Kidney International, Vol. 63, Supplement 83 (2003), pp. S50–S55

PREVENTION AND TREATMENT OF RENAL DISEASE

Identification of persons at high risk for kidney disease viatargeted screening: The NKF Kidney EarlyEvaluation Program

WENDY W. BROWN, ALLAN COLLINS, SHU-CHENG CHEN, KARREN KING, DONALD MOLONY,MONICA R. GANNON, GIGI POLITOSKI, and WILLIAM F. KEANE

St. Louis VA Medical Center, St. Louis University School of Medicine, St. Louis, Missouri; Minneapolis Medical ResearchFoundation, Minneapolis, Minnesota; Kansas City, Missouri; University of Texas Houston Health Science Center, Houston,Texas; The National Kidney Foundation, Inc., New York, New York; and Merck and Company, Inc., Horsham,Pennsylvania, USA

Identification of persons at high risk for kidney disease via will almost double to approximately 661,330 individualstargeted screening: The NKF Kidney Early Evaluation Pro- by the year 2010 [2].gram. Chronic kidney disease and the development of ESRDBackground. More than 340,000 individuals were receiving

due to type 2 diabetes mellitus and hypertension arerenal replacement therapy in the United States at the end ofparticularly common in minority populations. African1999; this number is projected to double by the year 2010.

Almost half had a primary diagnosis of diabetes mellitus partic- Americans have a 3 to 7 times greater risk of kidneyularly type 2, and more than one quarter a primary diagnosis disease than Caucasians, even for the same diagnosisof hypertension. Studies have demonstrated effective maneu-

[3–5]. Although the incidence is increasing for bothvers to prevent or delay the rate of progression of kidneygroups there is a clear disparity, with ESRD secondarydisease, and decrease morbidity and mortality. The objective

of early diagnosis is early detection of asymptomatic disease to both hypertension and diabetes increasing at a muchat a time when intervention has a reasonable potential to have greater rate in African Americans [1]. Hispanic Ameri-a positive impact on outcome. cans, Native Americans, Mexican Americans and AsianMethods. In 1997, the National Kidney Foundation launched

Americans are also at increased risk (Fig. 1) [1]. Of NativeKEEP� (Kidney Early Evaluation Program), a free commu-Americans and Hispanic Americans receiving renal re-nity-based screening that targets first order relatives of persons

with hypertension, diabetes or kidney disease, and those with placement therapy, almost 70% and 60%, respectively,a personal history of diabetes or hypertension. have a primary diagnosis of diabetes [1]. In addition,

Results. Of the 889 individuals screened in the pilot study,many of these minority individuals are socioeconomi-71.4% had at least one abnormality. The program includes ancally disadvantaged and may lack health insurance andeducational component and referral to a physician for follow-

up of abnormal values. have limited access to health care [6, 7].Conclusions. Targeted screenings are an effective means of One in nine Americans, more than 20 million people,

identifying persons at risk for kidney disease, and can identify has kidney disease; most don’t know it [8, 9]. Anotherindividuals at risk early enough in the course of their disease20 million Americans are at increased risk of kidneyto allow for effective intervention.disease [8]. Population surveys demonstrate that mostof these individuals with kidney disease or at risk forkidney disease are unaware of their risk [9]. In addition,More than 340,000 individuals were receiving renalpatients with chronic kidney disease have a significantlyreplacement therapy in the United States on Decemberincreased risk for cardiovascular events [8, 10]. The med-31, 1999 at a cost of $17.9 billion [1]. More than 45%ical costs and cost of lost productivity for these individu-of incident ESRD patients had a primary diagnosis of

diabetes mellitus, and more than 26% had a primary als are enormous.diagnosis of hypertension [1]. It is projected that the It has been predicted that in the next 10 years therenumber of patients requiring renal replacement therapy will be a 50% increase in the number of adult Americans

with diabetes [11]; 25 to 40% of these individuals willdevelop kidney disease. Type 2 diabetes in children andKey words: KEEP, chronic kidney disease, screening, diabetes, hyper-

tension, early intervention. adolescents has increased more than tenfold in the lastdecade [12–14] and correlates with increasing obesity, 2003 by the International Society of Nephrology

