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Higher prevalence of anemia with diabetes mellitus in moderate kidney insufficiency: The Kidney Early Evaluation Program
Kidney International, Vol. 67 (2005), pp. 1483–1488
Higher prevalence of anemia with diabetes mellitus in moderate kidney insufficiency: The Kidney Early Evaluation Program TAREK M. EL-ACHKAR, SUZANNE E. OHMIT, PETER A. MCCULLOUGH, ERROL D. CROOK, WENDY W. BROWN, RICHARD GRIMM, GEORGE L. BAKRIS, WILLIAM F. KEANE, and JOHN M. FLACK Department of Internal Medicine, Wayne State University, Detroit, Michigan; Chief of Weight Control Center, William Beaumont Hospital, Royal Oak, Michigan; Division of Nephrology, Wayne State University, and the John D. Dingell VAMC, Detroit, Michigan; Division of Nephrology, St. Louis University, St. Louis, Missouri; Department of Medicine, Hennepin County Medical Center, Minneapolis, Minnesota; and Rush Medical College, Chicago, Illinois
Higher prevalence of anemia with diabetes mellitus in moderate kidney insufficiency: The Kidney Early Evaluation Program. Background. The Kidney Early Evaluation Program (KEEP 2.0) cross-sectional, community-based study, targeted individuals at increased risk for kidney disease and measured blood glucose, creatinine, and hemoglobin. Methods. KEEP 2.0 screening data were used to determine the prevalence of anemia by level of kidney function and diabetes status. Estimated glomerular filtration rate (EGFR) was calculated using serum creatinine values, and categorized as ≥90, 60–89, 30–59 and <30 mL/min/1.73m2 . Anemia was defined as hemoglobin <12 g/dL in men and in women aged >50 years, and <11 g/dL in women ≤50 years. Diabetes was defined as participant-reported diagnosis, fasting glucose >125 mg/dL, or nonfasting glucose >200 mg/dL. Results. Data were available on 5380 participants screened from August 2000 through December 2001. Diabetes was present in 26.9% of participants, and anemia in 7.7%; 15.9% of participants had at least moderately reduced kidney function (EGFR <60 mL/min/1.73m2 ). In participants with diabetes, anemia prevalence at the 4 levels of descending EGFR were 8.7%, 7.5%, 22.2%, and 52.4%, compared with 6.9%, 5.0%, 7.9%, and 50.0% in persons without diabetes. In a multivariable model, participants of non-white race/ethnicity, those with diabetes and those with EGFR <30 or 30–59 mL/min/1.73m2 had significantly increased odds of anemia. In addition, a significant sex-diabetes interaction was identified; odds of anemia were 4-fold greater in men than women with diabetes relative to sex-matched participants without diabetes. Conclusion. Diabetes was independently correlated with anemia, more so in men than women, and may be linked to premature expression of anemia in persons with moderate reductions in kidney function.
Key words: anemia, diabetes, estimated glomerular filtration rate, hemoglobin, K/DOQI, kidney disease, kidney function. Received for publication July 7, 2004 and in revised form September 2, 2004 Accepted for publication October 14, 2004 C
2005 by the International Society of Nephrology
Anemia is a common feature of end-stage renal disease (ESRD), but it also accompanies lesser reductions in kidney function [1, 2]. The degree of anemia roughly approximates the severity of kidney dysfunction [3, 4]. Diabetes mellitus is a risk factor for chronic kidney insufficiency and is the leading cause of ESRD [5]. Diabetes-related anemia has been observed in the advanced uremia of diabetic nephropathy; however, diabetes affects the hematologic system in several ways [6]. Recent studies have linked anemia with relatively low serum erythropoietin in persons with either type 1 or type 2 diabetes even without advanced kidney disease or overt uremia [7–9]. Patients with diabetic nephropathy may have worse clinical outcomes related to anemia than other etiologies of kidney failure. Nevertheless, anemia in diabetes likely represents a complex interplay between diabetes, level of kidney function, and medication exposures. Anemia is a treatable condition that has been linked to left ventricular hypertrophy, cardiovascular morbidity, more rapid loss of kidney function, and poor quality of life [10, 11]. The Kidney Early Evaluation Program (KEEP 2.0) is an ongoing community-based health-screening program sponsored by the National Kidney Foundation (NKF) that identifies individuals at increased risk for kidney disease, and encourages them to seek follow-up health care. We used KEEP 2.0 data to examine the relationship of anemia with diabetes and kidney function, and to determine whether this relationship differed in men and women.
METHODS From August 2000 through December 2001, 135 screening programs in 33 states were carried out by 31 NKF affiliates. Eligible participants were at least 18 years old, with diabetes or hypertension, or with a family history of diabetes, hypertension, or kidney disease [12]. Some NKF affiliates targeted recruitment efforts in areas with large 1483
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African American populations because of their known high prevalence of diabetes and hypertension. All participants provided informed consent prior to data collection. Data were collected by questionnaire on demographic characteristics and medical history via participant self-report. Medication status was not obtained during KEEP health assessments. Systolic and diastolic blood pressures were measured, and blood specimens were collected and processed for determination of blood glucose, creatinine, and hemoglobin. In analyses presented here we focused on the following variables: age, sex, race/ethnicity, hemoglobin, blood glucose, and diabetes status, and serum creatinine to estimate glomerular filtration rate (EGFR). Diabetes was diagnosed by participant self-report, fasting glucose values >125 mg/dL, or nonfasting glucose levels >200 mg/dL. Serum creatinine values were considered abnormal if values were >1.5 mg/dL for men and >1.3 mg/dL for women [13]. Participant EGFR values (mL/min/1.73m2 ) were calculated using the simplified Modification of Diet in Renal Disease (MDRD) formula (186.3 × [serum creatinine, mg/dL −1.154 ] × [age, years −.203 ]); calculated values were multiplied by .742 for women, and by 1.21 for African Americans [abstract; Levey AS, Greene T, Kusek JW, Beck GJ, and MDRD Study Group. J Am Soc Nephrol 11:155A, 2000; A0828, 14] Based on stages of chronic kidney disease (CKD) from the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines, EGFR values were categorized using the following cut-points: ≥90 (CKD 1), 60–89 (CKD 2), 30–59 (CKD 3), and <30 (CKD 4, 5) mL/min/1.73m2 [15]. We grouped those with EGFR <15 mL/min/1.73m2 (CKD 5) with those having less severe dysfunction because of the small number of such individuals (N = 9). EGFR values <60 mL/min/1.73m2 (CKD 3–5) were considered abnormal, and indicated at least moderately reduced kidney function [15]. Participants were categorized as anemic based on the K/DOQI guidelines definition for anemia that warrants investigation in chronic renal insufficiency [K/DOQI—hemoglobin values <12.0 g/dL for men and for postmenopausal women (>50 years old), and <11.0 g/dL for premenopausal women (≤50 years old)] [10]. Statistical analyses were performed with the SAS statistical package (release 8.2; SAS Institute Inc., Cary, NC, USA). Descriptive analyses were used to characterize the study population by demographics, including sex, age, race/ethnicity, and by medical status, including mean hemoglobin, prevalence of anemia and of diabetes, and categories of kidney function. The associations of anemia prevalence or mean hemoglobin value with level of kidney function, stratified by diabetes status, were examined using chi-square statistics for categorical variables, and Wilcoxon rank-sum statistics or analysis of variance (ANOVA) techniques for continuous variables. Odds of
anemia by level of kidney function and diabetes status were also examined in multivariable logistic regression models, adjusted for age, sex, and race/ethnicity, with generation of odds ratios (OR) and consideration of interactions. Analyses presented here are limited to those individuals with complete data on key variables— diabetes, anemia, and EGFR.
