Post on 21-Jan-2016
Reciprocal Relationship :Renal Anemia, Diabetes &
CVD
Anaemia in diabetic renal disease: an underestimated and unrecognised risk factor?
Diabetes: a worldwide epidemic
Awareness of anaemia in people with diabetes - Europe
Questionnaire based interview with 1054 respondents in six European countries to assess the level of understanding and awareness of anaemia and its impact on quality of life amongst people with diabetes
32% had been given information on anaemia, less than 50% were aware of being tested for anaemia and only 14% attributed anaemia to diabetes
132 (12.5%) known to be anaemic
– one-fifth were not receiving any treatment
– 12 received blood transfusions
– 5 patients were on erythropoietin
– Remainder were given iron and/or vitamin supplements
Perceived state of health in those with anaemia was worse
Stevens et al Curr Med Res Opin 2003; 19: 395-401
Awareness of anaemia in people with diabetes - USA
504 respondents selected from a nationally representative panel of people with diabetes
26% were aware that they were at risk for anaemia
14% were aware that they had been diagnosed with anaemia
Of the 86% of patients not diagnosed with anaemia– 58% indicated they suffer from one or more symptoms often
associated with anaemia• 69% attributed the symptoms to diabetes• 66% attributed the symptoms to ageing
Roper Starch Worldwide 2001
Awareness of anaemia in physicians caring for people with diabetes
Unrecognised anaemia in patients with diabetes1
– cross sectional survey of 820 patients in a diabetic clinic
– 190 (23%) had unrecognised anaemia by WHO definition and 56 (7%) by KDOQI/EBPG definition
– risk of anaemia increased 2-3x in people with diabetes
Prevalence and degree of anaemia in diabetic patients with declining renal function2
– cross sectional survey of 119,730 patients in diabetes clinics and GPs surgeries
– 3507 (2.93%) had creatinine clearance < 90 ml/min
– 39.6% men and 43.9% women had unrecognised anaemia by WHO definition and 17.2% men and 25.8% women by KDOQI/EBPG definition
1. Thomas et al Diabetes Care 2003; 26:1164-11692. 2. Hasslacher et al IDF Paris 2003; poster 946
Awareness of anaemia in physicians caring for people with diabetes
Anaemia in diabetes – under recognised and under treated– prospective survey of all patients unknown to renal services with
serum creatinine >180 µmol/L in men and >135 µmol/L in women over a 2 year period
– 872 people with diabetes and chronic renal failure (median glomerular filtration rate 29.9 ml/min)
– 17.7% of patients had not had Hb levels checked at all
– of the remainder, 65.7% men and 53.6% women had unrecognised anaemia by WHO definition and 21.5% men and 27.8% women had Hb levels < 11 g/dL
John et al IDF Paris, 2003 poster 1315
Increasing awareness of anaemia in diabetic kidney disease
The Individualised Risk-profiling In DIabEtes Mellitus (IRIDIEM) study
An observational study of patients with diabetes and chronic kidney disease aiming to– document current management of diabetic nephropathy
– study the effect of individualised and evidence-based cardio- and reno-protective interventions on cardiovascular and metabolic risk profile and outcomes
IRIDIEM: Study design
Phase l
Pharmaco-epidemiological assessment(~2500 patients with diabetic nephropathy and risk factors)
Phase llEvidence-based educational guidance for individualising reno- and cardio-protective
interventions(~700 patients stage lll or lV CKD and risk factors)
Re-assessment of risk factor status
6 and 12 months after enrolment
Why should we be aware of anaemia in diabetic renal disease?
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
Anaemia develops early in chronic kidney disease 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
Why should we be aware of anaemia in diabetic renal disease?
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
Anaemia develops early in chronic kidney disease 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
Anaemia develops early in chronic kidney disease
Canadian multicenter cohort study WHO criteria
Levin et al, Am J Kidney Dis 1999; 34: 125-134
Prevalence (%)
Creatinine clearance (ml/min)
100
40
0
>50 35-49 25-34 <25
25
4451
87
20
60
80
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
Astor et al, Arch Int Med 2002; 162: 1401-1408
Hb
(g/d
L)
Glomerular filtration rate (ml/min)
5
10
15
20
60 30 15
Hb (men)Hb (women)
Prevalence of anaemia in early renal insufficiency – PAERI study
1716 subjects, mean age 68 Mean serum creatinine 2.2 mg/dL (194 µmol/L) Mean Hb 12 g/dL Odds ratio of Hb < 12 g/dL or < 10 g/dL 1.8x in diabetes
vs. no diabetes
McClellan et al, ASN 2001
Why should we be aware of anaemia in diabetic renal disease?
