Anaemia treatment in CKD, ESRD, and kidney transplant recipients

Iain C Macdougall BSc, MD, FRCP

Consultant Nephrologist and Honorary Senior Lecturer

Renal Unit, King’s College

Hospital, London, UK

Outline of presentation

Erythropoiesis in 2009

ESA therapy

Target Hb

Iron management

Anaemia management in kidney transplantation

The future

Hb

(g

/dL

)

15

10

5

Declining GFR (mL/min)

Development of renal anaemia prior to the availability of EPO therapy

DialysisCKD stages 1–2 Stage

3 Stage

4 Stage

5

120–60 59–30 29–15 < 15

NHANES data

Papayannopoulou T, et al. In: Hoffman R, et al., ed. Hematology: Basic Principles and Practice. 4th ed. 2005;267-288.

SCF, GM-CSF, IL-3

SCF, IL-1, IL-3, IL-6, IL-11

PluripotentStem Cell

Burst-Forming Unit-Erythroid Cells (BFU-E)

Colony-FormingUnit-ErythroidCells (CFU-E)

Reticulocytes RBCsErythro-blasts

Proerythro-blasts

About 8 Days

Iron

Erythropoietin

Erythropoiesis in CKDErythropoiesis in CKD in 2009

Pro-inflammatory cytokines (IL-1, TNFα, IL-6, IFNγ)

EPO production

EPO

+ +

Iron

Fas Ag

Apoptosis

─

hepcidin Fe absorption Fe transport Fe availability(EPO-R, Tf, TfR, Ferriportin, DMT-1)

─

Erythropoiesis in CKD in 2009

Papayannopoulou T, et al. In: Hoffman R, et al., ed. Hematology: Basic Principles and Practice. 4th ed. 2005;267-288.

SCF, GM-CSF, IL-3

SCF, IL-1, IL-3, IL-6, IL-11

PluripotentStem Cell

Burst-Forming Unit-Erythroid Cells (BFU-E)

Colony-FormingUnit-ErythroidCells (CFU-E)

Reticulocytes RBCsErythro-blasts

Proerythro-blasts

About 8 Days

Iron

Erythropoietin

Anti-Anaemic therapies in CKD

Outline of presentation

Erythropoiesis in 2009

ESA therapy

Target Hb

Iron management

Anaemia management in kidney transplantation

The future

Development of recombinant human EPO

1977 - human EPO isolated from 2,500 litres of urine

(Miyake et al)

1983 - gene for human EPO isolated and cloned

(FK Lin et al)

1986 - first clinical report in dialysis patients

1990 - r-HuEPO licensed for use in Europe

Epoetin alfa (Eprex)

Epoetin beta (NeoRecormon)

Hb

(g

/dL

)

15

10

5

Declining GFR (mL/min)

Development of renal anaemia prior to the availability of EPO therapy

DialysisCKD stages 1–2 Stage

3 Stage

4 Stage

5

120–60 59–30 29–15 < 15

Winearls CG, et al. (Lancet 1986; 2: 1175-8)

Eschbach JW, et al. (N Engl J Med 1987; 316:73-8)

Macdougall IC, et al. (Lancet 1990; 335: 489-93)

Macdougall et al., Lancet 1990; 335: 489-493.

0 2 4 6 8 10 12

6

8

10

12

14

Time (months)

Hb

(g

/dl)

EPO

Macdougall et al., Lancet 1990; 335: 489-493.

Mean baseline Hb = 6.3g/dl

Hb increment > 5g/dl

Strategies for treating renal anaemia

15

10

5

Time or creatinine

Prevention

Dialysis

Earlier start

Higher target

1990

19941998

2002

Hb (g/dl)

Anaemia therapy in CKD

Initially, Epoetin alfa (Eprex, Erypo) – 1990

Epoetin beta (NeoRecormon) – 1990

Epoetin alfaEpoetin beta

Anaemia therapy in CKD

Initially, Epoetin alfa (Eprex, Erypo) – 1990

Epoetin beta (NeoRecormon) – 1990

2nd generation ESA:-Darbepoetin alfa (Aranesp) – 2001

Epoetin alfaEpoetin beta

First extra N-linked

chain

Second extra N-linked

chain

Darbepoetin alfa: a molecule with two more N-linked glycosylation chains than r-HuEPO

Third-generation ESAs

C.E.R.A. (MIRCERA)Methoxy polyethylene glycol epoetin beta

– licensed 2007

C.E.R.A.

