R A M PRENAL ANEMIA MANAGEMENT PERIOD

A Call for the Early Recognition and

Appropriate Management of Anemia

in Chronic Renal Insufficiency

Acknowledgement

Amgen gratefully acknowledges their efforts.

© 2001 Amgen Inc. All rights reserved.

The RAMP concept presented in this monograph represents a collaboration of the following contributors:

Anatole Besarab, MD

W. Kline Bolton, MD

David N. Churchill, MD

Steven Fishbane, MD

Robert N. Foley, MD

Annamaria Kausz, MD

Alan S. Kliger, MD

Adeera Levin, MD

Jill S. Lindberg, MD

Allen R. Nissenson, MD

Brian J.G. Pereira, MD, MBA

Richard A. Sherman, MD

John C. Stivelman, MD

Paul M. Zabetakis, MD

1

Table of Contents

Introduction 2

Profile of the CRI Population 4

Complications and Comorbidities of CRI 6

The Anemia of CRI: Definition, Etiology, Prevalence 10

Adverse Sequelae of the Anemia of CRI 12

CRI, Anemia, and Cardiac Disease 16

Benefits of Anemia Management with rHuEPO in CRI 18

The RAMP: Heightened Vigilance for Anemia Treatment 22

Summary 24

Bibliography 25

2

IntroductionRi

sk o

f Com

orbi

d Co

nditi

ons

CRI ESRD

Renal replacementtherapy (RRT)

Time

(can develop at any time after onset of CRI)

Anemia

R • A • M • PRenal Anemia Management Per iod

RAMP

Cognitive Function/QOL

Renal Function

Cardiovascular Function

Sexual Function

ANEMIA CONTRIBUTES TO MANY MANIFESTATIONS OF CHRONIC KIDNEY DISEASE

• NHANES III data suggest up to 6,200,000 people in the United States may have CRI with estimated SCr values ≥1.5 mg/dL.11

• CRI-related anemia begins early during kidney disease;however, it is underrecognized and undertreated.3,23

• NIH Consensus Conference Statement on Morbidity and Mortality:Refer to a nephrologist when SCr levels reach >1.5 mg/dL in women and >2.0 mg/dL in men.1

• Partial correction of anemia with rHuEPO treat-ment in dialysis patients improves both cogni-tive function and brain electrophysiology, whichultimately enhances learning and memory.18

• Treatment of anemia with rHuEPO in CRIpatients shows significant improvement in Hb/Hct levels that results in improvements in health-related QOL.57

• Correction of anemia with rHuEPO is associated with significant improvement in patients’ energy level.32

• rHuEPO treatment increases Hb/Hct in uremicCRI patients, resulting in an improved exercisecapacity without affecting GFR. 31

• Anemia is an important predictor of LVH in CRI patients.41

• Each 1-g/dL decrease in mean Hb increases the risk of LVH by 6%.41

• LVH is present in nearly 40% of patients attending CRI clinics.41

• LVH is present in 74% of patients at initiation of dialysis.67

• Cardiovascular disease accounts for ~40% of deaths in dialysis patients.35

• Each 1-g/dL decrease in mean Hb is indepen-dently associated with a 14% increased risk of mortality in dialysis patients.42

• An increase in Hb levels following anemia treatmentwith rHuEPO has been associated with improve-ments in sexual function in dialysis patients.63

Figure 1—Anemia that develops in patients over the course of disease progression is responsible, partially or wholly, for manifestations that in the past have been attributed to uremia.5 As patients progress to ESRD, anemia has been shown tobe associated with the development of cardiac sequelae, increased hospitalization, and increased mortality.6–9, 69,70

KEY: rHuEPO= recombinant human erythropoietin; QOL=quality of life; GFR=glomerular filteration rate;Hb=hemoglobin; Hct=hematocrit; SCr=serum creatinine; NIH=National Institutes of Health; LVH=leftventricular hypertrophy; NHANES III=Third National Health and Nutrition Examination Survey.

Chronic renal insufficiency (CRI) is an insidious disease that can arise as a consequence of diabetes mellitus, hypertensive nephrosclerosis, chronic glomer-ulonephritis, polycystic kidney disease, and a host of other

disorders. Regardless of the etiology, CRI generally progresses over time to end-stage renal disease (ESRD),when either dialysis or renal transplantation is required tosustain life. The wide-reaching physiological consequences

3

Major Points

• CRI is prevalent in the general population.

• CRI is associated with a host of sequelae that advance as kidney disease progresses,contributing to significant morbidity and mortality.

• Anemia often develops early in CRI and is associated with many debilitating sequelae.

• The anemia of CRI is manageable.

• Hence, the anemia of CRI should be identified early and managed appropriately.

of CRI typically give rise to a host of sequelae, and patients who reach ESRD often have anemia, left ventricular hypertrophy (LVH), congestive heart failure(CHF), metabolic bone disease, and malnutrition. Clinicaltrials have demonstrated that many of these conditionsdevelop early in the course of CRI, greatly increasing the risk of morbidity and mortality over the course of disease progression.1–4, 68

Anemia is one of the most common manifest-ations of progressive CRI, and can develop at any time after its onset, often well before ESRD develops. Clinical evidence has demonstrated that the anemia that developsover the course of disease progression is partially or wholly responsible for many of the debilitating manifesta-tions that have historically been attributed to uremia(Figure 1).5 Symptoms such as lethargy, weakness,chest pain, and shortness of breath hamper quality of life(QOL) and affect patients’ ability to work, perform household chores, and participate in even the simplestactivities of daily life. As patients progress to ESRD,anemia has been shown to be associated with the devel-

opment of cardiac sequelae (such as LVH), increased hospitalization, and increased mortality.6-9, 69,70

Despite the negative short- and long-term ramifica-tions associated with anemia, it is a silent disorder that isoften underrecognized and undertreated in patients with CRI. Health Care Financing Administration data indicate that 51% of patients have hematocrit (Hct) levelsof less than 28% at the onset of dialysis, and that there is no evidence of anemia management in 80% ofthese patients.3

This educational monograph reviews scientific dataidentifying the need for a Renal Anemia ManagementPeriod (RAMP)—the critical time following the onset of CRIwhen anemia develops and requires diagnosis and treatment. On the basis of the preponderance of data illustrating the deleterious effects of anemia in CRI andESRD populations, it follows that appropriate managementof this treatable complication should be initiated as early as possible in the progression of CRI—well before ESRD develops.

4

PREVALENCE OF CRI IN THE UNITED STATES

≥1.7≥1.5 ≥2.0Serum Creatinine (mg/dL)

6,200,000

No.

of P

eopl

e

8,000,000

6,000,000

4,000,000

0

2,500,000800,000

Figure 2—Depending on the serum creatinine cutoff point, as many as 6,200,000 Americans may have CRI, according to the NIH’s Third National Health and Nutrition Examination Survey.11

Profile of the CRI Population

Defining and Identifying CRISerum creatinine (SCr) is a widely used indirect

measure of kidney function that is employed by many clinicians to confirm the diagnosis of CRI. On the basis ofdefinitions developed by the National Institutes of Health(NIH), CRI is diagnosed when SCr levels exceed 1.5 mg/dLin men, 1.2 mg/dL in women, or age-specific normal valuesin children. Although these SCr levels signal significant kid-ney impairment, the systemic manifestations of CRI aretypically minimal, and most patients are asymptomatic.10