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
Anaemia develops early in chronic kidney disease 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
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
Framingham study2
– increased incidence of cardiovascular disease in those with renal insufficiency
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):I80-932. Culleton et al Kidney Int 1999; 56: 2214-22193. Levin et al, Am J Kidney Dis 1999; 34: 125
Framingham study, N = 6223
0
5
10
15
20
25
ECG LVH CHD CHF CVD
Culleton et al Kidney Int 1999; 56: 2214-2219
8% mild CRF (males serum creatinine 136-265, females 120-265 µmol/L)
Percentage (%)
No renal insufficiencyChronic renal insufficiency
ECG LVH=echocardiogram left ventricular hypertrophyCHD=coronary heart diseaseCHF=congestive heart failureCVD=cardiovascular disease
Canadian multicenter cohort study of chronic kidney disease
•Prevalence of any cardiovascular disease and left ventricular hypertrophy by creatinine clearance
Per
cen
tag
e (%
)
Levin et al, Am J Kidney Dis 1999; 34: 125-134
Creatinine clearance (ml/min)
60
50
40
30
20
10
0>50 35-49 25-34 <25
Cardiovascular diseaseLeft ventricular hypertrophy
SOLVD study1 – increase relative risk of mortality of 1.44 and relative risk of
pump failure of 1.68 in subjects with glomerular filtration rate <60 ml/min compared with > 60 ml/min
HOPE study2 – cardiovascular disease mortality, myocardial infarction or stroke
22.2% in subjects with serum creatinine 124-200 µmol/L vs. 15.1% in those with serum creatinine < 124 µmol/L
Cardiovascular Health Study3 – OR 2.34 for cardiovascular disease in subjects with serum
creatinine > 132 µmol/L in males and > 114 µmol/L in females
Cardiovascular disease in early chronic kidney disease
1. Dries et al, J Am Coll Cardiol, 2000; 35 :681-6892. Mann et al, Ann Int Med, 2001;134:629-363. Manjunath et al, Kidney Int, 2003; 63: 1121-1129
Prevalence of cardiovascular abnormalities is higher among diabetic patients with CKDNewfoundland/Montreal study
18
24
38
32
48 50
0
10
20
30
40
50
60
Non-diabetic
Diabetic
p=0.003 p<0.00001 p=0.04Prevalence at dialysis start (%)
Foley et al Diabetologia 1997; 40: 1307-1312
CLVHIHD CF
IHD=ischaemic heart diseaseCF=cardiac failure CLVH = concentric left ventricular hypertrophy
1 1 1 1
3.2
1.2
2.32.6
0
0.5
1
1.5
2
2.5
3
3.5
IHD CCF Death CV Death
Non-diabetic
DiabeticRel
ativ
e r
isk
p=0.0003 p=ns p<0.0001 p<0.0001
CV = cardiovascularIHD = ischaemic heart disease CCF = chronic cardiac failure
Foley et al Diabetologia 1997; 40: 1307-1312
Prevalence of cardiovascular abnormalities is higher among diabetic patients with CKDNewfoundland/Montreal study
Why should we be aware of anaemia in diabetic renal disease?
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
Anaemia develops early in chronic kidney disease 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
Anaemia, chronic kidney disease and risk of stroke – the ARIC study, n = 13,716
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%
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)
Str
oke
rat
e
Abramson et al, Kidney Int 2003; 64: 610-615
0
2
4
6
8
10
12
Total sample Anaemic group Nonanaemic group
Cr Cl ≥ 60 ml/minCr Cl < 60 ml/min
2.06
3.7
1.52
10.53
2.122.85
Why should we be aware of anaemia in diabetic renal disease?
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
Anaemia develops early in chronic kidney disease 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
Effect of 1g/dL fall in Hb
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0CLVH LV Dil SDF CCF IHD Death
1
1.491.55
1.24
1
1.25
Foley et al Am J Kidney Dis 1996; 28: 53-61 .
