- Email: [email protected]
Relationships Between Metabolic Syndrome, Microalbuminuria, and C-Reactive Protein in Turkish Kidney Transplant Recipients
Relationships Between Metabolic Syndrome, Microalbuminuria, and C-Reactive Protein in Turkish Kidney Transplant Recipients M.H. Sipahioglua,*, A. Unala, H. Yazgacb, O. Tuncaa, T. Arikana, I. Kocyigita, B. Tokgoza, and O. Oymaka a Department of Nephrology, Erciyes University Medical Faculty, Kayseri, Turkey; and bDepartment of Internal Medicine, Erciyes University Medical Faculty, Kayseri, Turkey
ABSTRACT Aim. The aims of this study were to report the prevalence of metabolic syndrome (MS) in a cohort of Turkish kidney transplant recipients and to define the relationships between MS, microalbuminuria and C-reactive protein (CRP), which are cardiovascular risk factors, in kidney transplant setting. Methods. This cross sectional study included 170 adult renal transplantation recipients with a mean follow-up of 53.1 49.9 months. The diagnosis of MS was made according to the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) criteria. Microalbuminuria was defined as a urinary albumin/creatinine ratio of 30e300 mg/g. CRP levels 6.0 were classified as high CRP. Results. Mean age was 39.3 11 years. The prevalence of MS was 45.8% (n ¼ 78). The prevalence of microalbuminuria was not different in patients with MS compared to those without MS (39.7% vs 37%, P ¼ .428). In multivariate logistic regression analyses, systolic blood pressure (SBP) (odds ratio 1.68; 95% confidence interval [CI] 1.12e2.52; P ¼ .011) and high fasting glucose (odds ratio 2.82; 95% confidence interval [CI] 1.16e6.86; P ¼ .022) were significantly associated with microalbuminuria. When patients with MS and high CRP were compared with patients with normal CRP and without MS, microalbuminuria did not differ between the groups (P ¼ .213). Conclusion. The prevalence of MS in our kidney recipient cohort was found to be increased compared to general population. MS was not related to increased prevalence of microalbuminuria, even when combined with high CRP. Microalbuminuria was associated with elevated SBP and hyperglycemic status.
M
ETABOLIC SYNDROME (MS) is a cluster of metabolic and nonmetabolic abnormalities (glucose intolerance, dyslipidemia, obesity, and hypertension) [1]. Insulin resistance is thought to be main mechanism in MS pathogenesis [2]. There are several definitions for the MS, with the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III) being the most widely used [3]. The prevalence of MS differs widely according to age, ethnicity, and the definition used. In longterm renal transplant recipients, the prevalence of MS has ranged from 20% to 60% [4,5]. The presence of MS in transplant patients is related to increased risk of new-onset diabetes mellitus, cardiovascular complications, chronic allograft dysfunction, and reduced transplant and patient survival [6].
Microalbuminuria, which is a marker of systemic endothelial dysfunction, is common in MS [7]. The components of MS show a close relationship with microalbuminuria. In transplant recipients, microalbuminuria may be the result of both transplant- and nonetransplant-specific risks that result in glomerular injury, such as recurrent or de novo glomerulonephritis, transplant glomerulopathy, chronic rejection, hypertension, calcineurin inhibitor (CNI), and the mammalian target of rapamycin (mTOR) toxicity [8]. Microalbuminuria is also an early indicator of progressive renal
*Address correspondence to Murat Hayri Sipahioglu, MD, Erciyes University Medical Faculty, Department of Nephrology, Kayseri, Turkey. E-mail: [email protected]
0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.04.037
ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
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Table 1. Demographic, Clinical and Laboratory Data of Patients With and Without Metabolic Syndrome* With MS n ¼ 78 (45.8%)
Age (y) Male, n (%) Time after Tx (month) BMI (kg/m2) Waist circumference (cm) Men Women Immunosuppressive medication Tacrolimus, n (%) Cyclosporine, n (%) mTOR inhibitor, n (%) Mycophenolate, n (%) Use of steroid, n (%) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Fasting glucose (mg/dL) Triglyceride (mg/dL) HDL cholesterol (mg/dL) Creatinine (mg/dL) CRP (mg/dL) Hypertension, n (%) Hyperglycemia, n (%) Abdominal obesity, n (%) Microalbuminuria, n (%) High CRP, n (%) eGFR (mL/min/1.73 m2)
42 45 38 27.5
Without MS n ¼ 92 (54.2%)
(33.8e50) (57.7) (13e76) (24.8e30)
36.0 63 47 23.4
(29e42) (68.5) (15.5e79.5) (21.5e26.6)
100 (93.5e108) 94 (84.5e100.5)
89 (82e96) 80 (71.5e86.5)
67 (88.2) 9 (11.8) 4 (5.2) 63 (80.8) 73 (92.4) 130 (122.3e143) 85.5 (80e93) 96 (86e117.3) 188 (151e227) 39.5 (33e46.3) 1.1 (0.9e1.4) 3.54 (3.45e8.21) 75 (94.9%) 28 (35.9) 45 (57.7) 31 (39.7) 25 (32) 84.1 29.4
72 (82.8) 15 (17.2) 8 (8.7) 80 (87%) 79 (82.8) 125 (116e135.5) 83 (78e86) 90 (83e101.5) 111 (83e138) 44 (40e52) 1.2 (0.9e1.4) 3.45 (3.45e3.45) 65 (71.4%) 9 (9.8) 33 (35.8) 34 (37.0) 11 (11.9) 77.9 26.1
P
<.001 .097 .698 .001 <.001
.199 .523 .366 .271 .237 .011 .063 <.001 <.001 <.001 <.001 .001 <.001 <.001 <.001 .428 .001 .148
Abbreviations: MS, metabolic syndrome; Tx, transplantation; mTOR, mammalian target of rapamune. *Data were shown as mean standard deviation or median (25%e75% percentile) according to their distribution characteristics.
damage and in renal transplant recipients is related to chronic allograft disease [9]. Elevated levels of C-reactive protein (CRP) and lL-6 may indicate that MS is a proinflammatory condition [10,11]. Inflammation is associated with an increased risk for subsequent cardiovascular disease [12]. In this study, we aimed to report the prevalence of MS in a cohort of Turkish renal transplant recipients and to define the relationships between MS, microalbuminuria, and CRP, which are cardiovascular risk factors, in the kidney transplant setting.
