projap a15 pereira s122-s135€¦ · cardiovascular risk in patients with early ckd34,35 and the...

S122 THE AMERICAN JOURNAL OF MANAGED CARE MARCH 2002

AbstractChronic kidney disease (CKD) is a growing

public health problem. Morbidity and mortalityrates from CKD and end-stage renal diseaseremain high despite the advent of new knowledge,therapies, and clinical practice guidelines.Consequently, the reasons for the underdiagnosisand undertreatment of CKD must be addressedand appropriate preventive and therapeutic inter-ventions implemented. Managed care organiza-tions (MCOs) can facilitate this process byimplementing intervention programs that targetclinicians and patients with kidney disease. Theseprograms should promote 1) early detection ofCKD and comorbid conditions; 2) use of appropri-ate outcome measures to stratify patient care; 3)implementation of strategies to delay disease pro-gression and prevent or treat complications; and 4)adequate preparation for and timely initiation ofrenal replacement therapy. Early detection andproactive care of predialysis patients not onlyimprove outcomes and quality of life, but alsoreduce costs for society and MCOs.

Chronic kidney disease (CKD) isbeing increasingly recognized as amajor public health problem,

whose early detection and treatment canimprove outcomes and reduce costs.1–4

Yet, the prevention and treatment of CKDremain suboptimal.5–12 Morbidity and mor-tality rates from CKD and end-stage renaldisease (ESRD) remain high despite theadvent of new knowledge, therapies, andclinical practice guidelines (CPGs). Thechallenge before us is to educate health-care providers to suspect, detect, and treat

CKD early and aggressively to slow pro-gression toward ESRD. Early detectionand proactive care of CKD patients notonly improve outcomes and quality of life,but also reduce costs for society and man-aged care organizations (MCOs).

Prevalence, Causes, and Consequences ofChronic Kidney Disease

Because early disease is often asympto-matic, the prevalence of CKD and thestage at which the disease typically mani-fests clinically are unclear.4 The recentlyreleased National Kidney Foundation-Kidney Disease Outcomes Quality Initiative(NKF-K/DOQI) guidelines estimated that20 million Americans have CKD.3

Individuals with diabetes and/or hyperten-sion, certain minority groups (eg, African-Americans), and the elderly are at highrisk for CKD and also bear the lion’s shareof the associated complications, morbidi-ty, and mortality.13–16 Other causes of CKDinclude glomerulonephritis, interstitialnephritis, vasculopathy, obstructive uropa-thy, and cystic/hereditary/congenital kid-ney diseases.15

Data from the US Renal Data System(USRDS) show that the prevalence ofESRD more than doubled in the UnitedStates over the past decade.16 By the endof 1997, more than 300,000 patients werebeing treated for ESRD, including 79,102new patients entering treatment, 221,596patients receiving dialysis, and 36,036patients awaiting kidney transplantation.16

In addition, more than 63,000 ESRD

. . . CME/CPE . . .

Overcoming Barriers to the Early Detection andTreatment of Chronic Kidney Disease

and Improving Outcomes for End-Stage Renal Disease

Brian J.G. Pereira, MD

VOL. 8, NO. 4, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S123

Chronic Kidney Disease and Improving Outcomes for End-Stage Renal Disease

patients died in 1997, a death rate thatexceeds by more than 20% the death ratefrom advanced cancer of the colon orbreast.16 An estimated 651,330 Americanswill require treatment for ESRD by 2010.16

While heart disease rates are decliningand cancer rates are stabilizing, the preva-lence of ESRD is increasing.

One factor contributing to the increasingnumber of patients with ESRD is the “agingof America.”2,15 More than 50% of patientswho begin renal replacement therapy(RRT) are older than 65 years, indicative ofthe growing population of older Americans.2

However, no age group is immune to CKD;one fourth of the individuals undergoingRRT in 1997 were younger than 45 years.Furthermore, patients initiating dialysishave an average of 4 comorbid conditions,including diabetes, hypertension, and othertypes of cardiovascular disease (CVD) (eg,left ventricular hypertrophy [LVH], heartfailure).2 Hypertension accelerates the pro-gression of kidney disease and is a majorrisk factor for other types of CVD.17 The ris-ing prevalence of diabetes in the UnitedStates also may be fueling growth of theESRD population.13,15 Since the early1990s, hypertension has accounted forabout 25% of new cases of ESRD and dia-betes has accounted for 40% of patientsrequiring RRT.15,16 Improved survival ofpatients with diabetes and severe CVD maybe further increasing the prevalence ofESRD.15

Obstacles to Better End-Stage RenalDisease Outcomes: Factors EngenderingSuboptimal CKD Care

Suboptimal timing and quality of CKDcare (ie, pre-ESRD) is a significant sourceof ESRD-related morbidity and mortali-ty.6,7,18 Although early detection and man-agement of CKD can prevent diseaseprogression, reduce complications, andreduce costs, several studies suggest thatCKD is underdiagnosed and undertreat-ed.5–12,19 Raising clinicians’ awareness ofthe fact that the current care of CKDpatients is suboptimal is the first step ininitiating strategies to improve care. Thecurrent state of CKD care is discussedbelow.

Inadequate Focus on PreventiveCare. Because medicine has traditionallybeen oriented around acute events, practi-tioners are still learning the importance ofpreventive medicine. Modifiable risk fac-tors for progressive kidney damage thatare amenable to treatment include hyper-tension and hyperglycemia.3,20 Yet a uri-nalysis was obtained in only 62.7% ofpatients with diabetes in a recent study ofhospitalized hypertensive and diabeticpatients.21 In a study of CKD managementin northeastern nephrology clinics, glyco-sylated hemoglobin (HbAlc) levels wereavailable in only 28% of the patients withdiabetes.22

Asymptomatic Nature of EarlyChronic Kidney Disease. The absence ofsymptoms in patients with early kidneydisease complicates efforts to detect andtreat CKD early. Clinicians need to main-tain an adequate index of suspicion in allpatients, especially in those with medicalor sociodemographic risk factors for CKD.

Insufficient Attention to the Patient’sMedical History. Various factors (eg, timedemands, reimbursement structures) maycontribute to the constraints on clini-cians, leading to neglect of important com-ponents of the patient history.23 Obtaininga detailed, open-ended patient history,including a family history and medicationusage, facilitates early detection of CKD orits risk factors. Careful physical examina-tion for evidence of comorbid diseases orcomplications of CKD complements thisprocess.

Use of Inappropriate Measures ofKidney Function or Omission of Labora-tory Screening Tests. Many clinicians stilluse the serum creatinine (Cr) level or Crclearance as a definitive marker ofCKD24,25 instead of measuring or calculat-ing the best measure of overall kidneyfunction, the glomerular filtration rate(GFR).3 Furthermore, many do not per-form routine laboratory screening tests forCKD4,21 or its complications.21,22 Expertscurrently recommend use of validatedprediction equations that consider the


CME/CPE

patient’s serum Cr level, age, sex, race,and/or body size to estimate the GFR.3

New methods of calculating the GFR areunder investigation.26

Lack of Professional Agreement/Paucity of Reliable Clinical Evidence.Until the recent release of the NKF-K/DOQI CPGs, a uniform classification ofthe CKD stages did not exist and the termsused were ambiguous and overlapping.3

Along with limitations of the available data(eg, often obtained retrospectively, withinfrequent proof of causality),27 suchambiguity has limited the use of preven-tive and therapeutic interventions.

