Erythropoetin - From Bench to Bedside
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Transcript of Erythropoetin - From Bench to Bedside
K.Sampath kumar,MD,DM,FRCP
Meenakshi Mission Hospital
Madurai,India
“Erythropoietin – From Bench to Bedside "
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
.The mature hormone is composed of 165 amino acids
EPO biology
Bioengineered EPO possible only with mammalian cell lines due to addition of Sugar moiety
[Unlike Insulin for which bacteria can be utilised]
Native EPO versus Synthetic Darbopoietin
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
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
Kidney is a biological critmeter
Blood supplyDemand and
O2 Conc
45 % Hematocrit is not a randomNumber. It is optimises tissue Oxygen delivery with correct viscosityAnd fluidity
Normal hematocritOf 45 %
Oxygen sensorEPO Production
O2 content
RBC mass
Serum EPO
Na Reabsorption
Tissue 02
Critmeter at Cortico medullaryjunction – S3 seg of PCT
ProlylOHase
Ubiq.LigaseVHL
Proteosomedegrades
Hypoxia
EPO
HIF -2 a
HIF -2 a
HIF -2bOxygen increases HIF 2 alpha Destruction by Proteosome.
Hypoxia blocks this pathway
Paves way for EPO gene activation
Erythropoiesis
Practice Points in anemia management of CKD
9%17% 15% 10%
5%
8% 8% 15%14%
20%
43%
62%
0
20
40
60
80
100
<2 2-2.9 3-3.9 >4
Serum Creatinine (mg/dL)
Hct <30%
Hct 30% to 32.9%
Hct 33% to Normal
Pe
rce
nta
ge o
f P
atie
nts
W
ith
An
em
ia (
%)
N=1658
Develops early and worsens as CKD progresses
Anemia of CKD
7% 6%
10%
14%15% 15%
12%
9%
5%3%
2% 2%
0%
4%
8%
12%
16%
< 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
Mean 27.9 +/- 5.4Median 27.9
Anemia: At Onset of RRT
Why Anemia should be corrected in CKD
Why should we use EPO? Anemia correction benefits in CKD
Anemia is Associated with
Poor Survival of Patients with CKD
• 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)
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 Int2006;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
Due to the negative effects of anemia,1–3 early diagnosis and treatment in patients with CKD is recommended4,5
25.0
9.4
Rat
e p
er 1
00
pat
ien
t-ye
ars
Mean hemoglobin (g/dL) per decile
10.0
5.0
11.0 11.8 12.3 12.8 13.2 13.5 13.9 14.5 15.8
4.0
0.0
20.0
15.0
2.61.3 1.3 1.0 0.8 0.5 0.4 0.4 0.3
14.5
9.6
7.6 7.45.9 6.2
5.3 4.8
6.5
23.4
15.5
12.6
11.610.3
11.3
8.59.0
10.18.9
17.4
Death
CV hospitalization
ESRD
Levin, Am J Kid Dis 1999,
34:125-134
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
LV Mass Index
10 g/sq. m. Decrease 0.85 0.76 –0.96
Anemia is an Important Predictor of CVD
Longitudinal study of 246 patients with 1 year FU
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%
Diagnosis of Anemia
Learning Point 1
• Renal Anemia develops when GFR falls below 30 ml/min.
Point 2
• Exception – Diabetics develop anemia early – 45 ml/min
• In CKD 1,2,3 renal anemia is rare. Rule out other causes
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]
Investigation
Index
Smear
Retics
RBC
S.Iron
TIBC
%Tsat
Ferritin
Iron
Stool blood
GI loss
Spl situations
Deficiency
• B12
• Folate
Secondary
• PTH
• TB Gold
• GI Scopy
BM
• Aplasia
• MDS
Miscl
• LDH
• KT/V
• Immune Electroph.
Iron status
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
Functional Fe Def
FerritinNormal
>100
Transf.sat
Low
<20%
Hypochrcells
>10%
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
Parenteral forms of Iron
Point 4
•Retics of > 100 x 10 9 /L suggests active BM but enhanced blood loss due to hemolysis or bleed
ERA OF ESAs
Fishbane S. Curr Opin Nephrol Hypertens 2009;18:112–115Macdougall IC & Ashenden M. Adv Chron Kid Dis 2009;16:117–130
Darbepoeti
n
t1/2 25–72
hours
Epoetin dEpoetin a
t1/2 6–24 hours
MethoxyPEG-
epoetin b (CERA)
t1/2 130 hours
Epoetin bt1/2 6–24 hours
1989 2002 20071990
Biosimilarepoetins
HX575 and SB309
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
Normal Hematocrit study
Choir Study
CHOIR STUDY
CREATE STUDY
TREAT STUDY
CKD
DM/CVA
CANCER
PHYSIOLOGY
HD/PD/
TX
GENDER/GENES
AGE/
ALTIDUDE
IRON STATUS
LIFE STYLE
DISEASE SEVERITY
Point -6
• Caution while using EPO !
• Active malignancy
• History of Stroke
• CAD/CCF
• Uncontrolled HT
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 requirement
Less More
Besarab A, et al. Am J Kidney Dis 2002; 40: 439–446
IV route
More dose
Less immunogenic
S.C ROUTE
30% less dose
> Half Life
> Immunogenic
Retic count < 10 x 10 9/L
BM failure due to AB mediated
Pure red cell aplasia
• EPO Alfa
• S.C route
?Rubber stoppers
?Polysorbate 80
• B cell tolerance lost
• Immunogenic
Antibody against endo and exo EPO
• Transfusion dep
• PRCA
Trt -Hematide
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
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.
Darbepoetin in CKD: EPO
Comparison Significantly faster increase in Hb
* p<0.0001
Lullo, et al. Cardiorenal Med 2012;2:18–25
Hemoglobin variability and its impact on survival
A longitudinal survey of HD patients showing fluctuations in Hb with its
impact on survival
Hemoglobin variability worsens survival.Long acting EPO like Darbopoietinand CERA reduce this phenomenon.
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