Eprex Market Research

1
OPTA Education Initiative
OPTA Optimal Treatment of Renal
Anaemia Improving the Efficacy and Efficiencyof
Renal Anaemia Therapy
2
OPTA Rationale

• European Best Practice Guidelines and KDOQI
  Guidelines provide scientific evidence on
  optimal treatment of renal anaemia.
• European Surveys of Anaemia Management (ESAM I
  II,PRESAM, TRESAM) and Dialysis Outcomes and
  Practice Patterns Study (DOPPS) demonstrate
  relevant gaps between standards of care of
  anaemia treatment and daily practice.
• OPTA aims to transfer standards of care into
  daily practice and to optimise efficacy and
  efficiency of anaemia therapy by focusing on
  major and minor factors influencing treatment of
  renal anaemia.

3
Content

• Diagnosis and start of anaemia treatment
• Impact of anaemia in patients with chronic kidney
  disease
• Patient categorisation within stages of chronic
  kidney disease
• Treatment of anaemia in patients with chronic
  kidney disease
• Effects of epoetin therapy at a cellular level

4
Diagnosis and Start of Anaemia Treatment

• Reasons for delayed start of anaemia treatment
• In early stage of CKD anaemia is non-symptomatic,
  patients adapt to declining Hb-levels
• Under estimation that modest decreases in renal
  function lead to a decrease in Hb levels
• Late referral of patients with chronic kidney
  disease
• Late initiation of treatment

5
Epidemiology of Anaemia associated with Chronic
Renal Insufficiency
15.5
14.5
men
13.5
Haemoglobin mg/dl
12.5
women
11.5
10.5
gt80
7080
6070
5060
4050
3040
2030
lt20
Creatinine Clearance ml/min
Hsu et al., J Am Soc Nephrol 200013504510.
6
Prevalence of Anaemia by Glomerular Filtration
Rate
Relation kidney function haemoglobin
levelThird National Health and Nutrition
Examination Survey (19881994)
men
15
14
women
13
13
12
Haemoglobin g/dl
11
10
9
8
7
30
60
90
Creatinine Clearance ml/min
Astor BC et al., Arch Intern Med
200216214011408.
7
Prevalence of Anaemia by Serum Creatinine and
Glomerular Filtration Rate
100
Hb 10 g/dL Hb gt10 12 g/dL Hb 12 g/dL
80
13
60
Patients
40
20
0
1.6 lt2
2.5
30 lt60
lt15
Serum creatinine mg/dL
GFR mL/min/1,73 m2
McClellan W et al., Curr Med Res Opin
200420(9)15011510.
8
Diagnosis of Anaemia Recommendation

• Patients should receive a work-up for anaemia
• when creatinine clearance falls below
• 70 ml/min in man
• 50 ml/min in women
• when Hb-level falls below
• 11.5 g/dl in adult female patients1
• 13.5 g/dl in adult male patients1
• 12 g/dl in adult male patients aged gt 701
• 11g/dl in pre-pubertal subjects and
  pre-menopausal females2
• 12 g/dl in adult males and post-menopausal
  females2

1 Revised EBPGs, NDT 200419. 2 K/DOQI, Am J
Kidney Dis 200137.
9
Impact of Anaemia in CKD-Patients on

• Cardiovascular events/LVH
• Quality of life (ability to work, exercise
  capacity)
• Hospitalisations
• Impact on mortality
• Progression of chronic kidney disease

10
Impact of Anaemia in CKD-Patients

• Cardiovascular events/LVH
• Anaemia is independently associated with
  cardiovascular complications and the development
  of LVH.
• Hospitalisation
• Anaemia early in ESRD is associated with a
  greater rate of subsequent hospitalisations
• Quality of life
• Anaemia is associated with a reduction in
  quality of life, exercise capacity and cognitive
  function.