S-50

Brown et al: Design and rationale of KEEP S-51

Fig. 1. Dialysis incident rates by primary diagnosis and race.

poor dietary habits, lack of physical activity and a family diastolic blood pressure �90 mm Hg or current anti-hyper-history of type 2 diabetes in first- or second-degree rela- tensive therapy with prescription medication [9, 50]. Oftives [14–19]. As in adults, the prevalence and rate of these individuals with hypertension, almost half haveincrease of type 2 diabetes in young children is greatest not been prescribed medication, about one quarter havein minority populations [14–18, 20–22]. Total direct and been prescribed medication, but their blood pressure isindirect costs of caring for these patients with chronic not controlled, and only a quarter are on medication andkidney disease, exclusive of ESRD, exceeded $92 billion controlled [9]. Hyman and Pavlik noted most cases ofin 1992 [23]. uncontrolled hypertension occurred in individuals who

“have access to health care and relatively frequent con-tact with physicians” [50]. A study of over 1400 hyperten-EFFECTIVE INTERVENTIONS TO PREVENTsive patients with chronic kidney disease enrolled in theOR DELAY PROGRESSION OFModification of Diet in Renal Disease Study (MDRD)KIDNEY DISEASErevealed that 91.5% were treated with anti-hypertensive

The objective of early diagnosis is the early detection medication [51]. Unfortunately, only 54% of these pa-of asymptomatic disease when intervention has a reason-

tients had a blood pressure less than or equal to 140/90able potential to have a positive impact on outcome.

mm Hg, a threshold which is well above the target bloodNumerous studies have demonstrated that effective ma-pressure of �125/75 mm Hg for persons with chronicneuvers exist to prevent or delay the rate of progressionkidney disease with proteinuria.of kidney disease [11–24], and decrease morbidity and

A retrospective chart review of hospitalized Medicaremortality [25]. Excellent glycemic control in those withbeneficiaries with a primary or secondary diagnosis ofdiabetes [26–28], aggressive blood pressure controldiabetes or hypertension found low rates of screening[29–33], correction of dyslipidemias [34, 35], phospho-for kidney disease in this population. When evidence ofrous control [36], reduction of proteinuria with angioten-kidney disease was found, it was documented at dis-sin converting enzyme (ACE) inhibitors and/or angio-charge in less than 10% of patients with diabetes and lesstensin receptor blockers [37–43], reduction of cardiacthan 13% of those with hypertension, although 24.9% ofrisk factors [44], appropriate diet [45–47] and lifestylethose with diabetes had a serum creatinine �1.3 mg/dLmodification [48, 49] are some of the interventions thatand 31.3% had proteinuria �1�, and 21.9% of those withhave been shown to be effective.hypertension had a serum creatinine �1.3 mg/dL and8.3% proteinuria �1�. Only a third of diabetic patients

TRANSLATION OF CLINICAL ADVANCES and 12.5% of hypertensive patients with �1� protein-INTO CLINICAL PRACTICE uria were prescribed ACE inhibitors at discharge [52].

Unfortunately, the use of interventions to delay orprevent progression of kidney disease does not translate

IMPACT OF LATE DIAGNOSIS, SUBOPTIMALinto clinical practice. Approximately one quarter of theTREATMENT AND LATE REFERRALadult United States population, more than 43 million

Because of the failure to recognize early kidney dis-individuals, has a diagnosis of hypertension, defined asa mean systolic blood pressure �140 mm Hg, a mean ease potentially beneficial interventions are not insti-

Brown et al: Design and rationale of KEEPS-52

Table 1. Ethnic distribution of KEEP participantstuted. This results in increased morbidity and mortalityAleutian/Alaska Native/Eskimo/American Indian 0.4%[11, 53, 54], and greater cost to the patient and society.Asian 3.8%Furthermore, those who develop ESRD have a longerAfrican American 53.2%

initial hospitalization, are not appropriately educated Pacific Islander 2.8%Caucasian 29.1%about choice of modality and come to dialysis withoutOther/Not stated 10.7%dialysis access [53, 55].