RESULTS The population screened was composed of 6071 eligible participants, including 1956 men and 4115 women. Among these, complete data on key variables were available for 5380 (89%) participants; characteristics of this population by diabetes status are presented in Table 1. Participants were predominately women (67%), and African American or white (79%); participant mean age was 53 years (SD = 15.6). Diabetes was present in 27% of participants, including 30% of men and 25% of women (P = .001); 95% of those categorized as such reported a diabetes diagnosis. Only 5% of participants had abnormal serum creatinine values [13]; however, 16% had EGFR values less than 60 mL/min/1.73m2 , indicating at least moderately reduced kidney function [15]. Participants with diabetes were more likely than those without diabetes to have abnormal serum creatinine and EGFR values. Men were more likely than women to have abnormal serum creatinine values (8% vs. 4%, P < .001); however, women were slightly more likely than men to have EGFR values less than 60 mL/min/1.73m2 (17% vs. 15%, P = .06). Mean EGFR values did not significantly differ by sex [mean 81.5 (SD = 22.2, range 7–207) for men compared with mean 81.2 (SD = 23.6, range 10– 239) for women, P = .06]. Three percent of men and 10% of women had anemia according to the K/DOQI definition (P < .001) [10]. Twelve percent of participants with diabetes were categorized as anemic compared with 6% of those without diabetes. Prevalence of anemia by K/DOQI category of kidney function was examined for participants with and without diabetes (Fig. 1A). Anemia prevalence was significantly greater in persons with diabetes compared to persons without diabetes in the kidney function categories 30–59 mL/min/1.73m2 (22.2% vs. 7.9%, P < .001) and 60–89 mL/min/1.73m2 (7.5% vs. 5.0%, P = .015). Mean hemoglobin values were significantly lower in persons with diabetes compared to persons without diabetes (13.0 g/dL vs. 13.6 g/dL, P < .001) in the kidney function category of 30–59 mL/min/1.73m2 , but did not differ for persons with or without diabetes in the kidney function category of 60–89 mL/min/1.73m2 (13.7 g/dL for both, P = 1.0). No significant differences in anemia prevalence (P = .88) or mean hemoglobin values (11.5 g/dL vs. 11.9 g/ dL, P = .58) were detected at EGFR values below 30 mL/
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Table 1. Demographic characteristics and medical status of 5380 participants in a health screening program designed to identify individuals at increased risk for kidney disease (KEEP 2.0, August 2000–December 2001) Diabetes status Present (N = 1445, 26.9%)
Absent (N = 3935, 73.1%)
Total (N = 5380)
58.4 (18–101) 78.7 (10–208) 13.5 (7.1–18.1) N (%)
50.3 (18–100) 82.3 (7–239) 13.6 (5.7–18.6) N (%)
52.5 (18–101) 81.3 (7–239) 13.6 (5.7–18.6) N (%)
543 (37.6) 514 (35.6) 174 (12.0) 214 (14.8)
1752 (44.5) 1419 (36.1) 400 (10.2) 364 (9.3)
2295 (42.7) 1933 (35.9) 574 (10.7) 578 (10.7)
525 (36.3) 920 (63.7) 120 (8.3) 168 (11.6)
1244 (31.6) 2691 (68.4) 165 (4.2) 246 (6.3)
1769 (32.9) 3611 (67.1) 285 (5.3) 414 (7.7)
21 (1.5) 307 (21.2) 671 (46.4) 446 (30.9)
22 (0.6) 507 (12.9) 2072 (52.7) 1334 (33.9)
43 (0.8) 814 (15.1) 2743 (51.0) 1780 (33.1)
Mean age years (range) Mean EGFR mL/min/1.73m2 (range) Mean hemoglobin g/dL (range) Race/ethnicity African American White Hispanic Other/unknown Gender Men Women Abnormal creatinine Anemia EGFR mL/min/1.73m2 <30 [CKD 4, 5]a 30–59 [CKD 3] 60–89 [CKD 2] ≥90 [CKD 1] a
P value <0.001 <0.001 0.031 <0.001
0.001 <0.001 <0.001 <0.001
Stages of chronic kidney disease (CKD) [14].
60 52.4
50
Diabetes Non-diabetes
50
Table 2. Results from a multivariable logistic regression model evaluating factors associated with anemia among 5380 participants in a community health-screening program
40 P < 0.001
30
22.2
Anemia prevalence, %
20
P = 0.015 7.9
10 0
<30
7.5
30-59
8.7 5
6.9
>89
60-89
70 60
54.2 52.2
50
P = 0.038 P = 0.009
30 20.8
20
P < 0.001
P value
1.03 .26
1.02–1.04 .19–.35
<0.001 <0.001
3.04 2.12 2.07 Reference 1.63
2.32–3.99 1.42–3.17 1.41–3.03
<0.001 <0.001 <0.001
1.30–2.03
<0.001
12.32 1.38 .68 Reference
6.16–24.64 1.01–1.89 .53–.88
<0.001 0.045 0.003
16.2 10.1
10 0
23.5
95% CI
In a separate similar model, a statistically significant sex-diabetes interaction was observed (OR = 4.3, 95% CI 2.2–8.5, P < .001), indicating that relative to sex-matched nondiabetic participants, men with diabetes had greater odds of anemia than women with diabetes.
