Early detection of kidney disease in community settings: the kidney early evaluation program (KEEP)

ORIGINAL INVESTIGATIONS Pathogenesis and Treatment of Kidney Disease and Hypertension

Early Detection of Kidney Disease in Community Settings: The Kidney Early Evaluation Program (KEEP) Wendy Weinstock Brown, MD, MPH, Rosalind M. Peters, PhD, RN, Suzanne E. Ohmit, DrPH, William F. Keane, MD, Allan Collins, MD, Shu-Chen Chen, MS, Karren King, MSW, Michael J. Klag, MD, Donald A. Molony, MD, and John M. Flack, MD, MPH ● Background: Early identification of persons at risk for kidney disease provides an opportunity to prevent or delay its progression and decrease morbidity and mortality. Our hypothesis was that implementation of a targeted screening program in communities with high-risk populations would detect previously unidentified persons with or at high risk for chronic kidney disease (CKD) with a prevalence that exceeds that predicted for CKD in the general population. Methods: Persons with hypertension or diabetes or a first-order relative with hypertension, diabetes, or kidney disease were screened for kidney disease risk factors. Blood pressure, blood glucose level, serum creatinine level, hemoglobin level, microalbuminuria, hematuria, pyuria, body mass index, and estimated glomerular filtration rate (EGFR) were evaluated. Results: Six thousand seventy-one eligible persons were screened from August 2000 through December 2001: of these persons, 68% were women, 43% were African American, 36% were white, 10% were Hispanic, and 5% were Native American. Most reported high-school education or more (84%) and health insurance coverage (86%). Twenty-seven percent met the screening definitions for diabetes; 64%, for hypertension; 29%, for microalbuminuria; 8%, for anemia; 18%, for hematuria; 13%, for pyuria; 5%, for elevated serum creatinine level; 16%, for reduced EGFR; and 44%, for obesity. Among participants without a reported history of specified conditions, screening identified 82 participants (2%) with diabetes, 1,014 participants (35%) with hypertension, 277 participants (5%) with elevated serum creatinine levels, 839 participants (14%) with reduced EGFRs, and 1,712 participants (29%) with microalbuminuria. Thirty-five percent of participants with a history of diabetes had elevated serum glucose levels at screening (>180 mg/dL [10 mmol/L]), and 64% with a history of hypertension did not have blood pressure controlled to less than 140/90 mm Hg. Only 18% of participants with a history of diabetes and 31% with a reduced EGFR had blood pressure controlled to less than 130/80 mm Hg and less than 135/85 mm Hg, respectively. Conclusion: Targeted screening is effective in identifying persons with previously unidentified or poorly controlled kidney disease risk factors, as well as persons with a moderately decreased EGFR. Am J Kidney Dis 42:22-35. © 2003 by the National Kidney Foundation, Inc. INDEX WORDS: Chronic kidney disease (CKD); creatinine; diabetes; early intervention; estimated glomerular filtration rate (EGFR); hypertension; Kidney Disease Outcomes Quality Initiative (K/DOQI); Kidney Early Evaluation Program™ (KEEP 2.0™); microalbuminuria; screening.

K

IDNEY DISEASE is a common progressive health problem contributing to significant morbidity and mortality. In the United States, it is the ninth leading cause of death.1 The number of persons with end-stage renal disease

(ESRD) doubled between 1988 and 1997, and although the annual mortality rate for patients with ESRD has decreased in recent years, it is still greater than that for advanced cancer of the colon or breast.2 Human and economic costs of

From the Division of Nephrology, St Louis VA Medical Center, St Louis University School of Medicine, St Louis; College of Nursing; and Department of Medicine, Wayne State University, Detroit, MI; Hennepin County Medical Center, University of Minnesota Medical School, Minneapolis, MN; Minneapolis Medical Research Foundation, Minneapolis, MN; Johns Hopkins Medical Institutions, Baltimore, MD; and the University of Texas Houston Health Science Center, Houston, TX. Received August 17, 2002; accepted in revised form February 27, 2003. The Kidney Early Evaluation Program (KEEP) is a pro-

gram of the National Kidney Foundation, Inc. KEEP was supported by Ortho Biotech Products, LP, with additional support from Bayer Diagnostics; Satellite Laboratory Services of Redwood City, CA; Satellite Healthcare; and Ocean Spray. Address reprint requests to Wendy Weinstock Brown, MD, Professor in Internal Medicine, St Louis University School of Medicine, Director, Clinical Nephrology, St Louis VA Medical Center, 915 N Grand Blvd, St Louis, MO 631061621. E-mail: [email protected] © 2003 by the National Kidney Foundation, Inc. 0272-6386/03/4201-0003$30.00/0 doi:10.1016/S0272-6386(03)00405-0

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American Journal of Kidney Diseases, Vol 42, No 1 (July), 2003: pp 22-35

THE KIDNEY EARLY EVALUATION PROGRAM

ESRD are high: in 1999, more than 400,000 Americans required dialysis therapy and/or transplantation for kidney failure, and Medicare medical expenditure for ESRD care was more than $11 billion.3 Furthermore, the burden on the health of the population from chronic kidney disease (CKD) is much greater than that attributable to ESRD alone. The Third National Health and Nutrition Examination Survey (NHANES III) estimated that more than 5.5 million Americans have early stages of CKD, determined by elevated serum creatinine levels (ⱖ1.6 mg/dL [ⱖ141 ␮mol/L] for men and ⱖ1.4 mg/dL [ⱖ124 ␮mol/L] for women).4 The NHANES III found diabetes, hypertension, older age, male sex, and non-Hispanic black race to be positively associated with increased likelihood of elevated serum creatinine levels.4,5 In addition, familial aggregation of CKD has been found to occur in excess of that predicted by clustering of diabetes and hypertension within families.6 Numerous studies have shown that such effective interventions as excellent glycemic control in persons with diabetes,7-9 aggressive blood pressure control,10-14 correction of dyslipidemias,15,16 phosphorous control,17 reduction of proteinuria with angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers,18-20 reduction of cardiac risk factors,21 appropriate diet,22-24 and lifestyle modification25,26 can prevent kidney disease or delay its progression and decrease morbidity and mortality rates.2,27-30 The purpose of early diagnosis is early detection of asymptomatic disease at a time when intervention has a reasonable potential to have a positive impact on outcome. Mass screening of the general public for kidney disease is expensive, low yield, and not cost-effective. Therefore, primary objectives of this study were to: (1) evaluate the feasibility of detecting large numbers of previously unidentified persons with or at high risk for CKD in communities with at-risk populations, and (2) determine the prevalence of selected risk factors and level of kidney function within that group. After a pilot study conducted in 1997 in 21 cities found that 71.4% of 889 individuals screened had at least one abnormal test value,31 The Kidney Early Evaluation Program (KEEP 2.0) was developed. KEEP 2.0

