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1 Cardiovascular Disease in Early Stages of Chronic Kidney Disease in a Chinese Population LuXia Zhang,* Li Zuo,* Fang Wang,* Mei Wang,* ShuYu Wang, JiCheng Lv,* LiSheng Liu, and HaiYan Wang* *Institute of Nephrology and Division of Nephrology, Peking University First Hospital, and Beijing Hypertension League Institute, Beijing, China Cardiovascular disease (CVD) is one of the most serious complications of kidney disease, yet studies of CVD in early stage of chronic kidney disease (CKD) in Asian patients are very limited. Therefore, this study determined the prevalence and the spectrum of CVD in individuals with early-stage CKD and compared them with data of individuals without CKD. Compared with individuals with estimated GFR (egfr) >90 ml/min per 1.73 m 2, the prevalence of myocardial infarction, stroke, and total CVD of individuals with egfr 60 to 89 ml/min per 1.73 m 2 was increased by 91.4, 71.7, and 67.6%, respectively. For individuals with egfr 30 to 59 ml/min per 1.73 m 2, the percentage was 105.2, 289.1, and 200.7%, respectively. For each egfr category, stroke was more prevalent than myocardial infarction. Compared with individuals with egfr >90 ml/min per 1.73 m 2, participants with egfr 60 to 89 and 30 to 59 ml/min per 1.73 m 2 tended to have more cardiovascular risk factors, and there were strong unadjusted and adjusted associations between CVD with different stages of egfr (egfr >90 ml/min per 1.73 m 2 as reference). This is the first report on the prevalence and the spectrum of CVD in early stages of CKD in a community-based Chinese population. The spectrum of CVD in this Chinese population is different from reports of Western countries. Individuals with subtle decreased renal function seem much more likely to have multiple cardiovascular risk factors and have higher prevalence of CVD than those without CKD. J Am Soc Nephrol 17: , doi: /ASN Cardiovascular disease (CVD) is the leading cause of death among patients who are on dialysis. CVD mortality rates are approximately 10 to 30 times higher in patients who are on dialysis than in the general population, despite stratification for gender, race, and the presence of diabetes (1). It was recognized recently that earlier stage of chronic kidney disease (CKD) also is a risk factor for CVD mortality (2 7). In particular, this risk has been noted in patients who already have some form of CVD or in individuals who are at high risk for the development of CVD (2 7). In low-risk populations or community studies, the relationship between the level of kidney function and outcomes has not been as clear (8 11). The relationship between early stages of CKD and CVD, to the best of our knowledge, has never been tested in a community-based Chinese population, in whom genetic and environmental backgrounds are different from those of Western countries, and the profile of CVD is very different from that of white individuals (12,13). Therefore, we initiated this cross-sectional study among a population older than 40 yr in a metropolis of China to investigate the prevalence and the spectrum of CVD in Received April 27, Accepted June 17, Published online ahead of print. Publication date available at Address correspondence to: Dr. Haiyan Wang, Institute of Nephrology and Division of Nephrology, Peking University First Hospital, No 8. Xishiku Street, Beijing, China Phone: ; Fax: ; why@bjmu.edu.cn residents with early-stage CKD and compare them with data of residents without CKD. Materials and Methods Population All residents who were 40 yr or older and were served by a community hospital located in an urban district of Beijing were invited to participate in the study. Residents were contacted by telephone using their data that were available in the hospital and notified of the screening protocol by the local general practitioner from May through June Of the 5593 individuals who were older than 40 yr, 2353 (42.1%) volunteered to participate. Patients with diagnosis of ESRD were excluded from this study. The investigation started in July 2004 and ended in December All participants gave their informed consent. Definition of CVD All participants were asked, Have you ever been told by a doctor that you had a heart attack? and, Have you ever been told by a doctor that you had a stroke? Participants with an affirmative answer to either of these questions were deemed as having CVD. Definition of CKD Serum creatinine (Scr) was measured by means of enzymatic method on a Hitachi 7170 autoanalyzer (Hitachi, Tokyo, Japan). In addition, Scr of 57 fresh frozen serum samples (Scr range 0.42 to mg/dl) were analyzed in both our laboratory and the Cleveland Clinic Laboratory to ensure that Scr values in this study are equally calibrated with the Modification of Diet in Renal Disease (MDRD) study. A calibration equation was generated from the results (R ): MDRD Scr (mg/dl) 1.05 [Beijing Scr (mg/dl)] Copyright 2006 by the American Society of Nephrology ISSN: /

