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Anemia correction in patients with CKD –Which targets ?
Tilman Tilman B B DrüekeDrüekeInserm Inserm Unit 845 and Service de Unit 845 and Service de NéphrologieNéphrologieNecker Hospital, ParisNecker Hospital, Paris
Anemia and CKD
1)1) General aspectsGeneral aspects
2)2) Relation between anemia and outcomeRelation between anemia and outcome
–– Observational studiesObservational studies
–– Intervention studies (Intervention studies (RCTsRCTs))
–– Negative effects of full correction Negative effects of full correction -- Why ?Why ?
3) 3) Present anemia targetsPresent anemia targets
Anemia and CKD
1)1) General aspectsGeneral aspects
2)2) Relation between anemia and outcomeRelation between anemia and outcome
–– Observational studiesObservational studies
–– Intervention studies (Intervention studies (RCTsRCTs))
–– Negative effects of full correction Negative effects of full correction -- Why ?Why ?
3) 3) Present anemia targetsPresent anemia targets
Anemia as a function of decreasing GFRAnemia as a function of decreasing GFR
adapatedadapated from J from J PediatrPediatr (1988) 113: 1015; Blood (1979) 54: 877(1988) 113: 1015; Blood (1979) 54: 877
6060
5050
4040
3030
2020
1010
00
HctHct (%)(%)
100100 4040 2020 1010CreatinineCreatinine clearance (mL/min/1.73 mclearance (mL/min/1.73 m22))
Causes of anemia in chronic renal failure
• Erythropoietin deficiency• Deficiency states (iron, vitamins, malnutrition)
• Blood loss (G-I & vag. bleeding; blood sampling)
• Chronic inflammatory state
• Inhibition of erythropoiesis: uremic toxins (?)
• Shortening of RBC survival (hemolysis)
• Hyperparathyroidism / marrow fibrosis
• Aluminum overload
• Inadequate dialysis treatment
Caro J, J Lab Clin Med 1979;93:449-58
Relation between hematocrit und erythropoietin
Anemia and CKD
1)1) General aspectsGeneral aspects
2)2) Relation between anemia and outcomeRelation between anemia and outcome
–– Observational studiesObservational studies
–– Intervention studies (Intervention studies (RCTsRCTs))
–– Negative effects of full correction Negative effects of full correction -- Why ?Why ?
3) 3) Present anemia targetsPresent anemia targets
Time varying Hb values and relative risk for death in chronic HD patients (Observational study, 58 058 pts)
Regidor DL et al, JASN 2006; 17: 1181-91
• Implications:– Hb values >11 g/dL are associated with improved survival
• Limitations:– Relationship between Hb and outcomes may not be
causally determined– Increasing Hb levels >11 g/dL may not improve outcomes
Observational studies:implications and limitations
Hb, haemoglobin
Anemia and CKD
1)1) General aspectsGeneral aspects
2)2) Relation between anemia and outcomeRelation between anemia and outcome
–– Observational studiesObservational studies
–– Intervention studies (Intervention studies (RCTsRCTs))
–– Negative effects of full correction Negative effects of full correction -- Why ?Why ?
3) 3) Present anemia targetsPresent anemia targets
CKD 3–4
CKD 3–4
CKD 2–5
HD – CHF/CAD
CKD 3–5
HD – CHF/CAD
HD + CHF/CAD
Study population
36Sudden death, CV event
11–11.513–15
Openlabel603
DrüekeNEJM 2006;355: 2071–2084
16Death, CV event
11.313.5
OpenLabel1432
SinghNEJM 2006;355: 2085–2098
22LVMI9–10.512–14
OpenLabel172
LevinAJKD 2005;46: 799–811
22LVVI9.5–11.513.5–14.5
DoubleBlind596
ParfreyJASN 2005;16: 2180–2109
24∆ LVMI9–1012–13
OpenLabel155
RogerJASN 2004;15: 148–156
12LVMILVVI
9.5–10.513–14
OpenLabel146
FoleyKI 2000;58: 1325–1325
29Death, MI1014
OpenLabel1233
BesarabNEJM 1998;339: 584–590
Follow-up (months)
Primaryendpoint
Hb (g/dL)targetDesignNStudy
Major published randomized controlled trials of anaemia therapy and CV outcomes in CKD
CV, cardiovascular; CKD, chronic kidney disease; HD, haemodialysis; CHF, congestive heart failure; CAD, coronary artery disease; MI, myocardial infarction; LVMI, left ventricular myocardial infarction; LVVI, left ventricular volume index
13.5**17.4CABG (% patients)
93.2*95.8 Hypertension (% patients)
Standard Hb groupTarget Hb 11.3 g/dL
High Hb groupTarget Hb 13.5 g/dL
*p = 0.03**p = 0.05
Singh AK et al N Engl J Med 2006;355:2085–2098Hb, haemoglobin; CABG, coronary artery bypass grafting
CHOIR: difference in baseline CV disease
CREATE: implications and limitations
• Implications:“In patients with CKD early complete correction of anaemiadoes not reduce the risk of cardiovascular events.”
