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Anemia

in Chronic Kidney Disease

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Monograph: Anemia, A Hidden Epidemic
Key Points

• Anemia is a common complication of chronic kidney


disease (CKD)
• Anemia often develops early in the course of CKD
and worsens as CKD progresses
• Anemia is associated with an increased risk of
morbidity and mortality
• Treatment of anemia reduces morbidity/mortality risk
and improves quality of life (QOL) in patients with
CKD
Hemoglobin (Hb) Distribution
in the General Population
Hb Distribution in Women:
3000 13.3 ± 0.9 g/dL

Hb Distribution in Men:
2500
15.2 ± 0.9 g/dL

2000
Frequency

1500

1000

500

0
10 10.5 11 11.5 12 12.5 13 13.5 14 14.5 15 15.5 16 16.5 17 17.5 18

Hb Level (g/dL)
N=40,000 (NHANES III, 1988-1994)
Dallman PR, et al. In: Iron Nutrition in Health and Disease. London, UK: John Libbey & Co; 1996:65-74.
WHO Definition of Anemia vs.
Hb Distribution in General Population
Anemia in Men:
Hb <13 g/dL Hb Distribution in Women:
3000 13.3 ± 0.9 g/dL

Hb Distribution in Men:
2500
Anemia in Women: 15.2 ± 0.9 g/dL
Hb <12 g/dL
2000
Frequency

1500

1000

500

0
10 10.5 11 11.5 12 12.5 13 13.5 14 14.5 15 15.5 16 16.5 17 17.5 18

Hb Level (g/dL)
N=40,000 (NHANES III, 1988-1994)
1. World Health Organization. Geneva, Switzerland; 2001.
2. Dallman PR, et al. In: Iron Nutrition in Health and Disease. London, UK: John Libbey & Co; 1996:65-74.
Laboratory Reference Ranges

Parameter Male Female


Hb (g/dL) 14.0 – 17.4 12.3 – 5.3
Hct (%) 41.5 – 50.4 36.0 – 45.0
RBC count (106/µL) 4.5 – 5.9 4.5 – 5.1
Reticulocyte count (% of RBC count) 0.5 – 2.5
Mean corpuscular volume (fL) 80 – 96
Mean corpuscular Hb (MCH) (pg) 27.5 – 33.2
MCH concentration (g/dL) 33.4 – 35.5
Hb = hemoglobin; Hct = hematocrit; RBC = red blood cell

Perkins S. In: Lee G, et al, eds. Wintrobe’s Clinical Hematology (Vol. 2). 10th ed. Baltimore, Md: Lippincott, Williams &
Wilkins; 1998:2738.
Anemia in Chronic Kidney Disease
(CKD): Treatment Goals

• The NKF K/DOQI* Guidelines recommended target


range for dialysis patients: Hb 11 g/dL to 12 g/dL (Hct
33% to 36%)1
• The European Best Practice Guidelines advocate a
target of ≥11 g/dL for 85% of CKD patients2
– To achieve this goal, the mean Hb level for the
population should be 12.0 g/dL2 to 12.5 g/dL2

*National Kidney Foundation (NKF) Kidney Disease Outcome Quality Initiative (K/DOQI).

1. NKF-K/DOQI. Am J Kidney Dis. 2001;37(suppl 1):S182-S238.


2. Jacobs C, et al. Nephrol Dial Transplant. 2000;15(suppl 4):15-19.
Anemia Signs and Symptoms

Ludwig H, et al. Semin Oncol. 1998;25(suppl 7):2-6.


Causes of Anemia in CKD

• Kidneys unable to produce erythropoietin (EPO)


– Develops early, worsens as CKD progresses
– Normochromic, normocytic
• Ancillary factors
– Shortened life span of red blood cells (RBCs)
– Iron or other nutritional deficiency
– Infection and inflammation

Remuzzi G, et al. Brenner & Rector’s The Kidney. 6th ed. Philadelphia, Pa: WB Saunders Co; 2000:2079-2087.
Prevalence of Anemia*
Among Patients With CKD
100
90
Percentage of Patients

