- Email: [email protected]
Laboratory Predictors of Contrast-Induced Nephropathy After Neurointervention: A Prospective 3-Year Observational Study
Journal Pre-proof Laboratory Predictors of Contrast-Induced Nephropathy After Neurointervention: a Prospective 3-Year Observational Study Hoon Kim, M.D., Ph.D, Kwang Wook Jo, M.D., Ph.D PII:
S1878-8750(19)32804-9
DOI:
https://doi.org/10.1016/j.wneu.2019.10.166
Reference:
WNEU 13637
To appear in:
World Neurosurgery
Received Date: 22 July 2019 Revised Date:
23 October 2019
Accepted Date: 24 October 2019
Please cite this article as: Kim H, Jo KW, Laboratory Predictors of Contrast-Induced Nephropathy After Neurointervention: a Prospective 3-Year Observational Study, World Neurosurgery (2019), doi: https:// doi.org/10.1016/j.wneu.2019.10.166. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
Kim 1
Laboratory Predictors of Contrast-Induced Nephropathy After Neurointervention: a Prospective 3-Year Observational Study
Hoon Kim, Kwang Wook Jo
Hoon Kim, M.D., Ph.D. Department of Neurosurgery, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. He has no financial conflicts of interest or industry affiliations. He screened, acquired, and extracted data, and write this article. Kwang Wook Jo, M.D., Ph.D. Department of Neurosurgery, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. He has no financial conflicts of interest or industry affiliations. He conducted screening and data acquisition, and conceived and designed this study, and analyzed data and conducted interpretation of results, and is responsible for all aspects of the publication of this article.
Running title: Acute Kidney Injury After Neurointervention
*Correspondence: Kwang Wook Jo, M.D., Ph.D. Department of Neurosurgery, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 327 Sosa-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14647, Republic of Korea Tel: +82-32-340-2259 Fax: +82-32-340-7391 E-mail: [email protected]
Keywords: Acute kidney injury; Contrast-induced nephropathy; hsCRP; Neurointervention; Neutrophil gelatinase-associated lipocalin
1
Kim 2
Abbreviations and Acronyms AKI: Acute kidney injury CIN: Contrast-induced nephropathy CVA: Cerebrovascular accident GFR: Glomerular filtration rate hs-CRP: high-sensitivity C-reactive protein ICM: Iodinated contrast media PCI: Percutaneous coronary intervention RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease sCr: Serum creatinine uNGAL: Urine neutrophil gelatinase-associated lipocalin
2
Kim 1
ABSTRACT
OBJECTIVE: The purpose of this study was to assess the natural course of contrast-induced nephropathy (CIN) and to determine the predictive abilities of preprocedural high-sensitivity C-reactive protein (hs-CRP) and urine neutrophil gelatinase-associated lipocalin (uNGAL) for CIN after neurointervention procedures.
METHODS: We prospectively enrolled 176 patients who underwent an elective neurointervention procedure (diagnostic angiography or endovascular surgery). CIN was defined as an increase in serum creatinine of more than 0.5 mg/dL or an increase of at least 25% from the baseline value within 48 hours of contrast media exposure. The predictive value of hs-CRP and serial urine NGAL (baseline, 6, 24, and 48 hours) for the risk of CIN was assessed using multivariate logistic regression.
RESULTS: CIN occurred in 17 patients (9.46%). Multivariate analysis revealed that the CIN incidence was significantly associated with high baseline hs-CRP. All patients with CIN had creatinine return to baseline levels within 7 days. No patients required dialysis or suffered permanent sequelae as a result of a creatinine increase. During the 3-year follow-up period, no cerebro- or cardiovascular events occurred in the CIN group. However, 3 patients in the non-CIN group suffered a vascular event. One was a myocardial infarction, and 2 were ischemic strokes.
CONCLUSIONS: The incidence of CIN after neurointervention procedures was relatively high (9.46%). However, the natural course of CIN was favorable and did not affect cerebrovascular events. Additionally, patients with CIN typically recovered with supportive care within 7 days. Elevated preprocedural hs-CRP levels (>5 mg/dL) were a significant and independent predictor of CIN after neurointervention procedures.
1
Kim 2
INTRODUCTION Percutaneous cerebral angiography remains the gold standard diagnostic tool for evaluating cerebrovascular disease, while indications for neuro-interventional surgery are rapidly expanding. During this procedure, iodinated contrast media (ICM) is essential for improving the visualization of blood vessels. However, ICM may lead to unintentional contrast-induced nephropathy (CIN), which is the third most common cause of hospital-acquired acute kidney injury (AKI). The pathogenesis of CIN is poorly understood.1-4 CIN accounts for approximately 11% of AKIs.3,4 Reports of CIN incidence after cerebral angiography are rare. Serum creatinine (sCr) and urine output are well-established biomarkers for AKI; however, they are lagging indicators. sCr only becomes elevated after 50% of kidney function is lost, and it is not diagnostic for up to 52% of moderate and severe AKIs. Measuring urine output can be tedious and affected.5 Due to these limitations, a predictive biomarker is needed for early AKI detection. Urine neutrophil gelatinase-associated lipocalin (uNGAL) and highsensitivity C-reactive protein (hs-CRP) are promising indicators of AKI.6,7 The purpose of this study was to determine the incidence and natural course of CIN and to assess preprocedural hs-CRP and uNGAL in patients undergoing neurointervention procedures. We also sought to determine the association of CIN and vascular events during the follow-up period.
METHODS Patients Institutional review board approval of Bucheon St. Mary's Hospital of the Catholic University of Korea (HC11SISI0132) was obtained for all aspects of this study. This prospective single-center study was conducted from January 2012 to December 2013 to test the hypothesis that an increase in hs-CRP and uNGAL is related to CIN in patients undergoing neurointervention procedures. All participants signed an informed consent form according to the policy of the Catholic University of Korea before enrollment. All patients with cerebrovascular diseases who underwent an elective neuroendovascular procedure (diagnostic angiography : severe stenosis (>70%) or occlusion of cerebral arteries with relevant acute ischemic lesions on diffusion magnetic resonance imaging in the 2
Kim 3
corresponding arterial territory, carotid artery stenting, stenting for patients with severe symptomatic intracranial atherosclerotic stenosis, coil embolization of unruptured, or ruptured intracranial aneurysm) with contrast administration at our institution were screened. Exclusion criteria were pregnancy, heart failure, hemodynamic instability, bacterial infection, chronic renal disease dependent on dialysis, age younger than 18 or older than 85 years, preexisting severe renal impairment (glomerular filtration rate [GFR]<50 mL/min/1.73 m2), congestive heart failure, chronic obstructive pulmonary disease, recent or chronic inflammatory disease and receiving immunosuppression therapy, suspicious recent infectious disease (hs-CRP>10 mg/dL), known allergy or anaphylaxis to contrast medium, use of steroids or hyperosmolar agent (e.g., mannitol) during the peri- or postoperative period, use of Metformin 48 hours prior to neurointervention, and patients who did not want to participate in the study.
Neurointervention Procedure and Study Protocol All neurointervention procedures were performed by a neurosurgeon who specializes in interventional treatments, according to standard clinical practice. The contrast medium was iodixanol (VISIPAQUETM 320; GE Healthcare, Princeton, NJ, USA). During the procedure, all patients received a continuous infusion of heparinized normal saline to prevent thrombus formation and to maintain catheter patency. Perioperative patient management and postoperative intensive care were at the discretion of the attending neurosurgeon. After contrast exposure, all patients received isotonic (0.9%) saline intravenously at a rate of 1 mL/kg per hour for 24 hours. All patients also continued to take aspirin (100 mg/d) and clopidogrel (75 mg/d) for at least 3 months. This study required no changes to the previous standard care in our hospital, and the attending neurosurgeons were blinded to the CRP and uNGAL results throughout the perioperative period. Baseline blood and urine tests (including hs-CRP and uNGAL) were routinely conducted in all patients at admission. Time 0 (T0) was defined as the groin puncture time. Blood and urine samples were taken 6, 24, and 48 hours after T0. Urine samples were stored at -80°C until analysis. uNGAL analysis was performed with a commercial Human Lipocalin-2/NGAL Quantikine ELISA Kit (R&D Systems, Minneapolis, MN, USA).