Despite widespread use, SCr does not accuratelymeasure or represent true kidney function and is an insen-sitive marker of early CRI.2,10 –12 Factors such as changes indietary creatine absorption, fluctuations in muscle mass,and secretion of creatinine by renal tubules and extrarenalsources can lead to low or stable SCr concentrations, evenin the presence of severe renal damage. Indeed, studieshave shown that SCr levels can be within the normal range in the presence of a glomerular filtration rate (GFR)as low as 20 mL/min/1.73 m2.13 As a result, loss of kidney

function, especially in the early stages of renal deteriora-tion, may be missed when SCr alone is used to assessfunction or when isolated measurements are used. Theneed to follow trends in clinical and laboratory parametersover time is fundamental. Because deterioration in kidneyfunction occurs progressively, regular clinical and laborato-ry follow-up can proactively detect subtle changes indica-tive of worsening kidney function.1, 3,10 ,11,13

Several other laboratory tests may provide a morecomprehensive and accurate assessment of kidney function. The GFR—a direct measure of kidney function—provides the best overall index of kidney function.12 GFRcorrelates directly with the severity of renal impairment, isless likely to be affected by external variables,and declines before the onset of uremia. Patients with CRI typically have a GFR between 30 and 75mL/min/1.73m2.10,13 Because GFR is difficult to measure inclinical practice, most clinicians use an estimated value calculated from the SCr concentration and other factors.12

Screenings for microalbuminuria and proteinuria can also

5

Major Points

• SCr alone may not be an adequate indicator of kidney function.

• Loss of kidney function in the early stages of chronic kidney disease is often missed when isolated or insufficient assessments are used.

• The prevalence of CRI is high.

• The incidence of contributing risk factors, such as diabetes and hypertension, is increasing.

• The goal of early and comprehensive intervention is to improve patient outcomes and reduce the burden to society and the healthcare system.

be useful indicators that can signal the need for a more in-depth evaluation.2

Demographics of CRIThe best evaluation of the scope of the CRI population

was provided by the NIH’s Third National Health andNutrition Examination Survey (NHANES III). This 7-year retrospective analysis examined the occurrence of renalimpairment among a representative sample of the US population (N = 18,723); these data were used to project theprobable prevalence of CRI in the United States. Resultswere categorized on the basis of serum creatinine levelsand revealed an estimated population of 6,200,000 patientswith a serum creatinine of 1.5 mg/dL or higher (Figure 2).11

Causes of CRIA wide range of diseases can give rise to progressive

loss of kidney function. In the population as a whole,diabetes and high blood pressure are the most commoncauses of kidney damage. However, a host of other disor-ders, including glomerulonephritis, vasculitis, interstitialnephritis, and genetic and congenital disorders, are also sig-nificant contributors.10

The increasing incidence of hypertension and diabetes as causes of ESRD contributes significantly to thegrowing population of patients requiring attention. Many of these “high-risk” patients are not being identified andmanaged early, when timely interventions could delay or

arrest progression. A multicenter retrospective analysis of587 randomly selected Medicare patients diagnosed withdiabetes or hypertension revealed inconsistent methods ofscreening for kidney disease. Although serum creatininewas reviewed in most patients, microalbuminuria wasassessed in only 2% of patients with diabetes and 1% ofthose with hypertension. Similarly, a urinalysis was con-ducted in 68% of patients with diabetes and 59% of thosewith hypertension. Further, even when laboratory markersindicating renal insufficiency were present, more than 60%of patients failed to receive therapies that could havedelayed the progression of renal damage.2

Estimates of the enormity of the CRI patient population and reports on the inconsistent application ofkidney disease screening methods and therapies illustratethat the great majority of patients with CRI are not beingidentified and managed, pointing to the need for early, com-prehensive, nephrologist-directed interventions. This con-clusion is supported by the fact that only a minority ofpatients—20% to 25%—are referred to a nephrologistbefore dialysis is initiated. These results persist, despite theavailability of therapeutic approaches that may modify thecourse of disease (examples include control of hyper-tension and use of angiotensin-converting enzymeinhibitors and lipid-lowering agents). These and otherproven measures can potentially prevent the developmentof some of the more serious long-term sequelae associatedwith kidney disease.1

6

<2.5

Serum Albumin Level (g/dL)

% o

f Pat

ient

s

15%

35

30

25

20

15

10

5

02.6–3.0

22%

3.1–3.5

30%

3.6–4.0

23%

4.1+

10%

Figure 3—Data based on 110,843 patients who began dialysis in the United States between 1995 and 1997.4

*The evolution and consequences of anemia and cardiovascular disorders are addressed in subsequent sections of this monograph.

SERUM ALBUMIN LEVELS AT INITIATION OF DIALYSIS

As patients with CRI pass through the spectrum of deteriorating renal function, the kidneys become unable to fulfill normal metabolic and endocrine demands, resulting in a wide range of systemic manifest-ations. The disorders associated with CRI can develop earlyin the course of the disease and progressively worsen as kidney function declines. Numerous clinical studieshave proven that many of these disorders, when left uncontrolled, can lead to an increase in mortality.Common comorbidities of CRI include: (1) diabetes,(2) hypertension, (3) dyslipidemia, and (4) cardiovascular dis-ease*. CRI leads to these common complications:(1) hypoalbuminemia, (2) renal osteodystrophy, (3) anemia*,

(4) decreased exercise capacity, (5) cognitive dysfunction,and (6) sexual dysfunction.

Diabetes

Diabetes is the most common cause of ESRD, and itsmanagement is of considerable importance when caringfor patients with CRI. Patients with diabetes should bescreened regularly for microalbuminuria and if renal disease is detected, interventions should be employed todelay disease progression. Tight glycemic and blood pressure control, along with treatment of proteinuria,should also be considered.10

Complications and Comorbidities of CRI

7

Hypertension

A large body of evidence has shown that uncontrolledhypertension during CRI increases future cardiovascularmortality once patients reach ESRD. Hypertension is one ofthe key factors responsible for the evolution of LVH,diastolic dysfunction, coronary artery disease, and cerebrovascular disease. Data suggest that failure to controlblood pressure early in the course of CRI results in changes that are irreversible or only slowly reversible at theonset of ESRD.1

Dyslipidemia

Abnormalities in lipid metabolism appear to occurearly in the course of CRI—lipoprotein lipase activity falls at a GFR of 50 mL/min/1.73m2. Common lipid abnormalitiesinclude hypercholesterolemia, elevated ratio of low- tohigh-density lipoproteins, and elevated lipoprotein(a) levels.Hyperlipidemia is a primary contributor to atherosclerosisas patients progress to ESRD.14

Hypoalbuminemia

The pathogenesis of hypoalbuminemia in patientswith CRI is multifactorial: contributing factors include urinary albumin loss, altered serum oncotic pressure, anddecreased dietary protein. Hypoalbuminemia causes ormay contribute to several complications characteristic ofchronic kidney disease, such as altered blood volume and composition, edema formation, increased plateletaggregability, enhanced potential for drug toxicity,compromised renal function, and hyperlipidemia.14 In onestudy of 153 incident patients, it was found that 62% hadhypoalbuminemia at the start of dialysis.15 Another analysisexamining the prevalence of and factors associated withhypoalbuminemia at initiation of dialysis found that serumalbumin was ≤3.5 g/dL in 67% of patients (Figure 3).4

Renal Osteodystrophy

It is known that the factors mediating renal osteodys-trophy are present early in the course of CRI. Bone diseaseis caused by a number of interrelated disorders, including

hypocalcemia, phosphorus retention, impaired calcemicresponse to parathyroid hormone (PTH), altered degrada-tion of PTH by the kidney, disordered regulation of PTHrelease, altered vitamin D metabolism, and acid-base dis-orders of uremia. The resulting renal osteodystrophy syndrome can lead to severe bone erosion. The NIH hasrecommended that renal osteodystrophy be managedthroughout CRI to prevent the development of potentiallyirreversible secondary hyperparathyroidism.1,16

Cognitive DysfunctionPatients with chronic kidney disease typically develop

a neurobehavioral syndrome—characterized by confu-sion, inability to concentrate, decreased mental alertness,and impaired memory—that worsens as renal functiondeclines. Patients with the most severe form can develophallucinations, tremors, myoclonus, and seizures. In dialysis patients, it has been proven that uremic toxins andanemia play major roles.17,18

Quality of LifeQOL and psychosocial relations can be impaired

in the early stages of CRI. In a study by Klang and colleagues,19 patients (N = 38) were questioned to determine self-perception of their illness. Results indicatedthat patients with early-stage CRI had a negative perception of their illness that was associated withdecreased well-being and functional activity and anincrease in anxiety that contributed to an overall decreasein QOL (Figure 4).