23

focuses on individuals at increased risk for kidney disease and provides assessment of risk, individual counseling regarding recommendations for follow-up, and education about kidney disease and kidney disease risk factors. This initial report presents the KEEP 2.0 protocol and baseline characteristics of 6,071 participants screened from August 2000 through December 2001. METHODS

Participant Recruitment National Kidney Foundation (NKF) affiliates conducted 135 KEEP screening programs in 33 states. Screenings were advertised through local media (radio and television stations, newspapers), announcements by clergy from the pulpit, flyers, posters, and information provided to dialysis patients, with an emphasis on minority communities. Screening sites included churches, hospitals, health centers, schools, community centers, and dialysis units. Eligibility criteria for screening were age of 18 years or older and a first-degree relative with diabetes mellitus, hypertension, or kidney disease or a personal history of diabetes mellitus or hypertension. Recruitment efforts were concentrated in areas with large African-American populations because this group has a known high prevalence of diabetes and hypertension, two major risk factors for kidney disease, and a documented increased kidney disease risk for any level of hypertension and severity of diabetes.

Screening Protocol KEEP screenings were conducted by KEEP-trained and -certified NKF affiliate staff and lay and professional volunteers. After providing informed consent, individuals completed the Screening Questionnaire, a self-report instrument that collects information regarding sociodemographic status (eg, race/ethnicity, age, education), personal and family health history, and lifestyle behavior (eg, smoking). The Screening Questionnaire, along with a blood pressure measurement, established eligibility for screening based on inclusion criteria. Those who did not meet eligibility criteria were given educational material and encouraged to maintain a healthy lifestyle. Participant height and weight were obtained. Blood pressures were measured according to the guidelines presented in the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI).32 Blood glucose levels were tested using capillary blood (the Accucheck Advantage [Roche Pharmaceuticals, Mannheim, Germany] was the recommended glucose meter at the screening sites), and blood was obtained for measurement of hemoglobin (Hgb) and serum creatinine levels (Satellite Laboratory Services, Redwood City, CA). Spot urine specimens were collected and tested for microalbuminuria (Micral [Roche Pharmaceuticals, Indianapolis, IN] until September 2001, then Clinitek [Bayer Diagnostics, Tarrytown, PA]), pyuria, and hematuria (Bayer Diagnostics Multistick 7 dipstick). Additional assessment of

24

kidney function was done as a post hoc estimation of glomerular filtration rate (GFR).

Evaluation Criteria Screening values were compared with national norms to determine abnormal values and assess the prevalence of obesity, hypertension, diabetes, and decreased kidney function. The following criteria and definitions were used in this study. Obesity was determined based on body mass index (BMI) calculated using the formula: [(Weight in pounds * 0.4536)/(height in inches * 0.0254)] Participants were classified according to the 85th percentile as established in the NHANES survey guidelines in which BMI values of 30 or greater are considered obese.33 Glycemic status was evaluated in 2 ways: (1) participants who reported a history of diabetes and those with fasting blood glucose values greater than 125 mg/dL (7 mmol/L) or nonfasting blood glucose values greater than 200 mg/dL (11 mmol/L) were categorized as diabetic,34 and (2) participants with nonfasting blood glucose values of 180 mg/dL or greater (ⱖ10 mmol/L) were categorized as having elevated screening glucose levels. For hypertension, participants who reported current use of medications for hypertension and those with a systolic blood pressure (SBP) of 140 mm Hg or greater and/or diastolic blood pressure (DBP) of 90 mm Hg or greater at screening and who did not have diabetes or decreased kidney function based on estimated GFR (EGFR) were categorized as hypertensive.32 Participants with diabetes were considered to be hypertensive if SBP was 130 mm Hg or greater and/or DBP was 80 mm Hg or greater.35 Patients with an EFGR less than 60 mL/min/1.73 m2 were considered hypertensive if SBP was 135 mm Hg or greater and/or DBP was 85 mm Hg or greater.30 Kidney disease was assessed based on the presence or absence of microalbuminuria, pyuria, or hematuria; serum creatinine level; and EGFR. Microalbuminuria was evaluated by dipstick and considered present if reported as positive or trace or if microalbuminuria was greater than 20 mg/L (0.02 g/L). Elevated serum creatinine values were defined as 1.6 mg/dL or greater (ⱖ141 ␮mol/L) for men and 1.4 mg/dL or greater (ⱖ124 ␮mol/L) for women.4 EGFRs (mL/min/1.73 m2) were calculated using the Levey simplified Modification of Diet in Renal Disease (MDRD) formula: EGFR ⫽ (186.3 * [serum creatinine⫺1.154] * [age⫺0.203]) Calculated values were multiplied by 0.742 for women and 1.21 for African Americans.36,37 The Kidney Disease Outcomes Quality Initiative (K/DOQI) classification system was used to categorize kidney function based on EGFR from stage 0 to I (ⱖ90 mL/min) to stage IV to V (⬍30 mL/ min).2,30 Participants were considered to have a moderate reduction in kidney function if their EGFR values were less than 60 mL/min/1.73 m2. Anemia was defined as an Hgb level less than 12 g/dL (120 g/L) for men and women older than 50 years and less than 11 g/dL (110 g/L) for women 50 years or younger.

BROWN ET AL

Follow-Up Procedures At the completion of data collection, participants were given a copy of their test results and met individually with a physician who reviewed results of all screening values obtained on site, including blood pressure, blood glucose level, and results of urine dipstick testing. Participants with abnormal results were advised to contact their health care provider for a follow-up evaluation. A physician referral letter was provided for participants to take to that follow-up visit. Participants who did not have a health care provider and/or health insurance were given a list of local clinics and physicians who had agreed to see such participants for follow-up care. Participants also were given educational materials, including pamphlets about diabetes, hypertension, proteinuria, and CKD. Within a month of screening, participants were mailed a copy of all their test results (including Hgb, serum creatinine, and calculated creatinine clearance values). Participants with tests results outside normal limits that were not available the day of screening were personally contacted before they received the results package in the mail. Approximately 2 months after the screening, NKF national professional staff members contacted participants who had been encouraged to see their physician to determine if follow-up had occurred and whether abnormal test results had been corroborated.

