Epidemiology of Anaemia in CKD

The Burden of CKD

An Under-Recognised Condition

Stages of CKD by Glomerular Filtration Rate (GFR)

Stage DescriptionGFR

(mL/min/1.73m2)

1Kidney 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

NKF-K/DOQI. Am J Kidney Dis. 2002;39(Suppl 1):S1-S266

†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’

Stage

GFR

1 2 543

Diagnosis and treatment of

comorbid conditions

Estimate progression

Evaluate and treat

complications

Preparation for dialysis e.g. access

Dialysis if uraemia present

Kidney transplant or dialysis

Progression

≥90 60–90 30–60 15–30 <15

CKD as a Continuum

NKF-K/DOQI. Am J Kidney Dis. 2002;39(Suppl 1):S1-S266

Serum CreatinineMisleads CKD Diagnosis

CKD is silent and under-diagnosed in earlier stages Late diagnosis is often due to the incorrect perception

that serum creatinine (sCr) is a good measure of kidney function

Measures of Kidney Function

eGFR is used to assess kidney function

GFR can be measured using filtration markers such as inulin, iohexol or iothalamate but such methods are costly and cumbersome

sCr is an alternative that is easily measured but affected by factors such as age, gender, race & body size

Reviewed by Agarwal. Am J Kidney Dis 2005; 45:610-613

Serum Creatinineis Not a Good Measure of eGFR

120 mol/L 120 mol/LsCr130 mL/min30 mL/mineGFR

• Age

• Gender

• Body weight

• Muscle mass

• Race

Reproduction courtesy of PE Stevens

Diagnosis of Kidney FunctioneGFR

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

eGFR easily determined from routine analyses

Reviewed by Agarwal. Am J Kidney Dis 2005; 455:610-613

Serum CreatinineHides Early Renal Damage

sCr

(µm

ol/L

)

eGFR (mL/min/1.73m2)

35 70 105 140

600

400

200

0

2345 CKD stage

Adapted from D Newman

Serum CreatinineMisdiagnoses CKD

30 40 50 60

220

200

180

160

140

120

100

8030 40 50 60

Males Females

eGFR (ml/min/1.73m2)

Middleton et al. Renal Association 2004

eGFR (ml/min/1.73m2)

sCr

(µm

ol/L

)

220

200

180

160

140

120

100

80

sCr

(µm

ol/L

)

79.4%

27.7%

98.4%

81%

sCr or eGFR among patients with diabetes

GFR (mL/min/1.73m2)

CV events

0

10

30

40

20

≥60

30−

44

45−

59

15−

29

<1

5

Ra

tes

pe

r 1

00

pe

rso

n-y

ea

rs

Incr

ea

sin

g e

ve

nt

rate

Decreasing GFR

Hospitalisation

0

50

100

150

≥60

30−

44

45−

59

15−

29

<1

5

Ra

tes

pe

r 1

00

pe

rso

n-y

ea

rs

GFR (mL/min/1.73m2)

Death

Ra

tes

pe

r 1

00

pe

rso

n-y

ea

rs

0

5

10

15

≥60

30−

44

45−

59

15−

29

<1

5

GFR (mL/min/1.73m2)

Go et al. N Engl J Med. 2004;351:1296-1305

Prognosis Declines with CKD ProgressionCKD patients not on dialysis

1. El Nahas & Bello. Lancet. 2005;365:331-3402. Coresh et al. Am J Kidney Dis. 2003;41:1-12

3. Moeller et al. Nephrol Dial Transplant. 2002;17:2071-2076

CKD is Highly Prevalent Worldwide

Increasing prevalence expected

– aging population

– global epidemic of type 2 diabetes1

Patients with stage 1–4 CKD outnumber patients with stage 5 CKD by ~50:1 in the US2

