Adam T. Whaley-Connell, MD, James R. Sowers, MD, Joseph A. Vassalotti, MD, Moro O. Salifu, MD, MPH, Suying Li, PhD,

Prevalence and Associations of of CKD: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999-2004 1 Samy I. McFarlane, MD, MPH, Shu-Cheng Chen, MS, 2 3 Adam T. Whaley-Connell, MD, 3 4,5 1 James R. Sowers, MD, Joseph A. Vassalotti, MD, Moro O. Salifu, MD, MPH, Suying Li, PhD, 2 Changchun Wang, MS, 2 George Bakris, MD, 6 7 2 Peter A. McCullough, MD, MPH, Allan J. Collins, MD, 8,9 and Keith C. Norris, MD, on behalf of the Kidney Early Evaluation Program Investigators Background: Early identification of anemia of chronic kidney disease may be important for the development of preventive strategies. We compared anemia prevalence and characteristics in the National Kidney Foundation Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999-2004 populations. Methods: Clinical, demographic, and laboratory data were collected from August 2000 to December 31, 2006, from participants in KEEP, a community-based health-screening program targeting individuals 18 years and older with diabetes, hypertension, or family history of kidney disease, diabetes, or hypertension. was defined as hemoglobin level less than 13.5 g/dl for men and less than 12.0 g/dl for women (Kidney Disease Outcomes Quality Initiative [KDOQI] 2006) or less than 13.0 g/dl for men and less than 12.0 g/dl for women (World Health Organization [WHO]). Results: In KEEP (n 70,069), 68.3% of participants, and in NHANES (n 17,061), 52% of participants, were women. African Americans represented 33.9% of the KEEP and 11.2% of the NHANES cohorts, and Hispanics comprised 12.4% of KEEP and 13.2% of NHANES. Using the KDOQI classification, anemia was present in 13.9% and 6.3% of KEEP and NHANES participants, whereas using the WHO classification, anemia was present in 11.8% and 5.3%, respectively. In adjusted analysis of KEEP data, KDOQI-defined anemia was significantly more likely in men (odds ratio [OR], 1.30; 95% confidence interval [CI], 1.23 to 1.37); this pattern was reversed when using WHO-defined anemia (OR, 0.68; 95% CI, 0.64 to 0.72). Adjusted odds of anemia were greater for African American than white KEEP participants (OR, 2.98; 95% CI, 2.80 to 3.16; OR, 3.00; 95% CI, 2.81 to 3.20 for KDOQI- and WHO-defined anemia, respectively). Conclusion: was twice as common in the targeted KEEP chronic kidney disease screening program cohort than in the NHANES sample population. African Americans had a 3-fold increased likelihood of anemia compared with whites. Targeted screening can identify anemia in a high-risk population. Am J Kidney Dis 51(S2):S46-S55. 2008 by the National Kidney Foundation, Inc. INDEX WORDS: ; chronic kidney disease; diabetes; race; sex. hronic kidney disease (CKD) is highly C prevalent in the US population, with recent estimates indicating that up to 16.5% of 1 people aged 20 years or older have the disease. African Americans and other racial and ethnic 2,3 minority groups are at increased risk of CKD. is a common complication of CKD and is associated with increased risk of cardiovascular disease (CVD), morbidity, and mortality, par- 4,5 ticularly in high-risk populations. CVD risk in patients with CKD involves traditional and nontraditional risk factors. 4-9 Traditional risk factors From the 1 Division of Endocrinology, SUNY-Downstate and Kings County Hospital Centers, Brooklyn, NY; 2 Chronic Disease Research Group, Minneapolis Medical Research Foundation, Minneapolis, MN; 3 University of Missouri-Columbia School of Medicine, Columbia, MO; 4 National Kidney Foundation; 5 Department of Medicine, Division of Nephrology, Mount Sinai School of Medicine, New York, NY; 6 Hypertensive Diseases Unit, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Pritzker School of Medicine, Chicago, IL; 7 Department of Medicine, Divisions of Cardiology, Nutrition and Preventive Medicine, William Beaumont Hospital, Royal Oak, MI; 8 Charles R. Drew University of Medicine and Science; and 9 David Geffen School of Medicine, University of California, Los Angeles, CA. Received November 21, 2007. Accepted in revised form December 28, 2007. A list of the members of the Kidney Early Evaluation Program Investigators appears at the end of this article. Address correspondence to Samy I. McFarlane, MD, MPH, Department of Medicine, Box 50, State University of New York, Health Science Center at Brooklyn, Kings County Hospital Center, 450 Clarkson Ave, Brooklyn, NY 11203. E-mail: smcfarlane@downstate.edu 2008 by the National Kidney Foundation, Inc. 0272-6386/08/5104-0107$34.00/0 doi:10.1053/j.ajkd.2007.12.019 S46 American Journal of Kidney Diseases, Vol 51, No 4, Suppl 2 (April), 2008: pp S46-S55