2 2618 Journal of the American Society of Nephrology J Am Soc Nephrol 17: , 2006 Estimated GFR (egfr) was calculated with an abbreviated MDRD equation (14) by calibrated Scr. egfr was stratified into 90 (as reference group), 60 to 89, and 30 to 59 ml/min per 1.73 m 2. Spot urinary albumin-to-creatinine ratio (ACR) 30 mg/g was introduced to define albuminuria from a practical point of view. Albuminuria was measured by immunoturbidimetric methods (Audit Diagnostics, Cork, Ireland). Other Variables Sociodemographic characteristics, personal health history (e.g., hypertension, diabetes), and lifestyle behavior (e.g., smoking) were obtained by questionnaire. BP was measured according to the guidelines presented in Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (15). Fasting blood glucose, serum total cholesterol, LDL cholesterol, and HDL cholesterol also were measured. Statistical Analyses Data entry and management were performed on Epidata software. All analyses and calculations were performed by SPSS statistical package, version 10.0 (SPSS, Inc., Chicago, IL). Data were presented as mean SD for continuous variables and as proportions for categorical variables. Descriptive analyses were used to characterize the participant population by sociodemographic data (age and gender) and health status (e.g., hypertension, diabetes). Prevalence and mean values of selected conditions were examined using 2 statistics for categorical variables and Wilcoxon s rank sum for continuous values. The unadjusted odds ratios (OR) between different egfr staging ( 90, 60 to 89, and 30 to 59 ml/min per 1.73 m 2 ; 90 ml/min per 1.73 m 2 as the reference) and CVD were determined by univariate logistic regression analysis. The association between staging of egfr and CVD then was determined after adjustment for age and gender. Next, the association was assessed after adjustment for traditional risk factors (obesity, hypercholesteremia, low HDL cholesterol, diabetes, and systolic BP level) and/or nontraditional CVD risk factors. Results General Characteristics Complete information was available for 98.2% (n 2310) of participants examined. Participants who could not provide history of CVD and did not have results of Scr and/or ACR were excluded from further analysis. Two participants with egfr 30 ml/min per 1.73 m 2 were excluded from analysis. All participants were Chinese. General characteristics are given in Table 1. The mean age was yr (range 42 to 85), and 49.5% were men. Forty-seven percent (n 1086) of participants were categorized as hypertensive. Among them, 87.4% reported a history of hypertension. Twenty-eight percent (n 646) of participants were categorized as having diabetes, and 71.5% of them reported a history of diabetes. Indicators of Kidney Damage Overall prevalence of albuminuria was 6.2% (n 142). A total of 754 (32.7%) individuals had a egfr of 60 to 89 ml/min per 1.73 m 2, with the mean egfr being 78.7 ml/min per 1.73 m 2. A total of 67 (2.9%) individuals had an egfr of 30 to 59 ml/min per 1.73 m 2, with the mean egfr being 52.3 ml/min per 1.73 m 2. Prevalence of CVD The overall prevalence of self-reported myocardial infarction (MI) and stroke was 7.7% (n 178) and 12.1% (n 280), respectively. Twelve percent of participants with albuminuria reported history of MI compared with 7.4% of those without albuminuria (P 0.071; Figure 1). The prevalence of stroke among participants with albuminuria was higher than those without albuminuria (20.4 versus 11.6%; P 0.003). The overall prevalence of CVD in participants with albuminuria was 26.8% (n 38) and in participants without albuminuria was 17.2% (n 372; P 0.006). When analyzed by different stage of egfr, participants with lower egfr had a higher prevalence of MI, stroke, and CVD (Figure 2). Even for egfr between 60 and 89 ml/min per 1.73 m 2, there was a marked increase in prevalence of MI, stroke, and CVD. Compared with participants with egfr 90 ml/min per 1.73 m 2, the prevalence of MI, stroke, and total CVD of Table 1. General characteristics of the study population a General Characteristics Total (n 2,308) egfr 90 b (n 1,487) egfr 60 to 89 b (n 754) egfr 30 to 59 b (n 67) P Age (yr) Male (%) Obesity (%) c Diabetes (%) Hypertension (%) Systolic BP (mmhg) Diastolic BP (mmhg) Albuminuria d (%) Hypercholesteremia e (%) Low HDL cholesterol f (%) a egfr, estimated GFR. b Calculated with abbreviated Modification of Diet in Renal Disease (MDRD) equation (ml/min per 1.73 m 2 ). c Defined as body mass index 25 kg/m 2. d Defined as urinary albumin-to-creatinine ratio 30 mg/g. e Defined as serum cholesterol 5.72 mmol/l. f Defined as serum HDL 0.91 mmol/l.