Failure to Employ Strategies ThatDelay Disease Progression. Lack ofknowledge also may contribute to theundertreatment of early CKD. In the pastdecade several large clinical trials havebeen published that demonstrated thebenefit of angiotensin-converting enzyme(ACE) inhibitor therapy, and tight bloodpressure and glycemic control in slowingthe progression of CKD.28–33 In addition,the Heart Outcomes Prevention Evaluation(HOPE) study and the Microalbuminuria,Cardiovascular, and Renal Outcomes(MICRO-HOPE) substudy recently showedthat the ACE inhibitor ramipril reducedcardiovascular risk in patients with earlyCKD34,35 and the risk of overt nephropathyin patients with diabetes.35,36 Ramipril alsoappears to slow the progression of kidneydisease in hypertensive patients with CKDand proteinuria, and may offer benefit topatients without proteinuria.37 However,only one third or fewer patients with dia-betes and/or hypertension and abnormalkidney function were prescribed ACEinhibitors in 1 study.21 In a study of CKDmanagement in the northeastern UnitedStates, only 65% of patients with diabetesand 49% of patients overall were pre-scribed ACE inhibitors.22 Despite evidencethat tight blood pressure and glycemiccontrol improves outcomes,3 hypertensionremains inadequately treated in morethan half of CKD patients38 and blood glu-cose monitoring in patients with diabetesis suboptimal.22

Suboptimal Detection and Manage-ment of Malnutrition. Complications ofCKD (eg, malnutrition, anemia, osteodys-trophy, metabolic acidosis, dyslipidemia)account for most of dialysis-related mor-bidity and mortality.2,39 A variety of factors(eg, lack of knowledge, delayed referral toa nephrologist) may hinder appropriateprevention and management of thesecomplications. For example, manypatients have evidence of malnutrition atthe start of RRT,7,40 which is associatedwith an increased risk of death.41

However, a pre-ESRD evaluation by a die-titian is uncommon,42 despite the avail-ability of strategies to optimize CKDpatients’ nutritional status, such as dietarycounseling, vitamin and nutritional sup-plements, correction of uremic acidosiswith oral alkali agents, and judicious useof a low-protein diet.43

Inadequate Detection and Correctionof Anemia Associated With ChronicKidney Disease. Neglect of another com-mon and treatable uremic complication,anemia, has also been well document-ed.5,7,10,22,40,44–46 Anemia is primarily aresult of the inability of the kidneys tosecrete adequate amounts of erythropoi-etin, which is involved in the productionof red blood cells.47,48 Studies suggest thatanemia of CKD begins early and that manyCKD patients are anemic at first presenta-tion to a nephrologist.22,46 Anemia can pre-cipitate LVH, exacerbate angina pectoris,restrict aerobic capacity, limit cognitiveability, and diminish sexual function.49,50

In addition to being an important predic-tor of CVD in CKD patients,40,51–53 anemiais also associated with an increased risk ofdeath.25,54,55

The NKF-K/DOQI Clinical PracticeGuidelines for Anemia of Chronic KidneyDisease: Update 2000 indicate thatpatients should have hemoglobin (Hgb)and hematocrit (Hct) levels of 11 to 12g/dL and 33% to 36%, respectively.56

However, natural variations in Hgb/Hctconcentrations hinder efforts to maintainthese levels,57 and many clinicians maynot even aim for these targets.7,10,46,58


Although rates of correction of anemia indialysis patients have improved since theintroduction of recombinant human ery-thropoietin (r-HuEPO) therapy,59 manypatients beginning dialysis are still ane-mic.7,10,60 Most have never received ery-thropoietin to raise their Hct levels7,10,46

despite the benefits of this therapy, suchas decreased morbidity and mortality,improved exercise capacity, improvedhealth-related quality of life, and reducedLVH.40,53,59,61

An analysis of 155,076 Americans whobegan chronic dialysis therapy between1995 and 1997 showed that 51% of patientshad a Hct level < 28% and only 23% hadreceived erythropoietin pre-ESRD.7 Inaddition, trend analyses have shown thatpatients often do not receive sufficientdoses of erythropoietin, with many receiv-ing < 25% of the recommended amount.58

Other factors that contribute to inadequatecorrection of renal anemia include logisticsbarriers around the frequency of dosing ofr-HuEPO, economic disincentives, lack ofaccess to treatment (eg, no transportation),and lack of clinical knowledge.58,60

Inadequate Preparation for andTiming of Renal Replacement Therapy.Ideal preparation for RRT includes appro-priate patient education, informed choiceof RRT modality, and the timely placementof permanent vascular access.6,18,19,62,63

However, evidence suggests that thesesteps do not always take place.6,64 Forexample, patients are infrequentlyinstructed to protect the arm selected forpermanent vascular access.42 In fact, mostpatients experience a delay in obtainingpermanent access for initiating treatmentor begin RRT without such access.22,64,65

The timing of initiation dialysis is anotherindicator of the quality of care for patientswith kidney disease.6,18,66 However, kidneyfunction at the start of dialysis appears tovary widely among patients in the UnitedStates with ESRD, with a substantial per-centage of patients beginning dialysis atvery low levels of predicted GFR.8

Late Referral to a Nephrologist. Latereferral to a nephrologist is common in

the United States and is associated withpoor CKD care.67 These patients are morelikely to have hypoalbuminemia, a Hctlevel < 28%, and a predicted GFR < 5 mL ·min–1 · 1.73 m–2 at the start of dialysis, andless likely to have received erythropoietintherapy or have functioning permanentvascular access.5,67

Casual Use of Nephrotoxic Medica-tions. In 1 study, nonsteroidal anti-inflammatory drugs were prescribed to 6%of diabetic and 8.8% of hypertensivepatients with abnormal kidney function athospital discharge.21 The number of indi-viduals with CKD who purchase over-the-counter nephrotoxic drugs is unclear.Careful review of all of a patient’s medica-tions is a crucial part of appropriate med-ical care.

Imperfectly Organized Care Model/Lack of Continuity of Care. Most patientswith CKD require care from a team ofhealthcare providers rather than continu-ous care from 1 source; this team typical-ly includes multiple physicians (eg,primary care physicians [PCPs], nephrol-ogist, cardiologist) and a variety of ancil-lary team members (eg, nurses, dietitians,social workers).27 Although team careoffers advantages, inadequate communi-cation among health professionals maylead to redundant or conflicting therapeu-tic approaches or treatment discontinu-ities.27 The fragmented delivery of CKDand ESRD care has been associated withpoor outcomes and increased costs.68

Variability in the Quality of Care.Patients with the same stage of CKD donot all receive the same treatment. Notonly do patient age, sex, and race influ-ence diagnosis and treatment, but alsowhere the patient lives.16 For example,prescribing patterns of r-HuEPO for CKDpatients differ throughout the coun-try,7,10,16 as does the quality of dialysiscare.16 Also, the use of catheters variesamong facilities, a finding that is notexplained by geography, race, or for-profitversus not-for-profit models.27 These find-ings emphasize the need for clinician



adherence to professionally agreed-uponstandards of care.

