This document discusses anemia management in chronic kidney disease (CKD). It covers the mechanisms of anemia in CKD, including erythropoietin deficiency and iron deficiency. It reviews guidelines for hemoglobin targets and the use of erythropoiesis-stimulating agents (ESAs) to treat anemia. Larger studies on hemoglobin targets in both dialysis and non-dialysis CKD patients, such as the CHOIR and CREATE trials, found higher risks with higher hemoglobin targets and no benefits to quality of life. Iron deficiency is a major cause of ESA treatment failure in CKD patients.

1. Anemia management in CKD
Salwa Ibrahim, MD FRCP (Edin)
Cairo University
4th CKD course, 15-17 May 2016

2. Agenda
• Mechanism of anemia
• Hemoglobin Target
• KDIGO guidelines

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

4. Prevalence of anemia severity stratified by stage of chronic kidney disease

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

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

14. Diagnosis of anemia

17. Use of ESAs to treat anemia in CKD

18. ESA MAINTENANCE THERAPY

19. ESA DOSING

20. ESA ADMINISTRATION

22. HCT and Mortality in D-CKD
1.33
1.12
1.00
0.96
1.25
1.11
1.00 0.97
0
0.2
0.4
0.6
0.8
1
1.2
1.4
< 27% 27% to < 30% 30% to < 33% 33% to < 36%
Hct
All-cause death
Cardiac-related death

25. Largest Studies on Target Hgb in D-CKD
1. Normal Hematocrit Study ≈ 1233 pts (1265)
• Besareb et al NEJM 1998

26. Normal Hematocrit Study
P<0.001
*

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

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

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

35. (10.5 to 11.5 g per deciliter, group 2)

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

38. Phrommintikul et al al, Lancet 2007

42. ESA available in Egypt

43. 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

44. Recormon (Epoeitin beta)
• IV or SC

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