Re
lativ
e r
isk
CLVH = concentric left ventricular hypertrophyLV Dil = left ventricular dilatation SDF = systolic dysfunctionCCF = chronic cardiac failureIHD = ischaemic heart disease
Cause specific death rates for prevalent dialysis patients aged 20
USRDS 1997-1999
0
10
20
30
40
50
60
70
Acute MI Cardiac arrest Cardiac other
Deaths per 1000 patient
years
Diabetes mellitus
No diabetes mellitus
Mortality and haematocrit level: First year follow up, all dialysis patients
USRDS prevalent patients 1994-1997
Haematocrit
0
50
100
150
200
250
300
350
400
<30 30 - <33 33 - <36 36+
Deaths per 1000 patient
years
Diabetes mellitus
No diabetes mellitus
Conclusions
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
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
Aetiology of anaemia and
benefits of early treatment
in patients with diabetes
Diabetes and renal disease
WHO & IDF estimates suggest that in Europe there are already 32 million adults age 20-79 with diabetes
Diabetes is the commonest cause of end stage renal failure worldwide and up to 1 in 4 people with diabetes will develop diabetic kidney disease over the course of 20 years
Studies such as the RENAAL1 and UKPDS2 clearly demonstrate that the risk of mortality in diabetic kidney disease clearly outweighs the risk of progression to end stage renal disease
1. Keane et al Kidney Int 2003 63:1499-507 2. Adler et al Kidney Int 2003 63:225-32
Cardiovascular risk factors in chronic kidney disease
Traditional– older age– male gender– BP & LVH– LDL-C HDL-C– diabetes– smoking– inactivity– menopause
CKD related– RAS activity– ECFV overload
– Ca/PO4 abnormalities
– anaemia– MIA syndrome– oxidative stress– Homocysteine– thrombogenic factors– GFR
Diabetic kidney disease and anaemia
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
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
Potential causes of anaemia in chronic kidney disease
Decreased erythropoietin production Shortened red blood cell survival Iron deficiency Inhibition of erythropoiesis Malnutrition and other deficiencies Chronic inflammation
Anaemia in diabetic nephropathy Aetiology
Decreased erythropoietin levels resulting from:
Tubulointerstitial damage Autonomic dysfunction Use of ACE inhibitors?
Reviewed in Bilous Acta Diabetol 2002; 39: S15-19
Erythropoietin (EPO)
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)
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
Anaemia occurs early in diabetic nephropathy and is more severe than non-diabetic patients
Bosman et al Diabetes Care 2001; 24: 495-499
DN anaemic* DN normal GN Non-DN anaemic
Serum creatinine (mmol/l)
110(63–160)
88(64–133)
93(49–180)
68(59–148)
Proteinuria (g/day)
2.5(0.1–5.2)
0.6(0.1–2.9)
1.9(0.3–5.0)
Hb (g/dl)
10.6(8.7–12.0)
13.7(11.8–15.1)
13.7(11.6–16.3)
9.3(6.9–11.6)
Erythro-
poietin (IU/l)8.1
(2.5–19.0)8.5
(2.5–17.5)8.5
(2.5–17.0)57.7
(29.2–195.8)
*Anaemia <11.5 g/dl women, <12.0 g/dl men
DN=diabetic nephropathy; GN=glomerulonephritis
Low serum erythropoietin levels cause anaemia and may predict the severity of diabetic nephropathy
Bosman et al Diabetes Care 2001; 24: 495-499
0
2
4
6
6 8 10 12 14 16
Non-anaemia and microcytic anaemic control subjects, n=32 Diabetic nephropathy, n=26
Hb (g/dl)
ln E
PO
Erythropoietin-deficiency anaemia in diabetic nephropathyUnderlying autonomic neuropathy
15 type 1 diabetic patients with severe complications including autonomic neuropathy and normal (<122 µmol/L) serum creatinine
Compared with 18 controls matched for age and duration of diabetes but not for renal function
Winkler et al Diabetic Med 1999; 16: 813-819
Diabetes + AN
Diabetes
Number of patients
15 18
Duration (y) 22.7 25.2
Hb (g/dl) 11.1 13.7(p<0.01)
Serum creatinine (µmol/L)
86.9 66.4
Proteinuria 3 micro-albuminuria; 12 proteinuria
3 micro-albuminuria
AN = autonomic nephropathy
Erythropoietin-deficiency anaemia in diabetic nephropathy: Underlying autonomic neuropathy
0
2
4
6
6 8 10 12 14 16
Hb (g/dl)
ln E
PO
Iron deficient and normals, n=32 Diabetic nephropathy, n=26
Winkler et al Diabetic Med 1999; 16: 813-819
Iron deficiency and anaemia in chronic kidney disease
Women Men
(g/dL) P (g/dL) P
Fer ≥ 100 ng/mL & TSAT ≥ 20%
reference reference
Fer < 100 ng/mL & TSAT ≥ 20%
- 0.2 0.002 - 0.1 0.30
Fer ≥ 100 ng/mL & TSAT< 20%
- 0.3 0.001 - 0.4 0.004
Fer < 100 ng/mL & TSAT < 20%
- 0.6 <0.0001 - 0.8 <0.0001
Hsu et al, J Am Soc Nephrol 2002;13:2783-86
Fer=ferritinTSAT=transferrin saturation
Iron deficiency and anaemia in diabetes
Unrecognised anaemia in patients with diabetes Cross sectional survey of 820 patients in a diabetic clinic Mean Hb 13.9 g/dL (men) & 12.9 g/dL (women) 190 (23%) had unrecognised anaemia by WHO
definition and 56 (7%) by KDOQI/EBPG definition Most powerful predictors were transferrin saturation and
glomerular filtration rate accounting for 22% and 10% of the variance in Hb respectively
Thomas et al, Diabetes Care 2003;26:1164-1169
Why do we treat renal anaemia?