Workforce Shortages. Whereas an esti-mated 15,000 nephrologists will be neededby 2010, only 4200 exist today.27 As theshortage of specialists becomes moreacute, experts believe that PCPs will needto become more involved in the diagnosisand continuing care of CKD patients.1

Physician “extenders” (eg, nurses, nephrol-ogy nurse practitioners, physician assis-tants) can assist with such care, but thesepractitioners are also in short supply.27,69

Improving the Care of Chronic Kidney Disease Patients: the NationalKidney Foundation Kidney DiseaseOutcomes Quality Initiative Clinical Practice Guidelines

In 1995, the NKF launched the DialysisOutcomes Quality Initiative (DOQI) inresponse to concern about the quality ofcare for patients with kidney disease.3

This effort led to the development of CPGsrelated to key areas of dialysis care,including the management of anemia of

CKD and provision of adequate hemodial-ysis, peritoneal dialysis, and vascularaccess. These CPGs were published in1998 and updated in 2001.3

In developing the DOQI CPGs, expertsrecognized the need to improve the healthstatus of patients with ESRD to optimizedialysis outcomes. This prompted the NKFto broaden the focus of their guideline ini-tiative to encompass all phases of kidneydisease and their monitoring and manage-ment.3 The new initiative, called the KidneyDisease Outcomes Quality Initiative(K/DOQI), was launched in 2000.2,3

Early K/DOQI efforts included the 2000updates of the original NKF DOQI guide-lines and publication of the final NKF-DOQI CPG on nutrition. However, thecenterpiece of K/DOQI is the recentrelease of the NKF-K/DOQI ClinicalPractice Guidelines for Chronic KidneyDisease: Evaluation, Classification, andStratification.3 These CPGs designatestages of CKD (from mild impairment toESRD) and stress prevention/control ofcomorbid conditions and disease pro-gression. More specifically, they provide

CME/CPE

Table. Stages and Prevalence of Chronic Kidney Disease (Age ≥20 Years)

Prevalence*

GFRStage Description (mL · min–1 · 1.73 m–2) n (1000s) %

1 Kidney damage with normal or ↑GFR ≥90 5900 3.3

2 Kidney damage with mild ↓GFR 60 to 89 5300 3.0

3 Moderate ↓GFR 30 to 59 7600 4.3

4 Severe ↓GFR 15 to 29 400 0.2

5 Kidney failure <15 300 0.1

(or dialysis)

*Data for stages 1 through 4 from NHANES III (1988–1994).70 Population of 177 million adults aged ≥20 years.Data for stage 5 from USRDS (1998)71 include approximately 230,000 patients undergoing dialysis, and assume70,000 additional patients not on dialysis. GFR estimated from serum creatinine levels using MDRD Study equa-tion based on age, sex, race, and calibration for serum creatinine. For stages 1 and 2, kidney damage estimatedby spot albumin-to-creatinine ratio > 17 mg/g in men or > 25 mg/g in women on 2 measurements.GFR = glomerular filtration rate; MDRD = Modification of Diet in Renal Disease; NHANES = National Healthand Nutrition Examination Survey; USRDS = US Renal Data System.Source: National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease:Evaluation, classification, stratification, executive summary. K/DOQI, Kidney Disease Outcomes QualityInitiative. Am J Kidney Dis 2002;39(suppl 1). Reprinted with permission.



1) standardized terminology for classify-ing and evaluating kidney disease(Table), 2) an approach to disease strat-ification based on GFR, and 3) appropri-ate methods for monitoring kidneyfunction, comorbidity, and complications,from initial injury until ESRD.3 They alsowill serve as a springboard for the devel-opment of interventional CPGs that willguide the treatment of all stages of kidneydisease.3 Interventional K/DOQI CPGscurrently in development include thoserelated to hypertension, dyslipidemia, andbone disease.3

Optimizing Quality of Care

Optimizing quality of CKD care (eg,early detection, use of interventions todelay disease progression, modification ofcomorbid conditions, prevention of ure-mic complications, adequate preparationfor RRT) can slow the decline in kidneyfunction, reduce complications, and lowerhealthcare costs.72 Collectively, the avail-able and forthcoming NKF CPGs will out-line the following methods to optimizesome of these outcome measures:

Early Identification of Patients WithChronic Kidney Disease. Early detectionimproves outcomes by permitting theadvantages of early intervention (eg, slow-ing of disease progression; reduced com-plications). Obtaining a detailed patienthistory, combined with routine laboratorystudies and blood pressure assessment,facilitates this process. The new NKF-K/DOQI CPGs3 recommend that cliniciansassess the risk for development of CKD inall patients at routine health visits, basedon clinical and sociodemographic charac-teristics. At-risk individuals should under-go tests to establish the presence ofmarkers of kidney damage (eg, protein-uria, abnormal urine sediment, abnormalimaging studies), blood pressure level, andlevel of kidney function (ie, GFR).3

Patients with evidence of CKD (eg, mark-ers of kidney damage, abnormal GFR)should be further evaluated to determinethe underlying diagnosis, presence of anycomorbid conditions or complications,disease severity, risk of loss of kidney

function, and risk for cardiovascular dis-ease.3 Asymptomatic but at-risk individu-als should be instructed in risk factorreduction and undergo repeat periodicscreening, if appropriate.3

Use of Appropriate Measures toDetermine Disease Severity and Stage ofChronic Kidney Disease. Accurate deter-mination of the severity and stage of CKDfacilitates the selection of appropriateclinical interventions. The new NKF-K/DOQI CPGs3 state that disease severityshould be established based on the pres-ence of markers of kidney damage, pres-ence of high blood pressure, and level ofkidney function (ie, GFR), and that dis-ease stage should be assigned based on theGFR (Table).3 Prediction equations thatfactor in the serum Cr concentration aswell as the patient’s age, sex, race, and/orbody size should be used to estimate theGFR.3 In patients with an estimated GFR <15 mL · min–1 · 1.73 m–2, a 24-hour urinespecimen should also be obtained todetermine information that will facilitatedecisions regarding the need for RRT (ie,Cr clearance, Kt/V urea, estimated dietaryprotein intake).3 Screening for proteinuriatypically involves checks of untimed(“spot”) urine specimens.3,73

Use of Interventions to Slow Rate ofGlomerular Filtration Rate Decline.CKD patients experience a progressivedecline in kidney function (ie, GFR) thatcan be slowed by specific interventions.The new NKF-K/DOQI CPGs3 recommendthat clinicians determine the rate of GFRdecline to ascertain both the interval untilthe onset of kidney failure and the effec-tiveness of interventions. The rate of GFRdecline should be assessed by computingthe GFR from past and ongoing serum Crlevels and by identifying risk factors forfast declines (eg, type of kidney disease).Measurement of serum Cr for GFR esti-mates should be obtained at least yearlyand more frequently in certain patients.3

ACE inhibitors provide vasculoprotectionand renoprotection (ie, slow rate of GFRdecline; decrease progression of microal-buminuria to frank proteinuria)20,34–36,74 to


CME/CPE

diabetic and nondiabetic patients withCKD and are cost effective in patientswith diabetes.75 Their beneficial effect ismediated by factors in addition to adecrease in blood pressure and urinaryprotein excretion.74

The new NKF-K/DOQI CPGs3 also stressthe need for tight blood pressure controlin hypertensive CKD patients, by identifi-cation of target blood pressure levels anduse of appropriate pharmacologic andnonpharmacologic interventions.3 Expertsrecommend that blood pressure bereduced to 130/85 mm Hg17 or evenlower13,76–78 in patients with proteinuria inexcess of 1 g per 24 hours, hypertension,and/or diabetes. A recent meta-analysissuggests that antihypertensive regimensthat include ACE inhibitors are moreeffective than regimens without ACEinhibitors in slowing the progression ofnondiabetic kidney disease.74 Maintainingstrict glycemic control (HbAlc ≤ 6.05%) inCKD patients with diabetes also slows therate of GFR decline.3,20

Identification and Modification ofComorbid Conditions. Comorbid condi-tions that accompany CKD (eg, diabetes,hypertension, other CVD, neuropathy)contribute to high morbidity and mortali-ty among ESRD patients, and thus, war-rant effective prevention, timelydiagnosis, and prompt treatment. Forexample, CVD (eg, LVH, heart failure,coronary artery disease, peripheral vas-cular disease, cerebrovascular disease) ishighly prevalent among CKD patients79

and is a leading cause of morbidity andmortality.16,34,40,51 Therefore, the newNKF-K/DOQI CPGs recommend that cli-nicians assess the presence of both“traditional” and “nontraditional”(CKD-related) CVD risk factors (eg,hypertension, diabetes, smoking, abnor-mal lipid profiles, cardiac fibrosis andhypertrophy, malnutrition, enhancedsympathetic activity)40,79 in CKD patientsand implement risk factor reduction pro-grams, as necessary.3 Additional NKF-K/DOQI CPGs related to the managementof hypertension and dyslipidemia inpatients with CKD are in development.3