MortalityComorbid complications that develop during CRI can

contribute to an increase in short- and long-term mortalityover the course of disease progression. Cardiac disorders,anemia, hypoalbuminemia, and dyslipidemia are manageable conditions that have been shown to be associated with increased mortality. Studies have alsoshown that timely nephrologist-directed care can improvepatient outcomes. In one study that tracked patient mortality, for example, it was found that patients who died

8SICKNESS IMPACT PROFILE (SIP) IN CRI PATIENTS COMPARED WITH CONTROLS VS NORMALS

Figure 4—The overall SIP and its subcategories in predialytic uremic patients and a healthy reference group (graph shows means).19

Predialytic uremic patients

Reference group

Mea

n SI

P

20

15

10

5

0Overall

SIPPhysical Home

managementWorkRecreation

andpastime

Psychosocial EatingSleep andrest

within the first year of dialysis were under a nephrologist’scare for a median of 36 days before the onset of renalreplacement therapy. By comparison, in patients who survived more than 1 year, nephrologists had directed care for a median of 30 months.20 In a similar study,patients with ESRD who had been referred early in thecourse of CRI had substantially better survival than thosewho were referred later in their illness.21

These data have led the NIH to recommend thatpatients with CRI, including children, be referred to anephrologist early in the course of their disease to improvepatient outcomes.1

9

Major Points

• From onset of kidney disease to the time renal replacement therapy begins,

patients may develop significant complications and comorbidities.

• Common comorbidities of CRI include: (1) diabetes, (2) hypertension,

(3) dyslipidemia, and (4) cardiovascular disease.

• Common complications of CRI include: (1) hypoalbuminemia,

(2) renal osteodystrophy, (3) anemia, (4) decreased exercise capacity,

(5) cognitive dysfunction, and (6) sexual dysfunction.

• Poor outcomes have been associated with delayed or suboptimal care in CRI.

• Referral to a nephrologist early in the course of kidney disease may

help reduce the morbidity that begins before dialysis is initiated.

10

PERCENTAGE OF ANEMIC CRI PATIENTS (HCT <28%) TREATED WITH rHuEPO

Treated with rHuEPO

Not treated with rHuEPO

20%

80%

Figure 5—Of 67,057 patients with Hct <28% who required dialysis between April 1995 and June 1997, 80% did not receive rHuEPO therapy during CRI.3

The Anemia of CRI:Definition, Etiology, Prevalence

Anemia is a characteristic but often asymptomaticmanifestation of CRI. In normal individuals, hypoxia signalsthe kidneys to secrete the natural hormone erythropoietin,thereby stimulating the hematopoietic cascade responsi-ble for the production of red blood cells. In patients withprogressive CRI, the diseased kidneys are typically unableto secrete enough erythropoietin, and a normocytic,

normochromic anemia results. Other factors may also contribute to the severity of anemia in CRI: (1) a shortenedlife span for red blood cells, (2) iron or other nutritional deficiencies, (3) uremic inhibitors, and (4) etiologies such asinfection and inflammation that can inhibit normal redblood cell development. These factors should be activelyassessed and treated whenever possible.22

11

Major Points

• Anemia develops early in the course of chronic kidney disease.

• Anemia of CRI is often underrecognized and undertreated. Most patients do not receive

comprehensive anemia management before starting renal replacement therapy.

No clear definition of anemia in patients with CRI hasbeen established. In other fields of medicine, anemia isidentified when hemoglobin (Hb) levels are below the phys-iological normal ranges of 13 to 16 g/dL in men and 12 to 14 g/dL in women.23 In dialysis patients, a comprehensivereview of the benefits associated with higher Hb levels bythe National Kidney Foundation’s Kidney DiseaseOutcomes Quality Initiative (K/DOQI) Anemia Work Groupresulted in a recommended target Hb range of 11 to 12g/dL.6 Studies are under way to establish a clear target Hbrange for patients with CRI.

Anemia is an important predictor of morbidity andmortality and is prevalent early during the course of CRI—well before the need for renal replacement therapy.23,24,36,75 The overriding prevalence of anemia inpatients with CRI was demonstrated in a retrospective

analysis of factors associated with suboptimal care beforeinitiation of dialysis in the United States (N=131,484). In thisstudy, 68% of patients had Hct levels <30% immediatelybefore starting dialysis; 51% had Hct values <28%. Overall,only 23% of patients were receiving recombinant humanerythropoietin (rHuEPO) therapy before they began dialy-sis; rHuEPO had not been prescribed for 80% of patientswhose Hct levels were <28% (Figure 5).3

12

MANIFESTATIONS OF ANEMIA

• Lethargy

• Angina

• Malaise/depression

• Cardiac enlargement

• Impaired cognition

• Impaired immune system

• Anorexia

• Intolerance to cold

• Endocrine/ metabolic abnormalities

• Cardiorespiratory disturbances

• Gastrointestinal disturbances

• Pruritus

• Tendency toward bleeding

• Weakness

• Shortness of breath

• Exertional chest pain

• Impaired concentration

• Impaired libido/ impotence

• Insomnia

• Headache

• Pallor

• Neuromuscular disturbances

• Cutaneous disturbances

• Musculoskeletal symptoms

• Reduced exercise tolerance

Figure 6—Anemia contributes tomany manifestations ofchronic kidney disease.

The anemia of CRI can have debilitating effects thatcompromise QOL and are associated with significant mor-bidity and mortality. Manifestations of anemia are apparentthroughout the body and have historically been attributedto progressive kidney disease and uremia. Evidence, how-ever, demonstrates that anemia is partially or whollyresponsible for these symptoms.5

Systemic Effects of AnemiaCommonly cited manifestations of anemia, including

lethargy, weakness, increased angina, and shortness ofbreath, are outlined in Figure 6.

Adverse Sequelae of the Anemia of CRI

13

Anemia and HospitalizationSeveral studies have shown an association between

anemia and the risk of future hospitalization. In a retro-spective study of 362 patients with CRI conducted byHolland and Lam,25 the presence of anemia independentlypredicted hospitalization; that is, patients with anemia werehospital-free for a median of 13.3 months, compared with amedian of 21.5 months (P= 0.0593) for those with higher Hblevels.

Similar results have been observed as patientsprogress from CRI to ESRD. In a large, retrospective,observational study of 71,717 hemodialysis patients, anassociation was demonstrated between Hct levels and thefuture risk of hospitalization. Compared with the baselinegroup (Hct 30% to <33%), the risk of hospitalization forpatients with a Hct below 30% increased 14% to 30% beforeadjustment for disease severity (P= 0.0001) and 7% to 18%after adjustment (P= 0.0001). Patients in the 33% to <36%cohort had the lowest risk of hospitalization. Compared withthe baseline group, the risk was 0.93 with adjustment for disease severity and 0.88 without it (P= 0.0001).8

These results are supported by a 6-month retrospectiveanalysis by Collins et al of 66,761 Medicare hemodialysispatients. Compared with the group with Hct of 33% to<36%, hospitalization risks were 30% to 76% higher inthe group with Hct <30% (P<0.0001). Hct ≥33% wasassociated with the lowest risk of hospitalization.