40.4
40
Age years Male gender Race/ethnicity African American Hispanic Other White Diabetes EGFR mL/min/1.73m2 <30 30–59 60–89 ≥90
OR
4.8
<31
7.5 5.7
5.9 4.5
31-40 41-50 51-60 61-70 71-80
8.7
6.2
>80
Estimated GFR, mL/min/1.73m2 Fig. 1. Distributions of anemia prevalence, by K/DOQI categories, and by 10 mL/min/1.73m2 increments of estimated GFR, among participants with or without diabetes.
min/1.73m2 ; however, this category had a small number of studied subjects (N = 43). To more precisely evaluate the relationship of diabetes and anemia with level of kidney function, we consid-
ered EGFR divided into 10 mL/min/1.73m2 strata and re-examined the prevalence of anemia in persons with and without diabetes (Fig. 1B) [1]. Statistically significant (P < .05) differences in prevalence of anemia by diabetes status were present at each of the three EGFR categories between 31–60 mL/min/1.73m2 , but did not significantly differ for any of the other categories. In a multivariable logistic regression model that considered factors associated with odds of anemia, diabetes status, and both EGFR categories <30 and 30–59 mL/min/1.73m2 were significantly associated with increased likelihood of anemia (Table 2). Results from
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Table 3. Mean hemoglobin (HGB) for 10 mL/min/1.73m2 increments of EGFR stratified by diabetes status and sex EGFR mL/min/1.73m2 >80 71–80 61–70 51–60 41–50 31–40 <31
Men with diabetes 14.6 14.5 14.1 13.9 (P = 0.006) 13.3 (P < 0.001) 12.2 (P < 0.001) 12.2 (P < 0.001)
Men without diabetes
Women with diabetes
Mean HGB g/dL (P value a ) 14.7 13.0 14.9 13.4 14.8 13.4 14.7 13.1 14.3 12.9 14.2 12.4 12.8 (P < 0.001) 10.8 (P < 0.001)
Women without diabetes 12.9 13.2 13.3 13.5 13.2 13.0 11.2 (P < 0.001)
a P value for the difference in mean HGB at each strata from mean HGB at EGFR >80 mL/min/1.73m2 of corresponding column; only statistically significant (<0.05) values are presented.
these analyses also indicated increased odds of anemia with older age, among women, and among African American, Hispanic, and other non-white participants. In a similar separate model, a significant sex-diabetes interaction was identified (OR 4.3, 95% CI 2.2–8.5, P < .001), indicating that relative to sex-matched participants without diabetes, men with diabetes had greater odds of anemia than women with diabetes. In unadjusted analyses, men with diabetes were more likely than men without diabetes to have anemia (8.0% vs. 1.1%, OR 7.6, 95% CI 4.1–14.1, P < .001), as were women with diabetes compared to women without diabetes (13.7% vs. 8.6%, OR 1.7, 95% CI 1.3–2.1, P < .001); however, differential odds of anemia by diabetes status for men and women were apparent (Breslow-Day test for homogeneity of ORs, P < .001). Mean hemoglobin values were significantly lower for men with diabetes compared to men without diabetes (14.2 g/dL vs. 14.7 g/dL, P < .001), but were not different for women with and without diabetes (13.1 g/dL for both, P = .69). In Table 3, mean hemoglobin values were compared in 10 mL/min/1.73m2 increments of EGFR for men and women stratified by diabetes status; category-specific mean hemoglobin values at multiple EGFR strata were compared for differences with mean hemoglobin values at EGFR >80 mL/min/1.73m2 . Among men with diabetes, significantly lower mean hemoglobin values were observed at all EGFR categories less than 60 mL/min/ 1.73m2 . In contrast, among women with diabetes and among men and women without diabetes, significantly lower mean hemoglobin values were not apparent until more advanced levels of kidney dysfunction (EGFR <31 mL/min/1.73m2 ).
DISCUSSION We examined the prevalence of anemia across a broad range of kidney function according to diabetes status, among individuals at increased risk of kidney disease participating in a community-based screening program
that targeted persons with risk factors for CKD. There were significant differences in the prevalence of anemia (and mean hemoglobin values) between persons with and without diabetes at levels of moderately impaired kidney function (EGFR 30–59 mL/min/1.73m2 –CKD 3). This interesting relationship was less evident in the mildly impaired and normal levels of kidney function—EGFR ≥60 mL/min/1.73m2 (CKD 1, 2). At the level of severely impaired kidney function (EGFR <30 mL/min/1.73m2 – CKD 4, 5), anemia was frequently identified (51%), but with no significant difference in prevalence of anemia by diabetes status, possibly due to the small number of studied subjects. In multivariable models adjusted for participant demographic characteristics, diabetes status and both moderate (EGFR 30–59 mL/min/1.73m2 –CKD 3) and significant (EGFR <30 mL/min/1.73m2 –CKD 4, 5) reductions in kidney function were associated with increased odds of anemia. Both men and women with diabetes had increased prevalence of anemia; however, diabetes conferred greater odds of anemia in men than in women. Our findings of increased odds of anemia among older participants and among African American and Hispanic participants are consistent with findings from recent analyses of a population-based survey evaluating the health status of the United States population [2]. That study also found, as we did, greater overall prevalence of anemia among women compared with men; prevalence estimates were higher in our study for both men and women, as our study targeted an at-risk rather than general population. We used the K/DOQI definition of anemia that warrants investigation in chronic renal insufficiency [10]; however, several other definitions of anemia have been developed and published [2, 16, 17]. Analyses carried out using these other definitions (data not shown) generated similar results and identical conclusions, even though prevalence varied. We used the simplified Modification of Diet in Renal Disease (MDRD) formula to calculate EGFR values (mL/min/1.73m2 ); this validated formula was
El-Achkar et al: Anemia with diabetes and reduced kidney function