Subjective1
– well-being– life satisfaction– happiness– psychological affect
Objective1
– energy level– functional ability– activity level– health status
Others– cardiac status2
– blood transfusions3
– hospitalisation4
– mortality5
1. Evans et al J Am Med Soc. 1990; 263:825-8302. Winearls Nephrol Dial Transplant 1995; 10(suppl10):3-93. Fellner et al Kidney Int; 1993; 44:1309-13154 Churchill et al Clin Nephrol 1995; 43:184-1885. US Renal Data System 1998
What do we hope to achieve by the early treatment of renal anaemia?
Increased exercise capacity, improved quality of life, cognitive function and sexual function
Regression of left ventricular hypertrophy
Reduced mortality and hospitalisation
Reduced transfusion requirements
?Regression of chronic renal failure progression
What do we hope to achieve by the early treatment of renal anaemia?
Increased exercise capacity, improved quality of life, cognitive function and sexual function
Regression of left ventricular hypertrophy
Reduced mortality and hospitalisation
Reduced transfusion requirements
?Regression of chronic renal failure progression
Epoetin improves quality of life in predialysis patients
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
QOL following correction of anaemia
Moreno et al, Am J Kidney Dis 1996;27:548-56
Ka
rno
fsky
sca
le s
core
Age <60 years Age >60 years
50
60
70
80
90
Basal 6 months
QOL following correction of anaemia
Moreno et al, Am J Kidney Dis 1996;27:548-56
Age <60 yearsAge >60 years
Sic
knes
s im
pac
t p
rofi
le
sco
re
0
5
10
15
20
25
30
35
Basal 6 months
What do we hope to achieve by the early treatment of renal anaemia?
Increased exercise capacity, improved quality of life, cognitive function and sexual function
Regression of left ventricular hypertrophy
Reduced mortality and hospitalisation
Reduced transfusion requirements
?Regression of chronic renal failure progression
Correction of anaemia improves left ventricular hypertrophy in dialysis patients
22 dialysis patients studied by echocardiogram before and after correction of their anaemia with epoetin
Hb increased at least 3.0 g/dL over baseline
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
Adapted from Portolés et al Am J Kidney Dis 1997; 29: 541-548
Partial correction (n=11)
Reduction in LVMI with partial anaemia correction in predialysis patients
LVM
I (g/
m2 )
Baseline Hb = 9.0 g/dl
0
100
140
180
220
260Epoetin
p<0.05
178.2
147.3
6 MonthsHb = 11.7 g/dl
LVMI = left ventricular mass index
Mean value
111.2
p=0.0108
Epoetin
0
20
40
60
80
100
120
140
160
180
200
140.6126.9
Complete correction (n=9)
Baseline Partial Normal Hct = 23.6% Hct = 32.1% Hct = 39.1%
LVM
I (g/
m2 )
Reduction in LVMI with complete anaemia correction in predialysis patients
Adapted from Hayashi et al Am J Kidney Dis 2000; 35: 250-256LVMI = left ventricular mass index
What do we hope to achieve by the early treatment of renal anaemia?