in CKD Data From KEEP and NHANES Population S47 include diabetes, hypertension, obesity, dyslipidemia, smoking, and advanced age. 8 Nontraditional risk factors include hyperhomocysteinemia, hyperparathyroidism, hyperphosphatemia, endothelial dysfunction, diastolic dysfunction, and anemia, which is increasingly recognized in this patient population. 6,7,9 of CKD generally is attributed to absolute or relative erythropoietin deficiency. However, other factors, such as iron deficiency, blood loss, shortened red blood cell life span, and inflammation, may contribute to its development. 10,11 In the general population, anemia is more prevalent and severe in African Americans than whites. 12,13 Although racial and ethnic differences in anemia prevalence and severity were noted in patients with CKD, 14 the extent and characteristics of anemia in populations at risk of CKD are less well defined. Early identification of anemia, particularly in high-risk populations, could lead to effective preventive and therapeutic strategies to improve outcomes. Thus, better understanding of the characteristics of this population has potential public health benefits. We examined the prevalence and associations of anemia in participants in the Kidney Early Evaluation Program (KEEP), a large free communitybased CKD screening program, and compared them with the National Health and Nutrition Examination Survey (NHANES) 1999-2004, a representative sample of the US general population. KEEP targets high-risk populations; eligible participants are 18 years or older and have a personal or family history of diabetes or hypertension or a family history of kidney disease. Conversely, NHANES 1999-2004 surveys were targeted toward randomized cohorts that are generalizable to the US population. The objectives of this study are to: (1) assess the prevalence of anemia in the KEEP and NHANES populations by risk groups, including age, sex, race, diabetes, and CVD, by using National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) and World Health Organization (WHO) anemia definitions; (2) assess the prevalence of CKD stages in anemic patients across the different risk groups in the KEEP and NHANES cohorts; and (3) identify factors associated with significant odds of anemia in the CKD high-risk population of the KEEP program. METHODS Definitions KEEP and the NHANES database are fully described elsewhere in this supplement. 15 Disease definitions are as follows. History of diabetes is defined as self-reported diabetes or retinopathy, and history of hypertension, as selfreported hypertension. is defined as hemoglobin level less than 13.5 g/dl ( 135 g/l) for men and less than 12.0 g/dl ( 120 g/l) for women (KDOQI 2006) 10 or less than 13.0 g/dl ( 130 g/l) for men and less than 12.0 g/dl ( 120 g/l) for women (WHO). Obesity is defined as body mass index of 30 kg/m 2 or greater. History of CVD in KEEP is defined as self-reported heart attack, heart bypass surgery, heart angioplasty, stroke, heart failure, abnormal heart rhythm, or peripheral arterial disease (survey form in use before May 2005). NHANES defined history of CVD (applicable only to participants 20 years) as self-reported history of coronary heart disease, angina/angina pectoris, heart attack, congestive heart failure, or stroke. Estimated glomerular filtration rate (egfr) was determined by using the isotope-dilution mass spectrometry 4-variable Modification of Diet in Renal Disease Study equation. CKD is defined as egfr less than 60 ml/min/1.73 m 2 ( 1.0 ml/s/1.73 m 2 ) and/or albumin-creatinine ratio of 30 mg/g or greater. 16 CKD stages were defined as follows: stage 1, egfr greater than 90 ml/min/1.73 m 2 ( 1.50 ml/s/1.73 m 2 ) and/or albumin-creatinine ratio of 30 mg/g or greater; stage 2, egfr of 60 to 89 ml/min/1.73 m 2 (1.00 to 1.48 ml/s/1.73 m 2 ) and/or albumin-creatinine ratio of 30 mg/g or greater; stage 3, egfr of 30 to 59 ml/min/1.73 m 2 (0.50 to 0.98 ml/s/1.73 m 2 ); stage 4, egfr of 15 to 29 ml/min/1.73 m 2 (0.25 to 0.48 ml/s/1.73 m 2 ); and stage 5, egfr less than 15 ml/min/1.73 m 2 ( 0.25 ml/s/1.73 m 2 ). Statistical Analysis Prevalence of anemia was analyzed with risk factors by using both the KDOQI and WHO definitions. Multiple logistic regression was used to determine the independent relationships between anemia outcome and associations, including age; sex; race; screening year; education; smoking status; personal history of diabetes, hypertension, or CVD; family history of diabetes or hypertension; obesity; and CKD. P less than 0.05 is considered statistically significant. RESULTS The population screened for the KEEP program included 70,069 eligible participants. data were collected for all participants and data for key variables were collected for 51,727 (73.8%). The NHANES 1999-2004 cohort included 17,061 adult participants aged 18 years and older. Compared with NHANES, women and African Americans were overrepresented in KEEP. Of KEEP participants, 68.3% were women compared with 52% of NHANES participants (Table 1). Racial distribution in the KEEP popu-