Prevention and Treatment ofComplications of Decreased KidneyFunction. Complications of CKD con-tribute to the morbidity and mortality ofCKD and may appear in patients with onlymoderate decreases in their GFR.3 Thenew NKF-K/DOQI CPGs recommend thatany patient with a GFR < 60 mL · min–1 ·1.73 m–2 be assessed for anemia, malnutri-tion, bone disease, or disorders of calciumand phosphorus metabolism, as well asimpaired functioning and well-being.3

Abnormalities in other laboratory parame-ters (eg, decreased Hgb or cholesterollevel, hypoalbuminemia, metabolic acido-sis) also should prompt evaluation ofpotential complications.56,80

The NKF-K/DOQI Clinical PracticeGuidelines for Anemia of Chronic KidneyDisease: Update 2000 outline the appro-priate evaluation and treatment of anemiaof CKD,3,56 including the use of appropri-ate use of iron replacement and erythro-poietin therapy to achieve target Hgblevels (11 to 12 g/dL) and Hct levels (33%to 36%). Iron deficiency will occur in mosthemodialysis patients receiving r-HuEPObecause of the increased demand for iron(driven by the accelerated erythropoiesis)and ongoing blood losses.81 Poor ironintake and increased demand for iron arealso seen in patients receiving peritonealdialysis and r-HuEPO.81

The K/DOQI Clinical Practice Guide-lines for Nutrition in Chronic RenalFailure provide guidance about the man-agement of malnutrition in CKD patients,which may include dietary counseling,education, modification, or specializednutritional therapy.80 NKF-K/DOQI CPGsrelated to the management of bone dis-ease in CKD patients are currently indevelopment.3

Adequate Preparation for RenalReplacement Therapy. Adequate prepa-ration for and the timely initiation of RRTimprove outcomes and reduce costs. Avariety of NKF CPGs provide guidance onthese issues. The NKF-K/DOQI ClinicalPractice Guidelines for Vascular Access:



Update 2000 address issues related toestablishing and maintaining perma-nent vascular access for dialysis (eg,patient evaluation, types of dialysisaccess, preservation of sites, timing ofaccess placement, monitoring for com-plications).82 The NKF-K/DOQI ClinicalPractice Guidelines for Peri-tonealDialysis Adequacy: Update 2000 andthe NKF-K/DOQI Clinical Practice Guide-lines for Hemodialysis Adequacy: Update2000 outline methods to optimize dialy-sis outcomes.83,84

Early Referral to a Nephrologist.Whereas late referral to a nephrologist hasbeen associated with parameters of poorquality predialysis care (ie, hypoalbu-minemia, anemia, reduced erythropoietinuse, lower predicted GFR at the start ofdialysis),5,67 early referral is associatedwith lower morbidity and mortality rates,briefer hospital stays, longer RRT-free sur-vival, and lower costs.85–87 PCPs are morelikely to be the first to detect CKD andshould refer patients to a nephrologistearly.11

Correction of Anemia of Chronic KidneyDisease: Roles of Epoetin Alfa andDarbepoetin Alfa

Introduction to the Marketplace. Theintroduction of r-HuEPO more than adecade ago provided the first effectivetreatment for the anemia of CKD.45,88

Epoetin alfa, one type of r-HuEPO, is anamino acid glycoprotein manufactured byrecombinant DNA technology that has thesame biological effects as endogenous ery-thropoietin.89 Correction of anemia ofCKD with erythropoietin has been associ-ated with a variety of beneficial effects,including improved quality of life, partialregression of LVH, reduced frequency ofcardiac complications, and shorter hospi-tal stays.45,53,59,61,90,91

The US Food and Drug Administration’srecent approval of darbepoetin alfa (alsoknown as novel erythropoiesis-stimulatingprotein) should further enhance the care ofpatients with anemia of CKD. Darbepoetinalfa is an erythropoiesis-stimulating pro-tein that is produced in Chinese hamster

cells by recombinant DNA technology.92 Itrepresents a new generation of long-actingproteins that bind to the same receptor asr-HuEPO and stimulate erythropoiesis bythe same mechanism of action. However,structural differences (darbepoetin alfahas 2 more N-linked oligosaccharidechains) provide darbepoetin alfa withgreater in vivo potency, greater metabolicstability, and an approximately 3-foldlonger serum half-life.93–95 Thus, darbepo-etin alfa can be dosed less frequently thanr-HuEPO,93–95 enhancing patient conven-ience and compliance with treatment.96

Epoetin Alfa: Indications, Dosing,Tolerability, and Monitoring. Epoetin alfais indicated for the treatment of anemiaassociated with several conditions, includingchronic renal failure (ie, CKD).89,97 In dialy-sis or CKD patients, epoetin alfa is indicatedto raise or maintain the red blood cell leveland to decrease the need for blood transfu-sions.89,97

The recommended starting dose of epo-etin alfa is 50 to 100 Units/kg 3 timesweekly (TIW) in adults with anemia ofCKD and 50 Units/kg TIW in pediatricdialysis patients.89,97 The dose should bereduced as the Hct level approaches 36%(or increases by more than 4 points duringany 2-week interval) and increased if theresponse is unsatisfactory after 8 weeks oftherapy.89,97 The maintenance dose shouldbe individualized to maintain the Hct inthe suggested target range. Epoetin alfamay be given as an intravenous (IV) orsubcutaneous (SC) injection.89,97 Whenconsidered appropriate by the physician,a patient may self-administer these injec-tions.89,97 Epoetin alfa is usually adminis-tered as an IV bolus TIW in hemodialysispatients.89,97

Epoetin alfa is generally well tolerated.However, clinicians and patients shouldfamiliarize themselves with contraindica-tions, warnings, and precautions beforeinitiating treatment. In US studies of treat-ment in adult dialysis patients the mostfrequently reported adverse events of epo-etin alfa therapy were hypertension,headache, tachycardia, nausea/vomiting,clotted vascular access, shortness of


CME/CPE

breath, hyperkalemia, and diarrhea, whichare typical symptoms seen in this group ofpatients.89,97 There has been no evidenceof the development of antibodies to epoet-in alfa, and serious allergic reactions arerare.89,97

Patients with uncontrolled hyperten-sion should not be treated with epoetinalfa.89,97 Therefore, blood pressure must beadequately controlled prior to initiatingepoetin alfa therapy and closely monitoredand controlled during therapy.89,97 Becauseof the increased risk of seizures duringearly therapy, patients also should be mon-itored for neurologic symptoms.89,97

Patient monitoring also includes labo-ratory studies. Transferrin saturationshould be at least 20% and the ferritinlevel at least 100 ng/mL before therapy isbegun.89,97 Virtually all patients will eventu-ally require supplemental iron to increaseor maintain transferrin saturation to levelsthat will adequately support epoetin alfa-stimulated erythropoiesis.89,97 Other labo-ratory studies that should be conducted atregular intervals include complete bloodcounts and serum chemistry tests (eg,blood urea nitrogen, uric acid, creatinine,phosphorus, potassium).89,97

Darbepoetin Alfa: Indications,Dosing, Tolerability, and Monitoring.Darbepoetin alfa is also indicated for thetreatment of anemia associated withchronic renal failure (ie, CKD), includingpatients undergoing dialysis and predialy-sis patients.92 It is labeled for administra-tion as a single weekly IV or SC injection,and the recommended starting dose is0.45 µg/kg of body weight.92 Doses shouldbe slowly adjusted to attain, but notexceed, a target Hgb level of 12 g/dL.92 TheHgb level should be monitored weeklyduring initiation or adjustment of therapyand at least monthly thereafter.92