>1 million patients with CKD on dialysis worldwide

Approximately 250 000 new patients diagnosed with CKD each year3

Prevalence of CKDUS and Canada

Prevalence

CKDStage Description

GFR (mL/min/1.73 m2) US1,2 Canada3

1 Kidney damage with normal or GFR

≥90 5 600 000 478 500

2 Kidney damage with mild GFR 60−89 5 700 000 435 000

3 Moderate GFR 30−59 7 400 000 623 500

4 Severe GFR 15−29 300 000 29 000

5 Kidney failure <15 or dialysis 300 000 14 500

1. Coresh et al. J Am Soc Nephrol. 2005;16:180-1882. USRDS Annual Data Report. 1998

3. Stigant et al. CMAJ. 2003;168:1553-1560

Prevalence and Incidence of Patients Receiving RRT (US)

USRDS Annual Data Report. 2005

350 000

300 000

250 000

200 000

150 000

100 000

50 000

088 90 92 94 96 98 0002

Prevalent dialysispatients (2003: 324 826)

Prevalent transplantpatients (2003: 128 131)

Incident dialysispatients (2003: 100 499)

No. of patients

Year

RRT=renal replacement therapy

Incidence of Patients Receiving RRT (Europe)

0

40

80

120

160

Belgi

umSpa

in

Austri

a

Denm

ark

Greec

e

Scotla

nd

Nethe

rlands

Norway

Finlan

d All

90−91 98−99Incident rate (patients per million population)

Stengel et al. Nephrol Dial Transplant. 2003;18:1824-1833

Lysaght. J Am Soc Nephrol. 2002;13(Suppl 1):S37-S40

The Growing Prevalence of Patients with CKD on Dialysis Worldwide

0

500

1000

1500

2000

2500

1990 2005 2010

Year†Projected

No. of patients on dialysis (x1000)

Projected growth: 7% per year

2 095 000

426 000

1 492 000

††

1. El Nahas & Bello. Lancet. 2005;365:331-3402. USRDS Annual Data Report. 2005

CKD is Associated with High Treatment Costs

In Europe, dialysis alone takes up ~2% of healthcare budgets with <0.1% of the population needing treatment1

In the US in 2003, Medicare costs for stage 5 CKD were US $18 billion, 6.6% of total Medicare expenditure2

Costs of Stage 5 CKD Have Increased Over Time

Medicare expenditure per person per year (US $, thousands)

USRDS Annual Data Report. 2005Year

0

10

20

30

40

50

60

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

1. Astor et al. Arch Intern Med. 2002;162:1401-14082. Thorp et al. Dis Manag. 2006;9:115-121

3. McClellan et al. Curr Med Res Opin. 2004;20:1501-15103. Locatelli et al. Nephrol Dial Transplant. 2004;19:121-132

4. Silverberg. Nephrol Dial Transplant. 2003;18(Suppl 2):ii7-125. Perlman et al. Am J Kidney Dis. 2005; 45:658-666

Anaemia and CKD

Anaemia is highly prevalent in patients with CKD, and Hb levels decrease with declining GFR1

– anaemia becomes evident in stage 3 CKD2

– up to 50% of patients with stage 3–5 CKD may have anaemia3

Anaemia is associated with significant mortality and morbidity in patients with CKD4

Anaemia in patients with CKD increases the burden of CVD5

Quality of life (QoL) is negatively affected by anaemia in patients with CKD6

Increased Presence of Anaemia with Declining Kidney FunctionPatients enrolled in NHANES III

0

5

10

15

20

25

30

35

40

45

50

≥90 60−89 30−59 15−29

Astor et al. Arch Intern Med. 2002;162:1401-1408

Patients with anaemia (%)

GFR (mL/min per 1.73 m2)

44.1

5.21.8 1.3

Anaemia defined as Hb <12 g/dL in men, <11 g/dL in women; NHANES=National Healthand Nutritional Survey

Levin et al. Nephrol Dial Transplant. 2006;21:370-377

0 3 6 9 12 15 18 21 24 27 31 33 37

Months from Hb result

Probability of survival

Hb

≥13.0 g/dL

12−12.9 g/dL

11−11.9 g/dL

10−10.9 g/dL

<10 g/dL

Log-rank test: P=0.0001

0.75

0.80

0.85

0.90

0.95

1.00

0.70

Hb Levels Predict Survival Prior to Dialysis InitiationCKD patients not on dialysis