derived from measured GFR, and uses only demographic characteristics and serum creatinine values to estimate GFR [14]. Other formulas, including the widely used Cockcroft-Gault formula [18], have also been used to estimate level of kidney function (creatinine clearance). Analyses carried out using EGFR values calculated based on the body surface area adjusted-Cockcroft-Gault formula (data not shown) confirmed the findings presented. The relationship of diabetes to anemia has been classically related to advanced kidney damage and uremia. Anemia is a common manifestation of chronic kidney failure, and contributes to multiple adverse outcomes, possibly via decreased tissue oxygen delivery and utilization [10, 19]. A significant correlation between hematocrit and creatinine clearance was found to occur below 40 mL/min/1.73m2 in an earlier study, and when GFR fell below 20 mL/min/1.73m2 in another study [3, 4]. Hsu et al demonstrated that hematocrit decreased progressively below EGFR of 50 mL/min/1.73m2 in men and women, with men having a larger decrease in hematocrit [1]; this observation is consistent with our findings among KEEP participants. Similar observations were made recently using health status survey data from a representative sample of the United States population [2, 20]. It is important to note, however, that diabetes status was not considered in these studies. Low levels of erythropoietin have been observed in persons with anemia and either type 1 or type 2 diabetes, but without advanced renal disease or overt uremia [7–9]. For example, Bosman et al found that 13 of 27 patients with type 1 diabetes, nephropathy, and serum creatinine <2 mg/dL had unexplained anemia with relatively low erythropoietin levels, compared to none of 26 patients without diabetes but with glomerulonephritis [8]. Similarly, hemoglobin was lower in 19 patients with type 2 diabetes and kidney failure compared with 21 patients without diabetes who also had kidney failure and comparable serum creatinine levels [9]. These studies typically used clinic populations, had small sample sizes, and none documented, as we did, a link between anemia and a specific level of glomerular filtration rate in persons with diabetes. There are several plausible mechanisms that may explain the link between diabetes and anemia, as well as the differential diabetes-related anemia risk in men compared with women. Renal denervation attributable to diabetic autonomic neuropathy can reduce splanchnic sympathetic stimulation of erythropoietin production [7, 8, 21]. Also, diabetes may adversely affect peritubular and interstitial structures in the renal cortex, the site of erythropoietin production, even prior to the development of overt nephropathy. This may attenuate the release of erythropoietin in response to the hypoxic stimuli of anemia [8, 22]. Furthermore, both diabetes and reduced kidney function have been linked to depressed androgen levels
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[23]. Androgens stimulate erythropoiesis by increasing erythropoietin production and by direct augmentation of marrow stem cells [24]. Finally, kidney failure has been associated with reduced testosterone levels in men [25]. On the other hand, premenopausal and postmenopausal women with diabetes have higher bioavailable testosterone levels then women without diabetes [26]. An important issue to consider is what absolute drop in hemoglobin would be considered clinically relevant, thus prompting treatment in CKD. Despite the presence of guidelines for desirable hemoglobin in CKD [10], the issue remains controversial, as most publications deal with treatment after development of anemia, and none, as yet, has examined the effect of avoidance of anemia on clinical outcomes [27]. Recently, the contribution of anemia to cardiomyopathy in kidney failure has been examined [27, 28]. Previous studies have demonstrated that even minor drops in hemoglobin (0.5–1.0 g/dL) may augment the risk of developing left ventricular hypertrophy in persons with kidney dysfunction [29], may increase risks of mortality and heart failure [30], and may lead to a more rapid loss of kidney function in persons with diabetic nephropathy [11]. Our study has several limitations. First, we cannot rule out the possibility that other comorbid conditions, such as iron-deficiency or other etiologies of anemia, may have been differentially distributed across the KEEP population according to gender and diabetes status. Also, we have no information regarding the types of medications [e.g., renin angiotensin system (RAS) drugs, erythropoietin] participants were taking. This might be viewed as a major limitation of our study given that angiotensinconverting enzyme (ACE) inhibitors are recommended treatments for persons with diabetes, and are known to depress erythropoiesis [31]. However, if our findings were explained by use of RAS agents, we would have to postulate differential exposure and/or effect on erythropoiesis among men and women. Furthermore, we may have misclassified diabetes status given our lack of detailed information regarding medications, as well as because fasting blood glucose levels were not routinely available; however, 95% of those so categorized reported a diabetes diagnosis. In addition, our study has the limitations common to cross-sectional epidemiologic investigations that preclude the determination of causal associations. Finally, the study was a targeted-screening of individuals at risk for CKD and, thus, is not a representative sampling of the United States population. Self-selection bias is inherent when recruitment strategies rely on volunteer participants [12]; persons who participate in screening programs tend to be those who are health conscious and better educated. The predominance of women attending KEEP screenings is consistent with previous observations that women are more likely than men to utilize preventive health services [32, 33].
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CONCLUSION In a community-based screening, the prevalence of anemia was increased at less depressed levels of EGFR in persons with diabetes compared to persons without diabetes. Both men and women with diabetes had increased prevalence of anemia; however, diabetes conferred greater odds of anemia in men than in women. These observations are biologically plausible and provocative. Nevertheless, these findings require confirmation in other cohorts that have more complete patient-level data, including information on medication exposures. ACKNOWLEDGMENTS The Kidney Early Evaluation Program (KEEP)TM is a program of the National Kidney Foundation, Inc., and was supported by Ortho Biotech and Bayer Diagnostics. Reprint requests to John M. Flack, M.D., M.P.H., Wayne State University and the Detroit Medical Center, University Health Center, Suite 2E, 4201 St. Antoine, Detroit, MI 48201. E-mail: [email protected]
