Transcript Document

Epidemiology of Anaemia in CKD
The Burden of CKD
An Under-Recognised Condition
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
CKD as a Continuum
Diagnosis and
treatment of
comorbid
conditions
Estimate
progression
Evaluate and
treat
complications
Preparation
for dialysis
e.g. access
Dialysis if
uraemia
present
Stage
1
2
3
4
5
GFR
≥90
60–90
30–60
15–30
<15
Progression
Kidney
transplant
or dialysis
NKF-K/DOQI. Am J Kidney Dis. 2002;39(Suppl 1):S1-S266
Serum Creatinine
Misleads 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 Creatinine
is Not a Good Measure of eGFR
• Age
• Gender
• Body weight
• Muscle mass
• Race
sCr
eGFR
120 mmol/L
30 mL/min
120 mmol/L
130 mL/min
Reproduction courtesy of PE Stevens
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

eGFR easily determined from routine analyses
Reviewed by Agarwal. Am J Kidney Dis 2005; 455:610-613
Serum Creatinine
Hides Early Renal Damage
sCr (µmol/L)
600
400
200
5 4
3
2
CKD stage
0
35
70
105
140
eGFR (mL/min/1.73m2)
Adapted from D Newman
Serum Creatinine
Misdiagnoses CKD
sCr or eGFR among patients with diabetes
220
220
Males
200
180
sCr (µmol/L)
180
sCr (µmol/L)
Females
200
160
79.4%
140
120
160
98.4%
140
120
27.7%
81%
100
100
80
80
30
40
50
60
2
eGFR (ml/min/1.73m )
30
40
50
60
2
eGFR (ml/min/1.73m )
Middleton et al. Renal Association 2004
Prognosis Declines with CKD
Progression
CKD patients not on dialysis
Death
CV events
15
GFR (mL/min/1.73m2)
Rates per 100 person-years
GFR (mL/min/1.73m2)
<15
0
15−29
<15
0
30−44
10
5
45−59
20
15−29
<15
15−29
30−44
45−59
≥60
0
10
30−44
50
30
45−59
100
≥60
Rates per 100 person-years
40
≥60
150
Rates per 100 person-years
Increasing event rate
Hospitalisation
GFR (mL/min/1.73m2)
Decreasing GFR
Go et al. N Engl J Med. 2004;351:1296-1305
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
1. El Nahas & Bello. Lancet. 2005;365:331-340
2. Coresh et al. Am J Kidney Dis. 2003;41:1-12
3. Moeller et al. Nephrol Dial Transplant. 2002;17:2071-2076
Prevalence of CKD
US and Canada
Prevalence
CKD
Stage
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;16:180-188
2. USRDS Annual Data Report. 1998
3. Stigant et al. CMAJ. 2003;168:1553-1560
Prevalence and Incidence of
Patients Receiving RRT (US)
No. of patients
350 000
Prevalent dialysis
patients (2003: 324 826)
300 000
250 000
200 000
Prevalent transplant
patients (2003: 128 131)
150 000
100 000
Incident dialysis
patients (2003: 100 499)
50 000
0
88
90
92
94
96
98
00
02
Year
RRT=renal replacement therapy
USRDS Annual Data Report. 2005
Incidence of Patients Receiving
RRT (Europe)
Incident rate (patients per
million population)
160
90−91
98−99
120
80
40
ll
A
Fi
nl
an
d
ay
or
w
N
et
he
rla
n
ds
d
N
Sc
ot
la
n
re
ec
e
G
ar
k
en
m
D
Sp
ai
n
us
tr
ia
A
B
el
gi
um
0
Stengel et al. Nephrol Dial Transplant. 2003;18:1824-1833
The Growing Prevalence of Patients
with CKD on Dialysis Worldwide
No. of patients on
dialysis (x1000)
2500
Projected growth: 7% per year
2 095 000
2000
1 492 000
1500
1000
500
426 000
0
1990
2005
†
2010
†
Year
†Projected
Lysaght. J Am Soc Nephrol. 2002;13(Suppl 1):S37-S40
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
1. El Nahas & Bello. Lancet. 2005;365:331-340
2. USRDS Annual Data Report. 2005
Costs of Stage 5 CKD Have Increased
Over Time
Medicare expenditure per person per year (US $, thousands)
60
50
40
30
20
10
0
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
Year
USRDS Annual Data Report. 2005