80
70
60
62% Hct <30%
50 Hct 30% to 32.9%
43% Hct 33% to Normal
40
20%
30
20 14% 8% 8% 15%
10 5% 17% 15% 10%
0
9%
<2 2-2.9 3-3.9 >4
N=1658 Serum Creatinine (mg/dL)
*Anemia defined as Hct <30%
Kausz AT, et al. Dis Manage Health Outcomes. 2002;10:505-513.
Prevalence of Anemia
Among Patients With CKD (cont.)
Prevalence of Anemia
• In a study population of in Study Population
80%
patients starting 70% 68%

Percentage of Patients
dialysis, anemia was 60%
already prevalent 51%
50%

• Anemia is prevalent 40%

well before the need 30%

for renal replacement 20%

therapy (RRT) 10%


0%
Hct Hct
<30% <28%

N=155,076
Obrador GT, et al. J Am Soc Nephrol. 1999;10:1793-1800.
Anemia Often Goes Untreated
Prior to Dialysis
Treatment of CKD Patients
With Anemia (Hct <28%)
• 80% of patients starting
dialysis with Hct <28%
had not received 20%
rHuEPO treatment Treated

80%
Untreated

N=155,076
Obrador GT, et al. J Am Soc Nephrol. 1999;10:1793-1800.
The RAMP: Developed to Encourage
Early Diagnosis and Treatment
Risk of Complications

D
f CK
n o
s sio
Anemia can gr e
develop at any Pro
time during CKD ESRD
Renal Anemia
Management Period
(RAMP)

Time

Adapted from Besarab A, et al. Am J Kidney Dis. 2000;36(suppl 3):S13-S23.


Major Clinical Consequences
of Anemia in CKD
Increased Mortality

2.5
Independent Risk Factors for Mortality
Relative Risk

2 1.93 1.98
1.83
1.5 1.40
1.25 1.18
1 1.05

0.5
0

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LV
N=433; mean follow-up 41 months
Harnett JD, et al. Am J Kidney Dis. 1995;25(suppl 1):S3-S7.
Association Between Hb and
Mortality in CKD Patients

14%
For Every Increase
1-g/dL P=0.024 in Relative
Decrease in Risk of
Hb Mortality

N=432; mean follow-up 41 months


Foley RN, et al. Am J Kidney Dis. 1996;28:53-61.
Increased Hospitalizations
Anemia Decreases Number
• In a retrospective analysis of Hospital-Free Months
25

Median Number of Hospital-Free Months


of patients with CKD, the
21.5
presence of anemia was
independently associated 20
with an increased P=.0593
likelihood of 15 13.3
hospitalization
10

0
Hb Hb
N=362 ≤9.5 g/dL >9.5 g/dL
Holland DC, et al. Nephrol Dial Transplant. 2000;15:650-658.
Reduced Cognitive Function
and Exercise Capacity

• Anemia impairs cognitive functioning in


patients with CKD
• Anemia is a major cause of the decline in
exercise capacity seen in patients with CKD

1. Marsh JT, et al. Kidney Int. 1991;39:155-163.


2. Clyne N, et al. Nephron. 1992;60:390-396.
Cardiac Disease
Increase in Risk for Each 1-g/dL Decrease in Mean Hemoglobin
50 46%*
45 *P=0.018
Percentage Increase in Risk

†P=0.046
40
35
30 28%*

25
20%†
20
15
10
5
0
Left Ventricular Development Development
Dilatation of De Novo of Recurrent
N=432 ESRD patients Heart Failure Heart Failure
Foley RN, et al. Am J Kidney Dis. 1996;28:53-61.
Prevalence of Left Ventricular
Hypertrophy in Patients With CKD
Percentage of Patients With LVH

50 45.2%

40
30.8%
30 26.7%

20

10

0
CrCl >50 CrCl 25-49 CrCl <25
Creatinine Clearance (mL/min)
N=175
Levin A, et al. Am J Kidney Dis. 1996;27:347-354.
Anemia and LVH in CKD Patients
Chronic
Anemia

Hyperdynamic
State

Increased
Cardiac
Output to
Maintain
Tissue
Oxygenation

LVH
London G. Nephrol Dial Transplant. 2001;16(suppl 2):3-6.
Association Between Hb and
LVH in CKD Patients
6%
Increase
in Risk of LVH
For Every (Predialysis)1
1-g/dL
Decrease in
Hb
46%
Increase
in Risk of LV
Dilation
(ESRD)2

