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
Development of renal anaemia prior to
the availability of EPO therapy
Hb (g/dL)
15
10
5
CKD stages 1–2
Stage
3
Stage
4
120–60
59–30
29–15
Dialysis
Stage
5
< 15
Declining GFR (mL/min)
NHANES data
Erythropoiesis
in CKD
in 2009
Erythropoiesis
in CKD
Erythropoietin
SCF, IL-1, IL-3,
IL-6, IL-11
Iron
SCF, GM-CSF,
IL-3
About 8 Days
Pluripotent
Stem Cell
Burst-Forming Colony-Forming ProerythroUnit-Erythroid Unit-Erythroid
blasts
Cells (BFU-E)
Cells (CFU-E)
Erythroblasts
Reticulocytes
RBCs
Papayannopoulou T, et al. In: Hoffman R, et al., ed. Hematology: Basic
Principles and Practice. 4th ed. 2005;267-288.
Erythropoiesis in CKD in 2009
+
+
 Fas Ag
 EPO production
Iron
EPO
─
Pro-inflammatory
cytokines
(IL-1, TNFα, IL-6, IFNγ)
hepcidin
Apoptosis
─
 Fe absorption
 Fe transport
 Fe availability
(EPO-R, Tf, TfR,
Ferriportin, DMT-1)
Anti-Anaemic therapies in CKD
Erythropoietin
SCF, IL-1, IL-3,
IL-6, IL-11
Iron
SCF, GM-CSF,
IL-3
About 8 Days
Pluripotent
Stem Cell
Burst-Forming Colony-Forming ProerythroUnit-Erythroid Unit-Erythroid
blasts
Cells (BFU-E)
Cells (CFU-E)
Erythroblasts
Reticulocytes
RBCs
Papayannopoulou T, et al. In: Hoffman R, et al., ed. Hematology: Basic
Principles and Practice. 4th ed. 2005;267-288.
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)
Development of renal anaemia prior to
the availability of EPO therapy
Hb (g/dL)
15
10
Winearls CG, et al. (Lancet
Eschbach JW, et al.
1986; 2: 1175-8)
(N Engl J Med 1987; 316:73-8)
Macdougall IC, et al. (Lancet
1990; 335: 489-93)
5
CKD stages 1–2
Stage
3
Stage
4
120–60
59–30
29–15
Declining GFR (mL/min)
Dialysis
< 15
Stage
5
Macdougall et al., Lancet 1990; 335: 489-493.
14
Hb (g/dl)
12
10
Hb increment > 5g/dl
8
Mean baseline Hb = 6.3g/dl
6
EPO
0
2
4
6
8
10
12
Time (months)
Macdougall et al., Lancet 1990; 335: 489-493.
Strategies for treating renal anaemia
Hb (g/dl)
15
Prevention
Higher
target
2002
1998
1994
10
Earlier
start
1990
5
Dialysis
Time or creatinine
Anaemia therapy in CKD
 Initially,
Epoetin alfa (Eprex, Erypo) – 1990
Epoetin beta (NeoRecormon) – 1990
Epoetin alfa
Epoetin beta
Anaemia therapy in CKD
 Initially,
Epoetin alfa (Eprex, Erypo) – 1990
Epoetin beta (NeoRecormon) – 1990
 2nd generation ESA:Darbepoetin alfa (Aranesp) – 2001
Epoetin alfa
Epoetin beta
Darbepoetin alfa: a molecule with two more
N-linked glycosylation chains than r-HuEPO
First extra
N-linked
chain
Second extra
N-linked
chain
Third-generation ESAs
C.E.R.A. (MIRCERA)
Methoxy polyethylene glycol epoetin beta
– licensed 2007
C.E.R.A.
 Continuous Erythropoietin Receptor Activator
CERA
 PEGylated Epoetin beta
EPO
Epoetin delta (DYNEPOTM)
Biosimilar EPOs
 First biosimilar epoetins licensed
in Europe
– BinocritTM (Sandoz)
– RetacritTM (Hospira)
Current licensed ESAs in Europe
 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)
IV half-lives of ESA therapy
Simulation of EPO kinetics for short-acting
ESAs vs longer-acting ESAs*
Epoetin (TIW)
Plasma ESA (ng/ml)
100
10
1
0.1
0.01
0
12
24
*estimated values based on 6000 IU epoetin / week
36
48 days
Simulation of EPO kinetics for short-acting
ESAs vs longer-acting ESAs*
Epoetin (TIW)
Darbepoetin (QW)
Plasma ESA (ng/ml)
100
10
1
0.1
0.01
0
12
24
*estimated values based on 6000 IU epoetin / week
36
48 days
Simulation of EPO kinetics for short-acting
ESAs vs longer-acting ESAs*
Epoetin (TIW)
Darbepoetin (QW)
C.E.R.A. (QM)
Plasma ESA (ng/ml)
100
10
1
0.1
0.01
0
12
24
*estimated values based on 6000 IU epoetin / week
36
48 days
ESAs
Short-acting
Dosing frequency
x2 or x3 / week
Medium-acting
x1/wk or x1/2wks
Long-acting
x1/2wks or x1/mth
Outline of presentation