Anemia and Mortality

A growing body of evidence indicates that anemia isindependently associated with an increase in mortality in patients who progress from CRI to ESRD. Harnett andcolleagues26 studied 433 dialysis patients in three centersfor a mean of 41 months and found that anemia predictedmortality independent of age, diabetes mellitus, cardiacfailure, hypoalbuminemia, serum creatinine, mean arterialpressure, or echocardiographic heart disease. For every 1-g/dL decrease in Hb, the relative risk (RR) of mortalityincreased by 18% (P = 0.019).

Similarly, a large, retrospective, observational study of 75,283 hemodialysis patients showed an associationbetween higher Hct levels and improved patient survival.9

The authors concluded that, in a population of hemodialy-sis patients characterized during a 6-month entry periodand then followed for a full year, there was an associationbetween Hct level and survival. Patients whose Hct levelswere maintained between 33% and 36% had the bestchance of surviving into the next year. By comparison,patients whose Hct levels were <33% had a higher risk ofall-cause and cardiac death.

Additional data supporting this emerging body of evidence come from a 2–1/2 year retrospective analysis of 66,761 incident Medicare hemodialysis patients, whichrevealed that mortality risk was greatest in patients withHct levels <30%. Patients with Hct levels of 33% to <36%had a lower risk of mortality compared with those withlower Hct levels. Mortality among patients with Hcts ≥36%was not significantly different from that of patients whoseHct was 33% to <36%.

Anemia and Impaired Cognitive FunctionAnemia is a major contributor to decreased cognitive

function in patients with renal disease. Several mecha-nisms have been suggested to explain the deleteriouseffect of anemia on cognitive function, including: (1) a com-pensatory rise in cerebral blood flow may result inincreased delivery of toxins to the brain, (2) a decrease incerebral oxygen delivery and consumption may decreasethe effectiveness of brain functioning, and (3) Hb/Hct levelsmay not be adequate to oxygenate the brain.17, 27–29 Onestudy showed that optimal delivery of oxygen to the brainrequires a minimum Hb of 11 g/dL (Hct = 33%).28 Anotherdemonstrated a direct correlation between progressiveincreases in Hb and increased cerebral blood flow.29

Anemia and Exercise TolerancePatients with kidney disease typically have a low toler-

ance for exercise that can adversely affect their ability towalk independently, perform self-care, do housework, orpursue employment. The level of exercise tolerance in

14

patients with chronic kidney disease is low compared withage-predicted values. In fact, the energy required for occu-pational activities and those associated with daily living maypreclude the performance of even simple tasks.30 Studieshave shown that patients with CRI and anemia have a sig-nificant decrease in exercise capacity.31 Patients with anemia have peak VO2 values as low as half those ofhealthy, sedentary, age-matched individuals by the timethey reach ESRD.30 Studies conducted in the CRI population indicate that partial correction of anemia with rHuEPOresults in significant improvements in energy levels 32, 33

and exercise capacity.31, 34

These data suggest that appropriate management ofanemia may be as important in the period before dialysisas during dialysis. The NIH observes that predialysis treatment of anemia may be critical to reduce cardio-vascular morbidity and mortality, since complications suchas long-standing LVH associated with anemia may be poorly reversible—or irreversible—if delayed until dialysis.1

15

Major Points

• The anemia of CRI can have debilitating effects that are associated with

significant morbidity and mortality over the course of disease progression.

• Many symptoms of uremia are partially or wholly attributable to anemia

and are evident throughout the body.

• An emerging body of evidence suggests that anemia and its associated

complications and comorbidities start well before the onset of ESRD.

• Data suggest that anemia should be appropriately managed early in the course of CRI.

16PREVALENCE OF LVH IN PATIENTS WITH CRI

P=0.05

% o

f Pa

tien

ts w

ith

LVH

Categories of Renal Function Creatinine Clearance (mL/min)

30

25

35

40

45

50

20

15

10

5

0Ccr>50

26.7

Ccr 25-49

30.8

Ccr<25

45.2

Figure 7—The prevalence of LVH increases as renal function declines.41

CRI, Anemia, and Cardiac Disease

LVH in Patients with CRICardiovascular disease is the leading cause of death

in patients who progress from CRI to ESRD—50% of dialysis patients die of diseases of the cardiovascular system (excluding cerebrovascular disease).1, 35 The mostcommon cardiac abnormality found in patients with kidneydisease is LVH, accompanied by an associated impairmentof left ventricular filling.35–38 While LVH has been shown tobe a strong predictor of mortality in dialysis patients,26,39,40,71

it is also a significant problem in the CRI population andappears to develop early in the course of the disease.41,68

A prospective cohort study conducted in Canada revealedLVH in 74% of patients just starting dialysis (N=433).26

Similarly, a study investigating the prevalence of comorbid

conditions associated with CRI (N=175) found that while the overall prevalence of LVH was about 40%,the prevalence rose as kidney function declined:(1) 26.7% of patients whose creatinine clearance (Ccr) levels were >50 mL/min, (2) 30.8% of patients whose Ccr levels were 25 to 49 mL/min, and (3) 45.2% of patientswhose Ccr was <25 mL/min (P= 0.05) (Figure 7).41

LVH and AnemiaHypertrophy of cardiac muscle develops in response

to increased workloads, such as those caused by hypertension and anemia.37,68 Chronic anemia can cause ahyperdynamic state in which cardiac work and the cardiacindex increase. When Hb and Hct levels decrease, there is

17

Major Points

• Cardiovascular disease is the leading cause of death in dialysis

patients who progress from CRI to ESRD.

• LVH is the most common cardiovascular abnormality in patients

with kidney disease and is an important predictor of mortality.

• Recent data correlating the progression of anemia with worsening

of LVH may suggest approaches to early recognition and

management of the cardiac comorbidities of CRI.

a concomitant rise in cardiac output as the body attemptsto increase tissue oxygenation. Over time, this perpetualoverwork results in hypertrophy of the left ventricle.35, 37, 38, 68

The relationship between LVH and anemia has beenwell documented. In a study of 175 patients with CRI byLevin and colleagues,41 for each 1-g/dL decrease in Hb, therisk of LVH increased by 6% (P= 0.0062). Similarly, a studyreporting on 246 evaluable patients from a cohort of 446 patients with CRI found that for every 0.5-g/dL decreasein Hb, the RR of left ventricular growth increased by 32% (P= 0.004).66

The effect of anemia on LVH has also been shown inpatients who progress from CRI to ESRD. In a prospectivestudy conducted by Foley and colleagues,42 432 patients(261 on hemodialysis and 171 on peritoneal dialysis) werefollowed for an average of 41 months. After adjusting for diabetes, ischemic heart disease, age, blood pressure,and serum albumin levels, each 1-g/dL decrease in mean Hb was independently associated with an increase in left ventricular dilatation (odds ratio = 1.46;P= 0.018), development of de novo (RR=1.28; P= 0.018) orrecurrent (RR=1.20; P= 0.046) cardiac failure, and increasedmortality (RR=1.14; P= 0.024).

An analysis of 11 studies that investigated the effect of partial correction of anemia with rHuEPO on left ventric-ular mass in dialysis patients showed that, in every studybut one, an increase in Hct was associated with a reductionin left ventricular mass ranging from 11% to 35%.43-52,72 In onestudy, blood pressure was not adequately controlled, andthere was only a 2% reduction in left ventricular massdespite an increase in Hct, underscoring the need to ade-quately control blood pressure to fully realize the potentialcardiovascular benefits associated with rHuEPO-inducedhigher Hb/Hct levels.48

These data demonstrate the potential negative cardiac sequelae associated with uncontrolled, chronicanemia in the CRI population and highlight the need for further research into the impact of anemia managementinterventions early in the course of CRI.