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nephropathy: The RENAAL Study. Kidney Int 63:1499–1507, 2003 12. BROWN WW, PETERS RM, OHMIT SE, et al: Early detection of kidney disease in community settings: The Kidney Early Evaluation Program (KEEP). Am J Kidney Dis 42:22–35, 2003 13. JONES CA, MCQUILLAN GM, KUSEK JW, et al: Serum creatinine levels in the United States: the third National Health and Nutrition Examination Survey (NHANES III). Am J Kid Dis 32:1–9, 1998 14. LEVEY AS, BOSCH JP, LEWIS JB, et al: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Ann Intern Med 130:461–470, 1999 15. NATIONAL KIDNEY FOUNDATION: K/DOQI clinical practice guidelines for chronic Kidney disease: Evaluation, classification and stratification. Am J Kidney Dis 39:S1–S266, 2002 16. WORLD HEALTH ORGANIZATION: Nutritional Anemias: Report of a WHO Scientific Group, Geneva, Switzerland, World Health Organization, 1968 17. DALLMAN PR, YIP R, JOHNSON C: Prevalence and causes of anemia in the United States, 1976–1980 (NHANES II). Am J Clin Nutrition 39:437–445, 1984 18. COCKCROFT DW, GAULT MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41, 1976 19. LEVIN A, SINGER J, THOMPSON CR, et al: Prevalent left ventricular hypertrophy in the predialysis population: Identifying opportunities for intervention. Am J Kidney Dis 27:347–354, 1996 20. HSU CY, MCCULLOCH CE, CURHAN GC: Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: Results from the Third National Health and Nutrition Examination Survey. J Am Soc Nephrol 13:504–510, 2002 21. BIAGGIONI I, ROBERTSON D, KRANTZ S, et al: The anemia of primary autonomic failure and its reversal with recombinant erythropoietin. Ann Intern Med 121:181–186, 1994 22. SCHUSTER SJ, KOURY ST, BOHRER M, et al: Cellular sites of extrarenal and renal erythropoietin production in anaemic rats. Br J Haematol 81:153–159, 1992 23. ANDERSSON B, MARIN P, LISSNER L, et al: Testosterone concentrations in women and men with NIDDM. Diabetes Care 17:405–411, 1994 24. NAETS JP, WITTEK M. The mechanism of action of androgens on erythropoiesis. Ann NY Acad Sci 149:366, 1968 25. HOLDSWORTH S, ATKINS RC, DE KRETSER DM: The pituitarytesticular axis in men with chronic renal failure. N Engl J Med 296:1245–1249, 1977 26. PHILLIPS GB, TUCK CH, JING TY, et al: Association of hyperandrogenemia and hyperestrogenemia with type 2 diabetes in Hispanic postmenopausal women. Diabetes Care 23:74–79, 2000 27. DONNE RL, FOLEY RN: Anemia management and cardiomyopathy in renal failure. Nephrol Dial Transplant 17:37–40, 2002 28. FOLEY RN, PARFREY PS, SARNAK MJ: Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 32:112–119, 1998 29. LEVIN A, THOMPSON CR, ETHIER J, et al: Left ventricular mass index increase in early renal disease: Impact of decline in hemoglobin. Am J Kidney Dis 34:125–134, 1999 30. HARNETT JD, KENT GM, FOLEY RN, PARFREY PS: Cardiac function and hematocrit level. Am J Kidney Dis 25:3–7, 1995 31. KAMPER AL, NIELSEN OJ: Effect of enalapril on haemoglobin and serum erythropoietin in patients with chronic nephropathy. Scand J Clin Lab Invest 50:611–618, 1990 32. BERTAKIS KD, AZARI R, HELMS LJ, et al: Gender differences in the utilization of health care services. J Fam Pract 49:147–152, 2000 33. GREEN CA, POPE CR: Gender, psychosocial factors and the use of medical services: A longitudinal analysis. Soc Science Med 48:1363– 1372, 1999
Higher prevalence of anemia with diabetes mellitus in moderate kidney insufficiency: The Kidney Early Evaluation Program TAREK M. EL-ACHKAR, SUZANNE E. OHMIT, PETER A. MCCULLOUGH, ERROL D. CROOK, WENDY W. BROWN, RICHARD GRIMM, GEORGE L. BAKRIS, WILLIAM F. KEANE, and JOHN M. FLACK Department of Internal Medicine, Wayne State University, Detroit, Michigan; Chief of Weight Control Center, William Beaumont Hospital, Royal Oak, Michigan; Division of Nephrology, Wayne State University, and the John D. Dingell VAMC, Detroit, Michigan; Division of Nephrology, St. Louis University, St. Louis, Missouri; Department of Medicine, Hennepin County Medical Center, Minneapolis, Minnesota; and Rush Medical College, Chicago, Illinois
Higher prevalence of anemia with diabetes mellitus in moderate kidney insufficiency: The Kidney Early Evaluation Program. Background. The Kidney Early Evaluation Program (KEEP 2.0) cross-sectional, community-based study, targeted individuals at increased risk for kidney disease and measured blood glucose, creatinine, and hemoglobin. Methods. KEEP 2.0 screening data were used to determine the prevalence of anemia by level of kidney function and diabetes status. Estimated glomerular filtration rate (EGFR) was calculated using serum creatinine values, and categorized as ≥90, 60–89, 30–59 and <30 mL/min/1.73m2 . Anemia was defined as hemoglobin <12 g/dL in men and in women aged >50 years, and <11 g/dL in women ≤50 years. Diabetes was defined as participant-reported diagnosis, fasting glucose >125 mg/dL, or nonfasting glucose >200 mg/dL. Results. Data were available on 5380 participants screened from August 2000 through December 2001. Diabetes was present in 26.9% of participants, and anemia in 7.7%; 15.9% of participants had at least moderately reduced kidney function (EGFR <60 mL/min/1.73m2 ). In participants with diabetes, anemia prevalence at the 4 levels of descending EGFR were 8.7%, 7.5%, 22.2%, and 52.4%, compared with 6.9%, 5.0%, 7.9%, and 50.0% in persons without diabetes. In a multivariable model, participants of non-white race/ethnicity, those with diabetes and those with EGFR <30 or 30–59 mL/min/1.73m2 had significantly increased odds of anemia. In addition, a significant sex-diabetes interaction was identified; odds of anemia were 4-fold greater in men than women with diabetes relative to sex-matched participants without diabetes. Conclusion. Diabetes was independently correlated with anemia, more so in men than women, and may be linked to premature expression of anemia in persons with moderate reductions in kidney function.
Key words: anemia, diabetes, estimated glomerular filtration rate, hemoglobin, K/DOQI, kidney disease, kidney function. Received for publication July 7, 2004 and in revised form September 2, 2004 Accepted for publication October 14, 2004 C
2005 by the International Society of Nephrology
Anemia is a common feature of end-stage renal disease (ESRD), but it also accompanies lesser reductions in kidney function [1, 2]. The degree of anemia roughly approximates the severity of kidney dysfunction [3, 4]. Diabetes mellitus is a risk factor for chronic kidney insufficiency and is the leading cause of ESRD [5]. Diabetes-related anemia has been observed in the advanced uremia of diabetic nephropathy; however, diabetes affects the hematologic system in several ways [6]. Recent studies have linked anemia with relatively low serum erythropoietin in persons with either type 1 or type 2 diabetes even without advanced kidney disease or overt uremia [7–9]. Patients with diabetic nephropathy may have worse clinical outcomes related to anemia than other etiologies of kidney failure. Nevertheless, anemia in diabetes likely represents a complex interplay between diabetes, level of kidney function, and medication exposures. Anemia is a treatable condition that has been linked to left ventricular hypertrophy, cardiovascular morbidity, more rapid loss of kidney function, and poor quality of life [10, 11]. The Kidney Early Evaluation Program (KEEP 2.0) is an ongoing community-based health-screening program sponsored by the National Kidney Foundation (NKF) that identifies individuals at increased risk for kidney disease, and encourages them to seek follow-up health care. We used KEEP 2.0 data to examine the relationship of anemia with diabetes and kidney function, and to determine whether this relationship differed in men and women.