Erythropoiesis in 2009

ESA therapy

Target Hb

Iron management

Anaemia management in kidney transplantation

The future
Hb predicts survival in observational studies
HD patients
Ofsthun et al, Kidney Int 2003; 63: 1908-1914.
Hb predicts survival in observational studies
ND-CKD patients
Survival of CKD Patients by Hemoglobin Level
1.00
Hemoglobin
P ro b a b ility o f S u rviva l
0.95
>= 130 g/L
0.90
120-129 g/L
0.85
110-119 g/L
0.80
< 100 g/L
Log-Rank Test: p =0.0001
0.75
100-109 g/L
0.70
0
3
6
9
12
15
18
21
24
27
30
33
36
Months from Hg Result
Levin A. et al, Nephrol Dial Transplant 2006; 21: 370-377.
US Normal Haematocrit Trial
Besarab A et al. N Engl J Med 339: 584-590, 1998.
US Normal Haematocrit Trial
- probability of death or first non-fatal MI
60
Normal-haematocrit group
50
40
Low-haematocrit group
30
20
10
0
0
3
6
9
12
15
18
21
24
27
30
Months after randomization
Besarab et al. NEJM 1998; 339: 584-90.
CREATE
CHOIR
Primary endpoint
Time to first CV event (105 events)
Events: 58 vs 47
HR=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
Sources:– Lancet meta-analysis
– K/DOQI Anemia Guidelines update
(evidence review by Boston Tufts University Evidence Rating Group)
15
Hb (g/dl)
14
13
12
11
10
9
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?
REDUCED INTAKE
INCREASED LOSSES
 Poor appetite
 Occult G-I losses
 Poor G-I absorption
 Peptic ulceration
 Concurrent medication
 Blood sampling
– e.g. omeprazole
 Food interactions
 Dialyser losses
 Concurrent meds.
– e.g. aspirin
 Heparin on dialysis
Iron metabolism
PLASMA
Iron
stores
Monitoring iron status
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%
IV Iron Agents are Spheroid Particles with an
Iron Core and a Carbohydrate Shell
iron
oxyhydroxide
core
carbohydrate
shell
DOPPS III: Type of IV Iron Prescribed in HD patients
Polymaltose Other
100
3
Dextran
1
1
Fe-Oxide
Saccharate
Cideferron
1
7
0.3
1
9
1
1
Gluconate
8
29
36
Patients (%)
80
9
50
60
94
99
1
99
82
99
99
98
92
40
63
62
20
0
- Sucrose
40
10
1
2
ANZ
n = (393)
BE
CA
FR
GE
0
IT
(396)
(333)
(339)
(419)
(304)
Jpn
SP
SW
UK
US
(566)
(469) (449)
(334)
(1327)
Chondroitin SO4
DOPPS III data (2005-07), among prevalent cross-section of HD patients using IV iron.
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
Potential dangers of IV iron ?
Short-term
Anaphylactic reactions (iron dextran only; dextran Abs)
“Free iron” reactions (all IV iron preparations)
Long-term
Increased susceptibility to infection
Increased oxidative stress
Iron overload
Balance of benefits vs. risks of IV iron
Outline of presentation

Erythropoiesis in 2009

ESA therapy

Target Hb

Iron management

Anaemia management in kidney transplantation

The future
Prevalence of anaemia in European kidney
transplant recipients
Hb < 12 g/dl : 28.4%
Hb < 12 g/dl : 22.7%
Overall 24.5 % were anaemic
Hb < 12 g/dl : 25.5%
n = 4263 - 76 centres, 16 countries
Hb < 12 g/dl : 24.4%
Y Vanrenterghem et al., For TRESAM, Am J Transplantation 2003
Prevalence of severe anaemia in Europe
Overall 8.5% with severe anaemia
Hb < 11 g/dl
Hb < 10 g/dl
Among 8.5% patients with severe anaemia, 18% were on EPO therapy
Y. Vanrenterghem et al., for TRESAM, Am J Transplantation 2003.
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
Anti-EPO antibodies do not neutralise Hematide
EPO,
rHuEPO
Darbepoetin
alfa
C.E.R.A.
EPO-mimetic
peptide
Peg-rHuEPO
Anti-EPO
Antibodies
membrane
P
Jak2
Jak2
P
P
P
P
Jak2
Jak2
P
P
P
P
Jak2
Jak2
P
P
P
P
Jak2
Jak2
P
P
P
Signal
Transduction
Gene Activation
Survival, differentiation,
proliferation, and maturation of
RBC progenitors and precursors
Hematide in the Treatment of Antibody-Mediated Pure Red Cell Aplasia
60
14.0
50
13.0
40
12.0
30
11.0
20
10.0
10
9.0
0
0
0
8
9
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
8.0
BL
1
2
3
4
5
6
7
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
n = 13
13 13
11
11
10
9
8
7
8
6
7
7
6
6
7
6
(Data from three subjects were censored due to kidney transplantation)
58
6
6
6
6
6
6
6
6
5
6
6
5
4
3
2
Mean (SD) Hb Concentration (g/dL)
Percent Patients Receiving RBC Transfusions
During Each Study Month
I C Macdougall et al, ASN 2007 (updated in 2008)
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)
 Ferric hydroxide molecules
 Ribbon-like carboxymaltose
 Licensed in Europe
 Stable iron complex
 Low immunogenic potential – dextran-free
 Minimal detectable and releasable free iron
 No test dose required
 Rapid administration
– 200mg push
– 500mg in 6 mins
– 1000mg infusion in 15 mins
Ganz, 2006.
Ganz, 2006.
Iron transport
EPO: an all-purpose tissue-protective agent?
Savino R, Ciliberto G. Cell Death Differ. 2004;11 Suppl 1:S2-4.
EPO therapy: beyond Hb

Mediated via the anti-apoptotic action of EPO on nonerythroid 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