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Endocan Concentration and Chronic Inflammatory Process Among Heart Transplant Recipients
Endocan Concentration and Chronic Inflammatory Process Among Heart Transplant Recipients c _ P. Przybylowskia,*, G. Wasilewskib, E. Koc-Zórawska , and J. Malyszkoc a
First Chair of General Surgery, Jagiellonian University, Medical College, Krakow, Poland. Silesian Center for Heart Diseases, Zabrze, Poland; bDepartment of Cardiovascular Surgery and Transplantology, Jagiellonian University, Medical College, John Paul II Hospital, Cracow, Poland; and c2nd Department of Nephrology, Medical University of Bialystok, Bialystok, Poland
ABSTRACT Background. Endocan is a novel soluble dermatan sulfate proteoglycan derived from endothelium. It has the capacity of binding to different biologically active molecules associated with cellular signaling, adhesion, and regulating proliferation, differentiation, migration, and adhesion of different cell types in health and pathology. Its elevated level is connected with endothelial activation, neovascularization, and inflammation or carcinogenesis. Methods. The level of serum endocan among 131 heart transplant recipients on 3-drug immunosuppression (calcineurin inhibitor, mycophenolate mofetil/mycophenolic acid, steroid) in correlation with other markers of endothelial damage was determined. In addition, 22 healthy volunteers were studied. In cross-sectional study, markers were measured with the use of commercially available assays of endothelial damagedendocan and von Willebrand factor (VWF)dinflammationdhigh-sensitivity C-reactive protein (hsCRP), interleukin (IL) 6dand kidney functiondcystatin C. Results. The endocan, VWF, IL-6, hsCRP, and cystatin C levels were significantly higher in heart transplant recipients compared with healthy volunteers. In our cohort, endocan level was correlated with renal function (estimated glomerular filtration rate: r ¼ 0.21; P < .05), creatinine (r ¼ 0.21; P < .05), erythrocyte count (r ¼ 0.24; P < .01), hemoglobin (r ¼ 0.33; P < .01), N-terminal proeB-type natriuretic peptide (r ¼ 0.25; P < .01), cholesterol (r ¼ 0.22; P < .05), LDL (r ¼ 0.21; P < .05), New York Heart Association functional class (r ¼ 0.21; P < .05), hsCRP (r ¼ 0.32; P < .01), IL-6 (r ¼ 0.31; P < .01), and VWF (r ¼ 0.27; P < .01). In multifactorial analysis, the predictors of endocan levels were cholesterol level, cystatin C, and IL-6, predicting 54% of variability. Conclusions. Endocan concentration among heart transplant recipients is potentially connected with endothelial damage caused by subclinical inflammation resulting from hyperlipidemia.
P
ATIENTS with chronic kidney disease (CKD) face a high risk of adverse outcomes, such as kidney failure, cardiovascular events, and all-cause mortality. Heart transplant recipients are very prone to developing chronic kidney disease, hyperlipidemia, and hypertension and are more susceptible to carcinogenesis, which is the unavoidable adverse effect of immunosuppression. What is more, atherosclerosis is also more likely to develop in solid organ recipients. Those factors together cause a permanent
subclinical inflammatory process in the organism. Endocan is a novel soluble dermatan sulfate proteoglycan (PG) derived from endothelium. It has the capacity of binding to *Address correspondence to Piotr Przybylowski, MD, PhD, Department of Cardiovascular Surgery and Transplantology, Jagiellonian University, Medical College, John Paul II Hospital, Pradnicka str 80, Cracow, Poland. E-mail: piotr.przybylowski@uj. edu.pl
ª 2016 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2016.02.056
Transplantation Proceedings, 48, 1781e1785 (2016)
1781
1782
