Anemia and CKD Anemia and CKD

An UpdateAn Update

Prevalence of ESRD has been rising steadilyPrevalence of ESRD has been rising steadily

USRDS ADR, 2008

National Kidney Foundation – Kidney Disease Outcomes National Kidney Foundation – Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI)Quality Initiative (NKF-K/DOQI)

Stages of Chronic Kidney DiseaseStages of Chronic Kidney Disease

Stage DescriptionGFR

(ml/min/1.73 m2)

1Kidney Damage with Normal or

GFR>90

2 Kidney Damage with Mild GFR 60-89

3 Moderate GFR 30-59

4 Severe GFR 15-29

5 Kidney Failure<15 orDialysis

9%17% 15% 10%

5%

8% 8% 15%14%

20%

43%

62%

0

20

40

60

80

100

<2 2-2.9 3-3.9 >4Serum Creatinine (mg/ dL)

Hct <30%Hct 30% to 32.9%Hct 33% to Normal

*Anemia defined as at least two Hct values below the gender-specific norm (Hct value <42% for males; Hct value <36% for females) that were at least 30 days apart.

Kausz AT, et al. Dis Manage Health Outcomes. 2002;10:505-513.

Per

cen

tag

e o

f P

atie

nts

W

ith

An

emia

(%

)

CKD=chronic kidney disease; Hct=hematocrit.

N=1658

Anemia Is a Common Complication of CKDAnemia Is a Common Complication of CKD

• Anemia often develops early in the course of CKD and worsens as CKD progresses.

The Physiological Role of Erythropoietin

Decrease in oxygen delivery to the kidneys

Peritubular interstitial cells detect low oxygen levels in the blood Pro-erythroblasts

in red bone marrow mature more quickly into reticulocytes

More reticulocytes enter circulating blood

Larger number of red blood cells (RBC) in circulation

Increased oxygen delivery to tissues

Return to homeostasis when response brings oxygen delivery to kidneys back to normal

EPO

Peritubular interstitial cells secrete erythropoietin (EPO) into the blood

Major Stages of ErythropoiesisHematopoietic Stem Cell

BFU-E

CFU-E

Erythroblasts

Reticulocytes

Erythrocytes (RBCs)(Time to maturity = 12 days)

Erythropoietin Dependent

Bone Marrow

Circulation

Adapted from Bron D, et al. Semin Oncol. 2001;28:1-6.

Iron Dependent

• Retrospective analysis of pre-dialysis patients with CKD

Holland DC, et al. Nephrol Dial Transplant. 2000;15:650-658.

N=362

Hb ≤9.5 g/dL

Hb >9.5 g/dL

Anemia Associated With Decreased Number of Hospital-Free Months

P=0.0593

13.3

21.5

Med

ian

Nu

mb

er

of

Hosp

ital-

Fre

e M

on

ths

25

20

15

10

5

0

CKD=chronic kidney disease; Hb=hemoglobin.

Untreated Anemia Is Associated Untreated Anemia Is Associated With Increased HospitalizationsWith Increased Hospitalizations

What is the optimal Hb target range What is the optimal Hb target range of CKD patients?of CKD patients?

• –Rationale for observational trials• –Rationale for randomized controlled trials• –International guidelines and the updated EU-label

of ESAs• –Challenges in controlling Hbtarget levels in CKD

patients

Trial to Reduce Cardiovascular Events With Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT)Aranesp Therapy (TREAT)

1. Eschbach JW, et al. Ann Intern Med. 1989;111:992-1000. 2. Collins AJ, et al. Semin Nephrol. 2000;20:345-349.3. Collins AJ, et al. J Am Soc Nephrol. 2001;12:2465–2473.

ESAs=erythropoietin-stimulating agents; Hb=hemoglobin

Benefits of Treatment With Benefits of Treatment With ESAsESAs

• Treatment with ESAs to achieve partial correction of Hb levels is associated with– Improved quality of life1

– Reduced risk for mortality2

– Reduced risk of hospitalization3

• Recombinant human erythropoietin; rHuEPO – Forms: epoetin alfa, epoetin beta, epoetin delta*,

epoetin omega*• Acts by stimulating the proliferation, survival, and

differentiation of erythroid progenitors into reticulocytes1-4

• Approved for either intravenous (IV) or subcutaneous (SC) administration 2 to 3 times per week (often given less frequently in clinical practice)5

• Frequency of administration dictated partly by the short biologic half-life (~6–8 hours following a single IV injection)1-4

1. Egrie JC, et al. Immunobiology. 1986;172:213-224; 2. Graber SE, et al. Ann Rev Med. 1978;29:51-66; 3. Eschbach JW, et al. N Eng J Med. 1987;316:73-78; 4. Eschbach JW, et al. Ann Intern Med. 1989;111:992-1000.; 5. Papatheofanis FJ, et al. Curr Med Res Opin. 2006;22:837-842.