3
Kim 4
Definition of CIN The primary endpoint was the development of CIN, defined as an increase in sCr of at least 0.5 mg/dL (44 mmol/L) or at least 25% from baseline in the absence of an alternative cause within 48 to 72 hours after administration of contrast medium.1,2 The patients were divided into CIN and non-CIN groups. The estimated GFR for each patient was calculated with the Modification of Diet in Renal Disease Formula. We used RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) criteria to diagnose kidney injury.
Clinical Follow-Up Patients were followed every 3 to 6 months for 3 years in the outpatient clinic to monitor for vascular events. In case of loss to regular follow up, medical events were collected from patients or a caregiver through a telephone interview.
Statistical Analyses Categorical data are presented as the frequency (percentage); continuous data are presented as the mean ± standard deviation. Differences between means were compared using an unpaired t-test when the variables showed a normal distribution or the Mann–Whitney U test when they did not. We used the chi-square test or Fisher exact test to compare categorical variables. Significant variables in the univariate analysis were entered into a multivariate logistical regression model to identify predictive variables for adverse outcomes. A P-value < 0.05 (2 sided) was considered significant. Data were analyzed with SPSS 18.0 (SPSS Inc., Chicago, IL, USA).
RESULTS We evaluated 176 patients, 83 (47%) males, and 93 (53%) females, with a mean age of 61.6 years. Demographic and baseline data are summarized in Table 1. The CIN and non-CIN groups did not differ significantly in body mass index, procedure time, or amount of contrast dye. The common comorbidities were hypertension (104 patients, 59.1%) and diabetes mellitus (48 patients, 27.2%). Thirty-3 patients (18.8%) were taking an ACE inhibitor, and 105 patients (59.7%) were taking statins. CIN occurred in 17 patients (9.46%). Only high hs-CRP levels were correlated with CIN. 4
Kim 5
The relative increase in hs-CRP was significantly higher in the CIN group than the non-CIN group (P = 0.017) (Table 1). In a simple logistic regression analysis, and hs-CRP >5 was associated with CIN (P = 0.033) (Table 2). The proportion of patients with an hs-CRP >5 differed significantly between CIN and non-CIN groups in a multivariate logistic regression (P = 0.016; OR, 5.05; 95% CI, 1.34 to 18.9) (Table 3, Figure 1). Regarding hs-CRP, the area under the Receiver-operating characteristic (ROC) curve for predicting CIN is 0.749 (95% confidence interval (CI) : 0.632-0.866 ; p=0.001) (Figure 2) Even though serum creatine was elevated, NGAL did not change significantly (Figure 3). Mean sCr values over time showed that sCr increased 24 hours after neurointervention procedures in the CIN group (Figure 4). All patients in the CIN group received sufficient hydration with acetylcysteine (1800 mg/daily intravenous). Creatinine levels returned to baseline within 2 to 7 days. No patients required dialysis, and none suffered permanent sequelae as a result of a creatinine increase. During the 3 year follow-up period, no additional vascular events occurred in the CIN group. However, 3 patients in the non-CIN group suffered vascular events. One was a myocardial infarction, and 2 were ischemic strokes.
DISCUSSION Incidence and Natural Course of CIN The incidence and average in-hospital mortality of CIN have been reported at up to 12% and 6%, respectively.3 However, the exact risk factors for CIN are difficult to determine because the incidence of CIN varies widely depending on various factors such as pre-existing chronic kidney disease, the amount and type of contrast agent administered, and the radiologic procedure.3,8,9 More than half of CIN cases are complications of cardiac catheterization and intra-arterial coronary angiography, and nearly a third follow computed tomography scans.3 Our study followed patients undergoing cerebral angiography. In the present study, 176 patients underwent a neuroendovascular procedures. Although CIN occurred in 9.46% of patients, high levels of pre-procedure hs-CRP correlated with renal injury. The incidence of CIN was significantly higher among patients with high hs-CRP than those without. Similar results were found in patients with STEMI who underwent primary percutaneous coronary intervention (p-PCI).7,10 In our study, permanent AKI did not occur 5
Kim 6
during the follow-up period. No mortality or morbidity occurred in the acute period. The average time to recovery after the intravascular injection of contrast medium was 6.7 days (range 2 to 7 days).
Association of CIN with CVA After 3 Years of Follow-Up Kidney disease is a well-known risk factor of cardiovascular and cerebrovascular disease.11,12 An increased plasma hs-CRP concentration in the acute phase reflects systemic inflammation. CRP was predictive of adverse cardiovascular outcomes.13 CIN was not associated with additional cerebrovascular events in our study.
Biomarkers for CIN: Urine NGAL versus hs-CRP sCr is a lagging indicator of acute changes in kidney function because sCr may not change until about 50% of kidney function has already been lost.14,15 For this reason, it is not helpful for prevention or early diagnosis. In addition, sCr levels are affected by age, sex, muscle mass, muscle metabolism, medications, and hydration status. A new biomarker is needed for early diagnosis. NGAL is a 25-kD glycoprotein of the lipocalin family, which is synthesized and secreted by tubular epithelial cells of the proximal and distal segments.16 After AKI, NGAL increases more rapidly in urine and serum than does sCr.16,17 Consequently, NGAL is known as a protentional predictor of AKI caused by various conditions. A meta-analysis including 2538 patients, 487 (19.2%) patients developed AKI. This suggested that the NGAL levels in urine had a diagnostic and prognostic value for early AKI.18 Also, NGAL were accurate predictors of the need for renal replacement therapy in patients admitted to intensive care unit and postoperative AKI after liver transplantation or PCI.19,20 Even though emerging studies indicate that NGAL is predictive of CIN, it was not reliable in this study (Figure 2). NAGL was not related to serum creatine. Inflammation is a known risk factor for CIN. Among the many inflammatory markers, hsCRP is associated with an increased risk of CIN.21,22 Han et al.23 reported that AKI increased depending on the increase in CRP levels after coronary artery bypass grafting and Shacham et al.22 proposed that serum hs-CRP level >9 mg/L at admission is an independent predictor for AKI following primary PCI in STEMI patients. However, we excluded hs-CRP levels >10 mg/L because the cutoff point to define systemic inflammation has been in prior studies and 6
Kim 7
we want to exclude prior systemic inflammation.24,25 We chose an hs-CRP value of >5 mg/L as
the cutoff for the dichotomization of this cohort because it represents the upper limit of normal in our laboratory. We also investigated CIN and CVA for 3 years follow-up, hs-CRP levels of >5 mg/L were independent risk factors for further adverse cardiovascular events among patients with cardiovascular disease during 3 years follow-up and increased risk for postoperative vascular events in various procedure.26-28 Although in our study, preprocedural hs-CRP >5 mg/dL was associated with the development of reversible CIN after the neuro intervention procedures, there were no adverse events and no associated CVAs. For these patients, preprocedural hydration and close observation after the procedure may be needed.