S48 McFarlane et al Table 1. Prevalence by Risk Group: KEEP and NHANES 1999-2004 KEEP NHANES 1999-2004* (%) (%) Characteristics No. of Participants % KDOQI WHO No. of Participants % KDOQI WHO Age (y) 18-30 5,582 8.0 10.3 9.3 4,285 23.9 4.8 4.6 31-45 15,729 22.5 13.1 11.9 3,496 30.6 5.9 5.1 46-60 24,617 35.1 11.6 9.8 2,813 25.1 5.0 4.2 61-75 18,238 26.0 15.6 12.7 2,872 13.8 7.9 5.7 75 5,903 8.4 24.0 20.0 1,610 6.5 15.7 13.0 Sex Men 22,214 31.7 15.5 8.9 7,194 48.0 4.9 2.8 Women 47,855 68.3 13.2 13.2 7,882 52.0 7.6 7.6 Race/ethnicity White 32,096 46.8 9.9 8.0 7,305 71.4 4.4 3.5 African American 23,200 33.9 21.7 19.0 3,027 11.2 18.5 16.2 Other 13,223 19.3 10.6 9.1 4,744 17.5 6.8 6.1 Non-Hispanic 61,385 86.8 14.6 12.4 10,770 13.2 6.3 5.3 Hispanic 8,684 13.2 9.1 8.0 4,306 6.3 5.8 Education High school 10,679 15.5 16.7 14.1 5,144 21.6 8.6 7.5 High school 58,318 84.5 13.4 11.4 9,903 78.4 5.7 4.7 Current smoker Yes 7,952 12.1 9.8 7.8 2,940 24.9 3.6 2.9 No 58,029 88.0 14.3 12.3 10,553 75.1 7.2 6.1 Obesity status Body mass index 30,317 44.0 14.9 13.1 4,555 30.8 6.8 6.0 30 kg/m 2 Body mass index 38,579 56.0 13.2 10.9 10,111 69.2 5.8 4.8 30 kg/m 2 diabetes Yes 18,586 26.8 19.9 16.9 1,346 6.7 15.1 12.6 No 50,773 73.2 11.7 9.97 13,723 93.3 5.7 4.8 hypertension Yes 36,883 53.5 16.1 13.6 4,333 26.3 8.5 7.1 No 32,023 46.5 11.5 9.9 10,553 73.7 5.5 4.7 cardiovascular disease Yes 13,912 19.9 18.7 15.8 1,559 8.9 13.2 10.2 No 56,157 80.2 12.7 10.9 11,888 91.1 5.7 4.9 Abbreviations: KEEP, Kidney Early Evaluation Program; NHANES, National Health and Nutrition Examination Survey; WHO, World Health Organization: KDOQI, Kidney Disease Outcomes Quality Initiative. *All analyses related to smoking status or cardiovascular disease are limited to participants 20 years and older. KDOQI: hemoglobin level less than 13.5 g/dl ( 135 g/l) for men and less than 12 g/dl ( 120 g/l) for women. WHO: hemoglobin level less than 13.0 g/dl ( 130 g/l) for men and less than 12 g/dl ( 120 g/l) for women. lation was 33.9% African American, 12.4% Hispanic, and 46.8% white. The NHANES population was 11.2% African American, 13.2% Hispanic, and 71.4% white. Because KEEP is a screening program targeted toward high-risk populations, KEEP data differ from NHANES data in prevalence of CKD risk factors. Prevalences of obesity, diabetes, hypertension, and CVD were greater for KEEP than NHANES participants: obesity, 44% versus 30.8%; diabetes, 26.8% versus 6.7%; hypertension, 53.5% versus 26.3%; and CVD, 19.9% versus 8.9%. Smoking and low education level (less than high school) were more prevalent in the NHANES

in CKD Data From KEEP and NHANES Population S49 Table 2. Mean Hemoglobin Values for KEEP and NHANES 1999-2004 Participants by Sex and Racial Subgroups KEEP* (n 68,526) Hemoglobin (g/dl) NHANES 1999-2004 (n 15,076) All 13.7 1.5 14.5 0.05 Men 14.7 1.4 15.4 0.05 Women 13.2 1.4 13.6 0.05 White 14.0 1.4 14.6 0.04 African American 13.2 1.6 13.6 0.03 Other race 13.9 1.5 14.5 0.07 Hispanic 14.0 1.5 14.6 0.08 Non-Hispanic 13.7 1.5 14.5 0.05 Note: KEEP values, mean SD; NHANES values, mean SE. To convert hemoglobin in g/dl to g/l, multiply by 10. Abbreviations: KEEP, Kidney Early Evaluation Program; NHANES, National Health and Nutrition Examination Survey. *In KEEP, all P for sex, race, and ethnicity 0.001. study cohort than KEEP: smoking, 24.9% in NHANES versus 12.1% in KEEP, and low education level, 21.6% versus 15.5%. Using the KDOQI definition, the prevalence of anemia in KEEP participants was 2.2 times greater than in NHANES participants (13.9% versus 6.3%; Table 1). Greater anemia prevalence in KEEP was observed consistently across age and racial groups in both sexes and for each risk factor examined, including obesity, hypertension, diabetes, and CVD. (defined by KDOQI) was lower in current smokers compared with nonsmokers (KEEP, 9.8% versus 14.3%; NHANES, 3.6% versus 7.2%). Applying the WHO definition, results were similar, with anemia prevalence 2.2 times greater in the KEEP population than in the NHANES population (11.8% versus 5.3%). Results also were similar for smokers using the WHO anemia definition. Mean hemoglobin level was lower in KEEP (13.7 g/dl [137 g/l]) than NHANES participants (14.5 g/dl [145 g/l]; Table 2). KEEP mean hemoglobin values for patients with CKD by stage