Continuous Erythropoietin Receptor Activator

PEGylated Epoetin beta

CERA EPO

Epoetin delta (DYNEPOTM)

Biosimilar EPOs

First biosimilar epoetins licensed in Europe

– BinocritTM (Sandoz)

– RetacritTM (Hospira)

Epoetin alfa (Eprex)

Epoetin beta (NeoRecormon)

Darbepoetin alfa (Aranesp)

C.E.R.A. (MIRCERA)

Epoetin delta (Dynepo)

Biosimilar Epoetin alfa (Binocrit)

Biosimilar Epoetin zeta (Retacrit)

Current licensed ESAs in Europe

IV half-lives of ESA therapy

100

10

1

0.1

0.01

0 12 24 36 48 days

Epoetin (TIW)Plasma ESA (ng/ml)

*estimated values based on 6000 IU epoetin / week

Simulation of EPO kinetics for short-acting ESAs vs longer-acting ESAs*

100

10

1

0.1

0.01

0 12 24 36 48 days

Epoetin (TIW)

Darbepoetin (QW)Plasma ESA (ng/ml)

*estimated values based on 6000 IU epoetin / week

Simulation of EPO kinetics for short-acting ESAs vs longer-acting ESAs*

100

10

1

0.1

0.01

0 12 24 36 48 days

Epoetin (TIW)

Darbepoetin (QW)

C.E.R.A. (QM)

Plasma ESA (ng/ml)

*estimated values based on 6000 IU epoetin / week

Simulation of EPO kinetics for short-acting ESAs vs longer-acting ESAs*

ESAs

Short-acting

Medium-acting

Long-acting

Dosing frequency

x2 or x3 / week

x1/wk or x1/2wks

x1/2wks or x1/mth

Outline of presentation

Erythropoiesis in 2009

ESA therapy

Target Hb

Iron management

Anaemia management in kidney transplantation

The future

                                       

               

Ofsthun et al, Kidney Int 2003; 63: 1908-1914.

Hb predicts survival in observational studiesHD patients

Hb predicts survival in observational studiesND-CKD patients

Levin A. et al, Nephrol Dial Transplant 2006; 21: 370-377.

Months from Hg Result

Pro

ba

bili

ty o

f S

urv

iva

l

Survival of CKD Patients by Hemoglobin Level

0 3 6 9 12 15 18 21 24 27 30 33 36

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Hemoglobin

>= 130 g/L

120-129 g/L

110-119 g/L

100-109 g/L

< 100 g/L Log-Rank Test: p =0.0001

US Normal Haematocrit Trial

Besarab A et al. N Engl J Med 339: 584-590, 1998.

Low-haematocrit group

Normal-haematocrit group

Pro

bab

ility

of

dea

th o

r M

I (%

)

Months after randomization

0 3 6 9 12 15 18 21 24 27 30

60

50

40

30

20

10

0

US Normal Haematocrit Trial- probability of death or first non-fatal MI

Besarab et al. NEJM 1998; 339: 584-90.

CREATE CHOIR

Primary endpointTime to first CV event (105 events)

Events: 58 vs 47HR=0.78 (0.53–1.14)Log rank test p=0.20

CHOIR Trial 125 vs 97 events;p < 0.03

Hb target ranges – the evidence

15

14

10

11

12

13

9

Hb

(g

/dl)

Sources:- – Lancet meta-analysis – K/DOQI Anemia Guidelines update

(evidence review by Boston Tufts University Evidence Rating Group)

Outline of presentation

Erythropoiesis in 2009

ESA therapy

Target Hb

Iron management

Anaemia management in kidney transplantation

The future

Why are CKD patients prone to develop iron deficiency?

