1. Anemia Guidelines and The Use of Erythropoietin in Turkey
Kenan ATEŞ, MD
Department of Nephrology
Ankara University Faculty of Medicine

2. Anemia in chronic renal failure
Erythropoietin deficiency
GFR <40 ml/min
Erythropoesis inhibition
Hemolysis
ANEMİA
Blood loss
Iron deficiency
Normocytic normochromic
Folate/Vitamin B12 deficiency
Inflammation
Aluminium overload

3. Anemia is important Reduced quality of life
Decreased tissue oxygen
delivery and utilization
Decreased cognition and
mental acuity
Increased cardiac output
Altered menstrual cycles
Ventricular hypertrophy
Decreased sexual function
Cardiac enlargement
Impaired immune responsiveness
Angina pectoris
Growth retardation
Congestive heart failure
Decreased intellectual performance
Reduced quality of life
Poor patient rehabilitation
Decreased survival

4. Treatment of secondary
Treatment of anemia
Iron supplementation
Adequate dialysis
Adequate nutrition
Target
Hb/Hct Level
Treatment of secondary
hyperparathyroidism
Prevention of inflammation
ERYTHROPOIETIN

5. Not all dialysis patients will require treatment with EPO
Adequate dialysis HD
20%
Adequate nutrition
Iron supplementation PD
40%
Other measures

6. C O S T EPO therapy is a very expensive treatment One month cost 900 $
HEMODIALYSIS
900 $
EPO (6000 U/wk)
500 $

7. ANEMIA GUIDELINES

8. EUROPEAN BEST PRACTICE GUIDELINES
Anemia Guidelines
The aim of guidelines is to provide an evidence-based
standard of care for management of anemia in patients
with chronic renal failure
1996
NKF-DOQI GUIDELINES
1999
EUROPEAN BEST PRACTICE GUIDELINES
2003
TSN ANEMIA GUIDELINES

9. When to initiate the work-up of anemia
Pre-menopausal females
Pre-pubertal patients
Hb <11 g/dl (Hct <33%)
Post-menopausal females
Adult males
Hb <12 g/dl (Hct <37%)
NKF-DOQI GUIDELINES
EUROPEAN BEST PRACTICE GUIDELINES
TSN ANEMIA GUIDELINES

10. EUROPEAN BEST PRACTICE GUIDELINES
Evaluation of anemia
Hemoglobin and/or hematocrit
Red blood cell indices
Serum iron
Reticulocyte count
TIBC
Iron parameters
Serum ferritin
Transferrin saturation
Occult blood in stool
Percen. of hypochromic red cells
CRP
NKF-DOQI GUIDELINES
TSN ANEMIA GUIDELINES
EUROPEAN BEST PRACTICE GUIDELINES

11. Evaluation of anemia
A fuller work-up should also include the following, as indicated
Serum vitamin B12 and folic acid
Differential white blood count
Tests for hemolysis
Serum protein electroforesis
Hemoglobin electroforesis
TSN ANEMIA GUIDELINES
Bone marrow examination
EUROPEAN BEST
PRACTICE GUIDELINES
Serum aluminium

12. Erythropoietin deficiency EUROPEAN BEST PRACTICE GUIDELINES
Anemia is most likely due to EPO deficiency If
Impairment of renal function is present
A normocytic, normochromic anemia is present
No cause for anemia is detected by the work-up
NKF-DOQI GUIDELINES
EUROPEAN BEST PRACTICE GUIDELINES
TSN ANEMIA GUIDELINES

13. Indications for starting treatment with Erythropoietin
EPO treatment should be considered
when the Hb concentration is consistently less than
11 g/dl on repeating testing (Hct <33%)
when other causes of anemia have been excluded
NKF-DOQI GUIDELINES
EUROPEAN BEST PRACTICE GUIDELINES

14. Indications for starting treatment with Erythropoietin
TSN ANEMIA GUIDELINES
ASYMPTOMATIC
PATIENTS
SYMPTOMATIC
PATIENTS
Heart failure, angina
Hb <10 g/dl
Htc <30%
Higher Hb and/or Hct levels
EPO TREATMENT

15. Hematology work-up Treat with EPO if indicated
Serum creatinine 2 mg/dl
Check Hb
<12 g/dl in males and post-menopausal females
<11 g/dl in pre-menopausal females and pre-pubertal patients
Work-up No
Hematology
work-up
Normal
Fe deficiency
Treat with EPO
if indicated
Treat with iron
Anemia not corrected
Anemia corrected

