Transcript Hb (g/dL)
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