Age and Statin Use In elderly patients, CIN can develop due to multiple morbidities, physiologic aging of kidneys (structural and functional), etc.29,30 A previous study [Protective effect of Rosuvastatin and Antiplatelet Therapy On contrast-induced acute kidney injury and myocardial damage in patients with ACS (PRATO-ACS)] that focused on CIN during coronary intervention showed that old age increased the risk of developing CIN (8.7% in the <75 and 15.9% in the >75 groups) (OR, 2.001; 95% CI, 1.14 3.53; P = 0.017). Statin use before contrast medium exposure (especially high dose rosuvastatin) was associated with a significantly lower incidence of CIN.31 However, our study did not show a difference between age groups. This difference between studies is likely because our study excluded patients with lower baseline GFR (GFR <50), but PRATO-ACS included 86% elderly patients (>75 years) who had a baseline CrCl <60 mL/min. This explanation assumes that if renal function is above a moderate level, age is unlikely to be an absolute risk factor for CIN. Our study did not show an effect of statin on CIN because we used a low- to moderate-dose atorvastatin less often than high-dose rosuvastatin. Therefore, a high prophylactic dose of statin may be recommended to reduce CIN in elderly patients with reduced renal function.
Study Limitations This study has several limitations. Our study cohort was relatively small, and all patients were recruited from a single center and prospective observation trials. The number of CIN 7
Kim 8
events was small for multivariate analysis, so we had to be cautious of the natural history of CIN and the association between CIN and cerebrovascular events. Future multicenter
studies with larger cohorts should be conducted to confirm whether NGAL and hs-CRP can be used for early detection of risk factors in patients who receive CIN or undergo CINinduced neurointerventions.
CONCLUSIONS The incidence of CIN during the 3-year follow-up period was relatively high (9.46%), but the natural course of CIN was favorable. CIN mostly recovered with supportive care within 7 days. Preoperative hs-CRP > 5 mg/dL is considered to be a risk factor for CIN. These patients will likely require sufficient hydration, active prevention, and close observation before and after the procedure. CIN events are not related to the development of ischemic stroke during long term follow-up.
8
Kim 9
Funding This work was supported by the Institute of Clinical Medicine Research of Bucheon St. Mary's Hospital, Research Fund, 2012.
Conflict of interest statement No conflicts of interest.
9
Kim 10
REFERENCES 1.
Andreucci M, Solomon R, Tasanarong A. Side effects of radiographic contrast media: pathogenesis, risk factors, and prevention. Biomed Res Int. 2014;2014:741018. https://doi.org/10.1155/2014/741018.
2.
Chen WB, Liang L, Zhang B, et al. To evaluate the damage of renal function in CIAKI rats at 3T: using ASL and BOLD MRI. Biomed Res Int. 2015;2015:593060. https://doi.org/10.1155/2015/593060.
3.
Pannu N, Wiebe N, Tonelli M. Prophylaxis strategies for contrast-induced nephropathy. Jama. 2006;295:2765-2779. https://doi.org/10.1001/jama.295.23.2765.
4.
McCullough PA, Adam A, Becker CR, et al. Epidemiology and prognostic implications of contrast-induced nephropathy. Am J Cardiol. 2006;98:5k-13k. https://doi.org/10.1016/j.amjcard.2006.01.019.
5.
Hirsch R, Dent C, Pfriem H, et al. NGAL is an early predictive biomarker of contrastinduced
nephropathy
in
children.
Pediatr
Nephrol.
2007;22:2089-2095.
https://doi.org/10.1007/s00467-007-0601-4. 6.
Filiopoulos V, Biblaki D, Vlassopoulos D. Neutrophil gelatinase-associated lipocalin (NGAL): a promising biomarker of contrast-induced nephropathy after computed tomography. Ren Fail. 2014;36:979-986. https://doi.org/10.3109/0886022x.2014.900429.
7.
Liu Y, Tan N, Zhou YL, et al. High-sensitivity C-reactive protein predicts contrastinduced nephropathy after primary percutaneous coronary intervention. J Nephrol. 2012;25:332-340. https://doi.org/10.5301/jn.5000007.
8.
Hardiek K, Katholi RE, Ramkumar V, Deitrick C. Proximal tubule cell response to radiographic contrast media. Am J Physiol Renal Physiol. 2001;280:F61-70. https://doi.org/10.1152/ajprenal.2001.280.1.F61.
9.
Weisbord SD, Mor MK, Resnick AL, et al. Prevention, incidence, and outcomes of contrast-induced acute kidney injury. Arch Intern Med. 2008;168:1325-1332. https://doi.org/10.1001/archinte.168.12.1325.
10.
Jian-Wei Z, Yu-Jie Z, Shu-Jun C, Qing Y, Shi-Wei Y, Bin N. Impact of preprocedural high-sensitivity C-reactive protein on contrast-induced nephropathy in patients undergoing primary percutaneous coronary intervention. Angiology. 2014;65:402-407. 10
Kim 11
https://doi.org/10.1177/0003319713482177. 11.
Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation. 2003;108:2154-2169. https://doi.org/10.1161/01.Cir.0000095676.90936.80.
12.
Banerjee G, Wahab KW, Gregoire SM, et al. Impaired renal function is related to deep and mixed, but not strictly lobar cerebral microbleeds in patients with ischaemic stroke and TIA. J Neurol. 2016;263:760-764. https://doi.org/10.1007/s00415-0168040-4.
13.
Celik T, Iyisoy A, Kursaklioglu H, et al. The impact of admission C-reactive protein levels on the development of poor myocardial perfusion after primary percutaneous intervention in patients with acute myocardial infarction. Coron Artery Dis. 2005;16:293-299.
14.
Nguyen MT, Devarajan P. Biomarkers for the early detection of acute kidney injury. Pediatr Nephrol. 2008;23:2151-2157. https://doi.org/10.1007/s00467-007-0470-x.
15.
Devarajan P. Emerging biomarkers of acute kidney injury. Contrib Nephrol. 2007;156:203-212. https://doi.org/10.1159/000102085.
16.
McIlroy DR, Wagener G, Lee HT. Biomarkers of acute kidney injury: an evolving domain. Anesthesiology. 2010;112:998-1004. https://doi.org/10.1097/ALN.0b013e3181cded3f.
17.
Bachorzewska-Gajewska H, Malyszko J, Sitniewska E, Malyszko JS, Dobrzycki S. Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary interventions. Am J Nephrol. 2006;26:287-292. https://doi.org/10.1159/000093961.
18.
Haase M, Bellomo R, Devarajan P, Schlattmann P, Haase-Fielitz A. Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis. 2009;54:1012-1024. https://doi.org/10.1053/j.ajkd.2009.07.020.
19.
Albeladi FI, Algethamy HM. Urinary Neutrophil Gelatinase-Associated Lipocalin as a Predictor of Acute Kidney Injury, Severe Kidney Injury, and the Need for Renal 11
Kim 12
Replacement Therapy in the Intensive Care Unit. Nephron Extra. 2017;7:62-77. https://doi.org/10.1159/000477469. 20.
Nusca A, Miglionico M, Proscia C, et al. Early prediction of contrast-induced acute kidney injury by a "bedside" assessment of Neutrophil Gelatinase-Associated Lipocalin during elective percutaneous coronary interventions. PLoS One. 2018;13:e0197833. https://doi.org/10.1371/journal.pone.0197833.
21.
Yuan Y, Qiu H, Hu X, et al. Predictive value of inflammatory factors on contrastinduced acute kidney injury in patients who underwent an emergency percutaneous coronary intervention. Clin Cardiol. 2017;40:719-725. https://doi.org/10.1002/clc.22722.
22.
Shacham Y, Leshem-Rubinow E, Steinvil A, Keren G, Roth A, Arbel Y. High sensitive C-reactive protein and the risk of acute kidney injury among ST elevation myocardial infarction patients undergoing primary percutaneous intervention. Clin Exp Nephrol. 2015;19:838-843. https://doi.org/10.1007/s10157-014-1071-1.