different biologically active molecules associated with cellular signaling, adhesion, and regulating proliferation, differentiation, migration, and adhesion of different cell types in health and pathology [1]. Its elevated level is connected with endothelial activation, inflammation, or carcinogenesis. Raised levels of systemic inflammatory markers (interleukin-1, tumor necrosis factor a) induce endocan expression, so blood levels of this soluble PG may closely reflect the presence and severity of inflammation as well as the response to therapy. Recent research shows evidence that high endocan expression and level in tissues affected by above-mentioned states are associated with neovascularization and arterial wall remodeling. It was especially proved in tumorigenesis, with higher endocan concentration in fast-growing aggressive tumors such as glioblastoma and liposarcoma compared with slow-growing tumors such as low-grade gliomas of the brain [2,3]. Additional research shows evidence that raised endocan concentration is connected with the process of healing. Del Torro et al in 2010 published the outcomes of a study on different types of cells taking part in developing of growing blood vessels. “Tip cells” located at the growing end act as sensors and mediate vascular growth. Other cellsd“stalk cells,” which merely constitute the vessel walldhave no role in determining the growth. Endocan expression was preferentially greater in tip cells than in stalk cells [4]. The gene responsible for endocan coding is located in long arm of chromosome 5. The expression of this gene is regulated by cytokines, suggesting that it may play a role in endothelium-dependent pathologic disorders. Initially, endocan expression was considered to take place in lung tissue only, and later it was also detected in endothelial cells from microvasculature of skin, adipose tissue, and coronary and pulmonary arteries [5,6]. In acute infection (inflammation), endocan inhibits migration and homing of leukocytes by binding of the protein core of endocan with lymphocyte functioneassociated antigen 1, which has a negative effect on its interaction with endothelial intercellular adhesion molecule 1 [7]. Interestingly, circulating endocan levels are reduced in overweight and obese patients, so endocan may play some role in obesityassociated vascular disease.
METHODS We enrolled in the study 131 heart transplant recipients followed by the Department of Cardiovascular Surgery and Transplantology, Jagiellonian University Medical College, Krakow, Poland. The immunosuppressive regimen of the patients consisted of calcineurin inhibitor (tacrolimus or cyclosporine) in combination with mycophenolate mofetil or everolimus/sirolimus and prednisone. All of the patients maintained sufficient and stable graft function and showed no clinical signs of rejection. Blood for analysis was drawn in the morning, when patients appeared for routine office assessment after an overnight fast. Glomerular filtration rate (GFR) was estimated with the use of the simplified Modification of Diet in Renal Disease formula (eGFR ¼ 186.3 serum creatinine (mg/dL) 1.14 age 0.203 0.742 if female 1.21 if Afro-American) [8]. Complete
_ PRZYBYLOWSKI, WASILEWSKI, KOC-ZÓRAWSKA ET AL blood count, urea, serum lipids, and creatinine were studied by standard laboratory methods in the central laboratory of the hospital. The level of serum endocan among 131 heart transplant recipients on 3-drug immunosuppression in correlation with other markers of endothelial damage was determined. In cross-sectional study, markers of endothelial damage (endocan, von Willebrand factor [VWF]), of inflammation (high-sensitivity C-reactive protein [hsCRP], interleukin-[IL] 6), and of kidney function (cystatin C) were measured with the use of commercially available assays. In addition, 22 healthy volunteers were studied to serve as control subjects. Data were expressed as mean SD and analyzed with the use of Statistica 10.0 computer software (Tulsa, OK). The examination of the distribution normality of variables was done with the use of Shapiro-Wilk W test. The Mann-Whitney rank-sum U test or Student t test was used to compare differences between groups, with P < .05 considered to be statistically significant. Multiple regression analysis was used to determine independent factors affecting the dependent variable.