16. Target hematocrit/hemoglobin for erythropoietin therapy
11-12 g/dl
Hematocrit
33-36%
Variations in the target Hb may be required
in patients with co-morbidity
NKF-DOQI GUIDELINES
EUROPEAN BEST PRACTICE GUIDELINES
TSN ANEMIA GUIDELINES

17. Assesment of iron status BEST PRACTICE GUIDELINES
Serum iron
Total iron binding capacity
Transferrin saturation
Percentage of hypochromic red cells
Serum ferritin
Iron stores in bone marrow
NKF-DOQI GUIDELINES
RBC ferritin concentration
BEST PRACTICE GUIDELINES
TSN ANEMIA GUIDELINES

18. EUROPEAN BEST PRACTICE GUIDELINES
Target iron level
The patients should have sufficient iron to achieve and
maintain an Hb (Hct) of g/dl (33-36%)
OPTIMAL
Serum ferritin
>100 ng/ml
ng/ml
Transferrin saturation
>20%
30-40%
Hypochromic red cells
<10%
<2.5% (<5%)
NKF-DOQI GUIDELINES
TSN ANEMIA GUIDELINES
EUROPEAN BEST PRACTICE GUIDELINES

19. Monitoring iron status BEST PRACTICE GUIDELINES
Patients treated with Epo
Patients not treated with Epo
Hb/Hct stable
Hb <11 g/dl
Hct <33%
Hb g/dl
Hct 33-36%
Ferritin 100 ng/ml
TSAT 20%
Every 3 months
Every 3-6 months
Not receiving
IV iron
Receiving
IV iron
NKF-DOQI GUIDELINES
BEST PRACTICE GUIDELINES
Every month
Every 3 months
TSN ANEMIA GUIDELINES

20. Administration of supplemental iron
TSAT <20%
Ferritin <100 ng/ml
mg IV iron at every HD seans
for 8-10 doses
TSAT <20%
Ferritin <100 ng/ml
TSAT >20%
Ferritin >100 ng/ml
TSAT >50%
Ferritin >800 ng/ml
mg IV iron
at every HD seans
for 8-10 doses
mg IV iron
per week
IV iron therapy
should be withheld
for 3 months

21. EUROPEAN BEST PRACTICE GUIDELINES
Oral iron therapy
When oral iron is used
It should be given as 200 mg of elemental iron per day,
in two to three divided doses in the adult patient, and
2-3 mg/kg/day in the pediatric patient
NKF-DOQI GUIDELINES
EUROPEAN BEST PRACTICE GUIDELINES
TSN ANEMIA GUIDELINES

22. Route of administration of erythropoietin
INTRAVENOUS
INTRAPERITONEAL
SUBCUTANEOUS
INTRADERMAL
EPO should be administered SC in PD patients
The most effective route of EPO is SC in HD patients
NKF-DOQI GUIDELINES
EUROPEAN BEST PRACTICE GUIDELINES
TSN ANEMIA GUIDELINES

23. Initial erythropoietin administrationSC
units/kg/week, in two to three doses per week IV
units/kg/week, in three doses per week
NKF-DOQI GUIDELINES

24. Initial erythropoietin administration
The starting dose of EPO should be units/kg/week SC
The starting dose should be in the lower range IV
The starting dose should be in the upper range
EUROPEAN BEST PRACTICE GUIDELINES

25. Initial erythropoietin administrationSC
The starting dose should be 75 units/kg/week IV
The starting dose should be 150 units/kg/week
TSN ANEMIA GUIDELINES

26. Monitoring of Hb/Hct during erythropoietin therapy
Target Hb/Hct is not achieved
NKF-DOQI GUIDELINES
Every 1-2 weeks
BEST PRACTICE GUIDELINES
Every 1-2 weeks
TSN ANEMIA GUIDELINES
Every 2 weeks
Target Hb/Hct is achieved
NKF-DOQI GUIDELINES
Every 2-4 weeks
BEST PRACTICE GUIDELINES
Every 4-6 weeks
TSN ANEMIA GUIDELINES
Every 4 weeks

27. Titration of erythropoietin dosage
After initation of EPO
After a dose increase
If the increase in Hb (Hct) is
<0.7 g/dl (<2%) over a 2-4
week period
If the increase in Hb/Hct is
>2.5 g/dl (>8%) per month
If the Hb (Hct) exceeds
the target levels
Dose should be increased by
50%
Dose should be decreased by
25-50%
NKF-DOQI GUIDELINES
BEST PRACTICE GUIDELINES

