Article
Is Serum Cystatin C a Predictor of Acute Pulmonary Thromboembolism in Patients With Normal Renal Function?
Clinical and Applied Thrombosis/Hemostasis 201X, Vol XX(X) 1–6 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029613512416 cath.sagepub.com
Nuri Tutar, MD1, N. Aleyna Kemik, MD1, Insu Yılmaz, MD1, Hakan Bu¨yu¨kog˘lan, MD1, Asiye Kanbay, MD2, Ali Dogan, MD3, Fatma Sema Oyak, MD1, Inci Gu¨lmez, MD1, and Ramazan Demir, MD1
Abstract Early diagnosis is the key point in the management of acute pulmonary thromboembolism (PTE). There are no reports in the literature comparing the serum cystatin C levels in patients with acute PTE and normal volunteers. Therefore, in this study, we analyzed 50 patients with acute PTE and 45 healthy volunteers with normal renal function. The serum cystatin C level was significantly higher in the PTE group than in the non-PTE group (1.08 mg/dL [interquantile range (IQR) 0.79-1.56] and 0.85 mg/dL [IQR 0.77-1.03], respectively, P ¼ .017). When determining the presence of PTE, the highest value of sensitivity and specificity was set at a cutoff value of 1.15 mg/dL with 93.3% specificity, 46.0% sensitivity, 88.5% positive predictive value, and 60.9% negative predictive value. In the multivariate model, cystatin C was significantly associated with the presence of PTE (odds ratio: 12.34, 95% CI 2.64-57.75). In conclusion, cystatin C may be an indicator of acute PTE in patients with normal renal function. Keywords pulmonary embolism, cystatin C, diagnosis
Introduction Pulmonary thromboembolism (PTE) is the most common cause of vascular death after myocardial infarction and stroke and the leading preventable cause of death in hospital patients.1 Early diagnosis is the key point in the management of acute PTE, since immediate treatment is highly effective. Failure to diagnose acute PTE is a serious management error since 30% of untreated patients die, while only 8% die with effective therapy.2 The approach used to diagnose PTE is mainly based on noninvasive diagnostic strategies including clinical probability assessment, D-dimer measurement, and multidetector computed tomography (CT) angiography. However, various studies have examined the role of brain natriuretic peptide (BNP), Nterminal pro-BNP (NT-pro-BNP), C-reactive protein (CRP), troponin I or T, carbonic anhydrase IX (CA IX), and tenasin C in the risk stratification of patients with PTE.3-9 Cystatin C is a protease inhibitor that controls the proteolitic enzymes in the processes of blood coagulation, complement activation, and food digestion.10 It has been shown that cystatin C is a more sensitive marker of glomerular filtration rate (GFR) changes than serum creatinine (Scr),11 because its levels are not affected by muscle mass, age, inflammation, fever, or exogenous agents.12 Recent studies have shown that cystatin C is not only a candidate marker of impaired kidney function but is also
associated with coronary artery disease,13 congestive heart failure,14 carotid atherosclerosis,15 and peripheral vascular disease.16 In a report with relatively normal renal function patients, it was found that the serum level of cystatin C was significantly higher in patients with cardiovascular events than in patients without cardiovascular events.17 In a recent report, plasma cystatin C levels were evaluated to predict the prognosis of patients with acute PTE.18 They found that cystatin C elevation was associated with a poor 30-day prognosis in acute PTE. In another report, Brodin et al analyzed 83 incident venous thromboembolic events in 3251 patients during a median of 12.3 years of follow-up.19 They found that serum cystatin C levels were associated with the risk of venous
1
Department of Pulmonary Medicine, School of Medicine, Erciyes University, Kayseri, Turkey 2 Department of Pulmonary Medicine, School of Medicine, Medeniyet University, _Istanbul, Turkey 3 Department of Cardiology, School of Medicine, Erciyes University, Kayseri, Turkey Corresponding Author: Nuri Tutar, MD, Department of Pulmonary Medicine, Erciyes University School of Medicine, Kayseri, Turkey. Email: [email protected]
Downloaded from cat.sagepub.com at UNSW Library on August 19, 2015
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Clinical and Applied Thrombosis/Hemostasis XX(X)
thromboembolism in patients with normal kidney function. However, to the best of our knowledge, there are no reports in the literature comparing the serum cystatin C levels in patients with acute PTE and non-PTE. Therefore, we aimed to evaluate/compare the serum cystatin C levels in patients with acute PTE and non-PTE who had normal renal function. In addition, we compared the difference in levels of cystatin C in patients with massive, submassive, and nonmassive PTE and the correlation between the levels of cystatin C and D-dimer in acute PTE.
