Department of Surgery, Buddhist Tzu Chi General Hospital, Dalin Branch, Chia-Yi, Taiwan 4

Transcription

1 646 Journal of Atherosclerosis and Thrombosis Vol. 20,. 7 Original Article N-terminal Pro-B-Type Natriuretic Peptide is Associated with Arterial Stiffness Measured Using the Cardio-Ankle Vascular Index in Renal Transplant Recipients Yen-Cheng Chen 1, Ming-Che Lee 1, 6, Chung-Jen Lee 2, Guan-Jin Ho 1, Wen-Yao Yin 3, Yao-Jen Chang 4 and Bang-Gee Hsu 5, 6 Yen-Cheng Chen and Ming-Che Lee contributed equally to this work. 1 Department of Surgery, Buddhist Tzu Chi General Hospital, Hualien, Taiwan 2 Department of Nursing, Tzu Chi College of Technology, Hualien, Taiwan 3 Department of Surgery, Buddhist Tzu Chi General Hospital, Dalin Branch, Chia-Yi, Taiwan 4 Department of Surgery, Buddhist Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan 5 Division of Nephrology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan 6 School of Medicine, Tzu Chi University, Hualien, Taiwan Aim: Arterial stiffness is an established cardiovascular risk marker and an independent predictor of cardiovascular events and mortality in various groups of patients, including renal transplant recipients. Recent studies have noted that B-type natriuretic peptide (BNP) acts as a local paracrine molecule that modulates endothelial permeability and regeneration. The aim of this study was to evaluate the relationship between the serum N-terminal pro-bnp (NT-pro-BNP) level and arterial stiffness in renal transplant recipients. Methods: Fasting blood samples were obtained from 66 renal transplant recipients. The cardio-ankle vascular index was calculated using the waveform device (CAVI-VaSera VS-1000). The serum NTpro-BNP levels were measured using an electrochemiluminescence immunoassay. A CAVI value of 9 was used to define a high level of arterial stiffness. Results: Thirty-two patients (48.5%) were classified into the high arterial stiffness group. Diabetes (p=0.030), smoking (p<0.001), duration of kidney transplantation (p =0.001), body weight (p = 0.014), waist circumference (p=0.022), body mass index (p=0.001) and the fasting glucose (p = 0.021) and serum NT-pro-BNP (p<0.001) levels were higher in the high arterial stiffness group than in the low arterial stiffness group. A multivariate forward stepwise linear regression analysis showed that the log-nt-pro-bnp level (β: 0.459, p<0.001) remained an independent predictor of the CAVI value in the renal transplant recipients. Conclusions: The serum fasting NT-pro-BNP level is associated with arterial stiffness in renal transplant recipients. J Atheroscler Thromb, 2013; 20: Key words: N-terminal pro-b-type natriuretic peptide, Arterial stiffness, Cardio-ankle vascular index, Renal transplant recipients Address for correspondence: Bang-Gee Hsu, Division of Nephrology, Buddhist Tzu Chi General Hospital,. 707, Section 3, Chung-Yang Road, Hualien, Taiwan gee.lily@msa.hinet.net Received: January 1, 2013 Accepted for publication: April 8, 2013 Introduction N-terminal pro-b-type natriuretic peptide (NTpro-BNP), the inactive amino terminal fragment and biologically active form of B-type natriuretic peptide (BNP), is a cleavage product of the precursor pro-

2 NT-pro-BNT is Correlated with AS in KT Patients 647 BNP 1). BNP binds to its common receptor, guanylyl cyclase-a (GC-A), which leads to biological effects via a cyclic guanosine monophosphate (cgmp)-dependent pathway 2). Recent studies have noted that BNP acts on the GC-A receptor of neighboring endothelial cells and possibly participates in coordinating endothelial regeneration/hypertrophy and the accompanying angiogenesis 3). Donor large artery stiffness predicts a renal transplant recipient s cardiovascular and graft outcomes 4). Aortic stiffness and increased wave reflections are independent predictors of cardiovascular events in renal transplant recipients 5). The cardio-ankle vascular index (CAVI) is a new index of the overall stiffness of the arteries from the origin of the aorta to the ankle 6). Aim The aim of the present study was to determine the relationship between the serum NT-pro-BNP level and arterial stiffness measured using the CAVI in renal transplant recipients. Patients and Methods Patients Sixty-six renal transplant recipients treated at a medical center in