RESULTS
We enrolled in the study 131 heart transplant recipients (76% men and 24% women). The average age of the patients was 53.2 13.7 years, and their time after transplantation averaged 103.3 50.5 months. The most important clinical and biochemical parameters of both study and control groups are presented in Table 1. The markers of endothelial dysfunction and the markers of inflammation were significantly higher in heart transplant recipients compared with healthy volunteers (median [interquartile range] or mean SD): endocan: median 1.70 (0.5e10.6)
Table 1. Some Clinical and Biochemical Parameters in Heart Allograft Recipients (HT) Parameter
Age (y) Time after transplantation (mo) Hemoglobin (g/dL) Erythrocyte count (1012/mL) White blood cell count (103/mL) eGFR (mL/min/1.72 m2) NT-proBNP (pg/mL) Endocan (ng/mL) IL-6 (pg/mL) hsCRP (mg/L) VWF (mU/mL) NYHA EF (%) Cholesterol (mmol/L) HDL (mmol/L) LDL (mmol/L)
Control
HT
49.1 10.8 NA
53.2 13.7 103.3 50.5
13.87 0.89 4.76 0.98 5.69 1.65
12.87 1.99 4.48 0.67 6.53 2.68
96.9 13.0 4.74 (3.62e8.40) 0.6 (0.2e1.2) 0.02 (0.01e0.09) 4.74 (3.62e8.40) 1,018 126 NA NA 4.43 0.78 1.51 0.69 2.31 0.73
54.4 28.8*** 167 (19e3,979)*** 1.70 (0.5e10.6)*** 1.71 (0.5e53.6)*** 13.23 (0.3e32.0)*** 1,656 327** 1 (1e2) 55 10 4.76 1.16 1.35 0.51 2.64 0.90
Note. Data are presented as mean SD or median (interquartile range). Abbreviations: eGFR, estimated glomerular filtration rate (Modification of Diet in Renal Disease formula); NT-proBNP, N-terminal proeB-type natriuretic peptide; IL, interleukin; hsCRP, high-sensitivity C-reactive protein; VWF, von Willebrand factor; NYHA, New York Heart Association functional class; EF, ejection fraction; HDL, high-density lipoprotein; LDL, low-density lipoprotein. *P < .05; **P < .01; ***P < .001.
ENDOCAN CONCENTRATION AND CHRONIC INFLAMMATORY PROCESS
versus 0.6 (0.2e1.2) ng/mL; P < .001; VWF: 1,656 327 versus 1,018 126 mU/mL (P < .01); IL-6: 1.71 (0.5e53.6) versus 0.02 (0.01e0.09) pg/mL; P < .001; and hsCRP: 13.23 (0.3e32.0) versus 4.74 (3.62e8.40) mg/L; P < .001. Heart transplant recipients also had worse renal function than the control group. In our cohort, endocan level was correlated with renal function (eGFR): r ¼ 0.21 (P < .05; Fig 1); creatinine: r ¼ 0.21 (P < .05); erythrocyte count: r ¼ 0.24 (P < .01); hemoglobin: r ¼ 0.33 (P < .01); N-terminal proeB-type natriuretic peptide: r ¼ 0.25 (P < .01); cholesterol: r ¼ 0.22 (P < .05); low-density lipoprotein: r ¼ 0.21 (P < .05); New York Heart Association functional class: r ¼ 0.21 (P < .05); hsCRP: r ¼ 0.32 (P < .01; Fig 2); IL-6: r ¼ 0.31 (P < .01); and VWF: r ¼ 0.27 (P < .01). There was no correlation between endocan level and time after transplantation (Fig 3). In multifactorial analysis, the predictors of endocan levels were cholesterol level, cystatin C, and IL-6, predicting 54% of variability. DISCUSSION
In the past decade, the vascular endothelium has been shown to play a crucial role in such processes as inflammation, angiogenesis, coagulation, and tumorigenesis, primarily through regulation of receptor-ligand interactions and secretion of different mediators. One of the latter is endocan, secreted by endothelial cells in the skin, kidney, lungs, liver, brain, gastrointestinal tract, heart, and thyroid gland. Endocan has been shown to have prognostic value in various pathologic entities, such as cancer, sepsis, inflammatory disorders, hypertension, transplant rejection, and
