1. Healthcare

CIN 2011
6th Congress of Nephrology
in Internet
Erythropoiesis stimulating
agents in Chronic Kidney
Disease
Holger Schmid
KfH Nierenzentrum Muenchen – Laim, Munich, Germany
and
Department of Internal Medicine,
Medicine, University Hospital Munich –
Downtown Campus , University of Munich, Munich, Germany
Erythropoiesis stimulating agents in
Chronic Kidney Disease
-Outline
Outline-► Anemia
in CKD: pathogenesis and
consequences
► Treatment: ESAESA-classes, strategies and
target Hb levels
► Risks of ESA use
► ESA hyporesponsiveness
► Challenges in clinical research
► Conclusions
Abbreviations
►
►
►
►
►
►
►
►
►
►
►
►
►
►
►
►
CAD
CAPD
CHF
CKD
CV
EPO
ESA
ESRD
Hb
Hct
HD
HIF
LVH
PRCA
QOL
rHU EPO
coronary artery disease
continuous ambulatory peritoneal dialysis
congestive heart failure
chronic kidney disease
cardiovascular
erythropoietin
erythropoiesis stimulating agents
endend-stage renal disease
hemoglobin
hematocrit
hemodialysis
hypoxia inducible factor
left ventricular hypertrophy
pure red cell aplasia
quality of life
recombinant human erythropoietin
Anemia in CKD
► Prevalence
of anemia in CKD depends on severity
of renal insufficiency and definition
►
WHO definition of anemia
► Hb
< 13.0 g/dl for adult men and postmenopausal women
► Hb < 12.0 g/dl for pre
pre--menopausal women
► Predominantly
normocytic and normochromic
► At every CKD stage: Higher prevalence and more
pronounced severity of renal anemia in diabetic
compared to nonnon-diabetic patients
Anemia in CKD: Pathogenesis
► Human
Erythropoietin (EPO)
circulating 30.4 kDa glycoprotein growth factor (165 amino acids)
acts as primary stimulus to erythropoiesis
promotes terminal differentiation of erythroid progenitor (CFU(CFU-E)
into normoblasts and then erythrocytes
inhibits apoptosis of erythroid progenitors
produced primarily by peritubular interstitial cells in kidney`s deep
cortex and outer medulla (liver with only a minor contribution!)
► Anemia
predominantly due to reduced
erythropoietin production and only to a lesser
degree due to shortened red cell survival
► Reduced availability of iron and chronic
inflammation frequent contributory factors
Anemia in CKD: Pathogenesis
► Almost
all CKD patients without iron deficiency,
inflammation or infection, have an appropriate
erthyropoietic response to exogenous EPO
→ uraemic inhibition of erythropoiesis plays a
minor role in pathogenesis of renal anemia
► Other anemia forms may coexist in CKD
iron-, folate
ironfolate--, and vitamin B12
B12-- deficiency
chronic blood loss from gastrointestinal tract, blood
drawing, HD technique
Anemia in CKD: Consequences
►
►
►
►
►
►
Reduced oxygen delivery to tissues
→ adverse impact on organ function (particularly in patients with chronic
organ dysfunction)
Increased risk for
faster progression of renal failure
ischemic adverse events in patients with CHF or CAD
Reduced brain and cognitive function
Reduced quality of life
Increased LVH and left ventricular dilatation
NOTE:
Although a number of observational studies have associated anaemia
in CKD with an increased risk of death to date no prospective studies
have rigorously proven that renal anemia causes an increase in
mortality in patients with CKD
Anemia in CKD: Treatment in the
PrePre-ESA Era
► Androgens
Increase endogenous erythropoietin production,
sensitivity of erythroid progenitors to EPO effects and
prolong red blood cell survival
Side effects: virilisation, liver function test abnormalities,
increased risk of hepatocellular carcinoma !
► Red
blood cell transfusions
transfusions
Rapid raise of Hb levels and amelioration of symptoms
in ESRD
Significant complications: transfusiontransfusion-transmitted
infection, immunologic sensitization, iron overload
syndromes, volume overload and /or transfusion
reactions !