Darbepoetin alfa is generally well toler-ated and has a safety profile similar to thatof r-HuEPO.98,99 To date, in more than1500 patients treated with darbepoetinalfa, no cases of antibody formation havebeen documented.98,99 Blood pressure andHgb levels should be monitored carefullyin patients receiving darbepoetin alfa ther-

apy, and darbepoetin should not be usedin patients with uncontrolled hyperten-sion or sensitivity to the active substanceor any excipients.92

Predialysis patients may require lowermaintenance doses of darbepoetin alfathan dialysis patients92; nevertheless, theirHgb level, blood pressure, renal function,and fluid/electrolyte balance should bemonitored carefully.92 Darbepoetin alfa,because it decreases plasma volume, mayreduce the efficiency of dialysis, andhence, dialysis regimens may need to beadjusted accordingly.92

Effectiveness of Epoetin Alfa andDarbepoetin Alfa Therapies. Studiesevaluating the effectiveness of epoetinalfa therapy have produced consistentresults. In clinical trials, 95% of adultpatients experienced a clinically signifi-cant increase in Hct at starting doses of50 to 150 Units/kg TIW.89,97 Thesepatients were virtually transfusion-inde-pendent after about 2 months of thera-py.89,97 Clinical trials have also suggestedthat predialysis and dialysis patientsrespond to epoetin alfa therapy in a simi-lar manner. That is, both populationsdemonstrated a sustained dose-depend-ent rise in Hct, which was similar with IVor SC administration.89,97

A phase 3 clinical trial also evaluatedthe quality of life of patients receiving epo-etin alfa therapy.89,97,100,101 Patients whoseHct levels reached target range (32% to38%) showed significant improvement inmultiple quality-of-life parameters (eg,energy and activity level; functional abili-ty; health status; sleep, eating, and sex life;life satisfaction; well-being; happiness).They also demonstrated significantimprovement in energy and strength.101,102

Other studies have evaluated and com-pared the efficacy of darbepoetin alfa andr-HuEPO. In 2 open-label studies, darbe-poetin alfa or epoetin alfa was adminis-tered for correction of anemia to patientswith CKD who had not received prior ery-thropoietin therapy.92 The first studyassessed the response in dialysis patients,whereas the second evaluated theresponse in predialysis patients. Drug


dosages were adjusted in both studies, asnecessary, to maintain Hgb levels in thestudy target range (11 to 13 g/dL.) In thefirst study, 72% of the 90 patients treatedwith darbepoetin alfa and 84% of the 31patients treated with epoetin alfa achievedthe target Hgb range by 20 weeks.92 In thesecond study, 93% of the 129 patientstreated with darbepoetin alfa and 92% ofthe 37 patients treated with epoetin alfaachieved the target Hgb range by 24weeks.92

Conversion From RecombinantHuman Erythropoietin to DarbepoetinAlfa Therapy. Studies also have specifi-cally assessed the ability of darbepoetinalfa to maintain target Hgb levels inpatients when administered at a reduceddosing frequency compared with r-HuEPO.The results of these studies suggested thatpatients receiving r-HuEPO 2 or 3 timesper week could switch to darbepoetin alfaonce weekly, and those receiving r-HuEPOonce per week could switch to darbepoet-in alfa once every other week, and main-tain their Hgb levels.98,103–106 Data alsosuggest that the efficacy of SC and IV dar-bepoetin alfa therapy is similar.98,105,107

Darbepoetin alfa should be administeredevery other week to anemia patients withchronic renal failure currently receivingepoetin alfa every week. Moreover, therecommended darbepoetin alfa vialstrength is 25 µg every week and 60 µgevery other week.92

More recently, Jadoul et al108 reportedpreliminary studies that suggest that dar-bepoetin alfa could maintain Hgb levelswhen administered once every 4 weeks inchronic CKD patients previously treatedwith epoetin alfa every other week.Although additional studies are necessaryto confirm these results, they venturedthat “darbepoetin alfa will provide greaterflexibility in treating the anemia of CKDby simplifying anemia management forboth physicians and patients.’’108

Managed Care and Health Economics:Health Care Financing AdministrationEnd-Stage Renal Disease Data on the Effect of Correction of Anemia on

Patient Mortality, Hospitalization, and Costs

The cost of care for ESRD patients con-tinues to rise with the growing number ofpatients. In 1997, Medicare expendituresfor ESRD were estimated at $11.76 billion.1

These costs are projected to increase to$28.3 billion by 2010.1,109 Substantial geo-graphic variability in Medicare expendi-tures for ESRD also exists.110 These dataillustrate the need to improve the efficien-cy and quality of care for ESRD patients,including the use of interventions to reducethe risk and/or impact of complications.

Correction of anemia of CKD repre-sents an example of an intervention thatcan improve outcomes and reduce costs.A retrospective study of the associationbetween Hct level and mortality in aMedicare hemodialysis cohort showedthat patients with Hct levels < 30% were atsignificantly higher risk for all-cause andcause-specific death than patients withHct levels ranging from 30% to 33%.90

Conversely, patients with Hct levels of33% to 36% were at the lowest risk for all-cause and cardiac mortality. Another studyof Medicare r-HuEPO–treated patients91

Additional information can be found at the following electronic resources:

1. www.hcfa.gov/quality/3m.htmHCFA and ESRD Network Organization: 2000 Annual Report, ESRDClinical Performance Measures (CPMs) Project, formerly known as theESRD Core Indicators Project.

2. www.kidney.orgThe National Kidney Foundation (NKF) web site, with links to clinical prac-tice guidelines.

3. www.nephronline.orgContinually updated web resource for clinicians and renal patients.

4. www.renalweb.comThis site includes renal web dialysis outcomes, links to other webresources, news and essential articles in the field, links to PubMed searcheson MEDLINE, K/DOQI CPGs, information about reimbursement issues, and Medicare’s comparison of the quality of care at various US dialysisfacilities.

5. http://www.niddk.nih.gov/fund/reports/nkdep/images/NKDEP_finalsummary.pdfGovernment resource on CKD.

6. http://www.usrds.org/adr.htmOnline access to US Renal Data System (USRDS) Annual Data Reports.



CME/CPE

revealed a similar association between Hctlevel and risk of hospitalization. In thisstudy, patients with Hct levels < 30% wereat significantly increased risk for hospital-ization compared with patients with Hctlevels of 30% to 33%.91 Conversely, patientswith Hct levels of 33% to 36% were at low-est risk for future hospitalization.

Another study of Medicare hemodialy-sis patients evaluated the relationshipbetween Hct level and Medicare-allowableper-member-per-month (PMPM) expendi-tures.111 Compared with reference patientswith Hct levels of 30% to 33%, theMedicare-allowable PMPM expenditureswere significantly greater for patients withHct levels < 27% and 27% to 30%.111

Conversely, these expenditures were sig-nificantly less for patients with Hct levelsof 33% to 36% and 36% and higher.111

Other studies provide additional infor-mation about the costs of inadequatelymanaged renal anemia and the benefits ofappropriate treatment. Levin et al52,112

showed that each 0.5 g/dL decrease in theHgb was associated with an increased riskof LVH by 1.32, whereas each 6% increasein Hct resulted in a 50% decrease in hos-pital days.25 Other data have suggestedthat the cost of care is lower in patientswho receive epoetin alfa early.57,58

Collectively, these data suggest thatappropriate management of renal anemia,including erythropoietin therapy, canimprove outcomes and lower MCO costs.