Statistical Analysis Statistical analyses were generated using the SAS statistical program, version 8.0 (SAS Institute Inc, Cary, NC, 2001). Descriptive analyses were used to characterize the participant population by sociodemographic data (age, sex, race/ethnicity, health insurance status), health status (hypertension, diabetes, serum creatinine level, EGFR, microalbuminuria), and lifestyle factors (smoking, obesity). Prevalences and mean values of selected conditions by sex, age, and race/ethnicity were examined using chi-square statistics for categorical variables and Wilcoxon’s rank sum for continuous values. Multivariate analyses were performed to assess the association of screening population demographic and health characteristics with the presence of microalbuminuria or level of EGFR.

RESULTS

Sociodemographic Characteristics of Participants Of 6,851 individuals who attended the screening programs, 6,071 people were eligible for inclusion in this analysis based on inclusion criteria (Fig 1). Demographic and lifestyle data are listed in Table 1. Participants screened during the first 17 months of the KEEP program were predominately African American, women, middle aged (mean age, 52 ⫾ 15.6 [SD] years; range, 18 to 101 years), well educated, with some form of health insurance, and with access to health care providers.

THE KIDNEY EARLY EVALUATION PROGRAM

25

Fig 1. Eligibility criteria of participants at time of screening.

Lifestyle behaviors. Forty-five percent of participants reported a smoking history; 14% were current smokers. Forty-four percent of participants were considered obese (BMI ⱖ 30.0), including 46% of women and 39% of men. Health Characteristics of Subjects Diabetes mellitus. Twenty-seven percent (n ⫽ 1,580) of participants were categorized as diabetic, and 10% of participants had elevated screening glucose levels (Table 2). Twenty-five percent (n ⫽ 1,498) of participants reported a known history of diabetes, and 82 additional participants (2% of those without a history of known diabetes) met the screening definition for diabetes (Table 3). Among participants with a known history of diabetes, 35% had elevated glucose levels at screening (ⱖ180 mg/dL [ⱖ10 mmol/L]). Among participants without a history of diabetes, 2% had elevated serum glucose levels at screening (ⱖ180 mg/dL [ⱖ10 mmol/ L]). Only 18% of participants with a history of diabetes had blood pressure controlled to the

American Diabetes Association and National Diabetes Education Program recommended target blood pressure levels of less than 130/80 mm Hg,35 and only 23% had blood pressure controlled to the JNC VI goal of less than 130/85 mm Hg.32 Hypertension. Participants were categorized as hypertensive based on either reported use of antihypertensive medication or a measured blood pressure using JNC VI guidelines,32 based on the higher of their SBP or DBP values. JNC VI stages and participant results are listed in Table 2. Sixty-four percent of participants were categorized as hypertensive based on the hypertension definition (with comorbidities considered) described under evaluation criteria. At screening, 47% of participants were categorized as having elevated blood pressures (SBP ⱖ 140 mm Hg or DBP ⱖ 90 mm Hg); 17% of participants were at JNC VI stages II or III. Fifty-two percent of participants (n ⫽ 3,143) reported a history of hypertension and/or hypertension medication use at screening; 1,014 additional participants (35%

26

BROWN ET AL Table 1.

Age (y) Age categories (y) 18-30 31-45 46-60 61-75 ⬎75 Race/ethnicity African American White Hispanic Native American Asian/Pacific Islander Other/unknown ⱖHigh-school education Current smoker Obesity (BMI ⱖ 30.0) Health insurance coverage Doctor visit (within last year)

Sociodemographic Characteristics of Eligible Screening Population Men (n ⫽ 1,956)

Women (n ⫽ 4,115)

Total* (n ⫽ 6,071)

52.9 ⫾ 15.4 (18-101)

52.0 ⫾ 15.7 (18-100)

52.3 ⫾ 15.6 (18-101)

0.038

171 (8.7) 467 (23.9) 665 (34.0) 514 (26.3) 139 (7.1)

396 (9.6) 1,017 (24.7) 1,432 (34.8) 984 (23.9) 286 (7.0)

567 (9.3) 1,484 (24.4) 2,097 (34.5) 1,498 (24.7) 425 (7.0)

0.31

821 (42.0) 721 (36.9) 200 (10.2) 89 (4.6) 82 (4.2) 43 (2.2) 1,610 (83.6) 323 (17.6) 751 (38.8) 1,620 (85.0) 1,582 (80.9)

1,803 (43.8) 1,437 (34.9) 428 (10.4) 223 (5.4) 139 (3.4) 85 (2.1) 3,426 (84.5) 476 (12.4) 1,865 (46.1) 3,501 (86.7) 3,679 (89.4)

2,624 (43.2) 2,158 (35.6) 628 (10.3) 312 (5.1) 221 (3.6) 128 (2.1) 5,036 (84.2) 799 (14.1) 2,616 (43.7) 5,121 (86.1) 5,261 (86.7)

0.22

P

0.35 ⬍0.001 ⬍0.001 0.08 ⬍0.001

NOTE. Values expressed as mean ⫾ SD (range) or number (percent). *Percentages based on responding number, not total participant number.

of those without a history of hypertension) met the screening definition for hypertension (Table 3). Among participants with a hypertension history, 64% did not have blood pressure controlled to an SBP less than 140 mm Hg and DBP less than 90 mm Hg. Kidney disease. Assessment of kidney disease was based on the presence or absence of microalbuminuria, pyuria, or hematuria; serum creatinine level; and EGFR (Table 2). Three percent of participants (n ⫽ 156) reported a history of kidney disease at the time of screening. Microalbuminuria was found in 29% of participants, with 96% of those cases (n ⫽ 1,712) occurring in participants without a reported history of kidney disease (Table 3). Among participants with microalbuminuria, 34% met the study definition for diabetes and 14% met the study definition for elevated serum glucose levels. Eighteen percent of participants had hematuria and 13% had pyuria. Sixteen percent of participants with EGFR test results had EGFR values less than 60 mL/min/1.73 m2 (n ⫽ 898), and 93% of these participants (n ⫽ 839) with an EGFR less than 60 mL/min/1.73 m2 did not report a history of kidney disease (Table 3). Figure 2 shows the prevalence of microalbuminuria, abnormal se-