Anemia in CKD: ESA Treatment
►
rHu EPO
Produced by gene transfer into suitable mammalian cell lines
(e.g. Chinese hamster ovary cells)
Approved in 1989 by FDA for treatment of anemia associated
with CKD
NOTE: EPO is a generic term that encompasses all genetically
produced forms of erythropoietin
►
Currently available and future forms of erythropoietic agents for
treatment of ESRD
Unmodified recombinant rhu EPOs (“short(“short-acting”)
Long--acting ESAs
Long
EPO analogues (Biosimilar EPOs)
Investigational ESAs
Anemia in CKD: ESA Treatment
Unmodified recombinant rhu EPOs (“short-acting”) and Long-acting ESAs
ESA--Class
ESA
ESA
-Type
Mol.
Weight
(KDa)
Serum half
life (h) /
administration
route
BioavaiBioavailability (%)
Periodicity
Unmodified
Recombinant
Rhu EPOs
(“Short-(“Short
Acting”)
Epoetin
alfa
32
32--40
8.8 / i.v.
24
24..2 / s.c.
30
30--36
1-3 times/wk
6.8 / i.v.
19
19..4 / s.c.
23
23--42
1-3 times/wk
Epoetin
beta
Epoetin
omega
Epoetin
delta
LongLongActing
ESAs
DarbDarbEpoetin
alpha
40
25 / i.v.
49 / s.c.
37
Every 1-2 wk
C.E.R.A.
60
133 / i.v.
137 / s.c.
47
47--52
Every 2-4 wk
Anemia in CKD: ESA Treatment
EPO analogues (“Biosimilar” EPOs) and Investigational ESAs
ESA--Class
ESA
ESA
ESA-Type
Mol.
Weight
(KDa)
Serum half life
(h)/
administration
route
BioavaiBioavailability (%)
PerioPeriodicity
EPO
analogues
(Biosimilar
EPOs)
Epoetin alfa
?
n.a.
?
1-3
times/wk
Epoetin zeta
30
30..6
4-5 / i.v.
24 / s.c.
n .a .
1-3
times/wk
Synthetic, peptidepeptide- n.a.
based
erythropoietin-erythropoietin
receptor agonists
14
14--60 / p.o.
n .a .
Every
4 wks
Prolyl hydroxylase n.a.
inhibitors
(HIF stabilizers)
7-8 / p.o.
>75
Clinical
Trials
stopped
by FDA !
InvestigaInvestigational ESAs
Epoetin Biosimilars
►
►
►
Biosimilars = “follow“follow-on biologics”
Developed as consequence of patent expirations for rHU EPO
European Medicines Agency definition
“a biological medicinal product referring to an existing one and
submitted to regulatory authorities for marketing authorization by an
independent applicant after the existing agents' protection expires.
Biosimilars can resemble the agents on which they are modeled but
cannot fully copy their properties”. (Locatelli F. Oncologist 2009)
►
►
►
Rapidly increasing number worldwide (except in the United States of
North America)
Should provide cost savings and greater accessibility
NOTE:
Inherent differences may produce dissimilarities in clinical efficacy, safety
and immunogenicity as compared to the innovator rHU EPO
More thorough knowledge of biosimilars needed to ensure appropriate use
of these drugs
Investigational ESAs
►
Hematide
Synthetic peptidepeptide-based erythropoietin receptor agonist with no
structural homology to erythropoietin
Activates erythropoietin receptor and stimulates erythropoiesis
(Macdougall IC Curr Opin Inv Drugs 2008)
►
HIF (Hypoxia
(Hypoxia--inducible factor) stabilizers
Orally active antianemic therapies
Competitive inhibitors of HIF prolylprolyl-hydroyxlases and asparagyl
asparagyl-hydroxylase enzymes
Involved in the metabolisms of HIF and its transcriptional activity
Increase endogenous EPO production by preventing proteasomeproteasomemediated HIF degradation
Examples: prolyl hydroxylase inhibitors FGFG-2216 and FG
FG--4592
NOTE:
FDA has suspended any further clinical trials with HIF stabilizers, as a
female patient developed fatal hepatic necrosis temporally related to
the introduction of FGFG-2216
Recommended Target Hb levels
Target/dosage
EBPG II 2004
KDOQI 2006
Authors
recommendation
Definition of Anemia
by Hb (g/dl)
< 12.