23. Han SS, Kim DK, Kim SS, Chin HJ, Chae DW, Na KY. C-reactive protein predicts acute kidney injury and death after coronary artery bypass grafting. Ann Thorac Surg. 2017;104:804-810. https://doi.org/10.1016/j.athoracsur.2017.01.075. 24.
den Elzen WP, van Manen JG, Boeschoten EW, Krediet RT, Dekker FW. The effect of single and repeatedly high concentrations of C-reactive protein on cardiovascular and non-cardiovascular mortality in patients starting with dialysis. Nephrol Dial Transplant. 2006;21:1588-1595. https://doi.org/10.1093/ndt/gfk092.
25.
Tsirpanlis G. The pattern of inflammation and a potential new clinical meaning and usefulness of C-reactive protein in end-stage renal failure patients. Kidney Blood Press Res. 2005;28:55-61. https://doi.org/10.1159/000082165.
26.
Schulz S, Ludike H, Lierath M, et al. C-reactive protein levels and genetic variants of CRP as prognostic markers for combined cardiovascular endpoint (cardiovascular death, death from stroke, myocardial infarction, and stroke/TIA). Cytokine. 2016;88:71-76. https://doi.org/10.1016/j.cyto.2016.08.021.
27.
Owens CD, Ridker PM, Belkin M, et al. Elevated C-reactive protein levels are associated with postoperative events in patients undergoing lower extremity vein bypass surgery. J Vasc Surg. 2007;45:2-9; discussion 9. 12
Kim 13
https://doi.org/10.1016/j.jvs.2006.08.048. 28.
Vrsalovic M, Vucur K, Car B, Krcmar T, Vrsalovic Presecki A. C-reactive protein, renal function, and cardiovascular outcome in patients with symptomatic peripheral artery disease and preserved left ventricular systolic function. Croat Med J. 2015;56:351-356. https://doi.org/10.3325/cmj.2015.56.351.
29.
Sidhu RB, Brown JR, Robb JF, et al. Interaction of gender and age on post cardiac catheterization contrast-induced acute kidney injury. Am J Cardiol. 2008;102:14821486. https://doi.org/10.1016/j.amjcard.2008.07.037.
30.
Song W, Zhang T, Pu J, Shen L, He B. Incidence and risk of developing contrastinduced acute kidney injury following intravascular contrast administration in elderly patients. Clin Interv Aging. 2014;9:85-93. https://doi.org/10.2147/cia.S55157.
31.
Tropeano F, Leoncini M, Toso A, et al. Impact of rosuvastatin in contrast-induced acute kidney injury in the elderly: post hoc analysis of the PRATO-ACS trial. J Cardiovasc
Pharmacol
Ther.
https://doi.org/10.1177/1074248415599062.
13
2016;21:159-166.
Kim 14
Figure 1. Representative box plot showing the high-sensitivity C-reactive protein (CRP) distribution of the contrast-induced nephropathy (CIN) and non-CIN groups.
Figure 2. Regarding hs-CRP, the area under the Receiver-operating characteristic (ROC) curve for predicting CIN is 0.749 (95% confidence interval (CI) : 0.632-0.866 ; p=0.001)
Figure 3. Mean urine neutrophil gelatinase-associated lipocalin (NGAL) values over time. The graph shows no difference between the contrast-induced nephropathy (CIN) and nonCIN groups in urine NGAL for 48 hours after percutaneous cerebral angiography.
Figure 4. Mean serum creatinine values over time. The graph shows that serum creatinine increased 24 hours after percutaneous cerebral angiography in the contrast-induced nephropathy group.
14
Kim 1
Table 1. Baseline Patient Characteristics (n = 176) Variable
CIN (–) (n = 159 )
CIN (+) (n = 17)
P-value
Age (years)
61.3 ± 11.8
60.1 ± 11.7
0.694
Sex (female)
83 (52%)
10 (59%)
0.621
Body mass index (kg/m2)
24.2 ± 2.9
25.6 ± 2.1
0.614
Duration (min)
64.9 ± 35.2
65 ± 38.4
0.992
Dye
109.7 ± 39.3
100.2 ± 32.4
0.364
Statin
96 (61%)
9 (53%)
0.532
ACE inhibitor
28 (18%)
5 (29%)
0.242
Smoking
41 (26%)
8 (47%)
0.065
Alcohol
56 (35%)
7 (41%)
0.640
Diabetes mellitus
42 (26%)
6 (35%)
0.444
High blood pressure
93 (59%)
11 (65%)
0.641
Hemoglobin (g/dL)
13 ± 1.5
12.7 ± 1.7
0.508
Glucose
138.9 ± 48.3
127.3 ± 28.6
0.331
Total cholesterol (mg/dL)
174.5 ± 45.7
178.3 ± 41.7
0.743
HDL (mg/dL)
51.1 ± 30.2
52.9 ± 25.5
0.805
LDL (mg/dL)
106..1 ± 39.2
105.5 ± 36.7
0.867
hs-CRP (mg/dL)
1.35 ± 1.8
3.26 ± 2.91
0.017
BUN
14.7 ± 4.8
14.1 ± 4.4
0.537
Cr
0.87 ± 0.23
0.73 ± 0.18
0.018
eGFR
87.3 ± 21.4
104.7 ± 24.4
0.002
NGAL(ng/ml)
12.1 ± 14.2
15.9 ± 19.8
0.321
CIN, contrast-induced nephropathy;
HDL, high density lipoprotein; LDL, low density
lipoprotein; hs-CRP, high-sensitivity C-reactive protein; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; NGAL, neutrophil gelatinase-associated lipocalin.
1
Kim 2
Table 2. Simple Logistic Regression Analysis for Occurrence of CIN Variable
CIN (–)
CIN (+)
(n =159 )
(n =17 )
P-value
Odds
95%
ratio
confidence interval
Age >75
19 (11.9%)
2 (11.8%)
0.982
0.98
0.208–4.635
Dye >150 (mL)
19 (11.9%)
2 (11.8%)
0.982
0.98
0.208–4.635
Smoking
42 (26.4%)
8 (47.1%)
0.073
2.47
0.781–7.435
Anemia
49 (30.8%)
7 (41.2%)
0.383
1.571
0.565–4.37
10 (6.3%)
4 (23.5%)
0.033
4.585
1.261–16.66
84 (52%)
6 (35.3%)
0.169
0.487
0.172–1.381
15 (9.4%)
4 (23.5%)
0.093
2.954
0.854–10.212
hsCRP >5 (mg/dL) GFR <90 NGAL >30 (ng/ml)
CIN, contrast-induced nephropathy; hs-CRP, high-sensitivity C-reactive protein; GFR, glomerular filtration rate; NGAL, neutrophil gelatinase-associated lipocalin.