GENESIS OF KEEPinine in a central laboratory. Random urine specimensA mass, untargeted screening rarely captures morewere collected and tested by the dipstick method forthan a few percent of the eligible population, is notpyuria, hematuria and microalbuminuria. Creatininecost-effective and is an inefficient use of resources (Rclearance was calculated using the Cockcroft-Gault for-Glassock, personal communication; unpublished datamula [59].from C.A.R.E.: Computerized Assessment Risk Educa-

A physician reviewed all screening results except se-tion, also known as the “Indiana Project”) [56, 57]. Inrum creatinine with participants on site, and they were1991, the National Kidney Foundation of Indiana, ingiven a copy of their test results. Those with test resultscollaboration with the Diabetes Research and Trainingoutside the normal range were encouraged to follow-upCenter of Indiana University, developed a unique earlywith a physician and given a letter to present to theirdetection, intervention and prevention initiative for per-physician indicating the reason(s) for referral. Referralsons at increased risk for kidney disease. They screenedto local clinics or physicians was provided for individualsfirst order relatives of dialysis patients with diabeteswithout a physician and/or health insurance. Educationaland/or hypertension and found that 56% of 348 Indianamaterials about kidney disease, hypertension and diabe-participants were at risk of diabetes, hypertension and/ortes were provided to all participants. The NKF conductedkidney disease. Indiana’s data seemed to support theone and three month follow-up by telephone, to ascertainidea that targeted screenings identify a greater numberwhether follow up had occurred.of individuals at risk than a general public screening

(unpublished data; CARE, ibid). This project was ulti-mately adapted by the National Kidney Foundation and

RESULTSa national program was developed, the Kidney Early

Of the 889 individuals screened, 293 (33%) were maleEvaluation Program.and 596 (67%) female. Participants ranged in age from18 to over 85 years of age with the majority between 26

KEEP PILOT and 64 years. Twenty-five per cent had a family historyof kidney disease, 72.9% a family history of hypertensionThe KEEP Pilot was a free, community-based screen-and 57.5% a family history of diabetes. Fifty-one pering that took place in 21 cities in 1997. The objectivecent gave a history of pre-existing disease: 28.9% hyper-was to identify persons at risk for kidney disease bytension and 18.9% diabetes. Only 43 individuals gave ascreening persons with first order relatives with diabetes,history of known kidney disease (4.8%). The types ofhypertension or kidney disease, or those with a personalpre-existing disease and the percentages reporting pre-history of diabetes or hypertension.existing disease did not differ by ethnicity. Ethnicity ofScreenings were advertised via local media, and infor-the participants is shown in Table 1.mation provided to dialysis patients, with an emphasis on

Six hundred thirty-six individuals (71.4%) had abnor-minority communities. Screening sites included churches,mal test values and were encouraged to follow-up withhospitals, health centers, schools, community centers anda doctor. Three hundred ninety-four individuals (44.3%)dialysis units. Participants signed a consent form andhad two or more values outside the normal range andcompleted a Health Risk Assessment questionnaire. Eli-514 (57.8%) learned of at least one new condition. Tablegibility criteria for screening were age 18 years or older,2 shows the values outside the normal range for eachand a first-degree relative with diabetes, hypertensionscreening test and the individuals who were found toor kidney disease or a personal history of diabetes orhave a single abnormal value and had no prior historyhypertension. Participants were weighed and blood pres-of disease. Table 3 identifies the number of participantssure measured by the method presented in the Sixthlearning of one or more risk factors for diabetes, hyper-Report of the Joint National Committee on Prevention,tension and/or kidney disease. There were 420 individu-Detection, Evaluation and Treatment of High Bloodals identified with markers for kidney disease, some ofPressure [58].whom had more than one abnormality: 114 had an ele-Blood glucose levels were tested using capillary blood

and blood was obtained for measurement of serum creat- vated serum creatinine (1/4 of whom had a serum creati-

Brown et al: Design and rationale of KEEP S-53

Table 4. Screening diagnoses confirmed by participants’ physicianTable 2. Values outside of the normal range for each screening test

Single abnormal value—no Diagnosis Number of participantsprior history of disease

Abnormal value Diabetes mellitus 3Hypertension 24Screening test N of subjects N of subjects PercentKidney disease 6

Serum glucose 113 14 6.0 Advanced kidney disease 2Microalbuminuria 188 27 11.6 Referred to dialysis 1Pyuria 148 33 14.2Hematuria 179 48 20.6↑ Serum creatinine 126 37 15.9Diastolic hypertension 259 22 9.4Systolic hypertension 342 52 22.3 that they saw a physician stated that the physician hadTotal 233 100.0 confirmed the screening diagnose(s) (Table 4).