Summary

With the growing number of ESRDpatients, the time has come to focus thenational spotlight on CKD as a publichealth problem. Clinicians, patients, andhealthcare organizations need to be bettereducated about the benefits of early detec-tion and treatment of CKD. Reasons forthe underdiagnosis and undertreatment ofCKD must be addressed and appropriatepreventive and therapeutic interventionsimplemented. Improving medical partner-ships between clinicians and patients isone step toward optimizing care.Clinicians need to instruct patients inmethods of risk factor reduction and iden-tify means to slow progression of CKD.

Clinicians must remain alert to earlywarning signs, comply with the latestK/DOQI practice guidelines, and be willingto implement preventive and therapeuticinterventions. MCOs also need to take anactive role in improving ESRD outcomes.Their efforts should include implementa-tion of interventions to educate cliniciansand patients as well as the evaluation ofclinician performance based on appropri-ate outcome measures.

. . . REFERENCES . . .

1. Collins AJ. End-stage renal disease. Are we readyfor an emerging epidemic? Postgrad Med 2000;108:13-15.2. Eknoyan G, Levey AS, Levin NW, et al. Thenational epidemic of chronic kidney disease: Whatwe know and what we can do. Postgrad Med2001;110:23-29.3. National Kidney Foundation. K/DOQI clinicalpractice guidelines for chronic kidney disease:Evaluation, classification, stratification, executivesummary. K/DOQI, Kidney Disease OutcomesQuality Initiative. Am J Kidney Dis 2002;39(suppl 1).4. Nissenson AR, Pereira BJG, Collins AJ, et al.Prevalence and characteristics of individuals withchronic kidney disease in a large health maintenanceorganization. Am J Kidney Dis 2001;37:1177-1183.5. Nissenson AR, Collins AJ, Hurley J, et al.Opportunities for improving the care of patients withchronic renal insufficiency: Current practice patterns.J Am Soc Nephrol 2001;12:1713-1720.6. Obrador GT, Arora P, Kausz AT, Pereira BJG.Post-end-stage renal disease care in the United States:A state of disrepair. J Am Soc Nephrol 1998;9:S44-S54.7. Obrador GT, Ruthazer R, Arora P, Kausz AT,Pereira BJ. Prevalence of and factors associated withsuboptimal care before initiation of dialysis in theUnited States. J Am Soc Nephrol 1999;10:1793-1800.8. Obrador GT, Arora P, Kausz AT, et al. Level ofrenal function at the initiation of dialysis in the U.S.end-stage renal disease population. Kidney Int1999;56:2227-2235.9. Obrador GT, Pereira BJ. Initiation of dialysis:Current trends and the case for timely initiation. PeritDial Int 2000;20(suppl 2):S142-S149.10. Obrador GT, Roberts T, St Peter WL, Frazier E,Pereira BJ, Collins AJ. Trends in anemia at initiationof dialysis in the United States. Kidney Int 2001;60:1875-1884.11. Pereira BJG. Nephrology forum: Optimization ofpre-ESRD care: The key to improved dialysis outcomes.Kidney Int 2000;57:351-365.12. Pereira BJ. Introduction: New perspectives inchronic renal insufficiency. Am J Kidney Dis2000;36(suppl 3)S1-S3.13. Bakris GL, Williams M, Dworkin L, et al.Preserving renal function in adults with hypertensionand diabetes: A consensus approach. National KidneyFoundation Hypertension and Diabetes Executive



Committees Working Group. Am J Kidney Dis2000;36:646-661.14. Bolton WK, Kliger A. Chronic renal insufficiency:Current understandings and their implications. Am JKidney Dis 2000;36(suppl 3):S4-S12.15. Reikes ST. Trends in end-stage renal disease:Epidemiology, morbidity, and mortality. PostgradMed 2000;108(1):124-142.16. US Renal Data System. Annual Data Reports,1997, 1998, 1999, 2001. Bethesda, MD: NationalInstitutes of Health, National Institute of Diabetes andDigestive and Kidney Diseases; 1997, 1998, 1999,2001. Available at: http://www.usrds.org.17. Joint National Committee on Prevention,Detection, Evaluation, and Treatment of High BloodPressure. The Sixth Report of the Joint NationalCommittee on Prevention, Detection, Evaluation, andTreatment of High Blood Pressure. Bethesda, MD:National Institutes of Health, National Heart, Lung,and Blood Institute; 1997. NIH publication 98-4080.18. Obrador GT, Pereira BJ. Early referral to thenephrologist and timely initiation of renal replace-ment therapy: A paradigm shift in the management ofpatients with chronic renal failure. Am J Kidney Dis1998;31:398-417.19. Pereira BJ. Strategies for influencing outcomes inpre-ESRD and ESRD patients. Nephrol News Issues1998;12(10):55-56.20. Schmitz PG. Progressive renal insufficiency.Office strategies to prevent or slow progression of kid-ney disease. Postgrad Med 2000;108(1):145-154.21. McClellan WM, Knight DF, Karp H, Brown WW.Early detection and treatment of renal disease in hos-pitalized diabetic and hypertensive patients: Importantdifferences between practice and published guide-lines. Am J Kidney Dis 1997;29:368-375.22. Kausz AT, Khan SS, Abichandani R, et al.Management of patients with chronic renal insuffi-ciency in the Northeastern United States. J Am SocNephrol 2001;12:1501-1507.23. Beckman HB, Frankel RM. The effect of physi-cian behavior on the collection of data. Ann InternMed 1984;101:692-696.24. Levey, AS, Bosch JP, Lewis JB, et al., for theModification of Diet in Renal Disease Study Group.A more accurate method to estimate glomerular filtra-tion rate from serum creatinine: A new predictionequation. Ann Intern Med 1999;130:461-470.25. Pereira B. CKD care in the U.S. Presented at:Managed Care Roundtable: A Focus on ChronicKidney Disease; May 3-5, 2001; Chicago, IL.26. Lewis J, Agodoa L, Cheek D, et al. Comparisonof cross-sectional renal function measurements inAfrican Americans with hypertensive nephrosclerosisand of primary formulas to estimate glomerular filtra-tion rate. Am J Kidney Dis 2001;38:744-753.27. Fishbane S. Major issues in achieving qualityESRD outcomes. Presented at: Managed CareRoundtable: A Focus on Chronic Kidney Disease;May 3-5, 2001; Chicago, IL.28. Agodoa LY, Appel L, Bakris GL, et al. Effect oframipril vs amlodipine on renal outcomes in hyper-tensive nephrosclerosis: A randomized controlledtrial. JAMA 2001;285:2719-2728.29. Marin R, Ruilope LM, Aljama P, Aranda P,Segura J, Diez J. A random comparison of fosinopriland nifedipine GITS in patients with primary renal

