Anemia correction in patients with CKD – Which targets fileAnemia and CKD 1) General aspects 2) Relation between anemia and outcome – Observational studies – Intervention studies

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







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







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







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







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


● Hypertension


● 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


● Hypertension





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


● Hypertension





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


● Hypertension





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







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

Documents

Anemia correction in patients with CKD – Which targets fileAnemia and CKD 1) General aspects 2) Relation between anemia and outcome – Observational studies – Intervention studies