2
Kim 3
Table 3. Risk factors for CIN in a Multivariate Logistic Regression Adjusted OR
Variable
P-value
Smoking
0.124
2.32 (0.79 - 6.78)
NGAL >30
0.053
3.56 (0.98 - 12.8)
hsCRP > 5
0.016
5.05 (1.34 - 18.9)
(95% confidence interval)*
NGAL, neutrophil gelatinase-associated lipocalin; hs-CRP, high-sensitivity C-reactive protein. *Odds ratio (OR) was adjusted according to age, sex, medical history, dye amount, and laboratory parameters
3
AKI: Acute kidney injury CIN: Contrast-induced nephropathy CVA: Cerebrovascular accident GFR: Glomerular filtration rate hs-CRP: high-sensitivity C-reactive protein ICM: Iodinated contrast media PCI: Percutaneous coronary intervention RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease sCr: Serum creatinine uNGAL: Urine neutrophil gelatinase-associated lipocalin
AUTHOR DECLARATION TEMPLATE
We wish to draw the attention of the Editor to the following facts which may be considered as potential conflicts of interest and to significant financial contributions to this work. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We further confirm that any aspect of the work covered in this manuscript that has involved either experimental animals or human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript. We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). He/she is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author and which has been configured to accept email from [email protected]
Signed by all authors as follows:
Hoon Kim
Kwangwook Jo
S1878-8750(19)32804-9
DOI:
https://doi.org/10.1016/j.wneu.2019.10.166
Reference:
WNEU 13637
To appear in:
World Neurosurgery
Received Date: 22 July 2019 Revised Date:
23 October 2019
Accepted Date: 24 October 2019
Please cite this article as: Kim H, Jo KW, Laboratory Predictors of Contrast-Induced Nephropathy After Neurointervention: a Prospective 3-Year Observational Study, World Neurosurgery (2019), doi: https:// doi.org/10.1016/j.wneu.2019.10.166. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
Kim 1
Laboratory Predictors of Contrast-Induced Nephropathy After Neurointervention: a Prospective 3-Year Observational Study
Hoon Kim, Kwang Wook Jo
Hoon Kim, M.D., Ph.D. Department of Neurosurgery, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. He has no financial conflicts of interest or industry affiliations. He screened, acquired, and extracted data, and write this article. Kwang Wook Jo, M.D., Ph.D. Department of Neurosurgery, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. He has no financial conflicts of interest or industry affiliations. He conducted screening and data acquisition, and conceived and designed this study, and analyzed data and conducted interpretation of results, and is responsible for all aspects of the publication of this article.
Running title: Acute Kidney Injury After Neurointervention
*Correspondence: Kwang Wook Jo, M.D., Ph.D. Department of Neurosurgery, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 327 Sosa-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 14647, Republic of Korea Tel: +82-32-340-2259 Fax: +82-32-340-7391 E-mail: [email protected]
Keywords: Acute kidney injury; Contrast-induced nephropathy; hsCRP; Neurointervention; Neutrophil gelatinase-associated lipocalin
1
Kim 2
Abbreviations and Acronyms AKI: Acute kidney injury CIN: Contrast-induced nephropathy CVA: Cerebrovascular accident GFR: Glomerular filtration rate hs-CRP: high-sensitivity C-reactive protein ICM: Iodinated contrast media PCI: Percutaneous coronary intervention RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease sCr: Serum creatinine uNGAL: Urine neutrophil gelatinase-associated lipocalin
2
Kim 1
ABSTRACT
OBJECTIVE: The purpose of this study was to assess the natural course of contrast-induced nephropathy (CIN) and to determine the predictive abilities of preprocedural high-sensitivity C-reactive protein (hs-CRP) and urine neutrophil gelatinase-associated lipocalin (uNGAL) for CIN after neurointervention procedures.
METHODS: We prospectively enrolled 176 patients who underwent an elective neurointervention procedure (diagnostic angiography or endovascular surgery). CIN was defined as an increase in serum creatinine of more than 0.5 mg/dL or an increase of at least 25% from the baseline value within 48 hours of contrast media exposure. The predictive value of hs-CRP and serial urine NGAL (baseline, 6, 24, and 48 hours) for the risk of CIN was assessed using multivariate logistic regression.
RESULTS: CIN occurred in 17 patients (9.46%). Multivariate analysis revealed that the CIN incidence was significantly associated with high baseline hs-CRP. All patients with CIN had creatinine return to baseline levels within 7 days. No patients required dialysis or suffered permanent sequelae as a result of a creatinine increase. During the 3-year follow-up period, no cerebro- or cardiovascular events occurred in the CIN group. However, 3 patients in the non-CIN group suffered a vascular event. One was a myocardial infarction, and 2 were ischemic strokes.
CONCLUSIONS: The incidence of CIN after neurointervention procedures was relatively high (9.46%). However, the natural course of CIN was favorable and did not affect cerebrovascular events. Additionally, patients with CIN typically recovered with supportive care within 7 days. Elevated preprocedural hs-CRP levels (>5 mg/dL) were a significant and independent predictor of CIN after neurointervention procedures.
1
Kim 2
INTRODUCTION Percutaneous cerebral angiography remains the gold standard diagnostic tool for evaluating cerebrovascular disease, while indications for neuro-interventional surgery are rapidly expanding. During this procedure, iodinated contrast media (ICM) is essential for improving the visualization of blood vessels. However, ICM may lead to unintentional contrast-induced nephropathy (CIN), which is the third most common cause of hospital-acquired acute kidney injury (AKI). The pathogenesis of CIN is poorly understood.1-4 CIN accounts for approximately 11% of AKIs.3,4 Reports of CIN incidence after cerebral angiography are rare. Serum creatinine (sCr) and urine output are well-established biomarkers for AKI; however, they are lagging indicators. sCr only becomes elevated after 50% of kidney function is lost, and it is not diagnostic for up to 52% of moderate and severe AKIs. Measuring urine output can be tedious and affected.5 Due to these limitations, a predictive biomarker is needed for early AKI detection. Urine neutrophil gelatinase-associated lipocalin (uNGAL) and highsensitivity C-reactive protein (hs-CRP) are promising indicators of AKI.6,7 The purpose of this study was to determine the incidence and natural course of CIN and to assess preprocedural hs-CRP and uNGAL in patients undergoing neurointervention procedures. We also sought to determine the association of CIN and vascular events during the follow-up period.
METHODS Patients Institutional review board approval of Bucheon St. Mary's Hospital of the Catholic University of Korea (HC11SISI0132) was obtained for all aspects of this study. This prospective single-center study was conducted from January 2012 to December 2013 to test the hypothesis that an increase in hs-CRP and uNGAL is related to CIN in patients undergoing neurointervention procedures. All participants signed an informed consent form according to the policy of the Catholic University of Korea before enrollment. All patients with cerebrovascular diseases who underwent an elective neuroendovascular procedure (diagnostic angiography : severe stenosis (>70%) or occlusion of cerebral arteries with relevant acute ischemic lesions on diffusion magnetic resonance imaging in the 2
Kim 3
corresponding arterial territory, carotid artery stenting, stenting for patients with severe symptomatic intracranial atherosclerotic stenosis, coil embolization of unruptured, or ruptured intracranial aneurysm) with contrast administration at our institution were screened. Exclusion criteria were pregnancy, heart failure, hemodynamic instability, bacterial infection, chronic renal disease dependent on dialysis, age younger than 18 or older than 85 years, preexisting severe renal impairment (glomerular filtration rate [GFR]<50 mL/min/1.73 m2), congestive heart failure, chronic obstructive pulmonary disease, recent or chronic inflammatory disease and receiving immunosuppression therapy, suspicious recent infectious disease (hs-CRP>10 mg/dL), known allergy or anaphylaxis to contrast medium, use of steroids or hyperosmolar agent (e.g., mannitol) during the peri- or postoperative period, use of Metformin 48 hours prior to neurointervention, and patients who did not want to participate in the study.
Neurointervention Procedure and Study Protocol All neurointervention procedures were performed by a neurosurgeon who specializes in interventional treatments, according to standard clinical practice. The contrast medium was iodixanol (VISIPAQUETM 320; GE Healthcare, Princeton, NJ, USA). During the procedure, all patients received a continuous infusion of heparinized normal saline to prevent thrombus formation and to maintain catheter patency. Perioperative patient management and postoperative intensive care were at the discretion of the attending neurosurgeon. After contrast exposure, all patients received isotonic (0.9%) saline intravenously at a rate of 1 mL/kg per hour for 24 hours. All patients also continued to take aspirin (100 mg/d) and clopidogrel (75 mg/d) for at least 3 months. This study required no changes to the previous standard care in our hospital, and the attending neurosurgeons were blinded to the CRP and uNGAL results throughout the perioperative period. Baseline blood and urine tests (including hs-CRP and uNGAL) were routinely conducted in all patients at admission. Time 0 (T0) was defined as the groin puncture time. Blood and urine samples were taken 6, 24, and 48 hours after T0. Urine samples were stored at -80°C until analysis. uNGAL analysis was performed with a commercial Human Lipocalin-2/NGAL Quantikine ELISA Kit (R&D Systems, Minneapolis, MN, USA).