Methods and Materials The present prospective study was approved by the ethics review board of Erciyes University. All patients were informed about the study, and their written consent was obtained.
Study Population and Definitions In the present study, we analyzed 50 patients with acute PTE diagnosed by contrast-enhanced spiral computed chest tomography and 45 healthy volunteers. Patients with a history of coronary artery disease, or heart failure, previously diagnosed malignancy, history of previous PTE, apparent kidney failure (estimated GFR [eGFR] 60 mL/min/1.73 m2), and patients younger than 20 years and older than 80 years of age were excluded from the study. History of surgery was accepted as surgery during the past 6 weeks. Chronic respiratory disease was defined as chronic obstructive pulmonary disease, asthma, or interstitial lung disease, which were previously diagnosed. Massive PTE was defined as acute PTE with sustained hypotension (systolic blood pressure [SBP] 90 mm Hg for at least 15 minutes or requiring inotropic support, not due to a cause other than PE, such as arrhythmia, hypovolemia, sepsis, or left ventricular dysfunction), pulselessness, or persistent profound bradycardia (heart rate 40 bpm with signs or symptoms of shock). Submassive PTE was defined as acute PTE without systemic hypotension (SBP 90 mm Hg) but with right ventricular dysfunction (RVD). Nonmassive PTE was defined as acute PTE and the absence of the clinical markers of adverse prognosis that define massive or submassive PTE.20
Data Collection and Laboratory Measurements Sociodemographic characteristics, previous medical history, and details regarding lifestyle behaviors (smoking) were obtained by face to face interview. Height and weight were measured, and body mass index (BMI) was defined as weight in kilograms divided by height in square meters. Systolic blood pressure and diastolic blood pressure (DBP) were recorded at rest. Blood samples were taken within 24 hours of hospital administration. Blood samples for cystatin C were obtained and centrifuged, then stored at 80 C. Serum cystatin C levels were analyzed after blood samples were obtained from all study
patients, and it was determined with an particle-enhanced turbidimetric immunoassay method (Abbot, Wiesbaden, Germany). D-Dimer (Sysmex CA 700 System, Kobe, Japan) levels were measured in patients with acute PTE. Serum creatinine was measured by standard laboratory procedures, and eGFR was estimated with the Cockcroft-Gault Formula.21
Echocardiography Transthoracic echocardiography for the assessment of RV dysfunction was performed using a Vivid 7 (GE Medical Systems, Milwaukee, Wisconsin) echocardiographic system. Echocardiography was performed in patients within 48 hours of acute PTE diagnosis. The examinations were digitally recorded by an experienced echocardiographer blinded to the results of biochemical assays. Patients with 1 of the following were considered to have acute RV dysfunction:22 (1) RV dilatation (end-diastolic diameter >30 mm or RV/left ventricular enddiastolic diameter ratio >0.9 in 4-chamber view), (2) paradox septal systolic motion, and (3) pulmonary hypertension (Doppler pulmonary acceleration time 30 mm Hg).
