Kidney function is inversely associated with coronary artery calcification in men and women free of cardiovascular disease: TheFramingham Heart Study

Transcription

1 Kidney International, Vol. 66 (2004), pp Kidney function is inversely associated with coronary artery calcification in men and women free of cardiovascular disease: TheFramingham Heart Study CAROLINE S. FOX, MARTIN G. LARSON, MICHELLE J. KEYES, DANIEL LEVY, MELVIN E. CLOUSE, BRUCE CULLETON, and CHRISTOPHER J. O DONNELL NHLBI s Framingham Heart Study, Framingham, Massachusetts; Department of Endocrinology, Diabetes, and Hypertension, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts; Departments of Neurology, and Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, Massachusetts; Department of Mathematics, Boston University, Boston, Massachusetts; Department of Radiology, Beth Israel-Deaconess Hospital, Boston, Massachusetts; University of Calgary Foothills Hospital, Calgary, Alberta; Division of Cardiology, Department of Medicine, Massachussetts General Hospital, Boston, Massachusetts; and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Kidney function is inversely associated with coronary artery calcification in men and women free of cardiovascular disease: The Framingham Heart Study. Background. Among patients with end-stage renal disease (ESRD), the risk of cardiovascular disease is 10 to 20 times higher than the general population. Adults with ESRD have increased coronary-artery calcification (CAC) detected by electron-beam computed tomography (EBCT). Because the risk of coronary heart disease is increased even at moderate declines in kidney function, we sought to test whether high CAC scores are seen among those with mild reductions in kidney function. Methods. Men and women free of symptomatic cardiovascular disease underwent EBCT. Coronary calcium was quantified using the method described by Agatston. Renal function was estimated by glomerular filtration rate (GFR). Spearman correlation coefficients were used to test the association between GFR and CAC. Results. Three hundred nineteen subjects (162 men/157 women), mean age 60, were included. Mean GFR was 86 ± 23 ml/min/1.73 m 2 (range ; 10% with GFR <60 ml/min/ 1.73m 2 ). The median CAC scores by quartile of GFR were 85.9, 48.1, 7.9, and 2.7. Overall, the unadjusted correlation of GFR and CAC was 0.28 (P < ). This remained significant after adjustment for age and sex ( 0.11, P < 0.05), and additionally after adjustment for body mass index ( 0.11, P < 0.05), hypertension ( 0.11, P < 0.05), or total cholesterol ( 0.12, P = 0.04). A similar correlation was noted after multivariable adjustment ( 0.10, P < 0.08). This work was supported by the National Heart, Lung and Blood Institute s Framingham Heart Study (N01-HC-25195). Keywords: coronary calcification, kidney disease, risk factor. Received for publication March 31, 2004 and in revised form May 21, 2004 Accepted for publication June 2, 2004 C 2004 by the International Society of Nephrology Conclusion. Mild declines in kidney function are associated with subclinical coronary artery calcification in a sample of subjects free of clinically apparent cardiovascular disease. This might help explain the increased risk of cardiovascular disease among individuals with renal dysfunction. Larger ongoing studies are needed to better quantify this finding. Kidney disease increases the risk of coronary mortality [1] and all-cause mortality [2]. Among patients with end-stage renal disease (ESRD), the risk of cardiovascular disease is 10 to 20 times higher than in the general population [3], and cardiovascular disease accounts for 50% of all deaths in this population [4]. However, this increased risk occurs even at moderate reductions in kidney function, independently of cardiovascular risk factors [5, 6]. The mechanism of this increased risk of cardiovascular disease in individuals with kidney disease is not known. Coronary artery calcification (CAC), detected by electron-beam computed tomography (EBCT), is a sensitive marker for coronary artery disease [7]. There are significantly increased quantities of CAC in young adults with ESRD compared with healthy age-matched control patients [8 10]. Given the association between accelerated CAC in ESRD patients, one can hypothesize that an increased risk for CAC might be seen in subjects with mild to moderate kidney dysfunction. The documentation of increased CAC among individuals with moderate kidney disease might partially explain the elevated risk of coronary heart disease in those with kidney disease. Thus, we hypothesized that declining glomerular filtration rate (GFR), a measure of kidney function, is inversely associated with CAC as measured by EBCT in the Framingham Heart Study. 2017