1783
chronic kidney disease [9]. Sepsis and inflammation have associated endothelial dysfunction leading to pathologic states such as vasodilation, edema, coagulopathy, ischemia, and organ failure. Scherpereel et al observed that circulating endocan level in blood was related to the severity of sepsis and reflected the outcome for the patient [10]. Endocan also has diagnostic and prognostic implications in pulmonary inflammatory diseases. A recent study reported that plasma endocan was superior to CRP and white blood cell count in evaluating the severity of community-acquired pneumonia and had better correlation with pneumonia severity scores such as pneumonia severity index, CURB-65, and APACHE II scores [11]. Monitoring serum endocan could have an essential role as prognostic marker in cancers, sepsis, inflammation, and acute lung disorders. Endocan signaling pathway itself provides a valid target for antiangiogenic therapy. Endocan may reflect the degree of endothelial cell injury in renal allografts, and shows a trend of elevation in latestage CKD. Higher endocan levels were found in more advanced chronic kidney disease (CKD) stages in a dosedependent manner [12], as in our study. Li et al were the 1st to suggest using endocan as a marker of kidney graft failure and rejection [13]. Those authors concluded that endocan appeared to reflect the degree of endothelial cell injury in renal allografts and might have the potential to serve as a highly sensitive and specific marker for acute rejection after renal transplantation. In our study, endocan concentration among heart transplant recipients positively correlated with other markers of endothelial dysfunction and the markers of inflammation. What is more, we found
Correlation between eGFR by MDRD and endocan in heart transplant recipients r = -0.21, p<0.05 12
endocan concentration (ng/mL)
10
8
6
4
2
0 -20
0
20
40
60
80
100
eGFR by MDRD (mL/min/1.72m2)
120
140
160
180
Fig 1. Correlation between endocan and eGFR by MDRD.
_ PRZYBYLOWSKI, WASILEWSKI, KOC-ZÓRAWSKA ET AL
1784
Correlation between endocan and hsCRP in heart transplant recipients r = 0,32, p<0.01 9 8
endocan concentration (ng/mL)
7 6 5 4 3 2 1 0 -5
0
5
10
15
20
25
30
35
40
hsCRP (mg/L)
Fig 2. Correlation between endocan and hsCRP level.
hyperlipidemia, hypertension, and chronic kidney disease. The endocan concentration among heart transplant recipients could be a marker of the beginning of a pathologic process such as kidney function deterioration, graft rejection, infection/inflammation, hypertension or tumor
the correlation between endocan level and decreased renal function (endocan levels were inversely correlated with eGFR). Endocan concentration among heart transplant recipients is potentially connected with endothelial damage caused by subclinical inflammation resulting from
Correlation between time after heart transplantation and endocan level r =0,06, p>0.05 220 200
time after transplantation (months)
180 160 140 120 100 80 60 40 20 0 0
2
4
6 endocan (ng/mL)
8
10
12
Fig 3. Correlation between endocan level and time after transplantation.
ENDOCAN CONCENTRATION AND CHRONIC INFLAMMATORY PROCESS
progression. It could serve as a screening marker and the trigger to begin deeper diagnosis of those most commonly found pathologic states in the group of heart recipients in different time after transplantation.
