Anemia management in CKD

Salwa Ibrahim, MD FRCP (Edin)

Cairo University

4th CKD course, 15-17 May 2016

 Agenda

• Mechanism of anemia

• Hemoglobin Target

• KDIGO guidelines
 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
Prevalence of anemia severity stratified by stage of chronic kidney disease
 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
 Mechanism of anemia in CKD

• EPO deficiency

• Iron deficiency

• Uremia induced inhibition

• Shortened RBCs survival

• Nutritional deficiency (folate, B12)

 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)
 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
 Symptoms of anemia

• Fatigue

• Shortness of breath

• Diminished quality of life

• Palpitation
 Hazards of anemia in CKD

• LVH, CHF

• IHD

• Impaired immune system

• Diminished cognitive functions

• Progression of CKD
Diagnosis of anemia
Use of ESAs to treat anemia in CKD
ESA MAINTENANCE THERAPY
ESA DOSING
ESA ADMINISTRATION
 HCT and Mortality in D-CKD
1.4 1.33
All-cause death
1.25
1.2 Cardiac-related death
1.12 1.11
1.00 1.00 0.97
1 0.96

0.8

0.6

0.4

0.2

0
< 27% 27% to < 30% 30% to < 33% 33% to < 36%

Hct
 Largest Studies on Target Hgb in D-CKD

1. Normal Hematocrit Study ≈ 1233 pts (1265)

• Besareb et al NEJM 1998
Normal Hematocrit Study

P<0.001
*
 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
 CHOIR
1432 patients, 130 centers, US only
Epoetin-alfa

Median f/u 16 months

Randomization

High target Hb Low target Hb

(13.5 g/dl) (11.3 g/dl)
n=715 n=717
312 completed 36 mo 349 completed 36 mo
or withdrew at study termination or withdrew at study termination
with no primary event with no primary event
125 primary event 97 primary event
278 Withdrew before 278 Withdrew before
early termination of study early termination of study

Required RRT (47.1%) Required RRT (41.0%)

Withdrew for Other Reasons (21%) Withdrew for Other Reasons (22%)
 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

 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

(10.5 to 11.5 g per deciliter, group 2)
 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

 TREAT Study 2009

• The risk of stroke doubled in higher HB group

• The risk of cancer also increased with highr hemoglobin level

Phrommintikul et al al, Lancet 2007
ESA available in Egypt
 Eprex (Epoeitin alpha)
– IV or SC
– 3 x wk
– Most HD pts on this
– Initial dose 200-3000 units thrice weekly
– Half life 4-11 h IV and 19-25 h SC
 Recormon (Epoeitin beta)
• IV or SC
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
• 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
• 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
 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
 New class of ESA

• Hematinide ( synthetic peptide)

• HIF stabilizer (oral agent) used to stabilize HIF to

increase the transcription of EPO