1. Levin A, et al. Am J Kidney Dis. 1996;27:347-354.


2. Foley RN, et al. Am J Kidney Dis. 1996;28:53-61.
Anemia, CKD, and
Heart Failure (HF)
• Anemia is present Tang1 16%
in 16% to 48% of Anker2 17%
patients with HF1-5
Ezekowitz3 17%
• CKD is the most 20%
Mozaffarian4
common cause of
anemia in patients Al-Ahmad5 22%

with HF6 Herzog6 28%

Horwich7 30%

Kosiborod8 48%

0 5 10 15 20 25 30 35 40 45 50
Percentage of Heart Failure Patients With Anemia

1. Tang WHW, et al. ACC 2003. 5. Al-Ahmad A, et al. J Am Coll Cardiol. 2001;38:955-62.
2. Anker SD, et al. Circulation. 2002;106(suppl II):472. 6. Herzog CA, et al. J Card Fail. 2002;8(suppl):S63.
Abstract 2335. Abstract 228.
3. Ezekowitz JA, et al. Circulation. 2003;107:223-225. 7. Horwich TB, et al. J Am Coll Cardiol. 2002;39:1780-1786.
4. Mozaffarian D, et al. J Am Coll Cardiol. 2003;41:1933-1939. 8. Kosiborod M, et al. Am J Med. 2003;114:112-119.
Anemia: A Potent Multiplier of
Morbidity—Increased Hospitalizations
Number of Hospitalizations

1200
(Per 1000 Patient-Years)

1090
1000
816
800 761
600 547
400
200
0
HF HF + Anemia HF + CKD HF + CKD +
(N=152,584) (n=42,689) (n=20,720) Anemia
(n=9834)
N = 1.1 million (5% Medicare sample, 1996-1997)
1. Herzog CA, et al. HFSA, 2002. Abstract 228.
2. Herzog CA, et al. HFSA, 2002. Abstract 269.
Anemia: A Potent Multiplier of
Morbidity—Increased Comorbidities
Number of Comorbid Conditions

16
13.9
14
12.4
12 11.4
10 8.8
8
6
4
2
0
HF HF + Anemia HF + CKD HF + CKD +
(N=152,584) (n=42,689) (n=20,720) Anemia
(n=9834)
N = 1.1 million (5% Medicare sample, 1996-1997)
1. Herzog CA, et al. HFSA, 2002. Abstract 228.
2. Herzog CA, et al. HFSA, 2002. Abstract 269.
Anemia: A Potent Multiplier
of Mortality

No HF, No CKD, No Anemia 1


Anemia Only 1.9
CKD Only 2.05
HF Only 2.86
CKD, Anemia 3.37
HF, Anemia 3.78
HF, CKD 4.86
HF, CKD, Anemia 6.07

0 1 2 3 4 5 6 7
Relative Risk of 2-Year Mortality

N = 1.1 million (5% Medicare sample, 1996-1997)


Herzog CA, et al. HFSA, 2002. Abstract 226.
Anemia Associated With Increased
Risk of Stroke in CKD Patients
12
Stroke Rate (Per 1000 Person-

11 10.53 Creatinine clearance


10 ≥60 mL/min (n=11,626)
Years of Follow-Up)

9 Creatinine clearance
8 <60 mL/min (n=2090)
7
6
5
4 3.70
3 2.85
2.06 2.12
2 1.52
1
0
Total Population Anemic Population* Nonanemic Population
N = 13,716
*Anemia defined as Hb <12 g/dL for women and <13 g/dL for men
Abramson JL, et al. Kidney Int. 2003;64:610-615.
Anemia Management Options

• Watchful waiting
• Dietary changes
• Iron supplementation
• RBC transfusion
• Erythropoietic stimulating proteins
– Recombinant human erythropoietin (rHuEPO)
• eg, epoetin alfa, epoetin beta, epoetin omega
– Darbepoetin alfa
Erythropoietin Therapy

• Advantages
– Avoids the risks associated with transfusions
• Allergic/febrile reactions
• Transfusion-associated immunosuppression
• Disadvantages
– Response is not as rapid as with transfusions
• Response can take 4 weeks or longer
– With recombinant human erythropoietin (rHuEPO),
frequent dosing is required