* Not available in the US..

EpoetinEpoetin

Egrie JC, et al. Nephrol Dial Transplant. 2001;16 Suppl 3:3-13.Macdougall IC, et al. J Am Soc Nephrol. 1999;10:2392–2395.

Darbepoetin alfaDarbepoetin alfa

• 2 more carbohydrate chains and up to 8 more sialic acid residues than epoetin

• This extends the half-life by at least three fold and allows for decreased frequency of administration

C.E.R.AC.E.R.A

• CERA administered every 3 to 4 weeks is safe and effective for the treatment of anemia associated with CKD

• CERA's long duration of action is attributed to the addition of a large polymer chain into the erythropoietin molecule.

• The elimination half-life of CERA is approximately 130 hours.

1.Epogen (epoetin alfa) prescribing information, Amgen, Inc, Thousand Oaks, Calif.; 2. Procrit (epoetin alfa) prescribing information, Ortho Biotech Products, L.P., Raritan, New Jersey. 3. Provenzano R, et al. Clin Nephrol. 2005;64:113-123; 4. Provenzano R, et al. Clin Nephrol. 2004;61:392-405. 5. Aranesp (darbopoetin alfa) prescribing information, Amgen, Inc., Thousand Oaks, Calif. 6. Suryani MG, et al. Am J Kidney Dis. 2003;23:106-111; 7. Ling B, et al. Clin Nephrol. 2005;63:327-334. 8.

Agent Recommended Dose Clinical Practice Dose

Epoetin 50-100 units/kg administered either IV or SC, 3 times per week1,2

In the PROMPT study: 10,000 units (U) administered SC once weekly (QW), 20,000 U every two weeks (Q2W), 30,000 U every three weeks (Q3W) or 40,000 U every four weeks (Q4W)3

Darbepoetin alpha 0.45 g/kg, administered as a single IV or SC injection once weekly5

0.75 g/kg administered once every 2 weeks6

[Dose] administered SC once every 4 weeks7

C.E.R.A. 0.6 g/kg administered as a single IV or SC injection once every 2 weeks8

 

IV=intravenous; SC=subcutaneous.

How to Initiate ESA TherapyHow to Initiate ESA Therapy

Approach to normocytic anemiaApproach to normocytic anemia

Is there increased red cell production?

check reticulocyte count

normocytic anemia

increased

Is there evidence of hemolysis?

hemolytic anemia

yes

Is there evidence of:- renal failure anemia of renal failure- endocrine failure anemia of endocrine failure- chronic inflammation anemia of chronic disease

normal or decreased

recent bleed

no

consider bone marrow failure

bone marrow investigation

Inflammatory stimulus

Cytokines

T-cell & monocyte activation

target tissue

macrophages

kidney

bone marrow

retention of iron in macrophageserythropoietin production

response to erythropoietin

consequences

chronic infection,autoimmune disease,malignancy, etc

Iron Deficiency in CKDIron Deficiency in CKD

Pathophysiology of anemia of chronic diseasePathophysiology of anemia of chronic disease

interferon-TNF-IL-1, IL-6, IL-10

Adapted from Macdougall IC, et al. Kidney Int. 1996;50:1694-1699.

Week

Hb

(g

/dL

)

*

*

*

†

†

†

*P<0.05 vs IV iron.†P<0.005 vs IV iron.

All 37 patients entered the study iron replete with Hb <8.5 g/d L.

6

8

10

12

14

0 4 8 12 16

IV Iron

Oral Iron

No Iron

ESA=erythropoietin-stimulating agent; Hb=hemoglobin; IV=intravenous.

Importance of Iron Sufficiency Importance of Iron Sufficiency During ESA InitiationDuring ESA Initiation

National Kidney Foundation. Am J Kidney Dis. 2006;47(suppl 3):S1-S146.

KDOQI=Kidney Disease Outcomes Quality Initiative; ESAs=erythropoietin-stimulating agents; HD=hemodialysis; TSAT=transferrin saturation.

Avoiding Iron DeficiencyAvoiding Iron Deficiency

• 2006 KDOQI guidelines recommend the following goals of iron therapy during administration of ESAs– For HD patients:

• TSAT >20%

AND• Serum ferritin concentration >200 ng/mL

– For non-HD patients:

• TSAT >20%

AND• Serum ferritin concentration >100 ng/mL

Anemia SummaryAnemia Summary

• Anemia is a common and early complication of CKD

• Anemia is associated with an increased risk of morbidity and mortality

• Clinical use of ESAs for treatment of anemia requires vigilance regarding Hgb level, complications such as hypertension and resistance to response such as iron deficiency

• Increasing Hgb to >12 g/dL in patients with CKD is not recommended

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