Occult G-I losses

Peptic ulceration

Blood sampling

Dialyser losses

Concurrent meds.

– e.g. aspirin

Heparin on dialysis

INCREASED LOSSESREDUCED INTAKE

Poor appetite

Poor G-I absorption

Concurrent medication

– e.g. omeprazole

Food interactions

Iron metabolism

PLASMA

Iron stores

Ferritin

Serum iron/TIBC

TSAT

CHr% hypochromic RBC

Marrow stainable iron

Serum TfR

RBC ZPP

Minimum ranges:

Serum ferritin > 100 g/l

Hypochromic RBC < 10%

TSAT > 20%

Aim for :

Serum ferritin 200-500 g/l

Hypochromic RBC < 2.5%

TSAT 30-40%

Monitoring iron status

IV Iron Agents are Spheroid Particles with an IV Iron Agents are Spheroid Particles with an Iron Core and a Carbohydrate ShellIron Core and a Carbohydrate Shell

ironironoxyhydroxideoxyhydroxide

corecore

carbohydratecarbohydrateshellshell

DOPPS III: Type of IV Iron Prescribed in HD patientsP

ati

en

ts (

%)

DOPPS III data (2005-07), among prevalent cross-section of HD patients using IV iron.

2

99

62

99

100

9992

1

9

82 99

1

36

94

29

7 81

40

50

91 1 0.3 13 1 0.3 1

63

98

0

20

40

60

80

100

ANZ BE CA FR GE IT Jpn SP SW UK US

n = (393) (396) (333) (339) (419) (304) (566) (469) (449) (334) (1327)

- Sucrose

Fe-Oxide SaccharatePolymaltose Dextran

Chondroitin SO4

GluconateCideferronOther

Benefits of IV iron in CKD patients

IV iron can improve the anaemia of CKD even in the absence of ESA therapy

IV iron can significantly enhance the response to ESA therapy, even in iron-replete patients

Short-term

Anaphylactic reactions (iron dextran only; dextran Abs)

“Free iron” reactions (all IV iron preparations)

Potential dangers of IV iron ?

Long-term

Increased susceptibility to infection

Increased oxidative stress

Iron overload

Balance of benefits vs. risks of IV iron

Mortality risk

Oxidative

stress

Infection

risk

Anaphylaxis

Benefits of IV iron

Outline of presentation

Erythropoiesis in 2009

ESA therapy

Target Hb

Iron management

Anaemia management in kidney transplantation

The future

Y Vanrenterghem et al., For TRESAM, Am J Transplantation 2003

Hb < 12 g/dl : 28.4% Hb < 12 g/dl : 22.7%

Hb < 12 g/dl : 25.5% Hb < 12 g/dl : 24.4%

Overall 24.5 % were anaemic

n = 4263 - 76 centres, 16 countries

Prevalence of anaemia in European kidney transplant recipients

Hb < 11 g/dl Hb < 10 g/dl

Y. Vanrenterghem et al., for TRESAM, Am J Transplantation 2003.

Among 8.5% patients with severe anaemia, 18% were on EPO therapy

Prevalence of severe anaemia in Europe

Overall 8.5% with severe anaemia

Post-transplantation anaemia

Causes – iron deficiency – infections (CMV)– immunosuppresssive therapy– ACE-I / ARB therapy – impaired renal function ( EPO) – failing graft (pro-inflammatory cytokines)

ESA hyporesponsiveness in renal transplantation

Iron deficiency

Infection/inflammation

Underdialysis

Hyperparathyroidism

Aluminium toxicity Carnitine

deficiency PRCA

Blood loss

Haemolysis

B12/folate deficiency

Marrow disorders

Haemoglobinopathies

ACE inhibitors

Viral

(CMV, EBV, Parvovirus)

Malignancy

(e.g. lymphoma)

Immunosuppression

(Aza, MMF, SRL)

Outline of presentation

Erythropoiesis in 2009

ESA therapy

Target Hb

Iron management

Anaemia management in kidney transplantation

The future

Clin J Am Soc Nephrol, 2008

Hematide

EPO-mimetic peptide, now in Phase III clinical trials

Amino acid sequences completely unrelated to native EPO

Shows same functional / biological properties as EPO

What is different about Hematide?