12.0 males
< 11
11..5 females
< 13.
13.5 males
< 12.
12.0 females
n.a.
Target Hb (g/dl)
> 11
11..0;
Hb > 14.
14.0 not desirable
in HD patients
11
11..0 – 12.
12.0;
caution
when
maintaining Hb >13
13..0
10
10..5 – 12
12..0;
avoid Hb >13
13..0
Target Iron Status
TSAT (%)
Ferritin (ng/ml)
TSAT: lower limit 20,
TSAT:
20,
target 3030-50
Ferritin:: lower limit 100,
Ferritin
100,
target 200200-500
TSAT: n.a.
TSAT:
Ferritin:: lower limit 200
Ferritin
200,,
>500
not
routinely
recommended
TSAT: ≥ 20
TSAT:
Ferritin:: lower limit 200
Ferritin
200,,
target 300300-500,
500, >800
not recommended
Recommended EPO
starting dose
5050-150 IU/kg per wk
(≈ 4000
4000--8000 IU per
wk)
no specifically starting
dose, but individualized
dosing recommended
100-125 IU/kg per wk
100(≈ 9000 IU per wk)
Definition of large EPO
requirement
300 IU/kg per wk
(≈ 20.
20.000 IU per wk)
450 IU/kg per wk i.v.
(≈ 30.
30.000 IU per wk)
375 IU/kg per wk
(≈ 24
24..000 IU per wk)
adapted from Schmid H. et al. Cardiovasc Hematol Agents Med Chem. 2010
NOTE: KDIGO Clinical Practice guideline for Anemia expected in early 2012
ESA intervention in CKD
Selection of randomized controlled trials
►
Besarab et al
al.. NEJM 1998 Normal Haematocrit trial
Patients:: 1233
Patients
1233,, ESRD treated with HD + clinical evidence of CHF or IHD
Study Design
Design,, arms /primary endpoint:
endpoint: iv / sc Epoetin alfa;
alfa; High:
High: target
Hct 42 ± 3 (≈ Hb 14
14)); Low:
Low: target Hct 30 ± 3 (≈ Hb 10
10)); EP:
EP: composite of
death and 1st non
non--fatal MI (time to 1st event)
Main Results:
Results: Study terminated early (futility, safety concerns)
concerns);; more
patients in the higher arm reached the endpoint (n
(n..s.); physical function
score increased with Hct;
Hct; incidence of vascular access thrombosis higher in
high arm (243 vs.
vs. 176;
176; р=
р=0
0.001)
001)
►
Singh et al
al.. NEJM 2006 CHOIR
Patients:: 1432
Patients
1432,, eGFR 15
15--50
50,, Hb < 11
Study Design
Design,, arms /primary endpoint:
endpoint: sc Epoetin alfa:
alfa: High:
High: target Hb
11..3: EP:
EP: composite of 4 CV events (time to 1st event)
13
13..5; Low:
Low: target Hb 11
Main results:
results: Study terminated early (futility, safety ?)
?);; more patients in the
higher arm had at least one CV event;
event; no improvement in QOL;
QOL; trend
towards a higher rate of progression to RRT in high arm
ESA intervention in CKD
Selection of randomized controlled trials
►
Drüeke et al. NEJM 2006 CREATE
Patients: 603, eGFR 1515-35, Hb 1111-12.5
Study Design,
Design, arms /primary endpoint: sc Epoetin beta; High:
High: target
Hb 13.013.0-15.0;
15.0; Low:
Low: when Hb < 10.5→
10.5→ target 10.510.5-11.5; EP:
EP: composite of
8 CV events (time to 1st event)
Main Results:
Results: No difference in primary EP;
EP; improvement in QOL;
QOL; time to
dialysis shorter in higher arm
►
Pfeffer et al
al.. NEJM 2009 TREAT
Patients:: 4038
Patients
4038,, CKD not undergoing HD + type 2 diabetes + anemia
Study Design
Design,, arms /primary endpoint:
endpoint: sc darbepoetin alfa;
alfa; High:
High: Hb
13
13..0; Low:
Low: rescue when < 9.0; EP:
EP: composite outcomes of death or 4 CV
events and of death or ESRD
Main Results:
Results: No difference in primary EP:
EP: only modest improvement in
QOL;; Darbepoetin alfa rescue associated with increased risk of stroke
QOL
(р<
(р<0
0.001)
001); nonsignificant trend towards cumulation of cancercancer-related
adverse events in darbepoetin alfa group (6.9% vs.