Hualien, Taiwan in April 2010 were evaluated. The subjects included 42 men and 24 women, ranging in age from 31 to 73 years. The study was approved by the Protection of Human Subjects Institutional Review Board of Tzu-Chi University and Hospital. Patients were excluded if they had any of the following: acute infection, malignancy, acute rejection, acute myocardial infarction, pulmonary edema, heart failure at the time of blood sampling, an arterialvenous shunt or graft in the hands or refusal to provide informed consent for the study. Anthropometric Analysis Body weight was measured to the nearest halfkilogram with the patient in light clothing and without shoes. Height was measured to the nearest halfcentimeter, and waist circumference was measured to the nearest half-centimeter at the shortest point below the lower rib margin and the iliac crest. Body mass index (BMI) was calculated as the weight (kilograms) divided by the height squared (meters) 7-9). Biochemical Determinations Fasting blood samples of approximately 0.5 ml obtained to measure the complete blood cell count (Sysmex K-1000, Bohemia, NY, USA) and other fac- tors were immediately centrifuged at 3,000 g for 10 minutes after collection. The serum samples were stored at 4 and used for the biochemical analyses within one hour of collection. The serum levels of blood urea nitrogen (BUN), creatinine (Cre), fasting glucose, total cholesterol (TCH), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), lowdensity lipoprotein cholesterol (LDL-C), albumin, globulin, total calcium, phosphorus, glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) were measured using an autoanalyzer (COBAS Integra 800, Roche Diagnostics, Basel, Switzerland). The serum samples were assayed for NTpro-BNP using an electrochemiluminescence immunoassay on the Elecsys 2010 Immunoanalyzer (Roche Diagnostics, Indianapolis, IN, USA). The levels of serum intact parathyroid hormone (ipth) ((Diagnostic Systems Laboratories, Webster, Texas, USA) [Please clarify what DSL provided here.] were measured using a commercially available enzyme-linked immunosorbent assay (ELISA) 7-9). Cardio-Ankle Vascular Index Measurements The measurements were obtained in a quiet, temperature-controlled room after 10 minutes at rest with the patient in a supine position, according to recommendations. The CAVI was measured according to previously described methods (VaSera VS-1000, Fukuda Denshi Co. Ltd., Tokyo, Japan) 6, 10-12). Briefly, a cuff was applied to the bilateral upper arms and ankles with the subject in a supine position and the head held in the midline position. Then, the phonocardiography microphone and electrocardiography electrodes were placed. After resting for 10 minutes, the VaSera VS-1000 measured the blood pressure and pulse wave velocity and calculated the CAVI automatically. In this study, a CAVI value of 9 was used to define a high level of arterial stiffness and a CAVI value of <9 was used to define a low level of arterial stiffness. Statistical Analysis The data are expressed as the mean±standard deviation (SD) and were tested for normal distribution using the Kolmogorov-Smirnov test. Comparisons between patients were made using Student s independent t -test (two-tailed) for normally distributed data or the Mann-Whitney U test for parameters that presented with a non-normal distribution (GOT, GPT, fasting glucose, BUN, NT-pro-BNP). Data expressed as the number of patients were analyzed using the χ 2 test. Because the levels of glucose, BUN and NT-pro- BNP exhibited a non-normal distribution, we used

3 648 Chen et al. Discussion Our results showed that smoking, BMI and the levels of phosphorus and NT-pro-BNP are independent predictors of the CAVI values in renal transplant recipients. Arterial stiffness represents vascular damage and is a known independent predictor of cardiovascular mortality 13). Cardiovascular disease remains a major cause of mortality in renal transplant recipients, partially attributed to non-classic cardiovascular risk factors, including arterial stiffness 14, 15). In this study, 48.5% of the renal transplant recipients were classified into the high arterial stiffness group. There is convincing evidence that diabetes is associated with increased arterial stiffness 16). The CAVI values are reported to