Levin A et al., Am J Kidney Dis
199627347354. Roger SD, et al. J Am Soc
Nephrol 200415148156. Xia H et al., J Am Soc
Nephrol 19991013091316.
11
Impact of Anaemia in CKD-Patients Regression
of Left Ventricular Hypertrophy
Canadian/Australian multicentre trial
development of LVH
120 115 110 105 100
Hb 1213 g/dL (n75) Hb 910 g/dL (n80)
P0.019
LVMi g/m2
1-year
initial
2-year
Roger SD et al. J Am Soc Nephrol 200415148156.
12
Impact of Anaemia in CKD-Patients
Hospitalisation
Hospitalisation risk (Cox proportional hazard
model)
1.4 1.2 1.0 0.8 O.6
(n71.717)
Hospitalization risk
lt27
30 lt33 Baseline
27 lt30
33 lt36
36
Haematocrit
Patients with Hct levels lt30 had a 7 (with
severity of disease adjustment) and 31
(withoutseverity of disease adjustment)
increased risk of hospitalization compared with
the Hct groupof 30 33. Higher Hct levels of
33 36 were associated with reproducible
lowerhospitalization risks.
Xia H et al., J Am Soc Nephrol 19991013091316.
13
Impact of Anaemia in CKD-Patients Impact on
Mortality
Variations in risk of mortality for different
haematocrit values stratified into quintiles and
for erythropoietin use within the quintiles (n
4,866)
Risk of death associated with haematocrit
stratified into quintiles
Risk of death associated with EPO use within
haematocrit quintiles
Haematocrit in Quintiles
lt23.1
1.00
0.76
23.1-26.2
0.96
0.79
26.3-28.7
1.13
1.02
28.8-31.8
1.12
0.81
gt31.8
1.02
0.67
Missing haematocrit value
1.30
1.06
Fink JC et al., Am J Kidney Dis 200137348355.
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Impact of Anaemia in CKD-Patients Impact on
Mortality
Kaplan-Meier plots show survival of new end-stage
renal disease patients in Network 5 treated with
EPO before the initiation of dialysis versus
patients who were not treated. Histograms
represent risk of mortality associated with EPO
use within 3 tertiles of follow-up after starting
dialysis 019.3 month, 19.431.4 month and
31.5 month.
100
2.0
plt0.05
1.6
1.2
Survival
Relative risk of mortality
75
0.8
0.4
RR0.82
RR0.82
RR1.17
50
0
19.3
31.4
0
Time on dialysis since initiation month
Fink JC et al., Am J Kidney Dis 200137348355.
15
Impact of Anaemia in CKD-Patients Progression
of Chronic Kidney Disease
Mechanism of progression of kidney disease
Intermediate Factors HypertensionAnaemia
Environmental FactorsToxic exposuresMedications
SmokingDiet
Host FactorsAgeSexEthnicity Genetic
susceptibility Hypertension Diabetes mellitus
Renal DiseaseGlomerulosclerosisInterstitial
fibrosis
Renal Failure
Rossert et al. J Am Soc Nephrol. 200314 (Suppl
2)173-177.
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Potential Beneficial Effects of Epoetin Treatment
Epoetin
Increased number ofred blood cells
Anti-apoptotic effectson renal cells (?)
Increased oxygen delivery
Increased protection against oxidative stress
Decreased tubular damage
Decreased interstitial fibrosis
Rossert et al. J Am Soc Nephrol. 200314 ( Suppl
2)173-177.
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Treatment of Anaemia in Patients with Chronic
Kidney Disease Effect of Anaemia Treatment on
Progression of Renal Disease
Effect of EPO on the cumulative renal survival
rate in predialysis patients of three groups
100
80
60
Cumulative renal survival rate
40
Group I (untreated anaemic, overall)
20
Group II (treated anaemic, overall)
Group III (untreated nonanaemic, overall)
0
0
5
10
15
20
25
35
30
40
Time (months)
Kuriyama S et al., Nephron 199777176185.
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Treatment of Anaemia in Patients with Chronic
Kidney Disease Effect of Anaemia Treatment on
Progression of Renal Disease
Kaplan-Meier plots for doubling of creatinine,
renal replacement, or death (A), and replacement
or death (B) in the early () versus deferred
() treatment arms
A
B
1.0
1.0
0.8
0.8
0.6
0.6
Proportion alive without progression
Proportion alive without renal replacement
0.4
0.4
0.2
0.2
0
0
0
6
12
18
24
30
0
6
12
18
24
30
Follow-up months
Follow-up months
Gouva C et al, Kidney Int 200466753760.
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Patient Categorisation within Stages ofChronic
Kidney Disease

• CKD patient categories with high risk of anaemia
  development
• Diabetes mellitus
• Congestive heart failure
• Diseases e.g. vasculitis, lupus erythematosus
• Advanced age
• Kidney transplantation

20
Patient Categorisation within Stages ofChronic
Kidney Disease

• Patients with diabetes mellitus
• Display a higher incidence of anaemia in the
  earlier stagesof CKD.
• Risk of developing anaemia is two to three times
  higher than CKD patients with comparable kidney
  function.
• Lower Hb-levels are linked with
  development/worsening of diabetic complications
  (retinopathy, diabetic nephropathy).

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Patient Categorisation Anaemia in CKD Patients
with Diabetes
Anaemia with erythropoietin deficiency occurs
early in diabetic nephropathy

• 53 patients with chronic kidney disease
• 27 type 1 diabetic patients with diabetic
  nephropathy
• 26 patients with glomerulonephritis
• serum creatinine lt 180 µmol/l
• Results
• 13/27 diabetic patients with anaemia Hb 10.6
  0.9 g/dl
• 0/26 glomerulonephritis patients Hb 13.7
  1.4 g/d

Bosman DR et al., Diabetes Care 200124495499.
22
Patient Categorisation Anaemia in CKD Patients
with Diabetes
Anaemia is more severe in chronic kidney disease
patients with diabetes
Diabetic patients (n19)
Non-diabetic patients (n19)
Age (years)
59 11
56 13
Sex (male/female)
13 / 6
13 / 8
Serum creatinine (mg/dl)
3.5 1.6
3.8 1.5
Haemoglobin (g/dl)
9.5 2.1
11.2 2.0
Serum erythropoietin (mU/ml)
19.8 6.2
18.6 5.6
HbA1c
7.6 1.8

Ishimura E et al., J Nephrol. 1998118386.
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Patient Categorisation within Stages ofChronic
Kidney Disease

• Patients with congestive heart failure
• Anaemia is correlated with symptoms of
  congestive heart failure, even in patients with
• preserved renal function
• normal ejection fraction
• Patients with systemic diseases
• Inflammation/ elevated serum concentrations of
  C-reactive protein lead to
• decrease in Hb level
• decrease response to erythropoietin

24
Patient Categorisation within Stages ofChronic
Kidney Disease

• Patients with advanced age
• Elderly patients are more likely to develop
  anaemia
• Patients with kidney transplantation
• Post transplant anaemia has a prevalence of
  20-40.
• Risk factors in this patient group are
• decrease in kidney function (GFR)
• immunosuppressive drugs

25
Patient Segments within Stages ofChronic Kidney
Disease
Recommendation Chronic kidney disease patient
categories with Diabetes mellitus Congestive
heart failure Diseases e.g. vasculitis, lupus
erythematosus Advanced age Kidney
transplantation are at very high risk for
anaemia development and should receivea higher
level of attention and care
26
Treatment of Anaemia in Patients with Chronic
Kidney Disease Parameters and Conditions that
Need to be Monitored

• Major Parameters
• Kidney function by estimation of glomerular
  filtration rate
• Proteinuria1
• Iron status2
• Haemoglobin3
• C-reactive protein (CRP)4

1 24 h or spot urine protein/creatinine2
Ferritin and transferrin saturation distinguish
absolute or functional iron deficiency in 3
month intervals or according to stages of CKD3
Monitor at every visit, including white cell and
platelet count4 Monitor at every visit,
preferably high sensitivity CRP
27
Treatment of Anaemia in Patients with Chronic
Kidney Disease Parameters and Conditions that
Need to be Monitored

• Minor Parameters
• Parathyroid hormone1
• BMI and nutrition status (SGA)2
• Screen for blood loss or haemolysis3
• Serum B12 and folate levels4
• Haemoglobinopathies

1 Monitor PTH twice a year (under specific
conditions and stages of CKD every three months2
Determine BMI, body mass index and SGA,
subjective global assessment in 3 month
intervals or according to stages of CKD3 Order a
Coombs test for diagnosis of autoimmunolysis if
appropriate
28
Treatment of Anaemia in Patients with Chronic
Kidney Disease Major Treatment influencing
Factors

• Intravenous treatment with iron
• Inflammation and overt infection1
• Underlying disease and co-morbidity2
• Chronic allograft nephropathy (CAN) and type of
  immunosuppression
• Age and sex

1 i.e. diabetic ulcers or ADPKD cyst infection2
i.e.vasculitis, chronic inflammatory conditions,
congestive heart failure or fluid overload
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Treatment of Anaemia in Patients with Chronic
Kidney Disease Minor Treatment influencing
Factors

• BMI and nutrition
• Concomitant medication1
• Malignancies (recurrent and de novo)
• Occult blood loss and haemolytic anaemia2
• Parathyroid hormone
• Vitamin B12 and folate deficiency
• Proteinuria (interstitial nephritis)
• Hypothyroidism
• Haemoglobinopathy

1 NSAIDS, ACE-inhibitors and angiotensin-II
blockers2 Coombs test
30
Treatment of Anaemia in Patients withChronic
Kidney Disease

• Status quo of treatment of CKD patients
• Effect of anaemia treatment on progression of
  renal disease
• Parameters and conditions that need to be
  monitored
• Major treatment influencing factors
• Minor treatment influencing factors
• Management of major treatment influencing factors

31
Management of Major Treatment Influencing
Factors Recommendations

• Recommendation
• If the Hb of the patient is not gt 11g/dl, exclude
  any other factor before treatment that can be
  related to anaemia.
• Iron status should be measured and corrected
  before anaemia is treated. In practice, the EBPG
  for haemodialysis patients should be applied for
  CKD patients.
• Patients with absolute iron deficiency should be
  treated with intravenous iron administration, at
  least at the start of anaemia treatment.
• Epoetin treatment should be started when
  haemoglobin is below 11 to increase haemoglobin
  to above 11 g/dl (EBPG) with an option to further
  increase haemoglobin to 12.5 g/dl (K/DOQI).

32
Summary

• Anaemia has a significant impact on patients with
  CKD, and there is substantial room for
  improvement in its treatment
• Anaemia should be diagnosed and treated early to
  avoid a negative impact on the kidneys and the
  cardiovascular system
• Patients with CKD and diabetes mellitus, chronic
  heart failure,or kidney transplantation are at
  very high risk of developing anaemia and should
  receive a higher level of attention
• Efficiency of anaemia treatment can be improved
  by better management of the major
  treatment-influencing factors
• Erythropoietin stimulates erythroid progenitor
  cells, has anti-apoptotic effects, and stimulates
  angiogenesis

33
Treatment of Anaemia in Patients with Chronic
Kidney Disease Status Quo of Treatment of CKD
Patients I
PRESAM Hb levels at the start of dialysis
treatment
40 30 20 10 0
EPO dose IU/kg/week
lt 7.0
7.07.9
9.09.9
10.010.9
8.08.9
11.011.9
12.0
Haemoglobin concentration g/dL
Valderrabano, Nephrol Dial Transplant 200217
(Suppl 1)1318.
34
Treatment of Anaemia in Patients with Chronic
Kidney Disease Status Quo of Treatment of CKD
Patients II
PRESAM Start of EPO therapy
40 30 20 10 0
n 4095
Patients
Epoetin startedbefore dialysis
Dialysis startedfirst
Epoetin anddialysis startedsimultaneously
No Epoetin
PRESAM Hb at start of EPO-therapy
n 1085 1332
523
1155 Mean g/dL 10.3 8.9
9.2
9.4 above 11.0
g/dL 31 8
14 17
Valderrabano, Nephrol Dial Transplant 200217
(Suppl 1)1318.
35
Treatment of Anaemia in Patients with Chronic
Kidney Disease Status Quo of Treatment of CKD
Patients III
Anaemia prevalence (Hb lt 11g/dl) in diabetics and
non-diabetics with chronic kidney disease
80 60 40 20 0
Diabetics1 Non-diabetics2
Prevalence of anaemia
1.32
34
23
gt4
Serum creatinine mg/dL
1 DIANE retrospective data analysis of 3.811
diabetics in 377 diabetes centers in Germany 2
Jungers et al., Nephrol Dial Transplant
2002171621.
36
Treatment of Anaemia in Patients with Chronic
Kidney Disease Status Quo of Treatment of CKD
Patients IV
Anaemia prevalence in transplanted patients with
CKD
Serum creatinine gt 2 mg/dL N904
Serum creatinine lt 2 mg/dL N3.359
60.1
29.9
71
29
Anaemia No anaemia
Hb in males lt 13 g/dL, in females lt 12 g/ dL
Vanrenterghem et al. Am J Transplant 20033
835845.
37
Effects of Epoetin Therapy on Cellular Level

• Interest in the cellular effects of
  erythropoietin goes back to the early days of the
  clinical use of Epo
• search for an explanation of the epo-induced
  hypertension
• Binding of erythropoietin to the Epo-receptors on
  vascular smooth muscle cells increases Ca influx
• increased vascular resistance
• resistance to the vasodilatory action of
  nitric oxide
• During the last decade
• Epo receptors have been discovered in numerous
  adult tissues
• idea of an autocrine or paracrine action of
  Epo (e.g. in the brain)
• Erythropoietin has anti-apoptotic effects on
  different celltypes and stimulates angiogenesis

38
Effects of Epoetin Therapy on Cellular Level
Epo not only stimulates the erythroid progenitor
cells but also promotes their survival due to
prevention of apoptosis.
Ca
EPO receptor
EPO
Excitatory neurotransmitter
JAK2
MAPK
PI3-K
STAT5
ERK
Akt/PKB
NF-kB
Bax, Bcl-XL
BAD
DAN integrity
mitochondrion
nucleus

CASP-3
Cyt C leakage
Phosphatidylserine

CASP-1
Ghezzi,Brines, Cell Death and Differentiation
200411S37S44.
39
Effects of Epoetin Therapy on Cellular Level
Haemangioblast CD34
Endothelial Progenitor Cell CD34
Haematopoietic Progenitor Cell CD34
Lymphoid Precursor Cell
Myeloid Precursor Cell
EPO
Platelet Neutrophil Monocyte Basophil Eosinophil
T-lymphocyte B-lymphocyte
Erythrocyte
Endothelial cell
Bahlmann et al., NDT 2004192022.
40
Effects of Epoetin Therapy on Cellular Level
Erythropoietin an all-purpose tissue-protective
agent?
Brain
EPO
Heart
Savino, Ciliberto, Editorial Cell Death and
Differentiation 200411S2S4.
41
EPO Receptor Expression and Potential Functions
in Normal Non-erythroid Cells
Cell type
Function

• Astrocytes
• Cardiomyocytes
• Endothelial cells
• Megakaryocytes
• Mesangial cells
• Myeloid cell
• Neurons
• Renal cells
• Prostate epithelial cells
• Vascular smooth muscle cells

• Decreased apoptotic cell death
• Mitogenic
• Mitogenic
• Endothelin-I synthesis release
• Angiogenesis
• Maturation
• Increased proliferation in vitro
• Multilineage increase in vitro
• Immunmodulation
• Trophic effect
• Monoamine concentration
• Decreased apoptotic cell death
• Mitogenesis
• Mitogenesis
• Contraction

42
Effects of Epoietin Therapy on Cellular Level

• Perspectives
• The pleiotropic effects of epoetin
• observed in low doses, not relevant for
  haematopoetic activity
• evaluated so far on cellular levels
• offer probably new areas in renoprotection in
• acute and chronic renal failure
• during renal ischemia

43
Back up Slides
44
Back up Slides
2 groups randomised in immediate start or later
(Hb lt 9 g/dl) start of EPO-Therapy n 88
CKD-patients Duration of study 30 months
Gouva C et al, Kidney Int 200466753760
45
Back up Slides
3 groups randomised Anaemia/EPO,
Anaemia/-EPO, Anaemia-/-EPO N 108 CKD
patients Duration of study 36 weeks
Kuriyama S. et al. Nephron 199777176185