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
1.
Astor et al. Arch Intern Med. 2002;162:1401-1408
2. Thorp et al. Dis Manag. 2006;9:115-121
3. McClellan et al. Curr Med Res Opin. 2004;20:1501-1510
3. Locatelli et al. Nephrol Dial Transplant. 2004;19:121-132
4. Silverberg. Nephrol Dial Transplant. 2003;18(Suppl 2):ii7-12
5. Perlman et al. Am J Kidney Dis. 2005; 45:658-666
Increased Presence of Anaemia with
Declining Kidney Function
Patients enrolled in NHANES III
Patients with anaemia (%)
50
45
40
35
30
25
20
15
10
5
1.8
0
≥90
44.1
5.2
1.3
30−59
60−89
GFR (mL/min per 1.73 m2)
Anaemia defined as Hb <12 g/dL in men,
<11 g/dL in women; NHANES=National Health
and Nutritional Survey
15−29
Astor et al. Arch Intern Med. 2002;162:1401-1408
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 is Significantly Associated with
Mortality and Morbidity in Patients on Dialysis
Relative risk of death
Relative risk of hospitalisation
RR overall=0.95 per
1 g/dL higher Hb (P=0.03)
RR overall=0.96 per
1 g/dL higher Hb (P=0.02)
RR
1.4
1.29
1.22
1.2
1.09
1.02
1.07
1.00
1.00
1.0
0.91
0.8
<10
10−10.9
11−11.9
≥12
<10
10−10.9
11−11.9
≥12
Hb (g/dL) at study entry
RR=relative risk
Locatelli et al. Nephrol Dial Transplant. 2004;19:121-132
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
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
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)
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
†Before
6
12
18
24
30
36
42
48
158
177
97
121
56
61
2
2
Month
279
286
268
272
249
257
censoring of data on patients at the time of
initiation of dialysis
207
223
Drüeke et al. N Engl J Med. 2006;355:2071-2084
Impact of Stable Hb Maintenance
Greater mortality risk with Hb outside 11.0−12.9 g/dL
Unadjusted
n=58 058 incident
and prevalent patients
12000
Case mix
Case mix & MICS
3
10000
8000
2
6000
4000
1
2000
0
0.8
MICS=malnutrition-inflammation
complex syndrome
Number of patients
All-cause mortality hazard ratio
5
Hb level (6 months)
Regidor et al. J Am Soc Nephrol. 2006;17:1181-1191
Impact of Anaemia on CV Risk
Cardiovascular mortality hazard ratio
Greater CV risk with Hb outside 11.0–12.9 g/dL
Unadjusted
5
n=58 058 incident
and prevalent patients
Case mix
Case mix & MICS
3
2
1
0.8
Hb level (g/dL)
Regidor et al. J Am Soc
Nephrol. 2006;17:1181-1191
Anaemia Increases Risk of Stroke in Patients with CKD
Patients from the ARIC study
Stroke rate per
1000 person-years
15
Anaemia defined as Hb <13 g/dL in men,
<12 g/dL in women
Creatinine clearance
≥60 mL/min
10
<60 mL/min
5
0
Normal Hb
Anaemia
Abramson et al. Kidney Int. 2003;64:610-615
Anaemia May Increase the Risk of
Progression of CKD to Dialysis
Patients on dialysis (%)
60
Baseline Hb by quartile (Q, g/dL)
50 Q1: 6.8–11.3
Q2: 11.3–12.5
40 Q3: 12.5–13.8
Q4: 13.8–18.0
Q1 (n=378)*
Q2 (n=377)*
30
Q3 (n=363)*
20
Q4 (n=395)
10
0
0
*P<0.05 versus Q4
1
2
Time (years)
3
4
Mohanram et al. Kidney Int. 2004;66:1131-1138
Hb Increases Improve Quality of
Life
CKD patients not on dialysis
Overall KDQ score
LASA overall QoL score (mm)
65
26
60
25
24
55
23
50
22
Overall QoL
45
21
40
20
35
Overall KDQ
19
30
18
7
8
n=1326 patients not on dialysis
KDQ=kidney disease questionnaire
9
10
11
12
13
14
Hb level (g/dL)
Lefebvre et al. Curr Med Res Opin. 2006;22:1926-1937
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
Epidemiology of Anaemia in CKD
Summary

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
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.