3
Kim 4
Definition of CIN The primary endpoint was the development of CIN, defined as an increase in sCr of at least 0.5 mg/dL (44 mmol/L) or at least 25% from baseline in the absence of an alternative cause within 48 to 72 hours after administration of contrast medium.1,2 The patients were divided into CIN and non-CIN groups. The estimated GFR for each patient was calculated with the Modification of Diet in Renal Disease Formula. We used RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) criteria to diagnose kidney injury.
Clinical Follow-Up Patients were followed every 3 to 6 months for 3 years in the outpatient clinic to monitor for vascular events. In case of loss to regular follow up, medical events were collected from patients or a caregiver through a telephone interview.
Statistical Analyses Categorical data are presented as the frequency (percentage); continuous data are presented as the mean ± standard deviation. Differences between means were compared using an unpaired t-test when the variables showed a normal distribution or the Mann–Whitney U test when they did not. We used the chi-square test or Fisher exact test to compare categorical variables. Significant variables in the univariate analysis were entered into a multivariate logistical regression model to identify predictive variables for adverse outcomes. A P-value < 0.05 (2 sided) was considered significant. Data were analyzed with SPSS 18.0 (SPSS Inc., Chicago, IL, USA).
RESULTS We evaluated 176 patients, 83 (47%) males, and 93 (53%) females, with a mean age of 61.6 years. Demographic and baseline data are summarized in Table 1. The CIN and non-CIN groups did not differ significantly in body mass index, procedure time, or amount of contrast dye. The common comorbidities were hypertension (104 patients, 59.1%) and diabetes mellitus (48 patients, 27.2%). Thirty-3 patients (18.8%) were taking an ACE inhibitor, and 105 patients (59.7%) were taking statins. CIN occurred in 17 patients (9.46%). Only high hs-CRP levels were correlated with CIN. 4
Kim 5
The relative increase in hs-CRP was significantly higher in the CIN group than the non-CIN group (P = 0.017) (Table 1). In a simple logistic regression analysis, and hs-CRP >5 was associated with CIN (P = 0.033) (Table 2). The proportion of patients with an hs-CRP >5 differed significantly between CIN and non-CIN groups in a multivariate logistic regression (P = 0.016; OR, 5.05; 95% CI, 1.34 to 18.9) (Table 3, Figure 1). Regarding hs-CRP, the area under the Receiver-operating characteristic (ROC) curve for predicting CIN is 0.749 (95% confidence interval (CI) : 0.632-0.866 ; p=0.001) (Figure 2) Even though serum creatine was elevated, NGAL did not change significantly (Figure 3). Mean sCr values over time showed that sCr increased 24 hours after neurointervention procedures in the CIN group (Figure 4). All patients in the CIN group received sufficient hydration with acetylcysteine (1800 mg/daily intravenous). Creatinine levels returned to baseline within 2 to 7 days. No patients required dialysis, and none suffered permanent sequelae as a result of a creatinine increase. During the 3 year follow-up period, no additional vascular events occurred in the CIN group. However, 3 patients in the non-CIN group suffered vascular events. One was a myocardial infarction, and 2 were ischemic strokes.
DISCUSSION Incidence and Natural Course of CIN The incidence and average in-hospital mortality of CIN have been reported at up to 12% and 6%, respectively.3 However, the exact risk factors for CIN are difficult to determine because the incidence of CIN varies widely depending on various factors such as pre-existing chronic kidney disease, the amount and type of contrast agent administered, and the radiologic procedure.3,8,9 More than half of CIN cases are complications of cardiac catheterization and intra-arterial coronary angiography, and nearly a third follow computed tomography scans.3 Our study followed patients undergoing cerebral angiography. In the present study, 176 patients underwent a neuroendovascular procedures. Although CIN occurred in 9.46% of patients, high levels of pre-procedure hs-CRP correlated with renal injury. The incidence of CIN was significantly higher among patients with high hs-CRP than those without. Similar results were found in patients with STEMI who underwent primary percutaneous coronary intervention (p-PCI).7,10 In our study, permanent AKI did not occur 5
Kim 6
during the follow-up period. No mortality or morbidity occurred in the acute period. The average time to recovery after the intravascular injection of contrast medium was 6.7 days (range 2 to 7 days).
Association of CIN with CVA After 3 Years of Follow-Up Kidney disease is a well-known risk factor of cardiovascular and cerebrovascular disease.11,12 An increased plasma hs-CRP concentration in the acute phase reflects systemic inflammation. CRP was predictive of adverse cardiovascular outcomes.13 CIN was not associated with additional cerebrovascular events in our study.
Biomarkers for CIN: Urine NGAL versus hs-CRP sCr is a lagging indicator of acute changes in kidney function because sCr may not change until about 50% of kidney function has already been lost.14,15 For this reason, it is not helpful for prevention or early diagnosis. In addition, sCr levels are affected by age, sex, muscle mass, muscle metabolism, medications, and hydration status. A new biomarker is needed for early diagnosis. NGAL is a 25-kD glycoprotein of the lipocalin family, which is synthesized and secreted by tubular epithelial cells of the proximal and distal segments.16 After AKI, NGAL increases more rapidly in urine and serum than does sCr.16,17 Consequently, NGAL is known as a protentional predictor of AKI caused by various conditions. A meta-analysis including 2538 patients, 487 (19.2%) patients developed AKI. This suggested that the NGAL levels in urine had a diagnostic and prognostic value for early AKI.18 Also, NGAL were accurate predictors of the need for renal replacement therapy in patients admitted to intensive care unit and postoperative AKI after liver transplantation or PCI.19,20 Even though emerging studies indicate that NGAL is predictive of CIN, it was not reliable in this study (Figure 2). NAGL was not related to serum creatine. Inflammation is a known risk factor for CIN. Among the many inflammatory markers, hsCRP is associated with an increased risk of CIN.21,22 Han et al.23 reported that AKI increased depending on the increase in CRP levels after coronary artery bypass grafting and Shacham et al.22 proposed that serum hs-CRP level >9 mg/L at admission is an independent predictor for AKI following primary PCI in STEMI patients. However, we excluded hs-CRP levels >10 mg/L because the cutoff point to define systemic inflammation has been in prior studies and 6
Kim 7
we want to exclude prior systemic inflammation.24,25 We chose an hs-CRP value of >5 mg/L as
the cutoff for the dichotomization of this cohort because it represents the upper limit of normal in our laboratory. We also investigated CIN and CVA for 3 years follow-up, hs-CRP levels of >5 mg/L were independent risk factors for further adverse cardiovascular events among patients with cardiovascular disease during 3 years follow-up and increased risk for postoperative vascular events in various procedure.26-28 Although in our study, preprocedural hs-CRP >5 mg/dL was associated with the development of reversible CIN after the neuro intervention procedures, there were no adverse events and no associated CVAs. For these patients, preprocedural hydration and close observation after the procedure may be needed.
Age and Statin Use In elderly patients, CIN can develop due to multiple morbidities, physiologic aging of kidneys (structural and functional), etc.29,30 A previous study [Protective effect of Rosuvastatin and Antiplatelet Therapy On contrast-induced acute kidney injury and myocardial damage in patients with ACS (PRATO-ACS)] that focused on CIN during coronary intervention showed that old age increased the risk of developing CIN (8.7% in the <75 and 15.9% in the >75 groups) (OR, 2.001; 95% CI, 1.14 3.53; P = 0.017). Statin use before contrast medium exposure (especially high dose rosuvastatin) was associated with a significantly lower incidence of CIN.31 However, our study did not show a difference between age groups. This difference between studies is likely because our study excluded patients with lower baseline GFR (GFR <50), but PRATO-ACS included 86% elderly patients (>75 years) who had a baseline CrCl <60 mL/min. This explanation assumes that if renal function is above a moderate level, age is unlikely to be an absolute risk factor for CIN. Our study did not show an effect of statin on CIN because we used a low- to moderate-dose atorvastatin less often than high-dose rosuvastatin. Therefore, a high prophylactic dose of statin may be recommended to reduce CIN in elderly patients with reduced renal function.