vs. 6.4%, p=
p=0
0.53
53))
ESA intervention in CKD
summary
► Quality
Quality--ofof-life
improvements maximize in target
Hb 10–
10–12 g/dl (Palmer SC Annals of Int Med 2010)
► Following the findings of TREAT
→ Second position statement/paper of the
European Renal Best Practice (ERBP) Anemia
Working Group (Locatelli F et al. NDT 2010)
'Hb values of 1111-12 g/dL should be generally sought in
the CKD population without intentionally exceeding 13
g/dL'
doses of ESA therapy to achieve target Hb should also
be considered
Important risks of ESA use
► Hypertension
► Thrombosis
► Anti
Anti--EPO
antibody mediated pure red cell
aplasia (PRCA)
► ESA
ESA--associated Tumor progression
ESA--induced Hypertension
ESA
► In
25--35 % of rHu EPO treated patients,
25
particularly in those with use of titration doses
► Additional antihypertensive therapy often
required, but discontinuitation of rHU EPO
normally not needed
(Exceptional case: hypertensive encephalopathy!)
► aetiology incompletely understood
► probably multifactorial
► NOTE: attaining a normal haemoglobin does not
confer an added risk for hypertension
ESA--induced Thrombosis
ESA
►
►
ESA treatment increases hematocrit and blood viscosity
→ increased risk for vascular or graft thrombosis
United States Normal Haematocrit trial
(Besarab et al. NEJM 1998, 1233 HD patients)
Higher incidence of access thrombosis with normal Hb levels
►
►
►
rHU EPO treatment associated with increased thrombosis
events in arteriovenous grafts but not in fistulas
(Churchill DN et al. JASN 1994)
NOTE:
Smaller studies did not report an increased incidence of
access thrombosis!
Increase in thrombotic events has been noted in patients
with malignancy who have received ESA
ESA--induced PRCA
ESA
►
►
►
Associated with profound fall in Hb level and reticulocyte count
Diagnosis
bone marrow aspirate with demonstration of severe erythroid
hypoplasia
Anti--EPO antibodies demonstrated by radioimmunoprecipitation
Anti
assay (higher sensitivity and specifity than ELISA)
PRCA management
Transfusions for symptomatic anemia and ESA discontinuation
Immunosuppressive therapy (corticosteroids ± i.v. immunoglobulins,
corticosteroids + oral cyclophophamide or cyclosporine alone)
s.c. injection of hematide
NOTE:
NOTE:
Optimal duration of therapy and subsequent monitoring for antiantiEPO antibody mediated PRCA currently unknown!
ESA--induced Tumor progression
ESA
►
►
►
Cancer patients
Observational trials showed more rapid cancer progression and
reduced survival in ESA treated patients (e.g. head and neck
cancer, breast cancer patients)
Renal patients
no evidence that treatment of renal anemia results in higher rates
of malignant tumors
stable cancercancer-specific one
one--year death rates among prevalent HD
patients from 1991 to 2005, arguing for no increase since ESA
introduction in 1989
NOTE:
TREAT study (Pfeffer et al. NEJM 2009) revealed a nonsignificant trend
towards cumulation of cancercancer-related adverse events in the
darbepoetin alfa group (6.9% vs. 6.4%, p=0.53)!