1. Ludwig H, et al. Semin Oncol. 1998;25(suppl 7):2-6.


2. Goodnough LT, et al. N Engl J Med. 1999;340:438-447.
3. Heiss MM. Zentralbl Chir. 2000;125:842-846.
Erythropoietin Regulates
Red Blood Cell Production

Renal interstitial peritubular cells EPO stimulates the


detect low blood oxygen levels proliferation and differentiation
of erythroid progenitors into
reticulocytes, and prevents
Erythropoietin (EPO) secreted into apoptosis
the blood

EPO

More reticulocytes
enter circulating
blood
Increased oxygen
delivery
Reticulocytes differentiate into
to tissues erythrocytes, increasing the
erythron size

1. Dessypris E. In: Lee G, et al, eds. Wintrobe’s Clinical Hematology (Vol. 1). Baltimore, Md: Lippincott, Williams & Wilkins;
1998:169–192.
2. Bunn H. In: Isselbacher K, et al, eds. Harrison’s Principles and Practice of Internal Medicine. 13th ed.
New York, NY: McGraw-Hill; 1994:1717–1721.
Importance of Early Detection
of Anemia in CKD

• Anemia develops early in CKD


• Anemia worsens as CKD progresses
• Identification and treatment of anemia can
help reduce the risk of associated morbidities,
such as LVH

1. Besarab A, et al. Am J Kidney Dis. 2000;36(suppl 3):S13-S23.


2. NKF-K/DOQI. Am J Kidney Dis. 2002;37(suppl 1):S1-S266.
Management in Primary Care:
The Problem of Late Referrals
Findings at First Nephrology Visit in Boston-Area Chart Review
Mean SCr (mg/dL) 3.2
Mean estimated GFR (mL/min/1.73m2) 22.3
Hct <30% 38%
Tests for:
• Iron levels 18%
• Serum parathyroid hormone levels 15%
Abnormal calcium-phosphorus metabolism 55%
Use of rHuEPO in patients with Hct <30% 59%
• Use of iron in patients receiving rHuEPO 47%
Placement of permanent access prior to initiation
of dialysis in patients with known ESRD 41%

Kausz AT, et al. J Am Soc Nephrol. 2001;12:1501-1507.


Challenges of Anemia Treatment
Differ: CKD Versus ESRD

CKD ESRD
Variable reimbursements Universal coverage for drug
Lack of protocols rHuEPO and iron protocols
Irregular patient Easy accessibility to patients
encounters
Multiple, disintegrated Integrated lab and information
laboratory and information systems
systems and providers
No anemia managers Empowered anemia nurse
managers

Table courtesy of Mahesh Krishnan, MD, PPH.


Comfort Level of Primary Care
Providers With CKD Care

Transplantation Planning
Subjective Scale:
Access Planning
0 = Low Comfort
Nutrition Education 5 = High Comfort
Dialysis Education
CKD-Related Bone Disease
rHuEPO for Anemia
ACE Inhibitors
Hypertension

0 1 2 3 4 5
N=91 PCPs
Fishbane S. Internal Medicine News. 2001;suppl:14-15.
Beneficial Effects
of Anemia Treatment

• Partial correction of anemia to Hb 11 g/dL to


12 g/dL in patients with CKD may
– Reduce morbidity, hospitalization,
and mortality1-3
– Improve LV structure and function4,5
– Improve QOL,6,7 exercise capacity,8 cognitive
function,2 and sexual function3

1. Xia H, et al. J Am Soc Nephrol. 1999;10:1309-1316. 5. Portoles J, et al. Am J Kidney Dis. 1997;29:541-548.
2. Bedani PL, et al. Nephron. 2001;89:350-353. 6. Revicki DA, et al. Am J Kidney Dis. 1995;25:548-554.
3. Wu SC, et al. Scand J Urol Nephrol. 2001;35:136-140. 7. Furuland H, et al. Nephrol Dial Transplant. 2003;18:353-361.
4. Hayashi T, et al. Am J Kidney Dis. 2000;35:250-256. 8. Clyne N, et al. Nephron. 1992;60:390-396.
Anemia Treatment in CKD May
Result in Partial Regression of LVH
190
2 2
40 *Note: Normal LVMI =125 g/m .
† P<.001.
LVMI (g/m2)* ‡ P<.05.
170 35