are significantly different (P 0.001), as follows: non-ckd, 13.8 g/dl (138 g/l); stage 1, 13.5 g/dl (135 g/l); stage 2, 13.7 g/dl (137 g/l); stage 3, 13.5 g/dl (135 g/l); stage 4, 12.2 g/dl (122 g/l); and stage 5, 11.3 g/dl (113 g/l). Smoking,, and CKD Using the KDOQI definition, anemia was less prevalent in current smokers in both the KEEP (8.6% for smokers, 12.6% for nonsmokers) and NHANES (14.0%, 25.3%) populations (Table 3). Results were similar using WHO anemia guidelines. The prevalence of anemia by smoking status for KEEP and NHANES is shown in Fig 1, and prevalence of anemia by CKD stages is shown in Fig 2. Sex Differences Using the KDOQI definition, anemia was more prevalent in KEEP men than women (15.5% versus 13.2%; Table 1). Conversely, using the WHO definition with a greater threshold for detection in men, the prevalence of anemia was greater in women than men (13.2% versus 8.9%). Men had greater hemoglobin values than women in both databases (KEEP, 14.7 g/dl [147 g/l] versus 13.2 g/dl [132 g/l]; NHANES, 15.4 g/dl [154 g/l] versus 13.6 g/dl [136 g/l]; Table 2). In participants with anemia, using the KDOQI definition, greater proportions of men than women had advanced CKD (KEEP, 35.1% versus 27.6%; NHANES, 28.2% versus 15.7%; Table 4). Results were similar using the WHO anemia guidelines. We used a multivariate logistic regression model that considered the odds of anemia in KEEP participants, a high-ckd-risk population. Using KDOQI guidelines, men had greater odds of anemia than women (odds ratio [OR], 1.30; 95% confidence interval [CI], 1.23 to 1.37; P 0.001; Table 5). Conversely, using the WHO anemia definition, odds were lower for men than women (OR, 0.68; 95% CI, 0.64 to 0.72; P 0.001), reflecting the greater threshold of anemia detection in men, whereas the threshold for women was the same in the KDOQI and WHO definitions. Racial/Ethnic Differences Prevalences of anemia were greatest for African Americans in both the KEEP and NHANES cohorts (Table 1). In KEEP participants, using the KDOQI definition, prevalences of anemia were 21.7% for African Americans, 9.9% for whites, and 9.1% for Hispanics. NHANES data also showed a greater prevalence of anemia in African Americans. A similar pattern of racial

S50 McFarlane et al Table 3. Characteristics Distribution by Status: KEEP and NHANES KEEP NHANES 1999-2004* KDOQI WHO KDOQI WHO No No No No No. of participants 9,747 60,322 8,288 61,781 1,480 13,596 1,260 13,816 Age (y) 18-30 5.9 8.3 6.3 8.2 17.9 23.8 20.0 23.6 31-45 21.1 22.7 22.5 22.4 28.6 30.9 29.2 30.9 46-60 29.2 36.1 29.0 36.0 20.0 25.8 20.1 25.7 61-75 29.2 25.5 28.0 25.8 17.4 13.7 15.0 13.9 75 14.5 7.4 14.2 7.7 16.1 5.8 15.7 5.9 Sex Men 35.2 31.1 23.8 32.8 37.0 48.8 25.4 49.3 Women 64.8 68.9 76.2 67.2 63.0 51.2 74.6 50.7 Race/ethnicity White 32.9 49.1 31.3 49.0 50.1 73.5 47.6 73.4 African American 52.5 30.8 53.9 31.1 31.5 9.4 32.6 9.5 Other 14.6 20.1 14.8 19.9 18.4 17.1 19.8 17.0 Non-Hispanic 91.9 86.9 91.7 87.1 86.8 86.8 85.6 86.9 Hispanic 8.1 13.1 8.3 12.9 13.2 13.2 14.4 13.1 Education High school 18.6 15.0 18.4 15.1 29.0 20.7 29.8 20.7 High school 81.4 85.0 81.6 84.9 71.0 79.3 70.2 79.3 Current smoker Yes 8.6 12.6 8.0 12.6 14.0 25.3 13.2 25.2 No 91.4 87.4 92.0 87.4 86.0 74.7 86.8 74.8 Obesity status Body mass index 47.0 43.5 48.6 43.4 34.6 30.5 35.8 30.5 30 kg/m 2 Body mass index 53.1 56.5 51.4 56.6 65.4 69.5 64.2 69.5 30 kg/m 2 diabetes Yes 38.4 24.9 38.4 25.2 16.1 6.1 16.0 6.2 No 61.6 75.1 61.6 74.8 83.9 93.9 84.0 93.8 hypertension Yes 61.8 52.2 61.5 52.5 35.8 26.0 35.3 26.1 No 38.2 47.8 38.5 47.5 64.2 74.0 64.7 73.9 cardiovascular disease Yes 26.7 18.8 26.5 19.0 18.5 8.2 16.9 8.4 No 73.3 81.3 73.5 81.0 81.5 91.8 83.1 91.6 Note: Categorical values are expressed in percent. Abbreviations: KEEP, Kidney Early Evaluation Program; NHANES, National Health and Nutrition Examination Survey; WHO, World Health Organization: KDOQI, Kidney Disease Outcomes Quality Initiative. *All analyses related to smoking status or cardiovascular disease limited to participants aged 20 years or older. KDOQI: hemoglobin level less than 13.5 g/dl ( 135 g/l) for men and less than 12 g/dl ( 120 g/l) for women. WHO: hemoglobin level less than 13.0 g/dl ( 130 g/l) for men and less than 12 g/dl ( 120 g/l) for women. distribution was observed using WHO anemia criteria. Mean hemoglobin values were lowest in African Americans compared with other racial and ethnic groups in both KEEP and NHANES databases (Table 2), whereas values for Hispanics and whites were similar. In the KEEP cohort, average hemoglobin levels were 13.2 g/dl (132 g/l) for African Americans, 14.0 g/dl (140 g/l) for Hispanics, and 14.0 g/dl (140 g/l) for whites.