rum creatinine levels, pyuria, or hematuria by level of EGFR. Figure 3 shows the prevalence of diabetes and hypertension by K/DOQI category of EGFR. Despite the relatively high prevalence of microalbuminuria and low EGFR, only 5.4% of participants (n ⫽ 311) had elevated serum creatinine values, and 89% of participants (n ⫽ 277) with elevated serum creatinine levels did not report a history of kidney disease (Table 3). Only 31% of participants with an EGFR less than 60 mL/min/1.73 m2 and 27% of those with elevated serum creatinine levels had blood pressure controlled to K/DOQI comorbidity-specific blood pressure levels of less than 135/85 mm Hg.30 Only 23% of participants with an EGFR less than 60 mL/min/1.73 m2 and 20% with an elevated serum creatinine level had disease controlled to the JNC VI blood pressure target level of 130/85 mmHg or less.30,32 Anemia. Eight percent of participants met the definition of anemia: 3% of men and 10% of women (Table 2). Mean Hgb concentration was highest in Asians (14.0 ⫾ 1.5 g/dL [140 ⫾ 15 g/L]) and lowest in African Americans (13.2 ⫾. 1.5 g/dL [132 ⫾ 15 g/L]). Using the K/DOQI definition of anemia, 9.4% of African Americans

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27

Table 2.

Health Characteristics

Men (n ⫽ 1,956)

Family history of hypertension, diabetes, or kidney disease Glycemic control Diabetes (reported diabetes or blood glucose ⬎ 125 mg/dL if fasting, else ⬎ 200 mg/dL) Elevated nonfasting screening glucose (⬎ 180 mg/dL) Hypertension status Hypertension (antihypertensives or SBP ⬎ 139 mm Hg or DBP ⬎ 89 mm Hg) Comorbidity-specific hypertension (antihypertensives or SBP ⬎ 140 mm Hg and/or DBP ⬎ 90 mm Hg; if diabetic, SBP ⬎ 130 mm Hg and/or DBP ⬎ 80 mm Hg; if EGFR ⬍ 60 mL/min/1.73 m2 SBP ⬎ 135 mm Hg and/or DBP ⬎ 85 mm Hg) JNC VI hypertension classification Normal (SBP ⬍ 130 mm Hg, DBP ⬍ 85 mm Hg) High-normal (SBP 130-139 mm Hg, DBP 85-89 mm Hg) Stage I (SBP 140-159 mm Hg, DBP 90-99 mm Hg) Stage II (SBP 160-179 mm Hg, 100-109 mm Hg) Stage III (SBP ⱖ 180 mm Hg, DBP ⱖ 110 mm Hg) Kidney disease Elevated serum creatinine (men ⱖ 1.6 mg/dL, women ⱖ 1.4 mg/dL) Microalbuminuria (present if positive, trace, or ⬎ 20 mg/L) EGFR based on MDRD formula EGFR by K/DOQI classification (mL/min/ 1.73 m2) Stage 0-I (EGFR ⱖ 90) Stage II (EGFR 60-89) Stage III (EGFR 30-59) Stage IV-V (EGFR ⬍ 30) EGFR ⬍ 60 mL/min/1.73 m2 Anemia Hgb ⬍ 12 g/dL for men and women ⬎ 50 y; ⬍ 11 g/dL for women ⱕ 50 y) Hematuria Pyuria

Women (n ⫽ 4,115)

Total* (N ⫽ 6,071)

P

1,753 (89.6)

3,871 (94.1)

5,624 (92.6)

⬍0.001

577 (30.1)

1,003 (25.4)

1,580 (26.9)

⬍0.001

239 (12.6)

351 (9.0)

590 (10.1)

⬍0.001

1,238 (63.8)

2,414 (59.3)

3,652 (60.8)

0.001

1,321 (68.1)

2,538 (62.4)

3,859 (64.2)

⬍0.001

591 (30.5)

1,479 (36.6)

2,070 (34.6)

⬍0.001

358 (18.5)

715 (17.7)

1,073 (17.9)

635 (32.8)

1,159 (28.7)

1,794 (30.0)

254 (13.1)

515 (12.7)

769 (12.9)

101 (5.2)

176 (4.4)

277 (4.6)

156 (8.3)

155 (4.0)

311 (5.4)

⬍0.001

594 (30.4)

1184 (28.8)

1778 (29.3)

0.20

81.7 ⫾ 23.8 (10-239)

81.8 ⫾ 23.3 (7-239)

0.08

1,312 (33.8) 1,946 (50.1) 603 (15.5) 25 (0.6) 628 (16.2) 367 (9.9)

1,962 (34.1) 2,897 (50.3) 854 (14.8) 44 (0.8) 898 (15.6) 425 (7.7)

0.09

0.09 ⬍0.001

1,053 (18.1) 753 (12.9)

⬍0.001 ⬍0.001

82.0 ⫾ 22.3 (7-207)

650 (34.7) 951 (50.8) 251 (13.4) 19 (1.0) 270 (14.4) 58 (3.2) 231 (12.1) 65 (3.4)

822 (21.0)† 688 (17.4)

NOTE. Values expressed as number (percent) or mean ⫾ SD (range). To convert glucose in mg/dL to mmol/L, multiply by 0.05551; creatinine in mg/dL to ␮mol/L, multiply by 88.4; hemoglobin in g/dL to g/L, multiply by 10. *Percentages based on responding number not total participant number. †Women reporting not menstruating at the time of screening.

were anemic versus 4.3% of whites. By sex, mean Hgb level was highest in white women (13.4 ⫾ 1.2 g/dL [134 ⫾ 12 g/L]), lowest in African-American women (12.7 ⫾ 1.3 g/dL

[127 ⫾ 13 g/L]), highest in Asian men (15.0 ⫾ 1.2 g/dL [150 ⫾ 12 g/L]), and lowest in AfricanAmerican men (14.3 ⫾ 1.2 g/dL [143 ⫾ 12 g/L]). Hgb values did not differ significantly

28 Table 3.

BROWN ET AL New Conditions Identified Through KEEP 2.0 Screening

Condition

Diabetes Hypertension Kidney disease GFR ⬍ 60 mL/min/1.73 m2 1 Serum creatinine Microalbuminuria Pyuria Men Women Hematuria Men Women* Anemia Men Women

No. of Persons

Eligible Participants Without Known History of the Condition (%)

