Anemia of Chronic Kidney disease is a fascinating subject for the Basic Scientist and Practising Nephrologist.

1. “Erythropoietin – From Bench to
Bedside "
K.Sampath kumar,MD,DM,FRCP
Meenakshi Mission Hospital
Madurai,India

2. Focus of my talk
• Biology of Erythropoietin [EPO]
• Why EPO should come from Kidneys? Why
not Lungs ?
• Practical aspects of usage of EPO in clinic
• Major clinical trials
• Use / Abuse of EPO
• Conclusion

3. EPO biology
.The mature hormone is composed of 165 amino
acids

4. Bioengineered EPO possible only with mammalian cell lines
due to addition of Sugar moiety
[Unlike Insulin for which bacteria can be utilised]

5. Native EPO versus Synthetic Darbopoietin

12. Focus of my talk
• Biology of Erythropoietin [EPO]
• Why EPO is produced in Kidneys
• Practical aspects of usage of EPO in clinic
• Major clinical trials
• Cautionary notes
• Conclusion

13. Oxygen sensing at Kidney rather than
Lungs
• > 20% of cardiac output goes to Kidneys
• Richest blood supply per gram of tissue
• Blood supply independent of metabolic
demand
• 10% of oxygen supply only is utilised by
Kidneys

14. Kidney is a biological critmeter
Blood supply
Demand and
O2 Conc
45 % Hematocrit is not a random
Number. It is optimises tissue
Oxygen delivery with correct viscosity
And fluidity
Normal hematocrit
Of 45 %

15. Oxygen sensor
EPO Production
O2
content
RBC mass
Serum
EPO
Na Reabsorption
Tissue
02

17. Critmeter at Cortico medullary
junction – S3 seg of PCT

18. Prolyl
OHase
Ubiq.
Ligase
VHL
Proteosome
degrades
Hypoxia
EPO
HIF -2
a
HIF -2
a
HIF -2b
Oxygen increases HIF 2 alpha
Destruction by Proteosome.
Hypoxia blocks this pathway
Paves way for EPO gene activation
Erythropoiesis

20. Practice Points in anemia
management of CKD

21. Develops early and worsens as CKD progresses
9%
17% 15% 10%
5%
8% 8% 15%
14%
20%
43%
62%
100
80
60
40
20
0
<2 2-2.9 3-3.9 >4
Serum Creatinine (mg/dL)
Hct <30%
Hct 30% to 32.9%
Hct 33% to Normal
Percentage of Patients
With Anemia (%)
N=1658
Anemia of CKD

22. Anemia: At Onset of RRT
7% 6%
10%
14%
15% 15%
12%
9%
5%
Mean 27.9 +/- 5.4
Median 27.9
3%
2% 2%
16%
12%
8%
4%
0%
< 20 22-24 26-28 30-32 34-36 38-40
Hematocrit (%)
Obrador, J Am Soc Nephrol 1999, 10:1793-1800
131,484 patients who began dialysis between 4/1/95 and
6/30/97

23. Why should we use EPO?
Anemia Why Anemia correction should be corrected benefits in CKD
in CKD

24. Anemia is Associated with
Poor Survival of Patients with CKD
Due to the negative effects of anemia,1–3 early diagnosis and treatment in
patients with CKD is recommended4,5
• Dynamic, retrospective
cohort study among 8761
patients with CKD at
Kaiser Permanente
Northwest2
• Assessment of outcomes2
– Death
– Cardiovascular (CV)
hospitalization
– End-stage renal disease
(ESRD)
25.0
23.4
17.4
4.0
9.4
Rate per 100 patient-years
15.5
14.5
2.6
12.6
9.6
11.6
10.3
7.6 7.4
11.3
Death
CV hospitalization
ESRD
8.5
5.9 6.2
9.0
10.1
5.3 4.8
8.9
6.5
1.3 1.3 1.0 0.8 0.5 0.4 0.4 0.3
11.0 11.8 12.3 12.8 13.2 13.5 13.9 14.5 15.8
Mean hemoglobin (g/dL) per decile
20.0
15.0
10.0
5.0
0.0
1. Fishbane S. Heart Fail Clin 2008;4:401–410; 2. Thorp ML et al. Nephrology 2009;14:240–246; 3. Kovesdy CP et al. Kidney Int
2006;69:560–564; 4. Hörl WH et al. Nephrol Dial Transplant 2007;22(suppl 3):iii2–6; 5. Gouva C et al. Kidney Int 2004;66:753–760

25. Anemia is an Important Predictor of
CVD
Longitudinal study of 246 patients with 1 year FU
Unit RR 95% CI
Hemoglobin 0.5 g/dl Decrease 1.32 1.11 –
1.59
Systolic BP 5 mm Hg Increase 1.11 1.02 –
1.21
Levin, Am J Kid Dis 1999,
34:125-134
LV Mass
Index
10 g/sq. m. Decrease 0.85 0.76 –
0.96

26. NORMAL RBC PARAMETERS
RBC PARAMETER ADULT MEN ADULT FEMALE
HB 15 +/- 1.5 13+/- 1.5
HEMATOCRIT 46 40
RBC COUNT 5.2 4.6
RETICULOCYTES 1.6% 1.4%
MCV fl 88 88
MCH pg 30.4 30.4
MCHC 34.4 34.4
RDW 13 % 13%

27. Diagnosis of Anemia

28. Learning Point 1
• Renal Anemia develops when
GFR falls below 30 ml/min.

29. Point 2
• In CKD 1,2,3 renal anemia is rare.
Rule out other causes
• Exception – Diabetics develop
anemia early – 45 ml/min

30. Point 3
• Pure Renal anemia is
• Normocytic
• Normochromic
Either a low[Fe] or high MCV[B12,F]
Low MCH or MCHC strongly
suggest other contributory factors
[ Iron def or hemoglobinopathy]

31. Investigation
RBC
Index
Smear
Retics
Iron
S.Iron
TIBC
%Tsat
Ferritin
GI loss
Stool
blood

32. Spl situations
Deficiency
• B12
• Folate
Secondary
• PTH
• TB Gold
• GI Scopy
BM
• Aplasia
• MDS
Miscl
• LDH
• KT/V
• Immune
Electroph.