in CKD Data From KEEP and NHANES Population S51 WHO K/DOQI Figure 1. Prevalence of anemia by smoking status. Abbreviations: NHANES, National Health and Nutrition Examination Survey; KEEP, Kidney Early Evaluation Program; WHO, World Health Organization: KDOQI, Kidney Disease Outcomes Quality Initiative. Prevalence of anemia (%) 16 14 12 10 8 6 4 2 0 14.3 12.3 9.8 7.8 7.2 6.1 3.6 2.9 Current smoker Nonsmoker Current smoker Nonsmoker KEEP NHANES 99-04 Similarly, in the NHANES cohort, hemoglobin levels were 13.6 g/dl (136 g/l) for African Americans, 14.6 g/dl (146 g/l) for Hispanics, and 14.6 g/dl (146 g/l) for whites. In anemic KEEP participants, using the KDOQI definition, 52.5% were African American, 32.9% were white, and 8.1% were Hispanic (Table 3). Conversely, in anemic NHANES participants, 50.1% were white, 31.5% were African American, and 13.2% were Hispanic. This reflects the overrepresentation of African Americans in KEEP compared with NHANES. Results were similar using the WHO anemia guidelines. Compared with whites, African Americans in KEEP had greater odds of anemia (OR, 2.98; 95% CI, 2.80 to 3.16; P 0.001 for KDOQI criteria; OR, 3.00; 95% CI, 2.81 to 3.20; P 0.001 for WHO criteria; Table 5). Compared with non-hispanics, Hispanic participants had lower odds of anemia (OR, 0.79; 95% CI, 0.70 to 0.88; P 0.01 for KDOQI criteria; OR, 0.80; 95% CI, 0.71 to 0.90; P 0.001 for WHO criteria). Other Factors Associated With in the KEEP Population A greater proportion of advanced CKD (stages 3 to 5) was observed in anemic patients of all racial groups and various risk factors. However, it was not observed in the youngest KEEP age group (18 to 30 years), in which the prevalence of stage 1 CKD was greater (stage 1, 9.3%; stage 2, 2.4%; and stages 3 to 5, 3.0%; Table 4). Corresponding data were not available for the NHANES population because of unreliable estimates. Compared with the age group with the highest number of participants (ages 46 to 60 years), both younger and older age categories had greater odds of anemia by using the KDOQI definition, with the greatest odds observed in the WHO K/DOQI 80 70 Prevalence of anemia (%) 60 50 40 30 20 10 0 Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 CKD stages Figure 2. Prevalence of anemia by chronic kidney disease (CKD) stage in Kidney Early Evaluation Program. Abbreviations: WHO, World Health Organization: KDOQI, Kidney Disease Outcomes Quality Initiative.

Table 4. Prevalence of Chronic Kidney Disease Stages in Anemic Patients by Characteristics: KEEP and NHANES KDOQI* WHO S52 KEEP NHANES 1999-2004 KEEP NHANES 1999-2004 Chronic Kidney Disease Stage Chronic Kidney Disease Stage Chronic Kidney Disease Stage Chronic Kidney Disease Stage Characteristic None 1 2 3-5 None 1 2 3-5 None 1 2 3-5 None 1 2 3-5 No. of participants 5,150 317 482 2,583 960 299 81 72 4,327 277 411 2,262 825 254 62 60 Age (y) 18-30 85.4 9.3 2.4 3.0 93.6 4.7 NR NR 85.1 9.7 2.4 2.8 93.3 4.9 NR NR 31-45 83.0 6.0 4.9 6.1 88.0 5.6 NR NR 82.8 6.3 4.8 6.1 87.5 5.9 NR NR 46-60 69.5 4.4 5.6 20.6 75.8 NR NR NR 68.6 4.2 5.7 21.6 74.6 NR NR NR 61-75 46.9 2.1 6.4 44.6 47.5 NR 10.2 39.1 43.9 2.0 6.7 47.4 42.7 NR 11.1 43.3 75 31.4 0.7 6.4 61.5 26.9 NR 8.4 62.9 29.1 0.7 6.1 64.0 26.2 NR 8.1 64.9 Sex Men 55.3 3.1 6.5 35.1 58.1 NR 9.4 28.2 47.9 3.1 7.1 41.9 49.4 NR 12.0 34.0 Women 63.1 4.0 5.2 27.6 77.3 4.5 2.5 15.7 63.1 4.0 5.2 27.6 77.3 4.5 2.5 15.7 Race/ethnicity White 50.7 1.5 5.7 42.1 63.0 NR 5.3 28.9 48.7 1.6 5.9 43.9 62.6 NR 5.6 29.1 African American 67.4 4.9 5.6 22.1 75.7 6.6 5.8 11.9 66.6 4.9 5.6 22.9 75.5 6.9 4.8 12.8 Others 58.8 4.6 5.8 30.8 80.4 NR NR 11.4 58.1 4.8 5.3 31.8 80.1 NR NR NR Non-Hispanic 60.1 3.7 5.6 30.7 68.6 4.1 5.4 21.9 59.1 3.8 5.6 31.6 68.6 4.1 5.3 22.1 Hispanic 64.2 4.3 6.5 25.0 80.2 NR NR NR 64.4 4.3 6.2 25.1 80.2 NR NR NR Education High school 48.5 4.1 7.5 40.0 61.7 5.4 6.5 26.5 46.7 4.0 7.8 41.5 61.6 4.7 6.4 27.3 High school 63.1 3.63 5.2 28.1 73.5 4.1 4.5 17.9 62.3 3.7 5.2 28.8 73.8 4.5 4.3 17.4 Current smoker Yes 66.5 5.2 4.4 24.0 71.4 7.1 NR 14.6 65.7 5.5 4.9 23.9 71.2 NR NR 14.2 No 59.94 3.5 5.8 30.8 69.0 4.0 5.0 22.1 59.0 3.6 5.7 31.7 69.0 4.1 4.8 22.1 Obesity status Body mass index 30 kg/m 2 61.2 4.2 5.5 29.2 71.2 3.5 6.3 19 60.4 4.4 5.5 29.7 71.6 3.4 5.9 19.1 Body mass index 30 kg.m 2 59.6 3.22 5.8 31.3 72.1 4.9 4.5 18.5 58.5 3.2 5.8 32.5 72.4 5.1 4.6 18.0 diabetes Yes 47.3 3.7 7.4 41.6 37.4 