REFERENCES [1] Kali A, Shetty KS. Endocan: a novel circulating proteoglycan. Indian J Pharmacol 2014;46:579e83. [2] Sarrazin S, Maurage CA, Delmas D, et al. Endocan as a biomarker of endothelial dysfunction in cancer. J Cancer Sci Ther 2010;2:47e52. [3] Abid MR, Yi X, Yano K, et al. Vascular endocan is preferentially expressed in tumor endothelium. Microvasc Res 2006;72: 136e45. [4] Del Toro R, Prahst C, Mathivet T, et al. Identification and functional analysis of endothelial tip cell-enriched genes. Blood 2010;116:4025e33. [5] Tsai JC, Zhang J, Minami T, et al. Cloning and characterization of the human lung endothelial-cellespecific molecule-1 promoter. J Vasc Res 2002;39:148e59. [6] Aitkenhead M, Wang SJ, Nakatsu MN, et al. Identification of endothelial cell genes expressed in an in vitro model of
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angiogenesis: induction of ESM-1, (beta)ig-h3, and NrCAM. Microvasc Res 2002;63:159e71. [7] Béchard D, Scherpereel A, Hammad H, et al. Human endothelial-cell specific molecule-1 binds directly to the integrin CD11a/CD18 (LFA-1) and blocks binding to intercellular adhesion molecule-1. J Immunol 2001;167:3099e106. [8] Levey AS, Berg RL, Gassman JJ, et al. Modification of Diet in Renal Disease Study Group. Creatinine filtration, secretion and excretion during progressive renal disease. Kidney Int Suppl 1989;27:S73e80. [9] Afsar B, Takir M, Kostek O, et al. Endocan: a new molecule playing a role in the development of hypertension and chronic kidney disease? J Clin Hypertens (Greenwich) 2014;16:914e6. [10] Scherpereel A, Depontieu F, Grigoriu B, et al. Endocan, a new endothelial marker in human sepsis. Crit Care Med 2006;34: 532e7. [11] Kao SJ, Chuang CY, Tang CH, et al. Plasma endothelial cellespecific molecule-1 (ESM-1) in management of communityacquired pneumonia. Clin Chem Lab Med 2014;52:445e51. [12] Su YH, Shu KH, Hu CP, et al. Serum endocan correlated with stage of chronic kidney disease and deterioration in renal transplant recipients. Transplant Proc 2014;46:323e7. [13] Li S, Wang L, Wang C, et al. Detection on dynamic changes of endothelial cell specific molecule-1 in acute rejection after renal transplantation. Urology 2012;80:738.e1.
First Chair of General Surgery, Jagiellonian University, Medical College, Krakow, Poland. Silesian Center for Heart Diseases, Zabrze, Poland; bDepartment of Cardiovascular Surgery and Transplantology, Jagiellonian University, Medical College, John Paul II Hospital, Cracow, Poland; and c2nd Department of Nephrology, Medical University of Bialystok, Bialystok, Poland
ABSTRACT Background. Endocan is a novel soluble dermatan sulfate proteoglycan derived from endothelium. It has the capacity of binding to different biologically active molecules associated with cellular signaling, adhesion, and regulating proliferation, differentiation, migration, and adhesion of different cell types in health and pathology. Its elevated level is connected with endothelial activation, neovascularization, and inflammation or carcinogenesis. Methods. The level of serum endocan among 131 heart transplant recipients on 3-drug immunosuppression (calcineurin inhibitor, mycophenolate mofetil/mycophenolic acid, steroid) in correlation with other markers of endothelial damage was determined. In addition, 22 healthy volunteers were studied. In cross-sectional study, markers were measured with the use of commercially available assays of endothelial damagedendocan and von Willebrand factor (VWF)dinflammationdhigh-sensitivity C-reactive protein (hsCRP), interleukin (IL) 6dand kidney functiondcystatin C. Results. The endocan, VWF, IL-6, hsCRP, and cystatin C levels were significantly higher in heart transplant recipients compared with healthy volunteers. In our cohort, endocan level was correlated with renal function (estimated glomerular filtration rate: r ¼ 0.21; P < .05), creatinine (r ¼ 0.21; P < .05), erythrocyte count (r ¼ 0.24; P < .01), hemoglobin (r ¼ 0.33; P < .01), N-terminal proeB-type natriuretic peptide (r ¼ 0.25; P < .01), cholesterol (r ¼ 0.22; P < .05), LDL (r ¼ 0.21; P < .05), New York Heart Association functional class (r ¼ 0.21; P < .05), hsCRP (r ¼ 0.32; P < .01), IL-6 (r ¼ 0.31; P < .01), and VWF (r ¼ 0.27; P < .01). In multifactorial analysis, the predictors of endocan levels were cholesterol level, cystatin C, and IL-6, predicting 54% of variability. Conclusions. Endocan concentration among heart transplant recipients is potentially connected with endothelial damage caused by subclinical inflammation resulting from hyperlipidemia.