Lake Forest, Ill., United States) was used for biochemical analysis. Fresh spot urine samples were collected for the measurement of urinary albumin and creatinine. Microalbuminuria was defined as a urinary albumin-to-creatinine ratio (ACR) of 30 to 300 mg/g. CRP was measured using a Dade-Behring nephelometer (Dade Behring Diagnostics, Marburg, Germany). CRP levels 6.0 were classified as high CRP. Patients with a CRP value >45 mg/dL were excluded, as patients with extremely high values were thought to be acutely ill [13]. The eGFR was calculated by using Cockcroft-Gault equation. Blood pressure was measured as the average of 3 measurements with 1-minute intervals after a 6-minute rest.
Definitions MATERIALS AND METHODS This study was approved by the Institutional Review Board at Erciyes University. Written consent was obtained from each patient. Renal transplant recipients followed in the outpatient clinic of Semiha-Asım Kibar Transplantation Hospital were included the study. The recruitment took place between June and December 2013. Patients who were pregnant, who had malign diseases or active systemic infection, and patients with follow-up of less than 6 months were excluded.
The diagnosis of MS was made according to the NCEP-ATP III criteria. Subjects with 3 or more of the following criteria were defined as having MS: (1) high blood pressure (130/85 mm Hg) or on antihypertensive medications; (2) hypertriglyceridemia (150 mg/dL) or drug treatment for elevated triglycerides; (3) low serum-high density lipoprotein (HDL) cholesterol (in men <40 mg/dL, in women <50 mg/dL) or drug treatment for low HDL; (4) elevated fasting glucose (110 mg/dL) or use of antidiabetic medication; and (5) abdominal obesity (waist circumference 102 cm in men, 88 cm in women).
Measurements Weight, height, and waist circumference were measured according to standard protocols. Blood samples were drawn after an overnight fasting period of 8 to 12 hours to determine serum triglyceride, highdensity lipoprotein (HDL), blood urea nitrogen (BUN), creatinine, and glucose. An Abbott Architect c8000 device (Abbott Diagnostics,
Statistical Analysis The Statistical Package for the Social Sciences (SPSS Inc. version 20.0, Chicago, Ill., United States) was used to perform the analyses. Continuous data were expressed as means SD or median and interquartile ranges according to their distribution characteristics.
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SIPAHIOGLU, UNAL, YAZGAC ET AL Table 2. Association of Microalbuminuria With the Metabolic Syndrome Components as Continuous Variables
The Metabolic Syndrome Component
Waist circumference, cm Systolic blood pressure, þ10 mm Hg Diastolic blood pressure, þ10 mm Hg Fasting glucose, mg/dL Triglyceride, mg/dL HDL cholesterol, mg/dL
Unadjusted Odds Ratio (95% CI)
1.01 1.36 0.71 1.00 0.99 1.02
(0.98e1.04) (0.99e1.93) (0.40e1.28) (0.99e1.00) (0.99e1.00) (0.99e1.05)
P
.315 .081 .260 .685 .772 .079
Adjusted Model* Odds Ratio (95% CI)
1.03 1.68 0.54 1.00 0.99 1.02
(0.99e1.07) (1.12e2.52) (0.29e1.04) (0.99e1.01) (0.99e1.00) (0.99e1.05)
P
.075 .011 .066 .301 .584 .112
*Adjusted for age, sex, time after transplantation, use of angiotensin converting enzyme inhibitors, angiotensin receptor antagonist, and mTOR inhibitors.
Categorical data were presented as percentages. Continuous data were compared using the Student t test and the Mann-Whitney U (Wilcoxon) statistic. Categorical data were analyzed by c2 test to detect differences between groups. Multiple logistic regression analysis was used to determine the association of microalbuminuria with the components of MS, while controlling for covariates including age, sex, time after transplantation, and the use of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) or mTOR inhibitors. Factors with a P value <.20 were entered into a multivariate logistic regression model with stepwise backwards elimination of nonsignificant variables. We also used multivariate linear regression analysis to estimate the association between CRP levels and urinary ACR (dependent variable). Patients with macroalbuminuria (n ¼ 23) were not included in the multiple logistic regression and multivariate linear regression analyses. A P value .05 was used as the threshold for statistical significance.
RESULTS
A total of 170 kidney transplant recipients with a mean follow-up of 53.1 49.9 months were included in this crosssectional study. The mean age was 39.3 11 years; 108 (63%) were male patients. The prevalence of MS was 45.8% (n ¼ 78). The etiology of end-stage renal disease was hypertension in 36 (21.2%), glomerulonephritis in 17 (10%), diabetes mellitus in 11 (6.4%), others in 16 (9.4%), and unknown causes in 90 (52.9%). Table 1 shows the demographic, clinical and laboratory characteristics of patients according to MS status. Compared with the non-MS group, the MS group had greater age, higher BMI and waist circumference, higher SBP, and higher fasting serum glucose, triglyceride, and CRP levels. HDL levels were significantly lower in the MS group. Although serum creatinine level was significantly lower in the MS group, eGFR level did not show any difference (84.1 29.4 vs 77.9 26.1 mL/min/1.73 m2, P ¼ .148). The presence of high CRP status was significantly higher in subjects with MS group than in those with non-MS (32% vs 11%, P ¼ .001). The prevalence of microalbuminuria did not differ in both groups (39.7% vs 37%, P ¼ .428). In unadjusted continuous model, microalbuminuria was associated with none of MS components. After adjustment for age, gender, time after transplantation, use of ACE inhibitors or ARBs, and use of mTOR inhibitors, microalbuminuria showed a significant association with SBP (odds ratio 1.68; 95% confidence interval [CI] 1.12e2.52; P ¼ .011) (Table 2). In the adjusted categorical analysis model, presence of microalbuminuria was associated with blood glucose
component of MS (odds ratio 2.82; 95% CI 1.16e6.86; P ¼ .022) (Table 3). The risk of microalbuminuria was 2.8 times higher in patients with the fasting glucose component. Odds ratios for microalbuminuria by CRP levels and MS status were shown in Table 4. Kidney transplant recipients with high CRP and MS did not show an increased risk of microalbuminuria compared with recipients who had normal CRP without MS (P ¼ .213).