METHODS From August 2000 through December 2001, 135 screening programs in 33 states were carried out by 31 NKF affiliates. Eligible participants were at least 18 years old, with diabetes or hypertension, or with a family history of diabetes, hypertension, or kidney disease [12]. Some NKF affiliates targeted recruitment efforts in areas with large 1483
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African American populations because of their known high prevalence of diabetes and hypertension. All participants provided informed consent prior to data collection. Data were collected by questionnaire on demographic characteristics and medical history via participant self-report. Medication status was not obtained during KEEP health assessments. Systolic and diastolic blood pressures were measured, and blood specimens were collected and processed for determination of blood glucose, creatinine, and hemoglobin. In analyses presented here we focused on the following variables: age, sex, race/ethnicity, hemoglobin, blood glucose, and diabetes status, and serum creatinine to estimate glomerular filtration rate (EGFR). Diabetes was diagnosed by participant self-report, fasting glucose values >125 mg/dL, or nonfasting glucose levels >200 mg/dL. Serum creatinine values were considered abnormal if values were >1.5 mg/dL for men and >1.3 mg/dL for women [13]. Participant EGFR values (mL/min/1.73m2 ) were calculated using the simplified Modification of Diet in Renal Disease (MDRD) formula (186.3 × [serum creatinine, mg/dL −1.154 ] × [age, years −.203 ]); calculated values were multiplied by .742 for women, and by 1.21 for African Americans [abstract; Levey AS, Greene T, Kusek JW, Beck GJ, and MDRD Study Group. J Am Soc Nephrol 11:155A, 2000; A0828, 14] Based on stages of chronic kidney disease (CKD) from the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines, EGFR values were categorized using the following cut-points: ≥90 (CKD 1), 60–89 (CKD 2), 30–59 (CKD 3), and <30 (CKD 4, 5) mL/min/1.73m2 [15]. We grouped those with EGFR <15 mL/min/1.73m2 (CKD 5) with those having less severe dysfunction because of the small number of such individuals (N = 9). EGFR values <60 mL/min/1.73m2 (CKD 3–5) were considered abnormal, and indicated at least moderately reduced kidney function [15]. Participants were categorized as anemic based on the K/DOQI guidelines definition for anemia that warrants investigation in chronic renal insufficiency [K/DOQI—hemoglobin values <12.0 g/dL for men and for postmenopausal women (>50 years old), and <11.0 g/dL for premenopausal women (≤50 years old)] [10]. Statistical analyses were performed with the SAS statistical package (release 8.2; SAS Institute Inc., Cary, NC, USA). Descriptive analyses were used to characterize the study population by demographics, including sex, age, race/ethnicity, and by medical status, including mean hemoglobin, prevalence of anemia and of diabetes, and categories of kidney function. The associations of anemia prevalence or mean hemoglobin value with level of kidney function, stratified by diabetes status, were examined using chi-square statistics for categorical variables, and Wilcoxon rank-sum statistics or analysis of variance (ANOVA) techniques for continuous variables. Odds of
anemia by level of kidney function and diabetes status were also examined in multivariable logistic regression models, adjusted for age, sex, and race/ethnicity, with generation of odds ratios (OR) and consideration of interactions. Analyses presented here are limited to those individuals with complete data on key variables— diabetes, anemia, and EGFR.
RESULTS The population screened was composed of 6071 eligible participants, including 1956 men and 4115 women. Among these, complete data on key variables were available for 5380 (89%) participants; characteristics of this population by diabetes status are presented in Table 1. Participants were predominately women (67%), and African American or white (79%); participant mean age was 53 years (SD = 15.6). Diabetes was present in 27% of participants, including 30% of men and 25% of women (P = .001); 95% of those categorized as such reported a diabetes diagnosis. Only 5% of participants had abnormal serum creatinine values [13]; however, 16% had EGFR values less than 60 mL/min/1.73m2 , indicating at least moderately reduced kidney function [15]. Participants with diabetes were more likely than those without diabetes to have abnormal serum creatinine and EGFR values. Men were more likely than women to have abnormal serum creatinine values (8% vs. 4%, P < .001); however, women were slightly more likely than men to have EGFR values less than 60 mL/min/1.73m2 (17% vs. 15%, P = .06). Mean EGFR values did not significantly differ by sex [mean 81.5 (SD = 22.2, range 7–207) for men compared with mean 81.2 (SD = 23.6, range 10– 239) for women, P = .06]. Three percent of men and 10% of women had anemia according to the K/DOQI definition (P < .001) [10]. Twelve percent of participants with diabetes were categorized as anemic compared with 6% of those without diabetes. Prevalence of anemia by K/DOQI category of kidney function was examined for participants with and without diabetes (Fig. 1A). Anemia prevalence was significantly greater in persons with diabetes compared to persons without diabetes in the kidney function categories 30–59 mL/min/1.73m2 (22.2% vs. 7.9%, P < .001) and 60–89 mL/min/1.73m2 (7.5% vs. 5.0%, P = .015). Mean hemoglobin values were significantly lower in persons with diabetes compared to persons without diabetes (13.0 g/dL vs. 13.6 g/dL, P < .001) in the kidney function category of 30–59 mL/min/1.73m2 , but did not differ for persons with or without diabetes in the kidney function category of 60–89 mL/min/1.73m2 (13.7 g/dL for both, P = 1.0). No significant differences in anemia prevalence (P = .88) or mean hemoglobin values (11.5 g/dL vs. 11.9 g/ dL, P = .58) were detected at EGFR values below 30 mL/
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Table 1. Demographic characteristics and medical status of 5380 participants in a health screening program designed to identify individuals at increased risk for kidney disease (KEEP 2.0, August 2000–December 2001) Diabetes status Present (N = 1445, 26.9%)
Absent (N = 3935, 73.1%)
Total (N = 5380)
58.4 (18–101) 78.7 (10–208) 13.5 (7.1–18.1) N (%)
50.3 (18–100) 82.3 (7–239) 13.6 (5.7–18.6) N (%)
52.5 (18–101) 81.3 (7–239) 13.6 (5.7–18.6) N (%)
543 (37.6) 514 (35.6) 174 (12.0) 214 (14.8)
1752 (44.5) 1419 (36.1) 400 (10.2) 364 (9.3)
2295 (42.7) 1933 (35.9) 574 (10.7) 578 (10.7)
525 (36.3) 920 (63.7) 120 (8.3) 168 (11.6)
1244 (31.6) 2691 (68.4) 165 (4.2) 246 (6.3)
1769 (32.9) 3611 (67.1) 285 (5.3) 414 (7.7)
21 (1.5) 307 (21.2) 671 (46.4) 446 (30.9)
22 (0.6) 507 (12.9) 2072 (52.7) 1334 (33.9)
43 (0.8) 814 (15.1) 2743 (51.0) 1780 (33.1)
Mean age years (range) Mean EGFR mL/min/1.73m2 (range) Mean hemoglobin g/dL (range) Race/ethnicity African American White Hispanic Other/unknown Gender Men Women Abnormal creatinine Anemia EGFR mL/min/1.73m2 <30 [CKD 4, 5]a 30–59 [CKD 3] 60–89 [CKD 2] ≥90 [CKD 1] a
P value <0.001 <0.001 0.031 <0.001
0.001 <0.001 <0.001 <0.001
Stages of chronic kidney disease (CKD) [14].