NR 13.8 44.5 45.4 3.6 7.1 43.9 36.1 NR 14.1 47.4 No 69.1 3.8 4.4 22.7 76.0 4.4 3.5 16.1 69.0 3.9 4.6 22.5 76.1 4.9 3.3 15.7 hypertension Yes 49.7 3.4 6.4 40.5 47.3 3.1 7.4 42.2 48.0 3.39 6.5 42.2 47.0 2.6 7.7 42.7 No 78.5 4.3 4.4 12.8 82.0 5.2 3.9 8.9 78.6 4.5 4.4 12.5 81.9 5.6 3.5 9.1 cardiovascular disease Yes 46.2 3.2 7.3 43.3 35.3 NR NR 55.5 44.8 3.1 7.3 44.8 30.0 NR NR 61.7 No 65.8 3.9 5.0 25.3 76.6 4.9 4.8 13.7 65.1 4.1 5.0 25.9 76.6 5.2 4.7 13.5 Abbreviations: KEEP, Kidney Early Evaluation Program; NHANES, National Health and Nutrition Examination Survey; WHO, World Health Organization: KDOQI, Kidney Disease Outcomes Quality Initiative; NR, estimates not reliable. *KDOQI: hemoglobin level less than 13.5 g/dl ( 135 g/l) for men and less than 12 g/dl ( 120 g/l) for women. WHO: hemoglobin level less than 13.0 g/dl ( 130 g/l) for men and less than 12 g/dl ( 120 g/l) for women. McFarlane et al

in CKD Data From KEEP and NHANES Population S53 Table 5. Odds of From Multivariable Logistic Regressions: KEEP KDOQI* WHO Odds Ratio (95% confidence interval) P Odds Ratio (95% confidence interval) P Age (y) 18-30 1.17 (1.04-1.31) 0.01 1.27 (1.12-1.43) 0.001 31-45 1.35 (1.25-1.45) 0.001 1.48 (1.36-1.60) 0.001 46-60 1 1 61-75 1.23 (1.14-1.32) 0.001 1.17 (1.08-1.26) 0.001 75 2.20 (2.001-2.42) 0.001 2.06 (1.86-2.28) 0.001 Sex Women 1 1 Men 1.30 (1.23-1.37) 0.001 0.68 (0.64-0.72) 0.001 Race/ethnicity White 1 1 African American 2.98 (2.80-3.16) 0.001 3.00 (2.81-3.20) 0.001 Other 1.39 (1.27-1.52) 0.001 1.42 (1.29-1.57) 0.001 Non-Hispanic 1 1 Hispanic 0.79 (0.70-0.88) 0.001 0.80 (0.71-0.90) 0.001 Current smoker 0.63 (0.58-0.70) 0.001 0.62 (0.56-0.69) 0.001 Education high school 0.87 (0.81-0.94) 0.001 0.87 (0.80-0.94) 0.001 diabetes 1.73 (1.63-1.83) 0.001 1.76 (1.66-1.88) 0.001 hypertension 1.07 (1.01-1.14) 0.03 1.07 (1.00-1.14) 0.06 cardiovascular disease 1.29 (1.22-1.38) 0.001 1.29 (1.21-1.38) 0.001 Family history of diabetes 1.02 (1.00-1.08) 0.6 1.02 (0.96-1.09) 0.5 Family history of hypertension 0.95 (0.89-1.01) 0.09 0.97 (0.90-1.04) 0.4 Body mass index 30 kg/m 2 0.99 (0.94-1.04) 0.7 1.00 (0.96-1.06) 0.9 Chronic kidney disease 1.73 (1.63-1.84) 0.001 1.85 (1.74-1.97) 0.001 Cohort year 2000-2001 1 1 2002 1.14 (0.93-1.41) 0.2 1.15 (0.93-1.43) 0.2 2003 0.95 (0.77-1.16) 0.6 0.96 (0.77-1.19) 0.7 2004 1.14 (0.94-1.39) 0.02 1.15 (0.93-1.41) 0.2 2005 1.02 (0.83-1.24) 0.9 1.03 (0.83-1.26) 0.8 2006 1.10 (0.90-1.33) 0.4 1.12 (0.91-1.37) 0.3 Note: n 51,727. All listed variables are in the multivariable logistic regression. For example, analysis of cohort year is adjusted for other variables in the table. Abbreviations: KEEP, Kidney Early Evaluation Program; NHANES, National Health and Nutrition Examination Survey; WHO, World Health Organization: KDOQI, Kidney Disease Outcomes Quality Initiative. *KDOQI: hemoglobin level less than 13.5 g/dl ( 135 g/l) for men and less than 12 g/dl ( 120 g/l) for women. WHO: hemoglobin level less than 13.0 g/dl ( 130 g/l) for men and less than 12 g/dl ( 120 g/l) for women. oldest age group (age 75 years; OR, 2.20; 95% CI, 2.00 to 2.42; P 0.01; Table 5). Results were similar using WHO criteria. Other risk factors that significantly increased the odds of anemia included lower educational level, diabetes mellitus, hypertension, CVD, and CKD, with risk greatest for patients with diabetes and CKD (OR, 1.73; 95% CI, 1.63 to 1.83; P 0.001 for patients with diabetes; OR, 1.73; 95% CI, 1.63 to 1.84; P 0.001 for patients with CKD) using KDOQI guidelines. Results were similar using the WHO anemia definition (Table 5). DISCUSSION Our study highlights several major differences between a targeted community-based screening program (KEEP) and a generalizable population health survey (NHANES 1999-2004). Greater percentages of KEEP participants were at risk of CKD and anemia, including African Americans, who were 3 times more prevalent in KEEP than NHANES. Risk factors for CKD and CVD 5,9,14 also were better represented in KEEP populations than in NHANES. For example, obesity was 1.4 times; hypertension was 2 times; and