82 1,014

2 35

839 277 1,712

14 4.5 28

65 688

3.4 17.4

231 822

12.1 21

58 367

3.2 9.9

*Excludes women who said they were currently menstruating.

among age groups within each sex and race, but the same disparities persisted between race and sex. Mean Hgb level was lower in all ethnic groups except Pacific Islanders when the individual had diabetes mellitus or a family member with diabetes mellitus. Of those with diabetes mellitus, 11% were anemic compared with 5.8% of those without diabetes mellitus. Mean Hgb level was lower in African Americans and Pacific Islanders with hypertension and lower in whites, African Americans, and Asians with a family

member with hypertension. As expected, there was a decrease in mean Hgb level with decreasing EGFR, but African Americans had lower mean Hgb levels than whites at every K/DOQI level of EGFR. Mean Hgb level also was lower in whites, African Americans, and American Indian/Native Alaskans who had a family member with kidney disease. Associations of Health Status With Demographic Characteristics Sex differences were noted for a number of health indicators (Table 2). Men were significantly more likely than women to be classified as diabetic (P ⬍ 0.001), have hypertension (P ⬍ 0.001), and have an elevated serum creatinine level (P ⬍ 0.001). The likelihood of microalbuminuria did not significantly differ by sex. Women were more likely than men to be anemic (P ⬍ 0.001), have hematuria (P ⬍ 0.001), and have pyuria (P ⬍ 0.001). Women were slightly more likely than men to have reduced kidney function measured by an EGFR less than 60 mL/min/1.73 m2, but this was not statistically significant. Race/ethnicity differences also were noted for a variety of health indices (Table 4). Among women, African-American and white participants were significantly less likely than other racial groups to have diabetes, and AfricanAmerican women were most likely to have hypertension. White women were more likely than other women to have reduced kidney function measured by an EGFR less than 60 mL/min/1.73

Fig 2. Prevalence (%) of selected conditions by EGFR.

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29

Fig 3. Prevalence (%) of selected conditions by EGFR.

m2, but were least likely to have microalbuminuria. Among men, African-American participants were less likely than others to have diabetes or reduced kidney function measured by an EGFR less than 60 mL/min/1.73 m2. The likelihood of hypertension, elevated serum creatinine level, and microalbuminuria did not significantly differ by race/ethnicity among men. Age also influenced the prevalence of health indices (Table 5). The likelihood of hypertension, diabetes, and reduced kidney function (measured by an EGFR ⬍ 60 mL/min/1.73 m2, elevated serum creatinine level, and presence of microalbuminuria) all increased with age for both men and women. Eighty-three percent of participants older than 60 years met the screening definitions for hypertension, 39% met the screening definitions for diabetes, 32% had Table 4.

EGFRs less than 60 mL/min/1.73 m2, 10% had elevated serum creatinine levels, and 32% had microalbuminuria. An elevated serum creatinine level as defined for this screening correctly identified most individuals with significantly depressed EGFR only for men younger than 46 years. For all age strata, the number of women with an EGFR less than 60 mL/min/1.73 m2 was markedly underestimated by the serum creatinine level threshold chosen for this screening. Underestimation of number of individuals with reduced EGFRs increased with age for both men and women. Multivariate Analyses Persons of African-American, Native-American, or Asian/Pacific Islander race compared with whites and those with systolic or diastolic

Prevalence of Selected Health Conditions by Categories of Race/Ethnicity for Men and Women African American

Diabetes Men Women Hypertension Men Women EGFR ⬍ 60 mL/min/1.73 m2 Men Women 1 Serum creatinine (mg/dL) Men ⱖ 1.6 Women ⱖ 1.4 Microalbuminuria Men Women

White

Hispanic

Other

P

206 (25.7) 397 (23.2)

225 (31.8) 329 (23.7)

60 (30.9) 125 (29.6)

86 (40.6) 152 (35.1)

⬍0.001 ⬍0.001

546 (67.4) 1,170 (65.8)

501 (70.0) 875 (61.5)

123 (61.5) 217 (50.9)

151 (70.6) 276 (62.2)

0.11 ⬍0.001

68 (8.8) 171 (10.3)

121 (17.3) 307 (22.3)

41 (21.5) 64 (15.7)

40 (19.4) 86 (19.9)

⬍0.001 ⬍0.001

74 (9.6) 79 (4.7)

49 (7.0) 48 (3.5)

14 (7.3) 6 (1.5)

19 (9.2) 22 (5.1)

245 (29.8) 586 (32.5)

218 (30.3) 337 (23.5)

60 (30.0) 124 (29.0)

71 (33.2) 137 (30.7)

NOTE. Values expressed as number (percent). To convert creatinine in mg/dL to ␮mol/L, multiply by 88.4.

0.31 0.009 0.82 ⬍0.001

30

BROWN ET AL Table 5.

Prevalence of Selected Health Conditions by Age Category for Men and Women Age (y) 18-30

Diabetes Men Women Hypertension Men Women EGFR ⬍ 60 mL/min/1.73 m2 Men Women Elevated serum creatinine (mg/dL) Men ⱖ 1.6 Women ⱖ 1.4 Microalbuminuria Men Women

⬎75

31-45

46-60

61-75

P

12 (7.2) 31 (8.2)

65 (14.3) 168 (17.4)

206 (31.7) 366 (26.5)

233 (46.1) 349 (36.6)

61 (43.9) 89 (32.6)

⬍0.001 ⬍0.001

50 (29.4) 61 (15.6)

225 (48.8) 412 (41.4)

487 (73.8) 983 (69.2)

442 (86.5) 837 (85.6)

117 (84.8) 245 (86.3)

⬍0.001 ⬍0.001

4 (2.4) 10 (2.7)

24 (5.4) 61 (6.4)

60 (9.5) 156 (11.5)

120 (24.3) 280 (29.9)

62 (45.6) 121 (45.0)

⬍0.001 ⬍0.001

5 (3.0) 3 (0.8)

23 (5.2) 15 (1.6)

39 (6.2) 40 (2.9)

60 (12.2) 66 (7.0)

29 (21.3) 31 (11.5)

⬍0.001 ⬍0.001

48 (28.1) 96 (24.2)

123 (26.3) 285 (28.1)

197 (29.6) 420 (29.3)

167 (32.6) 287 (29.2)

59 (42.5) 96 (33.6)

0.005 0.10

NOTE. Values expressed as number (percent). To convert creatinine in mg/dL to ␮mol/L, multiply by 88.4.