P
ATIENTS with chronic kidney disease (CKD) face a high risk of adverse outcomes, such as kidney failure, cardiovascular events, and all-cause mortality. Heart transplant recipients are very prone to developing chronic kidney disease, hyperlipidemia, and hypertension and are more susceptible to carcinogenesis, which is the unavoidable adverse effect of immunosuppression. What is more, atherosclerosis is also more likely to develop in solid organ recipients. Those factors together cause a permanent
subclinical inflammatory process in the organism. Endocan is a novel soluble dermatan sulfate proteoglycan (PG) derived from endothelium. It has the capacity of binding to *Address correspondence to Piotr Przybylowski, MD, PhD, Department of Cardiovascular Surgery and Transplantology, Jagiellonian University, Medical College, John Paul II Hospital, Pradnicka str 80, Cracow, Poland. E-mail: piotr.przybylowski@uj. edu.pl
ª 2016 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2016.02.056
Transplantation Proceedings, 48, 1781e1785 (2016)
1781
1782
different biologically active molecules associated with cellular signaling, adhesion, and regulating proliferation, differentiation, migration, and adhesion of different cell types in health and pathology [1]. Its elevated level is connected with endothelial activation, inflammation, or carcinogenesis. Raised levels of systemic inflammatory markers (interleukin-1, tumor necrosis factor a) induce endocan expression, so blood levels of this soluble PG may closely reflect the presence and severity of inflammation as well as the response to therapy. Recent research shows evidence that high endocan expression and level in tissues affected by above-mentioned states are associated with neovascularization and arterial wall remodeling. It was especially proved in tumorigenesis, with higher endocan concentration in fast-growing aggressive tumors such as glioblastoma and liposarcoma compared with slow-growing tumors such as low-grade gliomas of the brain [2,3]. Additional research shows evidence that raised endocan concentration is connected with the process of healing. Del Torro et al in 2010 published the outcomes of a study on different types of cells taking part in developing of growing blood vessels. “Tip cells” located at the growing end act as sensors and mediate vascular growth. Other cellsd“stalk cells,” which merely constitute the vessel walldhave no role in determining the growth. Endocan expression was preferentially greater in tip cells than in stalk cells [4]. The gene responsible for endocan coding is located in long arm of chromosome 5. The expression of this gene is regulated by cytokines, suggesting that it may play a role in endothelium-dependent pathologic disorders. Initially, endocan expression was considered to take place in lung tissue only, and later it was also detected in endothelial cells from microvasculature of skin, adipose tissue, and coronary and pulmonary arteries [5,6]. In acute infection (inflammation), endocan inhibits migration and homing of leukocytes by binding of the protein core of endocan with lymphocyte functioneassociated antigen 1, which has a negative effect on its interaction with endothelial intercellular adhesion molecule 1 [7]. Interestingly, circulating endocan levels are reduced in overweight and obese patients, so endocan may play some role in obesityassociated vascular disease.
METHODS We enrolled in the study 131 heart transplant recipients followed by the Department of Cardiovascular Surgery and Transplantology, Jagiellonian University Medical College, Krakow, Poland. The immunosuppressive regimen of the patients consisted of calcineurin inhibitor (tacrolimus or cyclosporine) in combination with mycophenolate mofetil or everolimus/sirolimus and prednisone. All of the patients maintained sufficient and stable graft function and showed no clinical signs of rejection. Blood for analysis was drawn in the morning, when patients appeared for routine office assessment after an overnight fast. Glomerular filtration rate (GFR) was estimated with the use of the simplified Modification of Diet in Renal Disease formula (eGFR ¼ 186.3 serum creatinine (mg/dL) 1.14 age 0.203 0.742 if female 1.21 if Afro-American) [8]. Complete
_ PRZYBYLOWSKI, WASILEWSKI, KOC-ZÓRAWSKA ET AL blood count, urea, serum lipids, and creatinine were studied by standard laboratory methods in the central laboratory of the hospital. The level of serum endocan among 131 heart transplant recipients on 3-drug immunosuppression in correlation with other markers of endothelial damage was determined. In cross-sectional study, markers of endothelial damage (endocan, von Willebrand factor [VWF]), of inflammation (high-sensitivity C-reactive protein [hsCRP], interleukin-[IL] 6), and of kidney function (cystatin C) were measured with the use of commercially available assays. In addition, 22 healthy volunteers were studied to serve as control subjects. Data were expressed as mean SD and analyzed with the use of Statistica 10.0 computer software (Tulsa, OK). The examination of the distribution normality of variables was done with the use of Shapiro-Wilk W test. The Mann-Whitney rank-sum U test or Student t test was used to compare differences between groups, with P < .05 considered to be statistically significant. Multiple regression analysis was used to determine independent factors affecting the dependent variable.