DISCUSSION
Studies reporting a prevalence of MS in renal transplant recipients are limited. The prevalence of MS differs widely according to ethnic groups studied and the definition of MS used. de Vries et al reported 63% MS prevalence in 606 Caucasian kidney transplant recipients using NCEP-ATP criteria [4]. MS prevalence was found to be 34.5%, 37.7%, and 50% in the studies reported from Italy, Spain, and Australia, respectively, using the same criteria [5,14,15]. The studies from East Asian countries for which modified NCEP criteria for Asian people were used showed a prevalence of 32% in China and 23.8% in Japan [16,17]. Time after transplantation also has an effect on MS prevalence. In a cohort of 230 consecutive nondiabetic kidney transplant recipients, the prevalence of MS has been reported as 22.6% at 12 months, 37.7% at 36 months, and 64% at 6 years after transplantation [5]. A nationwide study in Turkey that included 1947 participants from the general population reported the prevalence of MS as 36.6% using ATP III criteria [18]. In the current study, the prevalence of MS was found to be 45.8%. These reports suggested that MS is more prevalent in our renal transplant recipients compared with the general population. The presence of MS is associated with impaired renal allograft function [4,5]. Several possible explanations have been proposed for the mechanism underlying the association between MS and renal dysfunction. The components of MS such as hypertension, hyperlipidemia, and alterations in glucose metabolism are risk factors for allograft dysfunction and directly damage the kidneys [19]. MS also is known as “insulin resistance syndrome” and it was shown that hyperinsulinemia may contribute to renal dysfunction [2]. Several studies have reported that insulin stimulates mesangial cell proliferation and production of mesangial matrix [20]. In the present study, serum creatinine levels were lower in the MS group compared to the non-MS group (median values 1.1 and 1.2 mg/dL, respectively, P < .001). However, there was no
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Table 3. Association of Microalbuminuria With Metabolic Syndrome Components as Dichotomized Variables The Metabolic Syndrome Component
Abdominal obesity Elevated blood pressure Elevated fasting glucose Elevated serum triglycerides Reduced serum HDL cholesterol
Unadjusted Odds Ratio (95% CI)
1.40 0.95 2.25 0.59 1.30
P
(0.65e3.01) (0.41e2.20) (0.98e5.15) (0.29e1.19) (0.64e2.62)
.382 .914 .054 .145 .463
Adjusted Model* Odds Ratio (95% CI)
1.71 1.06 2.82 0.57 1.25
(0.73e3.98) (0.41e2.75) (1.16e6.86) (0.27e1.17) (0.61e2.56)
P
.210 .892 .022 .126 .535
*Adjusted for age, sex, time after transplantation, use of angiotensin converting enzyme inhibitors, angiotensin receptor antagonist, and mTOR inhibitors.
significant difference in eGFR values between the 2 groups. We speculated that early renal function after transplantation, which was not included in the analysis, might have affected the result. In a recent study, Prasad et al showed there was no association between MS and graft survival in a cohort of 1182 kidney transplant recipients [21], as in our study. Microalbuminuria is early predictor of renal and cardiovascular disease. In renal transplant recipients, microalbuminuria has a well-established association with renal allograft loss [9]. The prevalence of microalbuminuria in MS patients (nontransplant recipients) has ranged between 12% and 20%. Studies showed that this prevalence was 13.7% in the United States, 20.8% in Japan, and 12% and 20.3% in China [7,22e24]. Because of this relatively common prevalence, microalbuminuria has been included into the World Health Organization’s definition of MS [25]. But more recent definitions, such as those from NCEP-ATP III, the International Diabetes Federation (IDF), the American Heart Association criteria, and the Harmonized (Consensus) definition, did not incorporate microalbuminuria as an MS criterion [3,26,27]. Microalbuminuria in stable renal transplant recipients is a highly prevalent condition. In a study in which macroalbuminuric recipients were excluded, prevalence of microalbuminuria was reported to be 48% [13]. In our renal recipient cohort, the prevalence of microalbuminuria (38.2%) also was high. The prevalence of microalbuminuria in patients with MS did not differ from prevalence in those without MS. (39.7 and 37.0%, respectively, P ¼ .428). Although the prevalence of microalbuminuria was higher in our renal recipient cohort, this increased ratio was not associated with MS status. Conditions that result in glomerular injury, such as recurrent or de novo glomerulonephritis, transplant glomerulopathy rather than MS may have confounded the relationship between MS and microalbuminuria. Several studies have examined the relationship between MS components and microalbuminuria. The National Health and Nutrition Examination Survey (NHANES III) reported that
microalbuminuria was associated with SBP and hyperglycemia components. This relationship was in present both in men and women [7]. Two different Chinese studies that included 1079 and 3532 participants from the general population showed that MS components related to microalbuminuria were hypertension and hyperglycemia [22,28]. A study from Japan by Hao et al revealed that microalbuminuria had a weak relationship with abdominal obesity (odds ratio 1.31; P ¼ .04), but had a strong relationship with hyperglycemia (odds ratio 2.64; P < .001) and high blood pressure (odds ratio 2.37; P < .001) [23]. In the current study, SBP was related to microalbuminuria in the model in which MS components were used as continues variables [OR (95% CI) ¼ 1.68 (1.12e2.52)]. On the other hand, impaired glucose metabolism was found to be related to microalbuminuria in the model in which MS components were used as dichotomized variables [OR (95% CI) ¼ 2.82 (1.16e6.86)]. CRP is used as a sensitive marker of inflammation. Data from population-based trials suggested that high CRP levels were associated with MS [29]. However, whether there is a relationship between high CRP and microalbuminuria remains controversial. Several studies of the general population have found a significant correlation [30,31]; but some studies reported no association [32]. In the study by Prasad et al that included 222 kidney recipients, microalbuminuria was associated with increasing CRP (odds ratio 1.129 per 1 g/L [95% CI 1.058e1.204], P ¼ .0002) [13]. Jiang et al studied the effect of alignment of high CRP and MS on microalbuminuria status in a population-based trial. They showed that when MS patients had high CRP levels, the risk for development of microalbuminuria was significantly increased [33]. In our renal recipient cohort, a total of 36 patients (21%) had high CRP levels. Patients with MS had significantly increased ratio of high CRP status compared to non-MS group (32% and 11.9%, respectively, P ¼ .001). This result supported the notion that MS is a proinflammatory condition. When recipients with microalbuminuria (n ¼ 65) were compared to those with normoalbuminuria (n ¼ 82), CRP levels and high CRP status did not show any difference (data were not shown).