hypertension, diabetes, or an EFGR less than 60 mL/min/1.73 m2 were significantly more likely to have microalbuminuria (Table 6). Older age, male sex, African-American race, and presence of diabetes, anemia, and/or microalbuminuria showed a significant association with EFGRs less than 60 mL/min/1.73 m2 (Table 7). Follow-Up Data Twenty-seven percent of the 5,707 participants with abnormal test results responded to a phone call Table 6.

or letter (Table 8). Of those who responded, 68% consulted a physician; 1 or more diagnoses were corroborated in 22% of those who saw a physician (227 of 1,053 participants who responded). Hypertension was corroborated in 148 persons; diabetes, in 53 persons; and kidney disease, in 74 persons (275 diagnoses in 227 persons). DISCUSSION

The worldwide epidemic of ESRD has led to concerns about the burden of mild to moderate

Multivariate Analysis: Associations of Population Demographic and Health Characteristics With Microalbuminuria

Age Male sex Race African American Native American Asian/Pacific Islander Other race White Ethnicity Hispanic Non-Hispanic Hypertension, systolic Hypertension, diastolic Diabetes Anemia EGFR ⬍ 60 mL/min/1.73 m2

Odds Ratio

95% Confidence Interval

P

1.0000 1.0470

0.9950-1.0040 0.9180-1.1940

0.8459 0.4977

1.4620 1.5480 1.4180 1.1020 Reference

1.2700-1.6840 1.1720-2.0450 1.0400-1.9320 0.7850-1.5480

⬍0.0001 0.0021 0.0272 0.5736

1.1750 Reference 1.1680 1.4380 1.6190 1.1980 1.3170

0.8650-1.5970

0.3017

1.0110-1.3500 1.2300-1.6820 1.4110-1.8570 1.0000-1.4360 1.1100-1.5640

0.0350 ⬍0.0001 ⬍0.0001 0.0504 0.0016

NOTE. N ⫽ 5,163 excluding noneligible, missing sex, missing race, missing hypertension, missing diabetes status, missing Hgb level, missing microalbuminuria, missing EGFR.

THE KIDNEY EARLY EVALUATION PROGRAM Table 7.

31

Multivariate Analysis: Associations of Population Demographic and Health Characteristics With Kidney Function

Age Male sex Race African American Native American Asian/Pacific Islander Other race White Ethnicity Hispanic Non-Hispanic Hypertension, systolic Hypertension, diastolic Diabetes Anemia Microalbuminuria

Odds Ratio

95% Confidence Interval

P

1.0640 0.7980

1.0570-1.0710 0.6670-0.9540

⬍0.0001 0.0134

0.3950 0.8210 0.8950

0.3260-0.4780 0.5740-1.1730 0.5940-1.3480

⬍0.0001 0.2779 0.5956

1.1260 Reference

0.7330-1.7280

0.5880

1.0070 Reference 1.1650 1.0310 1.2460 1.6310 1.2970

0.6820-1.4880

0.9713

0.9730-1.3960 0.8320-1.2770 1.0480-1.4810 1.3150-2.0230 1.0900-1.5420

0.0972 0.7809 0.0128 ⬍0.001 0.0033

NOTE. N ⫽ 5,163 excluding non-eligible, missing sex, missing race, missing hypertension, missing diabetes status, missing Hgb level, missing microalbuminuria, missing EGFR. Kidney function indicated by EGFR less than 60.

CKD in the general population.2,30 Mild CKD appears to be very common, as recently reported in the NKF K/DOQI guidelines.2,4,30 The adverse outcomes of CKD can be prevented or delayed Table 8.

through early detection and early intervention strategies. The KEEP 2.0 program shows the effectiveness of community-based targeted health screening programs in identifying large numbers

Results of Follow-Up in KEEP 2.0 Participants No. of Eligible Participants

Screening results Normal Abnormal Total Sent letter or called for follow-up Responded Did not respond Total Responded by Mail Phone Total Responders consulted physician Yes No Total Responders with ⱖ 1 diagnosis corroborated Yes No Total Corroboration of diagnosis in responders who consulted physician Yes No Total

Eligible Participants (%)

364 5,707 6,071

6 94 100

1,545 4,162 5,707

27.1 72.9 100

970 575 1,545

32.8 31.8 100

1,053 492 1,545

68.2 31.8 100

227 1,318 1,545

14.7 85.3 100

227 826 1053

21.6 78.4 100

32

of individuals at high risk for kidney disease and in increasing awareness of kidney disease among high-risk groups. The KEEP screenings identified 82 participants with previously undetected high blood glucose levels (2% of those without a history of diabetes), 1,014 participants with previously undetected high blood pressures (35% of those without history of hypertension), and 839 participants with reduced kidney function based on an EGFR less than 60 mL/min/1.73 m2 (14% of the screened population without previous knowledge of kidney disease). The level of blood pressure control shown in KEEP among participants with a hypertension history (64% uncontrolled) is consistent with other national findings that found 71% of Americans with hypertension did not have blood pressure controlled to less than 140/90 mm Hg.38 In addition, only 23% of participants with a history of diabetes and 23% with a reduced EGFR (⬍60 mL/min/1.73 m2) had their blood pressure controlled to the JNC VI recommended level of less than 130/85 mm Hg,32 only 18% of those with a history of diabetes achieved the American Diabetes Association/National Diabetes Education Program recommended goal of less than 130/80 mm Hg,35 and only 31% of those with a reduced EGFR achieved the blood pressure level of less than 135/85 mm Hg recommended by the K/DOQI guidelines.30 This level of control, although greater than the 11% reported in NHANES III,4 shows persistence of inadequate levels of blood pressure control in this screened population, placing them at risk for adverse cardiovascular and kidney outcomes. The prevalence of pyuria and hematuria in KEEP participants is much greater in women than men. In a recent analysis of NHANES III data, in a healthy adult population, 9.7% of women were identified with microalbuminuria versus 6.1% of men when women with hematuria or undergoing menstruation were excluded.39 In a similar mass screening study in an Israeli adult population, 8.1% of women showed hematuria versus 2.6% of men, and 3.9% and 4.9% of women and men had proteinuria, respectively.40 The increased prevalence of pyuria might mark a specific risk for kidney progression; namely, the presence of asymptomatic urinary tract infections, which appears to be of greater prognostic

