Prevalence and Associations of Anemia of CKD: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999-2004

Article Outline

• Abstract
• Methods
  • Definitions
  • Statistical Analysis
• Results
  • Smoking, Anemia, and CKD
  • Sex Differences
  • Racial/Ethnic Differences
  • Other Factors Associated With Anemia in the KEEP Population
• Discussion
• Acknowledgements
• References
• Copyright

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. Anemia 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

Anemia 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.

Index Words: Anemia, chronic kidney disease, diabetes, race, sex

Chronic kidney disease (CKD) is highly prevalent in the US population, with recent estimates indicating that up to 16.5% of people aged 20 years or older have the disease.¹ African Americans and other racial and ethnic minority groups are at increased risk of CKD.², ³ Anemia is a common complication of CKD and is associated with increased risk of cardiovascular disease (CVD), morbidity, and mortality, particularly in high-risk populations.⁴, ⁵ CVD risk in patients with CKD involves traditional and nontraditional risk factors.⁴, ⁵, ⁶, ⁷, ⁸, ⁹ Traditional risk factors 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 Anemia 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 community-based 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.

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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 self-reported hypertension. Anemia 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/m² 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 m² (<1.0 mL/s/1.73 m²) 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 m² (>1.50 mL/s/1.73 m²) and/or albumin-creatinine ratio of 30 mg/g or greater; stage 2, eGFR of 60 to 89 mL/min/1.73 m² (1.00 to 1.48 mL/s/1.73 m²) and/or albumin-creatinine ratio of 30 mg/g or greater; stage 3, eGFR of 30 to 59 mL/min/1.73 m² (0.50 to 0.98 mL/s/1.73 m²); stage 4, eGFR of 15 to 29 mL/min/1.73 m² (0.25 to 0.48 mL/s/1.73 m²); and stage 5, eGFR less than 15 mL/min/1.73 m² (<0.25 mL/s/1.73 m²).

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.

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Results 

The population screened for the KEEP program included 70,069 eligible participants. Anemia 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 population 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 study cohort than KEEP: smoking, 24.9% in NHANES versus 12.1% in KEEP, and low education level, 21.6% versus 15.5%.

Table 1. Anemia Prevalence by Risk Group: KEEP and NHANES 1999-2004

	KEEP				NHANES 1999-2004⁎
			Anemia (%)				Anemia (%)
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 kg/m2	30,317	44.0	14.9	13.1	4,555	30.8	6.8	6.0
Body mass index < 30 kg/m2	38,579	56.0	13.2	10.9	10,111	69.2	5.8	4.8
Self-reported 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
Self-reported 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
Self-reported 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.

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. Anemia (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).

Table 2. Mean Hemoglobin Values for KEEP and NHANES 1999-2004 Participants by Sex and Racial Subgroups

	Hemoglobin (g/dL)
	KEEP⁎ (n = 68,526)	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.

Smoking, Anemia, 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.

Table 3. Characteristics Distribution by Anemia Status: KEEP and NHANES

	KEEP				NHANES 1999-2004⁎
	KDOQI†		WHO‡		KDOQI†		WHO‡
	Anemia	No Anemia	Anemia	No Anemia	Anemia	No Anemia	Anemia	No Anemia
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 ≥ 30 kg/m2	47.0	43.5	48.6	43.4	34.6	30.5	35.8	30.5
Body mass index < 30 kg/m2	53.1	56.5	51.4	56.6	65.4	69.5	64.2	69.5
Self-reported 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
Self-reported 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
Self-reported 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.

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• 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.

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• 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.

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.

Table 4. Prevalence of Chronic Kidney Disease Stages in Anemic Patients by Characteristics: KEEP and NHANES

Characteristic	KDOQI⁎								WHO†
	KEEP				NHANES 1999-2004				KEEP				NHANES 1999-2004
	Chronic Kidney Disease Stage				Chronic Kidney Disease Stage				Chronic Kidney Disease Stage				Chronic Kidney Disease Stage
	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/m2	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.m2	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
Self-reported 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
Self-reported 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
Self-reported 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.

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.

Table 5. Odds of Anemia 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
Self-reported diabetes	1.73(1.63-1.83)	<0.001	1.76(1.66-1.88)	<0.001
Self-reported hypertension	1.07(1.01-1.14)	0.03	1.07(1.00-1.14)	0.06
Self-reported 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/m2	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.

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 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. 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 Anemia 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 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).

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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 CVD⁵, ⁹, ¹⁴ also were better represented in KEEP populations than in NHANES. For example, obesity was 1.4 times; hypertension was 2 times; and 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 Anemia is common in patients with diabetes and often goes unrecognized and untreated.¹⁷, ¹⁸, 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

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Acknowledgements 

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.

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