Table 4. Odds Ratios for Microalbuminuria by CRP Levels and Metabolic Syndrome Status Unadjusted Odds Ratio (95% CI)
Normal CRP without MS High CRP without MS Normal CRP with MS High CRP with MS
reference 1.37 (0.52e4.59) 2.59 (0.66e2.84) 0.64 (0.57e11.65)
P
Adjusted* Model Odds Ratio (95% CI)
P
.428 .395 .216
reference 1.63 (0.53e4.94) 1.37 (0.63e2.96) 2.63 (0.57e12.11)
.387 .421 .213
Abbreviations: CRP, C-reactive protein; MS, metabolic syndrome. *Adjusted for age, sex, time after transplantation, use of angiotensin converting enzyme inhibitors, angiotensin receptor antagonist, and mTOR inhibitors.
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The alignment of MS and high CRP status did not increase the microalbuminuria prevalence compared to normal CRP and non-MS status (odds ratio 2.63; 95% [CI] 0.57e12.11). This study has some limitations. First, because of the its cross-sectional nature, the present study provided the results in only one time-frame. Second, microalbuminuria detection was made only once. This may have potential error risk. Third, the recurrence or de novo glomerular disease may have confounded the association between MS and microalbuminuria. In conclusion, the prevalence of MS in our kidney recipient cohort was found to be increased compared to the general population. MS was not related to increased prevalence of microalbuminuria, even when it combined with high CRP. Microalbuminuria was associated with elevated SBP and hyperglycemic status. Longitudinal studies are needed to reveal the relationship between MS, microalbuminuria, and inflammation. REFERENCES [1] Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735e52. [2] Porrini E, Delgado P, Torres A. Metabolic syndrome, insulin resistance, and chronic allograft dysfunction. Kidney Int Suppl 2010: S42e6. [3] Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640e5. [4] de Vries AP, Bakker SJ, van Son WJ, et al. Metabolic syndrome is associated with impaired long-term renal allograft function; not all component criteria contribute equally. Am J Transplant 2004;4:1675e83. [5] Porrini E, Delgado P, Bigo C, et al. Impact of metabolic syndrome on graft function and survival after cadaveric renal transplantation. Am J Kidney Dis 2006;48:134e42. [6] Israni AK, Snyder JJ, Skeans MA, Kasiske BL. Clinical diagnosis of metabolic syndrome: predicting new-onset diabetes, coronary heart disease, and allograft failure late after kidney transplant. Transpl Int 2012;25:748e57. [7] Palaniappan L, Carnethon M, Fortmann SP. Association between microalbuminuria and the metabolic syndrome: NHANES III. Am J Hypertens 2003;16:952e8. [8] Ponticelli C, Graziani G. Proteinuria after kidney transplantation. Transpl Int 2012;25:909e17. [9] Halimi JM, Buchler M, Al-Najjar A, et al. Urinary albumin excretion and the risk of graft loss and death in proteinuric and nonproteinuric renal transplant recipients. Am J Transplant 2007;7:618e25. [10] Koh KK, Han SH, Quon MJ. Inflammatory markers and the metabolic syndrome: insights from therapeutic interventions. J Am Coll Cardiol 2005;46:1978e85. [11] Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14,719 initially healthy American women. Circulation 2003;107:391e7. [12] Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499e511.