18 REGRESSION OF LVH IN CRI PATIENTS

Basal 6 Months

P<0.05

LVM

I (g/

m2 )

220

200

180

160

140

120

100

Hb=9± 0.3 g/dL Hb=11.7± 0.4 g/dL

Figure 8—LVMI decreased significantly from baseline as Hb levels increased.54

Benefits of Anemia Managementwith rRuEPO in CRI

A large number of studies in patients with ESRD havesuggested that partial correction of anemia with rHuEPO toHb levels of 11 to 12 g/dL may lead to decreased morbidi-ty and may be associated with reduced hospitalization andmortality. A growing body of literature suggests similarresults are possible in the CRI population.73

Hb/Hct Levels and Left Ventricular FunctionAvailable published data involving small numbers

of respondents suggest that correcting anemia withrHuEPO can significantly reduce LVH; further research isneeded to substantiate beneficial outcomes in early ane-mia treatment. In a study by Hayashi and colleagues,53 the

baseline left ventricular mass index (LVMI) of patients witha mean Hct level of 23.6% ± 0.5% was 140.6 ± 12.1 g/m2

(N = 9). After 4 months of rHuEPO therapy, the mean Hctlevel had increased to 32.1% ± 1.8%, and LVMI decreasedto 126.9 ± 10.0 g/m2. Additional improvements were seenafter 12 months, when mean Hct level was 39.1% ± 2.4%and LVMI had decreased to 111.2 ± 8.3 g/m2. (All patientsreceived antihypertensive medications before being treat-ed.) Further research is warranted in this area.

A study conducted by Portoles and colleagues54 of 11 patients with CRI (8 of whom required antihypertensivemedication for control of their blood pressure prior to

19

beginning rHuEPO) observed a trend of decreased left ventricular thickness and a significant decrease in LVMI(from 178.2 ± 20.6 g/m2 to 147.3 ± 20.6 g/m2) as rHuEPOincreased Hb levels from a mean of 9.0 ± 0.3 g/dL to 11.7 ± 0.4 g/dL (Figure 8). The trend toward regression of LVH independent of blood pressure control confirms the role of anemia among the multiple factors associatedwith LVH in ESRD.

These results are supported by larger patient popula-tions. Data from a recent analysis of the Studies of LeftVentricular Dysfunction (SOLVD) database of more than6,000 patients with left ventricular dysfunction found thatHct levels were significantly related to survival in patientswith CRI. Mortality decreased progressively as Hctincreased.55 An additional study by Stewart and colleagues56 evaluated cross-sectional echocardiographicresults from 297 CRI patients and found that: (1) LVH develops early in the course of kidney disease and worsens as the disease progresses, and (2) Hb levels independently predict the elevation in LVMI, althoughblood pressure seems to be the major determinant.

Although further studies are required to validatethese results in CRI patients, more extensive evidence supporting the impact of partial correction of anemia withrHuEPO is available in patients who have progressed toESRD. It has been shown that correcting anemia withrHuEPO to improve oxygen transport and reduce the car-diac index in these patients has a favorable impact on LVH.After partial rHuEPO-induced correction of uremic anemia,a number of hemodynamic effects have been observed:

• Decreases in left ventricular end-diastolic diameter,left ventricular mass, left atrial diameter, and cardiac output

• Increases in venous tone, peripheral vascularresistance, blood viscosity, and tissue oxygenation

• Normalization of heart function and modificationsin arteriolar and venous circulation

• Reductions in myocardial ischemia as indicated by normalization of ST-segment depression on electrocardiogram and improvements in symptom-limited exercise performance and duration

In a study by Zehnder and colleagues43 of 12 hemo-dialysis patients (8 of whom had a history of arterial hypertension treated with antihypertensive medication),baseline Hb concentrations of 8.6 ± 0.7 g/dL wereincreased to 11.4 ± 1.2 g/dL with rHuEPO therapy. LVMIdecreased from a baseline of 222.7 ± 41 g/m2 to 155.4 ±25.1 g/m2 (P<0.001) after 18.8 ± 2.7 months of therapy(normal LVMI in adults is 98.9 ± 26.3 g/m2). Subgroup analy-sis showed that LVH improvement required concomitantcorrection of anemia and control of blood pressure.43

Similar results have been demonstrated in a wide range ofstudies that have consistently correlated rHuEPO-inducedcorrection of anemia with dramatic reductions (11% to35%) in left ventricular mass.44-52, 72

Hb/Hct Levels and QOLFor patients with chronic kidney disease, improve-

ment in the overall QOL is perhaps the most welcome benefit associated with partial correction of anemia withrHuEPO (Table 1). In a study of patients with CRI (N=14),partial correction of anemia with rHuEPO was associatedwith subjective improvements in sense of well-being, angi-na, appetite, and physical activity, and objective improve-ments in the maximal work rate seen during exercise.34

Likewise, a study by Revicki and colleagues57 of 83 patientswith CRI showed improvements in energy, physical funct-ion, home management, social activity, and cognitive functioning when rHuEPO increased Hct levels. Similarimprovements in QOL parameters were also reported in other studies of CRI patients treated with rHuEPO.31,33

A controlled study of 117 CRI patients evaluated theeffect of treating anemia with rHuEPO in patients whosebaseline Hb was ≤ 13 g/dL for men or ≤ 11 g/dL for women.Among patients evaluated, 60% reported an increase inenergy levels following correction of anemia, comparedwith 42% of those whose anemia was not corrected.Similarly, work capacity improved in 62% of patients inwhom anemia was corrected with rHuEPO, compared with38% of those who remained anemic.32

There is a considerable body of evidence demon-strating the benefits of anemia treatment with rHuEPO onQOL parameters in patients with ESRD. Moreno and colleagues58 used the Karnofsky scale and the Sickness

Impact Profile (SIP) to evaluate the effect of Hb level onQOL in 1,013 stable dialysis patients. Patients were dividedinto four groups based on Hb level: <8 g/dL, 8 to 10 g/dL, 10 to 12 g/dL, and >12 g/dL. Significant improve-ments were noted in physical dimension (P< 0.01) andglobal (P<0.05) SIP scores at each successive Hb level.

Hb/Hct Levels and Exercise Capacity

Anemia affects all facets of QOL but is often mostapparent in the realm of physical activity. Clyne and col-leagues31 studied the effect of rHuEPO-induced increasesin Hb levels on physical exercise capacity in patients withCRI and uremia (N=12). In this study, an increase in Hb from8.6 ± 0.8 g/dL to 11.7 ±1.1 g/dL resulted in a correspondingincrease in exercise capacity evaluated by bicycle ergome-ter (from 128 ± 45 W to 147 ± 57 W, P<0.01). A study byTeehan and colleagues65 examined the effect of correctinganemia with rHuEPO on 23 patients with CRI who had amean baseline Hct level of 28%. As Hct levels increased to36%, improvements were observed in the duration of

exercise, angina, and overall well-being. These results havebeen consistently duplicated in studies showing a directcorrelation between rHuEPO-induced increases in Hb/Hct levels and improved exercise capacity in patientswith CRI.31,34

Similar results have been seen in patients with ESRD.A number of studies have shown that partial correction ofanemia with rHuEPO is associated with increases in peakVO2 and exercise capacity.30,59-61 In general, these studieshave reported that increasing Hb levels to between 10.0and 11.7 g/dL (Hct between 30% and 35%) is associatedwith increases in peak VO2 of 20% to 25%.30 These datahave shown that rHuEPO-induced increases in Hb/Hct lev-els are associated with improvements in endurance, func-tional status, and physical performance.