BROWN ET AL

and pathological significance for women with diabetes and increases the risk for progressive kidney failure.41,42 However, the overall risk for progression to kidney failure in untreated proteinuric kidney disease appears to be greater in men,43 although women with proteinuric kidney disease showed less benefit from the MDRD dietary intervention.44 KEEP showed the effectiveness of targeted screening because the prevalence of reduced kidney function was greater in KEEP than in other studies. The NHANES III study selected a participant population representative of the noninstitutionalized US population and defined persons with reduced kidney function based on elevated serum creatinine levels of 1.6 mg/dL or greater (ⱖ141 ␮mol/L) in men and 1.4 mg/dL or greater (ⱖ124 ␮mol/L) in women. Results of that study estimated that 3% of Americans (3.3% of men and 2.7% of women; 5.6 million) have elevated serum creatinine levels.4 In KEEP, using identical cutoff values, 5.4% of participants were identified as having elevated serum creatinine levels, including 8.3% of men and 4.0% of women. Using the stages of kidney disease defined in the K/DOQI guidelines, it was estimated previously that 3.7% of Americans have an EGFR less than 60 mL/min/1.73 m2 2; in the KEEP study that targeted those at high risk for kidney disease, 16% of participants had reduced EGFRs. The KEEP screening population showed racial disparities in mean Hgb concentration. This racial disparity parallels that seen in incident patients entering the US ESRD program. USRDS data for prevalent dialysis patients show that African Americans have lower hematocrits despite being administered greater mean erythropoietin doses. The reason(s) for these racial disparities in anemia are unknown.3 In 2000, approximately 23.3% of US adults were current smokers45 compared with only 16% of the individuals in this screening population. Tobacco use has been shown to impair kidney function46 and is associated with a more rapid decline in kidney function in patients with hypertension47 or diabetic nephropathy.48 KEEP follow-up data were somewhat disappointing. Only 27% of those with abnormal screening results responded to a phone call or letter. However, of those who responded, 68% consulted with a physician, and one or more

THE KIDNEY EARLY EVALUATION PROGRAM

diagnoses were corroborated in 22% of those who saw a physician. It is not obvious why there is such a large disparity between abnormal screening results and physician diagnoses. Follow-up data were self-reported by participants and some could not remember what their doctor had said or whether their treatment had been altered. Such findings as an elevated blood pressure might vary with repeated determinations. However, the percentage of corroboration in follow-up was similar for all clinical characteristics measured, including such findings as reduced GFR, which are much less susceptible to temporal fluctuation. This finding from the follow-up interviews implies that some physicians may not recognize the importance of very early signs of kidney disease or kidney disease risk factors in the prevention or delay of CKD and its complications. In addition, because serum creatinine level identified far fewer subjects with reduced GFRs than documented in this study through direct estimates of GFR, it is very likely that creatinine levels provide a too-insensitive measure of renal dysfunction. The reliance of most physicians and hospital laboratories on serum creatinine levels to identify individuals at risk for and/or with kidney dysfunction may be problematic, especially for the more elderly population represented in this screening and identified in other national surveys with the greatest prevalence of kidney dysfunction. Our analysis does not allow us to determine what percentage of “nonresponders” consulted with a physician or had diagnoses corroborated. KEEP 2.0 is not a program designed to follow up participants longitudinally, but a screening program that seeks to uncover undiagnosed and undertreated individuals at high risk for kidney disease. Appropriate management of diabetes and hypertension are important to both the prevention and control of kidney disease and requires joint efforts on the part of health care providers and patients. Patients need to embrace lifestyle behaviors that decrease their risk for disease, eg, control weight, reduce alcohol and tobacco use and such selected over-the-counter medication exposures as nonsteroidal anti-inflammatory agents, and control such preexisting conditions as diabetes and hypertension. Health care providers need to ensure that they are implement-

33

ing the latest evidence-based guidelines in the diagnosis and treatment of kidney disease and its precursors. Data from KEEP 2.0 indicate that more work is needed in both these areas. Statistical analyses and comparison of the KEEP 2.0 cohort with national databases must be interpreted with caution. Although demographics of the KEEP database has remained remarkably consistent as this cohort has increased in size, it is a voluntary, self-selected, nonrandomized cohort. The main limitation of KEEP 2.0 findings is that it is a one-time “snapshot” of the target population. Meeting screening definitions is not necessarily equivalent to diagnosis. As noted in a recent study that evaluated the prevalence of albuminuria and renal insufficiency in adults participating in NHANES III, the presence or absence of albuminuria may be both patient and laboratory dependent.49 The American Diabetes Association suggests a minimum of 2 of 3 positive test results for microalbuminuria to establish that an individual patient has microalbuminuria.50 In addition, there will be regression to the mean when continuous variables (eg, blood pressure) are measured at more than 1 visit, which may provide a more accurate reflection of health status than the KEEP one-time screening result. Another potential limitation to the screening is the self-selection bias inherent when recruitment strategies rely on “volunteer” participants. Persons who participate in screening programs tend to be those who are health conscious and better educated. This is supported by the current study; high proportions of those screened had a highschool or greater education, had visited a physician within the last year, and were nonsmokers. In addition, we have no data on medications used, particularly ACE inhibitors and nonsteroidal anti-inflammatory drugs that might further impact on participants’ risk. Despite these limitations, KEEP successfully reached a substantial number of participants representing a broad spectrum of age, sex, racial/ethnic, and educational subgroups. An important issue that is not resolved by these successful efforts is how to reach high-risk individuals with less education and lower socioeconomic status who are not represented in this study. A component of this program as it moves forward is to develop innovative methods of