SIPAHIOGLU, UNAL, YAZGAC ET AL [13] Prasad GV, Bandukwala F, Huang M, Zaltzman JS. Microalbuminuria post-renal transplantation: relation to cardiovascular risk factors and C-reactive protein. Clin Transplant 2009;23:313e20. [14] Fabbian F, Bergami M, Molino C, et al. Risk factors for metabolic syndrome in stable Italian renal transplant patients. Clin Exp Nephrol 2011;15:560e6. [15] Armstrong KA, Campbell SB, Hawley CM, Nicol DL, Johnson DW, Isbel NM. Obesity is associated with worsening cardiovascular risk factor profiles and proteinuria progression in renal transplant recipients. Am J Transplant 2005;5:2710e8. [16] Cheung CY, Chan HW, Liu YL, et al. Prevalence of metabolic syndrome in Chinese renal transplant recipients. Hong Kong Med J 2008;14:379e84. [17] Naganuma T, Uchida J, Kinoshita Y, et al. The prevalence of metabolic syndrome in Japanese renal transplant recipients. Nephrology (Carlton) 2007;12:413e7. [18] Gundogan K, Bayram F, Gedik V, et al. Metabolic syndrome prevalence according to ATP III and IDF criteria and related factors in Turkish adults. Arch Med Sci 2013;9:243e53. [19] Joosten SA, Sijpkens YW, van Kooten C, Paul LC. Chronic renal allograft rejection: pathophysiologic considerations. Kidney Int 2005;68:1e13. [20] Sarafidis PA, Ruilope LM. Insulin resistance, hyperinsulinemia, and renal injury: mechanisms and implications. Am J Nephrol 2006;26:232e44. [21] Prasad GV, Huang M, Silver SA, et al. Metabolic syndrome definitions and components in predicting major adverse cardiovascular events after kidney transplantation. Transpl Int 2015;28:79e88. [22] Sheng CS, Hu BC, Fan WX, Zou J, Li Y, Wang JG. Microalbuminuria in relation to the metabolic syndrome and its components in a Chinese population. Diabetol Metab Syndr 2011;3:6. [23] Hao Z, Konta T, Takasaki S, et al. The association between microalbuminuria and metabolic syndrome in the general population in Japan: the Takahata study. Intern Med 2007;46:341e6. [24] Chen B, Yang D, Chen Y, Xu W, Ye B, Ni Z. The prevalence of microalbuminuria and its relationships with the components of metabolic syndrome in the general population of China. Clin Chim Acta 2010;411:705e9. [25] Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539e53. [26] Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143e421. [27] Alberti KG, Zimmet P, Shaw J. The metabolic syndromeea new worldwide definition. Lancet 2005;366:1059e62. [28] Li Q, Jia WP, Lu JQ, et al. [Relationship between the prevalence of microalbuminuria and components of metabolic syndrome in Shanghai]. Zhonghua Liu Xing Bing Xue Za Zhi 2004;25:65e8. [29] Frohlich M, Imhof A, Berg G, et al. Association between C-reactive protein and features of the metabolic syndrome: a population-based study. Diabetes Care 2000;23:1835e9. [30] Kshirsagar AV, Bomback AS, Bang H, et al. Association of C-reactive protein and microalbuminuria (from the National Health and Nutrition Examination Surveys, 1999 to 2004). Am J Cardiol 2008;101:401e6. [31] Nakamura M, Onoda T, Itai K, et al. Association between serum C-reactive protein levels and microalbuminuria: a population-based cross-sectional study in northern Iwate, Japan. Intern Med 2004;43:919e25. [32] Festa A, D’Agostino R, Howard G, Mykkanen L, Tracy RP, Haffner SM. Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: The Insulin Resistance Atherosclerosis Study. Kidney Int 2000;58:1703e10. [33] Jiang L, Huang W, Liang Y, et al. Metabolic syndrome, C-reactive protein and microalbuminuria in a rural Chinese population: a cross-sectional study. BMC Nephrol 2013;14:118.
ABSTRACT Aim. The aims of this study were to report the prevalence of metabolic syndrome (MS) in a cohort of Turkish kidney transplant recipients and to define the relationships between MS, microalbuminuria and C-reactive protein (CRP), which are cardiovascular risk factors, in kidney transplant setting. Methods. This cross sectional study included 170 adult renal transplantation recipients with a mean follow-up of 53.1 49.9 months. The diagnosis of MS was made according to the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) criteria. Microalbuminuria was defined as a urinary albumin/creatinine ratio of 30e300 mg/g. CRP levels 6.0 were classified as high CRP. Results. Mean age was 39.3 11 years. The prevalence of MS was 45.8% (n ¼ 78). The prevalence of microalbuminuria was not different in patients with MS compared to those without MS (39.7% vs 37%, P ¼ .428). In multivariate logistic regression analyses, systolic blood pressure (SBP) (odds ratio 1.68; 95% confidence interval [CI] 1.12e2.52; P ¼ .011) and high fasting glucose (odds ratio 2.82; 95% confidence interval [CI] 1.16e6.86; P ¼ .022) were significantly associated with microalbuminuria. When patients with MS and high CRP were compared with patients with normal CRP and without MS, microalbuminuria did not differ between the groups (P ¼ .213). Conclusion. The prevalence of MS in our kidney recipient cohort was found to be increased compared to general population. MS was not related to increased prevalence of microalbuminuria, even when combined with high CRP. Microalbuminuria was associated with elevated SBP and hyperglycemic status.
M
ETABOLIC SYNDROME (MS) is a cluster of metabolic and nonmetabolic abnormalities (glucose intolerance, dyslipidemia, obesity, and hypertension) [1]. Insulin resistance is thought to be main mechanism in MS pathogenesis [2]. There are several definitions for the MS, with the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III) being the most widely used [3]. The prevalence of MS differs widely according to age, ethnicity, and the definition used. In longterm renal transplant recipients, the prevalence of MS has ranged from 20% to 60% [4,5]. The presence of MS in transplant patients is related to increased risk of new-onset diabetes mellitus, cardiovascular complications, chronic allograft dysfunction, and reduced transplant and patient survival [6].
Microalbuminuria, which is a marker of systemic endothelial dysfunction, is common in MS [7]. The components of MS show a close relationship with microalbuminuria. In transplant recipients, microalbuminuria may be the result of both transplant- and nonetransplant-specific risks that result in glomerular injury, such as recurrent or de novo glomerulonephritis, transplant glomerulopathy, chronic rejection, hypertension, calcineurin inhibitor (CNI), and the mammalian target of rapamycin (mTOR) toxicity [8]. Microalbuminuria is also an early indicator of progressive renal
*Address correspondence to Murat Hayri Sipahioglu, MD, Erciyes University Medical Faculty, Department of Nephrology, Kayseri, Turkey. E-mail: [email protected]
0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.04.037
ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
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Transplantation Proceedings, 47, 1408e1412 (2015)
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Table 1. Demographic, Clinical and Laboratory Data of Patients With and Without Metabolic Syndrome* With MS n ¼ 78 (45.8%)
Age (y) Male, n (%) Time after Tx (month) BMI (kg/m2) Waist circumference (cm) Men Women Immunosuppressive medication Tacrolimus, n (%) Cyclosporine, n (%) mTOR inhibitor, n (%) Mycophenolate, n (%) Use of steroid, n (%) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Fasting glucose (mg/dL) Triglyceride (mg/dL) HDL cholesterol (mg/dL) Creatinine (mg/dL) CRP (mg/dL) Hypertension, n (%) Hyperglycemia, n (%) Abdominal obesity, n (%) Microalbuminuria, n (%) High CRP, n (%) eGFR (mL/min/1.73 m2)
42 45 38 27.5
Without MS n ¼ 92 (54.2%)
(33.8e50) (57.7) (13e76) (24.8e30)
36.0 63 47 23.4
(29e42) (68.5) (15.5e79.5) (21.5e26.6)
100 (93.5e108) 94 (84.5e100.5)
89 (82e96) 80 (71.5e86.5)
67 (88.2) 9 (11.8) 4 (5.2) 63 (80.8) 73 (92.4) 130 (122.3e143) 85.5 (80e93) 96 (86e117.3) 188 (151e227) 39.5 (33e46.3) 1.1 (0.9e1.4) 3.54 (3.45e8.21) 75 (94.9%) 28 (35.9) 45 (57.7) 31 (39.7) 25 (32) 84.1 29.4
72 (82.8) 15 (17.2) 8 (8.7) 80 (87%) 79 (82.8) 125 (116e135.5) 83 (78e86) 90 (83e101.5) 111 (83e138) 44 (40e52) 1.2 (0.9e1.4) 3.45 (3.45e3.45) 65 (71.4%) 9 (9.8) 33 (35.8) 34 (37.0) 11 (11.9) 77.9 26.1
P
<.001 .097 .698 .001 <.001
.199 .523 .366 .271 .237 .011 .063 <.001 <.001 <.001 <.001 .001 <.001 <.001 <.001 .428 .001 .148
Abbreviations: MS, metabolic syndrome; Tx, transplantation; mTOR, mammalian target of rapamune. *Data were shown as mean standard deviation or median (25%e75% percentile) according to their distribution characteristics.