60 52.4
50
Diabetes Non-diabetes
50
Table 2. Results from a multivariable logistic regression model evaluating factors associated with anemia among 5380 participants in a community health-screening program
40 P < 0.001
30
22.2
Anemia prevalence, %
20
P = 0.015 7.9
10 0
<30
7.5
30-59
8.7 5
6.9
>89
60-89
70 60
54.2 52.2
50
P = 0.038 P = 0.009
30 20.8
20
P < 0.001
P value
1.03 .26
1.02–1.04 .19–.35
<0.001 <0.001
3.04 2.12 2.07 Reference 1.63
2.32–3.99 1.42–3.17 1.41–3.03
<0.001 <0.001 <0.001
1.30–2.03
<0.001
12.32 1.38 .68 Reference
6.16–24.64 1.01–1.89 .53–.88
<0.001 0.045 0.003
16.2 10.1
10 0
23.5
95% CI
In a separate similar model, a statistically significant sex-diabetes interaction was observed (OR = 4.3, 95% CI 2.2–8.5, P < .001), indicating that relative to sex-matched nondiabetic participants, men with diabetes had greater odds of anemia than women with diabetes.
40.4
40
Age years Male gender Race/ethnicity African American Hispanic Other White Diabetes EGFR mL/min/1.73m2 <30 30–59 60–89 ≥90
OR
4.8
<31
7.5 5.7
5.9 4.5
31-40 41-50 51-60 61-70 71-80
8.7
6.2
>80
Estimated GFR, mL/min/1.73m2 Fig. 1. Distributions of anemia prevalence, by K/DOQI categories, and by 10 mL/min/1.73m2 increments of estimated GFR, among participants with or without diabetes.
min/1.73m2 ; however, this category had a small number of studied subjects (N = 43). To more precisely evaluate the relationship of diabetes and anemia with level of kidney function, we consid-
ered EGFR divided into 10 mL/min/1.73m2 strata and re-examined the prevalence of anemia in persons with and without diabetes (Fig. 1B) [1]. Statistically significant (P < .05) differences in prevalence of anemia by diabetes status were present at each of the three EGFR categories between 31–60 mL/min/1.73m2 , but did not significantly differ for any of the other categories. In a multivariable logistic regression model that considered factors associated with odds of anemia, diabetes status, and both EGFR categories <30 and 30–59 mL/min/1.73m2 were significantly associated with increased likelihood of anemia (Table 2). Results from
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Table 3. Mean hemoglobin (HGB) for 10 mL/min/1.73m2 increments of EGFR stratified by diabetes status and sex EGFR mL/min/1.73m2 >80 71–80 61–70 51–60 41–50 31–40 <31
Men with diabetes 14.6 14.5 14.1 13.9 (P = 0.006) 13.3 (P < 0.001) 12.2 (P < 0.001) 12.2 (P < 0.001)
Men without diabetes
Women with diabetes
Mean HGB g/dL (P value a ) 14.7 13.0 14.9 13.4 14.8 13.4 14.7 13.1 14.3 12.9 14.2 12.4 12.8 (P < 0.001) 10.8 (P < 0.001)
Women without diabetes 12.9 13.2 13.3 13.5 13.2 13.0 11.2 (P < 0.001)
a P value for the difference in mean HGB at each strata from mean HGB at EGFR >80 mL/min/1.73m2 of corresponding column; only statistically significant (<0.05) values are presented.
these analyses also indicated increased odds of anemia with older age, among women, and among African American, Hispanic, and other non-white participants. In a similar separate model, a significant sex-diabetes interaction was identified (OR 4.3, 95% CI 2.2–8.5, P < .001), indicating that relative to sex-matched participants without diabetes, men with diabetes had greater odds of anemia than women with diabetes. In unadjusted analyses, men with diabetes were more likely than men without diabetes to have anemia (8.0% vs. 1.1%, OR 7.6, 95% CI 4.1–14.1, P < .001), as were women with diabetes compared to women without diabetes (13.7% vs. 8.6%, OR 1.7, 95% CI 1.3–2.1, P < .001); however, differential odds of anemia by diabetes status for men and women were apparent (Breslow-Day test for homogeneity of ORs, P < .001). Mean hemoglobin values were significantly lower for men with diabetes compared to men without diabetes (14.2 g/dL vs. 14.7 g/dL, P < .001), but were not different for women with and without diabetes (13.1 g/dL for both, P = .69). In Table 3, mean hemoglobin values were compared in 10 mL/min/1.73m2 increments of EGFR for men and women stratified by diabetes status; category-specific mean hemoglobin values at multiple EGFR strata were compared for differences with mean hemoglobin values at EGFR >80 mL/min/1.73m2 . Among men with diabetes, significantly lower mean hemoglobin values were observed at all EGFR categories less than 60 mL/min/ 1.73m2 . In contrast, among women with diabetes and among men and women without diabetes, significantly lower mean hemoglobin values were not apparent until more advanced levels of kidney dysfunction (EGFR <31 mL/min/1.73m2 ).