Hct (%)
30
Hct† LVMI‡
150

25

130 20

Baseline After
6 months
N=11 rHuEPO
1. Portoles J, et al. Am J Kidney Dis. 1997;29:541-548.
2. Casale PN, et al. Ann Intern Med. 1986;10:173-178.
Regression of LVH in CKD
Patients Treated With rHuEPO1
Hemoglobin Left Ventricular Mass Index
Change = +2.7 g/dL Change = −30.9 g
P<.001 P<.05
15 200
Mean Hemoglobin (g/dL)

178.2

Left Ventricular Mass


11.7
147.3
150

Index (g/m2)
10 9.0
Normal2
100

5
50

0 0
Before rHuEPO After rHuEPO Before rHuEPO After rHuEPO
Treatment Treatment Treatment Treatment
(6 months) (6 months)

N=11
1. Portoles J, et al. Am J Kidney Dis. 1997;29:541-548.
2. Casale PN, et al. Ann Intern Med. 1986;105:173-178.
Benefits of Partial Correction
of Anemia With rHuEPO

• Decreases in LV end-diastolic diameter, left


atrial diameter, and cardiac output1
• Increases in venous tone, peripheral vascular
resistance, blood viscosity, and tissue
oxygenation2
• Reductions in myocardial ischemia, as indicated
by normalization of ST-segment depressions on
ECG and improvements in exercise tolerance3
1. Wizemann V, et al. Nephron. 1993;64:202-206.
2. London G. Nephrol Dial Transplant. 2001;16(suppl 2):3-6.
3. Wizemann V, et al. Nephron. 1992;62:161-165.
Significant Improvements in QOL
in rHuEPO-Treated Patients

Medical Outcomes Sickness


Study Short Form Impact Profile
• Energy • Home management
• Physical function • Alertness
• Role function • Social interaction
• Health distress • Sexual dysfunction
• Depression

N=83
Revicki DA, et al. Am J Kidney Dis. 1995;25:548-554.
QOL Benefits After Hb
Normalization in Dialysis Patients

• Patients randomized to normal (n=129) or subnormal


(n=124) target Hb groups
– Normal Hb: 13.5 g/dL to15 g/dL in women, 14.5 g/dL to
16 g/dL in men
– Subnormal Hb: 9 g/dL to12 g/dL
• Significant improvements in several QOL parameters
found in normal versus subnormal Hb groups
– Physical symptoms
– Fatigue
– Depression
– Frustration

N=416; n=253 dialysis patients


Furuland H, et al. Nephrol Dial Transplant. 2003;18:353-361.
Erythropoietic Proteins for Treatment
of Anemia in CKD Patients
• Recombinant human erythropoietin (rHuEPO) is a
recombinant protein with the same biological effects
as endogenous erythropoietin, including stimulation
of erythropoiesis (eg, epoetin alfa, epoetin beta,
epoetin omega)
• rHuEPO is administered 2 to 3 times per week, which
may require CKD patients on home dialysis or not yet
on dialysis to make special trips to the physician’s
office or clinic for the rHuEPO injection

Nissenson AR. Am J Kidney Dis. 2001;38:1390-1397.


Erythropoietic Proteins for Treatment
of Anemia in CKD Patients (cont.)
• Darbepoetin alfa is a new generation of long-acting
erythropoietic proteins developed to simplify the
management of anemia
– Two additional sialic acid–containing carbohydrate chains
increase in vivo biological activity by extending serum half-life
– Use of this long-acting form allows for less-frequent dosing
– Darbepoetin is as safe and effective as rHuEPO, but is
dosed once weekly or once every other week

1. Nissenson AR. Am J Kidney Dis. 2001;38:1390-1397. 3. VanRenterghem Y, et al. Kidney Int. 2002;62:2167-2175.
2. Nissenson AR, et al. Am J Kidney Dis. 2002;40:110-118. 4. Locatelli F, et al. Kidney Int. 2001;60:741-747.
Summary: Anemia in CKD
• Anemia is common in patients with CKD
• Anemia begins early in the course of declining
kidney function
• Both anemia and CKD are underdiagnosed
and undertreated
• Anemia is associated with significantly increased risk
of morbidity and mortality, including increased risks
of LVH and heart failure
• Treatment reduces morbidity/mortality risk and may
lead to improved QOL
• Anemia diagnosis and treatment should be initiated early
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