ESA hyporesponsiveness
►
►
Definition:
Definition:
(i) requirement of excessive doses during initiation of ESAESAtherapy, or
(ii) inability to achieve or maintain target Hb levels of 11
g/dl despite large EPO doses in ironiron-replete patients
Recommendations to achieve HB of 10 - 11 g/dl
NKF-DOQI Clinical Practice Guidelines
NKFGuidelines::
450 U/kg/wk i.v. EPO or 300 U/kg/wk s.c. EPO
revised European Best Practice Guidelines
Guidelines::
300 U/kg/wk EPO (~ 20
20..000 U/wk) or 1.5 mcg/kg/wk
darbepoetin alfa (~ 100 mcg/wk)
►
NOTE: Despite high doses of ESA approximately 5 - 10 %
NOTE:
of ESRD patients show a less than satisfactory response
ESA hyporesponsiveness
►
Major causes of EPO resistance
iron deficiency, infection or inflammation, underdialysis
Self--administering patients: poor adherence
Self
Exclude Vitamin B12, folate, thyroxin deficiency and severe
hyperparathyroidism
Aluminum toxicity no longer significant cause of partial ESA
resistance
►
►
►
Depending on ethnic origin hemoglobinopathy should be
excluded by Hb electrophoresis
Some patients on ACE inhibitors/angiotensin II Receptor
antagonists may require higher ESA doses
NOTE: Primary bone marrow disorders should be
investigated by bone marrow investigation only if all other
causes have been excluded
Challenges in clinical research
► Large
Large--scale
randomized clinical trials
comparing anemia management strategies
to assess safety, efficacy, and cost ?
► Do ESA doses rather than targeted Hb itself
mediate increased risk for adverse vascular
outcomes in ESRD ?
► Influence of fixed ESA doses and frequency
of ESA administration ?
Challenges in clinical research
► Evaluation
of ESA responsiveness and Hb variability
in association with mortality: is the degree of
hematopoietic responsiveness to ESA treatment
and not Hb target critical ?
► Contribution of Hepcidin to severity of anemia and
resistance to ESAs ?
► Candidate biomarkers for ESAESA- hyporesponders ?
► Impact of pharmacological interventions targeted
to prevent or reduce LVH in anemic or hypertensive
CKD patients ?
Challenges in clinical research
► Harm
associated with more intensive ESA
dosing due to higher Hb, higher ESA doses
or both ?
► Contribution of intrinsic disease (coexisting
illness, glycemic control in diabetic patients)
or extrinsic factors ?
► More individualized ESAESA-treatment
strategies needed ?
Conclusions I
► ESAs
have become the mainstay of anemia
treatment in ESRD
► Traditional recombinant human erythropoietin,
second generation erythropoietin analogues
including darbepoetin alfa and C.E.R.A. as well as
"biosimilar" erythropoietins currently available
► Search goes on for orally active antianaermic
drugs
► In ESRD observational studies revealed a strong
positive correlation between severity of anemia
and risk of poor outcome
Conclusions II
►
►
►
►
►
In ESRD correction of renal anemia under ESA treatment
reduced morbidity, mortality and hospitalization
Integration of ESA and i.v. iron therapy into standard
anemia management resulted in target Hb levels in vast
majority of ESRD patients
Optimal Hb target, dosing algorithm, and monitoring
approach for anemic ESRD patients currently unclear
Mortality data suggest that treating CKD patients to a Hb
level >13 g/dl can be harmful
Target Hb levels of 1010-12 g/dl seem reasonable, but
increasing ESA doses in hyporesponsive patients to achieve
a specific target is not
Conclusions III
►
►
►
►
►
Each patient should be treated according to a Hb target
with the lowest effective ESA dose
Avoid large fluctuations in Hb levels or prolonged periods
outside the Hb target
Most important complications in ESA treated patients are
hypertension, thrombosis, and PRCA
Despite great success of ESAs in clinical practice, ESAESAresistance and ESAESA-hyporesponsiveness are common
clinical problems
Large--scale randomized clinical trials comparing anemia
Large
management strategies are urgently needed, as adaption
of the Framingham approach seems not feasible in the
CKD patient