damage and in renal transplant recipients is related to chronic allograft disease [9]. Elevated levels of C-reactive protein (CRP) and lL-6 may indicate that MS is a proinflammatory condition [10,11]. Inflammation is associated with an increased risk for subsequent cardiovascular disease [12]. In this study, we aimed to report the prevalence of MS in a cohort of Turkish renal transplant recipients and to define the relationships between MS, microalbuminuria, and CRP, which are cardiovascular risk factors, in the kidney transplant setting.
Lake Forest, Ill., United States) was used for biochemical analysis. Fresh spot urine samples were collected for the measurement of urinary albumin and creatinine. Microalbuminuria was defined as a urinary albumin-to-creatinine ratio (ACR) of 30 to 300 mg/g. CRP was measured using a Dade-Behring nephelometer (Dade Behring Diagnostics, Marburg, Germany). CRP levels 6.0 were classified as high CRP. Patients with a CRP value >45 mg/dL were excluded, as patients with extremely high values were thought to be acutely ill [13]. The eGFR was calculated by using Cockcroft-Gault equation. Blood pressure was measured as the average of 3 measurements with 1-minute intervals after a 6-minute rest.
Definitions MATERIALS AND METHODS This study was approved by the Institutional Review Board at Erciyes University. Written consent was obtained from each patient. Renal transplant recipients followed in the outpatient clinic of Semiha-Asım Kibar Transplantation Hospital were included the study. The recruitment took place between June and December 2013. Patients who were pregnant, who had malign diseases or active systemic infection, and patients with follow-up of less than 6 months were excluded.
The diagnosis of MS was made according to the NCEP-ATP III criteria. Subjects with 3 or more of the following criteria were defined as having MS: (1) high blood pressure (130/85 mm Hg) or on antihypertensive medications; (2) hypertriglyceridemia (150 mg/dL) or drug treatment for elevated triglycerides; (3) low serum-high density lipoprotein (HDL) cholesterol (in men <40 mg/dL, in women <50 mg/dL) or drug treatment for low HDL; (4) elevated fasting glucose (110 mg/dL) or use of antidiabetic medication; and (5) abdominal obesity (waist circumference 102 cm in men, 88 cm in women).
Measurements Weight, height, and waist circumference were measured according to standard protocols. Blood samples were drawn after an overnight fasting period of 8 to 12 hours to determine serum triglyceride, highdensity lipoprotein (HDL), blood urea nitrogen (BUN), creatinine, and glucose. An Abbott Architect c8000 device (Abbott Diagnostics,
Statistical Analysis The Statistical Package for the Social Sciences (SPSS Inc. version 20.0, Chicago, Ill., United States) was used to perform the analyses. Continuous data were expressed as means SD or median and interquartile ranges according to their distribution characteristics.
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SIPAHIOGLU, UNAL, YAZGAC ET AL Table 2. Association of Microalbuminuria With the Metabolic Syndrome Components as Continuous Variables
The Metabolic Syndrome Component
Waist circumference, cm Systolic blood pressure, þ10 mm Hg Diastolic blood pressure, þ10 mm Hg Fasting glucose, mg/dL Triglyceride, mg/dL HDL cholesterol, mg/dL
Unadjusted Odds Ratio (95% CI)
1.01 1.36 0.71 1.00 0.99 1.02
(0.98e1.04) (0.99e1.93) (0.40e1.28) (0.99e1.00) (0.99e1.00) (0.99e1.05)
P
.315 .081 .260 .685 .772 .079
Adjusted Model* Odds Ratio (95% CI)
1.03 1.68 0.54 1.00 0.99 1.02
(0.99e1.07) (1.12e2.52) (0.29e1.04) (0.99e1.01) (0.99e1.00) (0.99e1.05)
P
.075 .011 .066 .301 .584 .112
*Adjusted for age, sex, time after transplantation, use of angiotensin converting enzyme inhibitors, angiotensin receptor antagonist, and mTOR inhibitors.
Categorical data were presented as percentages. Continuous data were compared using the Student t test and the Mann-Whitney U (Wilcoxon) statistic. Categorical data were analyzed by c2 test to detect differences between groups. Multiple logistic regression analysis was used to determine the association of microalbuminuria with the components of MS, while controlling for covariates including age, sex, time after transplantation, and the use of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) or mTOR inhibitors. Factors with a P value <.20 were entered into a multivariate logistic regression model with stepwise backwards elimination of nonsignificant variables. We also used multivariate linear regression analysis to estimate the association between CRP levels and urinary ACR (dependent variable). Patients with macroalbuminuria (n ¼ 23) were not included in the multiple logistic regression and multivariate linear regression analyses. A P value .05 was used as the threshold for statistical significance.