Locatelli et al. Nephrol Dial Transplant. 2004;19:121-132

1.29

1.09

1.00

1.07

<10 10−10.9 11−11.9 ≥12

1.22

1.021.00

0.91

0.8

1.0

1.2

1.4

<10 10−10.9 11−11.9 ≥12

Hb (g/dL) at study entry

RRRR overall=0.96 per

1 g/dL higher Hb (P=0.02)RR overall=0.95 per

1 g/dL higher Hb (P=0.03)

Relative risk of hospitalisationRelative risk of death

Anaemia is Significantly Associated with Mortality and Morbidity in Patients on Dialysis

RR=relative risk

Hospitalisation Risk Increases with Hb <11 g/dLDialysis patients

1.161.09

1.00 1.01

1.55

0.0

0.5

1.0

1.5

2.0

<8 8−9.99 10−10.99 11−11.99 ≥12

P=0.77P<0.0001 P=0.001 P=0.05

n=7998

Pisoni et al. Am J Kidney Dis. 2004;44:94-111

RR of hospitalisation

Hb level (g/dL)

The CHOIR and CREATE Studies: OverviewCKD 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 months700 patients completed trial

48 months476 patients completed trial

Primary Endpoints Composite(death, MI, HF, stroke)

Composite(sudden death, MI, acute HF, CVA, TIA, hosp for angina or arrhythmia, PVD complications)

Hb Targets Group 1: 13.5 g/dL†

Group 2: 11.3 g/dL†

Group 1: 13–15 g/dL Group 2: 10.5–11.5 g/dL

†Original targets before protocol amendment:

• Group 1: 13.0–13.5 g/dL• Group 2: 10.5–11.0 g/dL Singh et al. N Engl J Med. 2006;355:2085-2098

Drüeke et al. N Engl J Med. 2006;355:2071-2084

‡127 and 111 patients in groups 1 and 2, respectively, progressed to RRT during study

§127 and 111 patients in groups 1 and 2, respectively, progressed to RRT during study

Duration of Hb <11 g/dL Increases Mortality RiskDialysis patients

1.001.10 1.12

1.32

1.52

1.82

0

1

2

0 1−20 21−40 41−60 61−80 81−100

Time with Hb <11 g/dL over 2 years (%)

Ofsthun et al. Nephrol Dial Transplant. 2005;20(Suppl 5):v261 (abstract MP204)

Relative mortality risk

* ***

****

n=41 919

*P<0.05; **P<0.001

CHOIR: Increased Risk of Composite Event with Target Hb 13.5 g/dLStage 3–4 CKD patients

0 3 6 9 12 15 18 21 24 27 30 33 36 39

0.30

0.25

0.20

0.15

0.10

0.05

0.00

Pro

bab

ilit

y o

f co

mp

osi

te e

ven

t

Month

Hb target 13.5 g/dLHb target 11.3 g/dL

Patients at riskGroup 1 715 654 587 520 457 355 270 176 101 72 55 23Group 2 717 660 594 539 499 397 293 182 107 67 44 23

Time to the primary composite endpoint

Events: 125 vs 97HR=1.34 (1.03–1.74)Log rank test P=0.03

Singh et al. N Engl J Med. 2006;355:2085-2098

CREATE: No Significant Difference in Time to First CV EventCKD patients not on dialysis

Time to the primary endpoint of a first cardiovascular event†

†Before censoring of data on patients at the time of initiation of dialysis

100

90

80

70

60

50

40

30

20

10

0

Eve

nt-

free

Su

rviv

al (

%)

0 6 12 18 24 30 36 42 48

MonthPatients at riskGroup 1 301 279 268 249 207 158 97 56 2Group 2 302 286 272 257 223 177 121 61 2

Events: 58 vs 47HR=0.78 (0.53–1.14)Log rank test P=0.20

Hb target 13–15 g/dLHb target 10.5–11.5 g/dL

Drüeke et al. N Engl J Med. 2006;355:2071-2084

Impact of Stable Hb MaintenanceGreater mortality risk with Hb outside 11.0−12.9 g/dL

Regidor et al. J Am Soc Nephrol. 2006;17:1181-1191

MICS=malnutrition-inflammation complex syndrome

All-

cau

se m

ort

alit

y h

azar

d r

atio

Nu

mb

er of p

atients

1

0

Hb level (6 months)

n=58 058 incident and prevalent patients

9.0−

9.4

9.5−

9.9

10.0−

10.4

11.0−

11.4

11.5−

11.9

12.0−

12.4

12.5−

12.

