3. Introduction
• Anemia was first linked to CKD over 170 years ago by Richard
Bright
• Caused primarily by erythropoietin deficiency secondary to
renal mass loss
• EPO level is inappropriately low relative to the degree of
anemia
5. Erythropoeisis
• Erythropoeitin (EPO) is a glycoprotein hormone secreted
(90%) from endothelial cells in proximity to renal tubules
• EPO stimulates stem cells in the bone marrow to RBC
production
• Iron essential in latter phase as Hb incorporated into
reticulocytes and released into circulation as RBCs
– 2/3rds of iron in the body is in Hb
6. Mechanism of anemia in CKD
• EPO deficiency
• Iron deficiency
• Uremia induced inhibition
• Shortened RBCs survival
• Nutritional deficiency (folate, B12)
7. Iron deficiency
• CKD patients have increased iron losses, estimated at 1-3 g per year
in hemodialysis patients
• Causes include:
1. Chronic bleeding from uremia-associated platelet dysfunction
2. Frequent phlebotomy
3. Blood trapping in dialysis apparatus
4. Impaired dietary iron absorption (anorexia, use of phosphate binders, PPI
and H2 blockers)
8. Functional iron deficiency
• Impaired iron release from body stores (reticuloendothelial
cell iron blockade)
• Hepcidin excess accounts for impaired dietary iron absorption
and reticuloendothelial cell iron blockade
• Hepcidin produced by the liver binds and induces degradation
of iron exporter (ferroportin) on duodenal enterocytes,
reticuloendothelial macrophages, and hepatocytes to inhibit
iron entry into plasma
9.
10. Symptoms of anemia
• Fatigue
• Shortness of breath
• Diminished quality of life
• Palpitation
11. Hazards of anemia in CKD
• LVH, CHF
• IHD
• Impaired immune system
• Diminished cognitive functions
• Progression of CKD
27. Largest Studies on Target Hgb ND-CKD
1. The CREATE = 603 pts
– Drueke et al NEJM 2006
2. The CHOIR study = 1432 pts
– Singh et al NEJM 2006
28.
29. CHOIR
1432 patients, 130 centers, US only
Epoetin-alfa
Randomization
High target Hb
(13.5 g/dl)
n=715
312 completed 36 mo
or withdrew at study termination
with no primary event
125 primary event
278 Withdrew before
early termination of study
Required RRT (47.1%)
Withdrew for Other Reasons (21%)
Low target Hb
(11.3 g/dl)
n=717
349 completed 36 mo
or withdrew at study termination
with no primary event
97 primary event
278 Withdrew before
early termination of study
Required RRT (41.0%)
Withdrew for Other Reasons (22%)
Median f/u 16 months
30. Endpoints
Primary Endpoint: Composite event consist of
• Death
• Myocardial infarction
• Stroke
• CHF hospitalization (excluding RRT)
Singh et al,New Engl J Med 2006; 355:2085-98
31.
32. Summary (CHOIR)
• Increased risk with targeting Hb to 13.5 g/dL and achieving
12.6 g/dL (34% P=0.03)
• Strong trends for Death (48% P=0.07) and CHF Hospitalization
(41% P=0.07)
• Higher rate of Cardiovascular (23% P=0.03) and All
Hospitalization (18% P 0.03)
• No Incremental QOL of benefit with higher Hb
Singh et al,New Engl J Med 2006; 355:2085-98
36. Summary (CREATE)
• Increased risk with targeting higher Hb HR=0.78
• Improvement in QOL in both groups
• No benefit in LVH in the Group 1 with higher hemoglobin
37. TREAT Study 2009
• The risk of stroke doubled in higher HB group
• The risk of cancer also increased with highr hemoglobin level
45. Aranesp (Darbepoeitin)
– IV or SC
– extra carbohydrate chain, 3 x longer half life, hence can be
given weekly or fortnightly (non-dialysing pts)
– Initial dose 25 mcg weekly to 60 mcg twice monthly
46. • Methoxy polyethylene glycol-epoetin beta is the active
ingredient of a drug marketed by Roche under the brand
name Mircera
• Mircera is a long-acting erythropoietin receptor activator
(CERA) indicated for the treatment of patients with anemia
associated with CKD usually given once monthly (150 mcg)
• The drug stimulates erythropoiesis by interacting with the
erythropoietin receptor on progenitor cells in the bone
marrow
47. • It has a different receptor binding activity to other ESAs and
its reduced affinity for the erythropoietin receptor allows
continuous stimulation
• It has an in vivo half-life of around 135 hours as compared to
darbapoietin alfa which has a half life of around 21 hours, the
half life of which is three times that of the naturally occurring
erythropoietin in the body
• Mircera is supplied as a solution in pre-filled syringes for
intravenous or subcutaneous administration
48. Causes of EPO not working
• Iron deficiency ** most common **
• B12 & Folate deficiency
• Inflammation
• ACE inhibitors
• Hyperparathyroidism – bone marrow fibrosis
• Aluminium toxicity
• Inadequate dialysis
• Malignancies, including multiple myeloma
49. New class of ESA
• Hematinide ( synthetic peptide)
• HIF stabilizer (oral agent) used to stabilize HIF to
increase the transcription of EPO