J Am Soc Nephrol 17: 2617 2621, 2006 Cardiovascular Disease in CKD in a Chinese Population 2619 but still existed.

factor (albuminuria) for CVD (Table 2). After adjustment for all risk factors and risk markers for CVD, OR of egfr 60 to 89 and 30 to 59 ml/min per 1.73 m 2 were statistically significant: 1.

3 J Am Soc Nephrol 17: , 2006 Cardiovascular Disease in CKD in a Chinese Population 2619 but still existed. OR remained similar in magnitude after further adjustment for traditional (age, gender, obesity, hypercholesteremia, low HDL cholesterol, diabetes, and systolic BP level) and/or nontraditional risk factor (albuminuria) for CVD (Table 2). After adjustment for all risk factors and risk markers for CVD, OR of egfr 60 to 89 and 30 to 59 ml/min per 1.73 m 2 were statistically significant: (95% confidence interval to 1.677) and (95% confidence interval to 4.120). Figure 1. Cardiovascular disease (CVD) in participants with and without albuminuria. participants with egfr 60 to 89 ml/min per 1.73 m 2 was higher with 91.4, 71.7, and 67.6%, respectively. For participants with egfr 30 to 59 ml/min per 1.73 m 2, the number was 105.2, 289.1, and 200.7%, respectively. For each egfr category, stroke was more prevalent than MI. Risk Factors for CVD Compared with participants with egfr 90 ml/min per m 2, participants with egfr 60 to 89 and 30 to 59 ml/min per 1.73 m 2 tended to have more cardiovascular risk factors (Table 1), such as older age, obesity, diabetes, hypertension, hypercholesteremia, and albuminuria. There were strong unadjusted associations between CVD with different stages of egfr (egfr 90 ml/min per 1.73 m 2 as reference; Table 2). After adjustment for age and gender, the OR of different stages of egfr decreased Figure 2. CVD in participants stratified by different estimated GFR (egfr) stage. Discussion Our study demonstrated that in a Chinese population of individuals who were older than 40 yr, prevalence of CVD was markedly increased in early stage of CKD, and mildly decreased egfr was independently associated with CVD in this population; the spectrum of CVD was different from that in Western countries. By reviewing relevant publications that covered an 18-yr period (1986 through 2003), Vanholder et al. (16) concluded that there is an undeniable link between kidney dysfunction and cardiovascular risk, and the process of cardiovascular damage starts long before the dialysis stage is reached. For general or community-based population, however, the relationship has not been conclusive. In both the Framingham Study and the First National Health and Nutrition Examination Survey (NHANES I), the level of kidney function was not an independent risk factor for CVD outcomes (8,9), whereas in the Atherosclerosis Risk in Communities (ARIC) study and NHANES II, it was a risk factor for both CVD and all-cause mortality (10,11). One possible explanation might be related to different measures to ascertain the level of kidney function. Scr is less sensitive than egfr for detecting small differences in level of kidney function and therefore may be less likely to detect an association. Besides, differences in the study populations might contribute to the discrepancy (e.g., black individuals were part of the ARIC study but not the Framingham studies), so it is relevant to investigate the relationship between CVD and kidney function stage in different races. Our study indicated for the first time in a community-based Chinese population if individuals who were older than 40 yr that for individuals with mildly decreased renal function (egfr 60 to 89 and 30 to 59 ml/min per 1.73 m 2 ), there was a markedly increased prevalence of CVD. Further analysis indicated that individuals with mildly decreased egfr tended to have more traditional CVD risk factors (e.g., older age, obesity, hypertension). Although adjustments for these factors were made, mildly decreased renal function still was independently correlated with CVD. Albuminuria is an alternative marker for the presence of CKD (14), and there is a strong association between microalbuminuria and CVD in several cross-sectional studies (17 21). In our study, albuminuria was associated with elevated prevalence of CVD. After adjustment for presence of albuminuria, however, an independent association between mildly decreased kidney function and CVD still existed. Also, there might be other markers and factors than albuminuria (e.g., homocysteine, oxidative stress) that were not assessed in this study and contribute to the increased prevalence of CVD. In our study, stroke was the predominant form of CVD, both