Statistical Analysis SPSS 15.0 software (SPSS, Chicago, Illinois) was used for the basic statistical analysis. The Kolmogorov-Smirnov test was used to determine the normality of distributions of variables. Continuous variables with normal distribution are presented as mean value + standard deviation (SD). Median values with interquantile ranges (IQR, 25th to 75th percentiles) were used where normal distribution was absent. Statistical analysis of the parametric variables between the 2 groups was performed using Student t test; Mann-Whitney U test was used for nonparametric variables. Categorical variables were analyzed by the chi-square (w2) test. The correlation analysis was performed by Spearman correlation test for nonparametric results. The Kruskal-Wallis test was used to compare the cystatin C levels between the PTE subgroups. Receiver–operating characteristic (ROC) curves were analyzed to assess the optimal cutoff values of cystatin C for acute PTE. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the chosen cutoff value. Multiple logistic regression analysis was used to determine the predictors for acute PTE. Significant univariate variables with P < .1 were included in the multiple logistic regression analysis for the calculation of odds ratios (ORs) and 95% confidence intervals (CIs). All P values are 2 sided, and a P value of .05 >.05 >.05 >.05 >.05 >.05 >.05
32.0 32.0 22.0 34.0 26.0
33.3 35.5 24.4 0 20.0
>.05 >.05 >.05 .05
24.0
0
.05). The demographic characteristics of patients in the 2 groups are shown in Table 1. Figure 1 shows the comparison of cystatin C levels in the 2 groups. The cystatin C level was significantly higher in the PTE group than in the non-PTE group (1.08 mg/dL [IQR 0.79-1.56] and 0.85 mg/dL [IQR 0.77-1.03], respectively, P ¼ .017). When determining the presence of acute PTE, the highest value of total sensitivity and specificity was set at a cutoff value of 1.15 mg/dL with 46.0% sensitivity, 93.3% specificity, 88.5% PPV, and 60.9% NPV. The area under the ROC curve was calculated as 0.643 (P ¼ .011; Figure 2). Cystatin C levels were also higher in patients with acute PTE with 10 days hospital stay (n ¼ 18, 36%) than in those with .05). Pulmonary thromboembolism is divided into 3 subgroups as massive, submassive or nonmassive PTE.20 Right ventricular dysfunction has an important role in the stratification of patients as massive and submassive PTE.20,34 However, echocardiography is a user-dependent procedure and is not always readily available for a diagnostic workup and risk stratification of PTE. Therefore, the use of more inexpensive and widely available laboratory measurement of biomarkers may also be beneficial. At the same time, various studies examined the role of BNP, NT-pro-BNP, CRP, troponin I or T, CA IX, and tenasin C in the risk stratification of patients with PTE.3-9 In the present report, although the serum cystatin C levels were higher in patients with RVD than in patients without RVD, the difference was not statistically significant. The serum cystatin C levels were also high in patients with massive and submassive PTE, although again the difference was not statistically significant. This may be due to the low power of the study that contained only 50 patients with acute PTE. The history of chronic respiratory disease (26% of patients with acute PTE) may be the other reason that can be the cause of RVD. Our study has some limitations. First of all, we only included a relatively small number of patients and volunteers. The non-PTE group had no echocardiography and D-dimer levels, so we could not use D-dimer in a multivariate model. In addition, we analyzed only short-term mortality, and only 2 patients died in this period, so this is not enough to compare the biomarkers and echocardiographic findings between survivals and nonsurvivals.
