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 addtion 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

CREATE 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