33. Iron status

34. Anemia in CKD: Iron
Replacement
 All CKD patients + renal anemia requiring EPO should be
given supplemental iron to reach targets.
 Route: IV or oral in pre-dialysis -CKD or PD-CKD
 The preferred route is IV in CKD-HD
K-DOQI 2006

35. Functional Fe Def
Ferritin
Normal
>100
Transf.sat
Low
<20%
Hypochr
cells
>10%

36. Parenteral forms of Iron
Features Iron Dextran Iron Sucrose Ferric
Gluconate
Nature Dextran complex
covering iron
core
Sucrose
covering iron
oxide core
Iron bound with 1
gluconate + 4
sucrose
Mol. Wt 96-265 kd 34 – 60 kd 289 – 440 kd
Direct Iron
Transfer
No No No
Half life 40-60 hours 6 hrs 1 hrs
Vol.
Distribution
6 Liter 3.2 – 7.3 liter 6 liter
Renal Excret. Negligible < 5 % Nil

37. Point 4
• Retics of > 100 x 10 9 /L
suggests active BM but
enhanced blood loss due to
hemolysis or bleed

38. ERA OF ESAs
Darbepoeti
n
t1/2 25–72
hours
Epoetin d
HX575 and SB309
Fishbane S. Curr Opin Nephrol Hypertens 2009;18:112–115
Macdougall IC & Ashenden M. Adv Chron Kid Dis 2009;16:117–130
Epoetin a
t1/2 6–24
hours
Methoxy
PEG-epoetin
b
(CERA)
t1/2 130 hours
Epoetin b
t1/2 6–24
hours
1989 1990 2002 2007
Biosimilar
epoetins

39. Point-5 *****
• Trigger Hb for initiating ESA therapy
should be between 9 or 10 G/dL
• Target Hb LEVEL 10-12 G/dL
Why not a normal hematocrit be targetted in CKD?
Crux of controversy

41. Normal Hematocrit study

43. Choir Study

45. CHOIR STUDY

46. CREATE STUDY

50. TREAT STUDY

53. DM/CVA
CANCER
CKD
PHYSIOLO
GY
HD/PD/
TX
GENDER/
GENES
AGE/
ALTIDUDE
DISEASE
SEVERITY
LIFE STYLE
IRON
STATUS

54. Point -6
• Caution while using EPO !
• Active malignancy
• History of Stroke
• CAD/CCF
• Uncontrolled HT

55. EPO: Routes of administration
S.C. I.V.
Bioavailability 48.8% 100%
t 1/2 19-25 hrs 5-11 hrs
Effectiveness More less
Dose
Less More
requirement
Besarab A, et al. Am J Kidney Dis 2002; 40: 439–446

56. IV route
More dose
Less immunogenic
S.C ROUTE
30% less dose
> Half Life
> Immunogenic

57. Retic count < 10
x 10 9/L
BM failure due
to AB mediated
Pure red cell
aplasia

58. • EPO Alfa
• S.C route
?Rubber stoppers
?Polysorbate 80
Antibody against
endo and exo EPO
• B cell
tolerance lost
• Immunogenic
• Transfusion
dep
• PRCA
Trt -Hematide

60. Darbepoetin Alpha
 Long-acting protein
 2 more carbohydrate chains and up to 8 more sialic acid
residues
 Bind to same receptor as EPO
 Same mechanism of action as EPO
 Super-silation prolong in-vitro activity
 Clinical efficacy and Safety profile similar

61. Darbepoetin in Anemia:
Correction Phase
Dialysis patients SC/IV 0.45 μg/kg once weekly
Non- Dialysis patients
 0.45 μg/kg once weekly (or)
 0.75 μg/kg once every two weeks (or)
 1.5 μg/kg once monthly
 If  in Hb is < 1 g/dl in 4 wks,  the dose by 25%.
 Dose  not more frequently than once in four weeks
 If the  Hb is > 2 g/dl in 4 wks  the dose by 25%.
 If the Hb > 12 g/dl, a dose reduction should be made.

62. Darbepoetin in CKD: EPO
Comparison
Significantly faster increase in Hb
* p<0.0001
Lullo, et al. Cardiorenal Med 2012;2:18–25

63. Hemoglobin variability and its
impact on survival
A longitudinal survey of HD patients
showing fluctuations in Hb with its
impact on survival

67. Hemoglobin variability worsens survival.
Long acting EPO like Darbopoietin
and CERA reduce this phenomenon.

68. Conclusion
• Do not assume every anemia in CKD is EPO
responsive
• Look for clues for secondary causes
• Do not overcorrect hematocrit in CKD
• Know your patient profile well before EPO
therapy
• Start low and go slow
• Long acting EPO like DarboP is preferable