Conclusion The present study shows that serum cystatin C levels significantly increased in patients with acute PTE having normal renal function in comparison to the non-PTE patients. Elevated serum cystatin C level was also associated with prolonged hospitalization in patients with acute PTE. Serum cystatin C may be an indicator of acute PTE in patients with normal renal function from the point of PTE diagnosis and risk stratification. Acknowledgments _ The authors would like to thank Ismail Koc¸yig˘it for help with the study design, Ferhan Elmalı for data analysis, and S. Kader Ko¨se and Cevat Yazıcı for the biochemical measurement.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol. 2008;28(3): 370-372. 2. Tarbox AK, Swaroop M. Pulmonary embolism. Int J Crit Illn Inj Sci. 2013;3(1):69-72. 3. Pieralli F, Olivotto I, Vanni S, et al. Usefulness of bedside testing for brain natriuretic peptide to identify right ventricular dysfunction and outcome in normotensive patients with acute pulmonary embolism. Am J Cardiol. 2006;97(9):1386-1390. 4. Binder L, Pieske B, Olschewski M, et al. N-terminal pro-brain natriuretic peptide or troponin testing followed by echocardiography for risk stratification of acute pulmonary embolism. Circulation. 2005;112(11):1573-1579. 5. Celik A, Kocyigit I, Calapkorur B, et al. Tenascin-C may be a predictor of acute pulmonary thromboembolism. J Atheroscler Thromb. 2011;18(6):487-493. 6. Abul Y, Karakurt S, Ozben B, Toprak A, Celikel T. C-reactive protein in acute pulmonary embolism. J Investig Med. 2011; 59(1):8-14. 7. Jimenez D, Diaz G, Molina J, et al. Troponin i and risk stratification of patients with acute nonmassive pulmonary embolism. Eur Respir J. 2008;31(4):847-853. 8. Conroy S, Kamal I, Cooper J. Troponin testing: beware pulmonary embolus. Emerg Med J. 2004;21(1):123-124. 9. Abul Y, Ozsu S, Mentese A, Durmus I, et al. Carbonic anhydrase IX in the prediction of right ventricular dysfunction in patients with hemodynamically stable acute pulmonary embolism [published online April 23, 2013]. Clin Appl Thromb Hemost. 2013. 10. Maresˇ J, Stejskal D, Vavrousˇkova´ J, Urba´nek K, Herzig R, Hlusˇtı´k P. Use of cystatin C determination in clinical diagnostics. Biomed Papers. 2003;147(2):177-180. 11. Roos JF, Doust J, Tett SE, Kirkpatrick CM. Diagnostic accuracy of cystatin C compared to serum creatinine for the estimation of renal dysfunction in adults and children—a meta-analysis. Clin Biochem. 2007;40(5-6): 383-391. 12. Ferguson MA, Waikar SS. Established and emerging markers of kidney function. Clin Chem. 2012;58(4):680-689. 13. Luc G, Bard JM, Lesueur C, et al. Plasma cystatin-C and development of coronary heart disease: the Prime study. Atherosclerosis. 2006;185(2):375-380. 14. Sarnak MJ, Katz R, Stehman-Breen CO, et al. Cystatin C concentration as a risk factor for heart failure in older adults. Ann Intern Med. 2005;142(7):497-505. 15. Hoke M, Pernicka E, Niessner A, et al: Renal function and longterm mortality in patients with asymptomatic carotid atherosclerosis. Thromb Haemost. 2012;107(1):150-157.
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16. O’Hare AM, Newman AB, Katz R, et al. Cystatin C and incident peripheral arterial disease events in the elderly: results from the cardiovascular health study. Arch Intern Med. 2005;165(22):2666-2670. 17. Meng L, Yang Y, Qi LT, Wang XJ, Xu GB, Zhang BW. Elevated serum cystatin C is an independent predictor of cardiovascular events in people with relatively normal renal function. J Nephrol. 2012;25(3):426-430. 18. Kostrubiec M, Łabyk A, Pedowska-Włoszek J, et al. Neutrophil gelatinase-associated lipocalin, cystatin C and eGFR indicate acute kidney injury and predict prognosis of patients with acute pulmonary embolism. Heart. 2012;98(16):1221-1228. 19. Brodin EE, Brækkan SK, Vik A, Brox J, Hansen JB. Cystatin C is associated with risk of venous thromboembolism in subjects with normal kidney function—the Tromsø study. Haematologica. 2012;97(7):1008-1013. 20. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American heart association. Circulation. 2011;123(16):1788-1830. 21. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. 22. Grifoni S, Olivotto I, Cecchini P, et al. Utility of an integrated clinical, echocardiographic and venous ultrasonographic approach for triage of patients with suspected pulmonary embolism. Am J Cardiol. 1998;82(10):1230-1235. 23. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED Ddimer. Thromb Haemost. 2000;83(3):416-420. 24. Le Gal G, Righini M, Roy PM, et al. Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern Med. 2006;144(3):165-171.
