.011, odds ratio: 10.7). It was also noted in this study that urinary IL-18 at 24 hours contrast postadministration was found to be an independent predictive marker for late major cardiac events [relative risk: 2.09; P < 0.01). Malyszko et al37 found that IL-18 increased significantly within 2 hours after contrast angiography (P < 0.05) and peaked at 24 hours postprocedure (P < 0.01). However, a study by Bulent Gul et al51 of PCI patients identified no statistical difference between IL-18 levels in CIN patients or non-CIN controls at 24 or 72 hours postcontrast (P > 0.05) despite a CIN rate of 9.5%.
N-Acetyl-β-(D)-Glucosaminidase NAG is a high-molecular weight lysosomal enzyme found in many tissues of the body. It is a tubular brush border enzyme.52 It has not been extensively studied in the AKI literature. Because of its high molecular weight, it cannot pass into glomerular ultrafiltrate.53 However, this enzyme shows high activity in renal proximal tubular cells, and leaks into the tubular fluid as the ultrafiltrate passes through proximal tubules. When proximal tubular cells are damaged, such as by the use of radio-contrast agents, urinary NAG levels increase.
COMBINATION OF BIOMARKERS The possibility of combining biomarkers has yet to be fully studied and is an emerging concept in the field of renal biomarker
Contrast Coronary Angiography
analysis, with cost and sampling time posing logistic barriers. Endre and Pickering24 discuss how there are no published simultaneously sampled multiple-biomarker time courses among adults. Failure to demonstrate added benefit from multiple biomarkers may occur due to biomarker combinations selected. Theoretically, combining biomarkers could target different mechanisms of injury; however, if they are equally predictive at the same timepoint, then the rationale for their use is doubtful. Conversely, combining biomarkers in an either/ or approach depending on the biomarker window of opportunity, could be of use and warrants investigation.24 It has been proposed that using a panel of biomarkers simultaneously may increase the sensitivity and AUC for AKI prediction, although this has not been extensively assessed to date. In one such study, Han et al54 found that the combination of NGAL, KIM-1, and NAG significantly improved the AUC for AKI prediction to 0.80 and 0.84 immediately and 3 hours postcardiac surgery, respectively. Together, the combined biomarkers performed much better than any single biomarker in isolation. Further support for such an approach comes from a study comparing the predictive power of CysC for AKI post elective cardiac surgery. CysC used alone demonstrated a sensitivity of 71% and specificity of 92%; however, when all 5 tested biomarkers were used together (CysC, NGAL, IL-18, NAG, and retinol-binding protein), an excellent AUC of 0.98, P < 0.001, was demonstrated.55
CONCLUSION All patients undergoing iodinated contrast studies are at risk of CIN; the absolute number of studies worldwide is vast and expanding as healthcare technology develops alongside an ageing demographic populous carrying a higher burden of atherosclerotic disease. The health-economic challenge is considerable. To address this challenge, patients at highest CIN risk must be clearly identified to mitigate the associated morbidity and mortality. Patients with CKD represent a sizeable and disproportionate subpopulation of patients undergoing coronary angiography and PCI; within the highest risk group they are anticipated to derive the most benefit from timely CIN diagnosis and therapeutic intervention. Clinical research often focuses on the search for novel treatments but we must also develop novel diagnostics; case in point being the ineffectiveness of therapeutic interventions so far developed for CIN contrasted to the emerging potential for biomarkers. The effective management of CIN requires validated novel biomarkers to detect AKI at initiation, enabling timely therapeutic intervention. Currently available markers, such as creatinine fail to meet these requirements but emerging data for novel markers show promise. The authors are currently assessing the clinical utility of NGAL, L-FABP, KIM-1, CysC, IL-18, and NAG in a prospective study of elective patients with established CKD undergoing angiography/PCI. We hope this evidence will add to the available literature in further validating these markers and help bring us closer to their routine adoption in cardiac practice. REFERENCES
FIGURE 5. IL-18 release from proximal tubules. IL-18 indicates interleukin 18. Adapted from Am J Kidney Dis 2011;57:930–940. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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