S54 diabetes was 4 times more prevalent in KEEP than NHANES. Not surprisingly, the KEEP population had a greater rate of CKD, with an associated much greater prevalence of anemia; this value was 2.2 times greater than in the NHANES sample population. The greater prevalence of anemia observed in the KEEP cohort was consistent across sex, racial and ethnic groups, and CVD risk categories, except for smoking. The high prevalence of diabetes observed in the KEEP cohort, 26.8% compared with 6.7% in the NHANES sample population, likely is a major contributor to the greater prevalence of anemia in KEEP participants through its effect on risk of CKD and other mechanisms. 4 is common in patients with diabetes and often goes unrecognized and untreated. 17-19 Although egfr and iron stores are the strongest predictors of hemoglobin levels in patients with diabetes, these factors do not fully account for the increased prevalence of anemia in the diabetic population. 4,19 Other factors, such as absolute and/or relative erythropoietin deficiency, inflammation, and oxidative stress, may explain the development of anemia in patients with diabetes and CKD. Furthermore, accumulating evidence indicates that in patients with early diabetic nephropathy, anemia is a common finding and associated with erythropoietin deficiency. 4,17 Although men had greater hemoglobin values than women, they also had greater rates of more advanced CKD. The KDOQI definition with a lower threshold for anemia detection in men (13.5 g/dl [135 g/l]) thus was more reflective of the severity of CKD observed in men, resulting in a 30% greater risk of anemia in men than women. This is in contrast to the WHO anemia definition, with a lower hemoglobin cutoff value for men (13.0 g/dl [130 g/l]) or a greater threshold for diagnosing anemia in men, which reversed the odds of anemia between sexes; women had a 32% greater risk of anemia than men using WHO criteria. The greater prevalence of anemia in participants older than 60 years compared with those aged 46 to 60 years likely is a reflection of a greater rate of CKD in older participants and lower egfrs with aging. 20 Conversely, the greater risk of anemia in younger KEEP participants may represent mechanisms of anemia other than CKD, given the lower prevalence and less severe CKD in younger participants. It also could reflect higher representation of women and African Americans, groups with a greater risk of anemia independent of CKD. 12,13 The lower prevalence of anemia in current smokers in both the KEEP and NHANES populations is consistent with previous data indicating greater hemoglobin levels in smokers caused by secondary erythrocytosis. 21 Cigarette smoking appears to cause a generalized upward shift of the hemoglobin distribution curve, thus decreasing the utility of hemoglobin levels to detect anemia in smokers. 22 Treatment of anemia is by identification of underlying cause, which, in patients with CKD, may be either functional or actual iron deficiency with or without erythropoietic hormone resistance or deficiency. 23 KEEP data include insufficient specific medication data to address anemia treatment in this study. Findings from our study have potentially significant public health implications. Early recognition of anemia through a targeted screening program for populations at high risk of CKD may become important for the development of preventive and therapeutic strategies. Decreased working capacity, cognitive impairment, angina, and cardiorenal anemia syndrome, a triad of worsening anemia, worsening CKD, and worsening congestive heart failure, are potential consequences of anemia of CKD. 24 ACKNOWLEDGEMENTS McFarlane et al In addition to the authors listed, the Kidney Early Evaluation Program (KEEP) Investigators are Dennis Andress, MD, David Calhoun, MD, Bruce Johnson, MD, Claudine T. Jurkovitz, MD, MPH, Chamberlain I. Obialo, MD, Lesley A. Stevens, MD, and Michael G. Shlipak, MD. The authors thank Shane Nygaard, BA, and Nan Booth, MSW, MPH of the Chronic Disease Research Group for manuscript preparation and manuscript editing, respectively. Support: KEEP is a program of the National Kidney Foundation Inc and is supported by Amgen, Abbott, Genzyme, Ortho Biotech Products LP, and Novartis, with additional support provided by Siemens Medical Solutions Diagnostics, Lifescan, Suplena, and OceanSpray Cranberries. Financial Disclosure: Dr Vassalotti reports having received grant support from the Centers for Disease Control and Prevention, but has no conflicts of interest with the subject of this article. Dr Collins has received research support from Amgen. The other authors have no conflicts of interest with the subject matter of this manuscript.