25. Piazza G, Goldhaber SZ. Venous thromboembolism and atherothrombosis: an integrated approach. Circulation. 2010;121(19): 2146-2150. 26. Chandra D, Parisini E, Mozaffarian D. Meta-analysis: travel and risk for venous thromboembolism. Ann Intern Med. 2009;151(3): 180-190. 27. Leung-Tack J, Tavera C, Martinez J, Colle A. Neutrophil chemotactic activity is modulated by human cystatin C, an inhibitor of cysteine proteases. Inflammation. 1990;14(3):247-258. 28. Zhang Z, Lu B, Sheng X, Jin N. Cystatin C in prediction of acute kidney injury: a systemic review and meta-analysis. Am J Kidney Dis. 2011;58(3):356-365. 29. Coll E, Botey A, Alvarez L, Poch E, Darnell A. Serum cystatin C as a new marker for noninvasive estimation of glomerular filtration rate and as a marker for early renal impairment. Am J Kidney Dis. 2000;36(1):29-34. 30. Shankar A, Teppala S. Relationship between body mass index and high cystatin levels among US adults. J Clin Hypertens (Greenwich). 2011;13(12):925-930. 31. Cepeda J, Tranche-Iparraguirre S, Marı´n-Iranzo R, et al. Cystatin C and cardiovascular risk in the general population. Rev Esp Cardiol. 2010;63(4):415-422. 32. Takach Lapner S, Kearon C. Diagnosis and management of pulmonary embolism. BMJ. 2013;346:f757. 33. Brown MD, Rowe BH, Reeves MJ, Bermingham JM, Goldhaber SZ. The accuracy of the enzyme-linked immunosorbent assay D-dimer test in the diagnosis of pulmonary embolism: a meta-analysis. Ann Emerg Med. 2002;40(2):133-144. 34. Torbicki A, Perrier A, Konstantinides S, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the task force for the diagnosis and management of acute pulmonary embolism of the European society of cardiology (ESC). Eur Heart J. 2008;29(18):2276-2315.
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Is Serum Cystatin C a Predictor of Acute Pulmonary Thromboembolism in Patients With Normal Renal Function?
Clinical and Applied Thrombosis/Hemostasis 201X, Vol XX(X) 1–6 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029613512416 cath.sagepub.com
Nuri Tutar, MD1, N. Aleyna Kemik, MD1, Insu Yılmaz, MD1, Hakan Bu¨yu¨kog˘lan, MD1, Asiye Kanbay, MD2, Ali Dogan, MD3, Fatma Sema Oyak, MD1, Inci Gu¨lmez, MD1, and Ramazan Demir, MD1
Abstract Early diagnosis is the key point in the management of acute pulmonary thromboembolism (PTE). There are no reports in the literature comparing the serum cystatin C levels in patients with acute PTE and normal volunteers. Therefore, in this study, we analyzed 50 patients with acute PTE and 45 healthy volunteers with normal renal function. The serum cystatin C level was significantly higher in the PTE group than in the non-PTE group (1.08 mg/dL [interquantile range (IQR) 0.79-1.56] and 0.85 mg/dL [IQR 0.77-1.03], respectively, P ¼ .017). When determining the presence of PTE, the highest value of sensitivity and specificity was set at a cutoff value of 1.15 mg/dL with 93.3% specificity, 46.0% sensitivity, 88.5% positive predictive value, and 60.9% negative predictive value. In the multivariate model, cystatin C was significantly associated with the presence of PTE (odds ratio: 12.34, 95% CI 2.64-57.75). In conclusion, cystatin C may be an indicator of acute PTE in patients with normal renal function. Keywords pulmonary embolism, cystatin C, diagnosis
Introduction Pulmonary thromboembolism (PTE) is the most common cause of vascular death after myocardial infarction and stroke and the leading preventable cause of death in hospital patients.1 Early diagnosis is the key point in the management of acute PTE, since immediate treatment is highly effective. Failure to diagnose acute PTE is a serious management error since 30% of untreated patients die, while only 8% die with effective therapy.2 The approach used to diagnose PTE is mainly based on noninvasive diagnostic strategies including clinical probability assessment, D-dimer measurement, and multidetector computed tomography (CT) angiography. However, various studies have examined the role of brain natriuretic peptide (BNP), Nterminal pro-BNP (NT-pro-BNP), C-reactive protein (CRP), troponin I or T, carbonic anhydrase IX (CA IX), and tenasin C in the risk stratification of patients with PTE.3-9 Cystatin C is a protease inhibitor that controls the proteolitic enzymes in the processes of blood coagulation, complement activation, and food digestion.10 It has been shown that cystatin C is a more sensitive marker of glomerular filtration rate (GFR) changes than serum creatinine (Scr),11 because its levels are not affected by muscle mass, age, inflammation, fever, or exogenous agents.12 Recent studies have shown that cystatin C is not only a candidate marker of impaired kidney function but is also