• Limitations:– Underpowered to demonstrate a difference between the
groups due to lower than expected event rate (6% vs 15%)
Drüeke TB et al N Engl J Med 2006;355:2071–2084CKD, chronic kidney disease
High Hb13.5
Strd Hb11.3
CHOIR2
High Hb~14
Strd Hb~10
High Hb13–15
Strd Hb10.5–11.5Target Hb (g/dL)
Besarab3CREATE1
Differences between CREATE, CHOIR and the Besarab trial
11,215
12.6
6,276
~11.3 ~13.5~10.513.511.6Hb (g/dL)
153*146*5,0002,000Epo Dosing (U/wk)
30%
47%
66.0
27.0
10.1
28%
51%
66.3
27.3
10.1 10.210.211.611.6Hb (g/dL)
––24.924.2GFR (ml/min/1.73m2)
28%27%23%19%Hypertension as cause of CKD
42%46%20%21%DM as cause of CKD
656459.358.8Age
Bas
elin
eTr
eatm
ent
*U/kg/wk1. Drüeke TB et al N Engl J Med 2006;355:2071–2084
2. Singh AK et al N Engl J Med 2006;355:2085–20983. Besarab et al N Engl J Med 1998;339:584–590
Hb, haemoglobin; GFR, glomerular filtration rate; DM, diabetes mellitus; CKD, chronic kidney disease
Conclusions on the safety and efficacy of ESAs
• Data from observational studies indicate that Hb levels >11 g/dL are associated with improved outcomes, although relationship may not be causally determined.
• Hb levels >13 g/dL should be avoided as data from RCTs showed a trend towards increased CV events, no CV benefit and uncertain improvement in QoL.
ESAs, Erythropoiesis-stimulating agents; Hb, haemoglobin; RCTs, randomised controlled trials; CV, cardiovascular; QoL, quality of life
Anemia and CKD
1)1) General aspectsGeneral aspects
2)2) Relation between anemia and outcomeRelation between anemia and outcome
–– Observational studiesObservational studies
–– Intervention studies (Intervention studies (RCTsRCTs))
–– Negative effects of full correction Negative effects of full correction -- Why ?Why ?
3) 3) Present anemia targetsPresent anemia targets
Negative effects of complete anemia correction despite better tissue oxygenation with higher Hb –Why ?
● Hypertension
● Increased blood viscosity – post-HD hemoconcentration
● Increased platelet number & adhesiveness, thrombosis
● Impaired endothelial NO activity – high Epo dose harmful effects
● Increased iron needs oxidative stress
Increase in BPsyst by Epo in rats with 5/6th NxEpoetin vs no Rx (control) vs iron depletion (anemia)
Garcia DL et al, PNAS 1988:85:6142-6
Garcia DL et al, PNAS 1988:85:6142-6
Decrease in GFR by Epo in rats with 5/6th NxEpoetin vs no Rx (control) vs iron depletion (anemia)
Effect of EPO treatment on arterial function in chronic hemodialysis patients
Control rHuEpo
Forearm Blood Flow 6.3 ± 1.0 4.6 ± 1.4**(ml/100 ml.min)
Forearm Vasc. Resistance 14.2 ± 4.2 21.2 ± 7.0**(Units)
London et al, Kidney Int 1989; 36: 878-82
Negative effects of complete anemia correction despite better tissue oxygenation with higher Hb –Why ?
● Hypertension
● Increased blood viscosity – post-HD hemoconcentration
● Increased platelet number &
adhesiveness, thrombosis
● Impaired endothelial NO activity
CREATE : Increase in first CV events in group 1after start of dialysis, not predialysis
824On dialysis
3934Pre-dialysis
4758 Total number of patients
Standard Hgb
Target Hb 10.5-11.5 g/dL
High HgbTarget Hb 13-15 g/dL
Negative effects of complete anemia correction despite better tissue oxygenation with higher Hb –Why ?
● Hypertension
● Increased blood viscosity – post-HD hemoconcentration
● Increased platelet number &
adhesiveness, thrombosis
● Impaired endothelial NO activity
Stohlwetz PJ et al, Blood 2000; 95: 2983-9
Effect of epoetin on platelet number in humans before/after phlebotomy
Stohlwetz PJ et al, Blood 2000; 95: 2983-9
Effect of epoetin on platelet reactivity in humans before/after phlebotomy
Christensson AG et al, NDT 2001; 16: 313-19
No effect of full anemia correction on hemostasis in chronic hemodialysis patients
Negative effects of complete anemia correction despite better tissue oxygenation with higher Hb –Why ?