34

BROWN ET AL

reaching such individuals. This study shows the impact and value of community, professional, and private partnerships in providing outreach programs. Lay and professional volunteers, as well as the donation of materials, significantly ameliorated the costs of the KEEP screenings. In summary, the KEEP 2.0 screening protocol was effective in identifying significant numbers of persons with reduced kidney function, those with inadequate risk-factor control, and persons with previously unknown and undetected diabetes, hypertension, kidney disease, and kidney disease risk factors. Thus, the KEEP 2.0 protocol forms a basis for advocating continued targeted screening of high-risk populations. It is likely that the major venue for the prevention of kidney disease in the general population will be through more aggressive control of such precursors of kidney disease as diabetes and hypertension and the adoption of lifestyles that facilitate control of these risk factors. As larger numbers of at-risk individuals are identified, nephrologists and nephrology organizations will have a greater need to partner with primary care providers and their societies to ensure that appropriate guidelines and interventions are implemented. REFERENCES 1. Minino AM, Smith BL: Deaths: Preliminary data for 2000. Natl Vital Stat Rep 49:1-40, 2001 2. Eknoyan G, Levey AS, Levin NW, Keane WF: The national epidemic of chronic kidney disease: What we know and what we can do. Postgrad Med 110:23-29, 2001 3. US Renal Data System: USRDS 2001 Annual Data Report. Bethesda, MD, The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2001 4. Coresh J, Wei L, McQuillan G, et al: Prevalence of high blood pressure and elevated serum creatinine level in the United States. Arch Intern Med 161:1207-1216, 2001 5. 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 Kidney Dis 32:1-9, 1998 6. Lei HH, Perneger TV, Klag MJ, Whelton PK, Coresh J: Familial aggregation of renal disease in a population-based case-control study. J Am Soc Nephrol 7:1270-1276, 1998 7. Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977986, 1993 8. United Kingdom Prospective Diabetes Study Group: UK Prospective Diabetes Study 33: Intensive blood glucose control with sulphonylureas or insulin compared with con-

ventional treatment and risk of complications in patients with type 2 diabetes. Lancet 352:837-853, 1998 9. Ohkubo Y, Kishikawa H, Araki E, et al: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulindependent diabetes mellitus: A randomized, prospective 6-year study. Diabetes Res Clin Pract 18:103-117, 1995 10. Parving HH, Andersen AR, Smidt UM, et al: Effect of antihypertensive treatment on kidney function in diabetic nephropathy. Br Med J 294:1443-1447, 1987 11. Bjorck S, Nyberg G, Mulec H, et al: Beneficial effects of angiotensin converting enzyme inhibition on renal function in patients with diabetic nephropathy. Br Med J 293:471474, 1986 12. Ruggenenti P, Perna A, Remuzzi G: ACE inhibitors to prevent end-stage renal disease: When to start and why possibly never to stop: A post hoc analysis of the REIN trial results. J Am Soc Nephrol 12:2832-2837, 2001 13. Klahr S: Role of dietary protein and blood pressure in the progression of renal disease. Kidney Int 49:1783-1786, 1996 14. Mogensen CE: Long-term antihypertensive treatment inhibiting progression of diabetic nephropathy. Br Med J 285:685-688, 1982 15. Keane WF, O’Donnell MP, Kasiske BL, et al: Lipids and the progression of renal disease. J Am Soc Nephrol 1:S69-S74, 1990 (suppl 5) 16. Fried LF, Orchard TJ, Kasiske BL, for the Lipids and Renal Disease Progression Meta-Analysis Study Group: Effect of lipid reduction on the progression of renal disease: A meta-analysis. Kidney Int 59:260-269, 2001 17. Lau K: Phosphate excess and progressive renal failure: The precipitation-calcification hypothesis. Kidney Int 36:918-937, 1989 18. Parving HH, Lehnert H, Bro¨ chner-Mortensen J, et al: The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345:870-878, 2001 19. Brenner BM, Cooper ME, de Zeeuw D, et al: RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861-869, 2001 20. Lewis EJ, Hunsicker L, Bain RP, et al for the Collaborative Study Group: The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N Engl J Med 329:1456-1462, 1993 21. Brown WW, Keane W: Proteinuria and cardiovascular disease. Am J Kidney Dis 38:S8-S13, 2001 (suppl 1) 22. Fouque D, Laville M, Boissel JP, et al: Low-protein diets in chronic renal insufficiency: A meta-analysis. BMJ 304:214-218, 1992 23. Mitch WE: Dietary protein restriction in chronic renal failure: Nutritional efficacy, compliance, and progression of renal insufficiency. J Am Soc Nephrol 2:823-831, 1991 24. Klahr S, Levey AS, Beck GJ, et al: The effects of dietary protein restriction and blood pressure control on the progression of chronic renal disease. N Engl J Med 330:877884, 1994 25. Praga M, Hernan´ dez E, Andres A, et al: Effects of

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38. Burt V, Whelton P, Roccella E, et al: Prevalence of hypertension in the US adult population: Results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension 25:305-313, 1995 39. Jones CA, Francis ME, Eberhardt MS, et al: Microalbuminuria in the US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis 39:446459, 2002 40. Carel RS, Silverberg DS, Kaminsky R, Aviram A: Routine urinalysis (dipstick) findings in mass screening of healthy adults. Clin Chem 33:2106-2108, 1987 41. Goswami R, Bal CS, Tejaswi S, Punjabi GV, Kapil A, Kochupillai N: Prevalence of urinary tract infections and renal scars in patients with diabetes mellitus. Diabetes Res Clin Pract 53:181-186, 2001 42. Geerlings SE, Stolk RP, Camps MJ, et al: Asymptomatic bacteriuria may be considered a complication in women with diabetes. Diabetes Mellitus Women Asymptomatic Bacteriuria Utrecht Study Group. Diabetes Care 23:744-749, 2000 43. Neugarten J, Acharya A, Silbiger SR: Effect of gender on the progression of nondiabetic renal disease: A meta-analysis. J Am Soc Nephrol 11:319-329, 2000 44. Coggins CH, Lewis JB, Caggiula AW, Castaldo LS, Klahr S, Wang S-R: Differences between women and men with chronic renal disease. Nephrol Dial Transplant 13:14301437, 1998 45. Cigarette Smoking Among Adults—United States, 2000. MMWR Morb Mortal Wkly Rep 51:642-645, 2002 46. Gambaro G, Verlato F, Budakovic A, et al: Renal impairment in chronic cigarette smokers. J Am Soc Nephrol 9:562-567, 1998 47. Regalado M, Yang S, Wesson DE: Cigarette smoking is associated with augmented progression of renal insufficiency in severe essential hypertension. Am J Kidney Dis 35:687-694, 2000 48. Chuahirun T, Wesson DE: Cigarette smoking predicts faster progression of type 2 established diabetic nephropathy despite ACE inhibition. Am J Kidney Dis 39:376-382, 2002 49. Garg AX, Kiberd BA, Clark WF, Haynes RB, Clase CM: Albuminuria and renal insufficiency prevalence guides population screening: Results from the NHANES III. Kidney Int 61:2165-2175, 2002 50. American Diabetes Association: Diabetic Nephropathy. Diabetes Care 24:S69-S72, 2001 (suppl 1)