2 2018 Foxetal: Kidney function and coronary artery calcification METHODS The Framingham Heart Study began in 1948 with the enrollment of 5209 men and women, 28 to 62 years of age, with subjects undergoing examinations every 2 years [11, 12]. In 1971, 5124 men and women were enrolled into the Framingham Offspring Study, which included the children or spouses of the children of the original cohort. Offspring subjects underwent examinations approximately every 4 years; the design and methodology have been previously described [13, 14]. The current investigation is composed of 327 subjects from the Framingham Offspring Study who attended the sixth examination cycle and participated in a pilot study of EBCT imaging. Subjects were selected as previously described [15]. Of the first 3219 subjects attending the sixth examination cycle (1995 to 1998), 349 subjects with clinical cardiovascular disease, 357 who did not reside in New England, and 7 who were not between 35 and 84 years of age, were excluded from sampling. The remaining 2506 subjects were stratified by sex, age quartile, and Framingham coronary heart disease (CHD) risk score quintile. Subjects were randomly sampled from each stratum, and invited to undergo EBCT. Thirteen percent declined participation; refusals were handled by randomly selecting another person from that stratum. A total of 327 subjects underwent EBCT, 319 of which had serum creatinine assessment. Covariate data were obtained during the seventh cycle of the Framingham Heart Study ( ). Details regarding the methods of risk factor measurement and laboratory analysis have been described [16]. Each examination included a cardiovascular disease assessment and blood testing. Subjects with fasting glucose level 126 mg/dl (7.00 mmol/l), and/or receiving oral hypoglycemic or insulin treatment for diabetes were defined as diabetic. Subjects with a systolic blood pressure 140 mm Hg or diastolic blood pressure 90 mm Hg (average of 2 readings taken by the examining physician), or receiving medication for treatment of hypertension were defined as hypertensive. Fasting lipid measures included total and high-density lipoprotein (HDL) cholesterol. Smoking status was defined as smoking 1 or more cigarettes/day in the year preceding the examination. Body mass index was defined as weight (kg) divided by the square of height (m). GFR and EBCT determination GFR was estimated using the simplified Modification of Diet in Renal Disease (MDRD) Study equation [17, 18], defined as GFR = (serum creatinine) age (0.742 for women). Serum creatinine was Table 1. Baseline characteristics (N = 319) Age years 60 ± 9 %Male 51 Body mass index kg/m ± 5.4 Total cholesterol mg/dl 202 ± 37 HDL cholesterol mg/dl 51 ± 17 Glomerular filtration rate ml/min/1.73m 2 86 ± 23 Current smoking % 11 Hypertension % 45 Diabetes % 17 Values are expressed as mean ± SD unless otherwise indicated. measured using the modified Jaffe method. Because the measure of creatinine can vary across different laboratories, creatinine was calibrated using a 2-step process. First, NHANES III creatinine values were calibrated to the Cleveland Clinic Laboratory, requiring a correction factor of 0.23 mg/dl [19]. Then, mean creatinine values from Framingham, by sex-specific age groups (20 39, 40 59, 60 69, 70+), were aligned with the corresponding corrected NHANES III age-and sex-specific means. EBCT scans were conducted between 1998 and 1999 (Imatron C-150 XP scanner, GE Medical Systems, Waukesha, WI, USA) following previously published protocols [20, 21]. Scans were read preliminarily by a technologist and over-read by a radiologist (M.E.C.), blinded to clinical data. CAC scores were calculated using the method described by Agatston [20]. Reproducibility was assessed by rereading 20 scans (r = 0.97 for replicate readings), and image noise was determined by the SD of pixel numbers in a region of interest within the aorta. Statistical methods We calculated Spearman correlations for GFR and CAC, including unadjusted correlations, adjusted for age and sex, and adjusted for age, sex, plus 1 additional risk factor. Finally, we adjusted for age, sex, BMI, current tobacco use, diabetes, hypertension, total cholesterol, and HDL cholesterol. Covariate data were obtained from the seventh examination cycle. The SAS CORR procedure was used to perform correlation analyses [22]. A twosided P value of < 0.05 was considered statistically significant. For descriptive purposes, we graphed median and interquartile range of CAC by quartile of GFR. RESULTS EBCT imaging was performed on 327 participants, 319 of whom had creatinine measured. Baseline characteristics are shown in Table 1. GFR ranged from 31 to

3 Foxetal: Kidney function and coronary artery calcification 2019 Coronary artery calcium score Glomerular filtration rate Fig. 1. CAC scores by GFR quartile. Medians (solid lines) and interquartile ranges (boxes) are presented. Table 2. Correlation between GFR and CAC score Unadjusted Adjusted for age and sex Adjusted for age, sex, and risk factors BMI Current smoker Diabetes Hypertension Total cholesterol HDL cholesterol Adjusted for age, sex, and risk factors a P value b P c P (N = 319) 0.28 a 0.11 c 0.12 b 169 ml/min/1.73 m 2 ; 10% of participants had a GFR <60 ml/min/1.73 m 2. Higher median CAC scores were seen among lower quartiles of GFR (Fig. 1). Ranges for GFR quartiles among men were 39 to 72, 73 to 84, 84.4 to 96, and 96.1 to 169 ml/min/1.73 m 2, and among women were 31 to 70.1, 70.3 to 79, 80 