RESULTS
A total of 170 kidney transplant recipients with a mean follow-up of 53.1 49.9 months were included in this crosssectional study. The mean age was 39.3 11 years; 108 (63%) were male patients. The prevalence of MS was 45.8% (n ¼ 78). The etiology of end-stage renal disease was hypertension in 36 (21.2%), glomerulonephritis in 17 (10%), diabetes mellitus in 11 (6.4%), others in 16 (9.4%), and unknown causes in 90 (52.9%). Table 1 shows the demographic, clinical and laboratory characteristics of patients according to MS status. Compared with the non-MS group, the MS group had greater age, higher BMI and waist circumference, higher SBP, and higher fasting serum glucose, triglyceride, and CRP levels. HDL levels were significantly lower in the MS group. Although serum creatinine level was significantly lower in the MS group, eGFR level did not show any difference (84.1 29.4 vs 77.9 26.1 mL/min/1.73 m2, P ¼ .148). The presence of high CRP status was significantly higher in subjects with MS group than in those with non-MS (32% vs 11%, P ¼ .001). The prevalence of microalbuminuria did not differ in both groups (39.7% vs 37%, P ¼ .428). In unadjusted continuous model, microalbuminuria was associated with none of MS components. After adjustment for age, gender, time after transplantation, use of ACE inhibitors or ARBs, and use of mTOR inhibitors, microalbuminuria showed a significant association with SBP (odds ratio 1.68; 95% confidence interval [CI] 1.12e2.52; P ¼ .011) (Table 2). In the adjusted categorical analysis model, presence of microalbuminuria was associated with blood glucose
component of MS (odds ratio 2.82; 95% CI 1.16e6.86; P ¼ .022) (Table 3). The risk of microalbuminuria was 2.8 times higher in patients with the fasting glucose component. Odds ratios for microalbuminuria by CRP levels and MS status were shown in Table 4. Kidney transplant recipients with high CRP and MS did not show an increased risk of microalbuminuria compared with recipients who had normal CRP without MS (P ¼ .213).
DISCUSSION
Studies reporting a prevalence of MS in renal transplant recipients are limited. The prevalence of MS differs widely according to ethnic groups studied and the definition of MS used. de Vries et al reported 63% MS prevalence in 606 Caucasian kidney transplant recipients using NCEP-ATP criteria [4]. MS prevalence was found to be 34.5%, 37.7%, and 50% in the studies reported from Italy, Spain, and Australia, respectively, using the same criteria [5,14,15]. The studies from East Asian countries for which modified NCEP criteria for Asian people were used showed a prevalence of 32% in China and 23.8% in Japan [16,17]. Time after transplantation also has an effect on MS prevalence. In a cohort of 230 consecutive nondiabetic kidney transplant recipients, the prevalence of MS has been reported as 22.6% at 12 months, 37.7% at 36 months, and 64% at 6 years after transplantation [5]. A nationwide study in Turkey that included 1947 participants from the general population reported the prevalence of MS as 36.6% using ATP III criteria [18]. In the current study, the prevalence of MS was found to be 45.8%. These reports suggested that MS is more prevalent in our renal transplant recipients compared with the general population. The presence of MS is associated with impaired renal allograft function [4,5]. Several possible explanations have been proposed for the mechanism underlying the association between MS and renal dysfunction. The components of MS such as hypertension, hyperlipidemia, and alterations in glucose metabolism are risk factors for allograft dysfunction and directly damage the kidneys [19]. MS also is known as “insulin resistance syndrome” and it was shown that hyperinsulinemia may contribute to renal dysfunction [2]. Several studies have reported that insulin stimulates mesangial cell proliferation and production of mesangial matrix [20]. In the present study, serum creatinine levels were lower in the MS group compared to the non-MS group (median values 1.1 and 1.2 mg/dL, respectively, P < .001). However, there was no
METABOLIC SYNDROME, MICROALBUMINURIA AND CRP
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Table 3. Association of Microalbuminuria With Metabolic Syndrome Components as Dichotomized Variables The Metabolic Syndrome Component
Abdominal obesity Elevated blood pressure Elevated fasting glucose Elevated serum triglycerides Reduced serum HDL cholesterol
Unadjusted Odds Ratio (95% CI)
1.40 0.95 2.25 0.59 1.30
P
(0.65e3.01) (0.41e2.20) (0.98e5.15) (0.29e1.19) (0.64e2.62)
.382 .914 .054 .145 .463
Adjusted Model* Odds Ratio (95% CI)
1.71 1.06 2.82 0.57 1.25
(0.73e3.98) (0.41e2.75) (1.16e6.86) (0.27e1.17) (0.61e2.56)
P
.210 .892 .022 .126 .535
*Adjusted for age, sex, time after transplantation, use of angiotensin converting enzyme inhibitors, angiotensin receptor antagonist, and mTOR inhibitors.