28. Titration of erythropoietin dosage
After initation of EPO
After a dose increase
If the increase in Hb (Hct) is
<1.0 g/dl (<3%) over a 4-6
week period
If the increase in Hb/Hct is
>1.5 g/dl (>5%) per month
Dose should be decreased by
50%
Dose should be increased by
units/kg/week
TSN ANEMIA GUIDELINES

29. Inadequate response to erythropoietin
DEFINITION
NKF-DOQI GUIDELINES
Failure to achieve target Hb/Hct in the presence of adequate
iron stores at dose of 450 units/kg/wk IV or 300 units/kg/wk
SC within 4-6 months or
failure to maintain target Hb/Hct subsequently at that dose
EUROPEAN BEST PRACTICE GUIDELINES
Failure to attain the target Hb concentration while receiving
more than 300 units/kg/wk (~ units/wk) of EPO SC or
a continued need for such dosage to maintain the target

30. Inadequate response to erythropoietin
DEFINITION
TSN ANEMIA GUIDELINES
Despite the EPO therapy at dose of 300 units/kg/week,
no increase in Hb more than 2 g/dl within 12 weeks

31. Causes of inadequate response to erythropoietin
Iron deficiency
Osteitis fibrosa
Infection/inflamation
Aluminium overload
Chronic blood loss
Folate/Vitamin B12 deficiency
Malnutrition
Hemoglobinopathies
Hemolysis
Multiple myeloma
NKF-DOQI GUIDELINES
EUROPEAN BEST PRACTICE GUIDELINES

32. EPO RESISTANCE Infection Inflammation Malignancy CRP Non-compliance
Occult blood
in stool
Blood loss
Iron stores
Reticulocyte
LDH
Bilirubin
Blood smear
Hemolysis
Inadequate
Adequate
Vitamin
deficiency
Vitamin B12/Folate
Blood smear
PTH
Bone marrow
examination
Bone marrow
fibrosis
Aluminium
overload
Serum aluminium
TSN ANEMIA GUIDELINES
Hemoglobinopathies
Hb electrof.

33. LEGAL ARRANGEMENTS

34. Ministry of Finance 2003 Fiscal Year Budget Application Directions
Official Gazette: Date , Number 25011
Use of erythropoietin in patients with chronic renal failure
The target Hct level for EPO therapy is 30-35%
If the target Hct is achieved, EPO dose should be decreased
If the Hct level exceeds 40%, EPO therapy should be
interrupted until Hct is decreased to target level
If failure to achieve the target Hct within 3 months, EPO
therapy should be interrupted and causes of resistance
should be examined
EPO should be administered subcutaneously

35. Social Insurance Institution (SSK) 2002 Year Drug Application Directions
Item 30
Principles of erythropoietin usage
EPO therapy should be used when the Hb (Hct) is less than
8 g/dl (24%)
If the following conditions is determined during the initial
evaluation, EPO therapy should not be used
Iron deficiency
Chronic infection
Ischemic vascular disease
Blood loss
Aluminium overload
Uncontrolled hypertension
Hemolysis
Hyperparathyroidism
Vascular access thrombosis

36. Social Insurance Institution (SSK) 2002 Year Drug Application Directions
The target Hb (Hct) level is g/dl (30-33%)
If the Hb (Hct) level exceeds the 11 g/dl (33%), EPO therapy
should be interrupted
EPO Resistance: Despite the EPO therapy at dose of
150 units/kg/week, no increase in Hb/Hct within 3 months
If no increase in Hb/Hct level within two months, EPO
therapy should be interrupted
EPO should be administered subcutaneously

37. CURRENT ASPECTS OF ANEMIA THERAPY AND USE OF ERYTHROPOIETIN IN TURKEY

38. Use of erythropoietin in dialysis patients in Turkey%
TSN Registry

39. Use of erythropoietin in hemodialysis patients in Turkey%
Ministry of Health Data

40. Mean hemoglobin level in dialysis patients in Turkey
TSN Registry-2002

41. Percent of patients with hemoglobin 11 g/dl in Turkey%
TSN Registry

42. The success rate with erythropoietin in dialysis patients in Turkey%
TSN Registry-2002

43. Use of iron therapy in dialysis patients in Turkey%
TSN Registry-2002

44. Serum ferritin level in dialysis patients in Turkey%
TSN Registry-2002

45. Data of United Kingdom Renal Registry%

46. CONCLUSION
Anemia is present in the majority of the patients with CRF, and
when untreated, it is associated with poor clinical outcomes
Today, anemia treatment and use of erythropoietin is guided
by social security organisations in Turkey
Directions of erythropoietin usage suggested by these
organisations are cost-based but not evidence-based
Principles of anemia treatment in Turkey should be rearranged
according to TSN Anemia Guidelines