be higher in patients with diabetes 17). Diabetes is also an independent determinant of the CAVI in hypertensive patients 12). A high glucose level modulates the characteristics of the arterial wall, increasing stiffness within a relatively short time and resulting in an increase in the CAVI 6). Acute and chronic smoking have been found to be risk factors for increased arterial stiffness 18). One recent study noted that smoking increases the CAVI, while complete smoking cessation improves the CAVI 10). We also found that the incidence of diabetes and smoking and the levels of fasting glucose were higher in the high arterial stiffness group than in the low arterial stiffness group. The univariate linear analysis also showed that smoking and diabetes were positively correlated with the CAVI values in the renal transplant recipients. A previous study noted progressive arterial stiffening in renal transplant recipients during a longterm follow-up 19). We also found that the duration of kidney transplantation was higher in the high arterial stiffness group than in the low arterial stiffness group. A further analysis also showed that the duration of kidney transplantation was positively correlated with the CAVI values. Increased CAVI values are associated with higher amounts of visceral adipose tissue measured on computed tomography in asymptomatic Japanese subjects 20). Central obesity and an increased BMI have been demonstrated to be associated with impaired artethe log-glucose, log-bun and log-nt-pro-bnp values (logarithms of the levels of glucose, BUN and NTpro-BNP to base 10), which exhibited a normal distribution. Clinical variables that were correlated with the CAVI values in the renal transplant recipients were evaluated using univariate linear regression analyses. Variables that were significantly associated with the CAVI values in the renal transplant recipients were tested for independence using a multivariate forward stepwise regression analysis. The data were analyzed using the SPSS for Windows software program (version 19.0; SPSS, Inc., Chicago, IL, USA). A p-value of less than 0.05 was considered to be statistically significant. Results The demographic, biochemical and clinical characteristics of the 66 renal transplant recipients are presented in Tables 1 and 2. The comorbid conditions included diabetes (n =10; 15.2%) and hypertension (n =34; 51.5%). The prescribed therapeutic agents included tacrolimus (n =51; 75.8%), mycophenolate mofetil or mycophenolic acid (n =62; 93.9%), steroids (n =65; 98.5%), rapamycin (n =3; 4.5%) and cyclosporine (n =14; 21.2%). Diabetes (p =0.030) and smoking (p<0.001) were more frequent in the high arterial stiffness group than in the low arterial stiffness group. The two groups did not differ statistically in terms of gender, hypertension, transplantation model or the use of tacrolimus, mycophenolate mofetil or mycophenolic acid, steroids, rapamycin or cyclosporine. The clinical characteristics of the renal transplant recipients in the high arterial stiffness and low arterial stiffness groups are presented in Table 3. Thirty-two patients (48.5%) were classified into the high arterial stiffness group. The duration of kidney transplantation (p=0.001), body weight (p=0.014), waist circumference (p =0.022), BMI (p =0.001) and the fasting glucose (p=0.021) and serum NT-pro-BNP (p< 0.001) levels were higher in the high arterial stiffness group than in the low arterial stiffness group. The results of the univariate linear analysis of the CAVI levels in the renal transplant recipients are shown in Table 4. Smoking (p<0.001), diabetes (p = 0.034), age (p = 0.026), duration of kidney transplantation (p<0.001), body weight (p = 0.024), waist circumference (p =0.037), BMI (p =0.006) and the levels of log-bun (p =0.020), creatinine (p =0.014), phosphorus (p =0.026) and log-nt-pro-bnp (p<0.001) were positively correlated with the CAVI values in the renal transplant recipients. A multivariate forward stepwise linear regression analysis of the factors significantly associated with the CAVI values showed that smoking (β: 0.306, p =0.001), BMI (β: 0.246, p = 0.008), phosphorus (β: 0.211, p =0.020) and log-ntpro-bnp (β: 0.459, p<0.001) were independent predictors of the CAVI values in the renal transplant recipients (Table 4).