significant difference in eGFR values between the 2 groups. We speculated that early renal function after transplantation, which was not included in the analysis, might have affected the result. In a recent study, Prasad et al showed there was no association between MS and graft survival in a cohort of 1182 kidney transplant recipients [21], as in our study. Microalbuminuria is early predictor of renal and cardiovascular disease. In renal transplant recipients, microalbuminuria has a well-established association with renal allograft loss [9]. The prevalence of microalbuminuria in MS patients (nontransplant recipients) has ranged between 12% and 20%. Studies showed that this prevalence was 13.7% in the United States, 20.8% in Japan, and 12% and 20.3% in China [7,22e24]. Because of this relatively common prevalence, microalbuminuria has been included into the World Health Organization’s definition of MS [25]. But more recent definitions, such as those from NCEP-ATP III, the International Diabetes Federation (IDF), the American Heart Association criteria, and the Harmonized (Consensus) definition, did not incorporate microalbuminuria as an MS criterion [3,26,27]. Microalbuminuria in stable renal transplant recipients is a highly prevalent condition. In a study in which macroalbuminuric recipients were excluded, prevalence of microalbuminuria was reported to be 48% [13]. In our renal recipient cohort, the prevalence of microalbuminuria (38.2%) also was high. The prevalence of microalbuminuria in patients with MS did not differ from prevalence in those without MS. (39.7 and 37.0%, respectively, P ¼ .428). Although the prevalence of microalbuminuria was higher in our renal recipient cohort, this increased ratio was not associated with MS status. Conditions that result in glomerular injury, such as recurrent or de novo glomerulonephritis, transplant glomerulopathy rather than MS may have confounded the relationship between MS and microalbuminuria. Several studies have examined the relationship between MS components and microalbuminuria. The National Health and Nutrition Examination Survey (NHANES III) reported that
microalbuminuria was associated with SBP and hyperglycemia components. This relationship was in present both in men and women [7]. Two different Chinese studies that included 1079 and 3532 participants from the general population showed that MS components related to microalbuminuria were hypertension and hyperglycemia [22,28]. A study from Japan by Hao et al revealed that microalbuminuria had a weak relationship with abdominal obesity (odds ratio 1.31; P ¼ .04), but had a strong relationship with hyperglycemia (odds ratio 2.64; P < .001) and high blood pressure (odds ratio 2.37; P < .001) [23]. In the current study, SBP was related to microalbuminuria in the model in which MS components were used as continues variables [OR (95% CI) ¼ 1.68 (1.12e2.52)]. On the other hand, impaired glucose metabolism was found to be related to microalbuminuria in the model in which MS components were used as dichotomized variables [OR (95% CI) ¼ 2.82 (1.16e6.86)]. CRP is used as a sensitive marker of inflammation. Data from population-based trials suggested that high CRP levels were associated with MS [29]. However, whether there is a relationship between high CRP and microalbuminuria remains controversial. Several studies of the general population have found a significant correlation [30,31]; but some studies reported no association [32]. In the study by Prasad et al that included 222 kidney recipients, microalbuminuria was associated with increasing CRP (odds ratio 1.129 per 1 g/L [95% CI 1.058e1.204], P ¼ .0002) [13]. Jiang et al studied the effect of alignment of high CRP and MS on microalbuminuria status in a population-based trial. They showed that when MS patients had high CRP levels, the risk for development of microalbuminuria was significantly increased [33]. In our renal recipient cohort, a total of 36 patients (21%) had high CRP levels. Patients with MS had significantly increased ratio of high CRP status compared to non-MS group (32% and 11.9%, respectively, P ¼ .001). This result supported the notion that MS is a proinflammatory condition. When recipients with microalbuminuria (n ¼ 65) were compared to those with normoalbuminuria (n ¼ 82), CRP levels and high CRP status did not show any difference (data were not shown).
Table 4. Odds Ratios for Microalbuminuria by CRP Levels and Metabolic Syndrome Status Unadjusted Odds Ratio (95% CI)
Normal CRP without MS High CRP without MS Normal CRP with MS High CRP with MS
reference 1.37 (0.52e4.59) 2.59 (0.66e2.84) 0.64 (0.57e11.65)
P
Adjusted* Model Odds Ratio (95% CI)
P
.428 .395 .216
reference 1.63 (0.53e4.94) 1.37 (0.63e2.96) 2.63 (0.57e12.11)
.387 .421 .213
Abbreviations: CRP, C-reactive protein; MS, metabolic syndrome. *Adjusted for age, sex, time after transplantation, use of angiotensin converting enzyme inhibitors, angiotensin receptor antagonist, and mTOR inhibitors.
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The alignment of MS and high CRP status did not increase the microalbuminuria prevalence compared to normal CRP and non-MS status (odds ratio 2.63; 95% [CI] 0.57e12.11). This study has some limitations. First, because of the its cross-sectional nature, the present study provided the results in only one time-frame. Second, microalbuminuria detection was made only once. This may have potential error risk. Third, the recurrence or de novo glomerular disease may have confounded the association between MS and microalbuminuria. In conclusion, the prevalence of MS in our kidney recipient cohort was found to be increased compared to the general population. MS was not related to increased prevalence of microalbuminuria, even when it combined with high CRP. Microalbuminuria was associated with elevated SBP and hyperglycemic status. Longitudinal studies are needed to reveal the relationship between MS, microalbuminuria, and inflammation. REFERENCES [1] Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735e52. [2] Porrini E, Delgado P, Torres A. Metabolic syndrome, insulin resistance, and chronic allograft dysfunction. Kidney Int Suppl 2010: S42e6. [3] Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640e5. [4] de Vries AP, Bakker SJ, van Son WJ, et al. Metabolic syndrome is associated with impaired long-term renal allograft function; not all component criteria contribute equally. Am J Transplant 2004;4:1675e83. [5] Porrini E, Delgado P, Bigo C, et al. Impact of metabolic syndrome on graft function and survival after cadaveric renal transplantation. Am J Kidney Dis 2006;48:134e42. [6] Israni AK, Snyder JJ, Skeans MA, Kasiske BL. Clinical diagnosis of metabolic syndrome: predicting new-onset diabetes, coronary heart disease, and allograft failure late after kidney transplant. Transpl Int 2012;25:748e57. [7] Palaniappan L, Carnethon M, Fortmann SP. Association between microalbuminuria and the metabolic syndrome: NHANES III. Am J Hypertens 2003;16:952e8. [8] Ponticelli C, Graziani G. Proteinuria after kidney transplantation. Transpl Int 2012;25:909e17. [9] Halimi JM, Buchler M, Al-Najjar A, et al. Urinary albumin excretion and the risk of graft loss and death in proteinuric and nonproteinuric renal transplant recipients. Am J Transplant 2007;7:618e25. [10] Koh KK, Han SH, Quon MJ. Inflammatory markers and the metabolic syndrome: insights from therapeutic interventions. J Am Coll Cardiol 2005;46:1978e85. [11] Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14,719 initially healthy American women. Circulation 2003;107:391e7. [12] Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499e511.
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