in CKD Data From KEEP and NHANES Population S55 REFERENCES 1. Coresh J, Selvin E, Stevens LA, et al: Prevalence of chronic kidney disease in the United States. JAMA 298:2038-2047, 2007 2. Shoham DA, Vupputuri S, Diez Roux AV, et al: Kidney disease in life-course socioeconomic context: The Atherosclerosis Risk in Communities (ARIC) Study. Am J Kidney Dis 49:217-226, 2007 3. Tarver-Carr ME, Powe NR, Eberhardt MS, et al: Excess risk of chronic kidney disease among African-American versus white subjects in the United States: A populationbased study of potential explanatory factors. J Am Soc Nephrol 13:2363-2370, 2002 4. McFarlane SI, Salifu MO, Makaryus J, Sowers JR: and cardiovascular disease in diabetic nephropathy. Curr Diabetes Rep 6:213-218, 2006 5. McCullough PA, Lepor NE: The deadly triangle of anemia, renal insufficiency, and cardiovascular disease: Implications for prognosis and treatment. Rev Cardiovasc Med 6:1-10, 2005 6. Vlagopoulos PT, Sarnak MJ: Traditional and nontraditional cardiovascular risk factors in chronic kidney disease. Med Clin North Am 89:587-611, 2005 7. Levin A, Stevens L, McCullough PA: Cardiovascular disease and the kidney. Tracking a killer in chronic kidney disease. Postgrad Med 111:53-60, 2002 8. Uhlig K, Levey AS, Sarnak MJ: Traditional cardiac risk factors in individuals with chronic kidney disease. Semin Dial 16:118-127, 2003 9. El Atat FA, Stas SN, McFarlane SI, Sowers JR: The relationship between hyperinsulinemia, hypertension and progressive renal disease. J Am Soc Nephrol 15:2816-2827, 2004 10. National Kidney Foundation: KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for in Chronic Kidney Disease. Am J Kidney Dis 47:S11-S145, 2006 (suppl 3) 11. Nurko S: in chronic kidney disease: Causes, diagnosis, treatment. Cleve Clin J Med 73:289-297, 2006 12. Johnson-Spear MA, Yip R: Hemoglobin difference between black and white women with comparable iron status: Justification for race-specific anemia criteria. Am J Clin Nutr 60:117-121, 1994 13. Yip R, Schwartz S, Deinard AS: Hematocrit values in white, black, and American Indian children with comparable iron status. Evidence to support uniform diagnostic criteria for anemia among all races. Am J Dis Child 138:824-827, 1984 14. El Achkar TM, Ohmit SE, McCullough PA, et al: Higher prevalence of anemia with diabetes mellitus in moderate kidney insufficiency: The Kidney Early Evaluation Program. Kidney Int 67:1483-1488, 2005 15. Jurkovitz CT, Qiu Y, Wang C, Gilbertson DT, Brown WW: The Kidney Early Evaluation Program (KEEP): Program design and demographic characteristics of the population. Am J Kidney Dis 51:S3-S12, 2008 (suppl 2) 16. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: A more 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 130:461-470, 1999 17. Bosman DR, Winkler AS, Marsden JT, Macdougall IC, Watkins PJ: with erythropoietin deficiency occurs early in diabetic nephropathy. Diabetes Care 24:495-499, 2001 18. Weiner DE, Tighiouart H, Vlagopoulos PT, et al: Effects of anemia and left ventricular hypertrophy on cardiovascular disease in patients with chronic kidney disease. J Am Soc Nephrol 16:1803-1810, 2005 19. Stevens PE, O Donoghue DJ, Lameire NR: Anaemia in patients with diabetes: Unrecognised, undetected and untreated? Curr Med Res Opin 19:395-401, 2003 20. Thomas MC, MacIsaac RJ, Tsalamandris C, Power D, Jerums G: Unrecognized anemia in patients with diabetes: A cross-sectional survey. Diabetes Care 26:1164-1169, 2003 21. Teillet L, Preisser L, Verbavatz JM, Corman B: [Kidney aging: Cellular mechanisms of problems of hydration equilibrium]. Therapie 54:147-154, 1999 22. Nordenberg D, Yip R, Binkin NJ: The effect of cigarette smoking on hemoglobin levels and anemia screening. JAMA 264:1556-1559, 1990 23. National Kidney Foundation: KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for in Chronic Kidney Disease: 2007 Update of Hemoglobin Target. Am J Kidney Dis 50:471-530, 2007 24. Dowling TC: Prevalence, etiology, and consequences of anemia and clinical and economic benefits of anemia correction in patients with chronic kidney disease: An overview. Am J Health Syst Pharm 64:S3-S7, 2007 (suppl 8)