associated with coronary artery disease,13 congestive heart failure,14 carotid atherosclerosis,15 and peripheral vascular disease.16 In a report with relatively normal renal function patients, it was found that the serum level of cystatin C was significantly higher in patients with cardiovascular events than in patients without cardiovascular events.17 In a recent report, plasma cystatin C levels were evaluated to predict the prognosis of patients with acute PTE.18 They found that cystatin C elevation was associated with a poor 30-day prognosis in acute PTE. In another report, Brodin et al analyzed 83 incident venous thromboembolic events in 3251 patients during a median of 12.3 years of follow-up.19 They found that serum cystatin C levels were associated with the risk of venous
1
Department of Pulmonary Medicine, School of Medicine, Erciyes University, Kayseri, Turkey 2 Department of Pulmonary Medicine, School of Medicine, Medeniyet University, _Istanbul, Turkey 3 Department of Cardiology, School of Medicine, Erciyes University, Kayseri, Turkey Corresponding Author: Nuri Tutar, MD, Department of Pulmonary Medicine, Erciyes University School of Medicine, Kayseri, Turkey. Email: [email protected]
Downloaded from cat.sagepub.com at UNSW Library on August 19, 2015
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Clinical and Applied Thrombosis/Hemostasis XX(X)
thromboembolism in patients with normal kidney function. However, to the best of our knowledge, there are no reports in the literature comparing the serum cystatin C levels in patients with acute PTE and non-PTE. Therefore, we aimed to evaluate/compare the serum cystatin C levels in patients with acute PTE and non-PTE who had normal renal function. In addition, we compared the difference in levels of cystatin C in patients with massive, submassive, and nonmassive PTE and the correlation between the levels of cystatin C and D-dimer in acute PTE.
Methods and Materials The present prospective study was approved by the ethics review board of Erciyes University. All patients were informed about the study, and their written consent was obtained.
Study Population and Definitions In the present study, we analyzed 50 patients with acute PTE diagnosed by contrast-enhanced spiral computed chest tomography and 45 healthy volunteers. Patients with a history of coronary artery disease, or heart failure, previously diagnosed malignancy, history of previous PTE, apparent kidney failure (estimated GFR [eGFR] 60 mL/min/1.73 m2), and patients younger than 20 years and older than 80 years of age were excluded from the study. History of surgery was accepted as surgery during the past 6 weeks. Chronic respiratory disease was defined as chronic obstructive pulmonary disease, asthma, or interstitial lung disease, which were previously diagnosed. Massive PTE was defined as acute PTE with sustained hypotension (systolic blood pressure [SBP] 90 mm Hg for at least 15 minutes or requiring inotropic support, not due to a cause other than PE, such as arrhythmia, hypovolemia, sepsis, or left ventricular dysfunction), pulselessness, or persistent profound bradycardia (heart rate 40 bpm with signs or symptoms of shock). Submassive PTE was defined as acute PTE without systemic hypotension (SBP 90 mm Hg) but with right ventricular dysfunction (RVD). Nonmassive PTE was defined as acute PTE and the absence of the clinical markers of adverse prognosis that define massive or submassive PTE.20
Data Collection and Laboratory Measurements Sociodemographic characteristics, previous medical history, and details regarding lifestyle behaviors (smoking) were obtained by face to face interview. Height and weight were measured, and body mass index (BMI) was defined as weight in kilograms divided by height in square meters. Systolic blood pressure and diastolic blood pressure (DBP) were recorded at rest. Blood samples were taken within 24 hours of hospital administration. Blood samples for cystatin C were obtained and centrifuged, then stored at 80 C. Serum cystatin C levels were analyzed after blood samples were obtained from all study
patients, and it was determined with an particle-enhanced turbidimetric immunoassay method (Abbot, Wiesbaden, Germany). D-Dimer (Sysmex CA 700 System, Kobe, Japan) levels were measured in patients with acute PTE. Serum creatinine was measured by standard laboratory procedures, and eGFR was estimated with the Cockcroft-Gault Formula.21
Echocardiography Transthoracic echocardiography for the assessment of RV dysfunction was performed using a Vivid 7 (GE Medical Systems, Milwaukee, Wisconsin) echocardiographic system. Echocardiography was performed in patients within 48 hours of acute PTE diagnosis. The examinations were digitally recorded by an experienced echocardiographer blinded to the results of biochemical assays. Patients with 1 of the following were considered to have acute RV dysfunction:22 (1) RV dilatation (end-diastolic diameter >30 mm or RV/left ventricular enddiastolic diameter ratio >0.9 in 4-chamber view), (2) paradox septal systolic motion, and (3) pulmonary hypertension (Doppler pulmonary acceleration time 30 mm Hg).