RESULTS
We enrolled in the study 131 heart transplant recipients (76% men and 24% women). The average age of the patients was 53.2 13.7 years, and their time after transplantation averaged 103.3 50.5 months. The most important clinical and biochemical parameters of both study and control groups are presented in Table 1. The markers of endothelial dysfunction and the markers of inflammation were significantly higher in heart transplant recipients compared with healthy volunteers (median [interquartile range] or mean SD): endocan: median 1.70 (0.5e10.6)
Table 1. Some Clinical and Biochemical Parameters in Heart Allograft Recipients (HT) Parameter
Age (y) Time after transplantation (mo) Hemoglobin (g/dL) Erythrocyte count (1012/mL) White blood cell count (103/mL) eGFR (mL/min/1.72 m2) NT-proBNP (pg/mL) Endocan (ng/mL) IL-6 (pg/mL) hsCRP (mg/L) VWF (mU/mL) NYHA EF (%) Cholesterol (mmol/L) HDL (mmol/L) LDL (mmol/L)
Control
HT
49.1 10.8 NA
53.2 13.7 103.3 50.5
13.87 0.89 4.76 0.98 5.69 1.65
12.87 1.99 4.48 0.67 6.53 2.68
96.9 13.0 4.74 (3.62e8.40) 0.6 (0.2e1.2) 0.02 (0.01e0.09) 4.74 (3.62e8.40) 1,018 126 NA NA 4.43 0.78 1.51 0.69 2.31 0.73
54.4 28.8*** 167 (19e3,979)*** 1.70 (0.5e10.6)*** 1.71 (0.5e53.6)*** 13.23 (0.3e32.0)*** 1,656 327** 1 (1e2) 55 10 4.76 1.16 1.35 0.51 2.64 0.90
Note. Data are presented as mean SD or median (interquartile range). Abbreviations: eGFR, estimated glomerular filtration rate (Modification of Diet in Renal Disease formula); NT-proBNP, N-terminal proeB-type natriuretic peptide; IL, interleukin; hsCRP, high-sensitivity C-reactive protein; VWF, von Willebrand factor; NYHA, New York Heart Association functional class; EF, ejection fraction; HDL, high-density lipoprotein; LDL, low-density lipoprotein. *P < .05; **P < .01; ***P < .001.