4 NT-pro-BNT is Correlated with AS in KT Patients 649 Table 1. Clinical and analytical characteristics of the 66 renal transplant recipients Items Parameter Parameter Anthropometric data Biochemical data Height (cm) Body weight (kg) Body mass index (kg/m 2 ) CAVI White blood count ( 1,000/μL) Albumin (g/dl) Triglyceride (mg/dl) HDL-C (mg/dl) Fasting glucose (mg/dl) Blood urea nitrogen (mg/dl) GOT (IU/L) Phosphorus (mg/dl) ipth (pg/ml) ± ± ± ± ± ± ± ± ± ± ± ± ±72.59 Waist circumference (cm) Age (years) KT duration (months) Hemoglobin (g/dl) Globulin (g/dl) Total cholesterol (mg/dl) LDL-C (mg/dl) Creatinine (mg/dl) GPT (IU/L) Total Calcium (mg/dl) Calcium-phosphorous product NT-pro-BNP (pg/ml) 83.91± ± ± ± ± ± ± ± ± ± ± ± The data are expressed as the mean±sd. Abbreviations: KT, kidney transplantation; CAVI, cardio-ankle vascular index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; ipth, intact parathyroid hormone; GOT, glutamic oxaloacetic transaminase; GPT, glutamic pyruvic transaminase; NT-pro-BNP, N-terminal pro-b-type natriuretic peptide. Table 2. Baseline characteristics of the 66 renal transplant recipients with and without arterial stiffness Characteristic Low arterial stiffness group (%) High arterial stiffness group (%) p value Gender Male Female 21 (61.8) 13 (38.2) 21 (65.6) 11 (34.4) Diabetes 32 (94.1) 2 (5.9) 24 (75.0) 8 (25.0) * Hypertension 19 (55.9) 15 (44.1) 13 (40.6) 19 (59.4) Smoking 28 (82.4) 6 (17.6) 13 (40.6) 19 (59.4) Transplantation model Cadaveric Living 26 (76.5) 8 (23.5) 23 (71.9) 9 (28.1) Tacrolimus use 6 (17.6) 28 (82.4) 10 (31.2) 22 (68.8) Mycophenolate mofetil or mycophenolic acid use 1 (2.9) 33 (97.1) 3 (9.4) 29 (90.6) Steroid use 0 (0) 34 (100.0) 1 (3.1) 31 (96.9) Rapamycin use 34 (100.0) 0 (0) 29 (90.6) 3 (9.4) Cyclosporine use 28 (82.4) 6 (17.6) 24 (75.0) 8 (25.0) * p<0.05 was considered to be statistically significant. The data are expressed as the number of patients, and the analysis was performed using the χ 2 test.

5 650 Chen et al. Table 3. Clinical variables of the 66 renal transplant recipients with and without arterial stiffness Items Age (years) a KT duration (months) a Height (cm) a Body weight (kg) a Waist circumference (cm) a Body mass index (kg/m 2 ) a CAVI a White blood count ( 1,000/μL) a Hemoglobin (g/dl) a Albumin (g/dl) a Globulin (g/dl) a GOT (IU/L) b GPT (IU/L) b Total cholesterol (mg/dl) a Triglyceride (mg/dl) a High density lipoprotein (mg/dl) a Low density lipoprotein (mg/dl) a Fasting glucose (mg/dl) b Blood urea nitrogen (mg/dl) b Creatinine (mg/dl) a Total calcium (mg/dl) a Phosphorus (mg/dl) a Calcium-phosphorous product a Intact parathyroid hormone (pg/ml) a NT-pro-BNP (pg/ml) b Low arterial stiffness group (n =34) 50.15± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±66.63 High arterial stiffness group (n =32) 53.59± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± p value * * * * * The data are expressed as the mean±sd. Abbreviations: KT, kidney transplantation; CAVI, cardio-ankle vascular index; GOT, glutamic oxaloacetic transaminase; GPT, glutamic pyruvic transaminase; NT-pro-BNP, N-terminal pro-b-type natriuretic peptide. * p<0.05 was considered to be statistically significant according to Student s t-test or the Mann-Whitney U test. adata were tested using Student s t -test. bdata were tested using the Mann-Whitney U test. rial compliance 21, 22). In one study, the CAVI values were found to be significantly higher in the patients with metabolic syndrome, and weight reduction therapy with diet and exercise over a 3-month period significantly decreased the CAVI values 23). In this study, we found that body weight, waist circumference and BMI were higher in the high arterial stiffness group than in the low arterial stiffness group. The univariate