disease. J Hypertens 2001;19:1871-1876.30. Jafar TH, Stark PC, Schmid CH, et al. Proteinuriaas a modifiable risk factor for the progression of non-diabetic renal disease. Kidney Int 2001;60:1131-1140.31. Hovind P, Rossing P, Tarnow L, Smidt UM,Parving HH. Remission and regression in thenephropathy of type 1 diabetes when blood pressure iscontrolled aggressively. Kidney Int 2001;60:277-283.32. Shichiri M, Kishikawa H, Ohkubo Y, Wake N.Long-term results of the Kumamoto Study on optimaldiabetes control in type 2 diabetic patients. DiabetesCare 2000;23(suppl 2):B21-B29.33. The effect of intensive treatment of diabetes onthe development and progression of long-term com-plications in insulin-dependent diabetes mellitus. TheDiabetes Control and Complications Trial ResearchGroup. N Engl J Med 1993;329:977-986.34. Mann JFE, Gerstein HC, Pogue J, et al. Renalinsufficiency as a predictor of cardiovascular out-comes and the impact of ramipril: The HOPE ran-domized trial. Ann Intern Med 2001;134:629-636.35. Effects of ramipril on cardiovascular andmicrovascular outcomes in people with diabetes mel-litus: Results of the HOPE study and MICRO-HOPEsubstudy. Heart Outcomes Prevention EvaluationStudy Investigators. Lancet 2000;355:253-259.36. Gerstein HC. Diabetes and the HOPE study:Implications for macrovascular and microvasculardisease. Int J Clin Pract Suppl 2001 Jan;(117):8-12.37. Agodoa LY, Appel L, Bakris GL, et al. Effect oframipril vs amlodipine on renal outcomes in hyper-tensive nephrosclerosis: A randomized controlledtrial. JAMA 2001;285:2719-2728.38. Buckalew VM Jr, Berg RL, Wang SR, et al.Prevalence of hypertension in 1,795 subjects withchronic renal disease: The modification of diet inrenal disease study baseline cohort. Modification ofDiet in Renal Disease Study Group. Am J Kidney Dis1996;28:811-821.39. Zabetakis PM, Nissenson AR. Complications of chronic renal insufficiency: Beyond cardiovascu-lar disease. Am J Kidney Dis 2000;36(suppl 3):S31-S38.40. Drüeke TB. Aspects of cardiovascular burden inpre-dialysis patients. Nephron 2000;85(suppl 1):9-14.41. Held PJ. USRDS case-mix study. J Am Soc Nephrol1991;2:328.42. USRDS Dialysis Morbidity and Mortality Study:Wave 2. United States Renal Data System [slide 34].Am J Kidney Dis 1997;30(suppl 1):S67-S85.43. Bernhard J, Beaufrere B, Laville M, Fouque D.Adaptive response to a low-protein diet in predialysischronic renal failure patients. J Am Soc Nephrol 2001;12:1249-1254. 44. Besarab A, Levin A. Defining a renal anemiamanagement period. Am J Kidney Dis 2000;36(suppl3):S13-S23.45. Kausz AT. Anemia Management in Patients withChronic Renal Insufficiency. Am J Kidney Dis2000;36(suppl 3):S39-S51.46. Kazmi WH, Kausz AT, Khan S, et al. Anemia: Anearly complication of chronic renal insufficiency. AmJ Kidney Dis 2001;38:803-812.47. Besarab A, Bolton WK, Browne JK, et al. Theeffects of normal as compared with low hematocritvalues in patients with cardiac disease who are


CME/CPE

receiving hemodialysis and epoetin. N Engl J Med1998;339:584-590.48. Eschbach JW, Anderson JW. Anemia of end-stagerenal disease (ESRD). Kidney Int 1985;28:1-5.49. Erslev AJ. Erythropoietin. N Engl J Med 1991;324:1339-1344.50. Parfrey PS, Foley RN, Harnett JD, Kent GM,Murray DC, Barre PE. Outcome and risk factors forleft ventricular disorders in chronic uraemia. NephrolDial Transplant 1996;11:1277-1285.51. Harnett JD, Kent GM, Foley RN, Parfrey PS.Cardiac function and hematocrit level. Am J KidneyDis 1995;25(suppl 1):S3-S7.52. Levin A, Thompson CR, Ethier J, et al. Left ven-tricular mass index increase in early renal disease:Impact of decline in hemoglobin. Am J Kidney Dis1999;34:125-134.53. Tsakiris D. Morbidity and mortality reductionassociated with the use of erythropoietin. Nephron2000;85(suppl 1):2-8.54. Al-Ahmad A, Levey A, Rand W, et al. Anemiaand renal insufficiency as risk factors for mortality inpatients with left ventricular dysfunction [abstract]. J Am Soc Nephrol 2000;11:137A.55. Madore F, Lowrie EG, Brugnara C, et al. Anemiain hemodialysis patients: Variables affecting this out-come predictor. J Am Soc Nephrol 1997;8:1921-1929.56. IV. NKF-K/DOQI clinical practice guidelines foranemia of chronic kidney disease: Update 2000. Am JKidney Dis 2001;37(suppl 1):S182-S238.57. Collins A. HCFA ESRD data: Mortality, hospital-ization, and costs (impact on MCOs). Presented at:Managed Care Roundtable: A Focus on ChronicKidney Disease; May 3-5, 2001; Chicago, IL.58. Collins A. CRI/ESRD health economics (HCFApharmacoeconomic backcasting data on CRI andCKD). Presented at: Managed Care Roundtable: AFocus on Chronic Kidney Disease; May 3-5, 2001;Chicago, IL. 59. Collins AJ, Ma JZ, Xia A, Ebben J. Trends in ane-mia treatment with erythropoietin usage and patientoutcomes. Am J Kidney Dis 1998;32(suppl 4):S133-S141.60. Eschbach JW. Current concepts of anemia man-agement in chronic renal failure: Impact of NKF-DOQI. Semin Nephrol 2000;20:320-329.61. Revicki D, Brown R, Feeny D, et al. Health-relat-ed quality of life associated with recombinant humanerythropoietin therapy or predialysis chronic renaldisease patients. Am J Kidney Dis 1995;25:548-554.62. Brouwer DJ. Optimizing vascular access: A teamperspective using the National Kidney Foundation-Dialysis Outcomes Quality Initiative Guidelines. AdvRen Replace Ther 1999;6:93-96.63. Pereira BJ, Burkart JM, Parker TF 3rd. Strategiesfor influencing outcomes in pre-ESRD and ESRDpatients. Am J Kidney Dis 1998;32(suppl 4):S2-S4.64. Arora P, Kausz AT, Obrador GT, et al. Hospitalutilization among chronic dialysis patients. J Am SocNephrol 2000;11:740-746.65. USRDS DMMS 1. Am J Kidney Dis 1996;28(suppl2):S58-S78.66. Karsou SA, Jaber BL, Pereira BJG. Impact ofintermittent hemodialysis variables on clinical out-comes in acute renal failure. Am J Kidney Dis

2000;35:980-991.67. Arora P, Obrador GT, Ruthazer R, et al.Prevalence, predictors, and consequences of latenephrology referral at a tertiary care center. J Am SocNephrol 1999;10:1281-1286.68. Mosley C. Coordination of care in disease man-agement: Opportunities and financial issues. SeminDial 2000;13:346-350.69. Bolton WK. Nephrology nurse practitioners in a col-laborative care model. Am J Kidney Dis 1998;31:786-793.70. National Center for Health Statistics. The ThirdNational Health and Nutrition Examination Survey1988–1994 (NHANES III). Hyattsville, MD: US Centersfor Disease Control and Prevention, National Centerfor Health Statistics, US Department of Health andHuman Services; 1988–1994.71. US Renal Data System. USRDS 1998 AnnualData Report: Atlas of End-Stage Renal Disease in theUnited States. Bethesda, MD: National Institutes ofHealth, National Institute of Diabetes and Digestiveand Kidney Diseases; 1998. Available at: http://www.usrds.org/adr_1998.htm.72. Burkart JM, Pereira BJ, Parker TF 3rd. Strategiesfor influencing outcomes in pre-ESRD and ESRDpatients. J Am Soc Nephrol 1998;9(suppl):S2-S3.73. Keane WF. Proteinuria: Its clinical importanceand role in progressive renal disease. Am J KidneyDis 2000;35(suppl 1):S97-S105.74. Jafar TH, Schmid CH, Landa M, et al.Angiotensin-converting enzyme inhibitors and pro-gression of nondiabetic renal disease. Ann Intern Med2001;135:73-87.75. Rodby RA, Firth LM, Lewis EJ. An economicanalysis of captopril in the treatment of diabeticnephropathy. The Collaborative Study Group.Diabetes Care 1996;19:1051-1061.76. Klag MJ, Whelton PK, Randall BL, Neaton JD,Brancati FL, Stamler J. End-stage renal disease inAfrican-American and white men: 16-year MRFITfindings. JAMA 1997;277:1293-1298.77. Lazarus JM, Bourgoignie JJ, Buckalew VM, et al.,for the Modification of Diet in Renal Disease StudyGroup. Achievement and safety of a low blood pres-sure goal in chronic renal disease: The Modificationof Diet in Renal Disease Study Group. Hypertension1997;29:641-650.78. Weir MR. Diabetes and hypertension: How longshould you go and with which drugs? Am J Hypertens2001;14(suppl):17S-26S.79. Coresh J, Longenecker JC, Miller ER 3rd, YoungHJ, Klag MJ. Epidemiology of cardiovascular risk fac-tors in chronic renal disease. J Am Soc Nephrol1998;9(suppl):S24-S30.80. Clinical practice guidelines for nutrition in chronicrenal failure. K/DOQI, National Kidney Foundation.Am J Kidney Dis 2000;35(suppl 2):S1-S140.81. Nissenson AR, Strobos J. Iron deficiency inpatients with renal failure. Kidney Int Suppl1999;69:S18-S21.82. NKF-DOQI clinical practice guidelines for vascu-lar access: Update 2000. National Kidney Foundation-Dialysis Outcomes Quality Initiative. Am J Kidney Dis1997;30(suppl 3):S150-S191.83. II. NKF-K/DOQI clinical practice guidelines forperitoneal dialysis adequacy: Update 2000. Am J