Statistical Analysis SPSS 15.0 software (SPSS, Chicago, Illinois) was used for the basic statistical analysis. The Kolmogorov-Smirnov test was used to determine the normality of distributions of variables. Continuous variables with normal distribution are presented as mean value + standard deviation (SD). Median values with interquantile ranges (IQR, 25th to 75th percentiles) were used where normal distribution was absent. Statistical analysis of the parametric variables between the 2 groups was performed using Student t test; Mann-Whitney U test was used for nonparametric variables. Categorical variables were analyzed by the chi-square (w2) test. The correlation analysis was performed by Spearman correlation test for nonparametric results. The Kruskal-Wallis test was used to compare the cystatin C levels between the PTE subgroups. Receiver–operating characteristic (ROC) curves were analyzed to assess the optimal cutoff values of cystatin C for acute PTE. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the chosen cutoff value. Multiple logistic regression analysis was used to determine the predictors for acute PTE. Significant univariate variables with P < .1 were included in the multiple logistic regression analysis for the calculation of odds ratios (ORs) and 95% confidence intervals (CIs). All P values are 2 sided, and a P value of .05 >.05 >.05 >.05 >.05 >.05 >.05
32.0 32.0 22.0 34.0 26.0
33.3 35.5 24.4 0 20.0
>.05 >.05 >.05 .05
24.0
0
.05). The demographic characteristics of patients in the 2 groups are shown in Table 1. Figure 1 shows the comparison of cystatin C levels in the 2 groups. The cystatin C level was significantly higher in the PTE group than in the non-PTE group (1.08 mg/dL [IQR 0.79-1.56] and 0.85 mg/dL [IQR 0.77-1.03], respectively, P ¼ .017). When determining the presence of acute PTE, the highest value of total sensitivity and specificity was set at a cutoff value of 1.15 mg/dL with 46.0% sensitivity, 93.3% specificity, 88.5% PPV, and 60.9% NPV. The area under the ROC curve was calculated as 0.643 (P ¼ .011; Figure 2). Cystatin C levels were also higher in patients with acute PTE with 10 days hospital stay (n ¼ 18, 36%) than in those with .05). Pulmonary thromboembolism is divided into 3 subgroups as massive, submassive or nonmassive PTE.20 Right ventricular dysfunction has an important role in the stratification of patients as massive and submassive PTE.20,34 However, echocardiography is a user-dependent procedure and is not always readily available for a diagnostic workup and risk stratification of PTE. Therefore, the use of more inexpensive and widely available laboratory measurement of biomarkers may also be beneficial. At the same time, various studies examined the role of BNP, NT-pro-BNP, CRP, troponin I or T, CA IX, and tenasin C in the risk stratification of patients with PTE.3-9 In the present report, although the serum cystatin C levels were higher in patients with RVD than in patients without RVD, the difference was not statistically significant. The serum cystatin C levels were also high in patients with massive and submassive PTE, although again the difference was not statistically significant. This may be due to the low power of the study that contained only 50 patients with acute PTE. The history of chronic respiratory disease (26% of patients with acute PTE) may be the other reason that can be the cause of RVD. Our study has some limitations. First of all, we only included a relatively small number of patients and volunteers. The non-PTE group had no echocardiography and D-dimer levels, so we could not use D-dimer in a multivariate model. In addition, we analyzed only short-term mortality, and only 2 patients died in this period, so this is not enough to compare the biomarkers and echocardiographic findings between survivals and nonsurvivals.
Conclusion The present study shows that serum cystatin C levels significantly increased in patients with acute PTE having normal renal function in comparison to the non-PTE patients. Elevated serum cystatin C level was also associated with prolonged hospitalization in patients with acute PTE. Serum cystatin C may be an indicator of acute PTE in patients with normal renal function from the point of PTE diagnosis and risk stratification. Acknowledgments _ The authors would like to thank Ismail Koc¸yig˘it for help with the study design, Ferhan Elmalı for data analysis, and S. Kader Ko¨se and Cevat Yazıcı for the biochemical measurement.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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