DISCUSSIONThe KEEP Pilot screening program demonstrated thatTable 3. Number of participants learning of an abnormality that

placed them at increased risk targeted screenings are an effective means of identifyingpersons at risk for kidney disease, and can identify indi-N with % of 514 subjects withviduals at risk early enough in the course of their diseaseLearned of risk of finding % abnormal findingsto allow for effective intervention. The screening identi-Diabetesa 27 4.3 5.3

Hypertensionb 180 28.7 35.0 fied risk factors for diabetes, hypertension and/or kidneyKidney diseasec 420 67.0 81.7 disease in 71.4% of individuals screened. The largestTotal 627 100.0

group of individuals screened was between 35 and 54a Serum glucose �140 mg/dL years, an age group in which intervention might be ex-b Systolic blood pressure �140 mm Hg and/or diastolic blood pressure �90

mm Hg pected to have maximal benefit.c Increased serum creatinine (women �1.2 mg/dL; men �1.4 mg/dL) and/or The program also was effective in motivating some,microalbuminuria, hematuria, pyuria

but not all, persons with abnormal results to seek follow-up with a physician. It is also not clear why there wassuch a large discrepancy between abnormal test valuesand confirmation of screening diagnosis. The follow upnine �2.0 mg/dL), 171 had microalbuminuria, 137 haddata were self-reported by the participants. Some of thepyuria and 165 had hematuria.participants were not sure what their doctor did orOne hundred sixty-eight participants reported pre-whether their treatment regimen changed. Others couldexisting diabetes mellitus. More than 1/3 of these personsnot remember what their doctor said. This lack of con-

had one or more additional risk factors identified: 61 firmation of diagnoses by the patient’s physician is dis-had microalbuminuria; 33 had pyuria; 32 hematuria; 35 turbing and also may represent a lack of understandingincreased serum creatinine; 88 systolic hypertension and of the importance of even early signs of kidney disease54 diastolic hypertension. Thirteen of 511 persons with by some physicians. Some of the patients were told, fora family history of diabetes mellitus, 20 of 648 with a example, that a little protein in the urine was nothingfamily history of hypertension, and 7 of 225 with a family to worry about, or that a slightly elevated serum creati-history of kidney disease learned of their diabetes risk. nine was not of concern. In this regard, education of

primary care and other physicians and health care pro-Of those with a family history of diabetes, 46.7% learnedviders regarding significance of abnormal test valuesof a least one renal risk factor. Fifty seven per cent ofand appropriate interventions is particularly important.the participants identified with blood glucose greaterThese results also underscore the importance of provid-than 140 mg/dL were not aware that they might haveing physician and health care provider guidance for thediabetes. Either a positive family history of kidney dis-appropriate management of risks in patients with chronicease or hypertension significantly increased the risk forkidney disease.

a positive finding for individual subjects both for riskfactors for kidney disease and for markers of current ACKNOWLEDGMENTSkidney disease. In this pilot study, this increased risk was

The Kidney Early Evaluation Program (KEEP)� is a program ofseen across all ethnicities and in both genders. the National Kidney Foundation, Inc. The KEEP Pilot was supported

by Pfizer, with additional support from Satellite Healthcare, RedwoodFifty-two per cent (331 of 645) of those with abnormalCity, California.test values participated in follow-up. Of those who

Reprint requests to Wendy W. Brown, M.D, MPH, Division of Ne-sought follow-up with a physician, 203 of 331 (61.3%)phrology, St. Louis Veterans Administration Medical Center, 915 N.saw a doctor within three months of the health screening. Grand Blvd., St. Louis, Missouri 63106, USA.E-mail: wendy.brown@med.va.govThirty-six of the 203 participants (17.7%) who reported

Brown et al: Design and rationale of KEEPS-54

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