to 98, and 99 to 166 ml/min/1.73 m 2.The median CAC scores by quartile of GFR were 85.9, 48.1, 7.9, and 2.7. Overall, the unadjusted correlation of GFR and CAC was 0.28 (P < 0.001) (Table 2). This remained significant after adjustment for age and sex ( 0.11, P < 0.05). After further adjustment for individual risk factors, the correlations were attenuated, but still significant after adjustment for body mass index ( 0.11, P < 0.05), hypertension ( 0.11, P < 0.05), or total cholesterol ( 0.12, P = 0.04). A similar correlation was noted after multivariable adjustment ( 0.10, P < 0.08). DISCUSSION We have shown that in this cohort of men and women free of clinically overt cardiovascular disease, GFR is inversely associated with CAC. This relation remained true after adjustment for age and sex, but was attenuated after multivariable adjustment, suggesting that the association is at least partially a reflection of the importance of cardiovascular disease risk factors both in the development of CAC and kidney disease. This is the first study to demonstrate an inverse relation between kidney function and coronary calcification among individuals unselected for kidney disease. Similar studies conducted in dialysis patients demonstrated greater amounts of CAC than healthy age-matched controls [8 10]. The extent of coronary calcification has been shown to be associated with calcium [10], phosphorous [10], serum calcium-phosphorous product [8, 9], serum alkaline phosphatase [8], serum parathyroid hormone [9], and duration of ESRD and dialysis [9], suggesting that metabolic derangements evident in ESRD may be responsible for the observed increased coronary artery calcification. Further investigation is necessary to determine whether these metabolic factors could explain the inverse association seen in our study sample of participants with mild to moderate kidney disease. Limitations Our sample only contained 319 subjects. Although well represented across strata of age, sex, and cardiovascular risk, larger samples are necessary to fully elucidate the relation between GFR and CAC. In addition, the CAC quantification was conducted 2 to 4 years prior to measuring GFR, and the association between GFR and CAC may have been altered by progressive changes in kidney function. Kidney disease was defined by a single creatinine measure. It is not possible to determine whether subjects who fulfilled outcome criteria did so for at least a 3-month period. However, misclassification of subjects would be likely bias our results toward the null. GFR was estimated by using the simplified MDRD equation. The MDRD equation has been validated in subjects with GFR <90 ml/min/1.73 m 2 ; values outside of this range are extrapolated [23]. However, we were able to increase the accuracy of the MDRD equation by performing an indirect calibration to the laboratory that developed the equation. Our study sample is not nationally representative, nor is it ethnically diverse. However, the relations of risk factors to coronary heart disease outcomes observed in Framingham have recently been validated in 6 ethnically and geographically diverse cohorts, and they were found to be applicable in other populations [24]. Lastly, our data are consistent with a link between mildly reduced kidney function and coronary artery atherosclerosis, but it is uncertain whether CAC scores among subjects with mild kidney disease reflect intimal or medial calcification, or a combination of both. There is substantial evidence for an association of CAC with

4 2020 Foxetal: Kidney function and coronary artery calcification luminally obstructive coronary artery disease [25], and with histologic evidence of calcification in atherosclerotic plaques, rather than medial calcification [26]. However, medial calcification is common among ESRD patients [27], and may be a major etiologic factor in arterial stiffness, leading to worsening left ventricular hypertrophy [28, 29]. Among patients with diabetes, medial calcification has shown to be associated with increased risk for cardiovascular events [30]. While medial calcification may be common in ESRD patients, intimal calcification likely accompanies this process. An autopsy study of ESRD patients demonstrated a high prevalence of calcified intimal plaques [31], and a report looking at coronary calcification in 205 hemodialysis patients revealed a direct association between prevalence cardiovascular disease and CAC score [10]. Further research is necessary to determine the pathologic basis of coronary calcification among individuals with moderate kidney disease, and whether different types of calcification are associated with differential cardiovascular risk. Clinical implications Although it has been shown that kidney disease increases the risk of cardiovascular events [1, 5, 6], the mechanism of this increased risk is not known. While it has been suggested that the increased risk may be the result of shared cardiovascular disease risk factors [32], kidney disease is a strong and independent risk factor for the development of CVD [1, 5, 6]. Further research is necessary to determine whether metabolic