Hb/Hct Levels and Cognitive FunctionData from a study including 27 patients with ischemic

cerebrovascular disease indicate a direct correlationamong higher Hb/Hct levels, increased cerebral blood flow,and cognitive function.29 In a study by Marsh and col-leagues,17 rHuEPO was used to increase mean Hct levelsfrom a baseline of 23.7% to 36.5% (N=24), resulting inimproved levels of sustained attention and enhancedlearning and memory. It has been suggested that optimaldelivery of oxygen to the brain requires a minimum Hb of11 g/dL (Hct = 33%).28

Hb/Hct Levels and Sexual Function in Dialysis Patients

An increase in Hb following rHuEPO therapy has beenassociated with improvement in sexual function.62,63 In astudy of nine female and seven male dialysis patients, anincrease in mean Hb levels from a baseline of 7.3 ± 0.3 to11.3 ± 0.4 g/dL was accompanied by a significant decreasein prolactin values in both men and women.63 The authorsconcluded that improvements in sexual function appear to be linked to the normalization of elevated serum prolactin levels that accompanies the rHuEPO-inducedincrease in Hb.

20

�Vitality �Physical and social functioning

�Mental health �Social life

�Sexual satisfaction �Energy

�Functional ability �Sleep and eating behaviors

�Health status �Satisfaction with life

�Well-being �Psychological effect

�Happiness �Activity levels

QOL BENEFITS FROM ANEMIA

TREATMENT WITH rHuEPO

Table 1—Correction of anemia with rHuEPO in patients witheither CRI or ESRD has been associated with a widevariety of benefits.57,62,64

21

While additional data are required to confirm the benefits associated with correcting anemia in patients with CRI, current clinical results support early intervention to identify and appropriately manage anemia and other potential causes of morbidity and mortality in all patients diagnosed with CRI.

Major Points

• The management of anemia with rHuEPO is associated with numerous

clinical and QOL benefits.

• Although additional data are required, current clinical evidence

supports early intervention to identify and appropriately manage

the anemia associated with chronic kidney disease and to

proactively improve patient outcomes.

22

Risk

of C

omor

bid

Cond

ition

s

CRI ESRD

RAMP

Renal replacementtherapy (RRT)

Time

(can develop at any time after onset of CRI)

Anemia

RENAL ANEMIA MANAGEMENT PERIOD

Figure 9—The onset of anemia, which often develops well before the need for renal replacement therapy (RRT) during CRI, marksthe beginning of the Renal Anemia Management Period (RAMP). Adequate diagnosis and management of anemia during the RAMP may reduce those adverse sequelae related to anemia.

The RAMP: Heightened Vigilance for Anemia Treatment

Data indicate that anemia is a serious consequence ofCRI associated with significant short- and long-term clinicaland functional morbidities. Despite this preponderance ofevidence, US Renal Data System and NIH reports indicatethat anemia is often underrecognized and undertreated inthis population.

The information presented in this monograph provides support for establishing a Renal AnemiaManagement Period (RAMP) for patients with CRI. TheRAMP is defined as the time following the onset of CRI

when anemia develops and should be identified and man-aged appropriately (Figure 9).74 On the basis of the prepon-derance of data illustrating the deleterious effects of anemia in CRI and ESRD populations, it follows that anemiashould be identified early in the course of CRI and managed appropriately—well before ESRD develops. Thisapproach is supported by the corresponding benefits associated with rHuEPO-induced anemia correction,including improvements in parameters such as LVH,QOL, exercise capacity, cognitive and sexual function, hospitalization, and mortality.

23

Major Points

• The RAMP is a tool to increase awareness of the importance of early recognition and appropriate

management of anemia during CRI.

• Early intervention to manage anemia and other progressive comorbidities of CRI has the

potential to generate beneficial effects on the development of significant physiological sequelae.

• The nephrologist should take the lead in making management of the anemia of CRI a reality.

The RAMP concept was developed by a group ofprominent nephrologists to designate a critical time duringthe evolution of CRI when the identification of and decision to treat anemia is linked to a number of benefits—potentially having a positive impact on many of the comorbidities associated with the progression of kidneydisease. It is important to note that the RAMP model illus-trated in Figure 9 does not reflect data from a specificstudy. Rather, it depicts a compiled trend that becameapparent from the analysis of many studies.The RAMP pro-vides a conceptual framework for illustrating the spectrumof kidney disease—from CRI to ESRD. In the model, the lowend of the RAMP represents the onset of CRI, whenpatients have few comorbidities and QOL is only slightlyaffected. As the RAMP moves from CRI toward ESRD, ane-mia and its associated comorbidities can develop at anytime, negatively affecting QOL while impacting future mor-bidity and survival over the course of disease progression.The RAMP model emphasizes the progressive nature ofCRI and the need for early interventions to manage anemiaand other comorbidities, thereby preventing or controllingthe development of serious, potentially irreversible physio-logical damage.

Nephrologists and the Renal AnemiaManagement Period—A Call to Action

Epidemiological data consistently demonstrate thatpatient outcomes improve when nephrologists areinvolved in caring for renal patients early in the course of

kidney disease. Although the RAMP is currently a concep-tual framework, specific action steps can be envisioned tohelp make appropriate management of the anemia of CRIa reality. Sample steps could include the following:

• Establish collaborative relationships with primarycare physicians to ensure early evaluation ofpatients with CRI. While the primary care physician continues to provide everyday care, thenephrologist provides vital consultation on earlyguidelines for appropriately diagnosing and manag-ing anemia and other comorbidities associatedwith CRI.

• Develop screening methods to identify chronic kidney disease early, stressing the need to usemore accurate laboratory tests (such as calculated GFR).

• Follow trends in laboratory measurements. Isolatedvalues within the normal range may otherwise gounrecognized as a possible marker of early disease.

• Treat conditions such as anemia appropriately—early in the course of CRI—with the goal of pre-venting and/or minimizing associated morbiditiesand improving patient outcomes.

• Develop a therapeutic approach tailored to meetpatient and clinical needs.

24

Summary

This educational monograph provides scientific data supporting the need for aRenal Anemia Management Period (RAMP)—presented as a clinical management toolto emphasize the need for early recognition and appropriate management of anemiain patients with CRI. Primary concepts outlined in this monograph are as follows:

• The prevalence of CRI is high, affecting as many as 6,200,000 patients in the United States.

• Serum creatinine alone does not accurately reflect the severity of kidney damage. Other physiological parameters—including GFR (direct measurementor calculation)—provide a more accurate assessment of kidney function.

• CRI is not receiving optimal medical management.

• Cardiovascular disease (including LVH) is a major cause of morbidity and mortality that typically begins early in the course of CRI.

• Most patients with CRI have a deficiency of the hormone erythropoietin,which results in anemia.

• Anemia typically begins early in the course of CRI.

• Anemia of CRI is often underrecognized and undertreated.

• Anemia contributes to many comorbidities associated with CRI, including LVHand a decrease in QOL.

• The RAMP is a conceptual model illustrating the need for timely diagnosis of the anemia of CRI.

• Timely and appropriate management of the anemia of CRI can have a positiveimpact on patient outcomes and the quality and duration of life.

25

Bibliography

1. NIH Consensus Statement: Morbidity and Mortality ofDialysis. Bethesda, Md: National Institutes of Health:NIH Consensus Development Conference;1993.

2. McClellan WM, Knight DF, Karp H, Brown WW. Earlydetection and treatment of renal disease in hospital-ized diabetic and hypertensive patients: importantdifferences between practice and published guidelines. Am J Kidney Dis. 1997;29:368-375.