Peptide-based (epoetin, darbepoetin, CERA – all protein-based)

Not genetically-engineered in cells (unlike epoetin, darbepoetin, CERA)

Manufactured by synthetic peptide chemical techniques

? More stable at room temperature

? less immunogenic

Does not cross-react with antibodies against EPO – should not cause PRCA; can be used to treat

Ab+PRCA

First ESA to be tested de novo once-monthly in CKD patients

Jak2Jak2P P

P P

EPO,rHuEPO

EPO-mimetic peptide

Darbepoetinalfa

membrane

C.E.R.A.Peg-rHuEPO

Signal Transduction

Survival, differentiation, proliferation, and maturation of RBC progenitors and precursors

Gene Activation

Jak2Jak2P P

P P

Jak2Jak2P P

P P

Jak2Jak2P P

P P

Anti-EPO antibodies do not neutralise Hematide

Anti-EPO Antibodies

58

Hematide in the Treatment of Antibody-Mediated Pure Red Cell Aplasia I C Macdougall et al, ASN 2007 (updated in 2008)

n = 13 13 13 11 11 10 9 8 7 8 6 7 7 6 6 7 6 6 6 6 6 6 6 6 6 5 6 6 5 4 3 2

(Data from three subjects were censored due to kidney transplantation)

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0000

10

20

30

40

50

60

BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

Study Months

Per

ce

nt

Pa

tien

ts R

ec

eiv

ing

RB

C T

ran

sfu

sio

ns

D

uri

ng

Ea

ch

Stu

dy

Mo

nth

8.0

9.0

10.0

11.0

12.0

13.0

14.0

Me

an

(SD

) Hb

Co

nc

entra

tion

(g/d

L)

HIF stabilisers

HIF is the hypoxic sensor that upregulates EPO gene expression

HIF is broken down by a prolyl hydroxylase enzyme

An inhibitor of HIF hydroxylase has been synthesised (FibroGen)

It causes an increase in EPO levels, even in CKD patients

Upside

This enzyme inhibitor is orally-active

Downside

>100 other genes (e.g. VEGF) also turned on Rare development of severe liver toxicity (may be fatal)

New IV irons pending…….

2 new IV irons forthcoming:-– Ferumoxytol (US)

– Ferric carboxymaltose – FerinjectTM (Europe)

Advantages – ? safer

– no need for test dose – more rapid high-dose

bolus injection – main benefits in the pre-ESRD population

Ferric carboxymaltose (Ferinject)

Licensed in Europe

Stable iron complex

Low immunogenic potential – dextran-free

Minimal detectable and releasable free iron

Ferric hydroxide molecules Ribbon-like carboxymaltose

No test dose required

Rapid administration

– 200mg push

– 500mg in 6 mins

– 1000mg infusion in 15 mins

Ganz, 2006.

Ganz, 2006.

Iron transport

Savino R, Ciliberto G. Cell Death Differ. 2004;11 Suppl 1:S2-4.

EPO: an all-purpose tissue-protective agent?

EPO therapy: beyond Hb

Mediated via the anti-apoptotic action of EPO on non-erythroid cells

Relevant for acute cardiac, renal, and cerebral ischaemia

? Therapeutic benefit in :-– Acute MI

– Acute stroke– Reperfusion injury

– Post-transplantation

Conclusions

Our understanding of erythropoiesis in 2009 has advanced to include the role of hepcidin and pro-inflammatory cytokines

Until further evidence is forthcoming, we should generally target an Hb of 11–12 g/dl

Even in 2009, there is still a need for additional grade A level evidence in the management of anaemia in CKD

Several new ESAs and IV iron preparations are appearing, and the non-erythropoietic effects of ESAs are being explored