ENDOCAN CONCENTRATION AND CHRONIC INFLAMMATORY PROCESS
versus 0.6 (0.2e1.2) ng/mL; P < .001; VWF: 1,656 327 versus 1,018 126 mU/mL (P < .01); IL-6: 1.71 (0.5e53.6) versus 0.02 (0.01e0.09) pg/mL; P < .001; and hsCRP: 13.23 (0.3e32.0) versus 4.74 (3.62e8.40) mg/L; P < .001. Heart transplant recipients also had worse renal function than the control group. In our cohort, endocan level was correlated with renal function (eGFR): r ¼ 0.21 (P < .05; Fig 1); creatinine: r ¼ 0.21 (P < .05); erythrocyte count: r ¼ 0.24 (P < .01); hemoglobin: r ¼ 0.33 (P < .01); N-terminal proeB-type natriuretic peptide: r ¼ 0.25 (P < .01); cholesterol: r ¼ 0.22 (P < .05); low-density lipoprotein: r ¼ 0.21 (P < .05); New York Heart Association functional class: r ¼ 0.21 (P < .05); hsCRP: r ¼ 0.32 (P < .01; Fig 2); IL-6: r ¼ 0.31 (P < .01); and VWF: r ¼ 0.27 (P < .01). There was no correlation between endocan level and time after transplantation (Fig 3). In multifactorial analysis, the predictors of endocan levels were cholesterol level, cystatin C, and IL-6, predicting 54% of variability. DISCUSSION
In the past decade, the vascular endothelium has been shown to play a crucial role in such processes as inflammation, angiogenesis, coagulation, and tumorigenesis, primarily through regulation of receptor-ligand interactions and secretion of different mediators. One of the latter is endocan, secreted by endothelial cells in the skin, kidney, lungs, liver, brain, gastrointestinal tract, heart, and thyroid gland. Endocan has been shown to have prognostic value in various pathologic entities, such as cancer, sepsis, inflammatory disorders, hypertension, transplant rejection, and
1783
chronic kidney disease [9]. Sepsis and inflammation have associated endothelial dysfunction leading to pathologic states such as vasodilation, edema, coagulopathy, ischemia, and organ failure. Scherpereel et al observed that circulating endocan level in blood was related to the severity of sepsis and reflected the outcome for the patient [10]. Endocan also has diagnostic and prognostic implications in pulmonary inflammatory diseases. A recent study reported that plasma endocan was superior to CRP and white blood cell count in evaluating the severity of community-acquired pneumonia and had better correlation with pneumonia severity scores such as pneumonia severity index, CURB-65, and APACHE II scores [11]. Monitoring serum endocan could have an essential role as prognostic marker in cancers, sepsis, inflammation, and acute lung disorders. Endocan signaling pathway itself provides a valid target for antiangiogenic therapy. Endocan may reflect the degree of endothelial cell injury in renal allografts, and shows a trend of elevation in latestage CKD. Higher endocan levels were found in more advanced chronic kidney disease (CKD) stages in a dosedependent manner [12], as in our study. Li et al were the 1st to suggest using endocan as a marker of kidney graft failure and rejection [13]. Those authors concluded that endocan appeared to reflect the degree of endothelial cell injury in renal allografts and might have the potential to serve as a highly sensitive and specific marker for acute rejection after renal transplantation. In our study, endocan concentration among heart transplant recipients positively correlated with other markers of endothelial dysfunction and the markers of inflammation. What is more, we found
Correlation between eGFR by MDRD and endocan in heart transplant recipients r = -0.21, p<0.05 12
endocan concentration (ng/mL)
10
8
6
4
2
0 -20
0
20
40
60
80
100
eGFR by MDRD (mL/min/1.72m2)
120
140
160
180
Fig 1. Correlation between endocan and eGFR by MDRD.
_ PRZYBYLOWSKI, WASILEWSKI, KOC-ZÓRAWSKA ET AL
1784
Correlation between endocan and hsCRP in heart transplant recipients r = 0,32, p<0.01 9 8
endocan concentration (ng/mL)
7 6 5 4 3 2 1 0 -5
0
5
10
15
20
25
30
35
40
hsCRP (mg/L)
Fig 2. Correlation between endocan and hsCRP level.
hyperlipidemia, hypertension, and chronic kidney disease. The endocan concentration among heart transplant recipients could be a marker of the beginning of a pathologic process such as kidney function deterioration, graft rejection, infection/inflammation, hypertension or tumor
the correlation between endocan level and decreased renal function (endocan levels were inversely correlated with eGFR). Endocan concentration among heart transplant recipients is potentially connected with endothelial damage caused by subclinical inflammation resulting from
Correlation between time after heart transplantation and endocan level r =0,06, p>0.05 220 200
time after transplantation (months)
180 160 140 120 100 80 60 40 20 0 0
2
4
6 endocan (ng/mL)
8
10
12
Fig 3. Correlation between endocan level and time after transplantation.
ENDOCAN CONCENTRATION AND CHRONIC INFLAMMATORY PROCESS
progression. It could serve as a screening marker and the trigger to begin deeper diagnosis of those most commonly found pathologic states in the group of heart recipients in different time after transplantation.
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