linear analysis also showed that body weight, waist circumference and BMI were positively correlated with the CAVI values. BNP acts on the GC-A receptor of neighboring endothelial cells that improve endothelial dysfunction 3). BNP binds GC-A, which leads to biological effects via a cgmp-dependent pathway, and has an inhibitory effect on the renin-angiotensin-aldosterone axis 2). Olmesartan, an angiotensin Ⅱ receptor blocker, has been observed to significantly decrease the CAVI value after 12 months of treatment in comparison to that observed with amlodipine in type 2 diabetic patients with hypertension 24). The NT-pro-BNP level is well known to reflect left ventricular dysfunction 1). The CAVI is a parameter of arterial stiffness, which reflects left ventricular afterload 12). A high level of aortic stiffness, as demonstrated by a high CAVI value, results in left ventricular dysfunction reflected in the afterload. In such cases, the NT-pro-BNP level is elevated. A recent study noted that increased CAVI values are independently associated with elevated plasma BNP levels in hypertensive patients 12). In our study, the NT-pro-BNP levels were also higher in the high arterial stiffness group than in the low arterial stiffness

6 NT-pro-BNT is Correlated with AS in KT Patients 651 Table 4. Correlations between the cardio-ankle vascular index and other variables among the 66 renal transplant recipients Variables Univariate Multivariate r p value Beta p value Smoking Diabetes Age (years) Kidney transplant duration (months) Body weight (kg) Waist circumference (cm) Body mass index (kg/m 2 ) White blood count ( 1,000/μL) Hemoglobin (g/dl) Total cholesterol (mg/dl) Triglyceride (mg/dl) High density lipoprotein (mg/dl) Low density lipoprotein (mg/dl) Log-glucose (mg/dl) Log-BUN (mg/dl) Creatinine (mg/dl) Total calcium (mg/dl) Phosphorus (mg/dl) Calcium-phosphorous product Intact parathyroid hormone (pg/ml) Log-NT-pro-BNP (pg/ml) * * * * * * * * * * * The glucose, BUN and NT-pro-BNP levels exhibited skewed distributions and were therefore log-transformed before the analysis. * p<0.05 was considered to be statistically significant in the univariate linear regression analyses and multivariate stepwise linear regression analysis (adopted factors: smoking, diabetes, age, duration of kidney transplantation, body weight, waist circumference, body mass index and the levels of log-bun, creatinine, phosphorus and log-nt-pro-bnp). Abbreviations: Blood urea nitrogen, BUN; NT-pro-BNP, N-terminal pro-b-type natriuretic peptide;, not significant. group. The univariate linear analysis also showed that the log-nt-pro-bnp levels were positively correlated with the CAVI values in the renal transplant recipients. The CAVI value increases almost linearly in association with age in healthy persons without cardiovascular disease 6). Our study also noted that age is positively correlated with the CAVI value in renal transplant recipients. In addition, the CAVI value is independently correlated with the estimated glomerular filtration rate in the Japanese general population 25). Another study also showed that the CAVI value is closely associated with the cystatin C level 26). Furthermore, the CAVI value is significantly associated with the initial serum phosphorus level in dialysis patients 27). In this study, the univariate linear analysis showed that the log-bun, Cre and phosphorus levels are positively correlated with the CAVI values in renal transplant recipients. The multivariate forward stepwise linear regression analysis of the significant variables also showed that smoking, BMI and the levels of phosphorus and NT-pro-BNP are independent predictors of the CAVI values in renal transplant recipients. Certain immunosuppressive drugs influence arterial stiffness