913

.0−

13.

413

.5−

13.

9

10.5−

10.9

≥14

12000

6000

8000

4000

10000

2000

5

3

0.8

2

<9

Case mix

Case mix & MICS

Impact of Anaemia on CV RiskGreater CV risk with Hb outside 11.0–12.9 g/dL

Car

dio

vasc

ula

r m

ort

alit

y h

azar

d r

atio

1

Hb level (g/dL)

n=58 058 incident and prevalent patients

9.0−

9.4

9.5−

9.9

10.0−

10.4

11.0−

11.4

11.5−

11.9

12.0−

12.4

12.5−

12.

913

.0−

13.

413

.5−

13.

9

10.5−

10.9

≥14<9

5

3

2

0.8

Regidor et al. J Am Soc Nephrol. 2006;17:1181-1191

Case mix

Case mix & MICS

Anaemia Increases Risk of Stroke in Patients with CKDPatients from the ARIC study

0

5

10

15

Normal Hb Anaemia

Stroke rate per 1000 person-years

Abramson et al. Kidney Int. 2003;64:610-615

Creatinine clearance

≥60 mL/min

<60 mL/min

Anaemia defined as Hb <13 g/dL in men, <12 g/dL in women

Anaemia May Increase the Risk of Progression of CKD to Dialysis

*P<0.05 versus Q4

60

50

40

30

20

10

00 1 2 3 4

Patients on dialysis (%)

Time (years)

Q1 (n=378)*

Q2 (n=377)*

Q3 (n=363)*

Q4 (n=395)

Baseline Hb by quartile (Q, g/dL)Q1: 6.8–11.3Q2: 11.3–12.5Q3: 12.5–13.8Q4: 13.8–18.0

Mohanram et al. Kidney Int. 2004;66:1131-1138

65

60

55

50

45

40

35

30

26

25

24

23

22

21

20

19

187 8 9 10 11 12 13 14

LASA overall QoL score (mm) Overall KDQ score

Hb level (g/dL)

Overall QoL

Overall KDQ

Hb Increases Improve Quality of LifeCKD patients not on dialysis

Lefebvre et al. Curr Med Res Opin. 2006;22:1926-1937

n=1326 patients not on dialysisKDQ=kidney disease questionnaire

Mean units per patient per 4 weeks

0.6

0.5

0.4

0.3

0.2

0.1

0Pre 4 12 20 28 36 44 52

Weeks

Eschbach et al. Ann Intern Med. 1989:111:992-1000

*

*autologous blood donation ahead of elective hip surgery

Commencement ofanaemia therapy

Anaemia Treatment Greatly Reduces Blood TransfusionsDialysis patients

1. El Nahas & Bello. Lancet. 2005;365:331-340. 2. Astor et al. Arch Intern Med. 2002;162:1401-1408. 3. Locatelli et al 2004; Nephrol Dial Transplant. 2004;19:121-132. 4. Lefebvre et al.

Curr Med Res Opin. 2006;22:1929-1937. 5. Levin et al. Nephrol Dial Transplant. 2006;21:370-377 6. Regidor et al. J Am Soc Nephrol. 2006;17:1181-1191.

Epidemiology of Anaemia in CKDSummary

CKD prevalence is high and is expected to increase1

Anaemia is highly prevalent and worsens with declining kidney function2

Anaemia has a negative impact on QoL

Anaemia increases the risk of CV mortality and morbidity3 according to 1. number of episodes of Hb outside of target range

2. length of time Hb outside target range5

3. magnitude of Hb levels out of range6

Discussion continues on defining the upper and lower limits of target Hb range