4 2620 Journal of the American Society of Nephrology J Am Soc Nephrol 17: , 2006 Table 2. Unadjusted and adjusted OR and 95% CI of cardiovascular diseases associated with different stages of egfr a Adjusted Factors egfr 60 to 89 ml/min per 1.73 m 2 (OR 95% CI ) egfr 30 to 59 ml/min per 1.73 m 2 (OR 95% CI ) Unadjusted (1.514 to 2.369) (2.688 to 7.415) Adjusted for age and gender (1.002 to 1.617) (1.451 to 4.236) Adjusted for age, gender, obesity, (1.039 to 1.686) (1.465 to 4.306) hypercholesteremia, low HDL cholesterol, diabetes, and systolic BP level b Adjusted for age, gender, and albuminuria (1.008 to 1.628) (1.415 to 4.131) Adjusted for all of the above (1.031 to 1.677) (1.396 to 4.120) a CI, confidence interval; OR, odds ratio. b 130 (reference), 130 to 139, 140 to 159, and 160 mmhg. in all participants and in those with mildly decreased renal function, which was different from data of white individuals (12,13). Reports from the general population also indicated that cerebrovascular disease predominates in Asian individuals, and the number who die from stroke is more than three times of that for coronary heart disease (12,22). However, the exact mechanism of the difference is unclear, but at least the prevalence or the magnitude of the traditional risk factors seems unlikely to explain the differing spectrum of CVD among the specific defined included Asian individuals (23). There are certain limitations of our study. First, only selfreported prevalence of CVD was determined. The validity of self-reported MI and stroke events by questionnaire was between 70 and 80% in previous studies (24,25). This would tend to miss some cases of CVD and cause a bias toward the null. Second, when used in a Chinese population, the MDRD equation underestimated GFR in cases of near-normal GFR (26), thereby affecting the strength of the study. We believe that our study has useful features and raises important questions. The majority of studies that have evaluated associations between CVD and CKD come from Europe and North America (16). Our study extends the observation of link between CVD and CKD to an Asian population that is characterized by a relatively lower risk for CVD (12,13). Our study indicated that individuals with subtle decreased renal function seem much more likely to have multiple cardiovascular risk factors and have a higher prevalence of CVD than those without CKD, which is consistent with studies from white populations (16) and provide important information for the recognition of the relation between CVD and CKD. Furthermore, whereas mortality rates from CVD have been halved in many developed countries since the 1980s (27), they are still rising in most developing counties, including China (28). In Beijing, age-adjusted coronary heart disease mortality rates increased by 50% in men and 27% in women from 1984 to 1999 (29). Our study identified a specific population of individuals who have relatively higher prevalence of CKD and need multiple cardiovascular risk factor interventions and thus has significant meaning for prevention and treatment of CVD in China. Additional intervention studies to evaluate potential treatments of CVD in CKD are necessary. Acknowledgments We thank the Department of Clinical Laboratory, Peking University First Hospital, for performing tests of albuminuria. References 1. Foley RN, Parfrey PS, Sarnak MJ: Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 32[Suppl 3]: S112 S119, Flack JM, Neaton JD, Daniels B, Esunge P: Ethnicity and renal disease: Lessons from the Multiple Risk Factor Intervention Trial and the Treatment of Mild Hypertension Study. Am J Kidney Dis 21: 31 40, Manjunath G, Tighiouart H, Coresh J, Macleod B, Salem DN, Griffith JL, Levey AS, Sarnak MJ: Level of kidney function as a risk factor for cardiovascular outcomes in the elderly. Kidney Int 63: , Shlipak MG, Heidenreich PA, Noguchi H, Chertow GM, Browner WS, McClellan MB: Association of renal insufficiency with treatment and outcomes after myocardial infarction in elderly patients. Ann Intern Med 137: , Shulman NB, Ford CE, Hall WD, Blaufox MD, Simon D, Langford HG, Schneider KA: Prognostic value of serum creatinine and effect of treatment of hypertension on renal function. Results from the hypertension detection and follow-up program. The Hypertension Detection and Follow-up Program Cooperative Group. Hypertension 13: I80 I93, Wright RS, Reeder GS, Herzog CA, Albright RC, Williams BA, Dvorak DL, Miller WL, Murphy JG, Kopecky SL, Jaffe AS: Acute myocardial infarction and renal dysfunction: A high-risk combination. Ann Intern Med 137: , O Brien MM, Gonzales R, Shroyer AL, Grunwald GK, Daley J, Henderson WG, Khuri SF, Anderson RJ: Modest serum creatinine elevation affects adverse outcome after general surgery. Kidney Int 62: , Garg AX, Clark WF, Haynes RB, House AA: Moderate renal insufficiency and the risk of cardiovascular mortality: Results from the NHANES I. Kidney Int 61: , Culleton BF, Larson MG, Wilson PW, Evans JC, Parfrey PS, Levy D: Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. Kidney Int 56: , 1999