in renal transplant recipients. For example, cyclosporine A-free immunosuppressant regimens based on sirolimus decrease aortic stiffness in renal transplant recipients in comparison to cyclosporine immunosuppressant regimens 28). In the present study, no relationships were observed between tacrolimus, mycophenolate mofetil or mycophenolic acid, steroids, rapamycin or cyclosporine therapy and arterial stiffness. Further studies are needed to elucidate the relationship between arterial stiffness and immunosuppressant drugs in renal transplant recipients. There are some limitations to the current study. First, the number of enrolled patients was small, thereby weakening the statistical power. Second, this study had a cross-sectional design. Third, many drugs, including antihypertensives such as nitrates, beta-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, have a substantial impact on arterial stiffness, both acutely

7 652 Chen et al. Lee MC: Inverse association of serum long-acting natriuretic peptide and bone mass density in renal transplant recipients. Clin Transplant, 2012: 26: E105-E110 10) ike H, Nakamura K, Sugiyama Y, Iizuka T, Shimizu K, Takahashi M, Hirano K, Suzuki M, Mikamo H, Nakagami T, Shirai K: Changes in cardio-ankle vascular index in smoking cessation. J Atheroscler Thromb, 2010; 17: ) Kato A, Ishida J, Endo Y, Takita T, Furuhashi M, Maruyama Y, Odamaki M: Association of abdominal visceral adiposity and thigh sarcopenia with changes of arteriosclerosis in haemodialysis patients. Nephrol Dial Transplant, 2011; 26: ) Masugata H, Senda S, Inukai M, Murao K, Himoto T, Hosomi N, Murakami K, ma T, Kohno M, Okada H, Goda F: Association of cardio-ankle vascular index with brain natriuretic peptide levels in hypertension. J Atheroscler Thromb, 2012; 19: ) Cavalcante JL, Lima JA, Redheuil A, Al-Mallah MH: Aortic stiffness: current understanding and future directions. J Am Coll Cardiol, 2011; 57: ) Khoshdel AR, Carney SL: Arterial stiffness in kidney transplant recipients: an overview of methodology and applications. Urol J, 2008; 5: ) Liefeldt L, Budde K: Risk factors for cardiovascular disease in renal transplant recipients and strategies to minimize risk. Transpl Int, 2010; 23: ) Stehouwer CD, Henry RM, Ferreira I: Arterial stiffness in diabetes and the metabolic syndrome: a pathway to cardiovascular disease. Diabetologia, 2008; 51: ) Ibata J, Sasaki H, Kakimoto T, Matsuno S, Nakatani M, Kobayashi M, Tatsumi K, Nakano Y, Wakasaki H, Furuta H, Nishi M, Nanjo K: Cardio-ankle vascular index measures arterial wall stiffness independent of blood pressure. Diabetes Res Clin Pract, 2008; 80: ) Doonan RJ, Hausvater A, Scallan C, Mikhailidis DP, Pilote L, Daskalopoulou SS: The effect of smoking on arterial stiffness. Hypertens Res, 2010; 33: ) Strozecki P, Adamowicz A, Kozlowski M, Wlodarczyk Z, Manitius J: Progressive arterial stiffening in kidney transplant recipients. Ann Transplant, 2011; 16: ) Ohashi N, Ito C, Fujikawa R, Yamamoto H, Kihara Y, Kohno N: The impact of visceral adipose tissue and highmolecular weight adiponectin on cardio-ankle vascular index in asymptomatic Japanese subjects. Metabolism, 2009; 58: ) Windham BG, Griswold ME, Farasat SM, Ling SM, Carlson O, Egan JM, Ferrucci L, Najjar SS: Influence of leptin, adiponectin, and resistin on the association between abdominal adiposity and arterial stiffness. Am J Hypertens, 2010; 23: ) Hirai T, Okuno A, Souda T, Yonemoto S, Ymanaka K, Fujii N, Kishikawa H, Nishimura K, Ichikawa Y: Evaluation of arterial stiffness after successful renal transplantation using brachial-ankle pulse wave velocity. Transplant Proc, 2010; 42: ) Satoh N, Shimatsu A, Kato Y, Araki R, Koyama K, Okajima T, Tanabe M, Ooishi M, Kotani K, Ogawa Y: Evaluation of the cardio-ankle vascular