Increased exercise capacity, improved quality of life, cognitive function and sexual function
Regression of left ventricular hypertrophy
Reduced mortality and hospitalisation
Reduced transfusion requirements
?Regression of chronic renal failure progression
Building the evidence: Mortality & hospitalisation
Lombardy registry1
– all cause mortality and hospitalisation risks reduced with Hct levels >32% compared with <27% (n=5302)
Ma et al2
– RR mortality reduces as Hct rises, 1.51 at Hct < 27% to 0.9 at Hct 33-36% (n=96,369)
Xia et al3
– hospitalisation risks lowest in patients with Hct 33-36% (n=71,717)
1. Lombardy registry Nephrol Dial Transplant 1998;13:1642-442. Ma et al J Am Soc Nephrol 1999;10:610-6193. Xia et al J Am Soc Nephrol 1999;10:1309-1316
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 20012. Fink et al Am J Kidney Dis 2001;37:348-355
0
2
4
6
8
10
12
14
16
18
Epoetin therapy correlates with reduced mortality and less hospitalisation
Adapted from Locatelli et al Nephrol Dial Transplant 1998
Hct <27%
Patients with diabetes = 7.6%
Hospitalisation days per patient-year
Adjusted general mortality(n=5302)
Odds
rati
o
Adjusted CVmortality(n=5302)
rh EPO-treated haemodialysis patientsUntreated haemodialysis patients
0.8
0.6
0.4
0.2
0
1
p <0.001 p <0.05
Hct 27–32% Hct >32%
Adapted from Ma et al. J Am Soc Nephrol 1999; 10: 610-619
Mortality adjusted for risk factors [without severity of disease]
Relative risk of mortality according to haematocrit in US patients with end stage renal disease
0.5 1.0 1.5
33-36
30-33
27-30
<27
Hae
mat
ocrit
(%
)
Relative risk
(0.90)
(1.00)
(1.20)
(1.51)
2.0
n = 96,369Diabetes = 50%
Mortality, hospitalisation, and economic associations in HD patients aged 65 years
Incident Medicare HD cohort 1/1/1996 to 30/6/1998 Follow-up period: one year Variables
– age, gender, race, renal diagnosis, comorbidity, number of transfusions, number of access procedures, number of hospital days
Hct groups: <30, 30<33, 33<36, 36<39, 39+ Outcome: risk of death and first hospitalisation
Collins et al, ASN 2001
0.0
0.5
1.0
1.5
2.0
2.5
Relative risks of death and 95% CIRelative risks of death and 95% CI
< 30 30-<33 33-<36 36-<39 39
All-cause
Cardiac
Infection
reference
Collins et al, ASN 2001
Haematocrit
Rel
ativ
e ri
sk
Relative risks of hospitalisation & 95% CI
Relative risks of hospitalisation & 95% CI
Collins et al, ASN 2001
<30 30-<33 33-<36 36-<39 >=39
All-cause
Cardiac
Infection
reference
Haematocrit
Rel
ativ
e ri
sk
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Reduced mortality with anaemia treatment pre-dialysis
4,866 patients, median follow up 26.2 months 1,107 treated with epoetin pre-dialysis Relative risk of death for epoetin-treated
pre-dialysis = 0.8 Most significant survival benefit was in those with
the highest haematocrit Concluded that epoetin use pre-dialysis confers
survival benefit
Fink et al, Am J Kid Dis 2001;37:348-355
What do we hope to achieve by the early treatment of renal anaemia?
Increased exercise capacity, improved quality of life, cognitive function and sexual function
Regression of left ventricular hypertrophy
Reduced mortality and hospitalisation
Reduced transfusion requirements
?Regression of chronic renal failure progression
Reversal of anaemia by epoetin can retard progression of chronic renal failure
Adapted from Kuriyama et al Nephron 1997; 77: 176-185
Cum
ulat
ive
rena
l sur
viva
l rat
e (%
)
20
0
40
60
80
100
0 5 10 15 20 25 30 35 40
p=0.
0024
p=
0.31
11
p=0.
0003
Months of follow-up
Hct <30%, treated with epoetinHct >30%, untreatedHct <30%, untreated
n=108
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
Time or creatinine
CREATE trial (Cardiovascular risk Reduction by Early Anaemia Treatment with Epoetin beta)
Hb
(g
/dl)
15
12.5
10
Group 1(Hb 13-15 g/dl)
Group 2(Hb 10.5-11.5 g/dl)
•600 subjects glomerular filtration rate 15-35 ml/min randomised to 2 groups, early intervention and standard practise
Time or creatinine
CHOIR trial (Correction of Haemoglobin and Outcomes In Renal Insufficiency)
Hb
(g/
dl)
15
12.5
10
Group 1(Hb 13-13.5 g/dl)
Group 2(Hb 10.5-11.0 g/dl)
•2000 subjects GFR 15-50 ml/min randomised to 2 groups
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
Hb (g/dl)
16
14
12
10
8
6
16
14
12
10
8
6
Early intervention
Target Hb: 13–15 g/dl
Standard treatment
Target Hb: 10.5–11.5 g/dl
Inclusion:Hb 10.5–13.0 g/dlCreatinine clearance ≥30 ml/min
m
f
Time
n = 160
Randomisation
ACORD: Study design
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): 37-45
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)
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