DISCUSSION We examined the prevalence of anemia across a broad range of kidney function according to diabetes status, among individuals at increased risk of kidney disease participating in a community-based screening program
that targeted persons with risk factors for CKD. There were significant differences in the prevalence of anemia (and mean hemoglobin values) between persons with and without diabetes at levels of moderately impaired kidney function (EGFR 30–59 mL/min/1.73m2 –CKD 3). This interesting relationship was less evident in the mildly impaired and normal levels of kidney function—EGFR ≥60 mL/min/1.73m2 (CKD 1, 2). At the level of severely impaired kidney function (EGFR <30 mL/min/1.73m2 – CKD 4, 5), anemia was frequently identified (51%), but with no significant difference in prevalence of anemia by diabetes status, possibly due to the small number of studied subjects. In multivariable models adjusted for participant demographic characteristics, diabetes status and both moderate (EGFR 30–59 mL/min/1.73m2 –CKD 3) and significant (EGFR <30 mL/min/1.73m2 –CKD 4, 5) reductions in kidney function were associated with increased odds of anemia. Both men and women with diabetes had increased prevalence of anemia; however, diabetes conferred greater odds of anemia in men than in women. Our findings of increased odds of anemia among older participants and among African American and Hispanic participants are consistent with findings from recent analyses of a population-based survey evaluating the health status of the United States population [2]. That study also found, as we did, greater overall prevalence of anemia among women compared with men; prevalence estimates were higher in our study for both men and women, as our study targeted an at-risk rather than general population. We used the K/DOQI definition of anemia that warrants investigation in chronic renal insufficiency [10]; however, several other definitions of anemia have been developed and published [2, 16, 17]. Analyses carried out using these other definitions (data not shown) generated similar results and identical conclusions, even though prevalence varied. We used the simplified Modification of Diet in Renal Disease (MDRD) formula to calculate EGFR values (mL/min/1.73m2 ); this validated formula was
El-Achkar et al: Anemia with diabetes and reduced kidney function
derived from measured GFR, and uses only demographic characteristics and serum creatinine values to estimate GFR [14]. Other formulas, including the widely used Cockcroft-Gault formula [18], have also been used to estimate level of kidney function (creatinine clearance). Analyses carried out using EGFR values calculated based on the body surface area adjusted-Cockcroft-Gault formula (data not shown) confirmed the findings presented. The relationship of diabetes to anemia has been classically related to advanced kidney damage and uremia. Anemia is a common manifestation of chronic kidney failure, and contributes to multiple adverse outcomes, possibly via decreased tissue oxygen delivery and utilization [10, 19]. A significant correlation between hematocrit and creatinine clearance was found to occur below 40 mL/min/1.73m2 in an earlier study, and when GFR fell below 20 mL/min/1.73m2 in another study [3, 4]. Hsu et al demonstrated that hematocrit decreased progressively below EGFR of 50 mL/min/1.73m2 in men and women, with men having a larger decrease in hematocrit [1]; this observation is consistent with our findings among KEEP participants. Similar observations were made recently using health status survey data from a representative sample of the United States population [2, 20]. It is important to note, however, that diabetes status was not considered in these studies. Low levels of erythropoietin have been observed in persons with anemia and either type 1 or type 2 diabetes, but without advanced renal disease or overt uremia [7–9]. For example, Bosman et al found that 13 of 27 patients with type 1 diabetes, nephropathy, and serum creatinine <2 mg/dL had unexplained anemia with relatively low erythropoietin levels, compared to none of 26 patients without diabetes but with glomerulonephritis [8]. Similarly, hemoglobin was lower in 19 patients with type 2 diabetes and kidney failure compared with 21 patients without diabetes who also had kidney failure and comparable serum creatinine levels [9]. These studies typically used clinic populations, had small sample sizes, and none documented, as we did, a link between anemia and a specific level of glomerular filtration rate in persons with diabetes. There are several plausible mechanisms that may explain the link between diabetes and anemia, as well as the differential diabetes-related anemia risk in men compared with women. Renal denervation attributable to diabetic autonomic neuropathy can reduce splanchnic sympathetic stimulation of erythropoietin production [7, 8, 21]. Also, diabetes may adversely affect peritubular and interstitial structures in the renal cortex, the site of erythropoietin production, even prior to the development of overt nephropathy. This may attenuate the release of erythropoietin in response to the hypoxic stimuli of anemia [8, 22]. Furthermore, both diabetes and reduced kidney function have been linked to depressed androgen levels
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[23]. Androgens stimulate erythropoiesis by increasing erythropoietin production and by direct augmentation of marrow stem cells [24]. Finally, kidney failure has been associated with reduced testosterone levels in men [25]. On the other hand, premenopausal and postmenopausal women with diabetes have higher bioavailable testosterone levels then women without diabetes [26]. An important issue to consider is what absolute drop in hemoglobin would be considered clinically relevant, thus prompting treatment in CKD. Despite the presence of guidelines for desirable hemoglobin in CKD [10], the issue remains controversial, as most publications deal with treatment after development of anemia, and none, as yet, has examined the effect of avoidance of anemia on clinical outcomes [27]. Recently, the contribution of anemia to cardiomyopathy in kidney failure has been examined [27, 28]. Previous studies have demonstrated that even minor drops in hemoglobin (0.5–1.0 g/dL) may augment the risk of developing left ventricular hypertrophy in persons with kidney dysfunction [29], may increase risks of mortality and heart failure [30], and may lead to a more rapid loss of kidney function in persons with diabetic nephropathy [11]. Our study has several limitations. First, we cannot rule out the possibility that other comorbid conditions, such as iron-deficiency or other etiologies of anemia, may have been differentially distributed across the KEEP population according to gender and diabetes status. Also, we have no information regarding the types of medications [e.g., renin angiotensin system (RAS) drugs, erythropoietin] participants were taking. This might be viewed as a major limitation of our study given that angiotensinconverting enzyme (ACE) inhibitors are recommended treatments for persons with diabetes, and are known to depress erythropoiesis [31]. However, if our findings were explained by use of RAS agents, we would have to postulate differential exposure and/or effect on erythropoiesis among men and women. Furthermore, we may have misclassified diabetes status given our lack of detailed information regarding medications, as well as because fasting blood glucose levels were not routinely available; however, 95% of those so categorized reported a diabetes diagnosis. In addition, our study has the limitations common to cross-sectional epidemiologic investigations that preclude the determination of causal associations. Finally, the study was a targeted-screening of individuals at risk for CKD and, thus, is not a representative sampling of the United States population. Self-selection bias is inherent when recruitment strategies rely on volunteer participants [12]; persons who participate in screening programs tend to be those who are health conscious and better educated. The predominance of women attending KEEP screenings is consistent with previous observations that women are more likely than men to utilize preventive health services [32, 33].
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CONCLUSION In a community-based screening, the prevalence of anemia was increased at less depressed levels of EGFR in persons with diabetes compared to persons without diabetes. Both men and women with diabetes had increased prevalence of anemia; however, diabetes conferred greater odds of anemia in men than in women. These observations are biologically plausible and provocative. Nevertheless, these findings require confirmation in other cohorts that have more complete patient-level data, including information on medication exposures. ACKNOWLEDGMENTS The Kidney Early Evaluation Program (KEEP)TM is a program of the National Kidney Foundation, Inc., and was supported by Ortho Biotech and Bayer Diagnostics. Reprint requests to John M. Flack, M.D., M.P.H., Wayne State University and the Detroit Medical Center, University Health Center, Suite 2E, 4201 St. Antoine, Detroit, MI 48201. E-mail: [email protected]
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