anemia and ckd an update anemia and ckd an update
TRANSCRIPT
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