5 J Am Soc Nephrol 17: , 2006 Cardiovascular Disease in CKD in a Chinese Population Muntner P, He J, Hamm L, Loria C, Whelton PK: Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States. J Am Soc Nephrol 13: , Manjunath G, Tighiouart H, Ibrahim H, MacLeod B, Salem DN, Griffith JL, Coresh J, Levey AS, Sarnak MJ: Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol 41: 47 55, Wu Z, Yao C, Zhao D, Wu G, Wang W, Liu J, Zeng Z, Wu Y: Sino-MONICA project: A collaborative study on trends and determinants in cardiovascular diseases in China, Part i: Morbidity and mortality monitoring. Circulation 103: , Ecological analysis of the association between mortality and major risk factors of cardiovascular disease. The World Health Organization MONICA Project. Int J Epidemiol 23: , K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 39: S1 S266, Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA 289: , Vanholder R, Massy Z, Argiles A, Spasovski G, Verbeke F, Lameire N: Chronic kidney disease as cause of cardiovascular morbidity and mortality. Nephrol Dial Transplant 20: , Dell Omo G, Penno G, Giorgi D, Di Bello V, Mariani M, Pedrinelli R: Association between high-normal albuminuria and risk factors for cardiovascular and renal disease in essential hypertensive men. Am J Kidney Dis 40: 1 8, Hillege HL, Janssen WM, Bak AA, Diercks GF, Grobbee DE, Crijns HJ, Van Gilst WH, De Zeeuw D, De Jong PE: Microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med 249: , Bigazzi R, Bianchi S, Nenci R, Baldari D, Baldari G, Campese VM: Increased thickness of the carotid artery in patients with essential hypertension and microalbuminuria. J Hum Hypertens 9: , Wachtell K, Palmieri V, Olsen MH, Bella JN, Aalto T, Dahlof B, Gerdts E, Wright JT Jr, Papademetriou V, Mogensen CE, Borch-Johnsen K, Ibsen H, Devereux RB: Urine albumin/creatinine ratio and echocardiographic left ventricular structure and function in hypertensive patients with electrocardiographic left ventricular hypertrophy: The LIFE study. Losartan Intervention for Endpoint Reduction. Am Heart J 143: , Diercks GF, Hillege HL, van Boven AJ, Kors JA, Janssen WM, Grobbee DE, Crijns HJ, van Gilst WH: Relation between albumin in the urine and electrocardiographic markers of myocardial ischemia in patients without diabetes mellitus. Am J Cardiol 88: , World Health Organization: World Health Statistics Annual, 1993, Geneva, World Health Organization, Zhang XF, Attia J, D Este C, Yu XH: Prevalence and magnitude of classical risk factors for stroke in a cohort of 5092 Chinese steelworkers over 13.5 years of follow-up. Stroke 35: , Engstad T, Bonaa KH, Viitanen M: Validity of self-reported stroke: The Tromso Study. Stroke 31: , Colditz GA, Martin P, Stampfer MJ, Willett WC, Sampson L, Rosner B, Hennekens CH, Speizer FE: Validation of questionnaire information on risk factors and disease outcomes in a prospective cohort study of women. Am J Epidemiol 123: , Zuo L, Ma YC, Zhou YH, Wang M, Xu GB, Wang HY: Application of GFR-estimating equations in Chinese patients with chronic kidney disease. Am J Kidney Dis 45: , Tunstall-Pedoe H, Kuulasmaa K, Mahonen M, Tolonen H, Ruokokoski E, Amouyel P: Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA project populations. Monitoring trends and determinants in cardiovascular disease. Lancet 353: , Beaglehole R: Global cardiovascular disease prevention: Time to get serious. Lancet 358: , Critchley J, Liu J, Zhao D, Wei W, Capewell S: Explaining the increase in coronary heart disease mortality in Beijing between 1984 and Circulation 110: , 2004 Access to UpToDate on-line is available for additional clinical information at

Analytical Methods: the Kidney Early Evaluation Program (KEEP) The Kidney Early Evaluation program (KEEP) is a free, community based health

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