3. Obrador GT, Ruthazer R, Arora P, Kausz AT, Pereira BJG.Prevalence of and factors associated with suboptimalcare before initiation of dialysis in the United States. JAm Soc Nephrol. 1999;10:1793-1800.

4. Pereira BJG. Optimization of pre-ESRD care: the key to improved dialysis outcomes. Kidney Int. 2000;57:351-365.

5. Besarab A. Anemia in renal disease. In: Schrier RW,Gottschalk CW, eds. Diseases of the Kidney. 6th ed.Boston, Mass: Little Brown & Co; 1997:2581-2596.

6. National Kidney Foundation. NKF-K/DOQI clinical practice guidelines for anemia of chronic kidney dis-ease: update 2000. Am J Kidney Dis. 2001;37(Suppl 1):S182-S238.

7. Collins AJ, Ma JZ, Xia A, Ebben J. Trends in anemia treat-ment with erythropoietin usage and patient out-comes. Am J Kidney Dis. 1998;32(Suppl 4):S133-S141.

8. Xia H, Ebben J, Ma JZ, Collins AJ. Hematocrit levels andhospitalization risks in hemodialysis patients. J AmSoc Nephrol. 1999;10:1309-1316.

9. Ma JZ, Ebben J, Xia H, Collins AJ. Hematocrit level andassociated mortality in hemodialysis patients. J AmSoc Nephrol. 1999;10:610-619.

10. Healthy People 2010: Chronic Kidney Disease.Bethesda, Md: National Institutes of Health;1999:4.3-4.26.

11. Jones CA, McQuillan GM, Kusek JW, et al. Serum creati-nine levels in the US population: Third National Healthand Nutrition Examination Survey. Am J Kidney Dis.1998;32:992-999. (erratum 2000;35:178)

12. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, RothD. A more accurate method to estimate glomerularfiltration rate from serum creatinine: a new predictionequation. Ann Intern Med. 1999;130:461-470.

13. Obrador GT, Pereira BJG. Early referral to the nephrologistand timely initiation of renal replacement therapy: aparadigm shift in the management of patients withchronic renal failure. Am J Kidney Dis. 1998;31:398-417.

14. Anderson S, Kennefick TM, Brenner BM. Renal and sys-temic manifestations of glomerular disease. In:Brenner BM, ed. The Kidney. 5th ed. Philadelphia, Pa:WB Saunders Co; 1996:1981-2010.

15. Arora P, Obrador GT, Ruthazer R, et al. Prevalence,predictors, and consequences of late nephrologyreferral at a tertiary care center. J Am Soc Nephrol.1999;10:1281-1286.

16. Llach F, Bover J. Renal osteodystrophy. In: Brenner BM,ed. The Kidney. 5th ed. Philadelphia, Pa: WB SaundersCo; 1996:2187-2273.

17. Marsh JT, Brown WS, Wolcott D, et al. rHuEPO treatmentimproves brain and cognitive function of anemic dialysis patients. Kidney Int. 1991;39:155-163.

18. Nissenson AR. Epoetin and cognitive function. Am JKidney Dis. 1992;20(Suppl 1):21-24.

19. Klang B, Björvell H, Clyne N. Quality of life in predialyticuremic patients. Qual Life Res. 1996;5:109-116.

20. Innes A, Rowe PA, Burden RP, Morgan AG. Early deathson renal replacement therapy: the need for earlynephrological referral. Nephrol Dial Transplant.1992;7:467-471.

26

21. Khan IH, Catto GR, Edward N, MacLeod AM. Chronicrenal failure: factors influencing referral. QJM1994;87:559-564.

22. Remuzzi G, Rossi EC. Hematologic consequences ofrenal failure. In: Brenner BM, ed. The Kidney. 5th ed.Philadelphia, Pa: WB Saunders Co; 1996:2170-2186.

23. Levin A. Anaemia in the patient with renal insufficiency:documenting the impact and reviewing treatmentstrategies. Nephrol Dial Transplant. 1999;14:292-295.

24. Sarnak MJ, Levey AS. Cardiovascular disease and chronic renal disease: a new paradigm. Am J KidneyDis. 2000;35(Suppl 1):S117-S131.

25. Holland DC, Lam M. Predictors of hospitalization anddeath among pre-dialysis patients: a retrospectivecohort study. Nephrol Dial Transplant. 2000;15:650-658.

26. Harnett JD, Kent GM, Foley RN, Parfrey PS. Cardiac func-tion and hematocrit level. Am J Kidney Dis.1995;25(Suppl 1):S3-S7.

27. Biasioli S. Neurological aspects of dialysis. In: NissensonAR, Fine RN, Gentile DE, eds. Clinical Dialysis. 3rd ed.East Norwalk, Conn:Appleton & Lange; 1995:777-793.

28. Grotta JC, Manner C, Pettigrew LC, Yatsu FM. Red bloodcell disorders and stroke. Stroke. 1986;17:811-817.

29. Kusunoki M, Kimura K, Nakamura M, Isaka Y, Yoneda S,Abe H. Effects of hematocrit variations on cerebralblood flow and oxygen transport in ischemic cere-brovascular disease. J Cereb Blood Flow Metab.1981;1:413-417.

30. Painter P. The importance of exercise training in reha-bilitation of patients with end-stage renal disease. AmJ Kidney Dis. 1994;24(Suppl 1):S2-S9.

31. Clyne N, Jogestrand T. Effect of erythropoietin treatmenton physical exercise capacity and on renal function inpredialytic uremic patients. Nephron. 1992;60:390-396.

32. Teehan BP, Krantz S, Stone WA, et al. Double-blind,placebo-controlled study of the therapeutic use ofrecombinant human erythropoietin for anemia asso-ciated with chronic renal failure in predialysis

patients. The US Recombinant Human ErythropoietinStudy Group. Am J Kidney Dis. 1991;18:50-59.

33. Kleinman K, Schweitzer S, Perdue S, Bleifer KH, Abels RI.The use of recombinant human erythropoietin in thecorrection of anemia in predialysis patients and itseffect on renal function: a double-blind, placebo-con-trolled trial. Am J Kidney Dis. 1989;14:486-495.

34. Lim VS, DeGowin RL, Zavala D, et al. Recombinanthuman erythropoietin treatment in pre-dialysispatients: a double-blind placebo-controlled trial. AnnIntern Med. 1989;110:108-114.

35. United States Renal Data System. 1999 Annual DataReport. Bethesda, Md: National Institute of Diabetes &Digestive & Kidney Diseases; 1999.

36. Kausz AT, Khan SS, Abichandani R, et al. Managementof patients with chronic renal insufficiency in thenortheastern United States. J Am Soc Nephrol.2001;12:1501-1507.

37. Mandelbaum AP, Ritz E. Cardiac complications of uremia. In: Glassock RJ, ed. Current Therapy inNephrology and Hypertension. St. Louis, Mo: Mosby-Year Book, Inc; 1998:309-314.

38. Mann JFE. Hypertension and cardiovascular effects—long-term safety and potential long-term benefits of r-HuEPO. Nephrol Dial Transplant. 1995;10(Suppl 2):80-84.

39. Silberberg JS, Barre PE, Prichard SS, Sniderman AD.Impact of left ventricular hypertrophy on survival inend-stage renal disease. Kidney Int. 1989;36:286-290.

40. Foley RN, Parfrey PS. Cardiac disease in chronic uremia:clinical outcomes and risk factors. Adv Ren ReplaceTher. 1997:4:234-248.