derangements seen in ESRD can account for the inverse relation between increased coronary artery calcification and moderately reduced kidney function. Increased coronary artery calcification among those with moderately reduced kidney function may help explain the increased risk of cardiovascular disease in this population. ACKNOWLEDGMENT This data was presented in abstract form at the American Heart Association meeting, November, Reprint requests to Caroline S. Fox, M.D., MPH, 73 Mt. Wayte Ave Suite #2, Framingham, MA foxca@nhlbi.nih.gov REFERENCES 1. MANN JF, GERSTEIN HC, POGUE J, et al: Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: The HOPE randomized trial. Ann Intern Med 134: , CULLETON BF, LARSON MG, WILSON PW, et al: Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. Kidney Int 56: , FOLEY RN, PARFREY PS, SARNAK MJ: Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 32:S112 S119, U.S. RENAL DATA SYSTEM: USRDS 2002 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, MANJUNATH G, TIGHIOUART H, IBRAHIM H, et al: Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. JAmColl Cardiol 41:47 55, MANJUNATH G, TIGHIOUART H, CORESH J, et al: Level of kidney function as a risk factor for cardiovascular outcomes in the elderly. Kidney Int 63: , ARAD Y, SPADARO LA, GOODMAN K, et al: Prediction of coronary events with electron beam computed tomography. J Am Coll Cardiol 36: , GOODMAN WG, GOLDIN J, KUIZON BD, et al: Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 342: , OH J, WUNSCH R, TURZER M, et al: Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure. Circulation 106: , RAGGI P, BOULAY A, CHASAN-TABER S, et al: Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease? J Am Coll Cardiol 39: , DAWBER TR, MEADORS GF, MOORE FE: Epidemiologic approaches to heart disease: The Framingham study. Am J Public Health 41: , DAWBER TR, KANNEL WB, LYELL LP: An approach to longitudinal studies in a community: The Framingham Heart Study. Ann NY Acad Sci 107: , FEINLEIB M, KANNEL WB, GARRISON RJ, et al:the Framingham Offspring Study. Design and preliminary data. Prev Med 4: , KANNEL WB, FEINLEIB M, McNamara PM, et al:an investigation of coronary heart disease in families. The Framingham offspring study. Am J Epidemiol 110: , WANG TJ, LARSON MG, LEVY D, et al: C-reactive protein is associated with subclinical epicardial coronary calcification in men and women: The Framingham Heart Study. Circulation 106: , CUPPLES LA, D AGOSTINO RB: Some risk factors related to the annual incidence of cardiovascular disease and death using pooled repeated biennial measurements: Framingham Study, 30-year follow-up, in The Framingham Heart Study: An Epidemiological Investigation of Cardiovascular Disease, edited by Kannel WB, Polf PA, Garrison RJ, Washington, DC, Government Printing Office. NIH publication , section 34, LEVEY AS, BOSCH JP, LEWIS JB, et al: Amore accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130: , K/DOQI: Clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis 39:S1 246, CORESH J, ASTOR BC, MCQUILLAN G,et al: Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am J Kidney Dis 39: , AGATSTON AS, JANOWITZ WR, HILDNER FJ, et al: Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 15: , ACHENBACH S, ROPERS D, MOHLENKAMP S, et al: Variability of repeated coronary artery calcium measurements by electron beam tomography. Am J Cardiol 87: , A8, SAS INSTITUTE, INC.: SAS/STAT User s Guide, version 8, Cary, NC, SAS Institute, Inc., CORESH J, ASTOR BC, GREENE T, et al: Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 41:1 12, D AGOSTINO RB, SR., GRUNDY S, SULLIVAN LM, et al: Validation of the Framingham coronary heart disease prediction scores: Results of a multiple ethnic groups investigation. JAMA 286: , 2001

5 Foxetal: Kidney function and coronary artery calcification BIELAK LF, RUMBERGER JA, SHEEDY PF, et al: Probabilistic model for prediction of angiographically defined obstructive coronary artery disease using electron beam computed tomography calcium score strata. Circulation 102: , KAJINAMI K, SEKI H, TAKEKOSHI N, et al: Coronary calcification and coronary atherosclerosis: Site by site comparative morphologic study of electron beam computed tomography and coronary angiography. JAmColl Cardiol 29: , TOMSON C: Vascular calcification in chronic renal failure. Nephron Clin Pract 93:c124 c130, NIEDERHOFFER N, LARTAUD-IDJOUADIENE I, GIUMMELLY P, et al: Calcification of medial elastic fibers and aortic elasticity. Hypertension 29: , GUERIN AP, LONDON GM, MARCHAIS SJ, et al: Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 15: , EVERHART JE, PETTITT DJ, KNOWLER WC, et al:medial arterial calcification and its association with mortality and complications of diabetes. Diabetologia 31:16 23, SCHWARZ U, BUZELLO M, RITZ E, et al: Morphology of coronary atherosclerotic lesions in patients with end-stage renal failure. Nephrol Dial Transplant 15: , MUNTNER P, CORESH J, KLAG MJ, et al: History of myocardial infarction and stroke among incident end-stage renal disease cases and population-based controls: An analysis of shared risk factors. Am J Kidney Dis 40: , 2002