● Hypertension
● Increased blood viscosity – post-HD hemoconcentration
● Increased platelet number &
adhesiveness, thrombosis
● Impaired endothelial NO activity
Effect of EPO on carotid arteries of wild-type mice (14 days ± injury)
D’Uscio LV et al, Hypertension 2007;49:1142-8
Effect of EPO on carotid arteries of eNOS-/- mice (14 days ± injury)
D’Uscio LV et al, Hypertension 2007;49:1142-8
0.00211.73–11.74.05301Age (≥60 vs. <60 years)
0.8800.59–1.841.04301Baseline Hb (g/dL)
0.4200.50–5.371.63301Baseline Hb (≥11 vs. <11 g/dL)
0.06170.97–4.031.97301Baseline Hb (≥12 vs. <12 g/dL)
<0.00010.34–0.640.47295Max Hb (g/dL)
0.00060.07–0.490.19295Max Hb (>13 vs. ≤13 g/dL)
0.0060.14–0.720.32295Max Hb (>15 vs. ≤15 g/dL)
0.8490.95–1.041.00301Max weekly dose(per 1000 IU/week)
P95% CIRRPatient #Covariate
0 2 4 6 8 10 12 14Less risk Greater risk
Time to overall C-V mortality for covariates in group 1 (post-hoc analysis)
Hb, haemoglobin; RR, relative risk; CI, confidence interval
Negative effects of complete anemia correction despite better tissue oxygenation with higher Hb –Why ?
● Hypertension
● Increased blood viscosity – post-HD hemoconcentration
● Increased platelet number &
adhesiveness, thrombosis
● Impaired endothelial NO activity
Correlation between plasma AOPP and carotid wall thickness in chronic HD patients
Drüeke T et al, Circulation 2002;106:2212-7
Intima mediathickness
(µm)
Plasma AOPP (µmol/L)
r = 0.44, p < 0.02
0.2
0.3
0.4
0.150.0 116.7 183.3 250.0
Correlation between yearly dose of elemental ironand carotid artery wall thickness
500
580
660
740
820
900
0 1750 3500Dose of elemental iron (mg/year)
Intima-media thickness (µm)
875 2625
r = 0.368p = 0.0153
Drüeke T et al, Circulation 2002;106:2212-7
Anemia and CKD
1)1) General aspectsGeneral aspects
2)2) Relation between anemia and outcomeRelation between anemia and outcome
–– Observational studiesObservational studies
–– Intervention studies (Intervention studies (RCTsRCTs))
–– Negative effects of full correction Negative effects of full correction -- Why ?Why ?
3) 3) Present anemia targetsPresent anemia targets
Complete correction of anemia in CKD ?
• Greater risk of cardiovascular events and mortality ?
• Improved quality of life ?
Patients on dialysisPatients not on dialysis
No association between higher Hb targetsand relative mortality riskRecent meta-analysis from KDOQITM
Favours treatment Favours control
0.01 0.1 1 10 100Study Year #Pts
Roth 1994 83Kuriyama 1997 73
Gouva 2004 88
Levin 2005 172Rossert 2006 390Drüeke 2006 603Singh 20061432Macdougall 2007 197
Overall 3038
Risk ratio 95% CI
Favours treatment Favours control
0.2 0.5 5 10Study Year #Pts
Besarab 19981233Foley 2000 146Furuland 2003 416Parfrey 2005 596
Overall 2391
Risk ratio 95% CI210.1
p = 0.97
CI, confidence interval
p = 0.30
www.kidney.org KDOQITM anemia guidelines, 2007 update
Complete correction of anemia in CKD ?
• Greater risk of cardiovascular events and mortality ?
• Improved quality of life ?
Hemoglobin target 2007 in CKD patients (KDOQI)
• ESAs have a favorable safety and efficacy profile when used to achieve Hb target levels of 11 to 12 g/dL, not to exceed 13 g/dL.
• Important clinical questions regarding the impact of anemia treatment on cardiovascular outcomes remain unanswered. Additional RCTs are needed.
www.kidney.org KDOQITM anemia guidelines, 2007 update
Hemoglobin correction in CKD patients –additional common sense statements
• Correct anemia slowly.
• Don’t start with high epoetin doses.
• Adapt anemia correction to individual patient needs and comorbidities.
NO,ADMA
Homocysteine
AtherosclerosisArteriosclerosis
LVH, heart failure
C-V mortality
Altered tensile stress(hypertension)
Diabetes
Inflammation
Smoking
DyslipidemiaLp(a)
Genetic factors
Altered shear stress(change in blood flow)
Local growthfactors / inhibitors
Lipoprotein modifications(oxidation; glycation)
(AGE, AOPP)
AgeGender
Calcium, Phosphorus, Vitamin D, PTH
Uremic state
Endothelial dysfunctionAnemia