41. Levin A, Singer J, Thompson CR, Ross H, Lewis M.Prevalent left ventricular hypertrophy in the pre-dialysis population: identifying opportunities for intervention. Am J Kidney Dis. 1996;27:347-354.

42. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC,Barre PE. The impact of anemia on cardiomyopathy,morbidity, and mortality in end-stage renal disease.Am J Kidney Dis. 1996;28:53-61.

27

43. Zehnder C, Zuber M, Sulzer M, et al. Influence of long-term amelioration of anemia and blood pressure con-trol on left ventricular hypertrophy in hemodialyzedpatients. Nephron. 1992;61:21-25.

44. Silberberg J, Racine N, Barre P, Sniderman AD. Regressionof left ventricular hypertrophy in dialysis patients following correction of anemia with recombinanthuman erythropoietin. Can J Cardiol. 1990;6:1-4.

45. London GM, Zins B, Pannier B, et al. Vascular changes inhemodialysis patients in response to recombinanthuman erythropoietin. Kidney Int. 1989;36:878-882.

46. Macdougall IC, Lewis NP, Saunders MJ, et al. Long-termcardiorespiratory effects of amelioration of renalanaemia by erythropoietin. Lancet. 1990;335:489-493.

47. Canella G, La Canna G, Sandrini M, et al. Reversal of leftventricular hypertrophy following recombinant humanerythropoietin treatment of anaemic dialysed uraemicpatients. Nephrol Dial Transplant. 1991;6:31-37.

48. Carletti P, Bibiano L, Boggi R, Taruscia D, Mioli V. Doesanemia correction by rHuEPO improve uremic cardiopathy? Kidney Int. 1993;43(Suppl 41):S70-S71.

49. Löw-Freidrich I, Grützmacher P, März W, Bergmann M,Schoeppe W. Therapy with recombinant human erythropoietin reduces cardiac size and improvesheart function in chronic hemodialysis patients. Am JNephrol. 1991;11:54-60.

50. Pascual J, Teruel JL, Moya JL, Liaño F, Jiménez Mena M,Ortuño J. Regression of left ventricular hypertrophyafter partial correction of anemia with erythropoietinin patients on hemodialysis: a prospective study. ClinNephrol. 1991;35:280-287.

51. Goldberg N, Lundin AP, Delano B, Friedman EA,Stein RA. Changes in left ventricular size, wall thickness and function in anemic patients treatedwith recombinant human erythropoietin. Am Heart J.1992;124:424-427.

52. Martinez-Vea A, Bardaji A, García C, Ridao C, Richart C,Oliver JA. Long-term myocardial effects of correctionof anemia with recombinant human erythropoietin in

aged patients on hemodialysis. Am J Kidney Dis.1992;19:353-357.

53. Hayashi T, Suzuki A, Shoji T, et al. Cardiovascular effectof normalizing the hematocrit level during erythropoi-etin therapy in predialysis patients with chronic renalfailure. Am J Kidney Dis. 2000;35:250-256.

54. Portoles J, Torralbo A, Martin P, Rodrigo J, Herrero JA,Barrientos A. Cardiovascular effects of recombinanthuman erythropoietin in predialysis patients. Am JKidney Dis. 1997;29:541-548.

55. Al-Ahmad A, Levey A, Rand W, et al. Anemia and renalinsufficiency as risk factors for mortality in patientswith left ventricular dysfunction. J Am Soc Nephrol.2000;11:137A. Abstract.

56. Stewart, Gansevoort, McDonagh, et al. Left ventricularfunction and hypertrophy in patients with renal disease. J Am Soc Nephrol. 2000;11:167A. Abstract.

57. Revicki DA, Brown RE, Feeny DH, et al. Health-relatedquality of life associated with recombinant humanerythropoietin therapy for predialysis chronic renaldisease patients. Am J Kidney Dis. 1995;25:548-554.

58. Moreno F, Lopéz Gomez JM, Sanz-Guajardo D, Jofre R,Valderrábano F. Quality of life in dialysis patients: aSpanish multicenter study. Spanish CooperativeRenal Patients Quality of Life Study Group. NephrolDial Transplant. 1996; 11(Suppl 2): 125-129.

59. Guthrie M, Cardenas D, Eschbach JW, Haley NR,Robertson HT, Evans RW. Effects of erythropoietin onstrength and functional status of patients onhemodialysis. Clin Nephrol. 1993;39:97-102.

60. Braumann KM, Nonnast-Daniel B, Böning D, Böcker A,Frei U. Improved physical performance after treat-ment of renal anemia with recombinant human erythropoietin. Nephron. 1991;58:129-134.

61. Robertson HT, Haley NR, Guthrie M, Cardenas D,Eschbach JW, Adamson JW. Recombinant erythropoi-etin improves exercise capacity in anemic hemodial-ysis patients. Am J Kidney Dis. 1990;15:325-332.

62. Evans RW, Rader B, Manninen DL, and the Cooperative

28

Multicenter EPO Clinical Trial Group. The quality of lifeof hemodialysis recipients treated with recombinanthuman erythropoietin. JAMA. 1990;263:825-830.

63. Schaefer RM, Kokot F, Wernze H, Geiger H, Heidland A.Improved sexual function in hemodialysis patients onrecombinant erythropoietin: a possible role for pro-lactin. Clin Nephrol. 1989;31:1-5.

64. Beusterien KM, Nissenson AR, Port FK, Kelly M,Steinwald B, Ware JE. The effects of recombinanthuman erythropoietin on functional health and well-being in chronic dialysis patients. J Am Soc Nephrol.1996;7:763-773.

65. Teehan BP, Benz RL, Sigler MH, Brown JM. Early intervention with recombinant human erythropoietintherapy. Semin Nephrol. 1990;10(Suppl 1):28-34.

66. Levin A, Thompson CR, Ethier J, et al. Left ventricularmass index increase in early renal disease: impact of decline in hemoglobin. Am J Kidney Dis. 1999; 34:125-134.

67. Foley RN, Parfrey PS, Harnett JD, Kent GM et al. Clinicaland echocardiographic disease in patients startingend-stage renal disease therapy. Kidney Int.1995;47:186-192.

68. London, G. Pathophysiology of cardiovascular damagein the early renal population Nephrol Dial Transplant.2001;16(Suppl 2):3-6.

69. Collins A, St. Peter WL, Li SY, Ebben J, Chen S, Ma JZ.Hematocrit (Hct) levels 36-<39% are associated withlower hospitalization risk in Medicare hemodialysis(HD) patients. J Am Soc Nephrol. 2000;11:262A.Abstract.

70. Collins A, Li SY, St. Peter WL, Ebben J, Ma JZ. Changinghematocrit (Hct) levels: clinical predictors forhemodialysis (HD) patients to move from low (<30%)to higher (>30%) Hct levels. J Am Soc Nephrol.2000;11:261A. Abstract.

71. Middleton RJ, Parfrey PS, Foley RN. Left ventricularhypertrophy in the renal patient. J Am Soc Nephrol;2001;12: 1079-1084.

72. Wizemann V, Schäfer R, Kramer W. Follow-up of cardiacchanges induced by anemia compensation in nor-motensive hemodialysis patients with left-ventricularhypertrophy. Nephron. 1993;64:202-206.

73. Kausz AT, Obrador GT, Pereira BJ. Anemia managementin patients with chronic renal insufficiency. Am JKidney Dis. 2000;36(Suppl 3):S39-51.

74. Besarab A, Levin A. Defining a renal anemia manage-ment period. Am J Kidney Dis. 2000;36(Suppl 3):S13-S23.

75. Hsu CY, Bates DW, Kuperman GJ, Curhan GC. Relation-ship between hematocrit and renal function in menand women. Kidney Int. 2001;59:725-731.

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