Study Limitations This study has several limitations. Our study cohort was relatively small, and all patients were recruited from a single center and prospective observation trials. The number of CIN 7
Kim 8
events was small for multivariate analysis, so we had to be cautious of the natural history of CIN and the association between CIN and cerebrovascular events. Future multicenter
studies with larger cohorts should be conducted to confirm whether NGAL and hs-CRP can be used for early detection of risk factors in patients who receive CIN or undergo CINinduced neurointerventions.
CONCLUSIONS The incidence of CIN during the 3-year follow-up period was relatively high (9.46%), but the natural course of CIN was favorable. CIN mostly recovered with supportive care within 7 days. Preoperative hs-CRP > 5 mg/dL is considered to be a risk factor for CIN. These patients will likely require sufficient hydration, active prevention, and close observation before and after the procedure. CIN events are not related to the development of ischemic stroke during long term follow-up.
8
Kim 9
Funding This work was supported by the Institute of Clinical Medicine Research of Bucheon St. Mary's Hospital, Research Fund, 2012.
Conflict of interest statement No conflicts of interest.
9
Kim 10
REFERENCES 1.
Andreucci M, Solomon R, Tasanarong A. Side effects of radiographic contrast media: pathogenesis, risk factors, and prevention. Biomed Res Int. 2014;2014:741018. https://doi.org/10.1155/2014/741018.
2.
Chen WB, Liang L, Zhang B, et al. To evaluate the damage of renal function in CIAKI rats at 3T: using ASL and BOLD MRI. Biomed Res Int. 2015;2015:593060. https://doi.org/10.1155/2015/593060.
3.
Pannu N, Wiebe N, Tonelli M. Prophylaxis strategies for contrast-induced nephropathy. Jama. 2006;295:2765-2779. https://doi.org/10.1001/jama.295.23.2765.
4.
McCullough PA, Adam A, Becker CR, et al. Epidemiology and prognostic implications of contrast-induced nephropathy. Am J Cardiol. 2006;98:5k-13k. https://doi.org/10.1016/j.amjcard.2006.01.019.
5.
Hirsch R, Dent C, Pfriem H, et al. NGAL is an early predictive biomarker of contrastinduced
nephropathy
in
children.
Pediatr
Nephrol.
2007;22:2089-2095.
https://doi.org/10.1007/s00467-007-0601-4. 6.
Filiopoulos V, Biblaki D, Vlassopoulos D. Neutrophil gelatinase-associated lipocalin (NGAL): a promising biomarker of contrast-induced nephropathy after computed tomography. Ren Fail. 2014;36:979-986. https://doi.org/10.3109/0886022x.2014.900429.
7.
Liu Y, Tan N, Zhou YL, et al. High-sensitivity C-reactive protein predicts contrastinduced nephropathy after primary percutaneous coronary intervention. J Nephrol. 2012;25:332-340. https://doi.org/10.5301/jn.5000007.
8.
Hardiek K, Katholi RE, Ramkumar V, Deitrick C. Proximal tubule cell response to radiographic contrast media. Am J Physiol Renal Physiol. 2001;280:F61-70. https://doi.org/10.1152/ajprenal.2001.280.1.F61.
9.
Weisbord SD, Mor MK, Resnick AL, et al. Prevention, incidence, and outcomes of contrast-induced acute kidney injury. Arch Intern Med. 2008;168:1325-1332. https://doi.org/10.1001/archinte.168.12.1325.
10.
Jian-Wei Z, Yu-Jie Z, Shu-Jun C, Qing Y, Shi-Wei Y, Bin N. Impact of preprocedural high-sensitivity C-reactive protein on contrast-induced nephropathy in patients undergoing primary percutaneous coronary intervention. Angiology. 2014;65:402-407. 10
Kim 11
https://doi.org/10.1177/0003319713482177. 11.
Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation. 2003;108:2154-2169. https://doi.org/10.1161/01.Cir.0000095676.90936.80.
12.
Banerjee G, Wahab KW, Gregoire SM, et al. Impaired renal function is related to deep and mixed, but not strictly lobar cerebral microbleeds in patients with ischaemic stroke and TIA. J Neurol. 2016;263:760-764. https://doi.org/10.1007/s00415-0168040-4.
13.
Celik T, Iyisoy A, Kursaklioglu H, et al. The impact of admission C-reactive protein levels on the development of poor myocardial perfusion after primary percutaneous intervention in patients with acute myocardial infarction. Coron Artery Dis. 2005;16:293-299.
14.
Nguyen MT, Devarajan P. Biomarkers for the early detection of acute kidney injury. Pediatr Nephrol. 2008;23:2151-2157. https://doi.org/10.1007/s00467-007-0470-x.
15.
Devarajan P. Emerging biomarkers of acute kidney injury. Contrib Nephrol. 2007;156:203-212. https://doi.org/10.1159/000102085.
16.
McIlroy DR, Wagener G, Lee HT. Biomarkers of acute kidney injury: an evolving domain. Anesthesiology. 2010;112:998-1004. https://doi.org/10.1097/ALN.0b013e3181cded3f.
17.
Bachorzewska-Gajewska H, Malyszko J, Sitniewska E, Malyszko JS, Dobrzycki S. Neutrophil-gelatinase-associated lipocalin and renal function after percutaneous coronary interventions. Am J Nephrol. 2006;26:287-292. https://doi.org/10.1159/000093961.
18.
Haase M, Bellomo R, Devarajan P, Schlattmann P, Haase-Fielitz A. Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis. 2009;54:1012-1024. https://doi.org/10.1053/j.ajkd.2009.07.020.
19.
Albeladi FI, Algethamy HM. Urinary Neutrophil Gelatinase-Associated Lipocalin as a Predictor of Acute Kidney Injury, Severe Kidney Injury, and the Need for Renal 11
Kim 12
Replacement Therapy in the Intensive Care Unit. Nephron Extra. 2017;7:62-77. https://doi.org/10.1159/000477469. 20.
Nusca A, Miglionico M, Proscia C, et al. Early prediction of contrast-induced acute kidney injury by a "bedside" assessment of Neutrophil Gelatinase-Associated Lipocalin during elective percutaneous coronary interventions. PLoS One. 2018;13:e0197833. https://doi.org/10.1371/journal.pone.0197833.
21.
Yuan Y, Qiu H, Hu X, et al. Predictive value of inflammatory factors on contrastinduced acute kidney injury in patients who underwent an emergency percutaneous coronary intervention. Clin Cardiol. 2017;40:719-725. https://doi.org/10.1002/clc.22722.
22.
Shacham Y, Leshem-Rubinow E, Steinvil A, Keren G, Roth A, Arbel Y. High sensitive C-reactive protein and the risk of acute kidney injury among ST elevation myocardial infarction patients undergoing primary percutaneous intervention. Clin Exp Nephrol. 2015;19:838-843. https://doi.org/10.1007/s10157-014-1071-1.