Kidney Dis 2001;37(suppl 1):S65-S136.84. I. NKF-K/DOQI clinical practice guidelines forhemodialysis adequacy: Update 2000. Am J KidneyDis 2001;37(suppl 1):S7-S64.85. Ifudu O, Dawood M, Homel P, Friedman EA.Excess morbidity in patients starting uremia therapywithout prior care by a nephrologist. Am J Kidney Dis1996;28:841-845.86. Lindberg J, Churchill DN, Fishbane S. Researchdirections: New clinical frontiers. Am J Kidney Dis2000;36(suppl 3):552-561.87. McLaughlin K, Manns B, Culleton B, DonaldsonC, Taub K. An economic evaluation of early versuslate referral of patients with progressive renal insuffi-ciency. Am J Kidney Dis 2001;38:1122-1128.88. MacDougall IC. Present and future strategies inthe treatment of renal anemia. Nephrol DialTransplant 2001;16(suppl 5):50-55.89. Epogen® (epoetin alfa) [package insert]. ThousandOaks, CA: Amgen, Inc.; 1989–1999.90. Ma JZ, Ebben J, Xia H, Collins AJ. Hematocritlevel associated mortality in hemodialysis patients. J Am Soc Nephrol 1999;10:610-619.91. Xia H, Ebben J, Ma JZ, Collins AJ. Hematocritlevels and hospitalization risks in hemodialysispatients. J Am Soc Nephrol 1999;10:1309-1316.92. Aranesp™ (darbepoetin alfa) [package insert].Thousand Oaks, CA: Amgen, Inc.; 2001.93. Egrie JC, Browne JK. Development and character-ization of novel erythropoiesis stimulating protein(NESP). Nephrol Dial Transplant 2001;16(suppl 3):3-13.94. Egrie JC, Browne JK. Development and character-ization of novel erythropoiesis stimulating protein(NESP). Br J Cancer 2001;84(suppl 1):3-10.95. Macdougall IC, Gray SJ, Elston O, et al.Pharmacokinetics of novel erythropoiesis stimulatingprotein compared with epoetin alfa in dialysispatients. J Am Soc Nephrol 1999;10:2392-2395.96. Nissenson AR. Novel erythropoiesis stimulatingprotein for managing the anemia of chronic kidneydisease. Am J Kidney Dis 2001;38:1390-1397.97. Procrit® (epoetin alfa). [package insert]. ThousandOaks, CA/Raritan, NJ: Amgen, Inc./Ortho BiotechInc.; revised March 2000.98. Locatelli F, Olivares J, Walker R, et al. Novelerythropoiesis stimulating protein for treatment ofanemia in chronic renal insufficiency. Kidney Int2001;60:741-747.99. MacDougall IC. An overview of the efficacy andsafety of novel erythropoiesis stimulating protein(NESP). Nephrol Dial Transplant 2001;16(suppl13):14-21.100. Eschbach JW, Abdulhadi MH, Browne JK, et al.Recombinant human erythropoietin in anemicpatients with end-stage renal disease. Ann Intern Med1989;111:992-1000.

101. Evans RW, Rader B, Manninen DL, et al. Thequality of life of hemodialysis recipients treated withrecombinant human erythropoietin. JAMA 1990;263:825-830.102. Lundin AP, Akerman MJH, Chesler RM, et al.Exercise in hemodialysis patients after treatment withrecombinant human erythropoietin. Nephron1991;58:315-319.103. Coyne DW, Ling BN, Toto R, et al. Novel ery-thropoiesis stimulating protein (NESP) corrects anemiain dialysis patients when administered at reduceddose frequency compared to recombinant-human erythropoietin (r-HuEPO) [abstract]. J Am Soc Nephrol2000;11:263A.104. Graf H, Lacombe J-L, Braun J, Gomes da CostaAA. Novel erythropoiesis stimulating protein (NESP)effectively maintains hemoglobin (Hb) when adminis-tered at a reduced dose frequency compared withrecombinant human erythropoietin (rHuEpo) in ESRDpatients. J Am Soc Nephrol 2000;11:A1317A.105. Locatelli F, Olivares J, Walker R, Wilkie M,the European/Australian NESP 980202 StudyGroup. Novel erythropoiesis stimulating protein(NESP) administered subcutaneously corrects anemiain subjects with chronic renal insufficiency (CRI)when administered at a reduced dose frequencycompared with recombinant-human erythropoietin(r-HuEPO) [abstract]. J Am Soc Nephrol2000;11:283A.106. Vanrenterghem Y, Barany P, Mann J. Novelerythropoiesis stimulating protein (NESP) maintainshemoglobin (Hb) in ESRD patients when administeredonce weekly or once every other week. J Am SocNephrol 1999;10:A1365.107. Lerner GR, Kale AS, Warandy BA, et al. Thepharmacokinetics of novel erythropoiesis stimulatingprotein (NESP) in pediatric patients with chronic renalfailure (CRF) and end-stage renal disease [abstract]. J Am Soc Nephrol 2000;11:282A.108. Jadoul M, et al. New data on Aranesp dosedevery four weeks in anemic patients with chronicrenal failure. Abstract presented at: World Congress ofNephrology (WCN); October 2001; San Francisco,CA.109. Xue JL, Ma JZ, Louis TA, Collins AJ. Forecast ofthe number of patients with end-stage renal disease inthe United States to the year 2010. J Am Soc Nephrol2001;12:2753-2758.110. Hirth RA, Tedeschi PJ, Wheeler JR. Extent andsources of geographic variation in Medicare end-stagerenal disease expenditures. Am J Kidney Dis 2001;38:824-831.111. Collins AJ, Li S, Ebben J, et al. Hematocrit levelsand associated Medicare expenditures. Am J KidneyDis 2000;36:282-293.112. Levin A, Singer J, Thompson CR, Ross H, LewisM. Prevalent left ventricular hypertrophy in the pre-dialysis population: Identifying opportunities for inter-vention. Am J Kidney Dis 1996;27:347-354.

projap a15 pereira s122-s135€¦ · cardiovascular risk in patients with early ckd34,35 and the...

Documents