2 an increased burden of traditional cardiovascular risk factors, such as abnormalities in serum lipid concentrations and distribution (elevated triglycerides and lower high-density lipoprotein), diabetes mellitus, and hypertension [2, 12, 13] which are also part of the MetS construct. There is evidence to suggest that CKD progression and associated adverse CVD outcomes are related to severe vitamin D deﬁciency. The recent ﬁndings of vitamin D, being a modulator of both insulin resistance [14] and the renin-angiotensin system [15] and the implication of the renin-angiotensin system in local pancreatic islet structure and function [16, 17], suggest that perhaps renal dysfunction and MetS may share common pathological pathways. This overlap in associated risk factors combined with the potential modifying eﬀect of impaired renal function raises the question about whether the co- occurrence of both conditions would augment or attenuate the anticipated risk based on the eﬀect of the two risk factors individually. The purpose of this study is to understand the joint associations of the two conditions with CVD events in a multiethnic population which could lead to improvements in risk stratiﬁcation and determine whether participants with both conditions should be speciﬁcally targeted for more aggressive and early risk factor interventions. Because cystatin C appears to be more sensitive in detecting mild to moderate decrease in glomerular ﬁltration rate [18, 19], shows strong associations with incident cardiovascular events [20] and all cause mortality [20, 21], and is not aﬀected by age, gender, ethnicity, or muscle mass, this study focused on CKD deﬁned by reduced GFR using a cystatin C- based estimating equation [22]. 2. Materials and Methods 2.1. Study Population. The Multiethnic Study of Atheroscle- rosis (MESA) design has been previously described [23]. Brieﬂy, MESA is a prospective cohort study that began in July 2000 to investigate the prevalence, correlates, and progression of subclinical CVD. The study included 6814 men and women aged 45–84 years old recruited from 6 US communities (Baltimore, MD; Chicago, IL; Forsyth County, NC; Los Angeles County, CA; northern Manhattan, NY; St. Paul, MN). MESA cohort participants were 38% Caucasian (n = 2622), 28% African-American (n = 1893), 22% Hispanic (n = 1496), and 12% Chinese (n = 803). Individuals with a history of physician-diagnosed myocardial infarction, angina, heart failure, stroke, or transient ischemic attack, or who had undergone an invasive procedure for CVD (coronary artery bypass graft, angioplasty, valve replacement, pacemaker placement, or other vascular surgeries) were excluded from the study at baseline (2000–2002). After excluding participants with missing data on serum cystatin C (n = 58) and covariates (n = 1143), we had 5,613 participants at baseline with complete data on serum cystatin C, Mets, and covariates of interest. This study was approved by the Institutional Review Boards of each study site and written informed consent was obtained from all participants. 2.2. Laboratory Measures and Data Collection. Medical his- tory, anthropometric measurements, and laboratory data for Cardiology Research and Practice the present study were taken from the ﬁrst examination of the MESA cohort (July 2000–August 2002). Information about age, sex, ethnicity, and medical history were obtained by questionnaires. Resting blood pressure was measured using the Dinamap monitor PRO 100 (Critikon, Tampa, Fla, USA) automated oscillometric device. Three measurements were obtained at 1-min intervals with the subject in the seated position with back and arm supported after 5 min of rest with an appropriate-sized cuﬀ, with the cuﬀ at the level of the heart, using a standardized protocol. The average of the second and third measurements was recorded as the resting blood pressure. Hypertension was deﬁned as a systolic blood pressure ≥140 mm Hg, a diastolic blood pressure ≥90 mm Hg, or currently taking medications for blood pressure control [24]. Smoking use was deﬁned as never, former, and current smokers. Smoking ever is deﬁned as ≥100 cigarettes in one’s lifetime; current is deﬁned as having smoked a cigarette in the last 30 days. Diabetes was deﬁned as a fasting glucose ≥126 mg/dL or use of insulin or hypoglycemic medications. Plasma lipids (HDL cholesterol, triglycerides, and total cholesterol) were measured from blood samples obtained after a 12-hour fast and measured using a standardized kit (Roche Diagnostics). LDL cholesterol was calculated with the Friedewald equation [25]. Cystatin C was measured from frozen sera at a central laboratory (University of Vermont, Colchester, Vt, USA) using a BNII nephelometer (Dade Behring Inc, Deerﬁeld, Ill, USA) and a particle-enhanced immunonephelometric assay (N Latex Cystatin C; Dade-Behring) [26]. The analytical coeﬃcient of variation for this assay is 2.5%. Chronic kidney disease was deﬁned as cystatin C derived glomerular ﬁltration rate ≤60 mL/min/1.73 m2 using the for- mula derived and validated by Stevens et al. [22] (eGFRcysC = 76.7 ∗ cystatin C−1.19). The National Cholesterol Education Program/Adult Treatment Panel (NCEP ATP III) [5, 27] deﬁnition was used to classify participants having MetS in the MESA cohort. Three of ﬁve components are required for diagnosis. (1) Waist circumference ≥102 cm : men, ≥88 cm : women, (2) hypertension ≥130 mm Hg systolic or ≥85 mm Hg diastolic or use of medications for hypertension, (3) fasting blood glucose ≥100 mg/dL or treatment for impaired fasting glucose, (4) triglycerides ≥150 mg/dL or speciﬁc treatment, and (5) HDL-C ≤40 mg/dL in men and ≤50 mg/dL in women. A dummy variable with four categories for all the possible permutations of CKD and MetS was created. The categories were as follows: (a) no CKD and no MetS (CKD−/MetS−), (b) CKD and no MetS (CKD+/MetS−), (c) no CKD and MetS (CKD−/MetS+), and (d) both CKD and MetS (CKD+/MetS+). 2.3. Cardiovascular Events. A detailed description of events and the process of adjudication can be found at the MESA website (http://www.mesa-nhlbi.org). Brieﬂy, participants were contacted every 9–12 months to inquire about hospital admissions, cardiovascular diagnoses, and deaths. Hospi- tal records were abstracted for possible CVD events and were sent for review and classiﬁcation by an independent adjudication committee. For the purposes of this study, a