23. Han SS, Kim DK, Kim SS, Chin HJ, Chae DW, Na KY. C-reactive protein predicts acute kidney injury and death after coronary artery bypass grafting. Ann Thorac Surg. 2017;104:804-810. https://doi.org/10.1016/j.athoracsur.2017.01.075. 24.
den Elzen WP, van Manen JG, Boeschoten EW, Krediet RT, Dekker FW. The effect of single and repeatedly high concentrations of C-reactive protein on cardiovascular and non-cardiovascular mortality in patients starting with dialysis. Nephrol Dial Transplant. 2006;21:1588-1595. https://doi.org/10.1093/ndt/gfk092.
25.
Tsirpanlis G. The pattern of inflammation and a potential new clinical meaning and usefulness of C-reactive protein in end-stage renal failure patients. Kidney Blood Press Res. 2005;28:55-61. https://doi.org/10.1159/000082165.
26.
Schulz S, Ludike H, Lierath M, et al. C-reactive protein levels and genetic variants of CRP as prognostic markers for combined cardiovascular endpoint (cardiovascular death, death from stroke, myocardial infarction, and stroke/TIA). Cytokine. 2016;88:71-76. https://doi.org/10.1016/j.cyto.2016.08.021.
27.
Owens CD, Ridker PM, Belkin M, et al. Elevated C-reactive protein levels are associated with postoperative events in patients undergoing lower extremity vein bypass surgery. J Vasc Surg. 2007;45:2-9; discussion 9. 12
Kim 13
https://doi.org/10.1016/j.jvs.2006.08.048. 28.
Vrsalovic M, Vucur K, Car B, Krcmar T, Vrsalovic Presecki A. C-reactive protein, renal function, and cardiovascular outcome in patients with symptomatic peripheral artery disease and preserved left ventricular systolic function. Croat Med J. 2015;56:351-356. https://doi.org/10.3325/cmj.2015.56.351.
29.
Sidhu RB, Brown JR, Robb JF, et al. Interaction of gender and age on post cardiac catheterization contrast-induced acute kidney injury. Am J Cardiol. 2008;102:14821486. https://doi.org/10.1016/j.amjcard.2008.07.037.
30.
Song W, Zhang T, Pu J, Shen L, He B. Incidence and risk of developing contrastinduced acute kidney injury following intravascular contrast administration in elderly patients. Clin Interv Aging. 2014;9:85-93. https://doi.org/10.2147/cia.S55157.
31.
Tropeano F, Leoncini M, Toso A, et al. Impact of rosuvastatin in contrast-induced acute kidney injury in the elderly: post hoc analysis of the PRATO-ACS trial. J Cardiovasc
Pharmacol
Ther.
https://doi.org/10.1177/1074248415599062.
13
2016;21:159-166.
Kim 14
Figure 1. Representative box plot showing the high-sensitivity C-reactive protein (CRP) distribution of the contrast-induced nephropathy (CIN) and non-CIN groups.
Figure 2. Regarding hs-CRP, the area under the Receiver-operating characteristic (ROC) curve for predicting CIN is 0.749 (95% confidence interval (CI) : 0.632-0.866 ; p=0.001)
Figure 3. Mean urine neutrophil gelatinase-associated lipocalin (NGAL) values over time. The graph shows no difference between the contrast-induced nephropathy (CIN) and nonCIN groups in urine NGAL for 48 hours after percutaneous cerebral angiography.
Figure 4. Mean serum creatinine values over time. The graph shows that serum creatinine increased 24 hours after percutaneous cerebral angiography in the contrast-induced nephropathy group.
14
Kim 1
Table 1. Baseline Patient Characteristics (n = 176) Variable
CIN (–) (n = 159 )
CIN (+) (n = 17)
P-value
Age (years)
61.3 ± 11.8
60.1 ± 11.7
0.694
Sex (female)
83 (52%)
10 (59%)
0.621
Body mass index (kg/m2)
24.2 ± 2.9
25.6 ± 2.1
0.614
Duration (min)
64.9 ± 35.2
65 ± 38.4
0.992
Dye
109.7 ± 39.3
100.2 ± 32.4
0.364
Statin
96 (61%)
9 (53%)
0.532
ACE inhibitor
28 (18%)
5 (29%)
0.242
Smoking
41 (26%)
8 (47%)
0.065
Alcohol
56 (35%)
7 (41%)
0.640
Diabetes mellitus
42 (26%)
6 (35%)
0.444
High blood pressure
93 (59%)
11 (65%)
0.641
Hemoglobin (g/dL)
13 ± 1.5
12.7 ± 1.7
0.508
Glucose
138.9 ± 48.3
127.3 ± 28.6
0.331
Total cholesterol (mg/dL)
174.5 ± 45.7
178.3 ± 41.7
0.743
HDL (mg/dL)
51.1 ± 30.2
52.9 ± 25.5
0.805
LDL (mg/dL)
106..1 ± 39.2
105.5 ± 36.7
0.867
hs-CRP (mg/dL)
1.35 ± 1.8
3.26 ± 2.91
0.017
BUN
14.7 ± 4.8
14.1 ± 4.4
0.537
Cr
0.87 ± 0.23
0.73 ± 0.18
0.018
eGFR
87.3 ± 21.4
104.7 ± 24.4
0.002
NGAL(ng/ml)
12.1 ± 14.2
15.9 ± 19.8
0.321
CIN, contrast-induced nephropathy;
HDL, high density lipoprotein; LDL, low density
lipoprotein; hs-CRP, high-sensitivity C-reactive protein; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; NGAL, neutrophil gelatinase-associated lipocalin.
1
Kim 2
Table 2. Simple Logistic Regression Analysis for Occurrence of CIN Variable
CIN (–)
CIN (+)
(n =159 )
(n =17 )
P-value
Odds
95%
ratio
confidence interval
Age >75
19 (11.9%)
2 (11.8%)
0.982
0.98
0.208–4.635
Dye >150 (mL)
19 (11.9%)
2 (11.8%)
0.982
0.98
0.208–4.635
Smoking
42 (26.4%)
8 (47.1%)
0.073
2.47
0.781–7.435
Anemia
49 (30.8%)
7 (41.2%)
0.383
1.571
0.565–4.37
10 (6.3%)
4 (23.5%)
0.033
4.585
1.261–16.66
84 (52%)
6 (35.3%)
0.169
0.487
0.172–1.381
15 (9.4%)
4 (23.5%)
0.093
2.954
0.854–10.212
hsCRP >5 (mg/dL) GFR <90 NGAL >30 (ng/ml)
CIN, contrast-induced nephropathy; hs-CRP, high-sensitivity C-reactive protein; GFR, glomerular filtration rate; NGAL, neutrophil gelatinase-associated lipocalin.
2
Kim 3
Table 3. Risk factors for CIN in a Multivariate Logistic Regression Adjusted OR
Variable
P-value
Smoking
0.124
2.32 (0.79 - 6.78)
NGAL >30
0.053
3.56 (0.98 - 12.8)
hsCRP > 5
0.016
5.05 (1.34 - 18.9)
(95% confidence interval)*
NGAL, neutrophil gelatinase-associated lipocalin; hs-CRP, high-sensitivity C-reactive protein. *Odds ratio (OR) was adjusted according to age, sex, medical history, dye amount, and laboratory parameters
3
AKI: Acute kidney injury CIN: Contrast-induced nephropathy CVA: Cerebrovascular accident GFR: Glomerular filtration rate hs-CRP: high-sensitivity C-reactive protein ICM: Iodinated contrast media PCI: Percutaneous coronary intervention RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease sCr: Serum creatinine uNGAL: Urine neutrophil gelatinase-associated lipocalin
AUTHOR DECLARATION TEMPLATE
We wish to draw the attention of the Editor to the following facts which may be considered as potential conflicts of interest and to significant financial contributions to this work. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We further confirm that any aspect of the work covered in this manuscript that has involved either experimental animals or human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript. We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). He/she is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author and which has been configured to accept email from [email protected]
Signed by all authors as follows:
Hoon Kim
Kwangwook Jo