index, a new indicator of arterial stiffness independent of blood pressure, in obeand chronically 14). Our study did not assess the use of antihypertensive drugs in the evaluated patients. Therefore, our findings should be investigated in long-term prospective studies before any causal relationships between the serum NT-pro-BNP level and arterial stiffness in renal transplant recipients can be established. In conclusion, the present study indicates that an increased CAVI value is independently associated with an elevated serum fasting NT-pro-BNP level in renal transplant recipients. Conflicts of Interest/Disclosures The authors report no conflicts of interest or disclosures. Acknowledgement This study was supported by a grant from the Buddhist Tzu Chi General Hospital, Hualien, Taiwan (TCRD ). References 1) Nishikimi T, Kuwahara K, Nakao K: Current biochemistry, molecular biology, and clinical relevance of natriuretic peptides. J Cardiol, 2011; 57: ) Clerico A, Recchia FA, Passino C, Emdin M: Cardiac endocrine function is an essential component of the homeostatic regulation network: physiological and clinical implications. Am J Physiol Heart Circ Physiol, 2006; 290: H17-H29 3) Kuhn M: Endothelial actions of atrial and B-type natriuretic peptides. Br J Pharmacol, 2012; 166: ) Bahous SA, Stephan A, Blacher J, Safar M: Cardiovascular and renal outcome in recipients of kidney grafts from living donors: role of aortic stiffness. Nephrol Dial Transplant, 2012; 27: ) Verbeke F, Maréchal C, Van Laecke S, Van Biesen W, Devuyst O, Van Bortel LM, Jadoul M, Vanholder R: Aortic stiffness and central wave reflections predict outcome in renal transplant recipients. Hypertension, 2011; 58: ) Shirai K, Hiruta N, Song M, Kurosu T, Suzuki J, Tomaru T, Miyashita Y, Saiki A, Takahashi M, Suzuki K, Takata M: Cardio-ankle vascular index (CAVI) as a novel indicator of arterial stiffness: theory, evidence and perspectives. J Atheroscler Thromb, 2011; 18: ) Lee MC, Lee CJ, Ho GJ, Lee CC, Shih MH, Chou KC, Hsu BG: Hyperleptinemia positively correlated with metabolic syndrome in renal transplant recipients. Clin Transplant, 2010; 24: E124-E129 8) Lee MC, Lee CJ, Ho GJ, Chou KC, Shih MH, Hsu BG: Fasting adiponectin correlates inversely with metabolic syndrome in kidney transplantation patients. Transplant Proc, 2011; 43: ) Hsu BG, Ho GJ, Lee CJ, Yang YC, Chen YC, Shih MH,

8 NT-pro-BNT is Correlated with AS in KT Patients 653 sity and metabolic syndrome. Hypertens Res, 2008; 31: ) Miyashita Y, Saiki A, Endo K, Ban N, Yamaguchi T, Kawana H, Nagayama D, Ohira M, Oyama T, Shirai K: Effects of olmesartan, an angiotensin Ⅱ receptor blocker, and amlodipine, a calcium channel blocker, on Cardio- Ankle Vascular Index (CAVI) in type 2 diabetic patients with hypertension. J Atheroscler Thromb, 2009; 16: ) Kubozono T, Miyata M, Ueyama K, Nagaki A, Hamasaki S, Kusano K, Kubozono O, Tei C: Association between arterial stiffness and estimated glomerular filtration rate in the Japanese general population. J Atheroscler Thromb, 2009; 16: ) Nakamura K, Iizuka T, Takahashi M, Shimizu K, Mikamo H, Nakagami T, Suzuki M, Hirano K, Sugiyama Y, Tomaru T, Miyashita Y, Shirai K, ike H: Association between cardio-ankle vascular index and serum cystatin C levels in patients with cardiovascular risk factor. J Atheroscler Thromb, 2009; 16: ) Shen TW, Wang CH, Lai YH, Hsu BG, Liou HH, Fang TC: Use of cardio-ankle vascular index in chronic dialysis patients. Eur J Clin Invest, 2011; 41: ) Joannidès R, Monteil C, de Ligny BH, Westeel PF, Iacob M, Thervet E, Barbier S, Bellien J, Lebranchu Y, Seguin SG, Thuillez C, Godin M, Etienne I: Immunosuppressant regimen based on sirolimus decreases aortic stiffness in renal transplant recipients in comparison to cyclosporine. Am J Transplant, 2011; 11: