Transcript Document

Diabetes, Anemia and Chronic Kidney Disease
Josephine Carlos-Raboca,M.D., F.P.S.E.M.,
Endocrinology, Diabetes and Metabolism
Makati Medical Center
OUTLINE
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Defining Chronic Kidney Disease(Diabetic Renal
Disease)
Pathophysiology of Anemia in CKD
Effects of Anemia of CKD
Benefits of Early Treatment of Anemia
Clinical Trials with Epoietin beta
Conclusion
What is
Chronic Kidney Disease
(CKD) ?
Definition of
Chronic Kidney Disease (CKD)

CKD in early stages is characterised by kidney damage
and level of kidney function
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CKD in later stages is defined as an estimated
glomerular filtration rate (eGFR) for at least 3 months of
– eGFR <60 mL/min/1.73m2
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Stages of CKD are ranked by classifying severity of
disease with declining eGFR and kidney damage
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CKD is a serious complication of diabetes mellitus
NKF K/DOQI Clinical Practice Guidelines 2002: Am J Kidney Dis 2002; 39 (2 Suppl 1): S17-S31
Diagnosis of Kidney Function
eGFR

eGFR can be more accurately predicted from variables
such as age, gender, race and body sizes with sCr
– Commonly used prediction equations
• Cockcroft-Gault uses sCr, age, weight and sex
• MDRD (Modification of Diet in Renal Disease) in its simplest
form uses sCr, age, sex and race

eGFR is a better indicator of renal function than sCr
alone
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eGFR easily determined from routine analyses
Reviewed by Agarwal. Am J Kidney Dis 2005; 455:610-613
Glomerular Filtration Rate
GFR in mg/dL
GFR in umol/l
Where Constant is 1.23 for men and 1.04 for women
Stages of CKD
by Glomerular Filtration Rate (GFR)
Stage
Description
GFR
(mL/min/1.73m2)
1
Kidney damage† with
normal or  GFR
≥90
2
Mild  GFR
60−89
3
Moderate  GFR
30−59
4
Severe  GFR
15−29
5
Kidney failure
<15 or dialysis
†Kidney
damage is defined by the National Kidney Foundation as ‘pathologic abnormalities or
markers of damage, including abnormalities in blood or urine tests or imaging studies’
NKF-K/DOQI. Am J Kidney Dis. 2002;39(Suppl 1):S1-S266
Symptoms of
CKD
Diabetic kidney disease and anaemia
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Anaemia is prevalent in people with diabetic kidney
disease and is largely unrecognised and untreated
Anaemia occurs earlier in diabetic kidney disease than
is commonly recognised
Anaemia worsens with declining kidney function .
Astor et al. Arch Intern Med. 2002;162:1401-1408
Anaemia develops early in CKD
NHANES III
– 15,419 non-institutionalised adults over the age of 20
– Prevalence of anaemia (KDOQI) increased from 1% at glomerular
filtration rate of 60 ml/min to 9% at 30 ml/min and 33% at
15 ml/min
20
Hb (g/dL)
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Hb (men)
Hb (women)
15
10
5
60
30
15
Glomerular filtration rate (ml/min)
Astor et al, Arch Int Med 2002; 162: 1401-1408
Aetiology of anaemia
Red Blood Cell (RBC) Production
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2 000 000 cells/sec
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120 000 000 cells/min
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173 000 000 000 cells/day
Normal values in adults
RBC parameter
Men
Women
Hb (g/dL)
15.7±1.7
13.8±1.5
Haematocrit (%)
46.0±4.0
40.0±4.0
RBC count (x1012/L)
5.2±0.7
4.6±0.5
Adapted from Williams et al. In: Williams’ Hematology. 5th ed. 1995;8-15
Defining Anemia
Guideline
Definition of Anemia
European Best Practice Guidelines
(EBPG) 2004 Anemia Guideline
<12.0 g/d: in males and
postmenopausal females;
<11.0 g/dL in premenopausal
females and prepubertal patients
Kidney Disease Outcomes Quality
Initiative (KDOQI) 2006 Anemia
Guideline
<13.5 g/dL males
<12.0 g/dL females
Potential causes of anaemia in
chronic kidney disease
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Shortened red blood cell survival
Iron deficiency
Malnutrition and other deficiencies
Chronic inflammation
Decreased erythropoietin production
Inhibition of erythropoiesis
The Lifecycle of the RBC
120 days
Globin
Circulation
Amino
acids
Erythropoiesis
in bone marrow
Fe3+ Transferrin
Fe
Heme
Ferritin and
haemosiderin
Biliverdin
Bilirubin
Macrophage in spleen,
liver or red bone marrow
Bilirubin
Liver
EXCRETION
Erythropoietin (EPO)
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Produced predominantly by peritubular fibroblasts in the
kidneys and released in response to anaemia and
hypoxia

Release is modulated through the sympathetic nervous
system (ß-adrenergic receptors)
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Anaemia associated with EPO deficiency usually occurs
at a glomerular filtration rates below 35-40 ml/min but
may occur at higher levels in diabetic kidney disease
Regulation of Erythropoiesis
Feedback loop
Erythroid
marrow
Erythropoietin
RBCs
Kidney
Circulating
RBCs
O2
Adapted from Erslev & Beutler. In: Williams’ Hematology. 5th ed. 1995;425-441
The Role of Erythropoietin in Erythropoiesis
Stage 1: CD-34
Stem cell
pool
Progenitor cells
BFU-E, CFU-E
Stage 2: Erythron
Precursor cells
erythroblasts
Mature cells
GM-CSF
IL-3, IGF-1
SCF
Erythropoietin
Erslev & Besarab. Kidney Int. 1997;51:622-630
Erythropoietin Receptor
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508 amino acids, 66–78 kDa
glycoprotein
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Located on erythroid progenitor
cell surface
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Approximately 1000
erythropoietin receptors
per cell

Expression
– primarily on CFU-E
– small numbers on BFU-E
– no receptors present once
cells become reticulocytes
EPO
Membrane
P JAK2
P
STAT
P
JAK2 P
STAT
P
P
Target genes
Hb and Erythropoietin: the Anaemic Patient
with CKD
O2
Hb
transport
capacity
peripheral
hypoxia
kidney
peritubular
cells
DAMAGED
serum EPO
precursor cells
O2
transport
capacity
erythroblasts
ANAEMIA
Hb
erythrocytes
reticulocytes
INSUFFICIENT
Diabetes and Anaemia
Nephropathy (35%)
CKD
Neuropathy (50%)
↓Serum EPO
level
Diabetes
Anaemia
Hyperglycaemia
↓Serum EPO
response
RBC abnormalities
↓ RBC survival
Anaemia in CKD: Summary
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The hormone erythropoietin is the physiological
regulator of RBC production and lifespan
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In individuals with CKD, damage to the kidney
compromises erythropoietin production

Anaemia correlates with the severity of CKD
Effects of anaemia in diabetic renal
disease?
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The risk of coronary heart disease in people with diabetes
is 2-4x higher than the general population and the risk of
cerebrovascular disease up to 5x higher
The risks of cardiovascular disease develop early in the
course of chronic kidney disease and are increased by
diabetes
Combination of anaemia and chronic kidney disease
substantially increases stroke risks
Anaemia predicts  left ventricular mass, left ventricular
dilation, heart failure and death
Reciprocal Relationship :
Renal Anemia, Diabetes & CVD
Cardiovascular disease in early
chronic kidney disease

HDFP study1
– subjects with serum creatinine >150 µmol/L vs. < 150 µmol/L
OR for death after 8 years 2.2
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Framingham study2
– increased incidence of cardiovascular disease in those with
renal insufficiency
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Canadian multicenter cohort3
– incidence of cardiovascular disease already 35.2% in those
with glomerular filtration rate >50 ml/min and rose to 45.3%
in those with glomerular filtration rate <25 ml/min
1. Shulman et al Hypertension 1989; 13(5):I80-93
2. Culleton et al Kidney Int 1999; 56: 2214-2219
3. Levin et al, Am J Kidney Dis 1999; 34: 125
Anaemia in CKD

Anaemia in CKD induces
– increased cardiovascular (CV) workload leading to
left ventricular hypertrophy (LVH)
– reduced exercise capacity
– fatigue
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Anaemia in CKD is linked with
– increased CV morbidity and mortality
Framingham study, N = 6223
8% mild CRF (males serum creatinine 136-265, females 120-265 µmol/L)
Percentage (%)
No renal insufficiency
Chronic renal insufficiency
25
20
15
10
5
0
ECG LVH
CHD
CHF
CVD
ECG LVH=echocardiogram left ventricular hypertrophy
CHD=coronary heart disease
CHF=congestive heart failure
CVD=cardiovascular disease
Culleton et al Kidney Int 1999; 56: 2214-2219
CKD and Anaemia Increase the Risk of
CHF
Stage 5 CKD patients on dialysis (n=433)
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At start of dialysis
– 31% had CHF
– 19% had angina
– 14% had coronary artery disease
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On dialysis, for each 1 g/dL fall in Hb
– 42% increased risk of LVH
– 18% increased risk of CHF
– 14% increased risk of death
1. Foley et al. Kidney Int. 1995;47:186-192
2. Foley et al. Am J Kidney Dis. 1996;28:53-61
The Cardio-Renal Anaemia Syndrome
A vicious circle
Hypoxia
CKD
Anaemia
Serum EPO production
Apoptosis
Renal
vasoconstriction
Fluid
retention
Cardiac
output
Hypoxia
Sympathetic activity
TNF-α
Uraemia
CHF
CHF=congestive heart failure
Adapted from Silverberg et al. Kidney Int Suppl. 2003;(87):S40-S47
Anaemia, chronic kidney disease and risk
of stroke – the ARIC study, n = 13,716
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Community based cohort, 9 yr follow up
– mean age 54.1 ± 5.7, mean Hb 13.9, 10.6% diabetic
– 15 percent Cr Cl < 60 ml/min, mean blood pressure 120/71
– 85 percent Cr Cl ≥ 60 ml/min, mean blood pressure 121/74
– Use of anti-hypertensives 24.6% & 23.5%
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Lower Cr Cl associated with higher crude stroke rate
– Cr Cl < 60 ml/min, stroke rate 3.7
– Cr Cl ≥ 60 ml/min, stroke rate 2.06
Abramson et al, Kidney Int 2003; 64: 610-615
ARIC study – influence of anaemia (WHO)
10.53
Stroke rate
12
10
Cr Cl ≥ 60 ml/min
Cr Cl < 60 ml/min
8
6
4
3.7
2.06
2
1.52
2.12
2.85
0
Total sample
Anaemic group
Nonanaemic group
Abramson et al, Kidney Int 2003; 64: 610-615
Hospitalisation Risk Increases with Hb <11 g/dL
Dialysis patients
RR of hospitalisation
2.0
n=7998
1.55
1.5
1.16
1.09
1.00
1.01
1.0
0.5
P<0.0001
P=0.001
P=0.05
<8
8−9.99
10−10.99
P=0.77
0.0
11−11.99
≥12
Hb level (g/dL)
Pisoni et al. Am J Kidney Dis. 2004;44:94-111
Summary : CKD and CVD
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The association between chronic kidney disease and all
forms of cardiovascular disease begins early in the
evolution of chronic kidney disease, anaemia significantly
amplifies this association
Cardiovascular events and mortality in chronic kidney
disease are increased in patients with diabetic kidney
disease and are closely related to anaemia
Why do we treat renal anaemia?
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 Subjective1
–
–
–
–

well-being
life satisfaction
happiness
psychological affect
Others
–
–
–
–
cardiac status2
 blood transfusions3
 hospitalisation4
 mortality5
Objective1
–
–
–
–
energy level
functional ability
activity level
health status
1. Evans et al J Am Med Soc. 1990; 263:825-830
2. Winearls Nephrol Dial Transplant 1995; 10(suppl10):3-9
3. Fellner et al Kidney Int; 1993; 44:1309-1315
4 Churchill et al Clin Nephrol 1995; 43:184-188
5. US Renal Data System 1998
Epoetin improves quality of life in
predialysis patients
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83 predialysis patients entered into a parallel-group,
open-label clinical trial and randomised to
– epoetin
– no treatment

Epoetin treatment significantly improved anaemia and
–
–
–
–
–
energy
physical function
home management
social activity
cognitive function
Revicki et al Am J Kidney Dis 1995; 25: 548-554
Correction of anaemia improves left
ventricular hypertrophy in dialysis patients
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22 dialysis patients studied by echocardiogram before and
after correction of their anaemia with epoetin
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Hb increased at least 3.0 g/dL over baseline
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Correction of anaemia produced:
– decrease in left ventricular mass (p = 0.0004)
– decrease in left ventricular end-diastolic volume (p
<0.0001)
Adapted from Silverberg et al. Can J Cardiol 1990; 6: 1-4
Building the evidence:
Mortality & hospitalisation

Collins et al1
– Relative risk of death and/or hospitalisation lowest at Hct
levels of 36-39%

Fink et al2
– Pre-dialysis epoetin treatment leads to a relative risk of
mortality of 0.8 (n=4866, 1107 epoetin)
1. Collins et al J Am Soc Nephrol November 2001
2. Fink et al Am J Kidney Dis 2001;37:348-355
Mortality and haematocrit level: First year
follow up, all dialysis patients
Diabetes mellitus
No diabetes mellitus
400
350
300
Deaths per
1000 patient
years
250
200
150
100
50
0
<30
30 - <33 33 - <36
Haematocrit
36+
USRDS prevalent patients 1994-1997
Duration of Hb <11 g/dL Increases Mortality Risk
Dialysis patients
Relative mortality risk
2
1
**
1.82
n=41 919
1.00
**
**
1.52
61−80
*
1.10
*
1.12
1.32
1−20
21−40
41−60
0
0
81−100
Time with Hb <11 g/dL over 2 years (%)
*P<0.05; **P<0.001
Ofsthun et al. Nephrol Dial Transplant. 2005;20(Suppl 5):v261 (abstract MP204)
Hb Levels Predict Survival Prior to Dialysis Initiation
CKD patients not on dialysis
Probability of survival
1.00
0.95
Hb
≥13.0 g/dL
0.90
12−12.9 g/dL
0.85
0.80
11−11.9 g/dL
0.75
<10 g/dL
Log-rank test: P=0.0001
10−10.9 g/dL
0.70
0
3 6
9 12 15 18 21 24 27 31 33 37
Months from Hb result
Levin et al. Nephrol Dial Transplant. 2006;21:370-377
Anaemia Treatment Greatly Reduces Blood
Transfusions
Dialysis patients
Mean units per patient per 4 weeks
0.6
Commencement of
anaemia therapy
0.5
0.4
0.3
0.2
0.1
*
0
Pre 4
*autologous blood donation
ahead of elective hip surgery
12
20
28
36
44
52
Weeks
Eschbach et al. Ann Intern Med. 1989:111:992-1000
Building the evidence: delaying
progression of chronic renal failure
•
63 patients (serum creatinine > 300 μmol/L,
creatinine clearance < 15 mL/min/1.73 m2)
•
20 with Hb < 10 g/dL = study group (epoetin+)
43 with Hb > 10 g/dL= control group
•
Significant reduction in rate of progression of
chronic renal failure in study group, no change in
control group
Jungers et al Nephron Dial Transplant 2001; 16: 307-312
Trials in treatment of CKD anaemia

CREATE trial (Cardiovascular risk Reduction by Early
Anaemia Treatment with Epoetin beta)
CHOIR trial (Correction of Haemoglobin and Outcomes In
Renal Insufficiency)
ACORD (Anaemia CORrection in Diabetes)

Aims of the studies : to establish whether early intervention


–
–
–
–
prevents development of left ventricular hypertrophy
reduces cardiovascular mortality and morbidity
delays progression of chronic renal failure
reduces stroke and heart failure related hospitalisations
The CHOIR and CREATE Studies:
Overview
CKD patients not on dialysis
CHOIR
(n=1432)
CREATE
(n=605)
Patient Population
Stage 3–4 patients with renal
anaemia and not on renal ‡
replacement therapy (RRT)
Stage 3–4 CKD patients
with renal
§
anaemia not on RRT
Duration
16 months
700 patients completed trial
48 months
476 patients completed trial
Primary Endpoints
Composite
Composite
(death, MI, HF, stroke)
(sudden death, MI, acute HF, CVA, TIA,
hosp for angina or arrhythmia, PVD
complications)
Group 1: 13.5 g/dL†
 Group 2: 11.3 g/dL†

Hb Targets
†Original

targets before protocol amendment:
• Group 1: 13.0–13.5 g/dL
• Group 2: 10.5–11.0 g/dL
‡
127 and 111 patients in groups 1 and 2,
respectively, progressed to RRT during study
Group 1: 13–15 g/dL
 Group 2: 10.5–11.5 g/dL
§
127 and 111 patients in groups 1 and 2,
respectively, progressed to RRT during study
Singh et al. N Engl J Med. 2006;355:2085-2098
Drüeke et al. N Engl J Med. 2006;355:2071-2084
CHOIR: Increased Risk of Composite Event with
Target Hb 13.5 g/dL
Stage 3–4 CKD patients
Time to the primary composite endpoint
Probability of
composite event
0.30
Hb target 13.5 g/dL
Hb target 11.3 g/dL
0.25
0.20
0.15
0.10
Events: 125 vs 97
HR=1.34 (1.03–1.74)
Log rank test P=0.03
0.05
0.00
0
3
6
9
12 15 18 21 24 27 30 33 36 39
Patients at risk
Group 1
715 654 587 520 457 355
Group 2
717 660 594 539 499 397
Month
270 176 101
293 182 107
72
67
55
44
23
23
Singh et al. N Engl J Med. 2006;355:2085-2098
CREATE: No Significant Difference in
Time to First CV Event
CKD patients not on dialysis
Time to the primary endpoint of a first cardiovascular event†
Event-free Survival (%)
100
90
80
70
60
Hb target 13–15 g/dL
Hb target 10.5–11.5 g/dL
50
40
Events: 58 vs 47
HR=0.78 (0.53–1.14)
Log rank test P=0.20
30
20
10
0
0
Patients at risk
Group 1
301
Group 2
302
6
12
18
24
30
36
42
48
158
177
97
121
56
61
2
2
Month
279
286
268
272
249
257
207
223
†Before
censoring of data on patients at the time of
initiation of dialysis
Drüeke et al. N Engl J Med. 2006;355:2071-2084
The Anaemia CORrection in Diabetes
(ACORD) study

The ACORD study is investigating the effects of
anaemia correction with subcutaneous epoetin beta on
– cardiac structure
– cardiac function


In patients with early diabetic nephropathy
Primary endpoint
– effect of early anaemia treatment on left ventricular
hypertrophy as a cardiovascular risk marker
ACORD: Study design
Hb (g/dl)
16
14
16
m
Randomisation
f
12
Early intervention
Target Hb: 13–15 g/dl
14
Standard treatment
12
Target Hb: 10.5–11.5 g/dl
10
8
Inclusion:
Hb 10.5–13.0 g/dl
Creatinine clearance ≥30 ml/min
n = 160
6
10
8
6
Time
Maintaining the Right Hb Range
Summary

Efficacy of SC epoetin beta confirmed by Hb response according
to different Hb targets both in CREATE and ACORD

Complete Hb correction improves QoL and was not associated
with any consistent hazard

Trend towards decrease in LVMI with complete anaemia
correction among those with higher baseline LVMI
– In CREATE and ACORD annual CV event rate lower than
expected from previous studies

Prospective international randomised trials (CREATE, ACORD)
show no added benefit of complete Hb correction to 13-15 g/dL
on CV outcome measures and CKD progression
– But it may still be beneficial as CV event rates were low
European recommendations for optimising
treatment of renal anaemia

Indication for start of epoetin therapy:
– repeated Hb measurements <11g/dL
– after exclusion of non-renal causes of anaemia (bleeding,
nutritional deficiencies, hypothyroidism, iron deficiency,
haemolysis)

Target haemoglobin:
– general: Hb >11 g/dL (no upper limit)
– in CHD:
Hb 11-12 g/dL

Administration of epoetin:
– SC dosing preferred; IV dosing also an option in HD patients
– the goal is to increase Hb levels by 1–2 g/dL per month
van Ypersele de Strihou Nephrol Dial Transplant 1999; 14 (suppl 2): 37-4
Iron stores

Target
– serum ferritin > 100 g/l (aim for 200-500)
– hypochromic red blood cell count < 10%,
TSAT > 20% (aim for < 2.5% & 30-40%)
Level B

Treatment strategies
– predialysis and CAPD oral  intravenous
– HD will need intravenous
Level B
How should epoetin be administered to predialysis
patients with diabetes and anaemia?

EBPG & KDOQI recommend epoetin treatment for anaemia
due to CKD when Hb < 11 g/dL

Hb correction should be gradual to avoid:
– exacerbation of hypertension
– increased viscosity with adverse haemodynamics

Guidelines recommend an increase of Hb 0.5 g/dL
every 2 weeks

Common practice suggest a target Hb of 11–12 g/dL (or
?12-13 g/dL)
RECORMON DOSING GUIDE for CKD Patients
with Renal Anemia:
Correction Phase
Subcutaneous Administration Intravenous Administration
60 IU/kg Body weight per week
120 IU/kg Body Weight per Week
Dosage maybe increase every 4 weeks by 60IU/kg
BW/wk if the increase in PCV is <0.5 volume % per
week or <0.5 g/dL Hb every 2 weeks.
Dosage maybe increase every 4 weeks by 120IU/kg
BW/wk if the increase in PCV is <0.5 volume % per
week or <0.5g/dL Hb every 2 weeks.
Maintenance Phase:
Dose can be reduced to 50% or adjusted at intervals of one or two
weeks individually for the patients to maintain target Hb and Hct.
The clear differences
Epeotin Beta Recormon
Epoetin alpha
Half life
SC 12-28 hours
IV 4-12 hours
SC 12-18 hours
IV 4-6 hours
Stabilizers
Glycine
Poylsorbate 20
Urea
Calcium Chloride
Complex of 5 amino acids
Glycine
Polysorbate 80
Storage and handling
2-8 degrees centigrade
can be removed from refrigeration
and store at 25 degrees centigrade
for a single period of up to 3 days
Can tolerate shaking
2-8 degrees at all times
Can not tolerate shaking
Tolerability
Almost pain free at the injection site
With pain at the injection
site
Dose Recommendation
(Correction)
60 IU/kg Body weight/wk
100 IU/kg Body Weight
/wk
Shelf Life (PFS)
24 months
18 months
Conclusions

Anaemia is prevalent in diabetic kidney disease and occurs
earlier than is commonly recognised

Proven benefits of treatment of anaemia with epoetin
(± intravenous iron) include
– improved quality of life and performance status
– regression of left ventricular hypertrophy
– reduced transfusion requirements

Potential benefits of early anaemia treatment include
– reduced cardiovascular mortality and morbidity
– delayed progression of chronic renal failure
– reduced stroke and heart failure related hospitalisations
Thank you